Pharmaceutical compositions of antiplatelet agents and uses thereof

Abstract

A pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutical acceptable salt thereof, a cyclodextrin, and optionally a buffer. Further provided are methods of preparation for the pharmaceutical composition and methods of use thereof for treating vascular disease or inhibiting platelet aggregation.

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, a cyclodextrin, and optionally a buffering agent. The present application also relates to a preparation method for the pharmaceutical composition and a method of using it for treating vascular diseases or inhibiting platelet aggregation. [Background technology]

[0002] Clopidogrel is a known antiplatelet agent that is widely used worldwide and has the following properties:

[0003] [ka] It has the structure shown in FIG.

[0004] Clopidogrel is a prodrug. After entering the human body, about 85% of it will generate inactive metabolites through non-oxidative hydrolysis, and about 15% will undergo two-step oxidation under the action of hepatocyte cytochrome P450 isoenzymes (mainly human hepatic oxidizing enzyme CYP2C19) to generate the active metabolite H4:

[0005] [ka] Form.

[0006] However, clopidogrel has many disadvantages, including: 1) low solubility in aqueous solution, low conversion rate to active metabolites and therefore high loading dose (300-600mg) and slow onset of therapeutic effect (2 hours after administration of the loading dose); 2) metabolism of clopidogrel is mediated by CYP2C19 enzyme, so that antiplatelet differences are generated among different individuals due to different CYP2C19 expression levels, and some patients may develop resistance to clopidogrel; and 3) drug interactions due to the action of CYP2C19 enzyme. For the above reasons, the dosage form of the currently marketed clopidogrel product is oral tablet, but oral tablet cannot achieve fast-acting and therefore cannot meet the demand for emergency anticoagulation (especially for patients in acute phase).

[0007] In order to remedy the above-mentioned deficiencies, attempts have been made in the art to prepare clopidogrel as an injection. WO9717064 attempts to use mannitol and alanine to improve the stability of clopidogrel salt and prepare its freeze-dried powder, but the desired freeze-dried powder cannot be obtained because insoluble aggregates are easily formed during freeze-drying; WO0010534 discloses an injectable composition containing clopidogrel or its pharma-ceutically acceptable salt (preferably clopidogrel bisulfate), Pluronic F68, a basic pH adjusting agent and Solutol HS15 adapted for administration via injection, and a freeze-dried formulation of the injectable composition. This patent application claims that the tolerance of the injection can be improved, but no effect data is provided to prove this; moreover, the method is very laborious, the cost is high, and the injection is not favorable for clinical use due to certain irritation caused by the use of various pharmaceutical excipients. In fact, the rapid onset of therapeutic effect cannot be achieved even when clopidogrel is formulated into an injection. This is because the metabolism of clopidogrel must be mediated by the CYP2C19 enzyme, which is present only in the liver, and metabolic processes involving this enzyme are the rate-limiting step in the hepatic metabolic process.

[0008] Thus, there remains a need in the art to develop antiplatelet aggregation drugs and formulations thereof that are characterized by improved solubility and ability to be used for injection that meets the requirement for rapid anticoagulation. Summary of the Invention

[0009] The present disclosure provides novel anti-platelet aggregation compounds and pharmaceutical compositions thereof with improved solubility, stability, and drug efficacy.

[0010] The compounds of the present disclosure further irreversibly inhibit platelet coagulation activity by generating the active metabolite H4 in vivo under the action of hydrolytic enzymes.

[0011] [ka] or a pharma- ceutically acceptable salt thereof.

[0012] The compounds of the present disclosure have good solubility in water at pH 1-2, but when the pH increases, the solubility decreases significantly and the stability gradually decreases, and the compounds cannot be directly used as medicines. The inventors unexpectedly found that when the compounds of the present disclosure are mixed with cyclodextrin, the solubility of the compounds at pH 3-4 is improved, the stability of pharmaceutical formulations containing the compounds of the present disclosure as active ingredients is improved, and the drug effect and intracellular exposure of the compounds of the present disclosure are also significantly improved. This helps provide pharmaceutical formulations that can be easily administered and have fast-acting properties to meet the need for rapid anticoagulation in acute patients.

[0013] Thus, in one aspect, the present disclosure provides a method for producing a method for treating a cancer cell comprising: Compounds of formula (I):

[0014] [ka] or a pharma- ceutically acceptable salt thereof, and Cyclodextrin (In the formula,

[0015] [ka] indicates a double bond in the Z or E configuration; R 1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, each of which is selected from the group consisting of one or more R a is optionally replaced by; R 2 is -C(O)R b and; R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl; L is selected from the group consisting of a direct bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, each of which may be selected from one or more of R f is optionally replaced by; W is

[0016] [ka] W is selected from the group consisting of * The end is joined to L; R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl; R a each of which is hydrogen, halogen, hydroxyl, amino, cyano, nitro or -NR c R d independently selected from the group consisting of: R b is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, heteroaryl, -NR c R d AND -OR e selected from the group consisting of; R c and R d each is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, or amino; R eis selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl; R f each is independently selected from the group consisting of hydrogen, cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl; or The Two R's f together with the atom to which they are both attached form a saturated or partially unsaturated cycloalkyl or a saturated or partially unsaturated heterocyclyl, each of which is optionally substituted with cyano, halogen, hydroxyl, amino, and alkyl; R g is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, each of the hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, or amino; n is 0, 1, 2, 3, 4 or 5) The present invention provides a pharmaceutical composition comprising:

[0017] In another aspect, the present disclosure also provides a method for preparing a pharmaceutical composition of the present disclosure, comprising: mixing cyclodextrin with water to form a first mixture; Optionally, adding a buffer to the first mixture to form a second mixture; adding an acid to the second mixture to adjust the pH to 1 to 1.5, thereby forming a third mixture; adding a compound or a pharma- ceutically acceptable salt thereof to the third mixture to form a fourth mixture; adding a base to the fourth mixture to adjust the pH to 3-4, thereby forming a fifth mixture; and Optionally, adding water for injection to the fifth mixture to form a pharmaceutical composition. The present invention provides a method comprising:

[0018] In yet another aspect, the present disclosure provides a method for treating a vascular disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of the present disclosure.

[0019] In yet another aspect, the present disclosure provides a method for inhibiting platelet aggregation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of the present disclosure. [Brief description of the drawings]

[0020] [Figure 1] FIG. 1 shows concentrations of active metabolites in rat plasma following oral administration of (a) clopidogrel, Compound 1a and Compound 1b, and (b) clopidogrel, Compound 2a and Compound 2b at a dose of 10 mg / kg. [Diagram 2] FIG. 2 shows the concentrations of active metabolites in rat plasma following oral administration of clopidogrel at a dose of 10 mg / kg, oral administration of compound 3 at a dose of 2 mg / kg, and intravenous injection of compound 3 at a dose of 1 mg / kg. [Diagram 3]FIG. 3 shows the % inhibition of coagulation following oral administration of test compounds at doses of 10 mg / kg (clopidogrel), 0.5 mg / kg (compound 1a), and 2 mg / kg (compound 1b) in rats. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] The present disclosure relates to novel anti-platelet aggregation compounds and pharmaceutical compositions thereof, and methods of using such pharmaceutical compositions to treat vascular disease or inhibit platelet aggregation. When describing the compounds, compositions and methods of the present disclosure, the following terms have the following meanings, unless otherwise specified.

[0022] definition The definitions of specific functional groups and chemical terms are described in more detail below.For the purpose of this disclosure, chemical elements are identified according to the Periodic Table of Elements, CAS edition, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein.In addition, the general principles of organic chemistry and specific functional moieties and reactivity are described in Organic Chemistry, Thomas Sorrell, 2nd edition, University Science Books, Sausalito, 2006; Smith and March March's Advanced Organic Chemistry, 6th edition, John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3rd edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4th edition, Cambridge University Press, Cambridge, 2004, each of which is incorporated herein by reference in its entirety.

[0023] At various places in this disclosure, linking substituents are described. It is specifically intended that each linking substituent include both the front and back forms of the linking substituent. For example, -NR(CR'R")- includes both -NR(CR'R")- and -(CR'R")NR-. When a structure clearly requires a linking group, it is understood that the Markush variable recited for that group is the linking group. For example, when a structure requires a linking group and the Markush group definition for that variable recites "alkyl," it is understood that "alkyl" refers to a linking alkylene group.

[0024] If a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. If a substituent is listed without indicating the atom to which such substituent is bonded to the remainder of a compound of a given formula, then such substituent may be bonded through any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0025] " * " next to an atom of a compound indicates that the compound contains such atom as an asymmetric center in either the (R) or (S) configuration.

[0026] Any variable (e.g. R i When any radical R occurs more than one time in any constituent or formula of a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, a group R i When shown to be substituted with a moiety, the group may be substituted with up to two R i Each occurrence of R i is R i Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0027] As used herein, "C i~j" denotes a range of carbon atoms, where i and j are integers, the range of carbon atoms including the endpoints (i.e., i and j) and every integer point therebetween, where j is greater than i. For example, C 1~6 represents a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. In some embodiments, "C 1~12 The term denotes 1 to 12, in particular 1 to 10, in particular 1 to 8, in particular 1 to 6, in particular 1 to 5, in particular 1 to 4, in particular 1 to 3 or in particular 1 to 2 carbon atoms.

[0028] As used herein, the term "alkyl," whether part of another term or used independently, refers to a saturated, straight- or branched-chain hydrocarbon group that may be independently and optionally substituted with one or more substituents described below. i~jThe term "alkyl" refers to an alkyl having i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 12 carbon atoms. In some embodiments, the alkyl group contains 1 to 11 carbon atoms. In some embodiments, the alkyl group contains 1 to 11 carbon atoms, 1 to 10 carbon atoms, 1 to 9 carbon atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl-1-propyl (i-butyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (tertbutyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, and the like. 1~12 Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. 1~6 Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, and the like.

[0029] Alkyl groups can be further substituted with substituents that independently replace one or more hydrogen atoms on one or more carbon atoms of the alkyl group. Examples of such substituents include, but are not limited to, acyl, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, haloalkyl, haloalkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, phosphate, phosphonyl, phosphinyl, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid, sulfate, alkylsulfonyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, nitro, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. The alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl, heteroalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, and heteroaryl groups described below can also be similarly substituted.

[0030] As used herein, the term "alkenyl," either as part of another term or used independently, refers to a straight or branched chain hydrocarbon group having at least one carbon-carbon double bond, which may be optionally independently substituted with one or more substituents described herein, including groups having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In some embodiments, an alkenyl group contains 2-12 carbon atoms. In some embodiments, an alkenyl group contains 2-11 carbon atoms. In some embodiments, an alkenyl group contains 2-11 carbon atoms, 2-10 carbon atoms, 2-9 carbon atoms, 2-8 carbon atoms, 2-7 carbon atoms, 2-6 carbon atoms, 2-5 carbon atoms, 2-4 carbon atoms, 2-3 carbon atoms, and in some embodiments, an alkenyl group contains 2 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethylenyl (or vinyl), propenyl (allyl), butenyl, pentenyl, 1-methyl-2-buten-1-yl, 5-hexenyl, and the like.

[0031] As used herein, the term "alkynyl", either as part of another term or used independently, refers to a straight or branched chain hydrocarbon group having at least one carbon-carbon triple bond and optionally independently substituted with one or more substituents described herein. In some embodiments, an alkenyl group contains 2-12 carbon atoms. In some embodiments, an alkenyl group contains 2-11 carbon atoms. In some embodiments, an alkenyl group contains 2-11 carbon atoms, 2-10 carbon atoms, 2-9 carbon atoms, 2-8 carbon atoms, 2-7 carbon atoms, 2-6 carbon atoms, 2-5 carbon atoms, 2-4 carbon atoms, 2-3 carbon atoms, and in some embodiments, an alkynyl group contains 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

[0032] As used herein, the term "amino" refers to the -NH group. The amino group can also be substituted with one or more groups, such as alkyl, aryl, carbonyl, or other amino groups.

[0033] As used herein, the term "aryl", either as part of another term or used independently, refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, with at least one ring in the system being aromatic, and each ring in the system containing 3 to 12 ring members. Examples of "aryl" include, but are not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may have one or more substituents. Also included within the scope of the term "aryl", as used herein, are groups in which an aromatic ring is fused with one or more additional rings. In the case of polycyclic systems, only one of the rings need be aromatic (e.g., 2,3-dihydroindole), but all of the rings may be aromatic (e.g., quinoline). The second ring can also be fused or bridged. Examples of polycyclic aryls include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthoimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. Aryl groups may be optionally substituted at one or more ring positions with substituents as described above.

[0034] As used herein, the term "cycloalkyl", whether used as part of another term or independently, refers to monovalent non-aromatic saturated or partially unsaturated monocyclic and polycyclic ring systems in which all ring atoms are carbon and which contain at least three ring-forming carbon atoms. In some embodiments, a cycloalkyl can contain 3 to 12 ring-forming carbon atoms, 3 to 10 ring-forming carbon atoms, 3 to 9 ring-forming carbon atoms, 3 to 8 ring-forming carbon atoms, 3 to 7 ring-forming carbon atoms, 3 to 6 ring-forming carbon atoms, 3 to 5 ring-forming carbon atoms, 4 to 12 ring-forming carbon atoms, 4 to 10 ring-forming carbon atoms, 4 to 9 ring-forming carbon atoms, 4 to 8 ring-forming carbon atoms, 4 to 7 ring-forming carbon atoms, 4 to 6 ring-forming carbon atoms, 4 to 5 ring-forming carbon atoms. Cycloalkyl groups can be saturated or partially unsaturated. Cycloalkyl groups can be substituted. In some embodiments, a cycloalkyl group can be a saturated cyclic alkyl group. In some embodiments, the cycloalkyl group may be a partially unsaturated cyclic alkyl group that contains at least one double or triple bond in its ring system. In some embodiments, the cycloalkyl group may be monocyclic or polycyclic. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, adamantyl, norbornyl, fluorenyl, spiro-pentadienyl, spiro[3.6]-decanyl, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, and the like.

[0035] As used herein, the term "cyano" refers to --CN.

[0036] As used herein, the term "halogen" refers to an atom selected from fluorine (or fluoro), chlorine (or chloro), bromine (or bromo) and iodine (or iodo).

[0037] As used herein, the term "heteroatom" refers to nitrogen, oxygen, sulfur, or phosphorus, and includes any oxidized form of nitrogen, sulfur, or phosphorus, and any quaternized form of a basic nitrogen.

[0038] As used herein, the term "heteroalkyl" refers to an alkyl having at least one carbon atom substituted with a heteroatom selected from N, O, or S. A heteroalkyl can be a carbon atom or heteroatom group (i.e., the heteroatom can occur at the center or end of the group), and can be optionally and independently substituted with one or more substituents described herein. The term "heteroalkyl" includes alkoxy and heteroalkoxy groups.

