Antiplatelet drugs and their uses

Abstract

The present disclosure relates to compounds showing activity in inhibiting platelet aggregation and pharmaceutical compositions comprising these compounds, as well as methods for treating vascular diseases by administering these compounds or the pharmaceutical compositions.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 202180058245.8, application date July 28, 2021, and invention name “Antiplatelet drugs and their uses”. The original application is a national phase application of the international application with international application number PCT / CN2021 / 108875, which claims priority to the international application PCT / CN2020 / 105513 filed on July 29, 2020. Field of the Invention

[0002] The present disclosure relates generally to compounds that exhibit activity in inhibiting platelet aggregation and pharmaceutical compositions comprising these compounds, as well as methods of treatment by administering these compounds or the pharmaceutical compositions. Background Art

[0003] Recently, the number of patients with vascular diseases has increased significantly. Antithrombotic agents that inhibit platelet activation play an important role in preventing the occurrence and recurrence of these diseases and in their treatment.

[0004] Clopidogrel is a known and widely used antithrombotic drug worldwide and is a prodrug that requires biotransformation to become active. After absorption, 85% of clopidogrel is hydrolyzed to inactive carboxylic acid by esterases. The remaining 15% of clopidogrel undergoes a two-step oxidation process via hepatic cytochrome P450 isozymes (mainly CYP2C19). The transient active thiol metabolite specifically and irreversibly binds to the platelet P2Y12 receptor.

[0005] However, clopidogrel has many disadvantages, including inter-patient variability in antithrombotic effects and resistance to clopidogrel in some patients due to different CYP2C19 expression levels in different individuals; low conversion rate to active metabolites and therefore high loading dose (600 mg); slow onset of action (2 hours after loading dose); low solubility in aqueous solution; and no injectable formulation available for acute treatment; drug-drug interactions, etc.

[0006] Therefore, there is a need in the art to develop improved compounds that show activity in inhibiting platelet aggregation without the disadvantages listed above. Summary of the invention

[0007] The present disclosure provides compounds capable of inhibiting platelet aggregation, pharmaceutical compositions comprising these compounds, and methods of treating vascular diseases using the compounds or pharmaceutical compositions.

[0008] In one aspect, the present disclosure provides a compound having formula (I):

[0009]

[0010] or a pharmaceutically acceptable salt thereof,

[0011] in

[0012] represents a double bond in Z or E configuration;

[0013] R 1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl groups is optionally substituted by one or more R a replace;

[0014] R 2 -C(O)R b ;

[0015] 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, hydroxy, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl;

[0016] L is selected from the group consisting of a direct bond, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, a saturated or partially unsaturated cycloalkyl group, a saturated or partially unsaturated heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of the alkyl group, the alkenyl group, the alkynyl group, the heteroalkyl group, the heteroalkenyl group, the heteroalkynyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group is optionally replaced by one or more R f replace;

[0017] W is selected from the following group:

[0018]

[0019] The * end of W is connected to L;

[0020] 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, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxy, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl;

[0021] R aEach of which is independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, nitro or -NR c R d ;

[0022] R b is selected from the group consisting of hydrogen, hydroxy, 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 ;

[0023] R c and R d Each of is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, or amino;

[0024] 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, hydroxy, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl;

[0025] R f Each of which is independently selected from the group consisting of hydrogen, cyano, halogen, hydroxy, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl; or

[0026] Two R's f together with the atoms to which they are attached form a saturated or partially unsaturated cycloalkyl or a saturated or partially unsaturated heterocyclyl, wherein each of the cycloalkyl and heterocyclyl is optionally substituted with cyano, halogen, hydroxy, amino or alkyl;

[0027] 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, wherein each of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, or amino;

[0028] n is 0, 1, 2, 3, 4 or 5.

[0029] In some embodiments, the present disclosure provides compounds having a formula selected from the group consisting of:

[0030]

[0031]

[0032] or a pharmaceutically acceptable salt thereof.

[0033] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0034] In another aspect, the present disclosure provides a method for treating a vascular disease in an individual in need thereof, comprising administering to the individual an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0035] In another aspect, the present disclosure provides a method for inhibiting platelet aggregation in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0036] In another aspect, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a vascular disease.

[0037] In another aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure for use in treating a vascular disease.

[0038] In another aspect, the present disclosure provides compounds having the formula:

[0039]

[0040] In another aspect, the disclosure provides compounds having the formula:

[0041] BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 Shown are the concentrations of active metabolites in rat plasma after oral administration of (a) clopidogrel, Compound 1a, and Compound 1b, and (b) clopidogrel, Compound 2a, and Compound 2b at a dose level of 10 mg / kg.

[0043] Figure 2Shown are the concentrations of active metabolites in rat plasma following oral administration of clopidogrel at a dose level of 10 mg / kg, oral administration of Compound 3 at a dose level of 2 mg / kg, and intravenous administration of Compound 3 at a dose level of 1 mg / kg.

[0044] Figure 3 Shown is the inhibition (%) of aggregation following oral administration of test compounds in rats at dose levels of 10 mg / kg (clopidogrel), 0.5 mg / kg (compound 1a), and 2 mg / kg (compound 1b). DETAILED DESCRIPTION

[0045] For details, please refer to certain embodiments of the present disclosure, examples of which are illustrated in the accompanying structures and formulas. Although the present disclosure will be described in conjunction with the enumerated embodiments, it should be understood that it is not intended that the present disclosure will be limited to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications or equivalents, which may be included within the scope of the present disclosure as defined by the claims. Those skilled in the art will recognize that many methods or materials that can implement the present disclosure are similar or equivalent to those methods or materials described herein. The present disclosure is in no way limited to the methods or materials described. In the event that one or more of the incorporated references and similar materials (including but not limited to defined terms, term usage, the technology, etc.) are different from or contradictory to the present application, the present disclosure shall prevail. All references, patents, and patent applications cited in the present disclosure are incorporated herein by reference in their entirety.

[0046] It should be understood that certain features of the disclosure described in the context of different embodiments for the sake of clarity may also be provided in combination in a single embodiment. Conversely, various features of the disclosure described in the context of a single embodiment for the sake of brevity may also be provided separately or in any suitable sub-combination. It must be noted that, as used in the specification and the appended claims, the singular forms "a / an" and "the" include their plural forms unless the context clearly dictates otherwise. Thus, for example, a reference to a "compound" includes a plurality of compounds.

[0047] definition

[0048] Definitions of specific functional groups and chemical terms are described in more detail below.For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th ed., inside cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry as well as specific functional groups 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; the entire contents of each of which are incorporated herein by reference.

[0049] In various places of this disclosure, linking substituents are described. In particular, each linking substituent is intended to include both the forward and reverse forms of the linking substituent. For example, -NR(CR'R")- includes both -NR(CR'R")- and -(CR'R")NR-. Where a structure clearly requires a linking group, the Markush variable listed for that group is to be understood as a linking group. For example, if a structure requires a linking group and the Markush group definition of the variable lists "alkyl", then it is to be understood that the "alkyl" represents a linking alkylene group.

[0050] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then the substituent may be bonded to any atom on the ring. When a substituent is listed without indicating that the substituent is bonded to an atom in the remainder of a compound of a given formula, then the substituent may be bonded via any atom in the formula. Combinations of substituents and / or variables are permissible, but only if the combinations result in stable compounds.

[0051] When "*" is shown adjacent to an atom of a compound, it indicates that the compound contains the atom as an asymmetric center in either (R) or (S) stereoconfiguration.

[0052] When any variable (such as R i ) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown as having 0-2 R i If the group is partially substituted, then the group may optionally be substituted with up to two R i Partially substituted, and R i In each occurrence, independently selected from i Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0053] As used herein, the term “C i-j " indicates a range of carbon atoms, wherein i and j are integers, and the range of carbon atoms includes the endpoints (i.e., i and j) and every integer point therebetween, and wherein j is greater than i. For example, C 1-6 Indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, and six carbon atoms. In some embodiments, the term “C 1-12 ” indicates 1 to 12, especially 1 to 10, especially 1 to 8, especially 1 to 6, especially 1 to 5, especially 1 to 4, especially 1 to 3 or especially 1 to 2 carbon atoms.

[0054] As used herein, the term "alkyl", whether used as part of another term or independently, refers to a saturated straight or branched chain hydrocarbon group, which may be optionally substituted independently with one or more substituents as described below. i-j "Alkyl" refers to an alkyl group having i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms. In some embodiments, the alkyl group contains 1 to 9 carbon atoms. In some embodiments, the alkyl group contains 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. "C 1-10 Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 1-6Examples of "alkyl" are methyl, ethyl, n-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.

[0055] As used herein, the term "alkenyl", whether used as part of another term or independently, refers to a straight or branched hydrocarbon group having at least one carbon-carbon double bond, which may be optionally substituted independently with one or more substituents as described herein, and includes groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkenyl group contains 2 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethylenyl / vinyl, propenyl (allyl), butenyl, pentenyl, 1-methyl-2-but-1-enyl, 5-hexenyl, and the like.

[0056] As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon group having at least one carbon-carbon triple bond, whether used as part of another term or independently, which may be optionally substituted independently with one or more substituents described herein. In some embodiments, the alkynyl group contains 2 to 12 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkynyl group contains 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

[0057] As used herein, the term "amino" refers to -NH 2 The amino group may also be substituted by one or more groups such as alkyl, aryl, carbonyl or other amino groups.

[0058] As used herein, the term "aryl", whether used as part of another term or independently, refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 12 ring members. Examples of "aryl" include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, and the like, which may bear one or more substituents. As used herein, groups in which an aromatic ring is fused to one or more additional rings are also included within the scope of the term "aryl". In the case of a polycyclic ring system, only one ring is required to be aromatic (e.g., 2,3-dihydroindole), although all rings may be aromatic (e.g., quinoline). The second ring may also be fused or bridged. Examples of polycyclic aryl groups include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. Aryl groups may be substituted at one or more ring positions with substituents as described above.

[0059] Whether used as part of another term or independently, as used herein, the term "cycloalkyl" refers to monovalent non-aromatic, saturated or partially unsaturated monocyclic and polycyclic ring systems, wherein all ring atoms are carbon, and the ring system contains at least three ring-forming carbon atoms. In some embodiments, the cycloalkyl may 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 may be saturated or partially unsaturated. Cycloalkyl may be substituted. In some embodiments, the cycloalkyl may be a saturated cyclic alkyl. In some embodiments, the cycloalkyl group may be a partially unsaturated cyclic alkyl group containing at least one double bond 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]-decyl, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, and the like.

[0060] As used herein, the term "cyano" refers to -CN.

[0061] As used herein, the term "halogen" refers to an atom selected from fluorine (fluorine / fluoro), chlorine (chlorine / chloro), bromine (bromine / bromo) and iodine (iodine / iodo).

[0062] As used herein, the term "heteroatom" refers to nitrogen, oxygen, sulfur or phosphorus, and includes any oxidized form of the nitrogen or sulfur, and any quaternized form (including N-oxides) of a basic nitrogen.

[0063] As used herein, the term "heteroalkenyl" refers to an alkenyl group in which at least one of its carbon atoms is replaced by a heteroatom selected from N, O or S. The heteroalkenyl group may be carbonyl or heteroatomyl (i.e., the heteroatom may appear in the middle or at the terminal end of the group), and may be optionally substituted independently with one or more substituents described herein.

[0064] As used herein, the term "heteroalkynyl" refers to an alkynyl group in which at least one of its carbon atoms is replaced by a heteroatom selected from N, O or S. A heteroalkynyl group may be a carbon group or a heteroatom group (i.e., the heteroatom may appear in the middle or at a terminal end of the group), and may be optionally substituted independently with one or more substituents described herein.

[0065] As used herein, the term "heteroaryl" refers to an aryl group having one or more heteroatoms in addition to carbon atoms, whether used as part of another term or independently. The heteroaryl group may be monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl, and pteridinyl. Heteroaryl also includes polycyclic groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherein the attachment group or point of attachment is located on the heteroaromatic ring. Examples of polycyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, benzothiophenyl, benzofuranyl, benzo[1,3]dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, dihydroquinolyl, dihydroisoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, and the like.

[0066] As used herein, the term "heterocyclic group" refers to a saturated or partially unsaturated carbocyclic group, wherein one or more ring atoms are independently selected from oxygen, sulfur, nitrogen, phosphorus, etc., and the remaining ring atoms are carbon, wherein one or more ring atoms may be optionally independently substituted by one or more substituents. In some embodiments, the heterocyclic group is a saturated heterocyclic group. In some embodiments, the heterocyclic group is a partially unsaturated heterocyclic group having one or more double bonds in its ring system. In some embodiments, the heterocyclic group may contain any oxidized form of carbon, nitrogen or sulfur and any quaternized form of basic nitrogen. "Heterocyclic group" also includes groups in which the heterocyclic group is fused to a saturated, partially unsaturated or completely unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. Where possible, the heterocyclic group may be carbon-connected or nitrogen-connected. In some embodiments, the heterocyclic ring is carbon-connected. In some embodiments, the heterocyclic ring is nitrogen-connected. For example, a group derived from pyrrole may be pyrrole-1-yl (nitrogen-connected) or pyrrole-3-yl (carbon-connected). Furthermore, a group derived from imidazole may be imidazol-1-yl (nitrogen attached) or imidazol-3-yl (carbon attached).

[0067] In some embodiments, the term "3- to 12-membered heterocyclyl" refers to a 3- to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 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-dioxothietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, piperidinyl, morpholinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like. Examples of fused heterocyclic groups include, but are not limited to, phenyl fused rings or pyridyl fused rings, such as quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothiophenyl, 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, etc. Examples of spiro heterocyclic groups include, but are not limited to, spiropyranyl, spirooxazinyl, etc. Examples of bridged heterocyclic groups include, but are not limited to, morphanyl, hexamethylenetetramine, 3-aza-bicyclo[3.1.0]hexane, 8-aza-bicyclo[3.2.1]octane, 1-aza-bicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane (DABCO), and the like.

[0068] As used herein, the term "hydroxy" refers to -OH.

[0069] As used herein, the term "partially unsaturated" refers to a group that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (ie, fully unsaturated) moieties.

[0070] As used herein, the term "substituted", whether or not there is the term "optionally" in front, means that one or more hydrogens of the specified part are replaced by suitable substituents. It should be understood that "replacement" or "substituted" includes the following implicit restrictions: the substitution is consistent with the allowed valence of the substituted atom, and the substitution produces a stable or chemically feasible compound, such as a compound that will not spontaneously transform by rearrangement, cyclization, elimination, etc. Unless otherwise specified, the "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a specified group, the substituent can be the same or different at each position. It should be understood by those skilled in the art that the substituent itself can be substituted when appropriate. Unless specifically stated as "unsubstituted", reference to the chemical part herein should be understood to include substituted variants. For example, reference to "aryl" or "aryl" moieties implicitly includes both substituted and unsubstituted variants.

