Antiplatelet drugs and uses thereof

Abstract

The present invention relates to anti-platelet agents and uses thereof. The present disclosure relates to compounds that show activity in inhibiting platelet aggregation and pharmaceutical compositions comprising these compounds, as well as methods of treating vascular diseases by administering these compounds or the pharmaceutical compositions.

Description

[0001] This application is a divisional application of the Chinese Patent Application No. 202180058245.8, filed on July 28, 2021, entitled “Anti-platelet drugs and uses thereof”, which is a national stage application of the International Application No. PCT / CN2021 / 108875, which claims priority to the International Application No. PCT / CN2020 / 105513, filed on July 29, 2020. TECHNICAL FIELD

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

[0003] Recently, the number of patients with vascular diseases has significantly increased. Anti-thrombotic 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 widely known and used anti-thrombotic drug worldwide and is a prodrug that requires bioconversion to become active. After absorption, 85% of clopidogrel is hydrolyzed to an inactive carboxylic acid by esterases. The remaining 15% of clopidogrel undergoes a two-step oxidation process via hepatic cytochrome P450 isozymes, mainly CYP2C19. The transiently active thiol metabolite specifically and irreversibly binds to the platelet P2Y12 receptor.

[0005] However, clopidogrel has many drawbacks, including patient-to-patient variability in anti-thrombotic effect and resistance to clopidogrel in some patients due to different CYP2C19 expression levels in different individuals; low conversion rate to active metabolites and thus high loading dose (600 mg); slow onset of action (2 hours after loading dose); low solubility in aqueous solution; and no injection 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 drawbacks listed above. SUMMARY

[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 of Formula (I):

[0009]

[0010] or a pharmaceutically acceptable salt thereof,

[0011] wherein

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

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

[0014] R 2 is -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 alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl;

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

[0017] W is selected from the group consisting of:

[0018]

[0019] wherein 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 alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl;

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

[0022] R b is selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, heteroaryl, -NR c R d and -OR e ;

[0023] R c and R d each of R and R 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 alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl;

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

[0026] two R f together with the atoms to which they are attached form a saturated or partially unsaturated cycloalkyl or saturated or partially unsaturated heterocyclyl, wherein each of cycloalkyl and heterocyclyl is optionally substituted with cyano, halogen, hydroxyl, 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 a compound 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 a subject in need thereof, comprising administering to the subject 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 a compound having the following formula:

[0039]

[0040] In another aspect, the present disclosure provides a compound having the following formula:

[0041] BRIEF DESCRIPTION OF DRAWINGS

[0042] Figure 1 Concentrations of active metabolites in rat plasma following oral administration at a dose level of 10 mg / kg of (a) clopidogrel, Compound la, and Compound lb, and (b) clopidogrel, Compound 2a, and Compound 2b.

[0043] Figure 2The concentrations of the active metabolite in rat plasma were shown after 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 The inhibition (%) of agglutination was shown in rats after oral administration of the test compounds at dose levels of 10 mg / kg (clopidogrel), 0.5 mg / kg (compound 1a), and 2 mg / kg (compound 1b). Detailed Implementation

[0045] Please refer to certain embodiments of this disclosure for details, examples of which are illustrated in the accompanying structures and formulas. While this disclosure is described in conjunction with the enumerated embodiments, it should be understood that it is not intended to limit this disclosure to those embodiments. Rather, this disclosure is intended to cover all alternatives, modifications, or equivalents that may be included within the scope of this disclosure as defined in the claims. Those skilled in the art will recognize that many methods or substances similar to or equivalent to those described herein can implement this disclosure. This disclosure is by no means limited to the methods or substances described herein. In the event that one or more of the incorporated references and similar materials (including, but not limited to, defined terms, usages of terms, described techniques, etc.) differ from or contradict this application, this disclosure shall prevail. All references, patents, and patent applications cited in this disclosure are incorporated herein by reference in their entirety.

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

[0047] Definitions

[0048] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional group terms are generally defined as in that reference. Additionally, general principles of organic chemistry, and specific functional groups and reactivity are described in Organic Chemistry, Thomas Sorrell, 2ndEd., University Science Books, Sausalito, 2006; Smith and March’s March’s Advanced Organic Chemistry, 6thEd., John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3rdEd., VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4thEd., Cambridge University Press, Cambridge, 2004; each of which is incorporated herein by reference in its entirety.

[0049] Throughout the present disclosure, connecting substituents are described. In particular, each connecting substituent is intended to include both the forward and reverse versions of the connecting substituent. For example, -NR(CR'R")- includes both -NR(CR'R")- and -(CR'R")NR-. Where the structure explicitly requires a connecting group, the Markush variable recited in reference to that group should be understood as a connecting group. For example, if the structure requires a connecting group and the Markush group definition recites “alkyl,” then it should be understood that the “alkyl” represents a connecting alkylene group.

[0050] When a bond to a substituent is shown to cross a bond within a ring, then the substituent can be bonded to any atom on the ring. When the recited substituent does not indicate the atom to which the substituent is bonded to the remainder of the given compound, then the substituent can be bonded via any atom in the formula. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

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

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

[0053] As used herein, the term "C i-j " indicates a range of the number of carbon atoms, wherein i and j are integers, and the range of the number of carbon atoms includes the endpoints (i.e., i and j) and every integer point in between, 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] Whether used as part of another term or independently, the term "alkyl" as used herein refers to a saturated straight-chain or branched-chain hydrocarbon group, which can be optionally substituted independently with one or more substituents described below. The term "C 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. Examples of "C 1-10 alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. "C 1-6Examples of "alkyl" groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-l-butyl, 2-methyl-l-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] The term "alkenyl," whether used alone or as part of another term, as used herein, refers to a straight or branched hydrocarbon group having at least one carbon-carbon double bond, which can be optionally substituted independently with one or more substituents described herein, and includes groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. In some embodiments, an alkenyl group contains 2 to 12 carbon atoms. In some embodiments, an alkenyl group contains 2 to 11 carbon atoms. In some embodiments, an 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, an 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-l-enyl, 5-hexenyl, and the like.

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

[0057] The term "amino," as used herein, refers to a -NH2group. An amino group can also be substituted with one or more groups such as alkyl, aryl, carbonyl, or other amino groups.

[0058] The term "aryl," as used herein, whether used alone or as part of another term, refers to monocyclic and polycyclic ring systems having from 5 to 20 ring members in total, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains from 3 to 12 ring members. Examples of "aryl" include, but are not limited to, phenyl, biphenyl, naphthyl, anthryl, and the like, which can bear one or more substituents. Groups wherein an aromatic ring is fused or attached to one or more non-aromatic rings are also included within the scope of the term "aryl." In the case of polycyclic ring systems, only one ring need be aromatic (e.g., 2,3-dihydroindole), although all rings can be aromatic (e.g., quinoline). The second ring can also be fused or bridged. Examples of polycyclic aryl groups include, but are not limited to, benzofuryl, indanyl, phthalimidyl, naphthalimidyl, indolizinyl, or tetrahydronaphthyl, and the like. The aryl group can be substituted at one or more ring positions with substituents as described above.

[0059] The term "cycloalkyl," as used herein, whether used alone or as part of another term, refers to a monovalent non-aromatic, saturated or partially unsaturated, monocyclic and polycyclic ring system, wherein all ring atoms are carbon, and the ring system contains at least three ring-forming carbon atoms. In some embodiments, the cycloalkyl group can contain from 3 to 12 ring-forming carbon atoms, from 3 to 10 ring-forming carbon atoms, from 3 to 9 ring-forming carbon atoms, from 3 to 8 ring-forming carbon atoms, from 3 to 7 ring-forming carbon atoms, from 3 to 6 ring-forming carbon atoms, from 3 to 5 ring-forming carbon atoms, from 4 to 12 ring-forming carbon atoms, from 4 to 10 ring-forming carbon atoms, from 4 to 9 ring-forming carbon atoms, from 4 to 8 ring-forming carbon atoms, from 4 to 7 ring-forming carbon atoms, from 4 to 6 ring-forming carbon atoms, from 4 to 5 ring-forming carbon atoms. The cycloalkyl group can be saturated or partially unsaturated. The cycloalkyl group can be substituted. In some embodiments, the cycloalkyl group can be a saturated cyclic alkyl group. In some embodiments, the cycloalkyl group can be a partially unsaturated cyclic alkyl group containing at least one double or triple bond in its ring system. In some embodiments, the cycloalkyl group can 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]-decenyl, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, and the like.

[0060] The term "cyano," as used herein, means -CN.

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

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

[0063] As used herein, the term "heteroalkenyl" refers to an alkenyl group in which at least one of the carbon atoms is replaced with a heteroatom selected from N, O, or S. The heteroalkenyl group can be carbon-based or heteroatom-based (i.e., the heteroatom can appear at either the 1- or 2-position of the group) and can 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 the carbon atoms is replaced with a heteroatom selected from N, O, or S. The heteroalkynyl group can be carbon-based or heteroatom-based (i.e., the heteroatom can appear at either the 1- or 2-position of the group) and can be optionally substituted independently with one or more substituents described herein.