[0039] As used herein, the term "heteroalkenyl" refers to an alkenyl having at least one of its carbon atoms replaced with a heteroatom selected from N, O, or S. A heteroalkenyl can be a carbon or heteroatom group (i.e., the heteroatom can occur at the center or at the end of the group), which can be optionally substituted independently with one or more substituents described herein.

[0040] As used herein, the term "heteroalkynyl" refers to an alkynyl having at least one of its carbon atoms replaced with a heteroatom selected from N, O, or S. The heteroalkynyl can be a carbon or heteroatom group (i.e., the heteroatom can occur at the center or at the end of the group), which can be optionally substituted independently with one or more substituents described herein.

[0041] As used herein, the term "heteroaryl", whether used as part of another term or used independently, refers to an aryl having one or more heteroatoms in addition to carbon atoms. Heteroaryl groups can be monocyclic. Examples of monocyclic heteroaryls include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Heteroaryl groups can also be polycyclic, where the heteroaryl ring is fused with one or more aryl, cycloalkyl, or heterocyclyl rings, and the point of attachment is on the heteroaryl ring. Examples of polycyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthaloyl, quinazolinyl, quinoxalinyl, 4H-quinolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, benzoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0042] As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, etc., and the remaining ring atoms are carbon, and one or more ring atoms may be optionally and independently substituted with one or more substituents. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, the heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system. In some embodiments, the heterocyclyl may contain any oxidized form of carbon, nitrogen, or sulfur, and any quaternized form of a basic nitrogen. "Heterocyclyl" also includes groups in which the heterocyclyl group is fused to a saturated, partially unsaturated, or fully saturated (i.e., aromatic) carbocyclic or heterocyclic ring. The heterocyclyl group may be carbon- or nitrogen-bonded, where possible. In some embodiments, the heterocyclic ring is carbon-bonded. In some embodiments, the heterocyclic ring is nitrogen-bonded. For example, the group derived from pyrrole can be pyrrol-1-yl (nitrogen-linked) or pyrrol-3-yl (carbon-linked), and the group derived from imidazole can be imidazol-1-yl (nitrogen-linked) or imidazol-3-yl (carbon-linked).

[0043] In some embodiments, the term "3-12 membered heterocyclyl" refers to a 3-12 membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Fused, spiro, and bridged ring systems are also included within the scope of this definition. Examples of monocyclic heterocyclyls include, but are not limited to, oxetanyl, 1,1-dioxothienylpyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridinonyl, pyrimidinonyl, pyrazinonyl, pyrimidinonyl, pyridazinonyl, pyrrolidinyl, triazinonyl, and the like. Examples of fused heterocyclyls include, but are not limited to, phenyl or pyridinyl fused rings such as quinolinyl, isoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[4,3-a]pyridinyl and other groups. Examples of spiroheterocyclyls include, but are not limited to, spiropyranyl, spirooxazinyl, and the like. Examples of bridged heterocyclyls include, but are not limited to, morpholinyl, hexamethylenetetramino, 3-azabicyclo[3.1.0]hexane, 8-azabicyclo[3.2.1]octane, 1-azabicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane (DABCO), and the like.

[0044] As used herein, the term "hydroxyl" refers to an --OH group.

[0045] As used herein, the term "nitro" refers to the group --NO.sub.2.

[0046] As used herein, the term "partially unsaturated" refers to a group that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings that have multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully saturated) moieties.

[0047] As used herein, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety are replaced by a suitable substituent. It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the permitted valences of the substituted atom, and that the substitution results in a stable or chemically feasible compound that does not spontaneously undergo modification, for example, by rearrangement, cyclization, elimination, and the like. Unless otherwise indicated, an "optionally substituted" group may have suitable substitution at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a particular group, the substituents may be the same or different at each position. It will be understood by those skilled in the art that, where appropriate, a substituent may itself be substituted. It will be understood that references to chemical moieties herein include substituted variants, unless specifically indicated as "unsubstituted". For example, references to "aryl" groups or moieties implicitly include both substituted and unsubstituted variants.

[0048] As used herein, the terms "agglomerate," "agglutination," and "aggregation" have the same meaning.

[0049] compound The present disclosure provides novel compounds of formula (I) and pharma- ceutically acceptable salts thereof, synthetic methods for making the compounds, pharmaceutical compositions containing them, and various uses of the disclosed compounds.

[0050] In one aspect, the present disclosure provides a compound having formula (I):

[0051] [ka] or a pharma- ceutically acceptable salt thereof (In the formula,

[0052] [ka] indicates a double bond in the Z or E configuration; R 1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, each of which is selected from the group consisting of one or more R a is optionally replaced by; R 2 is -C(O)R b and; R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl; L is selected from the group consisting of a direct bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, each of which may be selected from one or more of R f is optionally replaced by; W is

[0053] [ka] W is selected from the group consisting of * The end is joined to L; R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl; R a each of which is hydrogen, halogen, hydroxyl, amino, cyano, nitro or -NR c R d independently selected from the group consisting of: R b is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, heteroaryl, -NR c R d AND -OR e selected from the group consisting of; Rc and R d each is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, or amino; R e is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl; R f each is independently selected from the group consisting of hydrogen, cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl; or The Two R's f together with the atom to which they are both attached form a saturated or partially unsaturated cycloalkyl or a saturated or partially unsaturated heterocyclyl, each of which is optionally substituted with cyano, halogen, hydroxyl, amino, and alkyl; R gis selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, or saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, each of the hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxy, or amino; n is 0, 1, 2, 3, 4 or 5) to provide.

[0054] In some embodiments, R 1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, amino, alkyl, and heteroalkyl, each of which is selected from one or more R a is optionally replaced by

[0055] In certain embodiments, R a Each of is independently selected from halogen, hydroxyl, cyano, or nitro.

[0056] In some embodiments, R 1 is one or more R a is halogen, cyano, hydroxyl, amino or alkyl optionally substituted with

[0057] In certain embodiments, R 1 is one or more R a is halogen, cyano or alkyl optionally substituted with

[0058] In certain embodiments, R 1 is fluoro, chloro, bromo, cyano, methyl or trifluoromethyl.

[0059] In some embodiments, n is 1, 2, or 3. In certain embodiments, n is 1 or 2. In certain embodiments, n is 1.

[0060] In some embodiments, R 2 is -C(O)R b and R b is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, -NR c R d AND -OR e is selected from the group consisting of:

[0061] In certain embodiments, R c and R d is independently selected from the group consisting of hydrogen, alkyl, and alkenyl, wherein each of the alkyl and alkenyl is optionally substituted with halogen or hydroxyl.

[0062] In certain embodiments, R e is selected from the group consisting of alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, and heteroaryl, each of which is optionally substituted with cyano, halogen, hydroxy, amino, or alkyl.

[0063] In some embodiments, R 2 is -C(O)R b and R b is hydrogen, hydroxyl, alkyl, saturated or partially unsaturated cycloalkyl, or -OR e It is.

[0064] In certain embodiments, R 2 is -C(O)R b and R b is a saturated cycloalkyl or -OR eand R e is alkyl.

[0065] In certain embodiments, R 2 is -C(O)R b and R b is the saturated C 3~6 Cycloalkyl or -OR e and R e is C 1~6 It is an alkyl.

[0066] In certain embodiments, R 2 is -C(O)R b and R b is cyclopropyl or -OR e and R e is methyl, ethyl, n-propyl or isopropyl.

[0067] In some embodiments, R 2 is -C(O)-cyclopropyl or -C(O)OCH3.

[0068] In some embodiments, R 3 is hydrogen or alkyl optionally substituted with halogen, hydroxyl, cyano or amino.

[0069] In some embodiments, R 3 is hydrogen.

[0070] In some embodiments, R 3 is alkyl optionally substituted with halogen, hydroxyl, cyano, or amino.

[0071] In certain embodiments, R 3 is C optionally substituted with halogen, hydroxyl, cyano or amino 1~6 It is an alkyl.

[0072] In certain embodiments, R 3 is methyl, ethyl, n-propyl or isopropyl.

[0073] In some embodiments, L is selected from the group consisting of a direct bond, alkyl, heteroalkyl, saturated or partially unsaturated cycloalkyl, and saturated or partially unsaturated heterocyclyl, each of which is selected from the group consisting of one or more R f is optionally replaced by

[0074] In certain embodiments, R f Each of is independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, alkyl, and heteroalkyl.

[0075] In certain embodiments, two R f together with the atom to which they are both attached form a saturated or partially unsaturated cycloalkyl, optionally substituted with cyano, halogen, hydroxyl, amino, and alkyl.

[0076] In some embodiments, L is a direct bond.

[0077] In some embodiments, L is one or more R f is alkyl optionally substituted with

[0078] In certain embodiments, L is one or more R f Optionally replaced by C 1~6 It is an alkyl.

[0079] In certain embodiments, L is one or more R f Optionally replaced by C 1~6 is alkyl, R f is independently selected from the group consisting of hydrogen, halogen, hydroxyl, methyl and ethyl.

[0080] In some embodiments, L is -CH2-, -CH(CH3)-, or -C(CH3)2-.

[0081] In some embodiments, W is

[0082] [ka] It is.

[0083] In some embodiments, W is

[0084] [ka] It is.

[0085] In some embodiments, W is

[0086] [ka] It is.

[0087] In some embodiments, W is

[0088] [ka] It is.

[0089] In some embodiments, W is

[0090] [ka] It is.

[0091] In some embodiments, W is

[0092] [ka] It is.

[0093] In some embodiments, R gis selected from the group consisting of hydrogen, alkyl, and heteroalkyl, each of which is optionally substituted with halogen, hydroxyl, cyano, or amino.

[0094] In certain embodiments, W is

[0095] [ka] (In the formula, R g is hydrogen or C 1~6 (It is alkyl) In certain embodiments, R g is hydrogen, methyl or ethyl.

[0096] In some embodiments, R 4 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, or aryl, each of which is optionally substituted with cyano, halogen, hydroxyl, amino, or alkyl.

[0097] In certain embodiments, R 4 is hydrogen, or alkyl or aryl optionally substituted with halogen, hydroxyl, cyano, or amino.

[0098] In certain embodiments, R 4 is optionally substituted with hydrogen, halogen, hydroxyl, cyano or amino; 1~6 C optionally substituted with alkyl, halogen, hydroxyl, cyano or amino 6~12 It is aryl.

[0099] In certain embodiments, R 4 is hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH(CH3)(NH2) or phenyl.

[0100] In some embodiments,

[0101] [ka] is a double bond in the E configuration.

[0102] In some embodiments,

[0103] [ka] is a double bond in the Z configuration.

[0104] In a further aspect, the present disclosure provides a method for producing a method for treating a cancer cell comprising:

[0105] [ka] [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R g , L and n are defined as above). or a pharma- ceutically acceptable salt thereof.

[0106] In some embodiments, R 1 is halogen. In certain embodiments, R 1 is fluoro, chloro or bromo.

[0107] In some embodiments, n is 1, 2, or 3. In certain embodiments, n is 1 or 2. In certain embodiments, n is 1.

[0108] In some embodiments, R 2 is -C(O)R b and R bis hydrogen, hydroxyl, alkyl, saturated cycloalkyl or -OR e In certain embodiments, R 2 is -C(O)R b and R b is a saturated cycloalkyl or -OR e and R e is alkyl. In certain embodiments, R 2 is -C(O)R b and R b is the saturated C 3~6 Cycloalkyl or -OR e and R e is C 1~6 In certain embodiments, R 2 is -C(O)R b and R b is cyclopropyl or -OR e and R e is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, R 2 is -C(O)-cyclopropyl or -C(O)OCH3.

[0109] In some embodiments, R 3 is hydrogen.

[0110] In some embodiments, R 3 is alkyl. In certain embodiments, R 3 is C 1~6 In certain embodiments, R 3 is methyl, ethyl, n-propyl or isopropyl.

[0111] In some embodiments, L is a direct bond.

[0112] In some embodiments, L is one or more R independently selected from hydrogen, halogen, hydroxyl, methyl, and ethyl. fIn certain embodiments, L is one or more R independently selected from hydrogen, halogen, hydroxyl, methyl, and ethyl. f Optionally replaced by C 1~6 In certain embodiments, L is -CH2-, -CH(CH3)-, or -C(CH3)2-.

[0113] In some embodiments, R 4 is hydrogen or alkyl optionally substituted with halogen, hydroxyl, cyano, or amino. In certain embodiments, R 4 is hydrogen or C optionally substituted with halogen, hydroxyl, cyano or amino 1~6 In certain embodiments, R 4 is hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3 or -CH(CH3)(NH2).

[0114] In some embodiments, R g is hydrogen or alkyl. In certain embodiments, R g is hydrogen or C 1~6 In certain embodiments, R g is hydrogen, methyl, or ethyl. In certain embodiments, R g is hydrogen.

[0115] In some embodiments,

[0116] [ka] is a double bond in the E configuration.

[0117] In some embodiments,

[0118] [ka] is a double bond in the Z configuration.

[0119] In a further aspect, the present disclosure provides a method for producing a method for treating a cancer cell comprising:

[0120] [ka] [ka] (In the formula, R 1 , R 2 , R 4 , R g , L and n are defined as above). or a pharma- ceutically acceptable salt thereof.

[0121] In some embodiments,

[0122] [ka] is a double bond in the E configuration.

[0123] In some embodiments,

[0124] [ka] is a double bond in the Z configuration.

[0125] In a further aspect, the present disclosure provides a method for producing a method for treating a cancer cell comprising:

[0126] [ka] [ka] (In the formula, R 1 , R 4 , R g , L and n are defined as above). or a pharma- ceutically acceptable salt thereof.

[0127] In some embodiments,

[0128] [ka] is a double bond in the E configuration.

[0129] In some embodiments,

[0130] [ka] is a double bond in the Z configuration.

[0131] In a further aspect, the present disclosure provides a method for producing a method for treating a cancer cell comprising:

[0132] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0133] The compounds provided herein are described with reference to both general formula and specific compound.In addition, the compounds of the present disclosure can exist in several different forms or derivatives, all of which are within the scope of the present disclosure.These include, for example, tautomers, stereoisomers, racemic mixtures, positional isomers, salts, solvate forms, amorphous forms, different crystal forms or polymorphs.

[0134] The compounds of the present disclosure may contain one or more asymmetric centers by selecting substituents, and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers.For example, the compounds provided herein may have asymmetric carbon centers, and therefore the compounds provided herein may have the (R) or (S) configuration at the carbon asymmetric center.Therefore, the compounds of the present disclosure may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of a mixture of stereoisomers.

[0135] As used herein, the term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. The term "diastereomers" refers to a pair of optical isomers that are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities.