[0071] Compound

[0072] The present disclosure provides novel compounds of formula (I) and pharmaceutically acceptable salts thereof, synthetic methods for making the compounds, pharmaceutical compositions containing the same, and various uses of the disclosed compounds.

[0073] In one aspect, the present disclosure provides a compound having formula (I):

[0074]

[0075] or a pharmaceutically acceptable salt thereof,

[0076] in

[0077] represents a double bond in Z or E configuration;

[0078] R 1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl groups is optionally substituted by one or more R a replace;

[0079] R 2 -C(O)R b ;

[0080] R 3is 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, hydroxy, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl;

[0081] L is selected from the group consisting of a direct bond, an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, a saturated or partially unsaturated cycloalkyl group, a saturated or partially unsaturated heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of the alkyl group, the alkenyl group, the alkynyl group, the heteroalkyl group, the heteroalkenyl group, the heteroalkynyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group is optionally replaced by one or more R f replace;

[0082] W is selected from the following group:

[0083]

[0084] The * end of W is connected to L;

[0085] 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, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxy, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl;

[0086] R a Each of which is independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, nitro or -NR c R d ;

[0087] R b is selected from the group consisting of hydrogen, hydroxy, 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 ;

[0088] R c and R d Each of is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, or amino;

[0089] 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, hydroxy, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl;

[0090] R f Each of which is independently selected from the group consisting of hydrogen, cyano, halogen, hydroxy, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl; or

[0091] Two R's f together with the atoms to which they are attached form a saturated or partially unsaturated cycloalkyl or a saturated or partially unsaturated heterocyclyl, wherein each of the cycloalkyl and heterocyclyl is optionally substituted with cyano, halogen, hydroxy, amino or alkyl;

[0092] 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, wherein each of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, or amino;

[0093] n is 0, 1, 2, 3, 4 or 5.

[0094] In some embodiments, R 1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, amino, alkyl and heteroalkyl, wherein each of the alkyl and heteroalkyl groups is optionally substituted by one or more R a replace.

[0095] In certain embodiments, R a Each of is independently selected from the group consisting of halogen, hydroxy, cyano and nitro.

[0096] In some embodiments, R 1 is halogen, cyano, hydroxyl, amino or optionally substituted by one or more R a Substituted alkyl.

[0097] In certain embodiments, R 1 is halogen, cyano or optionally substituted by one or more R a Substituted alkyl.

[0098] In certain embodiments, R 1 is fluorine, chlorine, bromine, cyano, methyl or trifluoromethyl.

[0099] In some embodiments, n is 1, 2, or 3. In certain embodiments, n is 1 or 2. In certain embodiments, n is 1.

[0100] In some embodiments, R 2 -C(O)R b , where R b is selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, -NR c R d AND-OR e .

[0101] In certain embodiments, R c and R d Each of 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 hydroxy.

[0102] In certain embodiments, R e Selected from the group consisting of alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl and heteroaryl, wherein each of the alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, amino or alkyl.

[0103] In some embodiments, R 2 -C(O)R b , where R b is hydrogen, hydroxy, alkyl, saturated or partially unsaturated cycloalkyl or -OR e .

[0104] In certain embodiments, R 2 -C(O)R b , where R b is a saturated cycloalkyl or -OR e , and R e It is an alkyl group.

[0105] In certain embodiments, R 2 -C(O)R b , where R b Saturated C 3-6 Cycloalkyl or -OR e , and R e C 1-6 alkyl.

[0106] In certain embodiments, R 2-C(O)R b , where R b Cyclopropyl or -OR e , and R e It is methyl, ethyl, n-propyl or isopropyl.

[0107] In some embodiments, R 2 is -C(O)-cyclopropyl or -C(O)OCH 3 .

[0108] In some embodiments, R 3 is hydrogen or alkyl which is optionally substituted by halogen, hydroxy, cyano or amino.

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

[0110] In some embodiments, R 3 is an alkyl group optionally substituted by halogen, hydroxy, cyano or amino.

[0111] In certain embodiments, R 3 is C optionally substituted by halogen, hydroxy, cyano or amino 1-6 alkyl.

[0112] In certain embodiments, R 3 It is methyl, ethyl, n-propyl or isopropyl.

[0113] In some embodiments, L is selected from the group consisting of a direct bond, an alkyl group, a heteroalkyl group, a saturated or partially unsaturated cycloalkyl group, and a saturated or partially unsaturated heterocyclyl group, wherein each of the alkyl group, the heteroalkyl group, the cycloalkyl group, and the heterocyclyl group is optionally substituted by one or more R f replace.

[0114] In certain embodiments, R f Each of is independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, alkyl, and heteroalkyl.

[0115] In some embodiments, two R f Together with the atoms to which it is attached, it forms a saturated or partially unsaturated cycloalkyl group which is optionally substituted by cyano, halogen, hydroxy, amino or alkyl.

[0116] In some embodiments, L is a direct bond.

[0117] In some embodiments, L is optionally replaced by one or more R f Substituted alkyl.

[0118] In certain embodiments, L is optionally substituted with one or more R f Substituted C 1-6 alkyl.

[0119] In certain embodiments, L is optionally substituted with one or more R f Substituted C 1-6 Alkyl, where R f Each of is independently selected from the group consisting of hydrogen, halogen, hydroxy, methyl and ethyl.

[0120] In some embodiments, L is -CH 2 -、-CH(CH 3 )- or -C(CH 3 ) 2 -.

[0121] In some embodiments, W is

[0122] In some embodiments, W is

[0123] In some embodiments, W is

[0124] In some embodiments, W is

[0125] In some embodiments, W is

[0126] In some embodiments, W is

[0127] In some embodiments, R g is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, wherein each of the alkyl and heteroalkyl is optionally substituted with halogen, hydroxy, cyano, or amino.

[0128] In certain embodiments, W is Where R g is hydrogen or C 1-6 In certain embodiments, R g is hydrogen, methyl or ethyl.

[0129] In some embodiments, R 4 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl or aryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl and aryl is optionally substituted with cyano, halogen, hydroxyl, amino or alkyl.

[0130] In certain embodiments, R 4 is hydrogen, or an alkyl or aryl group which is optionally substituted by halogen, hydroxy, cyano or amino.

[0131] In certain embodiments, R 4is hydrogen, optionally substituted by halogen, hydroxy, cyano or amino 1-6 Alkyl, optionally substituted by halogen, hydroxy, cyano or amino 6-12 Aryl.

[0132] In certain embodiments, R 4 Hydrogen, -CH 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-C(CH 3 ) 3 、-CH(CH 3 )(NH 2 ) or phenyl.

[0133] In some embodiments, The double bond is in E configuration.

[0134] In some embodiments, The double bond is in Z configuration.

[0135] In another aspect, the present disclosure provides a compound having a formula selected from the group consisting of:

[0136]

[0137]

[0138] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R g , L and n are as defined above.

[0139] In some embodiments, R 1 In certain embodiments, R 1 is fluorine, chlorine or bromine.

[0140] In some embodiments, n is 1, 2, or 3. In certain embodiments, n is 1 or 2. In certain embodiments, n is 1.

[0141] In some embodiments, R 2 -C(O)R b , where R b is hydrogen, hydroxy, alkyl, saturated cycloalkyl or -OR e In certain embodiments, R 2 -C(O)R b , where R b is a saturated cycloalkyl or -OR e, and R e In certain embodiments, R 2 -C(O)R b , where R b Saturated C 3-6 Cycloalkyl or -OR e , and R e C 1-6 In certain embodiments, R 2 -C(O)R b , where R b 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)OCH 3 .

[0142] In some embodiments, R 3 For hydrogen.

[0143] In some embodiments, R 3 In certain embodiments, R 3 C 1-6 In certain embodiments, R 3 It is methyl, ethyl, n-propyl or isopropyl.

[0144] In some embodiments, L is a direct bond.

[0145] In some embodiments, L is optionally replaced by one or more R f Substituted alkyl, the R f In certain embodiments, L is optionally substituted with one or more R f Substituted C 1-6 Alkyl, the R f is independently selected from hydrogen, halogen, hydroxyl, methyl and ethyl. In certain embodiments, L is -CH 2 -、-CH(CH 3 )- or -C(CH 3 ) 2 -.

[0146] In some embodiments, R 4 is hydrogen or alkyl optionally substituted with halogen, hydroxyl, cyano or amino. 4 is hydrogen or C optionally substituted by halogen, hydroxy, cyano or amino 1-6 In certain embodiments, R 4 Hydrogen, -CH 3 、-CH 2CH 3 、-CH(CH 3 ) 2 、-C(CH 3 ) 3 or -CH(CH 3 )(NH 2 ).

[0147] In some embodiments, R g is hydrogen or alkyl. g is hydrogen or C 1-6 In certain embodiments, R g is hydrogen, methyl or ethyl. g For hydrogen.

[0148] In some embodiments, The double bond is in E configuration.

[0149] In some embodiments, The double bond is in Z configuration.

[0150] In another aspect, the present disclosure provides a compound having a formula selected from the group consisting of:

[0151]

[0152]

[0153] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 4 , R g , L and n are as defined above. In some embodiments, The double bond is in E configuration.

[0154] In some embodiments, The double bond is in Z configuration.

[0155] In another aspect, the present disclosure provides a compound having a formula selected from the group consisting of:

[0156]

[0157]

[0158]

[0159] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 4 , R g , L and n are as defined above. In some embodiments, The double bond is in E configuration.

[0160] In some embodiments, The double bond is in Z configuration.

[0161] In another aspect, the present disclosure provides a compound having a formula selected from the group consisting of:

[0162]

[0163]

[0164]

[0165]

[0166]

[0167] or a pharmaceutically acceptable salt thereof.

[0168] The compounds provided herein are described with reference to general chemical formulae and specific compounds. In addition, the disclosed compounds may exist in many different forms or derivatives, all of which are within the scope of the present disclosure. These include, for example, tautomers, stereoisomers, racemic mixtures, regioisomers, salts, solvated forms, amorphous forms, different crystalline forms or polymorphs.

[0169] Depending on the substituent selection, the disclosed compounds may include one or more asymmetric centers, and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds provided herein may have an asymmetric carbon center, and therefore the compounds provided herein may have (R) or (S) stereo configuration at the carbon asymmetric center. Therefore, the disclosed compounds may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of a mixture of stereoisomers.

[0170] As used herein, the term "enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. The term "diastereomer" refers to a pair of optical isomers that are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity.

[0171] When a particular enantiomer is preferred, it may be provided in some embodiments as being substantially free of the relative enantiomer, and may also be referred to as "optically enriched". As used herein, "optically enriched" means that the compound is composed of a significantly larger proportion of one enantiomer. In certain embodiments, the compound is composed of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound is composed of at least about 95%, 98% by weight, or 99% by weight of the preferred enantiomer. The preferred enantiomer may be separated from the racemic mixture by any method known to those skilled in the art, such as by chromatography or crystallization, by synthesizing using stereochemically uniform starting materials, or by stereoselective synthesis. Optionally, derivatization may be performed before separating stereoisomers. The separation of a mixture of stereoisomers may be performed during the synthesis of the compounds provided herein at an intermediate step or it may be performed on the final racemic product. Absolute stereochemistry may be determined by X-ray crystallography of a crystalline product or a crystalline intermediate, which may be derivatized with a reagent containing a stereocenter of a known configuration if necessary. Alternatively, absolute stereochemistry can be determined by vibrational circular dichroism (VCD) spectroscopy. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, SH et al., Tetrahedron 33:2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions, p. 268 (ELEiel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0172] In some embodiments, a mixture of diastereomers is provided, for example, a mixture of diastereomers enriched with 51% or more of one of the diastereomers, including, for example, 60% or more, 70% or more, 80% or more, or 90% or more of one of the diastereomers.

[0173] In some embodiments, unless otherwise indicated, the compounds provided herein may have one or more double bonds that exist as Z or E isomers. In addition, the disclosure also encompasses compounds in the form of individual isomers that are substantially free of other isomers, and alternatively, in the form of mixtures of multiple isomers (e.g., racemic mixtures of enantiomers).

[0174] The disclosed compounds can also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be mutually converted via low energy barriers. For example, proton tautomers (also referred to as prototransfer tautomers) include mutual conversions via proton migration, such as keto-enols, amide-imidic acids, lactams-lactams, imine-enamine isomerizations and cyclic forms, wherein protons can occupy two or more positions of heterocyclic systems (e.g., 1H-imidazoles and 3H-imidazoles, 1H-1,2,4-triazoles, 2H-1,2,4-triazoles and 4H-1,2,4-triazoles, 1H-isoindoles and 2H-isoindoles and 1H-pyrazoles and 2H-pyrazoles). Valence tautomers include mutual conversions performed by rearrangement of some bonding electrons. Tautomers can be in equilibrium or spatially locked into a form by appropriate substitution. Unless otherwise specified, a compound of the disclosure identified by name or structure as a particular tautomeric form is intended to encompass the other tautomeric forms.

[0175] The present disclosure is also intended to include all isotopes of atoms in the compounds. Isotopes of atoms 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 the compounds of the present disclosure is also intended to include its isotopes, such as (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, 79Br, 81 Br, 124 I. 127 I and 131 1. In some embodiments, hydrogen comprises protium, deuterium, and tritium. In some embodiments, carbon comprises 12 C and 13 C. Isotopically enriched compounds of formula (I) may be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein, using appropriate isotopically enriched reagents and / or intermediates.

[0176] The compounds of the present disclosure may be formulated as or in the form of pharmaceutically acceptable salts. Unless specified to the contrary, the compounds provided herein include pharmaceutically acceptable salts of such compounds.

[0177] As used herein, the term "pharmaceutically acceptable" indicates that the substance or composition described is chemically and / or toxicologically compatible with the other ingredients making up the formulation and / or the individual being treated therewith.

[0178] As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salt" includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and are not biologically or otherwise undesirable. Pharmaceutically acceptable salt forms contemplated include, but are not limited to, monosalts, disalts, trisalts, tetrasalts, and the like. Pharmaceutically acceptable salts are nontoxic in the amounts and concentrations to which they are applied. The preparation of such salts can facilitate pharmacological use by changing the physical characteristics of the compound without preventing it from exerting its physiological effects. Useful changes in physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher concentrations of the drug.