[0065] Regardless of whether used as part of another term or independently, the term "heteroaryl" as used herein refers to an aryl group having one or more heteroatoms in addition to carbon atoms. The heteroaryl group can 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 groups also include polycyclic groups in which a heteroaromatic ring is fused with one or more aryl, cycloaliphatic, or heterocyclyl rings, where the connecting group or point of attachment is on the heteroaromatic ring. Examples of polycyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo[1,3]dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, dihydroquinolyl, dihydroisoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl, phenoxathiinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0066] As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, and the like, with the remaining ring atoms being carbon, wherein one or more ring atoms can be optionally independently substituted with one or more substituents. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, the heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system. In some embodiments, the heterocyclyl can contain any oxidized form of carbon, nitrogen or sulfur, and any quaternized form of basic nitrogen. "Heterocyclyl" also includes groups in which the heterocyclyl is fused to a saturated, partially unsaturated or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. Where possible, the heterocyclyl can be carbon-attached or nitrogen-attached. In some embodiments, the heterocycle is carbon-attached. In some embodiments, the heterocycle is nitrogen-attached. For example, a group derived from pyrrole can be a pyrrol-l-yl group (nitrogen-attached) or a pyrrol-3-yl group (carbon-attached). Further, a group derived from imidazole can be an imidazol-l-yl group (nitrogen-attached) or an imidazol-3-yl group (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 included within the scope of this definition. Examples of monocyclic heterocyclyl groups include, but are not limited to, oxetanyl, 1,1-dioxothietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, piperidinyl, morpholinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like. Examples of fused heterocyclyl groups include, but are not limited to, phenyl fused rings or pyridyl fused rings such as quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, carbazolyl, phenoxazinyl, phenothiazinyl, phenazinyl, imidazo[l,2-a]pyridinyl, [l,2,4]triazolo[4,3-a]pyridinyl, [l,2,3]triazolo[4,3-a]pyridinyl, and the like. Examples of spiro heterocyclyl groups include, but are not limited to, spirooxetanyl, spirooxazinyl, and the like. Examples of bridged heterocyclyl groups include, but are not limited to, morphanyl, hexamethylenetetraminyl, 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 that have multiple sites of unsaturation, but is not intended to include aromatic (i.e., completely unsaturated) moieties.

[0070] As used herein, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety is replaced with a suitable substituent. It should be understood that "substitution" or "substituted" includes the implicit proviso that the substitution is in accordance with permitted valence of the atom, and the substitution results in a stable or chemically feasible compound, e.g., a compound that does not spontaneously undergo rearrangement, cyclization, eliminations or other transformation, unless expressly invoked. An "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 with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. One of skill in the art will appreciate that substituents themselves can be substituted, as appropriate. Unless specifically stated otherwise, references to chemical moieties herein are understood to include both substituted and unsubstituted versions.

[0071] Compounds

[0072] The present disclosure provides novel compounds of Formula (I) and pharmaceutically acceptable salts thereof, synthetic processes 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 of Formula (I):

[0074]

[0075] or a pharmaceutically acceptable salt thereof,

[0076] wherein

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

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

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

[0080] R 3Selected from the group consisting of hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclic, aryl and heteroaryl, wherein each of the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocyclic, aryl and heteroaryl is optionally substituted by cyano, halogen, hydroxyl, amino, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl or heteroynyl;

[0081] L is selected from the group consisting of: straight-chain, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is optionally bounded by one or more R groups. f replace;

[0082] W is selected from the following group:

[0083]

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

[0085] R 4 Selected from the group consisting of hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclic, aryl and heteroaryl, wherein each of the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocyclic, aryl and heteroaryl is optionally substituted by cyano, halogen, hydroxyl, amino, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl or heteroynyl;

[0086] R a Each of these groups is independently selected from the group consisting of: hydrogen, halogen, hydroxyl, amino, cyano, nitro, or -NR. c R d ;

[0087] R b Selected from the following group: hydrogen, hydroxyl, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclic, aryl, heteroaryl, -NR c R d and -OR e ;

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

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

[0091] two R f are taken together with the atom to which they are attached to form a saturated or partially unsaturated cycloalkyl or saturated or partially unsaturated heterocyclyl, wherein each of cycloalkyl and heterocyclyl is optionally substituted with cyano, halogen, hydroxyl, 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, hydroxyl, amino, alkyl, and heteroalkyl, wherein each of alkyl and heteroalkyl is optionally substituted with one or more R a .

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

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

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

[0098] In certain embodiments, R 1 is fluoro, chloro, bromo, 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 is -C(O)R b , wherein R b is selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, -NR c R d , and -OR e .

[0101] In certain embodiments, each of R c and R d is independently selected from the group consisting of hydrogen, alkyl, and alkenyl, wherein each of alkyl and alkenyl is optionally substituted with halogen or hydroxyl.

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

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

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

[0105] In certain embodiments, R 2 is -C(O)R b , wherein R b is saturated C 3-6 cycloalkyl or -OR e , and R e is C 1-6 alkyl.

[0106] In certain embodiments, R 2-C(O)R b wherein R b is cyclopropyl or -OR e and R e is methyl, ethyl, n-propyl, or i-propyl.

[0107] In some embodiments, R 2 is -C(O)-cyclopropyl or -C(O)OCH3.

[0108] In some embodiments, R 3 is hydrogen or alkyl optionally substituted with halo, hydroxyl, cyano, or amino.

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

[0110] In some embodiments, R 3 is alkyl optionally substituted with halo, hydroxyl, cyano, or amino.

[0111] In certain embodiments, R 3 is C 1-6 alkyl optionally substituted with halo, hydroxyl, cyano, or amino.

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

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

[0114] In certain embodiments, each of R f is independently selected from the group consisting of hydrogen, halo, hydroxyl, amino, alkyl, and heteroalkyl.

[0115] In certain embodiments, two R f together with the atom to which they are attached form a saturated or partially unsaturated cycloalkyl optionally substituted with cyano, halo, hydroxyl, amino, or alkyl.

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

[0117] In some embodiments, L is alkyl optionally substituted with one or more R f .

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

[0119] In certain embodiments, L is optionally substituted C f alkyl, wherein each of R 1-6 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, methyl, and ethyl. f is independently selected from the group consisting of hydrogen, halogen, hydroxyl, methyl, and ethyl.

[0120] In some embodiments, L is -CH2-, -CH(CH3)-, or -C(CH3)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 alkyl and heteroalkyl is optionally substituted with halogen, hydroxyl, cyano, or amino.

[0128] In certain embodiments, W is wherein R g is hydrogen or C 1-6 alkyl. 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 alkyl or aryl optionally substituted with halogen, hydroxyl, cyano, or amino.

[0131] In certain embodiments, R 4 is hydrogen, C 1-6 alkyl optionally substituted with halogen, hydroxyl, cyano, or amino, C 6-12 aryl optionally substituted with halogen, hydroxyl, cyano, or amino.

[0132] In certain embodiments, R 4 is hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH(CH3)(NH2), or phenyl.

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

[0134] In some embodiments, is a double bond in the 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 is halogen. 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 is -C(O)R b , wherein R b is hydrogen, hydroxyl, alkyl, saturated cycloalkyl, or -OR e . In certain embodiments, R 2 is -C(O)R b , wherein R b is saturated cycloalkyl or -OR e , and R e is alkyl. In certain embodiments, R 2 is -C(O)R b , wherein R b is saturated C 3-6 cycloalkyl or -OR e , and R e is C 1-6 alkyl. In certain embodiments, R 2 is -C(O)Rb , where R b Cyclopropyl or -OR e And R e It is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 2 It is -C(O)-cyclopropyl or -C(O)OCH3.

[0142] In some embodiments, R 3 It is hydrogen.

[0143] In some embodiments, R 3 It is an alkyl group. In some embodiments, R 3 C 1-6 Alkyl group. In some embodiments, R 3 It can be methyl, ethyl, n-propyl or isopropyl.

[0144] In some embodiments, L is a straight key.

[0145] In some embodiments, L is optionally represented by one or more R f Substituted alkyl groups, the R f Independently selected from hydrogen, halogen, hydroxyl, methyl, and ethyl. In some embodiments, L is optionally separated by one or more R f Replacement C 1-6 Alkyl, the R f The element is independently selected from hydrogen, halogen, hydroxyl, methyl, and ethyl. In some embodiments, L is -CH2-, -CH(CH3)-, or -C(CH3)2-.

[0146] In some embodiments, R 4 It is hydrogen or an alkyl group optionally substituted with halogen, hydroxyl, cyano, or amino groups. In some embodiments, R 4 C is hydrogen or optionally substituted with halogen, hydroxyl, cyano or amino groups. 1-6 Alkyl group. In some embodiments, R 4 It can be hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3 or -CH(CH3)(NH2).

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

[0148] In some embodiments, It is an E-configuration double bond.

[0149] In some embodiments, is a double bond in the 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, is a double bond in the E configuration.

[0154] In some embodiments, is a double bond in the 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, is a double bond in the E configuration.

[0160] In some embodiments, is a double bond in the 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 formulas and specific compounds. In addition, the compounds of the present disclosure can exist in a number of 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 choice of substituents, the compounds of the present disclosure can comprise one or more asymmetric centers and can therefore occur as various stereoisomeric forms, such as enantiomeric and / or diastereomeric forms. For example, the compounds provided herein can have asymmetric carbon centers and therefore the compounds provided herein can have (R) or (S) stereoconfigurations at the carbon asymmetric centers. Thus, the compounds of the present disclosure can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can 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 reactivities.

[0171] When a particular enantiomer is preferred, in some embodiments it can be provided substantially free of the opposite enantiomer, and can also be referred to as "optically enriched." As used herein, "optically enriched" means that the compound is composed of a significantly greater 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%, or 99% by weight of the preferred enantiomer. The preferred enantiomer can be separated from a racemic mixture by any method known to those of skill in the art, for example, by chromatography or crystallization, by synthesis using stereochemically homogeneous starting materials, or by stereoselective synthesis. Optionally, derivatization can be performed prior to separation of the stereoisomers. Separation of a mixture of stereoisomers can occur at an intermediate step during synthesis of the compounds provided herein or it can occur on the final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of a crystalline product or crystalline intermediate which has been derivatized, if necessary, to introduce a chiral center of known absolute stereochemistry. Alternatively, absolute stereochemistry can be determined by vibrational circular dichroism (VCD) spectroscopy. See, for example, Jacques et al., Enantiomers, Racemates, and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H. et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions (Ed. E.L. Eliel, Univ. of Notre Dame Press, Notre Dame, IN, 1972) pp. 268.

[0172] In some embodiments, mixtures of diastereomers are provided, for example, mixtures of diastereomers that are enriched in one of the diastereomers by 51% or more, including, for example, mixtures of diastereomers in which one of the diastereomers is 60% or more, 70% or more, 80% or more, or 90% or more.