[0136] When a particular enantiomer is preferred, in some embodiments it may be provided substantially free of the opposite enantiomer, and may be referred to as "optically enriched". "Optically enriched", as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments, the compound is made up of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound is made up of at least about 95%, 98% or 99% by weight of the preferred enantiomer. The preferred enantiomer may be isolated from the racemic mixture by any method known to those skilled in the art, for example, by chromatography or crystallization, by using stereochemically uniform starting materials for synthesis, or by stereoselective synthesis. Optionally, derivatization may be performed prior to separation of stereoisomers. Separation of the mixture of stereoisomers may be performed at an intermediate step during the synthesis of the compounds provided herein, or it may be performed on the final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates derivatized, if necessary, with a reagent containing a stereogenic center of known configuration. Alternatively, absolute stereochemistry can be determined by vibrational circular dichroism (VCD) spectroscopy analysis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, SH et al., Tetrahedron 33:2725 (1977); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions 268 (E.L. Eliel, Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0137] In some embodiments, mixtures of diastereomers are provided, for example mixtures of diastereomers enriched in one of the diastereomers by 51% or more, for example containing 60% or more, 70% or more, 80% or more, or 90% or more of one of the diastereomers.

[0138] In some embodiments, the compounds provided herein may have one or more double bonds that can exist as either Z or E isomers, unless otherwise specified. The disclosure additionally encompasses the compounds as individual isomers substantially free of other isomers, or as mixtures of various isomers, e.g., racemic mixtures of enantiomers.

[0139] The compounds of the present disclosure may also exist in different tautomeric forms, and all such forms are encompassed within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible by a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions by migration of a proton, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerizations, and cyclic forms in which a proton may occupy more than one position of a heterocyclic ring system (e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole). Valence tautomers include interconversions by rearrangement of some of the bond electrons. Tautomers may be in equilibrium or sterically locked into one form by appropriate substitution. Compounds of the disclosure that are identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0140] The present disclosure is also intended to include all isotopes of atoms in a compound. Isotopes of an element include atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in a compound of the present disclosure are intended to include these isotopes, including but not limited to: 1 H, 2 H, 3 H, 11 C. 12 C. 13 C. 14 C. 14 N, 15 N, 16 O. 17 O. 18 O. 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I, 127 I and 131 In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes 12 C and 13 C. Isotopically-enriched compounds of formula (I) can be prepared without undue experimentation by conventional techniques well known to those of skill in the art, or by processes analogous to those described in the schemes and examples herein using appropriate isotopically enriched reagents and / or intermediates.

[0141] The compounds of the present disclosure can be formulated as or in the form of pharma- ceutically acceptable salts.Unless otherwise specified, the compounds provided herein include pharma- ceutically acceptable salts of such compounds.

[0142] As used herein, the term "pharmacologically acceptable" indicates that a substance or composition is chemically and / or toxicologically compatible with other ingredients comprising the formulation and / or the subject being treated therewith.

[0143] As used herein, the term "pharmaceutical acceptable salts" includes salts that retain the biological effectiveness of the free acids and bases of a particular compound, and are not biologically or otherwise undesirable, unless otherwise specified. Contemplated pharmaceutical acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and the like. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate pharmacological use by modifying the physical characteristics of a compound without preventing it from exerting its physiological effects. Useful modifications of physical properties include lowering the melting point to facilitate transmucosal administration, and increasing the solubility to facilitate the administration of higher concentrations of drugs.

[0144] Pharmaceutically acceptable salts include those containing acid addition salts such as sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetate, citric acid, lactate, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid and quinic acid.

[0145] Pharmaceutically acceptable salts also include base addition salts, such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines and zinc, when an acidic functional group, such as carboxylic acid or phenol, is present.See, for example, Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using the appropriate corresponding base.

[0146] Pharmaceutically acceptable salts can be prepared by standard techniques. The free base form of a compound can be isolated by dissolving it in a suitable solvent, such as an aqueous or aqueous alcoholic solution containing a suitable acid, and then evaporating the solution. Thus, if a particular compound is a base, the desired pharma-ceutically acceptable salt can be prepared by any suitable method available in the art, such as treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

[0147] Similarly, if a particular compound is an acid, the desired pharma- ceutically acceptable salt can be prepared by any suitable method, such as treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, etc. Representative examples of suitable salts include organic salts derived from amino acids, such as L-glycine, L-lysine and L-arginine, ammonia, primary, secondary or tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidone, piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0148] It will be understood that the compounds of the present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms), and solid forms (e.g., crystalline or polymorphic forms), and that the present disclosure is intended to encompass all such forms.

[0149] As used herein, the term "solvate" or "solvate form" refers to a solvent addition form that contains either a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to trap a certain molar ratio of solvent molecules in the crystalline solid phase, thereby forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more moles of water with one of the substances, where the water retains its molecular state as H2O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0150] As used herein, the terms "crystal form", "crystalline form", "polymorphic form" and "polymorph" may be used interchangeably and refer to crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors may cause one crystal form to predominate. Crystal polymorphs of a compound can be prepared by recrystallization under different conditions.

[0151] The present disclosure is intended to include all isotopes of atoms in a compound. Isotopes of an element include atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in a compound of the present disclosure are, but are not limited to, 1 H, 2 H, 3 H, 11 C. 12 C. 13 C. 14 C. 14 N, 15 N, 16 O. 17 O. 18 O. 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I, 127 I, and 131 In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes 12 C and13 Contains C.

[0152] Compound synthesis The synthesis of the compounds provided herein, including their pharma-ceutically acceptable salts, is illustrated in the synthesis schemes in the examples.The compounds provided herein can be prepared using any known organic synthesis technique and can be synthesized according to any of a myriad of possible synthesis routes, and therefore these schemes are illustrative only and are not meant to limit the other possible methods that can be used to prepare the compounds provided herein.In addition, the steps in the schemes are for better illustration and can be modified appropriately.The compound embodiments in the examples are synthesized for the purpose of investigation and possible submission to regulatory authorities.

[0153] The reaction for preparing the compounds of the present disclosure can be carried out in a suitable solvent, which can be easily selected by those skilled in the art of organic synthesis.A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, which can range from the freezing temperature of the solvent to the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of more than one solvent.Depending on the specific reaction step, the suitable solvent for a specific reaction step can be selected by those skilled in the art.

[0154] The preparation of the compounds of the present disclosure may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of suitable protecting groups, can be easily determined by those skilled in the art. The chemical nature of protecting groups is described, for example, in TW Greene and PGM Huts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003, and Peter GMW Huts, Greene's Protective Groups in Organic Synthesis, 5th Ed., Wiley & Sons, Inc., New York (1999), all of which are incorporated herein by reference in their entirety. th Edition, Wiley, 2014.

[0155] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic methods, such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-Vis) or mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography mass spectrometry (LCMS) or thin layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization" Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, vol. 6(6), pp. 874-883, the entirety of which is incorporated herein by reference) and normal phase silica gel chromatography.

[0156] Known starting materials of this disclosure can be synthesized by or according to methods known in the art or purchased from commercial suppliers. Analytical grade solvents and commercially available reagents were used without further purification unless otherwise noted.

[0157] Unless otherwise noted, all reactions in this disclosure were carried out under a positive pressure of nitrogen or argon or in anhydrous solvents with drying tubes, and reaction flasks were typically equipped with rubber septa for introduction of substrates and reagents via syringe. Glassware was oven-dried and / or heat-dried.

[0158] For illustrative purposes, the following Examples section shows synthetic routes for preparing the compounds of the present disclosure as well as key intermediates. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds of the present invention. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to generate various derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0159] Cyclodextrin The pharmaceutical compositions of the present disclosure include cyclodextrins. The term "cyclodextrin" refers to a cyclic molecule containing six or more α-D-glucopyranose units linked at the 1,4 positions. A cyclodextrin containing six sugar units is an α-cyclodextrin, a cyclodextrin containing seven sugar units is a β-cyclodextrin, and a cyclodextrin containing eight sugar units is a γ-cyclodextrin. Cyclodextrin derivatives are cyclodextrins in which some of the -OH groups have been modified to -OR, where each R is independently alkyl, hydroxyalkyl, glucosyl, maltosyl, cycloalkylalkyl, or -(CH2)4SO3. - Na +As used herein, the term "cyclodextrin" is intended to include cyclodextrin and its derivatives. Examples of alkyl derivatives of cyclodextrin include, but are not limited to, dimethyl-α-cyclodextrin, dimethyl-β-cyclodextrin, and dimethyl-γ-cyclodextrin. Examples of hydroxyalkyl derivatives of cyclodextrin include, but are not limited to, 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, and 2-hydroxypropyl-γ-cyclodextrin. Examples of sulfoalkyl ether derivatives of cyclodextrin include, but are not limited to, sulfobutylether-α-cyclodextrin, sulfobutylether-β-cyclodextrin, and sulfobutylether-γ-cyclodextrin. Examples of glycosyl derivatives of cyclodextrin include, but are not limited to, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, glucosyl-γ-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, and maltosyl-γ-cyclodextrin.

[0160] Cyclodextrins that can be used in the present disclosure include α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.

[0161] In some embodiments, the cyclodextrin is a β-cyclodextrin.

[0162] In some embodiments, the cyclodextrin is a β-cyclodextrin selected from sulfobutylether-β-cyclodextrin (SBECD), cyclobutylalkylether-β-cyclodextrin, or hydroxypropyl-β-cyclodextrin (HPCD).

[0163] Buffer The pharmaceutical compositions of the present disclosure may optionally include a buffering agent. The term "buffering agent" refers to any known agent that can be safely used in pharmaceutical compositions and has the ability to maintain or control the pH of the formulation within a desired range.

[0164] In some embodiments, the pharmaceutical compositions of the present disclosure include an acidic buffer to adjust the pH of the pharmaceutical composition to within about 3 to about 4. Examples of suitable acidic buffers include, but are not limited to, inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, etc.) and organic acids (e.g., oxalic acid, maleic acid, fumaric acid, lactic acid, malic acid, tartaric acid, citric acid, benzoic acid, acetic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, etc.). Acid salts of the acids listed above may also be used.

[0165] In some embodiments, the acidic buffer used in the pharmaceutical composition of the present disclosure is selected from phosphoric acid, hydrochloric acid, succinic acid, acetic acid, tartaric acid, lactic acid, citric acid, malic acid, or glycolic acid. In certain embodiments, the acidic buffer used in the pharmaceutical composition of the present disclosure is citric acid.

[0166] pH Adjustment Agent The pharmaceutical composition of the present disclosure may optionally include a pH adjusting agent. The term "pH adjusting agent" refers to an adjusting agent used in the art to adjust pH. pH adjusting agents include acidic pH adjusting agents and basic pH adjusting agents.

[0167] As used herein, an "acidic pH modifier" refers to an acidic pH modifier that is capable of absorbing a proton (H +) or is an electron pair acceptor under the Lewis definition. Examples of acids include, but are not limited to, alkanoic or carboxylic acids, sulfonic acids, and inorganic acids. Examples of alkanoic acids include, but are not limited to, formic acid, acetic acid, citric acid, lactic acid, oxalic acid, succinic acid, tartaric acid, malic acid, glycolic acid, and the like. Examples of inorganic acids include, but are not limited to, hydrogen halides (hydrofluoric acid, hydrochloric acid, hydrobromic acid, and the like), halogen oxygen acids (hypochlorous acid, perchloric acid, and the like), sulfuric acid, nitric acid, phosphoric acid, chromic acid, boric acid, and the like. Examples of sulfonic acids include, but are not limited to, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, and the like. Other acids will be known to those skilled in the art.

[0168] As used herein, a "basic pH modifier" refers to a compound that is capable of absorbing a proton (H + ) or is an electron pair donor under the Lewis definition. Examples of Bronsted-Lowry bases include, but are not limited to, alkali metal or alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, magnesium hydroxide, strontium hydroxide, barium hydroxide, and the like. Examples of Lewis bases include, but are not limited to, amines (e.g., ammonia, trimethylamine, triethylamine, diisopropylethylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, quinuclidine, and lithium diisopropylamide) and nucleophilic bases (e.g., butyllithium). Other bases will be known to those of skill in the art.

[0169] In some embodiments, the pH adjusting agent is HCl. In some embodiments, the pH adjusting agent is NaOH. In some embodiments, the pH adjusting agent is NaOH and HCl.

[0170] Pharmaceutical Compositions The present invention provides a pharmaceutical composition comprising a compound of formula (I) of the present disclosure, or a pharma- ceutically acceptable salt thereof, and a cyclodextrin.

[0171] In some embodiments, the pharmaceutical composition comprises:

[0172] [ka] This includes compounds of the formula:

[0173] In some embodiments, the cyclodextrin is β-cyclodextrin. In certain embodiments, the β-cyclodextrin is sulfobutylether-β-cyclodextrin, cyclobutylalkylether-β-cyclodextrin, or hydroxypropyl-β-cyclodextrin. In certain embodiments, the β-cyclodextrin is sulfobutylether-β-cyclodextrin or hydroxypropyl-β-cyclodextrin. In certain embodiments, the β-cyclodextrin is sulfobutylether-β-cyclodextrin. In certain embodiments, the β-cyclodextrin is hydroxypropyl-β-cyclodextrin.

[0174] Preparation of injections Prior to the present application, the difficulty of preparing an injectable formulation of the compound provided herein or a pharma- ceutically acceptable salt thereof was not known, and the type of solubilizer used to obtain an effective injectable formulation containing the compound or a pharma- ceutically acceptable salt thereof was not known. The inventors have surprisingly found that the use of cyclodextrin can help to obtain an effective injectable formulation of the compound provided herein or a pharma- ceutically acceptable salt thereof. By mixing the compound provided herein or a pharma- ceutical acceptable salt thereof with cyclodextrin, the resulting formulation not only has good solubility and stability at pH 3-4, but also significantly improves drug efficacy and intracellular exposure.

[0175] In some embodiments, the pharmaceutical compositions of the present disclosure are solutions and may also be referred to as injectable formulations.

[0176] In certain embodiments, the pharmaceutical composition of the present disclosure includes water to form an injectable formulation.The water can be any suitable water, such as distilled water or safe water for injection.In certain embodiments, the water can be safe water for injection.