[0179] Pharmaceutically acceptable salts include acid addition salts such as those containing 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, sulfamate, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamate, fumaric acid and quinic acid.

[0180] When an acidic functional group (such as carboxylic acid or phenol) is present, pharmaceutically acceptable salts also include base addition salts, such as those containing the following: benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines and zinc. See, for example, Remington's Pharmaceutical Sciences, 19th edition, Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using the appropriate corresponding bases.

[0181] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of the compound can be dissolved in a suitable solvent (such as an aqueous solution or water-alcohol solution containing a suitable acid), and then separated by evaporating the solution. Therefore, if the specific compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. to treat the free base, or with 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, pyranosyl acid (such as glucuronic acid or galacturonic acid), alpha-hydroxy acid (such as citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic acid (such as benzoic acid or cinnamic acid), sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid), etc. to treat the free base.

[0182] Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, etc. Illustrative examples of suitable salts include organic salts derived from amino acids (such as L-glycine, L-lysine and L-arginine), ammonia, primary, secondary and tertiary amines and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0183] It will also be understood that the compounds of the disclosure may exist in unsolvated forms, solvated forms (eg, hydrated forms), and solid forms (eg, crystalline or polymorphic forms), and that the disclosure is intended to encompass all such forms.

[0184] As used herein, the term "solvate" or "solvated form" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of a solvent. Some compounds have a tendency to entrap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with a molecule of a substance, wherein the water retains its H 2 Molecular state of O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0185] As used herein, the terms "crystal form", "crystalline form", "polymorphic form" and "polymorph" are used interchangeably and refer to crystal structures in which a compound (or its salt or solvate) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shapes, optical and electrical properties, stability and solubility. Recrystallization solvents, crystallization rates, storage temperatures and other factors can make one crystal form dominant. Crystalline polymorphs of a compound can be prepared by crystallization under different conditions.

[0186] The present disclosure is also intended to include all isotopes of atoms in the compounds. Isotopes of atoms 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 the compounds of the present disclosure is also intended to include its isotopes, such as (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. 18F. 19 F. 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I. 127 I and 131 1. In some embodiments, hydrogen comprises protium, deuterium, and tritium. In some embodiments, carbon comprises 12 C and 13 C.

[0187] Synthesis of compounds

[0188] The synthesis of the compound (including its pharmaceutically acceptable salt) provided herein is described in the synthesis scheme in the example. The compound provided herein can be prepared using any known organic synthesis technology and can be synthesized according to any of a variety of possible synthetic pathways, and therefore, these schemes are only illustrative and are not intended to limit other possible methods that can be used to prepare the compound provided herein. In addition, the steps in the scheme are to better illustrate and can be changed when appropriate. For the purpose of research and possible submission to the regulatory agency, the embodiment of the compound in the example is synthesized.

[0189] The reaction for preparing the disclosed compounds can be carried out in a suitable solvent, which can be easily selected by a technician in the field of organic synthesis. Suitable solvents can be at a temperature where the reaction is carried out, for example, at a temperature within the range of the freezing temperature of the solvent to the boiling temperature of the solvent, substantially not reacting with the starting material (reactant), intermediate or product. The specified reaction can be carried out in a solvent or a mixture of more than one solvent. Depending on the specific reaction step, the suitable solvent for the specific reaction step can be selected by a technician in the field.

[0190] The preparation of the disclosed compounds may involve the protection and deprotection of various chemical groups. The demand for protection and deprotection, and the selection of appropriate protecting groups can be easily determined by those skilled in the art. The chemical properties of protecting groups can be found in, for example, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd edition, Wiley & Sons, Inc., New York (1999); P. Kocienski, "Protective Groups", Georg Thieme Verlag, 2003; and Peter G. M. Wuts, "Greene's Protective Groups in Organic Synthesis", 5th edition, Wiley, 2014, all of which are incorporated herein by reference in their entirety.

[0191] The reaction can be monitored by any suitable method known in the art. For example, the reaction can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C), infrared spectroscopy (IR), spectrophotometry (e.g., UV-visible light), mass spectrometry, or by chromatography, such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS) or thin layer chromatography (TLC) to monitor product formation. Those skilled in the art can purify compounds 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, "Journal of Combinatorial Chemistry (J. Combi. Chem.)", 2004, 6 (6), 874-883, which is incorporated herein by reference in its entirety) and normal phase silica chromatography.

[0192] Known starting materials of the present disclosure can be synthesized by using or according to methods known in the art, or can be purchased from commercial suppliers. Unless otherwise noted, analytical grade solvents and commercially available reagents were used without further purification.

[0193] Unless otherwise specified, the reactions of the present disclosure were carried out under a positive pressure of nitrogen or argon or in anhydrous solvents with dried tubes, and the reaction flasks were usually equipped with rubber septa for the introduction of substrates and reagents via syringes. Glassware was oven-dried and / or heat-dried.

[0194] For illustrative purposes, the following examples partially show synthetic routes and key intermediates for preparing compounds of the present disclosure. It will be appreciated by those skilled in the art that other synthetic routes can be used to synthesize the compounds of the present invention. Although specific starting materials and reagents are described, other starting materials and reagents can be easily replaced to provide a variety of derivatives and / or reaction conditions. In addition, many compounds prepared by the methods described below can be further adjusted according to the present disclosure using conventional chemical reactions known to those skilled in the art.

[0195] In one aspect, the present disclosure provides compounds having the formula:

[0196]

[0197] In some embodiments, the above compounds can be used as intermediates in the preparation of compounds of the present disclosure.

[0198] In another aspect, the present disclosure provides compounds having the formula:

[0199]

[0200] In some embodiments, the above compounds can be used as intermediates in the preparation of compounds of the present disclosure.

[0201] Uses of Compounds

[0202] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof that can inhibit platelet aggregation. Therefore, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is suitable for use as a medical drug, and is particularly suitable for use as a therapeutic agent or preventive agent for various thrombotic diseases.

[0203] As used herein, the term "therapy" is intended to have its ordinary meaning, i.e., to treat a disease so as to completely or partially relieve one, some or all of its symptoms, or to correct or counteract the underlying pathology, thereby achieving a beneficial or desired clinical outcome. For the purposes of this disclosure, beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms, alleviation of the extent of the disease, stabilization of the disease state (i.e., no deterioration), delay or slowing of disease progression, improvement or alleviation of the disease condition, and relief (partial or complete relief), whether detectable or undetectable. "Therapy" may also mean an extension of survival compared to the expected survival without therapy. Situations requiring therapy include situations in which a condition or illness has been suffered, as well as situations in which a condition or illness is prone to be suffered, or in order to prevent a condition or illness. Unless there is a specific indication to the contrary, the term "therapy" also encompasses prevention. The terms "therapeutic" and "therapeutically" should be interpreted in a corresponding manner.

[0204] The term "treat" is used synonymously with "therapy." Similarly, the term "treatment" can be viewed as "administering therapy," where "therapy" is as defined herein.

[0205] As used herein, the term "prevention" is intended to have its ordinary meaning and includes primary prevention, which is used to prevent the development of a disease, and secondary prevention, which temporarily or permanently protects a patient from exacerbating or worsening the disease or developing new symptoms associated with the disease once the disease has developed.

[0206] In some embodiments, the compounds of the present disclosure may be converted to active thiol metabolites after administration. In some embodiments, the compounds of the present disclosure may be converted to active thiol metabolites after oral administration. In some embodiments, the compounds of the present disclosure may be converted to active thiol metabolites after intravenous injection.

[0207] For prodrugs of active thiol metabolites, it is desirable that the prodrug remain stable (resistant to the environment) while being converted to the active thiol metabolite at a high conversion rate in the target tissue. In addition, it is desirable that the prodrug have a rapid onset of action and thus a low loading dose and low side effects, and have a high solubility in aqueous solution to allow formulation into an injection for emergency and surgical use.

[0208] In certain embodiments, the compounds provided herein can be hydrolyzed via hydrolases to form active thiol metabolites. Since hydrolases have high in vivo activity and wide distribution in the intestinal tract, liver, and blood plasma, the compounds provided herein can be converted into active thiol metabolites in vivo with high conversion rates and less inter-patient variability, thereby providing rapid onset of antiplatelet effects without the need to use high loading doses. In addition, since the metabolism of the compounds provided herein is mediated by hydrolases rather than CYP enzymes, the use of these compounds is not limited by potential interactions with other CYP targeted drugs.

[0209] In some embodiments, the compounds provided herein show a faster onset of antiplatelet effect than clopidogrel at the same dose. In some embodiments, the compounds provided herein show an onset of antiplatelet effect less than clopidogrel at a dose lower than clopidogrel. In some embodiments, when the dose is 1 / 2 of the clopidogrel dose, the compounds provided herein show an onset of antiplatelet effect less than clopidogrel. In some embodiments, when the dose is 1 / 3 of the clopidogrel dose, the compounds provided herein show an onset of antiplatelet effect less than clopidogrel. In some embodiments, when the dose is 1 / 4 of the clopidogrel dose, the compounds provided herein show an onset of antiplatelet effect less than clopidogrel. In some embodiments, when the dose is 1 / 5 of the clopidogrel dose, the compounds provided herein show an onset of antiplatelet effect less than clopidogrel.

[0210] In some embodiments, at a dose that is 1 / 5 of the dose of clopidogrel, the compounds provided herein exhibit an onset of antiplatelet effect of 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 even less than 30 minutes.

[0211] In some embodiments, as measured in phosphate buffer, the compounds provided herein show improved water solubility compared to clopidogrel. In some embodiments, as measured in aqueous buffered solution, the compounds provided herein show an aqueous solubility greater than 0.2 mg / ml, greater than 0.3 mg / ml, greater than 0.4 mg / ml, greater than 0.5 mg / ml, greater than 0.6 mg / ml, greater than 0.7 mg / ml, greater than 0.8 mg / ml, greater than 0.9 mg / ml, greater than 1 mg / ml or even greater.

[0212] The improved solubility of the compounds provided herein provides an opportunity to expand the use of the compounds in inhibiting platelet aggregation. In certain embodiments, the compounds provided herein can be formulated into injections for emergency and surgical administration. In certain embodiments, the compounds provided herein can be formulated into oral administration to inhibit platelet aggregation for a long time.

[0213] In another aspect, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for treating a vascular disease.

[0214] In another aspect, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a vascular disease.

[0215] Pharmaceutical composition

[0216] For administration purposes, in some embodiments, the compounds provided herein are administered as the raw chemical substance or formulated into a pharmaceutical composition.

[0217] Thus, in another aspect, provided are pharmaceutical compositions comprising one or more compounds of the present disclosure, or pharmaceutically acceptable salts thereof.

[0218] In some embodiments, the pharmaceutical composition of the present disclosure comprises a compound selected from any one of formulas (I) to (VII) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure comprises a first compound selected from any one of formulas (I) to (VII) or a pharmaceutically acceptable salt thereof and one or more additional compounds of the same formula, but the first compound and the additional compound are not the same molecule.

[0219] As used herein, the term "pharmaceutical composition" refers to a formulation containing a molecule or compound of the disclosure in a form suitable for administration to a subject.

[0220] In some embodiments, the pharmaceutical compositions of the present disclosure comprise a therapeutically effective amount of one or more compounds of Formula (I) to (VII) or a pharmaceutically acceptable salt thereof.

[0221] As used herein, the term "therapeutically effective amount" refers to the amount of a molecule, compound, or composition comprising the molecule or compound that treats, ameliorates, or prevents an identified disease or condition, or shows a detectable therapeutic or inhibitory effect. The effect can be detected by any analytical method known in the art. The precise effective amount for an individual will depend on the individual's weight, stature, and health; the nature and extent of the condition; the rate of administration; the therapeutic agent or combination of therapeutic agents selected for administration; and the judgment of the prescribing physician. The therapeutically effective amount for a given situation can be determined by routine experiments within the skill and judgment of the clinician.

[0222] In another aspect, provided are pharmaceutical compositions comprising one or more molecules or compounds of the present disclosure, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0223] As used herein, the term "pharmaceutically acceptable excipient" refers to an excipient suitable for preparing a pharmaceutical composition that is generally safe, non-toxic, and biologically and otherwise desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. As used herein, "pharmaceutically acceptable excipient" includes one and more than one such excipient. The term "pharmaceutically acceptable excipient" also encompasses "pharmaceutically acceptable carriers" and "pharmaceutically acceptable diluents".

[0224] The specific excipient used will depend on the means and purpose for which the disclosed compounds are to be administered. The solvent is generally selected based on a solvent recognized as safe by those skilled in the art to be administered to a mammal (including a human). In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), etc. and mixtures thereof.

[0225] In some embodiments, suitable excipients may include buffers such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; chloride); phenol, butyl alcohol or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, dextrin or substituted dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (such as Zn-protein complexes); and / or nonionic surfactants such as TWEEN®. TM 、PLURONICS TM or polyethylene glycol (PEG).

[0226] In some embodiments, suitable excipients may include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, slip agents, processing aids, colorants, sweeteners, aromatics, flavoring agents and other known additives to provide the best presentation of drugs (i.e., compounds disclosed herein or their pharmaceutical compositions) or to help manufacture pharmaceutical products (i.e., medicaments). Active pharmaceutical ingredients may also be coated in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly (methyl methacrylate) microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in coarse emulsions, respectively. Such technology is disclosed in Remington's Pharmaceutical Sciences, 16th edition, Osol, A., ed. (1980). "Liposomes" are vesicles comprising various types of lipids, phospholipids and / or surfactants, which are suitable for delivering drugs (compounds disclosed herein and optional chemotherapeutic agents) to mammals (including humans). The components of liposomes are typically arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.

[0227] The pharmaceutical compositions provided herein may be in any form that permits administration of the composition to an individual, including but not limited to humans, and is formulated to be compatible with the intended route of administration.

[0228] Multiple approaches are considered for the pharmaceutical composition provided herein, and therefore the pharmaceutical composition provided herein can be supplied in bulk or unit dosage form depending on the expected route of administration. For example, for oral, buccal and sublingual administration, powders, suspensions, granules, lozenges, pills, capsules, soft capsules and caplets are acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions and solutions are acceptable as liquid dosage forms. For injection administration, emulsions and suspensions are acceptable as liquid dosage forms, and powders suitable for reconstitution with suitable solutions are acceptable as solid dosage forms. For inhalation administration, solutions, sprays, dry powders and aerosols can be acceptable dosage forms. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions and patches can be acceptable dosage forms. For vaginal administration, vaginal suppositories, tampons, creams, gels, pastes, foams and sprays can be acceptable dosage forms.