[0173] In some embodiments, the compounds provided herein can have one or more double bonds existing in either the Z or E isomeric form, unless otherwise indicated. In addition, the present disclosure also encompasses the compounds in the form of individual isomers substantially free of other isomers and, alternatively, as mixtures of various isomers, such as racemic mixtures of enantiomeric isomers.

[0174] The compounds of the present disclosure can also exist in different tautomeric forms, and all such forms are encompassed within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to different energy structures that are interconvertible via a low energy barrier. For example, prototropic tautomers (also known as proton-shift tautomers) include interconversions via proton migration, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerization, and cyclic forms in which a proton can occupy two or more positions of a heterocyclic system (e.g., 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole, and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole). Valence tautomers include interconversions by rearrangement of some of the bonding electrons. Tautomers can be in equilibrium or spatially locked into one form by appropriate substitution. Unless otherwise specified, a compound of the present disclosure identified by name or structure as one particular tautomeric form is intended to include the other tautomeric forms.

[0175] The present disclosure is also intended to include all isotopes of atoms occurring in the present compounds. Isotopes of atoms include atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, any hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in a compound of the present disclosure is also intended to include 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 I. In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes 12 C and 13 C. Isotopically enriched compounds of Formula (I) can be prepared without undue experimentation by routine techniques well known to those skilled in the art or by methods analogous to those described in the schemes and examples herein, using appropriately isotopically enriched reagents and / or intermediates.

[0176] The compounds of the present disclosure can be formulated into or be in the form of a pharmaceutically acceptable salt. 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 is chemically and / or toxicologically compatible with the other materials with which it is combined to form the pharmaceutical formulation and / or the individual to whom it is administered.

[0178] As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salt" includes salts that retain the biological effectiveness and non-deleterious properties of the free acids and bases of the designated compounds and are not biologically or otherwise undesirable. Pharmaceutically acceptable salt forms contemplated include, but are not limited to, mono-, di-, tri-, tetra- salts, etc. The pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical characteristics of a compound without adversely affecting its physiological function. Useful alterations in physical characteristics include reduction of melting point to facilitate transmucosal administration and increased 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, mesylate, esylate, besylate, tosylate, cyclohexylsulfamate, and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric, maleic, sulfuric, phosphoric, sulfamic, acetic, citric, lactic, tartaric, malonic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexylsulfamic, fumaric, and quinic acids.

[0180] When an acidic functional group is present, such as a carboxylic acid or phenol, pharmaceutically acceptable salts include base addition salts such as those including benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butyl amines, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkyl amines, and zinc. See, e.g., Remington's Pharmaceutical Sciences, 19th Ed., 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 standard techniques.

[0181] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid, and then isolated by evaporation of the solution. Thus, if a particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method, e.g., by treatment with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; 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, pyranosidyl 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 acids, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, and the like, by treatment with an inorganic base or organic base, such as amine bases, primary, secondary, or tertiary amines, alkali metal or alkaline earth metal hydroxides, and the like.

[0182] Similarly, if a particular compound is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, e.g., by treatment with an inorganic or organic base, such as amine bases, primary, secondary, or tertiary amines, alkali metal or alkaline earth metal hydroxides, and the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine, lysine, and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyl ethylpiperidine, piperidine, morpholine, or piperazine; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0183] It is also understood that the compounds of the disclosure can exist in unsolvated as well as solvated forms (e.g., hydrates) and as solid forms (e.g., crystalline or polymorph forms), and that the disclosure is intended to cover all such forms.

[0184] As used herein, the term "solvate" or "solvated form" refers to a solvent addition form of a compound that typically contains either stoichiometric or non-stoichiometric amounts of a solvent. Some compounds have a propensity for occuring in solvated forms. If the solvent is water, the solvate formed is a hydrate; if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates of a compound of the disclosure are formed by the combination of water molecules with molecules of the compound, wherein the water retains its molecular state as H2O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0185] As used herein, the terms "crystalline form," "crystalline forms," "polymorphic form" and "polymorph" are used interchangeably and mean a crystal structure in which a compound (or salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystalline forms of a compound often have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors can cause one crystalline form to dominate over another. Crystalline polymorphs of a compound can be prepared by crystallization under different conditions.

[0186] The disclosure is also intended to include all isotopes of atoms occurring in the compounds. Isotopes of atoms include atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, any hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in a compound of the disclosure also includes 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、 79 Br、 81 Br、 124 I、 127 I and 131 I. In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes 12 C and 13 C.

[0187] Synthesis of compounds

[0188] The synthesis of the compounds provided herein, including pharmaceutically acceptable salts thereof, is illustrated in the synthetic schemes in the Examples. The compounds provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes, and thus, the schemes are merely illustrative and are not intended to limit other possible methods that can be used to prepare the compounds provided herein. Furthermore, the steps in the schemes are to be better illustrated and can be changed as appropriate. Examples of synthesizing the compounds in the Examples are for research and possible submission to regulatory agencies.

[0189] The reactions for preparing the compounds of the present disclosure can be carried out in suitable solvents which can be readily selected by one of ordinary skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials, intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. The specified reactions can be carried out in one solvent or a mixture of more than one solvent. The choice of a suitable solvent will depend, in part, on the particular reaction step or steps involved in the synthesis.

[0190] Preparation of the compounds of the present disclosure can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rdedition, Wiley & Sons, Inc., New York (1999); P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003; and Peter G. M. Wuts, Greene's Protective Groups in Organic Synthesis, 5thedition, Wiley, 2014, all of which are incorporated herein by reference in their entirety.

[0191] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,1H,13C), infrared spectroscopy (IR), spectrophotometry (e.g., UV-vis), mass spectrometry, or by chromatographic means, such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin layer chromatography (TLC). 1 H or 13 C), infrared spectroscopy (IR), spectrophotometry (e.g., UV-vis), mass spectrometry, or by chromatographic means, such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin layer chromatography (TLC). Compounds can be purified by a variety of methods, including high-performance liquid chromatography (HPLC) (“Preparative LC-MS Purification: Improved Compound Specific Method Optimization,” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs, J. Combi. Chem. 2004, 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 known methods in the art, or can be purchased from commercial suppliers. Unless otherwise indicated, analytical grade solvents and commercial reagents were used without further purification.

[0193] Unless otherwise stated, the reactions of the present disclosure are performed under an inert atmosphere in dry solvents with dry reagents. The reaction vessels are typically equipped with a condenser, a heating / cooling mantle, and a stir bar. Glassware is oven or heat dried and / or nitrogen purged. The progress of the reaction is measured by conventional methods.

[0194] For illustrative purposes, the following Examples section shows synthetic routes for preparing compounds of the present disclosure, as well as key intermediates. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0195] In one aspect, the present disclosure provides a compound having the following 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 a compound having the following formula:

[0199]

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

[0201] Use of compounds

[0202] In one aspect, the present disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, which is capable of inhibiting platelet aggregation. Accordingly, the compounds of the present disclosure or a pharmaceutically acceptable salt thereof are useful as a medicinal product, and are particularly useful as a therapeutic or prophylactic agent for various thrombotic diseases.

[0203] As used herein, the term "treatment" is used synonymously with "therapy." Similarly, the term "treatment" can be considered to mean "administration of a therapy," where "therapy" is as defined herein.

[0204] The term "treatment" is used synonymously with "therapy." Similarly, the term "treatment" can be considered to mean "administration of a 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 for preventing the development of a disease and secondary prevention when a disease has already developed to protect the patient temporarily or permanently against an intensification or aggravation of the disease or against the onset of new symptoms associated with the disease.

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

[0207] For a prodrug of an active thiol metabolite, it is required that the prodrug remains stable (resistant to the environment) while being converted to the active thiol metabolite in the target tissue with high conversion rate. In addition, it is required that the prodrug has a fast onset time and thus has a low loading dose and low side effects, has a high solubility in aqueous solution to allow formulation into injection for emergency and surgery.

[0208] In some embodiments, the compounds provided herein can undergo a hydrolysis process via hydrolytic enzymes to form an active thiol metabolite. Because hydrolytic enzymes have high in vivo activity and wide distribution in the intestine, liver, and plasma, the compounds provided herein can be converted to the active thiol metabolite in vivo with high conversion rate and small inter-patient variability, thus providing a fast onset of anti-platelet effect without the need for using high loading doses. Furthermore, because the metabolism of the compounds provided herein is mediated by hydrolytic enzymes 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 time of anti-platelet effect than clopidogrel at the same dose. In some embodiments, the compounds provided herein show a less onset time of anti-platelet effect than clopidogrel at a lower dose than clopidogrel. In some embodiments, the compounds provided herein show a less onset time of anti-platelet effect than clopidogrel at a dose that is 1 / 2 of the dose of clopidogrel. In some embodiments, the compounds provided herein show a less onset time of anti-platelet effect than clopidogrel at a dose that is 1 / 3 of the dose of clopidogrel. In some embodiments, the compounds provided herein show a less onset time of anti-platelet effect than clopidogrel at a dose that is 1 / 4 of the dose of clopidogrel. In some embodiments, the compounds provided herein show a less onset time of anti-platelet effect than clopidogrel at a dose that is 1 / 5 of the dose of clopidogrel.

[0210] In some embodiments, the compounds provided herein show an onset time of anti-platelet effect that is 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 at a dose that is 1 / 5 of the dose of clopidogrel.

[0211] In some embodiments, the compounds provided herein show an improved aqueous solubility compared to clopidogrel, as measured in phosphate buffer. In some embodiments, the compounds provided herein show an aqueous solubility that is 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, as measured in a buffered aqueous solution.

[0212] The improved solubility of the compounds provided herein provides an opportunity to expand the use of the compounds in inhibiting platelet aggregation. In some embodiments, the compounds provided herein can be formulated for injection administration for emergency and surgical use. In some embodiments, the compounds provided herein can be formulated for oral administration for long-term inhibition of platelet aggregation.

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

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

[0215] Pharmaceutical compositions

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

[0217] Thus, in another aspect, there is provided a pharmaceutical composition comprising one or more compounds of the disclosure, or a pharmaceutically acceptable salt thereof.