[0177] In some embodiments, the injectable formulation comprises 0.1 to 10 mg / mL of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the content of the compound of formula (I) or a pharma- ceutically acceptable salt thereof in the injectable formulation is any value within the above range. For example, if necessary, the content of the compound of formula (I) or a pharma- ceutically acceptable salt thereof in the injectable formulation is at least 0.1 mg / mL, at least 0.2 mg / mL, at least 0.3 mg / mL, at least 0.4 mg / mL, at least 0.5 mg / mL, at least 0.6 mg / mL, at least 0.7 mg / mL, at least 0.8 mg / mL, at least 0.9 mg / mL, at least 1 mg / mL, at least 1.2 mg / mL, at least 1.2 mg / mL, at least 1.3 mg / mL, at least 1.4 mg / mL, at least 1.5 mg / mL, at least 1.6 mg / mL, at least 1.7 mg / mL, at least 1.8 mg / mL, at least 1.9 mg / mL, at least 2.0 mg / mL, at least 2.5 ... It may be at least 1.8 mg / mL, at least 1.9 mg / mL, at least 2 mg / mL, at least 2 mg / mL, at least 3 mg / mL, at least 4 mg / mL, at least 5 mg / mL, at least 6 mg / mL, at least 7 mg / mL, at least 8 mg / mL, at least 9 mg / mL, or at least 10 mg / mL, and at most 10 mg / mL, at most 9 mg / mL, at most 8 mg / mL, at most 7 mg / mL, at most 6 mg / mL, at most 5 mg / mL, at most 4 mg / mL, at most 3 mg / mL, at most 2 mg / mL, at most 1 mg / mL, or at most 0.9 mg / mL.

[0178] In some embodiments, the injectable formulation contains 0.2-10 mg / mL, 0.3-5 mg / mL, 0.4-2 mg / mL, 0.5-1 mg / mL, or 0.6-0.9 mg / mL of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0179] In some embodiments, the injectable formulation contains 20 to 400 mg / mL of cyclodextrin. In some embodiments, the content of cyclodextrin in the injectable formulation is any value within the above range. For example, depending on the circumstances, the content of cyclodextrin in the injectable formulation may be at least 20 mg / mL, at least 25 mg / mL, at least 30 mg / mL, at least 35 mg / mL, at least 40 mg / mL, at least 45 mg / mL, at least 50 mg / mL, at least 60 mg / mL, at least 70 mg / mL, at least 80 mg / mL, at least 90 mg / mL, at least 100 mg / mL, at least 110 mg / mL, at least 120 mg / mL, at least 130 mg / mL, at least 140 mg / mL, at least 150 mg / mL, at least 160 mg / mL, at least 170 mg / mL, at least 180 mg / mL, at least 190 mg / mL, at least 200 mg / mL, at least 210 mg / mL, at least 220 mg / mL, at least 230 mg / mL, at least 240 mg / mL, or at least 250 mg / mL, and more. at most 400mg / mL, at most 390mg / mL, at most 380mg / mL, at most 370mg / mL, at most 360mg / mL, at most 350mg / mL, at most 340mg / mL, at most 330mg / mL, at most 320mg / mL, at most 310mg / mL, at most 300mg / mL, at most 290mg / mL, at most 280mg / mL, at most 270mg / mL, at most 260mg / mL, at most 250mg / mL L, at most 240 mg / mL, at most 230 mg / mL, at most 220 mg / mL, at most 210 mg / mL, at most 200 mg / mL, at most 190 mg / mL, at most 180 mg / mL, at most 170 mg / mL, at most 160 mg / mL, at most 150 mg / mL, at most 140 mg / mL, at most 130 mg / mL, at most 120 mg / mL, at most 110 mg / mL, or at most 100 mg / mL.In some embodiments, the injectable formulation contains 30-300 mg / mL, 40-300 mg / mL, 50-250 mg / mL, 60-200 mg / mL, 70-150 mg / mL, or 80-100 mg / mL of cyclodextrin.

[0180] In some embodiments, the weight ratio of the cyclodextrin to the compound of formula (I) or its pharma- ceutically acceptable salt is 50:1 to 400:1, and the weight of the pharma- ceutically acceptable salt of the compound of formula (I) is based on the weight of the compound of formula (I) contained therein. In some embodiments, the weight ratio of the cyclodextrin to the compound of formula (I) or its pharma- ceutically acceptable salt is any value within the above range. For example, optionally the weight ratio of cyclodextrin to the compound of formula (I) or a pharma- ceutically acceptable salt thereof is at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 100:1, at least 110:1, at least 120:1, at least 130:1, at least 140:1, at least 150:1, at least 160:1, at least 170:1, at least 180:1, at least 190:1, at least 200:1, at least 210:1, at least 220:1, at least 230:1, at least 240:1, or at least 250:1, and at most 400:1, at most 390:1, at most 380:1, at most 370:1, at most 360:1, at most 350:1, at most 340:1, at most 330:1, at most 320:1, at most 310:1, at most 300:1, at most 290:1, at most 280:1, at most 270:1, at most 260:1, at most 250:1, at most 240:1, at most 230:1, at most 220:1, at most 210:1, at most 200:1, at most 190:1, at most 180:1, at most 170:1, at most 160:1, at most 150:1, at most 140:1, at most 130:1, or at most 120:1, wherein the weight of the pharma- ceutically acceptable salt of a compound of formula (I) is based on the weight of the compound of formula (I) contained therein.

[0181] In some embodiments, the weight ratio of cyclodextrin to the compound of Formula (I) or pharma- ceutically acceptable salt thereof is 50:1 to 300:1, 50:1 to 250:1, 60:1 to 250:1, 70:1 to 200:1, 80:1 to 150:1, or 90:1 to 120:1, and the weight of the pharma- ceutically acceptable salt of the compound of Formula (I) is based on the weight of the compound of Formula (I) contained therein.

[0182] In some embodiments, the injection formulation further comprises a buffer. In some embodiments, the buffer is an acidic buffer. In certain embodiments, the acidic buffer can be selected from phosphoric acid, hydrochloric acid, succinic acid, acetic acid, tartaric acid, lactic acid, citric acid, malic acid, glycolic acid, or hydrates thereof. In certain embodiments, the acidic buffer is citric acid or hydrates thereof. In certain embodiments, the acidic buffer is citric acid monohydrate. In certain embodiments, the injectable formulation comprises 1-3 mg / mL citric acid monohydrate, e.g., 1-2.8 mg / mL, 1-2.6 mg / mL, 1-2.4 mg / mL, 1-2.2 mg / mL, 1-2 mg / mL, 1-1.9 mg / mL, 1-1.8 mg / mL, 1-1.7 mg / mL, 1-1.6 mg / mL, 1-1.5 mg / mL, 1-1.4 mg / mL, 1-1.3 mg / mL, 1-1.2 mg / mL, or 1-1.1 mg / mL citric acid monohydrate.

[0183] In some embodiments, the injectable formulation has a pH of 3 to 4. The pH of the injectable formulation can be any pH within the pH ranges listed above, such as 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0. In some embodiments, the injectable formulation has a pH of 3.5 to 4. In some embodiments, the injectable formulation has a pH of 3.5. In some embodiments, the injectable formulation has a pH of 4.

[0184] If necessary, the pH can be adjusted by adding a pH adjusting agent so that the pH is within the above pH range. For example, an acidic pH adjusting agent and / or a basic pH adjusting agent can be added to adjust the pH. In some embodiments, the pH adjusting agent is an inorganic acid, for example, a hydrogen halide, such as HCl. In some embodiments, the basic pH adjusting agent is an alkali metal hydroxide or an alkaline earth metal hydroxide, for example, an alkali metal hydroxide, such as NaOH. In some embodiments, NaOH and HCl can be added to adjust the pH of the injectable formulation, so that the pH is within the above pH range.

[0185] In some embodiments, the injectable formulation comprises: 0.4 to 2 mg / mL of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (the weight of the pharma-ceutically acceptable salt of the compound of formula (I) is based on the weight of the compound of formula (I) contained therein); 40-250 mg / mL cyclodextrin; Optionally, a buffering agent; Optionally, a pH adjuster; and water and has a pH of 3 to 4.

[0186] In some embodiments, the injectable formulation comprises: 0.5-1 mg / mL of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (the weight of the pharma- ceutically acceptable salt of the compound of formula (I) is based on the weight of the compound of formula (I) contained therein); 50-150 mg / mL cyclodextrin; Optionally, a buffering agent; Optionally, a pH adjuster; and water and has a pH of 3 to 4.

[0187] In some embodiments, the injectable formulation comprises: 0.6-0.9 mg / mL of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (the weight of the pharma-ceutically acceptable salt of the compound of formula (I) is based on the weight of the compound of formula (I) contained therein); 60-120 mg / mL cyclodextrin; Optionally, a buffering agent; Optionally, a pH adjuster; and water and has a pH of 3 to 4.

[0188] In some embodiments, the injectable formulation comprises: 0.6-0.9 mg / mL of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (the weight of the pharma-ceutically acceptable salt of the compound of formula (I) is based on the weight of the compound of formula (I) contained therein); 70-110 mg / mL cyclodextrin; Optionally, a buffering agent; Optionally, a pH adjuster; and water and has a pH of 3 to 4.

[0189] In some embodiments, the injectable formulation comprises: 0.7-0.9 mg / mL of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (the weight of the pharma-ceutically acceptable salt of the compound of formula (I) is based on the weight of the compound of formula (I) contained therein); 80-100 mg / mL cyclodextrin; Optionally, a buffering agent; Optionally, a pH adjuster; and water and has a pH of 3 to 4.

[0190] In some embodiments, the injectable formulation comprises a buffering agent. In certain embodiments, the injectable formulation comprises an acidic buffering agent. In certain embodiments, the injectable formulation comprises citric acid monohydrate. In certain embodiments, the injectable formulation comprises 1-2.5 mg / mL citric acid monohydrate. In certain embodiments, the injectable formulation comprises 1-2.3 mg / mL citric acid monohydrate. In certain embodiments, the injectable formulation comprises 1-2.1 mg / mL citric acid monohydrate.

[0191] In some embodiments, the weight ratio of cyclodextrin to the compound or pharma- ceutically acceptable salt thereof in the injectable formulation is 80:1 to 150:1, 90:1 to 120:1, or 100:1 to 120:1, and the weight of the pharma- ceutically acceptable salt of the compound is based on the weight of the compound contained therein.

[0192] In some embodiments, the injectable formulations may also optionally contain common additives used in formulations, such as other solubilizing agents or cosolvents, such as poloxamer, propylene glycol, PEG400, TWEEN80, polyoxyethylene sorbitan monolaurate, etc.; isotonicity agents, such as potassium chloride, sodium chloride, glucose, glycerol, mannitol, sorbitol, etc.; stabilizers, such as sorbol, sodium edetate, etc.; and antioxidants, such as glycine, ascorbic acid, sodium citrate, etc.

[0193] The amount of the compound of formula (I) or a pharma- ceutically acceptable salt thereof in the injectable formulation of the present disclosure can be measured after storage of the formulation under various conditions. In some embodiments, the amount of the compound of formula (I) or a pharma- ceutically acceptable salt thereof is measured after storage of the formulation at 5°C. In some embodiments, the amount of the compound of formula (I) or a pharma- ceutically acceptable salt thereof is measured after storage of the injectable formulation at 15°C. In some embodiments, the amount of the compound of formula (I) or a pharma- ceutically acceptable salt thereof is measured after storage of the injectable formulation at 25°C. In some embodiments, the amount of the compound of formula (I) or a pharma- ceutically acceptable salt thereof is measured after storage of the injectable formulation at 40°C. In some embodiments, the amount of the compound of formula (I) or a pharma- ceutically acceptable salt thereof is measured after storage of the injectable formulation for 1 hour, 2 hours, 3 hours, or 4 hours.

[0194] Lyophilized preparations The pharmaceutical composition of the present disclosure may also be a lyophilized composition, which may also be referred to as a lyophilized formulation.

[0195] The lyophilized formulation of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and cyclodextrin.The compound of formula (I) or a pharmaceutically acceptable salt thereof can comprise the compound of formula (I) or a pharmaceutically acceptable salt thereof in various forms.For example, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be amorphous or crystalline, or a mixture thereof.In some embodiments, the lyophilized formulation of the present invention comprises the amorphous compound of formula (I) or a pharmaceutically acceptable salt thereof and cyclodextrin.

[0196] The lyophilized formulations of the present disclosure can be contained in any suitable container, such as a sealed vial. In some embodiments, the present disclosure provides a sealed vial containing the lyophilized formulation.

[0197] The lyophilized formulation of the present disclosure can be obtained by lyophilizing the injectable formulation of the present disclosure.

[0198] Preparation method for pharmaceutical composition When formulating the pharmaceutical formulations of the present disclosure, a compound of formula (I) or a pharma- ceutically acceptable salt thereof is added to an acidic cyclodextrin solution to raise the pH, and then a certain amount of water for injection is added to bring the total volume to the desired volume, such that the time to formulate the liquid may be shortened and the solubility and stability of the resulting pharmaceutical composition may be improved.

[0199] In some embodiments, the disclosure provides a method for preparing a pharmaceutical composition of the disclosure, comprising: mixing cyclodextrin with water to form a first mixture; Optionally, adding a buffer to the first mixture to form a second mixture; adding an acidic pH adjuster to the second mixture to adjust the pH to 1 to 1.5, thereby forming a third mixture; adding a compound of formula (I) or a pharma- ceutically acceptable salt thereof to the third mixture to form a fourth mixture; adding a basic pH adjuster to the fourth mixture to adjust the pH to 3 to 4, thereby forming a fifth mixture; and Optionally, adding water for injection to the fifth mixture to form a pharmaceutical composition. The present invention provides a method comprising:

[0200] In some embodiments, the method for preparing the pharmaceutical composition of the present disclosure comprises adding a buffer to the first mixture to form a second mixture. In certain embodiments, the buffer is citric acid, such as citric acid monohydrate.

[0201] In some embodiments, the acidic pH adjusting agent is HCl. In some embodiments, the basic pH adjusting agent is NaOH.

[0202] In some embodiments, the pharmaceutical composition can be sterile filtered through a filter membrane (e.g., a 0.22 μm filter membrane) and filled into vials, which are sealed and terminally sterilized.

[0203] In some embodiments, one of skill in the art can formulate the pharmaceutical compositions of the present disclosure as a solution for direct use or as a pre-concentrate that is diluted before use.

[0204] In some embodiments, the pharmaceutical composition can be further lyophilized, thereby forming a lyophilized composition.

[0205] Use of the pharmaceutical composition The compounds of formula (I) or pharma- ceutically acceptable salts thereof provided herein are capable of inhibiting platelet aggregation and are therefore suitable for use as therapeutic or prophylactic agents for various thrombotic disorders.

[0206] As used herein, the term "therapy" shall have its usual meaning of treating a disease to completely or partially alleviate one, some, or all of the symptoms of the disease, or to correct or compensate for the underlying pathology, thereby achieving a beneficial or desired clinical outcome. For the purposes of this disclosure, beneficial or desired clinical outcome includes, but is not limited to, alleviation of symptoms, attenuation of the extent of the disease, stable (i.e., not worsening) state of the disease, delay or slowing of disease progression, improvement or alleviation of the disease condition, and remission (whether partial or total), whether detectable or undetectable. "Therapy" may also mean a longer survival period compared to the expected survival period in the absence of the treatment. People in need of therapy include those who already have a condition or disease as well as those who are prone to have a condition or disease or those in whom a condition or disease should be prevented. The term "therapy" also encompasses prevention unless specifically indicated otherwise. The terms "therapeutic" and "therapeutic" should be interpreted in a corresponding manner.