[0229] The amount of active ingredient in the unit dosage form of the composition is a therapeutically effective amount and varies according to the specific treatment involved. As used herein, the term "therapeutically effective amount" refers to the amount of a molecule, compound, or composition comprising the molecule or compound that treats, improves, or prevents an identified disease or condition or shows a detectable therapeutic or inhibitory effect. The effect can be detected by any analytical method known in the art. The precise effective amount for an individual will depend on the individual's weight, stature, and health; the nature and extent of the condition; the rate of administration; the therapeutic agent or combination of therapeutic agents selected for administration; and the judgment of the prescribing physician. The therapeutically effective amount for a given situation can be determined by routine experiments within the skill and judgment of the clinician.

[0230] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of oral administration formulations.

[0231] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of tablet formulations. Pharmaceutically acceptable excipients suitable for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives such as ethyl paraben or propyl paraben; and antioxidants such as ascorbic acid. Tablet formulations may be uncoated or coated with coatings to regulate their disintegration and subsequent absorption of active ingredients in the gastrointestinal tract, or to improve their stability and / or appearance, in either case, conventional coating agents and procedures well known in the art are used.

[0232] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin); or in the form of soft gelatin capsules in which the active ingredient is mixed with water or oil (e.g., peanut oil, liquid paraffin, or olive oil).

[0233] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an aqueous suspension, which generally contains the active ingredient in fine powder form and one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum arabic; a dispersant or wetting agent, such as lecithin, or a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), or a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxyhexadecanoic acid), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitan monooleate), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives (for example, ethyl or propyl p-hydroxybenzoate), antioxidants (for example, ascorbic acid), coloring agents, flavoring agents and / or sweetening agents (for example, sucrose, saccharin or aspartame).

[0234] In certain embodiments, the pharmaceutical composition of the present disclosure can be in the form of an oily suspension, which generally contains a suspended active ingredient in a vegetable oil (such as peanut oil, castor oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspension can also contain a thickener, such as beeswax, hard paraffin or cetyl alcohol. Sweeteners (such as those stated above) and flavoring agents can be added to provide a palatable oral formulation. These compositions can be preserved by adding an antioxidant (such as ascorbic acid).

[0235] In certain embodiments, the pharmaceutical composition of the present disclosure may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil; or a mineral oil, such as liquid paraffin; or a mixture of any of these oils. Suitable emulsifiers may be, for example, naturally occurring gums, such as gum arabic or gum tragacanth; naturally occurring phospholipids, such as soybeans, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of the partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The emulsion may also contain sweeteners, flavorings, and preservatives.

[0236] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweeteners, such as glycerol, propylene glycol, sorbitol, aspartame or sucrose; demulcents; preservatives; flavoring and / or coloring agents.

[0237] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of formulations for injectable administration.

[0238] In certain embodiments, the pharmaceutical composition of the present disclosure can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension can be prepared according to known techniques using those suitable dispersants or wetting agents and suspending agents mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. The acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils can be used as solvents or suspension media conventionally. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used to prepare injectables.

[0239] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an inhaled administration formulation.

[0240] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of aqueous and non-aqueous (e.g., in fluorocarbon propellants) aerosols containing any suitable solvent and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH adjusters, surfactants, bioavailability modifiers, and combinations of these. Carriers and stabilizers vary with the requirements of a particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins (such as serum albumin), sorbitan esters, oleic acid, lecithin, amino acids (such as glycine), buffers, salts, sugars, or sugar alcohols.

[0241] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of formulations for topical or transdermal administration.

[0242] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels, and aqueous or oily solutions or suspensions, which can generally be obtained by formulating the active ingredient with conventional topically acceptable excipients, such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0243] In certain embodiments, the pharmaceutical compositions provided herein may be formulated in the form of transdermal skin patches well known to those of ordinary skill in the art.

[0244] In addition to those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art, and are therefore included in the present disclosure. Such excipients and carriers are described in, for example, "Remington's Pharmaceutical Sciences" Mark Publishing Company, New Jersey (1991), "Remington: The Science and Practice of Pharmacy", University of the Sciences in Philadelphia, 21st edition, LWW (2005), which is incorporated herein by reference.

[0245] In certain embodiments, the pharmaceutical composition of the present disclosure can be formulated into a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable for use in human individuals and other mammals in a single dose, each unit containing a predetermined amount of active substance calculated to be combined with a suitable pharmaceutical excipient to produce a desired therapeutic effect. The amount of the compound provided herein in a unit dosage form will vary according to the condition to be treated, the individual to be treated (e.g., age, body weight, and response of the individual), a specific route of administration, the actual compound administered, and its relative activity and the severity of individual symptoms.

[0246] In some embodiments, the dosage of the pharmaceutical composition of the present disclosure can be 0.001-1000 mg / kg body weight / day, for example, 0.001-1000 mg / kg body weight / day, 0.001-900 mg / kg body weight / day, 0.001-800 mg / kg body weight / day, 0.001-700 mg / kg body weight / day, 0.001-600 mg / kg body weight / day, 0.001-500 mg / kg body weight / day. day, 0.001-400 mg / kg body weight / day, 0.001-300 mg / kg body weight / day, 0.001-200 mg / kg body weight / day, 0.001-100 mg / kg body weight / day, 0.001-50 mg / kg body weight / day, 0.001-40 mg / kg body weight / day, 0.001-30 mg / kg body weight / day, 0.001-20 mg / kg body weight / day, 0.001-10 mg / kg body weight / day, 0.001-5 mg / kg body weight / day, 0.001-1 mg / kg body weight / day, 0.001-0.5 mg / kg body weight / day, 0.001-0.4 mg / kg body weight / day, 0.001-0.3 mg / kg body weight / day, 0.001-0.2 mg / kg body weight / day, 0.001-0.1 mg / kg body weight / day, 0.005-0.1 mg / kg body weight / day, 0.01 In some cases, the dosage amount below the lower limit of the aforementioned range may be more than enough, and in other cases, a larger dose can be used without causing any harmful side effects, provided that the larger dose is first divided into several small doses for use throughout the day. For additional information on routes of administration and dosing regimens, see Volume 5, Chapter 25.3 in Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press 1990, which is specifically incorporated herein by reference.

[0247] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for oral administration. In some embodiments, the unit dose for oral administration contains one or more compounds provided herein in the following amounts: about 1 mg to about 1000 mg, for example, about 5 mg to about 1000 mg, about 10 mg to about 1000 mg, about 15 mg to about 1000 mg, about 20 mg to about 1000 mg, about 25 mg to about 1000 mg, about 30 mg to about 1000 mg, about 40 mg to about 1000 mg, about 50 mg to about 1000 mg, about 60 mg to about 1000 mg, about 70 mg to about 1000 mg, about 80 mg to about 1000 mg, about 90 mg to about 1000 mg, about 100 mg to about 1000 mg, about 200 mg to 1000 mg, about 300 mg to about 1000 mg, about 400 mg to about 1000 mg, about 500 mg to about 1000 mg, about 1 mg to about 1000 mg. In some embodiments, the dosage unit may be administered to an individual 1 to 6 times daily, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, etc. In some embodiments, the dosage unit may be administered to an individual 1 to 6 times daily, depending on the severity of the individual's symptoms.

[0248] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for oral administration in treatments of duration greater than 1 week, greater than 2 weeks, greater than 3 weeks, greater than 1 month, greater than 2 months, greater than 3 months, greater than 4 months, greater than 5 months, greater than 6 months, greater than 7 months, greater than 8 months, greater than 9 months, greater than 10 months, greater than 11 months, greater than 1 year, or even longer.

[0249] In some embodiments, pharmaceutical compositions of the present disclosure are formulated for parenteral administration, such as via intravenous, subcutaneous or intramuscular injection. In some embodiments, the unit dose for parenteral administration contains one or more compounds provided herein in an amount of about 0.1 mg to about 500 mg of one or more compounds provided herein, such as about 0.2 mg to about 500 mg, about 0.3 mg to about 500 mg, about 0.4 mg to about 500 mg, about 0.5 mg to about 500 mg, about 1 mg to about 500 mg, about 5 mg to about 500 mg, about 10 mg to about 500 mg, about 20 mg to about 500 mg, about 30 mg to about 500 mg, about 40 mg to about 500 mg, about 50 mg to about 500 mg, about 0.5 mg to about 400 mg, about 0.5 mg to about 300 mg, about 0.5 mg to about 200 mg, about 0.5 mg to about 100 mg, about 0.5 mg to about 90 mg, about 0.5 mg to about about 0.5 mg to about 100 mg, about 150 mg to about 200 mg, about 200 mg to about 700 mg, about 300 mg to about 600 mg, or about 400 mg to about 500 mg, such as about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, etc.

[0250] In some embodiments, pharmaceutical compositions intended for administration by injection may be prepared by combining one or more compounds of the present disclosure with sterile distilled water, sesame oil, peanut oil, or propylene glycol aqueous solution to form a solution. In some embodiments, the pharmaceutical composition may include a surfactant or other dissolving excipient, which is added to facilitate the formation of a homogeneous solution or suspension. In some embodiments, the pharmaceutical composition may further include one or more additional agents selected from the group consisting of a wetting agent, a suspending agent, a preservative, a buffer, and an isotonic agent.

[0251] In certain embodiments, the pharmaceutical composition intended to be administered by injection can be administered with a syringe. In certain embodiments, the syringe is disposable. In certain embodiments, the syringe is reusable. In certain embodiments, the syringe is pre-filled with a pharmaceutical composition provided herein.

[0252] In another aspect, a veterinary composition is also provided, comprising one or more molecules or compounds of the present disclosure or pharmaceutically acceptable salts thereof and a veterinary carrier. A veterinary carrier is a substance suitable for the purpose of administering the composition, and may be a solid, liquid or gaseous substance that is originally inert or acceptable in the veterinary field and is compatible with the active ingredient. These veterinary compositions can be administered parenterally, orally or by any other desired route.

[0253] Pharmaceutical compositions or veterinary compositions can be packaged in a variety of ways depending on the method for administering the drug. For example, the article for distribution may include a container in which a composition of suitable form is deposited. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, etc. The container may also include an anti-disassembly assembly to prevent easy access to the contents of the package. In addition, a label describing the contents of the container is attached to the container. The label may also include appropriate warnings. The composition may be packaged in a unit dose or multi-dose container (e.g., sealed ampoules and vials) and may be stored under a freeze-drying (lyophilized) condition, requiring only the addition of a sterile liquid carrier (e.g., water) for injection immediately before use. Ready-to-use injection solutions and suspensions are prepared by sterile powders, granules, and lozenges of the types described previously.

[0254] In another aspect, a pharmaceutical composition comprising one or more compounds of the present disclosure or a pharmaceutically acceptable salt thereof as a first active ingredient and a second active ingredient is also provided.

[0255] In some embodiments, the second active ingredient has complementary activities to the compounds provided herein such that they do not adversely affect each other. The ingredients are preferably present in combination in amounts effective for the intended purpose.

[0256] Treatment of the disease

[0257] In another aspect, the present disclosure provides a method for treating a vascular disease, comprising administering to an individual in need thereof an effective amount of a compound provided herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0258] In some embodiments, the vascular disease is selected from atherothrombosis, ischemia, stroke, cerebral thrombosis, arterial thrombosis, thrombotic cerebrovascular disease, cardiovascular disease, and thrombosis.

[0259] In another aspect, the present disclosure provides a method of inhibiting platelet aggregation in a subject in need thereof, comprising administering to the subject an effective amount of a compound provided herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0260] Examples

[0261] For illustrative purposes, the following examples are included. However, it should be understood that these examples do not limit the present disclosure and are intended only to show methods for practicing the present disclosure. Those skilled in the art will recognize that the chemical reactions described may be easily applicable to the preparation of a variety of other compounds of the present disclosure, and alternative methods for preparing compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, non-exemplary compounds according to the present disclosure may be successfully synthesized by modifications apparent to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks known in the art in addition to the reagents and building blocks, and / or by routinely changing reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered to be applicable to the preparation of other compounds of the present disclosure.

[0262] Example 1

[0263]

[0264]

[0265] Step 1. Synthesis 1-2

[0266]

[0267] In N 2 A solution of 1-1 (56.7 g, 310 mmol) in DCM (500 mL) was stirred in an ice bath (T < 5 °C) under protection. mCPBA (107.0 g, 620 mmol) was added portionwise to the above solution. After the addition, the resulting mixture was stirred at 20 °C for 4 hours. The mixture was poured into Na 2 S 2 O 3 (90.0 g) and NaHCO 3 (45.0 g) in water (300 mL). The resulting mixture was extracted with DCM (300 mL*2). The combined organic layers were purified by Na 2 SO 4 Dried 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.

[0268] Step 2. Synthesis 1-3

[0269]

[0270] 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 minutes and then stirred at 40° C. overnight. The reaction mixture was then concentrated in vacuo. Saturated Na 2 CO 3 (400 mL), and then extracted with EtOAc (400 mL*2). The organic layer was washed with Na 2 SO 4 Dried 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.

[0271] LC-MS[M+1-100] + =238.1

[0272] 1 H NMR (400MHz, chloroform-d) δ7.97(d,J=7.2Hz,2H),7.59(s,1H),7.46(t,J=7.7Hz,2H),4.24(d,J=16.3Hz,1H),4.17-3.81(m,1H),3 .73(s,1H),3.60(s,1H),2.92(t,J=24.3Hz,2H),2.72(s,1H),2.12(d,J=16.8Hz,1H),1.71(d,J=11.6Hz,1H),1.46(s,9H).

[0273] Step 3. Synthesis 1-4

[0274]

[0275] 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.

[0276] Step 4. Synthesis of 1-5

[0277]

[0278] 1-4 (263.0 g, 583.1 mmol) was added to NH 3 / MeOH (7M, 2.0 L) was added with NaBH 4 (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 light yellow oil.

[0279] Step 5. Synthesis of 1-6

[0280]

[0281] With stirring at 0 °C in N 2 Downward NaBH 4 To a solution of 1-4-(1-hydroxy-2-nitropropene) (1.1 g, 28.8 mmol) in DMF (1.0 L) was added NaH (20.7 g, 864.6 mmol). 1-5 (200.0 g, 576.4 mmol) was added dropwise at 0°C, followed by stirring at 0°C for 1 hour. Subsequently, chloromethyl isopropyl carbonate (100.7 g, 662.8 mmol) was added at 0°C, and the resulting mixture was stirred at room temperature for 1 hour. 2 O (1.0 L) was added to the mixture, followed by extraction with EtOAc (1.0 L*3). The organic layer was washed with brine and 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo 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.