[0218] In some embodiments, the pharmaceutical composition of the disclosure comprises a compound selected from any one of formulae (I) to (VII), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the disclosure comprises a first compound selected from any one of formulae (I) to (VII), or a pharmaceutically acceptable salt thereof, and one or more additional compounds of the same formula, but the first compound and additional compounds 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 an individual.

[0220] In some embodiments, the pharmaceutical composition of the disclosure comprises a therapeutically effective amount of one or more compounds of formulae (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 said molecule or compound that will treat, ameliorate, or prevent an identified disease or condition, or show 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 upon the subject's body weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the judgment of the prescribing physician. Therapeutically effective amounts for a given situation can be determined by routine experimentation within the skills and judgment of the clinician.

[0222] In another aspect, there is provided a pharmaceutical composition comprising one or more molecules or compounds of the disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0223] As used herein, the term “pharmaceutically acceptable excipient” refers to an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and biologically or otherwise

[0224] The particular excipient used will depend on the means and purpose of the preparation of the compounds of the disclosure for administration. The solvent is generally selected based on the solvents that are recognized by those skilled in the art as safe to administer to mammals, including humans, from the compounds of the disclosure. Generally, 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), and the like, and mixtures thereof.

[0225] In some embodiments, suitable excipients can include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl 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, dextrins, or substituted dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN TM , PLURONICS TM or polyethylene glycol (PEG).

[0226] In some embodiments, suitable excipients can include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, and other known additives to provide an optimal presentation of the pharmaceutical (i.e., a compound of the present disclosure or a pharmaceutical composition thereof) or help manufacture a pharmaceutical product (i.e., a medicament). The active pharmaceutical ingredients can also be coated by, e.g., agglutination techniques or by complex coacervation techniques, such as, e.g., microencapsulated by coacervation techniques or by interfacial polymerization, e.g., hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). "Liposomes" are small vesicles that are formed from various types of lipids, phospholipids, and / or surfactants that are suitable for use in delivering drugs (such as the compounds disclosed herein and optional chemotherapeutic agents) to mammals, including humans. The components of a liposome typically are arranged in a bilayer formation similar to the lipid arrangement of biological membranes.

[0227] The pharmaceutical compositions provided herein can be in any form that allows the composition to be administered to an individual (including, but not limited to, a human) and that is compatible with the intended route of administration.

[0228] Multiple routes are contemplated for the pharmaceutical compositions provided herein, and thus the pharmaceutical compositions provided herein can be supplied in bulk or unit dosage form, depending on the intended route of administration. For example, for oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, 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 a suitable solution 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, pessaries, tampons, creams, gels, pastes, foams, and sprays can be acceptable dosage forms.

[0229] The amount of active ingredient in a unit dose of a composition is therapeutically effective and varies according to the particular treatment involved. As used herein, the term "therapeutically effective amount" means an amount of a molecule, compound, or composition comprising said 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 a subject will depend upon the subject's body weight, size, and health; the nature and extent of the conditions; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the judgment of the prescribing physician. Therapeutically effective amounts for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0230] In some embodiments, the pharmaceutical compositions of the present disclosure can be in the form of an oral administration formulation.

[0231] In certain embodiments, the pharmaceutical compositions of the present disclosure can be in the form of a tablet formulation. Pharmaceutically acceptable excipients suitable for tablet formulations include, for example, inert diluents, such as lactose, sodium carbonate, calcium phosphate, or calcium carbonate; granulating and disintegrating agents, such as corn starch, or alginic acid; binding agents, such as starch; lubricating agents, such as magnesium stearate, stearic acid, or talc; preservatives, such as ethyl or propyl p-hydroxybenzoate; and antioxidants, such as ascorbic acid. Tablet formulations can be uncoated or they can be coated, e.g., with a coating agent and process known in the art.

[0232] In certain embodiments, the pharmaceutical compositions of the present disclosure can be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, such as, for example, calcium carbonate, calcium phosphate, or kaolin; or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as, for example, peanut oil, liquid paraffin, or olive oil.

[0233] In certain embodiments, the pharmaceutical compositions of the present disclosure can be in the form of aqueous suspensions, generally containing the active ingredient in the form of a fine suspension. One or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing agents or wetting agents, such as lecithin, or a condensed product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), or a condensed product of an alkylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), or a condensed product of an alkylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensed product of an alkylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate), can be included. The aqueous suspensions can also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate), antioxidants (such as ascorbic acid), coloring agents, flavoring agents, and / or sweetening agents (such as sucrose, saccharin, or aspartame).

[0234] In certain embodiments, the pharmaceutical compositions of the present disclosure can be in the form of oil suspensions, generally containing the active ingredient in a vegetable oil (e.g., arachis oil, castor oil, olive oil, sesame oil, or coconut oil), or in a mineral oil (e.g., liquid paraffin). Oil suspensions can further comprise a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents (such as those set forth above) and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant (e.g., ascorbic acid).

[0235] In certain embodiments, the pharmaceutical compositions of the present disclosure can be in the form of oil suspensions, generally containing the active ingredient in a vegetable oil (e.g., arachis oil, castor oil, olive oil, sesame oil, or coconut oil), or in a mineral oil (e.g., liquid paraffin). Oil suspensions can further comprise a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents (such as those set forth above) and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant (e.g., ascorbic acid).

[0236] In certain embodiments, the pharmaceutical compositions provided herein can be in the form of a syrup or elixir, which can contain a sweetening agent, such as glycerin, propylene glycol, sorbitol, aspartame, or sucrose; a demulcent; a preservative; a flavoring agent and / or a coloring agent.

[0237] In some embodiments, the pharmaceutical compositions of the present disclosure can be in the form of an injectable administration formulation.

[0238] In certain embodiments, the pharmaceutical compositions of the present disclosure can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

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

[0240] In certain embodiments, the pharmaceutical compositions of the present disclosure can be in the form of an aqueous and non-aqueous (e.g., in fluorocarbon propellants) aerosol, which contains any suitable solvent and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH adjusting agents, surfactants, bioavailability modifiers, and combinations of these. The carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics or polyethylene glycols), innocuous proteins (such as serum albumulin), sorbitol 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 can be in the form of a topical or transdermal administration formulation.

[0242] In certain embodiments, the pharmaceutical compositions provided herein can be in the form of a cream, ointment, gel 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 and oils, waxes, paraffins, starch, 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 can be formulated in the form of a transdermal skin patch, as 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 thus included in the present disclosure. Such excipients and carriers are described, for example, in "Remingtons Pharmaceutical Sciences," Mack Publishing Company, New Jersey (1991), "Remington: The Science and Practice of Pharmacy," edited by University of the Sciences in Philadelphia, 21st edition, LWW (2005), which are incorporated herein by reference.

[0245] In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suited as unitary dosages for human individuals and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient. The quantity of a compound provided herein in a unit dosage form will vary depending on the condition being treated, the individual being treated (e.g., the age, weight, and response of the individual), the particular route of administration, the actual compound being administered, and its relative bioavailability, and the severity of the individual's symptoms.

[0246] In some embodiments, the amount of the pharmaceutical composition of the present disclosure to be administered can be between 0.001-1000 mg / kg body weight / day, e.g., 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, 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, 0.01-0.1 mg / kg body weight / day, 0.02-0.1 mg / kg body weight / day, 0.03-0.1 mg / kg body weight / day, 0.04-0.1 mg / kg body weight / day, 0.05-0.1 mg / kg body weight / day, 0.06-0.1 mg / kg body weight / day, 0.07-0.1 mg / kg body weight / day, 0.08-0.1 mg / kg body weight / day, or 0.09-0.1 mg / kg body weight / day. In some cases, an amount of administration below the lower limit of the aforesaid ranges can be more than adequate, while in other cases still larger doses can be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day. For further information on routes of administration and dosing schedules, see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Editor-in-Chief), 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, a unit dose for oral administration contains one or more compounds provided herein in an amount of about 1 mg to about 1000 mg, e.g., 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 500 mg, about 10 mg to about 500 mg, about 50 mg to about 500 mg, about 100 mg to about 500 mg, about 200 mg to about 500 mg, about 300 mg to about 500 mg, about 400 mg to about 500 mg, e.g., 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 can 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 a treatment of 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, the pharmaceutical compositions of the present disclosure are formulated for parenteral administration, e.g., by intravenous, subcutaneous, or intramuscular injection. In some embodiments, a 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, e.g., 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 80 mg, about 0.5 mg to about 70 mg, about 0.5 mg to about 60 mg, about 0.5 mg to about 50 mg, about 0.5 mg to about 40 mg, about 1 mg to about 90 mg, about 5 mg to about 90 mg, about 10 mg to about 80 mg, about 20 mg to about 70 mg, about 30 mg to about 60 mg, or about 40 mg to about 50 mg, e.g., 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, a pharmaceutical composition intended for administration by injection can be prepared by combining one or more compounds of the present disclosure with sterile, distilled water, sesame oil, peanut oil, or aqueous propylene glycol solution to form a solution. In some embodiments, the pharmaceutical composition can include a surfactant or other solubilizing excipient, which is added to facilitate formation of a homogenous solution or suspension. In some embodiments, the pharmaceutical composition can further include one or more additional agents selected from the group consisting of wetting agents, suspending agents, preservatives, buffering agents, and isotonic agents.

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

[0252] In another aspect, there is also provided a veterinary composition comprising one or more molecules or compounds of the disclosure, or a pharmaceutically acceptable salt thereof, and a veterinary carrier. A veterinary carrier is a material with which the composition is administered for the purpose of the application, and can be a solid, liquid, or gaseous material which is otherwise inert or acceptable in the veterinary art, and is compatible with the active ingredient. These veterinary compositions can be administered parenterally, orally, or by any other desired route.

[0253] Pharmaceutical or veterinary compositions can be packaged in a variety of ways depending on the method used to administer the medicament. For example, articles for distribution can include containers into which the compositions in an appropriate form are deposited. Suitable containers are known to those of skill in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cans, and the like. The containers can also include a tamper-proof enclosure to prevent easy access to the contents of the package. Additionally, the containers have attached a label which describes the contents of the container. The label can also include appropriate warnings. Compositions can be packaged in unit- or multi-dose containers, such as sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition, requiring only the addition of the sterile liquid carrier, such as water, for injection immediately prior to use. Ready-to-use injectable solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described.