[0207] The term "treatment" is used synonymously with "therapy." Similarly, the term "treating" can be considered as "utilizing therapy," where "therapy" is as defined herein.

[0208] As used herein, the term "prevention" shall have its ordinary meaning and includes primary prevention, whereby the onset of a disease is prevented, and secondary prevention, whereby a disease has already occurred and the patient is protected, either temporarily or permanently, from aggravation or worsening of the disease or from the development of new symptoms associated with the disease.

[0209] In some embodiments, the compounds of the present disclosure can be converted into active thiol metabolites after administration.For the prodrug of active thiol metabolites, it is desirable that the prodrug converts into active thiol metabolites in target tissues with high conversion rate while remaining stable (environmental resistance).Furthermore, it is desirable that the prodrug has fast onset of action, therefore low loading dose, low side effects, and high solubility in aqueous solution, which allows formulation into injections for emergency and surgical use.

[0210] In some embodiments, the compounds provided herein can form active thiol metabolites through hydrolysis process mediated by hydrolases.Due to the high in vivo activity and wide range of hydrolases in intestine, liver and plasma, the compounds provided herein can be converted to active thiol metabolites in vivo with higher conversion rate and smaller inter-patient variability, thereby providing fast onset of antiplatelet effect without needing to use high loading dose.In addition, since the metabolites of the compounds provided herein are mediated by hydrolases rather than CYP enzymes, the use of these compounds is not limited by potential interactions with other CYP targeting drugs.

[0211] As used herein, the terms "thiol metabolite," "thiol active metabolite," and "active thiol metabolite" are used interchangeably and refer to compound H4, described above.

[0212] In some embodiments, the compounds provided herein exhibit a faster onset of antiplatelet activity than clopidogrel at the same dosage. In some embodiments, the compounds provided herein exhibit a smaller onset of antiplatelet activity than clopidogrel at a lower dosage than clopidogrel. In some embodiments, at half the dosage of clopidogrel, the compounds provided herein exhibit a smaller onset of antiplatelet activity than clopidogrel. In some embodiments, at one-third the dosage of clopidogrel, the compounds provided herein exhibit a smaller onset of antiplatelet activity than clopidogrel. In some embodiments, at one-fourth the dosage of clopidogrel, the compounds provided herein exhibit a smaller onset of antiplatelet activity than clopidogrel. In some embodiments, at one-fifth the dosage of clopidogrel, the compounds provided herein exhibit a smaller onset of antiplatelet activity than clopidogrel.

[0213] In some embodiments, at a dosage that is one-fifth that of clopidogrel, the compounds provided herein exhibit an onset of antiplatelet effect in less than 120 minutes, less than 110 minutes, less than 100 minutes, less than 90 minutes, less than 80 minutes, less than 70 minutes, less than 60 minutes, less than 50 minutes, less than 40 minutes, or less than 30 minutes.

[0214] The improved solubility of the compound provided herein or its pharmaceutically acceptable salt provides the opportunity to broaden the use of the compound in inhibiting platelet aggregation.In some embodiments, the compound provided herein or its pharmaceutically acceptable salt can be formulated for injection administration for emergency and surgical use.

[0215] Thus, the pharmaceutical compositions comprising the compounds of formula (I) or pharma- ceutically acceptable salts thereof provided herein are used for injection administration for emergency and surgical procedures.

[0216] The mode of administration of the pharmaceutical composition of the present disclosure is not particularly limited, and the pharmaceutical composition may be administered to a subject in a suitable manner depending on the age, sex, degree of disease, and the like of the subject. For example, the pharmaceutical composition of the present disclosure may be administered alone intravenously, intraarteriole, intramuscularly, intradermally, subcutaneously, intrathecally, or intraperitoneally. In some embodiments, the pharmaceutical composition of the present disclosure is injected intramuscularly. In some embodiments, the pharmaceutical composition of the present disclosure is injected intravenously. In some embodiments, the pharmaceutical composition of the present disclosure is injected subcutaneously. In addition, the pharmaceutical composition of the present disclosure may be mixed with other injections and administered in the form of a mixture of the pharmaceutical composition of the present disclosure and other injections. The other injections that can be used are not particularly limited, and commercially available injections such as glucose injections, xylitol injections, D-mannitol injections, fructose injections, saline, dextran 40 injections, dextran 70 injections, amino acid injections, Ringer's solution, lactate-Ringer's solution, and the like may be used.

[0217] The compositions of the present disclosure may be in the form of an injectable formulation and used directly via injection, or may be diluted before use and then used via injection, or may be in the form of a lyophilized formulation and used after reconstitution.

[0218] As used herein, "reconstitution" includes dissolving the lyophilized composition using water for injection and then mixing the resulting solution with other injectables, or mixing the lyophilized composition directly with an injectable.

[0219] In some embodiments, the present disclosure provides a method for treating a vascular disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of the present disclosure.

[0220] In certain embodiments, the vascular disease is selected from atherothrombosis, ischemia, stroke, cerebral thrombosis, arterial thrombosis, thrombotic cerebrovascular disease, cardiovascular disease, and blood clots.

[0221] In other embodiments, the present disclosure provides a method for inhibiting platelet aggregation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of the present disclosure. EXAMPLES

[0222] I. Compound For illustrative purposes, the following examples are included. However, it should be understood that these examples do not limit the present disclosure, but are only intended to suggest a method of carrying out the present disclosure. Those skilled in the art will recognize that the described chemical reactions can be easily adapted to prepare some other compounds of the present disclosure, and alternative methods of preparing the compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, the synthesis of compounds not exemplified according to the present disclosure can be successfully carried out by modifications obvious to those skilled in the art, such as by appropriately protecting blocking groups, by using other suitable reagents and building blocks known in the art other than those described, and / or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure.

[0223] Synthesis Example 1

[0224] [ka] [ka]

[0225] Synthesis of Step 1.1-2

[0226] [ka]

[0227] A solution of 1-1 (56.7 g, 310 mmol) in DCM (500 mL) was stirred in an ice bath (T<5° C.) under N2 protection. mCPBA (107.0 g, 620 mmol) was added to the above solution in portions. After addition, the resulting mixture was stirred at 20° C. for 4 h. The mixture was poured into a solution of Na2S2O3 (90.0 g) and NaHCO3 (45.0 g) in water (300 mL) with stirring. The resulting mixture was extracted with DCM (300 mL×2). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (petroleum ether / EtOAc=100 / 1 to 5 / 1) to give 1-2 (67.0 g, 98% yield) as a yellow oil.

[0228] Synthesis of steps 2.1-3

[0229] [ka]

[0230] A mixture of 1-2 (67.0 g, 337 mmol), thiobenzoic acid (56.7 g, 370 mmol) and tetrabutylammonium chloride (4.67 g, 17 mmol) in toluene (300 mL) was stirred at room temperature for 20 min and then at 40 °C overnight. The reaction mixture was then concentrated under vacuum. To the residue was added saturated Na2CO3 (400 mL) with stirring and then extracted with EtOAc (400 mL x 2). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (petroleum ether / EtOAc = 10 / 1 to 5 / 1) to give 1-3 (87.5 g, 77% yield) as a white solid.

[0231] LC-MS [M+1-100] + = 238.1 1H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J = 7.2 Hz, 2H), 7.59 (s, 1H), 7.46 (t, J = 7.7 Hz, 2H), 4.24 (d, J = 16.3 Hz, 1H), 4.17-3.81 (m, 1H), 3.73 (s, 1H), 3.60 (s, 1H), 2.92 (t, J = 24.3 Hz, 2H), 2.72 (s, 1H), 2.12 (d, J = 16.8 Hz, 1H), 1.71 (d, J = 11.6 Hz, 1H), 1.46 (s, 9H).

[0232] Synthesis of steps 3.1-4

[0233] [ka]

[0234] To a solution of 1-3 (157.0 g, 467.3 mmol) in DCM (1.5 L) was added TBSCl (141.2 g, 935 mmol) and imidazole (159.0 g, 2.34 mol). The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 10 / 1) to give 1-4 (273.0 g, 94% yield) as a white solid. LC-MS [M+1-100] + = 352.1.

[0235] Synthesis of steps 4.1-5

[0236] [ka]

[0237] To a solution of 1-4 (263.0 g, 583.1 mmol) in NH3 / MeOH (7 M, 2.0 L) was added NaBH4 (222 mg, 5.8 mmol). The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 20 / 1) to give 1-5 (210.0 g, 100% yield) as a pale yellow oil.

[0238] Synthesis of steps 5.1-6

[0239] [ka]

[0240] To a solution of NaBH4 (1.1 g, 28.8 mmol) in DMF (1.0 L) was added NaH (20.7 g, 864.6 mmol) at 0 °C under stirring under N2. 1-5 (200.0 g, 576.4 mmol) was added dropwise at 0 °C and then stirred at 0 °C for 1 h. Then isopropyl chloromethyl carbonate (100.7 g, 662.8 mmol) was added at 0 °C and the resulting mixture was stirred at room temperature for 1 h. H2O (1.0 L) was added to the mixture and then extracted with EtOAc (1.0 L × 3). The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel chromatography (Petroleum / EtOAc = 20 / 1) to give 1-6 (135.0 g, 50% yield) as a colorless oil.

[0241] 1H NMR (400 MHz, Chloroform-d) δ 5.25 (q, J = 12.0 Hz, 2H), 4.92-4.79 (m, 1H), 3.85 (d, J = 58.8 Hz, 2H), 3.45 (s, 1 H), 2.97-2.74 (m, 3H), 2.13-2.02 (m, 1H), 1.59-1.47 (m, 1H), 1.41 (s, 9H), 1.25 (dd, J = 15.5, 4.6 Hz, 6H), 0.89 (s, 9H), 0.19-0.01 (m, 6H).

[0242] Synthesis of steps 6.1-7

[0243] [ka]

[0244] To a solution of 1-6 (129.0 g, 278.6 mmol) in THF (1.1 L) was added Et3N.3HF (135.0 g, 835.9 mmol) and stirred under reflux for 16 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether / EtOAc = 3 / 1) to give 1-7 (80.0 g, 82% yield) as a pale yellow oil.

[0245] Synthesis of steps 7.1-8

[0246] [ka]

[0247] To a solution of 1-7 (30.0 g, 86.9 mmol) in DCM (300 mL) was added Dess-Martin periodinane (72.9 g, 171.9 mmol) and the resulting mixture was stirred at 25 °C for 4 h. After completion, the above reaction mixture was added to a mixed solution of saturated Na2S2O3 / saturated NaHCO3 (600 mL / 600 mL) and then extracted with EtOAc (400 mL x 2). The combined organic layer was washed with saturated NaHCO3, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether / EtOAc = 20 / 1 to 8 / 1) to give 1-8 (22.0 g, 73% yield) as a colorless oil.

[0248] Step 8. Synthesis of 1-9 and 1-10

[0249] [ka]

[0250] To a solution of tert-butyl 2-(diethoxyphosphoryl)acetate (11.4 g, 43.2 mmol) in THF (100 mL) was added LiHMDS (37.4 mL, 37.4 mmol) at -60 °C under N2 and stirred at -60 °C for 30 min. Then, 1-8 (10.0 g, 28.8 mmol) was added dropwise at -60 °C and the resulting mixture was stirred at 0-10 °C for 1 h. The reaction mixture was then added to saturated NH4Cl (300 mL) and then extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (petroleum ether / EtOAc=60 / 1) to give 1-9 (2.5 g, 19% yield) as a pale yellow oil and 1-10 (1.3 g, 10% yield) as a pale yellow oil.

[0251] 1-9: 1H NMR (400 MHz, chloroform-d) δ 5.68 (s, 1H), 5.47 (d, J = 15.2 Hz, 1H), 5.24 (s, 1H), 4.89-4.94 (m, 2H), 3.95 (s, 1H), 3.87-3.92 (m, 1H), 3.79 (s, 1H), 3.17-3.19 (m, 1H), 2.15-2.16 (m, 1H), 1.87-1.90 (m, 1H), 1.48 (s, 9H), 1.43 (s, 9H), 1.29 (d, J = 4 Hz, 6H).

[0252] 1-10: 1 HNMR (400 MHz, chloroform-d) δ 5.74 (s, 1H), 5.48 (s, 1H), 5.27 (d, J = 12 Hz, 1H), 5.14 (d, J = 12 Hz, 1H), 4.85-4.89 (m, 1H), 4.25-4.26 (m, 1H), 3.93-3.94 (m, 2H), 3.15 (s, 1H), 2.01-2.04 (m, 1H), 1.85-1.88 (m, 1H), 1.46 (s, 9H), 1.44 (s, 9H), 1.28 (d, J = 4 Hz, 6H).

[0253] Synthesis of ステップ9.1-11

[0254]

change

[0255] To a solution of 1-9 (3.0 g, 6.7 mmol) in DCM (20 mL) was added TFA (10 mL) at 0° C., then the reaction was stirred at 0° C. for 30 min. After completion, the reaction mixture was added to a solution of saturated NaHCO3 (100 mL) and then extracted with DCM (100 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give crude 1-11 (3.0 g, >100% yield) as a yellow oil, which was used in the next step without further purification. LC-MS [M+1] + = 346.1

[0256] Synthesis of steps 10.1-13

[0257] [ka]

[0258] To a solution of 1-11 (3.0 g, crude) in CH3CN (15 mL) was added 1-12 (2.6 g, 6.7 mmol) and KHCO3 (1.35 g, 13.5 mmol). The resulting mixture was stirred at 40 °C for 2 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (C18, CH3CN / H2O = 80 / 20) to give 1-13 (1.8 g, 51% yield) as a white solid. LC-MS [M+1] + = 528.2.

[0259] Steps 11 and 12. Synthesis of 1a-1 and 1a-2

[0260] [ka]

[0261] A solution of 1-13 (1.8 g, 3.4 mmol) in TFA (10 mL) was stirred at room temperature for 30 min. After completion, the reaction mixture was added to a solution of saturated NaHCO3 (100 mL) and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with saturated NaHCO3, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography (C18, CH3CN / H2O = 80 / 20) to give 1a (550 mg, 34% yield). 1a was purified by chiral column chromatography to give 1a-1 and 1a-2.