[0282] 1 H 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, 1H), 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).

[0283] Step 6. Synthesis of 1-7

[0284]

[0285] To a solution of 1-6 (129.0 g, 278.6 mmol) in THF (1.1 L) was added Et3 N.3HF (135.0 g, 835.9 mmol) was stirred at 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 light yellow oil.

[0286] Step 7. Synthesis 1-8

[0287]

[0288] 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 saturated Na 2 S 2 O 3 / saturated NaHCO 3 (600mL / 600mL) mixed solution, then extracted with EtOAc (400mL*2). 3 The combined organic layers were washed with Na 2 SO 4 Dried 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.

[0289] Step 8. Synthesis of 1-9 and 1-10

[0290]

[0291] at -60 °C in N 2 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) and stirred at -60 °C for 30 minutes. 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 hour. The reaction mixture was then added to saturated NH 4 Cl (300 mL), then extracted with EtOAc (150 mL * 2). The combined organic layer was washed with brine and purified by Na 2 SO 4Dried 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.

[0292] 1-9: 1 H 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).

[0293] 1-10: 1 HNMR (400 MHz, CHLOROFORM-d) δ5.74 (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).

[0294] Step 9. Synthesis of 1-11

[0295]

[0296] To a solution of 1-9 (3.0 g, 6.7 mmol) in DCM (20 mL) was added TFA (10 mL) at 0 °C, and the reaction was then stirred at 0 °C for 30 min. Upon completion, the reaction mixture was added to saturated NaHCO 3 The organic layer was added to the solution (100 mL) and then extracted with DCM (100 mL). 2 SO 4 Dried 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

[0297] Step 10. Synthesis of 1-13

[0298]

[0299] 1-11 (3.0 g, crude material) was added to CH 3 To a solution of 1-12 (2.6 g, 6.7 mmol) and KHCO 3 (1.35 g, 13.5 mmol). The resulting mixture was stirred at 40°C for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure and purified by reverse phase column chromatography (C18, CH 3 CN / H 2 The residue was purified by 4% paraformaldehyde (0=80 / 20) to give 1-13 (1.8 g, 51% yield) as a white solid. LC-MS [M+1] + =528.2.

[0300] Steps 11 and 12. Synthesis of 1a-1 and 1a-2

[0301]

[0302] A solution of 1-13 (1.8 g, 3.4 mmol) in TFA (10 mL) was stirred at room temperature for 30 min. Upon completion, the reaction mixture was added to saturated NaHCO 3 The solution was added (100 mL), and then extracted with EtOAc (100 mL*3). The combined organic layers were washed with saturated NaHCO 3 Washing, Na 2 SO 4 The filtrate was concentrated under reduced pressure and purified by reverse phase column chromatography (C18, CH 3 CN / H 2 The residue was purified by HPLC-MS / MS (500 ng / mL, 4% yield). 1a was purified by chiral column chromatography to give 1a-1 and 1a-2.

[0303] 1a:

[0304] LC-MS[M+1] + =472.1

[0305] 11H 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).

[0306] 1a - 1:

[0307] 1 1H NMR (400 MHz, CDCl 3 ) 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).

[0308] 1a - 2:

[0309] 1 1H NMR (400 MHz, CDCl 3 ) 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).

[0310] Step 13. Synthesis of 1 - 14

[0311]

[0312] 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 hour. After completion, the reaction mixture was added to saturated NaHCO 3 The solution was added (100 mL) and then extracted with DCM (100 mL*3). The combined organic layers were purified by Na 2 SO 4 Dried 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

[0313] Step 14. Synthesis of 1-15

[0314]

[0315] 1-14 (2.0 g, crude material) was reacted with CH 3 To a solution of 1-12 (1.5 g, 4.0 mmol) and KHCO 3 (800 mg, 8.0 mmol). The resulting mixture was stirred at 40°C for 2 hours and then concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18, CH 3 CN / H 2 The residue was purified by HPLC-MS / MS[M+1] (500 mg, 24% yield) to give 1-15 as a white solid. + =528.2

[0316] Steps 15 and 16. Synthesis of 1b-1 and 1b-2

[0317]

[0318] 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 saturated NaHCO 3 The solution was added (30 mL) and then extracted with EtOAc (30 mL*3). The combined organic layers were washed with saturated NaHCO 3 Washing, Na 2 SO 4 The filtrate was concentrated under reduced pressure and purified by reverse phase column chromatography (C18, CH 3 CN / H 2O=80 / 20), and then by prep-HPLC (mobile phase: A(H 2 O) / B (MeCN); ratio range: A / B (80% / 20%) to A / B (55% / 45%) (10 minutes) and to A / B (20% / 80%) (35 minutes); Rt of peak: (67% of B); V = 80 ml / min, wavelength 214 nm), and prep-TLC (DCM / MeOH = 10 / 1) to purify the residue to give 1b (50 mg, 11% yield). 1b was purified by chiral column chromatography to give 1b-1 and 1b-2.

[0319] 1b:

[0320] LC-MS[M+1] + =472.1

[0321] 1 H NMR (400 MHz, CDCl 3 )δ7.58(d,J=5.6Hz,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=12.0,6.3Hz,1H),5.19-5.11(m,1H),4.92-4.83(m,1H),4.80(s,1H),3.70(d,J=4.6Hz,3 H),3.52(dd,J=34.3,12.2Hz,1H),3.19(d,J=12.9Hz,0.5H),2.98(d,J=12.5Hz,0.5H),2.90-2. 84(m,0.5H),2.78-2.61(m,1.5H),2.31-2.16(m,1H),1.97-1.82(m,1H),1.28(d,J=5.4Hz,6H).

[0322] 1b-1:

[0323] 1 H NMR (400 MHz, CDCl 3)δ7.60-7.57(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=12.1Hz,1H),5.14(d,J=12.0Hz,1H),4.91-4.81(m,1H),4.79(s,1H),3.69(s ,3H),3.47(d,J=12.4Hz,1H),2.97(d,J=12.5Hz,1H),2.86(d,J=10.6Hz,1H),2.72(dd, J=22.5,10.6Hz,1H),2.29-2.20(m,1H),1.92(d,J=14.3Hz,1H),1.27(d,J=6.2Hz,6H).

[0324] 1b-2:

[0325] 1 H NMR (400 MHz, CDCl 3 )δ7.62-7.56(m,1H),7.41-7.38(m,1H),7.30-7.26(m,2H),5.77(s,1H),5.43(s ,1H), δ5.27(d,J=12.1Hz,1H),5.17(d,J=12.0Hz,1H),4.91-4.86(m,1H),4.80(s ,1H),3.71(s,3H),3.56(d,J=12.4Hz,1H),3.17(d,J=12.4Hz,1H),2.66(d,J=8. 0Hz, 2H), 2.20-2.17 (m, 1H), 1.87 (d, J = 14.4Hz, 1H), 1.29 (dd, J = 6.2, 2.5Hz, 6H).

[0326] Example 2

[0327]

[0328] Step 1. Synthesis of 2-2 and 2-3

[0329]

[0330] at -60 °C in N 2To 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) and stirred at -60 °C for 1 hour. 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 hours. The reaction mixture was then added to saturated NH 4 Cl (1000 mL). The resulting mixture was extracted with EtOAc (500 mL*2). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo 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.

[0331] 2-2: 1 H NMR (400 MHz, CDCl 3 )δ5.76(s,1H),5.50(d,J=15.8Hz,1H),5.23(d,J=12.1Hz,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=23.1,11.5Hz,1H),1.42(s,9H),1.31-1.24(m,9H).

[0332] 2-3: 1 H NMR (400 MHz, CDCl 3 )δ5.83(s,1H),5.48(s,1H),5.28(d,J=12.1Hz,1H),5.16(d,J=12.1Hz,1H),4.94-4.82(m,1H),4.32-4.09(m,3H),4.0 3-3.85(m,2H),3.23-3.05(m,1H),2.08-1.98(m,1H),1.89(dd,J=14.2,1.9Hz,1H),1.44(s,10H),1.31-1.23(m,10H).

[0333] Step 2. Synthesis of 2-4

[0334]

[0335] 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 saturated NaHCO 3 solution (200 mL). The resulting mixture was then extracted with DCM (200 mL). 2 SO 4 The organic layer was dried 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.

[0336] LC-MS[M+1-100] + =318.1

[0337] Step 3. Synthesis of 2a

[0338]

[0339] 2-4 (3.0 g, crude material) was added to CH 3 To a solution in CN (15 mL) were added 1-12 (2.8 g, 7.2 mmol) and KHCO 3 (1.4 g, 14.4 mmol). The resulting mixture was stirred at 40°C for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure and purified by reverse phase column chromatography (C18, CH 3 CN / H 2 The residue was purified by HPLC-MS / MS (50% yield).

[0340] LC-MS[M+1] + =500.1

[0341] 1 H NMR (400 MHz, CDCl 3 )δ7.66-7.52(m,1H),7.43-7.32(m,1H),7.25(s,2H),5.80(s,1H),5.22(d,J=12.2Hz ,1H),4.97-4.79(m,3H),4.49(dd,J=63.7,12.8Hz,1H),4.18-3.99(m,2H),3.78(s,1 H),3.71(d,J=7.6Hz,3H),3.47(dd,J=38.1,13.2Hz,1H),2.72(dd,J=45.3,17.4Hz,2 H), 2.32 (s, 1H), 1.87 (d, J = 13.7Hz, 1H), 1.30 (d, J = 6.1Hz, 6H), 1.24 (t, J = 7.2Hz, 3H).

[0342] Step 4. Synthesis of 2-5

[0343]

[0344] 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 saturated NaHCO 3 The resulting mixture was then extracted with DCM (20 mL). The organic layer was washed with Na 2 SO 4 Dried 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.

[0345] LC-MS[M+1-100] + =318.1

[0346] Step 5. Synthesis of 2b

[0347]

[0348] 2-5 (120.0 mg, crude material) was added to CH 3 To a solution in CN (3 mL) were added 1-12 (88 mg, 0.23 mmol) and KHCO 3 (92 mg, 0.92 mmol). The resulting mixture was stirred at 40°C for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure and purified by reverse phase column chromatography (C18, CH 3 CN / H 2 The residue was purified by HPLC-MS / MS (50% SDS-PAGE, 5% HPLC-MS / MS ...

[0349] LC-MS[M+1] + =500.1.

[0350] 1 H NMR (400 MHz, CDCl 3)δ7.59(d,J=5.1Hz,1H),7.38(d,J=6.4Hz,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=11.9,5.4Hz,1H),5.15(dd,J=11.9,4.6Hz,1H),4.93-4.81(m,1H),4.77(s,1H),4.23-4.06(m,2H),3. 69(d,J=3.9Hz,3H),3.51(d,J=11.9Hz,0.5H),3.42(d,J=12.1Hz,0.5H),3.14(d,J=12.3Hz,0.5H),2.97-2.80(m ,1H),2.77-2.67(m,0.5H),2.63(d,J=7.5Hz,1H),2.31-2.10(m,1H),1.88(dd,J=21.5,15.1Hz,1H),1.26(s,9H).

[0351] Example 3

[0352]

[0353] Step 1. Synthesis of 3-3

[0354]

[0355] 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 hours. Thereafter, 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 K were added to the above solution. 2 CO 3 (88.32 g, 0.64 mol). After addition, the mixture was stirred at 16 ° C for 2 hours. The reactant 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.

[0356] 1H 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).

[0357] Step 2. Synthesis 3-4

[0358]

[0359] 3-3 (79.0 g, 0.18 mol) and Et 3 A solution of N.3HF (90.4 g, 0.54 mol) in THF (800 mL) was refluxed for 16 hours. 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.

[0360] Step 3. Synthesis 3-5

[0361]

[0362] 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 addition, the mixture was stirred at 20°C for 30 min. 2 SO 3 Aqueous solution (500 mL), saturated NaHCO 3 The resulting mixture was washed with aqueous solution (500 mL*2) and brine. The organic layer was separated and purified by Na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo 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.

[0363] Step 4. Synthesis of 3-7-Z and 3-7-E

[0364]

[0365] at -60 °C in N 2To a solution of 3-6 (37.9 g, 0.15 mol) in anhydrous THF (500 mL) was added LiHMDS (151 mL, 0.15 mol) at ambient temperature. The resulting mixture was stirred at -60 ° C for 30 minutes, 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 hour. The resulting mixture was then added to saturated NH 4 Cl (100 mL, aqueous solution), and the resulting mixture was extracted with EtOAc (500 mL*2). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry and filter. The filtrate was concentrated in vacuo 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).

[0366] 3-7-Z

[0367] 1 H 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).

[0368] 3-7-E

[0369] 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).

[0370] Step 5. Synthesis of 3-8

[0371]

[0372] 3-7-Z (5.5 g, 13.2 mmol) and TsOH.H.sub.2 were stirred at 20 °C. 2O (5.0 g, 26.4 mmol) in DCM (60 mL) for 16 h. 3 The reaction mixture was diluted with aqueous solution (100 mL) and extracted with DCM (50 mL*2). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo 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

[0373] Step 6: Synthesis 3-10

[0374]

[0375] 3-8 (3.0 g, 9.4 mmol) was added to CH 3 To a solution in CN (10 mL) were added 3-9 (3.6 g, 9.4 mmol) and KHCO 3 (2.8 g, 28.2 mmol). The resulting mixture was stirred at 40°C for 4 hours. After completion, the reaction mixture was concentrated under reduced pressure and purified by reverse phase column chromatography (C18, CH 3 CN / H 2 The residue was purified by HPLC-MS / MS[M+1] (M+1): 404-406 (E) (R) to afford 3-10 (2.5 g, 53% yield) as a yellow oil. + =500.2

[0376] Steps 7 and 8. Synthesis of 3b-1 and 3b-2

[0377]

[0378] 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 hour. After completion, the reaction was added to saturated NaHCO 3 The solution was added into aqueous solution (50 mL) and extracted with DCM (50 mL*3). The combined organic layer was washed with brine and purified by Na 2 SO 4 Dried and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by Prep-TLC (DCM / MeOH=10 / 1) to give 3 (800 mg, 36% yield). 3 was purified by chiral column chromatography to give 3b-1 and 3b-2. 3:

[0380] LC-MS[M+1] + =444.1.

[0381] 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).

[0382] 3b-1:

[0383] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.61 (d, J = 7.5 Hz, 2H), 7.56 - 7.41 (m, 2H), 6.10 (s, 1H), 5.71 (s, 1H), 5.52 (s, 1H), 5.27 (q, J = 12.2 Hz, 2H), 3.98 (s, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 3.71 - 3.56 (m, 1H), 3.35 - 3.14 (m, 1H), 3.01 - 2.71 (m, 1H), 2.06 (d, J = 15.0 Hz, 1H).