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

[0255] In some embodiments, the second active ingredient has complementary activity to the compounds provided herein, such that it does not adversely affect the other. The ingredients are desirably present in a combination in an amount effective for the intended purposes.

[0256] Method of treatment of a disease

[0257] In another aspect, the 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 thereof, or a pharmaceutical composition.

[0258] In some embodiments, the vascular disease is selected from the group consisting of atherosclerotic thrombosis, ischemia, stroke, cerebral thrombosis, arterial thrombosis, thrombotic cerebrovascular disease, cardiovascular disease, and thrombus.

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

[0260] Examples

[0261] For purposes of illustration, the following examples are included. It will be understood, however, that these examples do not limit the disclosure and are merely intended to suggest a method of practicing the disclosure. Those skilled in the art will recognize that the chemical reactions described can readily be adapted to prepare a number of other compounds of the disclosure, and alternative methods for preparing compounds of the disclosure are deemed to be within the scope of the disclosure. For example, non-exemplified compounds according to the disclosure can be synthesized by the techniques of the disclosure or by modifications to the techniques apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by utilizing other appropriate reagents and building blocks in place of those illustrated, and / or by making routine modifications to reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as being applicable to the preparation of other compounds of the disclosure.

[0262] Example 1

[0263]

[0264]

[0265] Step 1. Synthesis of 1-2

[0266]

[0267] A solution of 1-1 (56.7 g, 310 mmol) in DCM (500 mL) was stirred in an ice bath (T < 5 °C) under N2protection. mCPBA (107.0 g, 620 mmol) was added to the above solution portionwise. After addition, the resulting mixture was stirred at 20 °C for 4 h. The mixture was poured into a solution of Na2S2O3 (90.0 g) and NaHCO3 (45.0 g) in water (300 mL) with stirring. The resulting mixture was extracted with DCM (300 mL*2). The combined organic layers were dried over Na2SO4and 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 of 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 min, and then stirred at 40 °C overnight. The reaction mixture was then concentrated in vacuo. To the residue was added saturated Na2CO3 (400 mL) with stirring, followed by extraction with EtOAc (400 mL*2). The organic layer was dried over Na2SO4, and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (petroleum ether / EtOAc = 10 / 1 to 5 / 1) to give 1-3 (87.5 g, 77% yield) as a white solid.

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

[0272] 1 H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J = 7.2 Hz, 2H), 7.59 (s, 1H), 7.46 (t, J = 7.7 Hz, 2H), 4.24 (d, J = 16.3 Hz, 1H), 4.17 - 3.81 (m, 1H), 3.73 (s, 1H), 3.60 (s, 1H), 2.92 (t, J = 24.3 Hz, 2H), 2.72 (s, 1H), 2.12 (d, J = 16.8 Hz, 1H), 1.71 (d, J = 11.6 Hz, 1H), 1.46 (s, 9H).

[0273] Step 3. Synthesis of 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] To a solution of 1-4 (263.0 g, 583.1 mmol) in NH3 / MeOH (7 M, 2.0 L) was added NaBH4(222 mg, 5.8 mmol). The resulting mixture was stirred at room temperature overnight, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 20 / 1) to give 1-5 (210.0 g, 100% yield) as a light yellow oil.

[0279] Step 5. Synthesis of 1-6

[0280]

[0281] To a solution of NaBH4(1.1 g, 28.8 mmol) in DMF (1.0 L) was added NaH (20.7 g, 864.6 mmol) at 0 °C with stirring under N2. 1-5 (200.0 g, 576.4 mmol) was added dropwise at 0 °C, followed by stirring at 0 °C for 1 h. Then, 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 h. H2O (1.0 L) was added to the mixture, followed by extraction with EtOAc (1.0 L*3). The organic layer was washed with brine, dried over Na2SO4and 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 Et3N.3HF (135.0 g, 835.9 mmol) and stirred at reflux for 16 h. Upon 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 of 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. Upon completion, the above reaction mixture was added to a mixture of saturated Na2S203 / saturated NaHC03(600 mL / 600 mL) followed by extraction with EtOAc (400 mL*2). The combined organic layers were washed with saturated NaHC03, dried over Na2S04and 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] To a solution of tert-butyl 2-(diethoxyphosphoryl)acetate (11.4 g, 43.2 mmol) in THF (100 mL) was added LiHMDS (37.4 mL, 37.4 mmol) at -60 °C under N2and stirred at -60 °C for 30 min. Then 1-8 (10.0 g, 28.8 mmol) was added dropwise at -60 °C and the resulting mixture was stirred at 0-10 °C for 1 h. Then the reaction mixture was added to saturated NH4CI (300 mL) followed by extraction with EtOAc (150 mL*2). The combined organic layers were washed with brine, dried over Na2S04and 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 light yellow oil and 1-10 (1.3 g, 10% yield) as a light yellow oil.

[0292] 1-9: 1H NMR (400 MHz, Chloroform-d) δ 5.68 (s, 1H), 5.47 (d, J = 15.2 Hz, 1H), 5.24 (s, 1H), 4.89-4.94 (m, 2H), 3.95 (s, 1H), 3.87-3.92 (m, 1H), 3.79 (s, 1H), 3.17-3.19 (m, 1H), 2.15-2.16 (m, 1H), 1.87-1.90 (m, 1H), 1.48 (s, 9H), 1.43 (s, 9H), 1.29 (d, J = 4 Hz, 6H).

[0293] 1-10: 1 H NMR (400 MHz, Chloroform-d) δ 5.74 (s, 1H), 5.48 (s, 1H), 5.27 (d, J = 12 Hz, 1H), 5.14 (d, J = 12 Hz, 1H), 4.85-4.89 (m, 1H), 4.25-4.26 (m, 1H), 3.93-3.94 (m, 2H), 3.15 (s, 1H), 2.01-2.04 (m, 1H), 1.85-1.88 (m, 1H), 1.46 (s, 9H), 1.44 (s, 9H), 1.28 (d, J = 4 Hz, 6H).

[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, followed by stirring the reaction at 0 °C for 30 min. Upon completion, the reaction mixture was added to saturated NaHC03solution (100 mL), followed by extraction with DCM (100 mL). The organic layer was dried over Na2S04and 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] To a solution of 1-11 (3.0 g, crude) in CH3CN (15 mL) was added 1-12 (2.6 g, 6.7 mmol) and KHCO3 (1.35 g, 13.5 mmol). The resulting mixture was stirred at 40 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (C18, CH3CN / H2O = 80 / 20) to give 1-13 (1.8 g, 51% yield) as a white solid. LC-MS [M+1] = 528.2. + = 472.1

[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 a saturated NaHCO3 solution (100 mL) followed by extraction with EtOAc (100 mL*3). The combined organic layers were washed with saturated NaHCO3, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (C18, CH3CN / H2O = 80 / 20) to give 1a (550 mg, 34% yield). 1a was purified by chiral column chromatography to give 1a-1 and 1a-2.

[0303] 1a:

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

[0305] 1 H NMR (400 MHz, Chloroform-d) δ 7.59 (s, 1H), 7.38 (d, J = 4 Hz, 1H), 7.32-7.26 (m, 2H), 5.86 (s, 1H), 5.22 (dd, J = 12.2, 2.6 Hz, 1H), 5.00-4.83 (m, 3H), 4.50 (dd, J = 66.2, 11.9 Hz, 1H), 3.82 (s, 1H), 3.70 (d, J = 4.9 Hz, 3H), 3.52 (dd, J = 37.9, 12.9 Hz, 1H), 2.92-2.64 (m, 2H), 2.45-2.30 (m, 1H), 1.95-1.84 (m, 1H), 1.30 (d, J = 6.2 Hz, 6H).

[0306] 1a-1:

[0307] 1H NMR (400 MHz, CDC13) 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 H NMR (400 MHz, CDC13) 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, stirred at 0 °C for 1 h. Upon completion, the reaction mixture was added to saturated NaHC03solution (100 mL), followed by extraction with DCM (100 mL*3). The combined organic layers were dried over Na2S04and 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] To a solution of 1-14 (2.0 g, crude) in CH3CN (20 mL) was added 1-12 (1.5 g, 4.0 mmol) and KHCO3 (800 mg, 8.0 mmol). The resulting mixture was stirred at 40 °C for 2 h, and then concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18, CH3CN / H2O = 80 / 20) to give 1-15 (500 mg, 24% yield) as a white solid. LC-MS [M+1] = 528.2 +

[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 for 30 min at 0 °C. After completion, the reaction was added to saturated NaHCO3 solution (30 mL), then extracted with EtOAc (30 mL*3). The combined organic layers were washed with saturated NaHCO3, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (C18, CH3CN / H2O = 80 / 20), followed by prep-HPLC (mobile phase: A (H2O) / B (MeCN); ratio range: A / B (80% / 20%) to A / B (55% / 45%) (10 min) and to A / B (20% / 80%) (35 min); peak’s Rt: (67% of B); V = 80 mL / min, wavelength 214 nm), and prep-TLC (DCM / MeOH = 10 / 1) to give 1b (50 mg, 11% yield). 1b was purified by chiral column chromatography to give 1b-1 and 1b-2.

[0319] 1b:

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

[0321] 1 ​​H NMR (400 MHz, CDC13) δ 7.58 (d, J = 5.6 Hz, 1H), 7.44 - 7.36 (m, 1H), 7.27 (s, 2H), 5.77 - 5.65 (m, 1H), 5.41 (s, 1H), 5.25 (dd, J = 12.0, 6.3 Hz, 1H), 5.19 - 5.11 (m, 1H), 4.92 - 4.83 (m, 1H), 4.80 (s, 1H), 3.70 (d, J = 4.6 Hz, 3H), 3.52 (dd, J = 34.3, 12.2 Hz, 1H), 3.19 (d, J = 12.9 Hz, 0.5H), 2.98 (d, J = 12.5 Hz, 0.5H), 2.90 - 2.84 (m, 0.5H), 2.78 - 2.61 (m, 1.5H), 2.31 - 2.16 (m, 1H), 1.97 - 1.82 (m, 1H), 1.28 (d, J = 5.4 Hz, 6H).