[0262] 1a: LC-MS [M+1] + = 472.1 1 H NMR (400 MHz, Chloroform-d) δ 7.59 (s, 1H), 7.38 (d, J = 4 Hz, 1H), 7.32-7.26 (m, 2H), 5.86 (s, 1H), 5.22 (dd, J = 12.2, 2.6 Hz, 1H), 5.00-4.83 (m, 3H), 4.50 (dd, J = 66.2, 11.9 Hz, 1H), 3.82 (s, 1H), 3.70 (d, J = 4.9 Hz, 3H), 3.52 (dd, J = 37.9, 12.9 Hz, 1H), 2.92-2.64 (m, 2H), 2.45-2.30 (m, 1H), 1.95-1.84 (m, 1H), 1.30 (d, J = 6.2 Hz, 6H).

[0263] 1a-1: 11H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.46 - 7.43 (m, 1H), 7.33 (dd, J = 6.3, 2.7 Hz, 2H), 5.91 (s, 1H), 5.27 (d, J = 12.3 Hz, 1H), 5.04 - 4.87 (m, 3H), 4.49 (d, J = 13.7 Hz, 1H), 3.88 (s, 1H), 3.75 (s, 3H), 3.58 (d, J = 14.0 Hz, 1H), 2.87 (s, 2H), 2.44 (s, 1H), 1.95 (dd, J = 14.2, 3.3 Hz, 1H), 1.35 (d, J = 6.2 Hz, 6H).

[0264] 1a-2: 1 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.44 (dt, J = 8.2, 3.1 Hz, 1H), 7.35 - 7.31 (m, 2H), 5.92 (s, 1H), 5.25 (d, J = 12.3 Hz, 1H), 5.07 (s, 1H), 4.94 (td, J = 12.5, 6.5 Hz, 2H), 4.68 (d, J = 13.4 Hz, 1H), 3.87 (s, 1H), 3.76 (s, 3H), 3.50 (d, J = 13.4 Hz, 1H), 2.90 (s, 1H), 2.75 (d, J = 12.3 Hz, 1H), 2.44 (s, 1H), 1.96 (d, J = 13.2 Hz, 1H), 1.34 (d, J = 6.3 Hz, 6H).

[0265] Synthesis of Step 13.1 - 14

[0266]

Chemical Structure

[0267] To a solution of 1-10 (1.8 g, 4.0 mmol) in DCM (10 mL) was added TFA (5 mL) at 0° C. and stirred at 0° C. for 1 h. After completion, the reaction mixture was added to a solution of saturated NaHCO3 (100 mL) and then extracted with DCM (100 mL×3). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give crude 1-14 (2.0 g, >100% yield) as a yellow oil, which was used in the next step without further purification. LC-MS [M+1] + = 346.1

[0268] Synthesis of steps 14.1-15

[0269] [ka]

[0270] To a solution of 1-14 (2.0 g, crude) in CH3CN (20 mL) was added 1-12 (1.5 g, 4.0 mmol) and KHCO3 (800 mg, 8.0 mmol). The resulting mixture was stirred at 40 °C for 2 h and then concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18, CH3CN / H2O = 80 / 20) to give 1-15 (500 mg, 24% yield) as a white solid. LC-MS [M+1] + = 528.2

[0271] Steps 15 and 16. Synthesis of 1b-1 and 1b-2

[0272] [ka]

[0273] To a solution of 1-15 (500 mg, 0.95 mmol) in DCM (2 mL) was added TFA (3 mL) at 0° C. and stirred at 0° C. for 30 min. After completion, the reaction was added to a solution of saturated NaHCO3 (30 mL) and then extracted with EtOAc (30 mL×3). The combined organic layer was washed with saturated NaHCO3, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase column chromatography (C18, CH3CN / HO=80 / 20), followed by preparative HPLC (mobile phase: A(HO) / B(MeCN); ratio range: A / B(80% / 20%) to A / B(55% / 45%) for 10 min and A / B(20% / 80%) for 35 min; Rt of peak: (67% of B); V=80 mL / min, wavelength 214 nm), and preparative TLC (DCM / MeOH=10 / 1) to give 1b (50 mg, 11% yield). 1b was purified by chiral column chromatography to give 1b-1 and 1b-2.

[0274] 1b: LC-MS [M+1] + = 472.1 1 H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 5.6 Hz, 1H), 7.44-7.36 (m, 1H), 7.27 (s, 2H), 5.77-5.65 (m, 1H), 5.41 (s, 1H), 5.25 (dd, J = 12.0, 6.3 Hz, 1H), 5.19-5.11 (m, 1H), 4.92-4.83 (m, 1H), 4.80 (s, 1H), 3.70 (d, J = 4.6 Hz, 3H), 3.52 (dd, J = 34.3, 12.2 Hz, 1H), 3.19 (d, J = 12.9 Hz, 0.5H), 2.98 (d, J = 12.5 Hz, 0.5H), 2.90-2.84 (m, 0.5 H), 2.78-2.61 (m, 1.5 H), 2.31-2.16 (m, 1 H), 1.97-1.82 (m, 1H), 1.28 (d, J = 5.4 Hz, 6H).

[0275] 1b-1: 1 1H NMR (400 MHz, CDCl3) δ 7.60 - 7.57 (m, 1H), 7.41 - 7.39 (m, 1H), 7.33 - 7.26 (m, 2H), 5.64 (s, 1H), 5.41 (s, 1H), 5.25 (d, J = 12.1 Hz, 1H), 5.14 (d, J = 12.0 Hz, 1H), 4.91 - 4.81 (m, 1H), 4.79 (s, 1H), 3.69 (s, 3H), 3.47 (d, J = 12.4 Hz, 1H), 2.97 (d, J = 12.5 Hz, 1H), 2.86 (d, J = 10.6 Hz, 1H), 2.72 (dd, J = 22.5, 10.6 Hz, 1H), 2.29 - 2.20 (m, 1H), 1.92 (d, J = 14.3 Hz, 1H), 1.27 (d, J = 6.2 Hz, 6H).

[0276] 1b - 2: 1 1H NMR (400 MHz, CDCl3) δ 7.62 - 7.56 (m, 1H), 7.41 - 7.38 (m, 1H), 7.30 - 7.26 (m, 2H), 5.77 (s, 1H), 5.43 (s, 1H), δ 5.27 (d, J = 12.1 Hz, 1H), 5.17 (d, J = 12.0 Hz, 1H), 4.91 - 4.86 (m, 1H), 4.80 (s, 1H), 3.71 (s, 3H), 3.56 (d, J = 12.4 Hz, 1H), 3.17 (d, J = 12.4 Hz, 1H), 2.66 (d, J = 8.0 Hz, 2H), 2.20 - 2.17 (m, 1H), 1.87 (d, J = 14.4 Hz, 1H), 1.29 (dd, J = 6.2, 2.5 Hz, 6H).

[0277] Synthesis Example 2

[0278]

Chem.

[0279] Step 1. Synthesis of 2-2 and 2-3

[0280] [ka]

[0281] To a solution of ethyl 2-(diethoxyphosphoryl)acetate (20.6 g, 86.5 mmol) in THF (300 mL) was added KHMDS (75 mL, 74.9 mmol) under N2 at -60 °C and stirred at -60 °C for 1 h. Then 2-1 (20.0 g, 57.6 mmol) was added dropwise at -60 °C and the resulting mixture was stirred at -10 °C for 0.5 h. The reaction mixture was then added to saturated NH4Cl (1000 mL). The resulting mixture was extracted with EtOAc (500 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel chromatography (petroleum ether / EtOAc = 60 / 1) to give 2-3 (7.5 g, 30% yield) as a pale yellow oil and 2-2 (4.5 g, 18% yield) as a pale yellow oil.

[0282] 2-2: 1 H NMR (400 MHz, CDCl3) δ 5.76 (s, 1H), 5.50 (d, J = 15.8 Hz, 1H), 5.23 (d, J = 12.1 Hz, 1H), 4.97-4.83 (m, 2H), 4.23-4.06 (m, 3H), 4.01-3.91 (m, 1H), 3.91-3.77 (m, 2H), 3.28-3.12 (m, H,), 2.23- 2.10 (m, 1H), 1.88 (dd, J = 23.1, 11.5 Hz, 1H), 1.42 (s, 9H), 1.31-1.24 (m, 9 H).

[0283] 2-3: 1H NMR (400 MHz, CDCl3) δ 5.83 (s, 1H), 5.48 (s, 1H), 5.28 (d, J = 12.1 Hz, 1H), 5.16 (d, J = 12.1 Hz, 1H), 4.94-4.82 (m, 1H), 4.32-4.09 (m, 3H), 4.03-3.85 (m, 2H), 3.23-3.05 (m, 1H), 2.08-1.98 (m, 1H), 1.89 (dd, J = 14.2, 1.9 Hz, 1H), 1.44 (s, 10H), 1.31-1.23 (m, 10H).

[0284] Synthesis of steps 2.2-4

[0285] [ka]

[0286] To a solution of 2-3 (3.0 g, 7.2 mmol) in DCM (20 mL) was added TFA (9 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 30 min. After completion, the resulting mixture was added to a solution of saturated NaHCO3 (200 mL). The resulting mixture was then extracted with DCM (200 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give crude 2-4 (3.0 g, >100% yield) as a yellow oil, which was used in the next step without further purification.

[0287] LC-MS [M+1-100] + = 318.1

[0288] Synthesis of step 3.2a

[0289] [ka]

[0290] To a solution of 2-4 (3.0 g, crude) in CH3CN (15 mL) was added 1-12 (2.8 g, 7.2 mmol) and KHCO3 (1.4 g, 14.4 mmol). The resulting mixture was stirred at 40 °C for 1 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (C18, CH3CN / H2O = 80 / 20) to give 2a (1.7 g, 47% yield).

[0291] LC-MS [M+1] + = 500.1 1 H NMR (400 MHz, CDCl3) δ 7.66-7.52 (m, 1H), 7.43-7.32 (m, 1H), 7.25 (s, 2H), 5.80 (s, 1H), 5.22 (d, J = 12.2 Hz, 1H), 4.97-4.79 (m, 3H), 4.49 (dd, J = 63.7, 12.8 Hz, 1H), 4.18-3.99 (m, 2H), 3.78 (s, 1H), 3.71 (d, J = 7.6 Hz, 3H), 3.47 (dd, J = 38.1, 13.2 Hz, 1H), 2.72 (dd, J = 45.3, 17.4 Hz, 2H), 2.32 (s, 1H), 1.87 (d, J = 13.7 Hz, 1H), 1.30 (d, J = 6.1 Hz, 6H), 1.24 (t, J = 7.2 Hz, 3H).

[0292] Synthesis of steps 4.2-5

[0293] [ka]

[0294] To a solution of 2-2 (100 mg, 0.26 mmol) in DCM (3 mL) was added TFA (0.6 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 30 min. After completion, the reaction mixture was added to a solution of saturated NaHCO3 (20 mL). The resulting mixture was then extracted with DCM (20 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give crude 2-5 (120.0 mg, >100% yield) as a yellow oil, which was used in the next step without further purification.

[0295] LC-MS [M+1-100] + = 318.1

[0296] Synthesis of step 5.2b

[0297] [ka]

[0298] To a solution of 2-5 (120.0 mg, crude) in CH3CN (3 mL) was added 1-12 (88 mg, 0.23 mmol) and KHCO3 (92 mg, 0.92 mmol). The resulting mixture was stirred at 40 °C for 1 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (C18, CH3CN / H2O = 80 / 20) to give 2b (23 mg, 20% yield).

[0299] LC-MS [M+1] + = 500.1. 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J= 5.1 Hz, 1H), 7.38 (d, J = 6.4 Hz, 1H), 7.32-7.25 (m, 2H), 5.74 (s, 0.5H), 5.61 (s, 0.5H), 5.43 (s, 1H), 5.25 (dd, J = 11.9, 5.4 Hz, 1H), 5.15 (dd, J = 11.9, 4.6 Hz, 1H), 4.93-4.81 (m, 1H), 4.77 (s, 1H), 4.23-4.06 (m, 2H), 3.69 (d, J = 3.9 Hz, 3H), 3.51 (d, J = 11.9 Hz, 0.5H), 3.42 (d, J = 12.1 Hz, 0.5H), 3.14 (d, J = 12.3 Hz, 0.5H), 2.97-2.80 (m, 1H), 2.77-2.67 (m, 0.5H), 2.63 (d, J = 7.5 Hz, 1H), 2.31-2.10 (m, 1H), 1.88 (dd, J = 21.5, 15.1 Hz, 1H), 1.26 (s, 9H).

[0300] Synthesis example 3

[0301]

change

[0302] Synthesis of ステップ1.3-3

[0303]

change

[0304] A solution of 3-2 (79.98 g, 0.64 mol) and KI (142.76 g, 0.86 mol) in acetone (1.5 L) was stirred at 16 °C for 16 h. Then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMF (1.5 L) and 3-1 (150.0 g, 0.43 mol) and K2CO3 (88.32 g, 0.64 mol) were added to the above solution. After the addition, the mixture was stirred at 16 °C for 2 h. The reaction was diluted with water (3 L) and extracted with EtOAc (1 L × 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 20 / 1) to give 3-3 (79.0 g, 28% yield) as a colorless oil.

[0305] 1 H NMR (400 MHz, Chloroform-d) δ 5.36-5.25 (m, 2H), 4.02-3.91 (m, 1H), 3.88-3.83 (m, 1H), 3.80 (s, 3H), 3.52-3.41 (m, 1H), 2.98-2.84 (m, 2H), 2.84-2.74 (m, 1H), 2.14-2.06 (m, 1H), 1.44 (s, 9H), 0.89 (s, 9H), 0.12 (s, 6H).

[0306] Synthesis of steps 2.3-4

[0307] [ka]

[0308] A solution of 3-3 (79.0 g, 0.18 mol) and Et3N.3HF (90.4 g, 0.54 mol) in THF (800 mL) was refluxed with stirring for 16 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 3 / 1) to give 3-4 (41.0 g, 68% yield) as a colorless oil.

[0309] Synthesis of steps 3.3-5

[0310] [ka]

[0311] To a solution of 3-4 (41.0 g, 0.12 mol) in DCM (500 mL) was added Dess-Martin (64.9 g, 0.15 mol) at 20° C. After the addition, the mixture was stirred at 20° C. for 30 min. The resulting mixture was washed with saturated aqueous Na2SO3 (500 mL), saturated aqueous NaHCO3 (500 mL×2) and brine. The organic layer was separated, dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel chromatography (petroleum / EtOAc=3 / 1) to give 3-5 (37.0 g, 92% yield) as a yellow oil.

[0312] Step 4. Synthesis of 3-7-Z and 3-7-E

[0313] [ka]

[0314] To a solution of 3-6 (37.9 g, 0.15 mol) in dry THF (500 mL) was added LiHMDS (151 mL, 0.15 mol) at -60 °C under N2. The resulting mixture was stirred at -60 °C for 30 min, and then 3-5 (37.0 g, 0.11 mol) was added dropwise at -60 °C. The reaction mixture was warmed to 0 °C and stirred at 0-10 °C for 1 h. The resulting mixture was then added to saturated NH4Cl (100 mL, aq.) and the resulting mixture was extracted with EtOAc (500 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by silica gel chromatography (petroleum ether / EtOAc = 50 / 1) to give 3-7-Z (7.0 g, 14% yield) and 3-7-E (14 g, 28% yield).