[0384] 3b-2:

[0385] 1 1H NMR (400 MHz, CDCl 3)δ7.64(s,1H),7.56(d,J=7.6Hz,1H),7.45(s,2H),6.06(s,1H),5.50(s,1H),5.44(s,1H),5.33(d,J=12.0Hz,1H),5.22(d,J=11.9Hz,1H),4 .02-3.97(m,1H),3.86(d,J=10.8Hz,1H),3.81(s,6H),3.49(d,J=13.6Hz,1H),3.12-3.07(m,1H),2.71-2.66(m,1H),2.03(d,J=14.8Hz,1H).

[0386] Example 4

[0387]

[0388] Step 1. Synthesis of 4-2

[0389]

[0390] 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 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMF (1 L). 1-5 (150.0 g, 0.43 mol) and K were added to the above solution. 2 CO 3 (120 g, 0.864 mol). After addition, the resulting mixture was stirred at 20 ° C for 2 hours. The reactant 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.

[0391] Step 2. Synthesis of 4-3

[0392]

[0393] 4-2 (250 g, 0.43 mol) and Et 3 A solution of N.3HF (210 g, 1.296 mol) in THF (1 L) was continued for 16 hours. The resulting mixture was concentrated under reduced pressure and the residue was diluted with EA (1.5 L). The resulting solution was washed with brine (500 ml*2) and the organic layer was separated and washed with Na 2 SO 4The mixture was dried 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.

[0394] 1 H NMR (400MHz, CDCl3) δ4.19(d,J=12.1Hz,1H),3.98(s,1H),3.72(s,1H),3.52(d,J=15.2Hz,2H),2.90-2.78(m,1 H),2.77-2.67(m,1H),2.66-2.56(m,1H),2.11(s,3H),2.02(d,J=12.0Hz,1H),1.63-1.49(m,1H),1.45(s,9H).

[0395] Step 3. Synthesis of 4-4

[0396]

[0397] 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 mixture was treated with saturated Na 2 S 2 O 3 Solution (1L), saturated NaHCO 3 solution (1L*2), the reaction mixture was washed with brine, and then 2 SO 4 Dry and concentrate in vacuo. 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.

[0398] 1 H NMR (400 MHz, CDCl 3 )δ4.29(d,J=17.9Hz,1H),4.16(d,J=18.4Hz,1H),3.82(s,1H),3.48(d,J=15.6Hz,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).

[0399] Step 4. Synthesis of 4-6-Z and 4-6-E

[0400]

[0401] at -60 °C N 2 To a solution of 4-5 (77 g, 0.302 mol) in anhydrous THF (800 mL) was added LiHMDS (303 mL, 0.303 mol) at -60 °C. The reaction mixture was stirred for 30 minutes at -60 °C, 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 hour. The reaction mixture was then added to saturated NH 4 Cl solution (800 mL) and extracted with EtOAc (700 mL*2). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo 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 light orange oil and 4-6-E (15 g, 11% yield) as an off-white solid. LC-MS [M+1] + +23=464.2.

[0402] 4-6-Z

[0403] 1 H NMR (400 MHz, CDCl 3 )δ5.74(s,1H),4.27(s,1H),4.07-3.83(s,2H),3.68(d,J=15.1Hz,1H),3.44(d,J=15.2Hz,1H),3. 25-3.10(m,1H),2.09(s,3H),2.02(d,J=14.6Hz,1H),1.85(d,J=13.7Hz,1H),1.54-1.32(m,18H).

[0404] 4-6-E

[0405] 1 H NMR (400MHz, CDCl3) δ5.59(s,1H),5.49(d,J=15.6Hz,1H),4.00(d,J=15.7Hz,1H),3.95-3.80(m,1H),3.6 1(s,1H),3.40-3.14(m,3H),2.21-2.11(m,1H),2.08(s,3H),1.89(d,J=11.4Hz,1H),1.52-1.42(m,18H).

[0406] Step 5: Synthesis 4-7

[0407]

[0408] 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 hours. 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.

[0409] Steps 6 and 7. Synthesis of 4b-1 and 4b-2

[0410]

[0411] To a solution of 4-7 (15 g, crude material, 0.023 mol) and 4-8 (5 mL) in DCM was added Et 3 N. After the addition, the mixture was stirred at 20°C for 4 hours. 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, aqueous solution). The organic layer was separated, washed with brine, and purified by Na 2 SO 4 Dry and concentrate under reduced pressure. Pass through reverse phase column (C18, ACN / H 2 The residue was purified by HPLC-MS / MS (HPLC-MS / MS=70 / 30) to afford 4 (1.8 g, 16.7% yield). 4 was purified by chiral column chromatography to afford 4b-1 and 4b-2. 4:

[0413] LC-MS [M+1]+ = 468.1.

[0414] 1 H NMR (400 MHz, CDCl 3 )δ7.57(d,J=6.7Hz,1H),7.40(d,J=6.2Hz,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=4.5Hz,3H),3.60-3.52(m,1.5H),3.50-3. 36(m,1.5H),3.17(d,J=12.3Hz,0.5H),2.97(d,J=12.4Hz,0.5H),2.90-2.82(m,0.5H),2.8 0-2.70(m,0.5H),2.66(d,J=8.6Hz,1H),2.30-2.13(m,1H),2.06(s,3H),1.93-1.81(m,1H).

[0415] 4b-1:

[0416] 1 H NMR (400 MHz, CDCl 3 )δ7.71-7.63(m,1H),7.50-7.43(m,1H),7.38-7.32(m,2H),5.89(s,1H),5.29(d,J=4.0Hz,1H),4.94(s,1H),3.77(s,3H),3.67(dd,J=21.5, 13.7Hz, 2H), 3.48 (d, J = 15.2Hz, 1H), 3.35 (d, J = 12.4Hz, 1H), 2.79 (t, J = 13.1Hz, 2H), 2.37-2.32 (m, 1H), 2.12 (s, 3H), 1.90 (d, J = 14.3Hz, 1H).

[0417] 4b-2:

[0418] 1 H NMR (400 MHz, CDCl 3 )δ7.69-7.62(m,1H),7.52-7.44(m,1H),7.41-7.31(m,2H),5.78(s,1H), 5.28(d,J=4.3Hz,1H),4.95(s,1H),3.76(s,3H),3.62(t,J=15.4Hz,2H), 3.46(d,J=15.3Hz,1H),3.17(d,J=12.4Hz,1H),3.05-3.00(m,1H),2.87( t,J=12.4Hz,1H),2.45-2.40(m,1H),2.11(s,3H),1.95(d,J=14.3Hz,1H).

[0419] Example 5

[0420]

[0421] Step 1: Synthesis 5-3

[0422]

[0423] 5-1 (10 g, 28.8 mmol) and K in DMF (100 ml) were added at 20 °C. 2 CO 35-2 (7.6 g, 31.6 mmol) was added to a mixture of 4.8 g, 34.6 mmol) in portions. After addition, the mixture was stirred at 20°C for 2 hours. The mixture was poured into water (300 mL), extracted with EA (200 mL), and the organic layer was washed with brine and purified by Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=10 / 1) to give 5-3 (4.4 g, 33% yield) as a colorless oil.

[0424] 1 H NMR (400 MHz, CDCl 3 )δ5.21(s,2H),3.89(d,J=15.2Hz,1H),3.74(s,1H),3.49(s,1H),3.03(ddd,J=13.1,9.8,3.1Hz,1H),2.97 -2.77(m,2H),2.19-2.02(m,1H),δ1.60-1.49(m,1H),1.44(s,9H),1.20(s,9H),0.89(s,9H),0.11(s,6H).

[0425] Step 2. Synthesis of 5-4

[0426]

[0427] To a solution of 5-3 (4.4 g, 9.5 mmol) in THF (40 mL) was added Et 3 N.3HF (4.6 g, 28.6 mmol) was added and the resulting mixture was stirred at 50° C. for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=5 / 1) to give 5-4 (2.5 g, 76% yield) as a colorless oil.

[0428] Step 3. Synthesis of 5-5

[0429]

[0430] To a solution of 5-4 (2.5 g, 7.2 mmol) in DCM (25 mL) was added Dess-Martin Periodinane (3.9 g, 9.4 mmol), and the resulting mixture was stirred at 25° C. for 30 min. After completion, the reaction mixture was poured into saturated Na 2 S 2 O 3 / saturated NaHCO 3(50 mL, 1:1) mixed solution. The resulting mixture was extracted with DCM (20 mL*2). The combined organic layer was washed with brine and purified by Na 2 SO 4 The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether / EtOAc=3 / 1) to give 5-5 (2.0 g, 80% yield) as a colorless oil.

[0431] Step 4. Synthesis of 5-7

[0432]

[0433] At -60°C N 2 To a solution of 5-6 (1.2 g, 4.8 mmol) in THF (15 mL) was added LiHMDS (4.8 mL, 1 M in THF, 4.8 mmol) and stirred at -60 °C for 30 minutes. To the resulting mixture was added 5-5 (1.5 g, 4.4 mmol) at -60 °C. After addition, the reaction mixture was stirred at 0-10 °C for 1 hour. The reaction mixture was then poured into saturated NH 4 Cl (20 mL) solution, the resulting mixture was extracted with EtOAc (20 mL * 2). The combined organic layer was washed with brine and 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=20 / 1) to give 5-7 (310 mg, 16% yield) as a colorless oil.

[0434] 1 H NMR (400 MHz, CDCl 3 )δ5.75(s,1H),5.58(s,1H),5.29(d,J=12.0Hz,1H),5.18(d,J=12.0Hz,1H),4.39-4.10(m,1H),4.00(s,2H ), 3.18 (s, 1H), 2.08 (dd, J = 16.1, 9.9Hz, 1H), 1.91 (d, J = 13.8Hz, 1H), 1.49 (d, J = 12.7Hz, 18H), 1.21 (s, 9H).

[0435] Step 5. Synthesis of 5-8

[0436]

[0437] 5-7 (450 mg, 1.01 mmol) and TsOH. 2A mixture of O (289 mg, 1.5 mmol) in DCM (10 mL) was stirred at 40 °C for 2 h. After completion, the reaction mixture was poured into saturated NaHCO 3 The solution (20 mL) was added and the resulting mixture was extracted with DCM (20 mL*2). The combined organic layers were washed with Na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo to give crude 5-8 (450 mg, yield >100%) as a colorless oil.

[0438] LC-MS[M+1] + =344.3

[0439] Step 6. Synthesis of 5-10

[0440]

[0441] To 5-8 (crude material, 1.01 mmol) CH 3 CN (5 mL) solution was added with 5-9 (389 mg, 1.01 mmol) and KHCO 3 (400 mg, 4.04 mmol). The resulting mixture was stirred at 40° C. for 3 hours and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether / EtOAc=20 / 1) to give 5-10 (50 mg, 9% yield) as a light yellow oil.

[0442] LC-MS[M+1] + =526.3

[0443] 1 H NMR (400 MHz, CDCl 3 )δ7.60(d,J=6.4Hz,1H),7.39(d,J=7.7Hz,1H),7.25(d,J=11.8Hz,2H),5.68(s, 1H),5.51(d,J=3.7Hz,1H),5.26(d,J=12.1Hz,1H),5.14(d,J=12.0Hz,1H),4.77 (s,1H),3.70(s,3H),3.52(d,J=11.9Hz,1H),3.10(d,J=12.0Hz,1H),2.59(d,J= 8.5Hz,2H),2.28-2.09(m,1H),1.84(d,J=14.3Hz,1H),1.47(s,9H),1.18(s,9H).

[0444] Step 7. Synthesis 5

[0445]

[0446] To a solution of 5-10 (50 mg, 0.095 mmol) in DCM (0.5 mL) was added TFA (0.5 mL) at 0° C. After addition, the mixture was stirred at 0° C. for 3 h. The resulting mixture was poured into saturated NaHCO 3 (2 mL) mixture and extracted with DCM (2 mL * 2). The combined organic layer was washed with brine and 2 SO 4 Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM / MeOH=20 / 1) to give 5 (10 mg, 22% yield).

[0447] LC-MS[M+1] + =470.1

[0448] 1 H NMR (400 MHz, CDCl 3 )δ7.57(d,J=6.4Hz,1H),7.45-7.35(m,1H),7.32-7.13(m,2H),5.77(s,0.5H),5.64(s,0.5H),5.42(s,1H) ,5.23(dd,J=12.0,8.0Hz,1H),5.13(dd,J=12.0,6.4Hz,1H),4.80(s,1H),3.70(d,J=4.4Hz,3H),3.55(dd,J =26.1,12.2Hz,1H),3.15(d,J=12.2Hz,0.5H),2.95(d,J=12.5Hz,0.5H),2.85(d,J=10.6Hz,0.5H),2.73(t ,J=11.4Hz,0.5H),2.65(d,J=7.9Hz,1H),2.32-2.12(m,1H),1.88(t,J=15.8Hz,1H),1.16(d,J=3.3Hz,9H).

[0449] Example 6

[0450]

[0451] Step 1: Synthesize 6-3

[0452]

[0453] To 6-1 (5.00 g, 14.4 mmol) and Et2O3 in DCM (50 mL) at 20 °C was added 6-1 (5.00 g, 14.4 mmol) and Et2O3 in DCM (50 mL). 3To a mixture of N (2.3 g, 20.0 mmol) was added 6-2 (1.76 g, 18.7 mmol) in portions. After addition, the mixture was stirred at 20 °C for 0.5 h. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=20 / 1) to give 63 (3.60 g, 62% yield) as a colorless oil.

[0454] Step 2: Synthesis 6-4

[0455]

[0456] To a solution of 6-3 (3.5 g, 8.6 mmol) in THF (40 mL) was added Et 3 N.3HF (4.12 g, 25.9 mmol) was added and the resulting mixture was stirred at 50°C for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=3 / 1) to give 6-4 (2.2 g, 88% yield) as a colorless oil.

[0457] 1 H NMR (400 MHz, CDCl 3 )δ4.18(dd,J=13.3,4.3Hz,1H),3.91(s,1H),3.82(s,3H),3.53(s,1H),3.33(td,J =11.0,4.3Hz,1H),2.91(s,1H),2.87-2.59(m,2H),2.19-2.03(m,1H),1.45(s,9H).