[0322] 1b-1:

[0323] 1 H NMR (400 MHz, CDC13) δ 7.58 (d, J = 5.6 Hz, 1H), 7.44 - 7.36 (m, 1H), 7.27 (s, 2H), 5.77 - 5.65 (m, 1H), 5.41 (s, 1H), 5.25 (dd, J = 12.0, 6.3 Hz, 1H), 5.19 - 5.11 (m, 1H), 4.92 - 4.83 (m, 1H), 4.80 (s, 1H), 3.70 (d, J = 4.6 Hz, 3H), 3.52 (dd, J = 34.3, 12.2 Hz, 1H), 3.19 (d, J = 12.9 Hz, 0.5H), 2.98 (d, J = 12.5 Hz, 0.5H), 2.90 - 2.84 (m, 0.5H), 2.78 - 2.61 (m, 1.5H), 2.31 - 2.16 (m, 1H), 1.97 - 1.82 (m, 1H), 1.28 (d, J = 5.4 Hz, 6H).

[0324] 1b-2:

[0325] 1H NMR (400 MHz, CDC13) δ 7.62-7.56 (m, 1H), 7.41-7.38 (m, 1H), 7.30-7.26 (m, 2H), 5.77 (s, 1H), 5.43 (s, 1H), δ 5.27 (d, J = 12.1 Hz, 1H), 5.17 (d, J = 12.0 Hz, 1H), 4.91-4.86 (m, 1H), 4.80 (s, 1H), 3.71 (s, 3H), 3.56 (d, J = 12.4 Hz, 1H), 3.17 (d, J = 12.4 Hz, 1H), 2.66 (d, J = 8.0 Hz, 2H), 2.20-2.17 (m, 1H), 1.87 (d, J = 14.4 Hz, 1H), 1.29 (dd, J = 6.2, 2.5 Hz, 6H).

[0326] Example 2

[0327]

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

[0329]

[0330] To a solution of ethyl 2-(diethoxyphosphoryl)acetate (20.6 g, 86.5 mmol) in THF (300 mL) was added KHMDS (75 mL, 74.9 mmol) at -60 °C under N2, stirred for 1 h at -60 °C. Then 2-1 (20.0 g, 57.6 mmol) was added dropwise at -60 °C, and the resulting mixture was stirred for 0.5 h at -10 °C. Then the reaction mixture was added to saturated NH4Cl (1000 mL). The resulting mixture was extracted with EtOAc (500 mL*2). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (petroleum ether / EtOAc = 60 / 1) to give 2-3 (7.5 g, 30% yield) as a light yellow oil and 2-2 (4.5 g, 18% yield) as a light yellow oil.

[0331] 2-2: 1H NMR (400 MHz, CDC13) δ 5.76 (s, 1H), 5.50 (d, J = 15.8 Hz, 1H), 5.23 (d, J = 12.1 Hz, 1H), 4.97 - 4.83 (m, 2H), 4.23 - 4.06 (m, 3H), 4.01 - 3.91 (m, 1H), 3.91 - 3.77 (m, 2H), 3.28 - 3.12 (m, H,), 2.23 - 2.10 (m, 1H), 1.88 (dd, J = 23.1, 11.5 Hz, 1H), 1.42 (s, 9H), 1.31 - 1.24 (m, 9H).

[0332] 2-3: 1 H NMR (400 MHz, CDC13) δ 5.83 (s, 1H), 5.48 (s, 1H), 5.28 (d, J = 12.1 Hz, 1H), 5.16 (d, J = 12.1 Hz, 1H), 4.94 - 4.82 (m, 1H), 4.32 - 4.09 (m, 3H), 4.03 - 3.85 (m, 2H), 3.23 - 3.05 (m, 1H), 2.08 - 1.98 (m, 1H), 1.89 (dd, J = 14.2, 1.9 Hz, 1H), 1.44 (s, 10H), 1.31 - 1.23 (m, 10H).

[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. Upon completion, the resulting mixture was added to saturated NaHC03solution (200 mL). The resulting mixture was then extracted with DCM (200 mL). The organic layer was dried over Na2S04and 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] To a solution of 2-4 (3.0 g, crude) in CH3CN (15 mL) was added 1-12 (2.8 g, 7.2 mmol) and KHCO3 (1.4 g, 14.4 mmol). The resulting mixture was stirred at 40 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (C18, CH3CN / H2O = 80 / 20) to give 2a (1.7 g, 47% yield).

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

[0341] 1 H NMR (400 MHz, CDC13) δ 7.66 - 7.52 (m, 1H), 7.43 - 7.32 (m, 1H), 7.25 (s, 2H), 5.80 (s, 1H), 5.22 (d, J = 12.2 Hz, 1H), 4.97 - 4.79 (m, 3H), 4.49 (dd, J = 63.7, 12.8 Hz, 1H), 4.18 - 3.99 (m, 2H), 3.78 (s, 1H), 3.71 (d, J = 7.6 Hz, 3H), 3.47 (dd, J = 38.1, 13.2 Hz, 1H), 2.72 (dd, J = 45.3, 17.4 Hz, 2H), 2.32 (s, 1H), 1.87 (d, J = 13.7 Hz, 1H), 1.30 (d, J = 6.1 Hz, 6H), 1.24 (t, J = 7.2 Hz, 3H).

[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. Upon completion, the reaction mixture was added to saturated NaHC03solution (20 mL). The resulting mixture was then extracted with DCM (20 mL). The organic layer was dried over Na2S04and 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] To a solution of 2-5 (120.0 mg, crude) in CH3CN (3 mL) was added 1-12 (88 mg, 0.23 mmol) and KHCO3 (92 mg, 0.92 mmol). The resulting mixture was stirred at 40 °C for 1 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (C18, CH3CN / H2O = 80 / 20) to give 2b (23 mg, 20% yield).

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

[0350] 1 H NMR (400 MHz, CDC13) δ 7.59 (d, J = 5.1 Hz, 1 H), 7.38 (d, J = 6.4 Hz, 1 H), 7.32 - 7.25 (m, 2 H), 5.74 (s, 0.5 H), 5.61 (s, 0.5 H), 5.43 (s, 1 H), 5.25 (dd, J = 11.9, 5.4 Hz, 1 H), 5.15 (dd, J = 11.9, 4.6 Hz, 1 H), 4.93 - 4.81 (m, 1 H), 4.77 (s, 1 H), 4.23 - 4.06 (m, 2 H), 3.69 (d, J = 3.9 Hz, 3 H), 3.51 (d, J = 11.9 Hz, 0.5 H), 3.42 (d, J = 12.1 Hz, 0.5 H), 3.14 (d, J = 12.3 Hz, 0.5 H), 2.97 - 2.80 (m, 1 H), 2.77 - 2.67 (m, 0.5 H), 2.63 (d, J = 7.5 Hz, 1 H), 2.31 - 2.10 (m, 1 H), 1.88 (dd, J = 21.5, 15.1 Hz, 1 H), 1.26 (s, 9 H).

[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 h. After that, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMF (1.5 L), and to the above solution was added 3-1 (150.0 g, 0.43 mol) and K2CO3 (88.32 g, 0.64 mol). After the addition, the mixture was stirred at 16 °C for 2 h. The reaction was diluted with water (3 L) and extracted with EtOAc (1 L*3). The combined organic layers were 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] 1 H NMR (400 MHz, Chloroform-d) δ 5.36-5.25 (m, 2H), 4.02-3.91 (m, 1H), 3.88-3.83 (m, 1H), 3.80 (s, 3H), 3.52-3.41 (m, 1H), 2.98-2.84 (m, 2H), 2.84-2.74 (m, 1H), 2.14-2.06 (m, 1H), 1.44 (s, 9H), 0.89 (s, 9H), 0.12 (s, 6H).

[0357] Step 2. Synthesis of 3-4

[0358]

[0359] A solution of 3-3 (79.0 g, 0.18 mol) and Et3N.3HF (90.4 g, 0.54 mol) in THF (800 mL) was refluxed with stirring for 16 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 3 / 1) to give 3-4 (41.0 g, 68% yield) as a colorless oil.

[0360] Step 3. Synthesis of 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. The resulting mixture was washed with saturated aqueous Na2S03solution (500 mL), saturated aqueous NaHC03solution (500 mL*2) and brine. The organic layer was separated, dried over Na2S04and 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] To 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 -60 °C under N2atmosphere. The resulting mixture was stirred at -60 °C for 30 min, then 3-5 (37.0 g, 0.11 mol) was added dropwise at -60 °C. The reaction mixture was allowed to warm up to 0 °C and stirred at 0-10 °C for 1 h. The resulting mixture was then added to saturated NH4CI (100 mL, aqueous solution) and the resulting mixture was extracted with EtOAc (500 mL*2). The combined organic layers were washed with brine, dried over Na2S04and filtered. 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] 1H 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] A solution of 3-7-Z (5.5 g, 13.2 mmol) and TsOH.H2O (5.0 g, 26.4 mmol) in DCM (60 mL) was stirred at 20 °C for 16 h. Thereafter, the reaction mixture was diluted with saturated aqueous NaHCO3solution (100 mL) and extracted by DCM (50 mL*2). The combined organic layers were washed with brine, dried over Na2SO4and 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 of 3-10

[0374]

[0375] To a solution of 3-8 (3.0 g, 9.4 mmol) in CH3CN (10 mL) was added 3-9 (3.6 g, 9.4 mmol) and KHCO3(2.8 g, 28.2 mmol). The resulting mixture was stirred at 40 °C for 4 h. Upon completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse-phase column chromatography (C18, CH3CN / H2O = 90 / 10) to give 3-10 (2.5 g, 53% yield) as a yellow oil. LC-MS [M+1] + = 500.2

[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 h. After completion, the reaction was added to saturated aqueous NaHC03solution (50 mL) and extracted with DCM (50 mL*3). The combined organic layers were washed with brine, dried over Na2S04and 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 H 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 H 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).