[0315] 3-7-Z 1H NMR (400 MHz, Chloroform-d) δ 5.76 (s, 1H), 5.50 (s, 1H), 5.32 (d, J = 12 Hz, 1H), 5.17 (d, J = 12 Hz, 1H), 4.32-3.87 (m, 3H), 3.79 (s, 3H), 3.24-3.03 (m, 1H), 2.13-2.00 (m, 1H), 1.93-1.85 (m, 1H), 1.47 (s, 9H), 1.45 (s, 9H).

[0316] 3-7-E 1 H NMR (400 MHz, Chloroform-d) δ 5.68 (s, 1H), 5.52-5.43 (s, 1H), 5.26 (d, J = 12.4 Hz, 1H), 4.96 (d, J = 12.4 Hz, 1H), 3.97-3.85 (m, 2H), 3.80 (s, 3H), 3.79-3.75 (m, 1H), 3.27-3.13 (m, 1H), 2.21-2.09 (m, 1H), 1.93-1.83 (m, 1H), 1.48 (s, 9H), 1.43 (s, 9H).

[0317] Synthesis of steps 5.3-8

[0318] [ka]

[0319] A solution of 3-7-Z (5.5 g, 13.2 mmol) and TsOH.H2O (5.0 g, 26.4 mmol) in DCM (60 mL) was stirred at 20 °C for 16 h. Then the reaction mixture was diluted with saturated aqueous NaHCO3 (100 mL) and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to give 3-8 (3 g, 71% yield) as a yellow oil, which was used in the next step without further purification. LC-MS [M+1] + = 318.1

[0320] Step 6: Synthesis of 3-10

[0321] [ka]

[0322] To a solution of 3-8 (3.0 g, 9.4 mmol) in CH3CN (10 mL) was added 3-9 (3.6 g, 9.4 mmol) and KHCO3 (2.8 g, 28.2 mmol). The resulting mixture was stirred at 40 °C for 4 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (C18, CH3CN / H2O = 90 / 10) to give 3-10 (2.5 g, 53% yield) as a yellow oil. LC-MS [M+1] + = 500.2

[0323] Step 7 Synthesis of 3

[0324] [ka]

[0325] To a solution of 3-10 (2.5 g, 5.0 mmol) in DCM (20 mL) was added TFA (5 mL) and stirred at 20° C. for 1 h. After completion, the reaction was added to a solution of saturated aqueous NaHCO3 (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (DCM / MeOH=10 / 1) to give 3 (800 mg, 36% yield).

[0326] 3: LC-MS [M+1] + = 444.1. 1H NMR (400 MHz, Chloroform-d) δ 7.60-7.54 (m, 1H), 7.41-7.36 (m, 1H), 7.31-7.22 (m, 2H), 5.77 (s, 0.5H), 5.65 (s, 0.5H), 5.43-5.37 (m, 1H), 5.30-5.23 (m, 1H), 5.19-5.12 (m, 1H), 4.81-4.77 (m, 1H), 3.76 (s, 3H), 3.69 (d, J = 4.4 Hz, 3H), 3.54 (d, J = 12.4 Hz, 0.5H), 3.45 (d, J = 12.4 Hz, 0.5H), 3.17 (d, J = 12.4 Hz, 0.5H), 2.96 (d, J = 12.4 Hz, 0.5H), 2.85 (d, J = 12.0 Hz, 0.5H), 2.73 (d, J = 12.0 Hz, 0.5H), 2.70-2.62 (m, 1H), 2.30-2.13 (m, 1H), 2.02-1.82 (m, 1H).

[0327] Synthesis example 4

[0328]

change

[0329] Synthesis of ステップ1.4-2

[0330]

change

[0331] A solution of 4-1 (64 g, 0.43 mol) and KI (96.3 g, 0.86 mol) in acetone (0.8 L) was stirred at 20 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMF (1 L). To the above solution was added 1-5 (150.0 g, 0.43 mol) and K2CO3 (120 g, 0.864 mol). After the addition, the resulting mixture was stirred at 20 °C for 2 h. The reaction was diluted with water (2 L) and extracted with EtOAc (600 L × 2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-2 (250 g, 100% yield) as a dark oil, which was used in the next step without further purification.

[0332] Synthesis of step 2.4-3

[0333] [ka]

[0334] A solution of 4-2 (250 g, 0.43 mol) and Et3N.3HF (210 g, 1.296 mol) in THF (1 L) was stirred at 40° C. for 16 h. The resulting mixture was concentrated under reduced pressure and the residue was diluted with EA (1.5 L). The formed solution was washed with brine (500 ml×2), and the organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=3 / 1) to give 4-3 (108 g, 73% yield) as a white solid. LC-MS [M+1] + -100 = 246.2.

[0335] 1H NMR (400 MHz, CDCl3) δ 4.19 (d, J = 12.1 Hz, 1H), 3.98 (s, 1H), 3.72 (s, 1H), 3.52 (d, J = 15.2 Hz, 2H), 2.90 - 2.78 (m, 1H), 2.77 - 2.67 (m, 1H), 2.66 - 2.56 (m, 1H), 2.11 (s, 3H), 2.02 (d, J = 12.0 Hz, 1H), 1.63 - 1.49 (m, 1H), 1.45 (s, 9H).

[0336] Synthesis of step 3.4-4

[0337] [ka]

[0338] To a solution of 4-3 (108 g, 0.313 mol) in DCM (1 L) was added Dess-Martin (159 g, 0.375 mol) at 20° C. After addition, the resulting mixture was stirred at 20° C. for 30 min. The reaction mixture was washed with saturated Na2S2O3 solution (1 L), saturated NaHCO3 solution (1 L×2), brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum / EtOAc=3 / 1) to give 4-4 (80.0 g, 74.5% yield) as an orange oil. LC-MS [M+1] + +Na=366.1.

[0339] 1 H NMR (400 MHz, CDCl3) δ 4.29 (d, J = 17.9 Hz, 1H), 4.16 (d, J = 18.4 Hz, 1H), 3.82 (s, 1H), 3.48 (d, J = 15.6 Hz, 1H), 3.44 - 3.32 (m, 2H), 3.27 (s, 1H), 2.43 - 2.29 (m, 1H), 2.16 (s, 3H), 2.09 - 2.04 (m, 1H), 1.46 (s, 9H).

[0340] Step 4. Synthesis of 4-6-Z and 4-6-E

[0341] [ka]

[0342] To a solution of 4-5 (77 g, 0.302 mol) in dry THF (800 mL) was added LiHMDS (303 mL, 0.303 mol) at -60 °C under N2. The reaction mixture was stirred at -60 °C for 30 min, after which 4-4 (80 g, 0.233 mol) was added dropwise at -60 °C. The resulting mixture was stirred at 0-10 °C for 1 h. The reaction mixture was then added to saturated NH4Cl solution (800 mL) and extracted with EtOAc (700 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by silica gel chromatography (petroleum ether / EtOAc = 20 / 1) to give 4-6-Z (12 g, 9% yield) as a pale orange oil and 4-6-E (15 g, 11% yield) as an off-white solid. LC-MS [M+1] + +23= 464.2.

[0343] 4-6-Z 1 H NMR (400 MHz, CDCl3) δ 5.74 (s, 1H), 4.27 (s, 1H), 4.07 - 3.83 (s, 2H), 3.68 (d, J = 15.1 Hz, 1H), 3.44 (d, J = 15.2 Hz, 1H), 3.25 - 3.10 (m,1H), 2.09 (s, 3H), 2.02 (d, J = 14.6 Hz, 1H), 1.85 (d, J = 13.7 Hz, 1H), 1.54 - 1.32 (m, 18H).

[0344] 4-6-E 1H NMR (400 MHz, CDCl3) δ 5.59 (s, 1H), 5.49 (d, J = 15.6 Hz, 1H), 4.00 (d, J = 15.7 Hz, 1H), 3.95- 3.80 (m, 1H), 3.61 (s, 1H), 3.40 - 3.14 (m, 3H), 2.21- 2.11 (m, 1H), 2.08 (s, 3H), 1.89 (d, J = 11.4 Hz, 1H), 1.52- 1.42 (m,18H).

[0345] Step 5: Synthesis of 4-7

[0346] [ka]

[0347] A solution of 4-6-Z (10 g, 0.023 mol) and TFA (20 ml) in DCM (80 mL) was stirred at 20° C. for 2 h. The resulting mixture was concentrated in vacuo to give 4-7 (15 g, 100% yield) as a dark oil, which was used in the next step without further purification. LC-MS [M+1] + = 286.2.

[0348] Synthesis of steps 6 and 7.4

[0349] [ka]

[0350] A solution of 4-7 (15 g, crude, 0.023 mol) and 4-8 (5 mL) in DCM was added dropwise to Et3N at 20° C. After the addition, the mixture was stirred at 20° C. for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EA (200 mL) and water (300 ml). The pH value was adjusted to 3 with HCl (1 M, aq.). The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase column (C18, ACN / H2O=70 / 30) to give 4 (1.8 g, 16.7% yield).

[0351] 4: LC-MS [M+1]+ = 468.1. 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 6.7 Hz, 1H), 7.40 (d, J = 6.2 Hz, 1H), 7.32-7.23 (m, 2H), 5.79 (s, 0.5H), 5.67 (s, 0.5H), 5.23 (s, 1H), 4.77 - 4.67 (m, 1H), 3.71 (d, J = 4.5 Hz, 3H), 3.60- 3.52 (m, 1.5H), 3.50 - 3.36 (m, 1.5H), 3.17 (d, J = 12.3 Hz, 0.5H), 2.97 (d, J = 12.4 Hz, 0.5H), 2.90- 2.82 (m, 0.5H), 2.80- 2.70 (m, 0.5H), 2.66 (d, J = 8.6 Hz, 1H), 2.30- 2.13 (m, 1H), 2.06 (s, 3H), 1.93- 1.81 (m, 1H).

[0352] II. Pharmaceutical Compositions

[0353] [Example 1] The pharmaceutical composition was prepared according to the composition shown in Table 1 below. SBECD was added to 36 mL of water for injection, and the mixture was stirred until SBECD was completely dissolved. Citric acid monohydrate was then added, and the resulting mixture was stirred until citric acid monohydrate was completely dissolved. Hydrochloric acid was then added to adjust the pH to 1.2. Compound 1b-2 was added to the solution, and the mixture was stirred until the compound was completely dissolved. Sodium hydroxide was added to the resulting solution to adjust the pH to 4, and then water for injection was added to a volume of 60 mL.

[0354] [Table 1]

[0355] [Example 2] The pharmaceutical composition was prepared according to the composition shown in Table 2 below. SBECD was added to 36 mL of water for injection, and the mixture was stirred until SBECD was completely dissolved. Citric acid monohydrate was then added, and the resulting mixture was stirred until citric acid monohydrate was completely dissolved. Hydrochloric acid was then added to adjust the pH to 1.2. Compound 1b-2 was added to the solution, and the mixture was stirred until the compound was completely dissolved. Sodium hydroxide was added to the resulting solution to adjust the pH to 4, and then water for injection was added to a volume of 60 mL.

[0356] [Table 2]

[0357] [Example 3] The pharmaceutical composition was prepared according to the composition shown in Table 3 below. SBECD was added to 36 mL of water for injection, and the mixture was stirred until SBECD was completely dissolved. Citric acid monohydrate was then added, and the resulting mixture was stirred until citric acid monohydrate was completely dissolved. Hydrochloric acid was then added to adjust the pH to 1.2. Compound 1b-2 was added to the solution, and the mixture was stirred until the compound was completely dissolved. Sodium hydroxide was added to the resulting solution to adjust the pH to 4, and then water for injection was added to a volume of 60 mL.

[0358] [Table 3]

[0359] [Example 4] A pharmaceutical composition was prepared according to the composition shown in Table 4 below. HPCD was added to 30 mL of water for injection, and the mixture was stirred until the HPCD was completely dissolved. Then, hydrochloric acid was added to adjust the pH to 1.2. Compound 1b-2 was added to the solution, and the mixture was stirred until the compound was completely dissolved. Sodium hydroxide was added to the resulting solution to adjust the pH to 4, and then water for injection was added to a volume of 50 mL.

[0360] [Table 4]

[0361] [Example 5] The pharmaceutical composition was prepared according to the composition shown in Table 5 below. SBECD was added to 36 mL of water for injection, and the mixture was stirred until SBECD was completely dissolved. Citric acid monohydrate was then added, and the resulting mixture was stirred until citric acid monohydrate was completely dissolved. Hydrochloric acid was then added to adjust the pH to 1.2. Compound 1b-2 was added to the solution, and the mixture was stirred until the compound was completely dissolved. Sodium hydroxide was added to the resulting solution to adjust the pH to 3.5, and then water for injection was added to a volume of 60 mL.

[0362] [Table 5]

[0363] [Example 6] The pharmaceutical composition was prepared according to the composition shown in Table 6 below. SBECD was added to 20 mL of water for injection, and the mixture was stirred until SBECD was completely dissolved. Then, hydrochloric acid was added to adjust the pH to 1.2. Compound 1b-2 was added to the solution, and the mixture was stirred until the compound was completely dissolved. Sodium hydroxide was added to the resulting solution to adjust the pH to 4, and then water for injection was added to a volume of 28 mL.

[0364] [Table 6]

[0365] [Example 7] The pharmaceutical composition was prepared according to the composition shown in Table 7 below. SBECD was added to 36 mL of water for injection, and the mixture was stirred until SBECD was completely dissolved. Citric acid monohydrate was then added, and the resulting mixture was stirred until citric acid monohydrate was completely dissolved. Hydrochloric acid was then added to adjust the pH to 1.2. Compound 1b-2 was added to the solution, and the mixture was stirred until the compound was completely dissolved. Sodium hydroxide was added to the resulting solution to adjust the pH to 4, and then water for injection was added to a volume of 56 mL.

[0366] [Table 7]

[0367] [Example 8] A pharmaceutical composition was prepared according to the composition shown in Table 8 below. SBECD was added to 36 mL of water for injection, and the mixture was stirred until SBECD was completely dissolved. Citric acid monohydrate was then added, and the resulting mixture was stirred until citric acid monohydrate was completely dissolved. Hydrochloric acid was then added to adjust the pH to 1.2. Compound 1b-2 was added to the solution, and the mixture was stirred until the compound was completely dissolved. Sodium hydroxide was added to the resulting solution to adjust the pH to 4, and then water for injection was added to a volume of 112 mL.