[0458] Step 3. Synthesis of 6-5

[0459]

[0460] To a solution of 6-4 (2.2 g, 7.56 mmol) in DCM (20 mL) was added Dess-Martin Periodinane (4.1 g, 9.82 mmol), and the resulting mixture was stirred at 25° C. for 10 min. After completion, the reaction mixture was poured into saturated Na 2 S 2 O 3 / saturated NaHCO 3 (40 mL, 1:1) mixed solution. The resulting mixture was extracted with DCM (20 mL*2). The combined organic layer was washed with brine and purified by Na 2 SO 4Dried and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / EtOAc=5 / 1) to give 6-5 (1.9 g, 87% yield) as a colorless oil.

[0461] Step 4. Synthesis of 6-7

[0462]

[0463] At -60°C N 2 To a solution of 6-6 (1.0 g, 3.80 mmol) in THF (10 mL) was added LiHMDS (3.8 mL, 1 M in THF, 3.8 mmol) and stirred at -60 °C for 30 minutes. To the resulting mixture was added 6-5 (1.0 g, 3.46 mmol) at -60 °C. After addition, the reaction mixture was stirred at 0-10 °C for 1 hour. The reaction mixture was then poured into saturated NH 4 Cl (20 mL) solution, the resulting mixture was extracted with EtOAc (20 mL * 2). The combined organic layer was washed with brine and 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo. The reaction was repeated 5 times, the residues were combined and purified by silica gel chromatography (petroleum ether / EtOAc=20 / 1) to give 6-7 (50 mg, 3.7% yield) as a white solid.

[0464] 1 H NMR (400 MHz, CDCl 3 )δ5.74(s,2H),4.36(s,1H),3.98(s,1H),3.92-3.78(s,3H),3.77-3.48(m,1H),3.21(s,1H),2.24-1.88(m,2H),1.59-1.38(m,18H).

[0465] Step 5. Synthesis of 6-8

[0466]

[0467] 6-7 (30 mg, 0.0775 mmol) and TsOH. 2 A mixture of O (22 mg, 0.116 mmol) in DCM (1 mL) was stirred at 40 °C for 2 h. After completion, the reaction mixture was poured into saturated NaHCO 3 The solution (5 mL) was added and the resulting mixture was extracted with DCM (2 mL*2). The combined organic layers were washed with Na 2 SO 4Dried and filtered. The filtrate was concentrated in vacuo to give crude 6-8 as a light yellow oil (crude material, yield > 100%).

[0468] LC-MS[M+1] + =288.2

[0469] Step 6. Synthesis of 6-10

[0470]

[0471] To 6-8 (crude material, 0.0775 mmol) CH 3 CN (1 mL) solution was added with 6-9 (30 mg, 0.0775 mmol) and KHCO 3 (31 mg, 0.31 mmol). The resulting mixture was stirred at 40° C. for 3 hours and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by Prep-TLC (petroleum ether / EtOAc=10 / 1) to give 6-10 (10 mg, 28% yield) as a colorless oil.

[0472] LC-MS[M+1] + =470.2

[0473] 1 H NMR (400 MHz, CDCl 3 )δ7.58(dd,J=8.0,5.3Hz,1H),7.39(d,J=8.2Hz,1H),7.27(d,J=4.9Hz,2H) ,5.71(s,1H),5.61(d,J=54.0Hz,1H),4.76(s,1H),3.80(s,3H),3.70(s,3H ),3.18(q,J=12.6Hz,1H),3.11-2.86(m,2H),2.78-2.54(m,1H),2.18(dd,J =28.3, 12.9Hz, 1H), 1.95 (dd, J = 22.6, 14.5Hz, 1H), 1.46 (t, J = 11.9Hz, 9H).

[0474] Step 7. Synthesis 6

[0475]

[0476] To a solution of 6-10 (10 mg, 0.032 mmol) in DCM (0.5 mL) was added TFA (0.5 mL) at 0°C. After addition, the mixture was stirred at 0°C for 3 hours. The resulting mixture was poured into saturated NaHCO 3 (3 mL) mixture and extracted with DCM (2 mL*2). The combined organic layers were washed with brine and purified by Na2 SO 4 Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH=20 / 1) to give 6 (5 mg, 38% yield).

[0477] LC-MS[M+1] + =414.1

[0478] 1 H NMR (400 MHz, CDCl 3 )δ7.56(s,1H),7.40(s,1H),7.27(s,2H),5.70(d,J=31.6Hz,2H),4.79(s,1H),3.79(s,3H),3.71(s,3H),3.25(s,1 H), 3.12 (dd, J = 48.2, 12.7Hz, 1H), 2.91 (s, 0.5H), 2.84-2.56 (m, 1.5H), 2.23 (s, 1H), 1.97 (dd, J = 34.1, 17.2Hz, 1H).

[0479] Example 7

[0480]

[0481] Step 1. Synthesis of 7-2

[0482]

[0483] To a solution of 7-1 (2 g, 5.97 mmol) in DCM (20 mL) was added Dess-Martin Periodinane (3.03 g, 7.16 mol), and the resulting mixture was stirred at 25° C. for 1 hour. After completion, the reaction mixture was poured into saturated Na 2 S 2 O 3 / saturated NaHCO 3 (40 mL, 1:1) mixed solution. The resulting mixture was extracted with DCM (20 mL*2). The combined organic layer was washed with brine and purified by Na 2 SO 4 The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / EtOAc=5 / 1) to give 7-2 (1.3 g, 65% yield) as a light yellow oil.

[0484] 1 H NMR (400MHz, cdcl 3)δ7.95(d,J=7.3Hz,2H),7.59(t,J=7.4Hz,1H),7.45(t,J=7.7Hz,2H),4.49-4.29(m,2H),4. 05(d,J=17.6Hz,2H),3.48(s,1H),2.58-2.33(m,1H),2.25-2.11(m,1H),1.57-1.44(s,9H).

[0485] Step 2. Synthesis of 7-4

[0486]

[0487] At -60°C N 2 To a solution of 7-3 (1.1 g, 4.3 mmol) in THF (15 mL) was added LiHMDS (4.3 mL, 1 M in THF, 4.3 mmol), and the resulting mixture was stirred at -60 °C for 30 minutes. 7-2 (1.3 g, 3.9 mmol) was added dropwise to the above mixture at -60 °C. After addition, the reaction mixture was stirred at 0-10 °C for 1 hour. The reaction mixture was then poured into saturated NH 4 Cl (30 mL) solution, the resulting mixture was extracted with EtOAc (20 mL * 2). The combined organic layer was washed with brine and 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=20 / 1) to give 7-4 (65 mg, 3.8% yield) as a white solid.

[0488] 1 H NMR (400 MHz, CDCl 3 )δ7.98(d,J=7.4Hz,2H),7.59(d,J=6.6Hz,1H),7.47(t,J=7.1Hz,2H),5.99(s,1H),5.79(s,1H),4.55-4.35(m,1H) ,4.20-3.91(m,1H),3.83-3.64(m,1H),3.35-3.12(m,1H),2.17(s,1H),2.03(d,J=14.0Hz,1H),1.62-1.36(m,18H).

[0489] Step 3. Synthesis of 7-5

[0490]

[0491] 7-4 (60 mg, 0.138 mmol) and TsOH. 2A mixture of O (39 mg, 0.207 mmol) in DCM (2 mL) was stirred at 40 °C for 2 h. After completion, the reaction mixture was poured into saturated NaHCO 3 The solution (4 mL) was added and the resulting mixture was extracted with DCM (2 mL*2). The combined organic layers were washed with Na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo to give crude 7-5 (50 mg, yield > 100%) as a light yellow oil.

[0492] Step 4. Synthesis of 7-7

[0493]

[0494] To 7-5 (crude material, 0.138 mmol) CH 3 CN (2 mL) solution was added with 7-6 (53 mg, 0.138 mmol) and KHCO 3 (55 mg, 0.552 mmol). The resulting mixture was stirred at 40 °C for 3 hours. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / EtOAc=10 / 1) to give 7-7 (20 mg, 28% yield) as a white solid.

[0495] LC-MS[M+1] + =516.3

[0496] Step 5. Synthesis of 7

[0497]

[0498] To a solution of 7-7 (20 mg, 0.039 mmol) in DCM (1 mL) was added TFA (1 mL) at 0° C. After addition, the mixture was stirred at 0° C. for 3 h. The resulting mixture was poured into saturated NaHCO 3 (4 mL) mixture and extracted with DCM (2 mL*2). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH=20 / 1) to give 7 (10 mg, 45% yield).

[0499] LC-MS[M+1] + =460.1

[0500] 1 H NMR (400 MHz, CDCl 3)δ7.89(d,J=8.2Hz,2H),7.58(dd,J=7.3,2.1Hz,1H),7.51(dd,J=8.9,5.9Hz,1H),7.42-7.35( m,3H),7.29-7.25(m,2H),6.01(s,1H),5.75(s,0.5H),5.64(s,0.5H),4.77(d,J=4.5Hz,1H),3 .70(d,J=4.2Hz,3H),3.28(d,J=12.8Hz,1H),3.12(dd,J=34.1,12.4Hz,1H),2.93(d,J=12.3Hz ,1H),2.73(d,J=9.2Hz,0.5H),2.68-2.57(m,1H),2.33-2.14(m,0.5H),1.88(t,J=17.4Hz,1H).

[0501] Example 8

[0502]

[0503] Step 1: Synthesize 8-3

[0504]

[0505] To a solution of 8-1 (5.00 g, 14.4 mmol) in THF (50 ml) was added NaH (0.688 g, 17.2 mmol, 60%, dispersion in paraffin) in portions at 0°C. After addition, the mixture was stirred at 0°C for 1 hour. 8-2 (1.86 g, 17.2 mmol) was added at 0°C and stirred at 0°C for 0.5 hour. The reaction mixture was poured into saturated NH 4 Cl (100 ml) solution, extracted with EA (50 ml), the organic layer was washed with brine, 2 SO 4 Dried and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / EtOAc=10 / 1) to give 8-3 (3.9 g, 65% yield) as a colorless oil.

[0506] 1 H NMR (400 MHz, CDCl 3)δ3.88-3.66(m,1H),3.64-3.42(m,3H),3.18(d,J=33.4Hz,1H),3.15-3.02(m,1H),3.03-2.90(m,6H), 2.28-2.13(m,1H),1.99(d,J=9.4Hz,1H),1.41(d,J=14.9Hz,9H),0.91-0.77(m,9H),0.14-0.02(m,6H).

[0507] LC-MS[M+1-100] + =319.2

[0508] Step 2: Synthesize 8-4

[0509]

[0510] To a solution of 8-3 (3.9 g, 9.3 mmol) in THF (40 mL) was added Et 3 N.3HF (4.5 g, 28.0 mmol) was added and the resulting mixture was stirred at 50 °C for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=3 / 1) to give 8-4 (2.4 g, 85% yield) as a white solid.

[0511] 1 H NMR (400 MHz, CDCl 3 )δ4.29(dd,J=8.2,5.2Hz,1H),4.10(m,1H),3.50-3.31(m,2H),2.99(s,6H),2.75(s,1H),2.64(d d, J=13.2, 9.7Hz, 1H), 1.96 (ddd, J=13.2, 6.6, 2.9Hz, 1H), 1.67-1.54 (m, 1H), 1.46-1.37 (s, 9H).

[0512] LC-MS[M+1-100] + =205.1

[0513] Step 3. Synthesis of 8-5

[0514]

[0515] To a solution of 8-4 (2.4 g, 7.9 mmol) in DCM (30 mL) was added Dess-Martin Periodinane (8.3 g, 19.7 mmol), and the resulting mixture was stirred at 25° C. for 3 h. After completion, the reaction mixture was poured into saturated Na2 S 2 O 3 / saturated NaHCO 3 (40 mL, 1:1) mixed solution. The resulting mixture was extracted with DCM (20 mL*2). The combined organic layer was washed with brine and purified by Na 2 SO 4 Dried and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / EtOAc=5 / 1) to give 8-5 (1.6 g, 67% yield) as a white solid.

[0516] LC-MS[M+1-56] + =247.1

[0517] Step 4. Synthesis of 8-7

[0518]

[0519] At -60°C N 2 To a solution of 8-6 (1.5 g, 5.8 mmol) in THF (20 mL) was added LiHMDS (5.8 mL, 1 M in THF, 5.8 mmol) and stirred at -60 °C for 30 minutes. To the resulting mixture was added 8-5 (1.6 g, 5.3 mmol) dropwise at -60 °C. After addition, the reaction mixture was stirred at 0-10 °C for 1 hour. The reaction mixture was then poured into saturated NH 4 Cl (20 mL) solution, the resulting mixture was extracted with EtOAc (20 mL * 2). The combined organic layer was washed with brine and 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo. The reaction was repeated 5 times, the residues were combined and purified by silica gel chromatography (petroleum ether / EtOAc=20 / 1) to give 8-7 (100 mg, 4.7% yield) as a white solid.

[0520] LC-MS[M+Na] + =423.3

[0521] 1 H NMR (400 MHz, CDCl 3 )δ5.90(s,1H),5.18(d,J=14.0Hz,1H),4.41(s,1H),4.19(d,J=16.1Hz,1H),3.77(s,1 H), 3.33 (s, 1H), 2.98 (s, 6H), 2.13 (s, 1H), 2.01-1.80 (m, 1H), 1.44 (d, J = 10.3Hz, 18H).

[0522] Step 5. Synthesis of 8-8

[0523]

[0524] 8-7 (50 mg, 0.125 mmol) and TsOH. 2 A mixture of O (36 mg, 0.188 mmol) in DCM (1 mL) was stirred at 40 °C for 2 h. After completion, the reaction mixture was poured into saturated NaHCO 3 The solution (2 mL) was added and the resulting mixture was extracted with DCM (2 mL*2). The combined organic layers were washed with Na 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo to give crude 8-8 as a light yellow oil (crude material, yield > 100%).

[0525] LC-MS[M+1] + =301.1

[0526] Step 6. Synthesis of 8-10

[0527]

[0528] To CH 8-8 (crude material, 0.125 mmol) 3 CN (1 mL) solution was added with 8-9 (38.1 mg, 0.100 mmol) and KHCO 3 (50 mg, 0.500 mmol). The resulting mixture was stirred at 40° C. for 3 hours and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by Prep-TLC (petroleum ether / EtOAc=10 / 1) to give 8-10 (10 mg, 16% yield) as a light yellow solid.