[0384] 3b-2:​

[0385] 1 H NMR (400 MHz, CDC13) δ 7.64 (s, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.45 (s, 2H), 6.06 (s, 1H), 5.50 (s, 1H), 5.44 (s, 1H), 5.33 (d, J = 12.0 Hz, 1H), 5.22 (d, J = 11.9 Hz, 1H), 4.02-3.97 (m, 1H), 3.86 (d, J = 10.8 Hz, 1H), 3.81 (s, 6H), 3.49 (d, J = 13.6 Hz, 1H), 3.12-3.07 (m, 1H), 2.71-2.66 (m, 1H), 2.03 (d, J = 14.8 Hz, 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 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMF (1 L). To the above solution was added 1-5 (150.0 g, 0.43 mol) and K2CO3 (120 g, 0.864 mol). After addition, the resulting mixture was stirred at 20 °C for 2 h. The reaction was diluted with water (2 L) and extracted by EtOAc (600 L*2). The combined organic layers were 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] A solution of 4-2 (250 g, 0.43 mol) and Et3N.3HF (210 g, 1.296 mol) in THF (1 L) was stirred at 40 °C for 16 h. The resulting mixture was concentrated under reduced pressure and the residue was diluted with EA (1.5 L). The formed solution was washed with brine (500 ml*2) and the organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 3 / 1) to give 4-3 (108 g, 73% yield) as a white solid. LC-MS [M+1]+ -100 = 246.2.

[0394] 1 H NMR (400 MHz, CDC13) δ 4.19 (d, J = 12.1 Hz, 1H), 3.98 (s, 1H), 3.72 (s, 1H), 3.52 (d, J = 15.2 Hz, 2H), 2.90-2.78 (m, 1H), 2.77-2.67 (m, 1H), 2.66-2.56 (m, 1H), 2.11 (s, 3H), 2.02 (d, J = 12.0 Hz, 1H), 1.63-1.49 (m, 1H), 1.45 (s, 9H).

[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 reaction mixture was washed with saturated Na2S203solution (1 L), saturated NaHC03solution (1 L*2), brine, dried over Na2S04and concentrated 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 orange oil. LC-MS [M+1] + +Na = 366.1.

[0398] 1 H NMR (400 MHz, CDC13) δ 4.29 (d, J = 17.9 Hz, 1H), 4.16 (d, J = 18.4 Hz, 1H), 3.82 (s, 1H), 3.48 (d, J = 15.6 Hz, 1H), 3.44-3.32 (m, 2H), 3.27 (s, 1H), 2.43-2.29 (m, 1H), 2.16 (s, 3H), 2.09-2.04 (m, 1H), 1.46 (s, 9H).

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

[0400]

[0401] 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 under N2. The reaction mixture was stirred at -60 °C for 30 min before 4-4 (80 g, 0.233 mol) was added dropwise at -60 °C. The resulting mixture was stirred at 0-10 °C for 1 h. Then the reaction mixture was added to a saturated NH4Cl solution (800 mL) and extracted with EtOAc (700 mL*2). The combined organic layers were washed with brine, dried over Na2S04and 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, CDC13) δ 5.74 (s, 1H), 4.27 (s, 1H), 4.07-3.83 (s, 2H), 3.68 (d, J = 15.1 Hz, 1H), 3.44 (d, J = 15.2 Hz, 1H), 3.25-3.10 (m, 1H), 2.09 (s, 3H), 2.02 (d, J = 14.6 Hz, 1H), 1.85 (d, J = 13.7 Hz, 1H), 1.54-1.32 (m, 18H).

[0404] 4-6-E

[0405] 1 H NMR (400 MHz, CDC13) δ 5.59 (s, 1H), 5.49 (d, J = 15.6 Hz, 1H), 4.00 (d, J = 15.7 Hz, 1H), 3.95-3.80 (m, 1H), 3.61 (s, 1H), 3.40-3.14 (m, 3H), 2.21-2.11 (m, 1H), 2.08 (s, 3H), 1.89 (d, J = 11.4 Hz, 1H), 1.52-1.42 (m, 18H).

[0406] Step 5: Synthesis of 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 h. The resulting mixture was concentrated in vacuo to give 4-7 (15 g, 100% yield) as a dark oil which was used in the next step without further purification. LC-MS [M+1] + = 286.2.

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

[0410]

[0411] To a solution of 4-7 (15 g, crude, 0.023 mol) and 4-8 (5 mL) in DCM was added Et3N dropwise at 20 °C. After the addition, the mixture was stirred at 20 °C for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EA (200 mL) and water (300 ml). The pH value was adjusted to 3 with HC1 (1 M, aqueous solution). The organic layer was separated, washed with brine, dried over Na2S04and concentrated under reduced pressure. The residue was purified by reverse phase column (C18, ACN / H20 = 70 / 30) to give 4 (1.8 g, 16.7% yield). 4 was purified by chiral column chromatography to give 4b-1 and 4b-2. 4:

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

[0414] 1 H NMR (400 MHz, CDC13) δ 7.57 (d, J = 6.7 Hz, 1H), 7.40 (d, J = 6.2 Hz, 1H), 7.32 - 7.23 (m, 2H), 5.79 (s, 0.5H), 5.67 (s, 0.5H), 5.23 (s, 1H), 4.77 - 4.67 (m, 1H), 3.71 (d, J = 4.5 Hz, 3H), 3.60 - 3.52 (m, 1.5H), 3.50 - 3.36 (m, 1.5H), 3.17 (d, J = 12.3 Hz, 0.5H), 2.97 (d, J = 12.4 Hz, 0.5H), 2.90 - 2.82 (m, 0.5H), 2.80 - 2.70 (m, 0.5H), 2.66 (d, J = 8.6 Hz, 1H), 2.30 - 2.13 (m, 1H), 2.06 (s, 3H), 1.93 - 1.81 (m, 1H).

[0415] 4b-1:

[0416] 1H NMR (400 MHz, CDC13) δ 7.71 - 7.63 (m, 1H), 7.50 - 7.43 (m, 1H), 7.38 - 7.32 (m, 2H), 5.89 (s, 1H), 5.29 (d, J = 4.0 Hz, 1H), 4.94 (s, 1H), 3.77 (s, 3H), 3.67 (dd, J = 21.5, 13.7 Hz, 2H), 3.48 (d, J = 15.2 Hz, 1H), 3.35 (d, J = 12.4 Hz, 1H), 2.79 (t, J = 13.1 Hz, 2H), 2.37 - 2.32 (m, 1H), 2.12 (s, 3H), 1.90 (d, J = 14.3 Hz, 1H).

[0417] 4b-2:

[0418] 1 H NMR (400 MHz, CDC13) δ 7.71 - 7.63 (m, 1H), 7.50 - 7.43 (m, 1H), 7.38 - 7.32 (m, 2H), 5.89 (s, 1H), 5.29 (d, J = 4.0 Hz, 1H), 4.94 (s, 1H), 3.77 (s, 3H), 3.67 (dd, J = 21.5, 13.7 Hz, 2H), 3.48 (d, J = 15.2 Hz, 1H), 3.35 (d, J = 12.4 Hz, 1H), 2.79 (t, J = 13.1 Hz, 2H), 2.37 - 2.32 (m, 1H), 2.12 (s, 3H), 1.90 (d, J = 14.3 Hz, 1H).

[0419] Example 5

[0420]

[0421] Step 1: Synthesis of 5-3

[0422]

[0423] To a mixture of 5-1 (10 g, 28.8 mmol) and K2CO3 (4.8 g, 34.6 mmol) in DMF (100 ml) was added 5-2 (7.6 g, 31.6 mmol) portion wise at 20 °C. After addition, the mixture was stirred at 20 °C for 2 h. The mixture was poured into water (300 mL), extracted with EA (200 mL), the organic layer was washed with brine, dried over Na2SO4, 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 colorless oil.

[0424] 1H NMR (400 MHz, CDC13) δ 5.21 (s, 2H), 3.89 (d, J = 15.2 Hz, 1H), 3.74 (s, 1H), 3.49 (s, 1H), 3.03 (ddd, J = 13.1, 9.8, 3.1 Hz, 1H), 2.97 - 2.77 (m, 2H), 2.19 - 2.02 (m, 1H), 61.60 - 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 Et3N.3HF (4.6 g, 28.6 mmol) and the resulting mixture was stirred at 50 °C for 16 h. Upon 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 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. Upon completion, the reaction mixture was poured into a mixture of saturated Na2S203 / saturated NaHC03(50 mL, 1:1). The resulting mixture was extracted with DCM (20 mL*2). The combined organic layers were washed with brine, dried over Na2S04and filtered. 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 colorless oil.

[0431] Step 4. Synthesis of 5-7

[0432]

[0433] 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) at -60 °C under N2. The resulting mixture was stirred at -60 °C for 30 min. 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 h. Then the reaction mixture was poured into a saturated NH4Cl (20 mL) solution, and the resulting mixture was extracted with EtOAc (20 mL*2). The combined organic layers were washed with brine, dried over Na2SO4, 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, CDC13) δ 5.75 (s, 1H), 5.58 (s, 1H), 5.29 (d, J = 12.0 Hz, 1H), 5.18 (d, J = 12.0 Hz, 1H), 4.39-4.10 (m, 1H), 4.00 (s, 2H), 3.18 (s, 1H), 2.08 (dd, J = 16.1, 9.9 Hz, 1H), 1.91 (d, J = 13.8 Hz, 1H), 1.49 (d, J = 12.7 Hz, 18H), 1.21 (s, 9H).

[0435] Step 5. Synthesis of 5-8

[0436]

[0437] A mixture of 5-7 (450 mg, 1.01 mmol) and TsOH.H2O (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 a saturated NaHCO3 solution (20 mL), and the resulting mixture was extracted with DCM (20 mL*2). The combined organic layers were dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give crude 5-8 (450 mg, >100% yield) as a colorless oil.