[0368] [Table 8]

[0369] [Examples 9 to 11] The pharmaceutical compositions were prepared in the same manner as in Example 1, according to the compositions shown in Table 9 below.

[0370] [Table 9]

[0371] III.Biochemical analysis Biochemical assays Assay 1: Pharmacokinetics in rats Pharmacokinetic studies were performed using male Sprague-Dawley rats.

[0372] Test compounds (clopidogrel and exemplary compounds provided herein) were administered orally or intravenously to rats under fasting conditions. Blood samples were collected via the jugular vein at 5, 15, 30, 60 and 120 minutes with EDTA-K2 (anticoagulant), 3'-methoxyphenacyl bromide (MPBr, derivatization reagent) and phenylmethylsulfonyl fluoride (PMSF, stabilizer). Plasma samples were then collected by centrifugation at 1500g for 10 minutes at 2-8°C and stored at -80°C after separation. Plasma samples were loaded into an LC-MS / MS instrument after extraction to determine the concentration of thiol active metabolites. The concentration results in rat plasma are shown in Figures 1 and 2.

[0373] As shown in Figure 1, at a dosage level of 10 mg / kg, compounds 1a, 1b and 2a provided herein reach peak concentration of thiol active metabolites in less than 20 minutes after administration, compared with clopidogrel, which reaches peak concentration of thiol active metabolites in about 30 minutes after administration.In addition, the peak concentration of thiol active metabolites for compounds 1a, 1b and 2a is significantly higher than that for clopidogrel.These results indicate that compounds 1a, 1b and 2a provide faster and more efficient release of active metabolites than clopidogrel.

[0374] As shown in Figure 2, when orally administered, compound 3 provided herein reaches a peak concentration of thiol active metabolites at about 20 minutes after administration at a dose level of 2 mg / kg, compared to clopidogrel at an even higher dose level of 10 mg / kg, which reaches a peak concentration of thiol active metabolites at about 30 minutes after administration.When administered intravenously, compound 3 provided herein reaches a peak concentration of thiol active metabolites at about 6 minutes after administration at a dose level of only 1 mg / kg.These results indicate that compound 3 provides faster and more efficient release of active metabolites than clopidogrel.

[0375] Assay 2: Antiaggregatory effect in rats Male Sprague-Dawley rats were used for ex vivo platelet aggregation experiments. After the rats were orally administered (clopidogrel, exemplary compounds provided herein and vehicle (control)), blood was collected via the jugular vein at 0.5, 1 and 2 hours using 3.8% (w / v) sodium citrate solution as an anticoagulant (1 / 9 volume of whole blood). The blood samples with citrate were centrifuged at a low speed of 1000 rpm for 5 minutes to obtain platelet-rich plasma (PRP). After separation of PRP, the remaining blood was further centrifuged at a high speed of 3000 rpm for 10 minutes to obtain platelet-poor plasma (PPP). The number of platelets in PRP was measured by a hematology analyzer (Siemens, ADVIA2120), and the PPP was 4×10 8 / mL.

[0376] Platelet aggregation was determined using turbidimetric aggregometry method with an automated platelet aggregometer (PRECIL LBY-NJ4). The aggregometer was pre-warmed to 37° C., and a sample of PRP (290 μL) was added to a cuvette and placed in the automated platelet aggregometer. After 5 min of pre-incubation, the aggregometer was calibrated using PPP to indicate 100% aggregation and PRP to indicate 0% aggregation. Finally, a volume of 10 μL of ADP solution (final concentration 10 μM) was added to the PRP sample for initial platelet aggregation. Platelet aggregation was monitored for 5 min and the maximum platelet aggregation (%) was reported within the period. The antiaggregatory effect of the test compounds was evaluated by: Inhibition (%) = (maximum platelet aggregation (%) of control - maximum platelet aggregation (%) of test compound) / (maximum platelet aggregation (%) of control) x 100 The results were expressed as percent inhibition determined from the correlation coefficient.

[0377] The inhibition (%) results for the test compounds are shown in Figure 3. The dose levels were 10 mg / kg, 0.5 mg / kg and 2 mg / kg for clopidogrel, 1a and 1b, respectively. As can be seen from Figure 2, clopidogrel reaches a maximum inhibition of platelet aggregation at about 45% at about 120 minutes after administration, while compound 1b shows a maximum inhibition of about 45% at about 60 minutes after administration at a dose level much lower than clopidogrel, indicating a much faster onset of action and a much higher potency than clopidogrel.

[0378] IV. Stability of Formulations The formulation samples obtained in the examples were each treated as follows: the samples were filtered through a 0.22 μm filter membrane and placed in a clear glass vial. The water bath was adjusted to 25° C., and the sample vial containing the formulation was placed in the water bath. The stability of the formulation samples was measured at 0 hours, 1 hour, 2 hours, and 4 hours.

[0379] The stability of the samples was determined by the following method: The content of the samples was analyzed using ultra-high performance liquid chromatography / ultraviolet detector. The chromatographic conditions were as follows: Chromatographic column: ACQUITY UPLC BEH C18 1.7μm 2.1×100mm; Mobile phase A: 0.1% formic acid in water; Mobile phase B: 0.1% formic acid in acetonitrile;

[0380] The relevant results are shown in the table below.

[0381] [Table 10]

[0382] As can be seen from Table 10, the content of compound 1b-2 in the samples of different examples was more than 97% at 4 hours, indicating that the formulations of the present disclosure have good stability under different component ratios and different formulation concentrations.

[0383] V. Drug Effect Experiments The formulations of Examples 1 to 3 above were each diluted to 0.12 mg / mL (based on compound 1b-2) using 0.9% sodium chloride injection to obtain formulations 1 to 3. In addition, citric acid monohydrate was dissolved in water for injection, and sodium hydroxide was added to adjust pH to 4, then water for injection was added to make the total volume to the desired volume, so as to obtain the first solution, the content of citric acid was 2mg / mL; the first solution was mixed with 0.9% sodium chloride injection according to the ratio of 3:17 to obtain the second solution; citric acid monohydrate was dissolved in water for injection, and hydrochloric acid was added to adjust pH to 1, then water for injection was added to make the total volume to the desired volume, so as to obtain the third solution, the content of citric acid was 2mg / mL; compound 1b was added to an appropriate amount of the third solution to completely dissolve, then an appropriate amount of the second solution was added, and sodium hydroxide solution was added to adjust pH to 4.0±0.04, then the second solution was added until the content of compound 1b-2 was 0.12mg / mL (based on compound 1b-2), so as to obtain formulation 4.

[0384] The test animals, male beagle dogs, were divided into 4 groups, and the above-mentioned formulations 1 to 4 were administered to each group by intravenous infusion at a dose of 5 mL / Kg / h for 0.5 hours, and the following experiment was carried out.

[0385] PK experiment: Animals in each group collected 0.5 mL of whole blood via the carotid artery before dosing and 0.17, 0.33, 0.5, 1, 2, 4, 8, and 24 hours after dosing. The collected whole blood was immediately transferred to a blood collection tube containing 3'-methoxyphenacyl bromide (MPBr, derivatization reagent), phenylmethylsulfonyl fluoride solution (PMSF, stabilizer), and EDTA-K2. The mixtures were mixed homogeneously, centrifuged, and plasma was collected and stored at -70°C or lower. The plasma samples were processed and then assayed using an LC-MS / MS instrument (Shimadzu 20A / API4000 Qtrap LC-MS instrument) to determine the peak concentration of thiol active metabolites (C max ) and area under the curve (AUC 0-t ) was determined. The results are shown in Table 11 below.

[0386] [Table 11]

[0387] As can be seen from Table 11, the exposure in experimental animals was significantly improved for formulations corresponding to those disclosed herein compared to formulation 4, which did not contain cyclodextrin.

[0388] PD experiment: Each group of animals collected 1.8 mL of whole blood via the carotid artery before administration and 0.17, 0.5, 2, 4, 8, 24, 48, 72, and 96 hours after administration, and the whole blood was mixed with an anticoagulant, 3.2% sodium citrate, according to a 1:9 volume ratio for anticoagulation, thus obtaining sodium citrate-anticoagulated blood samples.

[0389] A portion of each of the above sodium citrate-anticoagulated blood samples was taken for platelet counting by using a Mindray fully automated hematology analyzer; the remaining sodium citrate-anticoagulated blood samples were each centrifuged at room temperature and 100g for 10 minutes (brake switched off) to prepare PRP and determine PLT concentration. Then, PPP was isolated by centrifugation at room temperature and 2000g for 10 minutes (brake switched off) to determine PLT concentration. At the same time, an aggregation inducer (ADP, 150 μM) was prepared.

[0390] The reaction system for determining platelet aggregation rate was 145μL PRP+5μL inducer. During the determination, the instrument was first calibrated with PPP plasma at 100% and PRP at 0%; when PRP was determined, 145μL PRP was added to the bottom of the reaction cup, mixed evenly, and the cup was preheated at 37℃ for 1 min, then 5μL of aggregation inducer was added, and the maximum aggregation rate under ADP stimulation for 10 min was determined, which was used to evaluate the anti-platelet aggregation ability.

[0391] Meanwhile, the inhibition rate was calculated using the following formula: Inhibition rate = (maximum aggregation rate at time of administration - maximum aggregation rate before administration) / maximum aggregation rate before administration × 100%

[0392] The results are shown in Table 12 below.

[0393] [Table 12]

[0394] As can be seen from Table 12, compared to formulation 4 without cyclodextrin, the formulation corresponding to the formulation of the present disclosure exhibited a significant increase in the inhibition rate in experimental animals at 10 minutes, as well as a faster rate of onset of therapeutic effect and better drug efficacy.

[0395] The foregoing description is considered as merely illustrative of the principles of the disclosure. Moreover, it is not intended that the invention be limited to the precise configuration and steps shown above, since numerous modifications and changes will be readily apparent to those skilled in the art. Accordingly, all suitable modifications and equivalents may be deemed to fall within the scope of the invention as defined by the following claims.

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, and cyclodextrin A pharmaceutical composition comprising: (In the formula, 【Chemistry 2】 represents a double bond in the Z or E configuration; R １ is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl is selected from the group consisting of one or more R ａ optionally substituted with; R ２ is -C(O)R ｂ and R ３ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl; L is selected from the group consisting of a direct bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from the group consisting of one or more R ｆ optionally substituted with; W is 【Transformation 3】 and W is selected from the group consisting of ＊ The end is attached to L; R ４ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl; R ａ each of which is hydrogen, halogen, hydroxyl, amino, cyano, nitro, or —NR ｃ R ｄ are independently selected from the group consisting of: R ｂ is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, heteroaryl, -NR ｃ R ｄ and -OR ｅ selected from the group consisting of: R ｃ and R ｄ each is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, or amino; R ｅ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl; R ｆ each is independently selected from the group consisting of hydrogen, cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl; or Two R's ｆ together with the atom to which they are both attached form a saturated or partially unsaturated cycloalkyl or a saturated or partially unsaturated heterocyclyl, each of which is optionally substituted with cyano, halogen, hydroxyl, amino, and alkyl; R ｇ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, each of the hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, or amino; n is 0, 1, 2, 3, 4 or 5.

2. 2. The pharmaceutical composition of claim 1, wherein the cyclodextrin is a β-cyclodextrin, preferably, the β-cyclodextrin is sulfobutylether-β-cyclodextrin, cyclobutylalkylether-β-cyclodextrin, or hydroxypropyl-β-cyclodextrin.

3. The pharmaceutical composition is a solution, Optionally, the solution comprises 0.1-10 mg / mL, 0.2-10 mg / mL, 0.3-5 mg / mL, 0.4-2 mg / mL, 0.5-1 mg / mL, or 0.6-0.9 mg / mL of the compound or a pharmaceutically acceptable salt thereof; Optionally, the solution comprises 20-400 mg / mL, 30-300 mg / mL, 40-300 mg / mL, 50-250 mg / mL, 60-200 mg / mL, 70-150 mg / mL, or 80-100 mg / mL of cyclodextrin; optionally, the weight ratio of the cyclodextrin to the compound or pharmaceutically acceptable salt thereof is from 50:1 to 400:1, from 50:1 to 300:1, from 50:1 to 250:1, from 60:1 to 250:1, from 70:1 to 200:1, from 80:1 to 150:1, or from 90:1 to 120:1, wherein the weight of the pharmaceutically acceptable salt of the compound is based on the weight of the compound contained therein; Optionally, the pharmaceutical composition further comprises a buffering agent; Preferably, the buffer is an acidic buffer; Preferably, the acidic buffer is selected from phosphoric acid, hydrochloric acid, succinic acid, acetic acid, tartaric acid, lactic acid, citric acid, malic acid, glycolic acid, or hydrates thereof; Preferably, the acidic buffer is citric acid monohydrate; Preferably, the solution comprises 1-3 mg / mL, 1-2.5 mg / mL, or 1-2 mg / mL citric acid monohydrate. The pharmaceutical composition of claim 1.

4. 4. The pharmaceutical composition of claim 3, having a pH of 3 to 4.

5. The compound 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 [Chemistry 4-5] [Chemistry 4-6] 10. The pharmaceutical composition of claim 1, having a formula selected from the group consisting of: 【Request Item 6】 【Chemistry 5】 The pharmaceutical composition of claim 5 , wherein is a double bond in the Z configuration, and / or R 1 is halogen and n is 1.

7. The compound is 【Chemistry 6-1】 【Chemistry 6-2】 【Transformation 6-3】 【Chemistry 6-4】 having a formula selected from the group consisting of: Preferably, the compound is 【Transformation 7】 The pharmaceutical composition of claim 1, wherein

8. A method for preparing a pharmaceutical composition according to any one of claims 1 to 7, comprising: mixing cyclodextrin with water to form a first mixture; Optionally, adding a buffer to the first mixture to form a second mixture; adding an acidic pH adjuster to the second mixture to adjust the pH to 1 to 1.5, thereby forming a third mixture; adding a compound or a pharmaceutically acceptable salt thereof to the third mixture to form a fourth mixture; adding a basic pH adjuster to the fourth mixture to adjust the pH to 3-4, thereby forming a fifth mixture; and optionally, adding water for injection to the fifth mixture to form a pharmaceutical composition. Including, Optionally, the method further comprises lyophilizing said pharmaceutical composition to form a lyophilized composition.

9. A medicament for treating a vascular disease in a subject in need thereof, comprising the pharmaceutical composition of any one of claims 1 to 7; Preferably, the vascular disease is selected from atherothrombosis, ischemia, stroke, cerebral thrombosis, arterial thrombosis, thrombotic cerebrovascular disease, cardiovascular disease and blood clots.

10. A pharmaceutical for inhibiting platelet aggregation in a subject in need of inhibition of platelet aggregation, comprising the pharmaceutical composition of any one of claims 1 to 7.

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