[0529] LC-MS[M+1] + =483.2

[0530] 1 H NMR (400 MHz, CDCl 3)δ7.63-7.55(m,1H),7.40-7.32(m,1H),7.29-7.18(m,2H),5.63(s,1.5H),5.49(s ,0.5H),4.73(d,J=5.0Hz,1H),3.69(d,J=1.1Hz,3H),3.29-3.08(m,1H),3.07-2.98 (m,1H),2.93(d,J=19.1Hz,6H),2.89(d,J=11.8Hz,0.5H),2.76(td,J=12.0,2.5Hz, 0.5H),2.70-2.57(m,1H),2.29-2.04(m,1H),2.04-1.83(m,1H),1.50-1.41(m,9H).

[0531] Step 7. Synthesis 8

[0532]

[0533] To a solution of 8-10 (10 mg, 0.021 mmol) in DCM (0.5 mL) was added TFA (0.5 mL) at 0°C. After addition, the mixture was stirred at 0°C for 3 hours. The resulting mixture was poured into saturated NaHCO 3 (3 mL) solution and extracted with DCM (2 mL*2). The combined organic layer was washed with brine and purified by Na 2 SO 4 Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH=20 / 1) to give 8 (4 mg, 45% yield).

[0534] LC-MS[M+1] + =427.1

[0535] 1 H NMR (400 MHz, CDCl 3)δ7.64-7.52(m,1H),7.41-7.35(m,1H),7.32-7.18(m,2H),5.71(d,J=39.7Hz,1H) ,5.42-5.31(m,1H),δ4.76(d,J=2.6Hz,1H).3.69(d,J=5.0Hz,3H),3.36(d,J=12.1 Hz,0.5H),3.27(d,J=12.2Hz,0.5H),3.18(d,J=12.1Hz,0.5H),2.98(s,6H),2.89( d,J=11.7Hz,0.5H),2.79-2.62(m,2H),2.33-2.11(m,1H),1.91(t,J=15.9Hz,1H).

[0536] Example 9

[0537]

[0538] Step 1: Synthesize 9-2

[0539]

[0540] To compound 9-SM (11.0 g, 85.3 mmol) was added dimethylamine (1.76 g, 18.7 mmol) in portions at 20°C. After addition, the mixture was stirred at 20°C for 0.5 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=20 / 1) to give 9-2 (7.8 g, 69% yield) as a colorless oil.

[0541] Step 2: Synthesize 9-3

[0542]

[0543] To a solution of 9-1 (5.00 g, 14.4 mmol) in THF (50 mL) was added NaH (0.700 g, 17.3 mmol) in portions at 0°C, and after the addition, the mixture was stirred at 0°C for 1 hour. 9-2 (2.37 g, 17.3 mmol) was added at 0°C, and stirred at 0°C for 0.5 hours. The mixture was poured into saturated NH 4 Cl (100 mL) solution, extracted with EA (50 mL), the organic layer was washed with brine, 2 SO 4 Dried and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / EtOAc=10 / 1) to give 9-3 (4.8 g, 65% yield) as a colorless oil.

[0544] 1H NMR (400 MHz, CDCl 3 )δ5.25(s,2H),3.90(d,J=3.6Hz,1H),3.75(s,1H),3.48(s,1H),3.09-2.94(m,2H),2.94-2 .79(m,8H),2.19-2.06(m,1H),1.43(d,J=2.0Hz,9H),0.97-0.73(m,9H),0.14-0.02(m,6H).

[0545] Step 3: Synthesize 9-4

[0546]

[0547] To a solution of 9-3 (4.7 g, 10.5 mmol) in THF (50 mL) was added Et 3 N.3HF (5.0 g, 31.5 mmol) was added and the resulting mixture was stirred at 50° C. for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=3 / 1) to give 9-4 (3.2 g, 91% yield) as a colorless oil.

[0548] 1 H NMR (400 MHz, CDCl 3 )δ5.34(d,J=12.1Hz,1H),5.18(d,J=12.1Hz,1H),4.25(d,J=10.8Hz,1H),4.10-3.70(m,1H),3.42(s,1H),3.10(s, 1H), 2.90 (d, J = 7.7Hz, 6H), 2.86-2.68 (m, 2H), 2.66 (dd, J = 13.1, 9.7Hz, 1H), 2.08-1.92 (m, 1H), 1.47-1.35 (m, 9H).

[0549] Step 4. Synthesis of 9-5

[0550]

[0551] To a solution of 9-4 (3.0 g, 8.98 mmol) in DCM (30 mL) was added Dess-Martin Periodinane (5.7 g, 13.47 mmol), and the resulting mixture was stirred at 25° C. for 10 min. After completion, the reaction mixture was poured into saturated Na 2 S 2 O 3 / saturated NaHCO 3(100 mL, 1:1) mixed solution. The resulting mixture was extracted with DCM (50 mL*2). The combined organic layer was washed with brine and purified by Na 2 SO 4 Dried and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / EtOAc=5 / 1) to give 9-5 (2.2 g, 74% yield) as a light orange oil.

[0552] 1 H NMR (400 MHz, CDCl 3 )δ5.22(d,J=12.1Hz,1H),5.12(d,J=12.1Hz,1H),4.24(d,J=17.5Hz,1H),δ4.16-4.06(m,1H),3.72(t,J=5.3Hz,2H),3 .48(ddd,J=13.7,9.5,4.1Hz,1H),2.90(d,J=10.3Hz,6H),2.34(dd,J=9.5,5.0Hz,1H),2.15-1.96(m,1H),1.44(s,9H).

[0553] Step 5. Synthesis of 9-7

[0554]

[0555] At -60°C N 2 To a solution of 9-6 (1.7 g, 6.6 mmol) in THF (20 mL) was added LiHMDS (6.6 mL, 1 M in THF, 6.6 mmol) and stirred at -60 °C for 30 minutes. 9-5 (2.0 g, 6.0 mmol) was added dropwise to the resulting mixture at -60 °C. After addition, the reaction mixture was stirred at 0-10 °C for 1 hour. The reaction mixture was then poured into saturated NH 4 Cl (50 mL) solution, the resulting mixture was extracted with EtOAc (30 mL * 2). The combined organic layer was washed with brine and 2 SO 4 Dried and filtered. The filtrate was concentrated in vacuo. The reaction was repeated 5 times, the residues were combined and purified by silica gel chromatography (petroleum ether / EtOAc=20 / 1) to give 9-7 (1.0 g, 28.8% yield) as a yellow oil.

[0556] 1 H NMR (400 MHz, CDCl 3)δ5.72(s,1H),5.51(s,1H),5.29(s,0.5H),5.26(s,0.5H),5.07(d,J=12.0Hz,1H),4.40-4.04(m,1H),3.97(d,J=20.3Hz,2H ), 3.15 (s, 1H), 2.88 (d, J = 5.3Hz, 6H), 2.03 (dd, J = 16.7, 10.0Hz, 1H), 1.86 (d, J = 13.9Hz, 1H), 1.45 (dd, J = 12.1, 5.8Hz, 18H).

[0557] Step 6. Synthesis of 9-8

[0558]

[0559] 9-7 (800 mg, 1.8 mmol) and TsOH. 2 A mixture of O (469 mg, 2.72 mmol) in DCM (8 mL) was stirred at 40 °C for 2 h. After completion, the reaction mixture was poured into saturated NaHCO 3 The solution (30 mL) was added and the resulting mixture was extracted with DCM (10 mL*2). The combined organic layers were washed with Na 2 SO 4 Dried and filtered. The filtrate was concentrated and purified by silica gel chromatography (DCM / MeOH=20 / 1) to give 9-8 (185 mg, 31% yield) as a colorless oil.

[0560] LC-MS[M+1] + =331.2

[0561] Step 7. Synthesis of 9-10

[0562]

[0563] To CH 9-8 (185 mg, 0.56 mmol) 3 CN (2 mL) solution was added with 9-9 (194 mg, 0.50 mmol) and KHCO 3 (224 mg, 2.24 mmol). The resulting mixture was stirred at 40° C. for 3 hours and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by Prep-TCL (petroleum ether / EtOAc=10 / 1) to give 9-10 (200 mg, 69.8% yield) as a colorless oil.

[0564] LC-MS[M+1] + =513.2

[0565] 1H NMR (CDCl 3 (400MHz,)δ7.61-7.57(m,1H),7.37(m,1H),7.28-7.22(m,2H),5.68(s,0.5H),5.51(s,0.5H),5.48(t,J=4 .4Hz,1H),5.28-5.21(m,1H),5.06(dd,J=12.0,7.8Hz,1H),4.75(s,1H),3.68(d,J=3.8Hz,3H),3.53-3.47( m,0.5H),3.40(d,J=11.4Hz,0.5H),3.08(d,J=12.1Hz,0.5H),2.92-2.79(m,6.5H),2.71(dt,J=11.9,6.0Hz ,1H),2.59(dd,J=10.2,2.5Hz,1H),2.29-2.11(m,1H),1.89(dd,J=14.3,2.2Hz,1H),1.43(d,J=6.6Hz,9H).

[0566] Step 8. Synthesis 9

[0567]

[0568] To a solution of 9-10 (200 mg, 0.39 mmol) in DCM (3 mL) was added TFA (3 mL) at 0° C. After addition, the mixture was stirred at 0° C. for 3 h. The resulting mixture was poured into saturated NaHCO 3 (15 mL) mixture and extracted with DCM (5 mL*2). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dried and filtered. The filtrate was concentrated under reduced pressure to give 9 (50 mg, 28% yield) as a white solid.

[0569] LC-MS[M+1] + =457.2

[0570] 1 H NMR (CDCl 3(400MHz,)δ7.61-7.54(m,1H),7.42-7.36(m,1H),7.30-7.22(m,2H),5.75(s,0.5H),5.62(s,0.5H),5 .40(s,1H),5.29-5.20(m,1H),5.09(dd,J=12.1,7.2Hz,1H),4.79(d,J=2.7Hz,1H),3.69(dd,J=4.7,2 .6Hz,3H),3.57(d,J=11.8Hz,0.5H),3.49(d,J=12.1Hz,0.5H),3.15(d,J=12.4Hz,0.5H),2.93(d,J=1 2.4Hz,0.5H),2.90-2.80(m,6H),2.72(m,1H),2.64(d,J=7.1Hz,1H),2.19(m,1H),1.96-1.82(m,1H). Example 10

[0571] Biochemical analysis

[0572] Analysis 1: Pharmacokinetics in rats

[0573] Male Sprague-Dawley rats were used for pharmacokinetic experiments.

[0574] Test compounds (clopidogrel and exemplary compounds provided herein) were administered orally or intravenously to fasted rats. The rats were treated with EDTA-K via the jugular vein at 5, 15, 30, 60 and 120 minutes. 2 Blood samples were collected by centrifugation at 1500 g for 10 minutes at 2-8 ° C and stored at -80 ° C after separation. After extraction, the plasma samples were loaded into the LC-MS / MS instrument to determine the concentration of thiol-active metabolites. Figure 1 and 2 The concentration results in rat plasma are shown in .

[0575] like Figure 1 As shown, at a dose level of 10 mg / kg, compared to clopidogrel, which reaches a peak concentration of thiol-active metabolites at about 30 minutes after administration, compounds 1a, 1b and 2a provided herein reach peak concentrations in less than 20 minutes after administration. In addition, the peak concentrations of thiol-active metabolites of compounds 1a, 1b and 2a are significantly higher than those of clopidogrel. These results indicate that compounds 1a, 1b and 2a provide faster and more effective release of active metabolites compared to clopidogrel.

[0576] like Figure 2 As shown, when administered orally, the compound 3 provided herein with a dose level of 2 mg / kg reaches a peak concentration at about 20 minutes after administration, compared to clopidogrel with a much 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, the compound 3 provided herein with a dose level of only 1 mg / kg reaches a peak concentration of thiol-active metabolites at about 6 minutes after administration. These results indicate that, compared to clopidogrel, compound 3 provides faster and more effective release of active metabolites.

[0577] Other compounds provided herein show comparable, or even faster and more effective release of active metabolites compared to clopidogrel.

[0578] Analysis 2: Antiagglutination in rats

[0579] Male Sprague-Dawley rats were used for in vitro platelet aggregation experiments. After oral administration to rats (clopidogrel, exemplary compounds provided herein, and vehicle (control group)), blood was collected via the jugular vein at 0.5 hours, 1 hour, and 2 hours, using 3.8% (w / v) sodium citrate solution as an anticoagulant (1 / 9 volume of whole blood). The citrate-containing blood sample was centrifuged at a low speed of 1000 rpm for 5 minutes to obtain platelet-rich plasma (PRP). After separating PRP, the remaining blood was further centrifuged at a high speed of 3000 rpm for 10 minutes to obtain platelet-free plasma (PPP). The number of platelets in PRP was measured by a hematology analyzer (Siemens, ADVIA2120) and adjusted to 4×10 by PPP. 8 / mL.

[0580] Platelet aggregation was determined by turbidimetric agglutination using an automatic platelet agglutinometer (PRECIL LBY-NJ4). The agglutinometer was first warmed to 37°C, and the PRP (290 μL) sample was added to a cuvette and placed in the automatic platelet agglutinometer. After 5 minutes of pre-incubation, the aggregation instrument was calibrated using PPP to represent 100% agglutination and PRP to represent 0% agglutination. Finally, a 10 μL volume of ADP solution (final concentration of 10 μM) was added to the PRP sample to start platelet aggregation. Platelet aggregation was monitored for 5 minutes and the maximum platelet aggregation (%) was reported over the duration. The anti-aggregation effect of the test compound was expressed as inhibition (%) determined by the following relationship:

[0581] Inhibition (%) = (maximum platelet aggregation degree of the control group (%) - maximum platelet aggregation degree of the test compound (%)) / (maximum platelet aggregation degree of the control group (%)) * 100

[0582] The inhibition (%) results of the test compounds are shown in Figure 3 For clopidogrel, 1a, and 1b, the dose levels were 10 mg / kg, 0.5 mg / kg, and 2 mg / kg, respectively. Figure 2 It can be seen that clopidogrel reaches a maximum platelet aggregation inhibition of about 45% within about 120 minutes after administration, while compound 1b reaches a maximum inhibition of about 45% within 60 minutes after administration at a much lower dose level than clopidogrel, indicating that its onset time is much earlier than clopidogrel and its potency is much stronger than clopidogrel.

[0583] Other compounds provided herein may exhibit faster onset of action and higher potency than clopidogrel.

[0584] The above description is only regarded as an illustration of the principle of the present disclosure. In addition, since many modifications and variations will be apparent to those skilled in the art, it is not desirable to limit the present invention to the exact configuration and process as shown above. Therefore, all suitable modifications and equivalents may be regarded as falling within the scope of the present invention as defined by the appended claims.

Claims

1. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, having the following structure:

3. Use of the compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting platelet aggregation.

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