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

[0439] Step 6. Synthesis of 5-10

[0440]

[0441] To a solution of 5-8 (crude, 1.01 mmol) in CH3CN (5 mL) was added 5-9 (389 mg, 1.01 mmol) and KHCO3 (400 mg, 4.04 mmol). The resulting mixture was stirred at 40 °C for 3 h 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, CDC13) δ 7.60 (d, J = 6.4 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 11.8 Hz, 2H), 5.68 (s, 1H), 5.51 (d, J = 3.7 Hz, 1H), 5.26 (d, J = 12.1 Hz, 1H), 5.14 (d, J = 12.0 Hz, 1H), 4.77 (s, 1H), 3.70 (s, 3H), 3.52 (d, J = 11.9 Hz, 1H), 3.10 (d, J = 12.0 Hz, 1H), 2.59 (d, J = 8.5 Hz, 2H), 2.28 - 2.09 (m, 1H), 1.84 (d, J = 14.3 Hz, 1H), 1.47 (s, 9H), 1.18 (s, 9H).

[0444] Step 7. Synthesis of 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 a saturated NaHCO3 (2 mL) mixture and extracted with DCM (2 mL*2). The combined organic layers were washed with brine, dried over Na2SO4, 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] 1H NMR (400 MHz, CDC13) δ 7.57 (d, J = 6.4 Hz, 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, 8.0 Hz, 1H), 5.13 (dd, J = 12.0, 6.4 Hz, 1H), 4.80 (s, 1H), 3.70 (d, J = 4.4 Hz, 3H), 3.55 (dd, J = 26.1, 12.2 Hz, 1H), 3.15 (d, J = 12.2 Hz, 0.5H), 2.95 (d, J = 12.5 Hz, 0.5H), 2.85 (d, J = 10.6 Hz, 0.5H), 2.73 (t, J = 11.4 Hz, 0.5H), 2.65 (d, J = 7.9 Hz, 1H), 2.32 - 2.12 (m, 1H), 1.88 (t, J = 15.8 Hz, 1H), 1.16 (d, J = 3.3 Hz, 9H).

[0449] Example 6

[0450]

[0451] Step 1: Synthesis of 6-3

[0452]

[0453] To a mixture of 6-1 (5.00 g, 14.4 mmol) and Et3N (2.3 g, 20.0 mmol) in DCM (50 mL) was added 6-2 (1.76 g, 18.7 mmol) portion wise at 20 °C. 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 colorless oil.

[0454] Step 2: Synthesis of 6-4

[0455]

[0456] To a solution of 6-3 (3.5 g, 8.6 mmol) in THF (40 mL) was added Et3N.3HF (4.12 g, 25.9 mmol) and the resulting mixture was stirred at 50 °C for 16 h. 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 colorless oil.

[0457] 1H NMR (400 MHz, CDC13) δ 4.18 (dd, J = 13.3, 4.3 Hz, 1H), 3.91 (s, 1H), 3.82 (s, 3H), 3.53 (s, 1H), 3.33 (td, J = 11.0, 4.3 Hz, 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. Upon completion, the reaction mixture was poured into a mixture of saturated Na2S203 / saturated NaHC03(40 mL, 1:1). The resulting mixture was extracted with DCM (20 mL*2). The combined organic layers were washed with brine, dried over Na2S04and 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] To a solution of 6-6 (1.0 g, 3.80 mmol) in THF (10 mL) was added LiHMDS (3.8 mL, 1M in THF, 3.8 mmol) at -60 °C under N2and stirred at -60 °C for 30 min. 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 h. Then the reaction mixture was poured into a saturated NH4C1 (20 mL) solution and the resulting mixture was extracted with EtOAc (20 mL*2). The combined organic layers were washed with brine, dried over Na2S04and filtered. The filtrate was concentrated in vacuo. The reaction was repeated 5 times and 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] 1H NMR (400 MHz, CDC13) δ 5.74 (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] A mixture of 6-7 (30 mg, 0.0775 mmol) and TsOH.H20 (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 NaHC03solution (5 mL), and the resulting mixture was extracted with DCM (2 mL*2). The combined organic layers were dried over Na2S04and filtered. The filtrate was concentrated in vacuo to give crude 6-8 (crude, yield >100%) as a light yellow oil.

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

[0469] Step 6. Synthesis of 6-10

[0470]

[0471] To a solution of 6-8 (crude, 0.0775 mmol) in CH3CN (1 mL) was added 6-9 (30 mg, 0.0775 mmol) and KHCO3(31 mg, 0.31 mmol). The resulting mixture was stirred at 40 °C for 3 h 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] 1H NMR (400 MHz, CDC13) δ 7.58 (dd, J = 8.0, 5.3 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.27 (d, J = 4.9 Hz, 2H), 5.71 (s, 1H), 5.61 (d, J = 54.0 Hz, 1H), 4.76 (s, 1H), 3.80 (s, 3H), 3.70 (s, 3H), 3.18 (q, J = 12.6 Hz, 1H), 3.11 - 2.86 (m, 2H), 2.78 - 2.54 (m, 1H), 2.18 (dd, J = 28.3, 12.9 Hz, 1H), 1.95 (dd, J = 22.6, 14.5 Hz, 1H), 1.46 (t, J = 11.9 Hz, 9H).

[0474] Step 7. Synthesis of 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 h. The resulting mixture was poured into a mixture of saturated NaHC03(3 mL) and extracted with DCM (2 mL*2). The combined organic layers were washed with brine, dried over Na2S04and 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, CDC13) δ 7.56 (s, 1H), 7.40 (s, 1H), 7.27 (s, 2H), 5.70 (d, J = 31.6 Hz, 2H), 4.79 (s, 1H), 3.79 (s, 3H), 3.71 (s, 3H), 3.25 (s, 1H), 3.12 (dd, J = 48.2, 12.7 Hz, 1H), 2.91 (s, 0.5H), 2.84 - 2.56 (m, 1.5H), 2.23 (s, 1H), 1.97 (dd, J = 34.1, 17.2 Hz, 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 h. Upon completion, the reaction mixture was poured into a mixture of saturated Na2S203 / saturated NaHC03(40 mL, 1 : 1). The resulting mixture was extracted with DCM (20 mL*2). The combined organic layers were washed with brine, dried over Na2S04, 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 7-2 (1.3 g, 65% yield) as a light yellow oil.

[0484] 1 H NMR (400 MHz, cdcl3) δ 7.95 (d, J = 7.3 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 4.49-4.29 (m, 2H), 4.05 (d, J = 17.6 Hz, 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] 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) at -60 °C under N2, and the resulting mixture was stirred at -60 °C for 30 min. To the above mixture was added 7-2 (1.3 g, 3.9 mmol) dropwise at -60 °C. After the addition, the reaction mixture was stirred at 0-10 °C for 1 h. Then the reaction mixture was poured into a saturated NH4C1 (30 mL) solution, and the resulting mixture was extracted with EtOAc (20 mL*2). The combined organic layers were washed with brine, dried over Na2S04, 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] 1H NMR (400 MHz, CDC13) δ 7.98 (d, J = 7.4 Hz, 2H), 7.59 (d, J = 6.6 Hz, 1H), 7.47 (t, J = 7.1 Hz, 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 = 14.0 Hz, 1H), 1.62 - 1.36 (m, 18H).

[0489] Step 3. Synthesis of 7-5

[0490]

[0491] A mixture of 7-4 (60 mg, 0.138 mmol) and TsOH.H20 (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 NaHC03solution (4 mL), and the resulting mixture was extracted with DCM (2 mL*2). The combined organic layers were dried over Na2S04and filtered. The filtrate was concentrated in vacuo to give crude 7-5 (50 mg, >100% yield) as a light yellow oil.

[0492] Step 4. Synthesis of 7-7

[0493]

[0494] To a solution of 7-5 (crude, 0.138 mmol) in CH3CN (2 mL) was added 7-6 (53 mg, 0.138 mmol) and KHCO3(55 mg, 0.552 mmol). The resulting mixture was stirred at 40 °C for 3 h. 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 a mixture of saturated NaHC03(4 mL) and extracted with DCM (2 mL*2). The combined organic layers were washed with brine, dried over Na2S04, 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, CDC13) δ 7.89 (d, J = 8.2 Hz, 2H), 7.58 (dd, J = 7.3, 2.1 Hz, 1H), 7.51 (dd, J = 8.9, 5.9 Hz, 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 = 4.5 Hz, 1H), 3.70 (d, J = 4.2 Hz, 3H), 3.28 (d, J = 12.8 Hz, 1H), 3.12 (dd, J = 34.1, 12.4 Hz, 1H), 2.93 (d, J = 12.3 Hz, 1H), 2.73 (d, J = 9.2 Hz, 0.5H), 2.68 - 2.57 (m, 1H), 2.33 - 2.14 (m, 0.5H), 1.88 (t, J = 17.4 Hz, 1H).

[0501] Example 8

[0502]

[0503] Step 1: Synthesis of 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 liquid) portionwise at 0 °C. After the addition, the mixture was stirred at 0 °C for 1 h. 8-2 (1.86 g, 17.2 mmol) was added at 0 °C and stirred at 0 °C for 0.5 h. The reaction mixture was poured into a saturated NH4Cl (100 ml) solution, extracted with EA (50 ml), the organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, 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, CDC13) δ 3.88 - 3.66 (m, 1H), 3.64 - 3.42 (m, 3H), 3.18 (d, J = 33.4 Hz, 1H), 3.15 - 3.02 (m, 1H), 3.03 - 2.90 (m, 6H), 2.28 - 2.13 (m, 1H), 1.99 (d, J = 9.4 Hz, 1H), 1.41 (d, J = 14.9 Hz, 9H), 0.91 - 0.77 (m, 9H), 0.14 - 0.02 (m, 6H).

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

[0508] Step 2: Synthesis of 8-4

[0509]

[0510] To a solution of 8-3 (3.9 g, 9.3 mmol) in THF (40 mL) was added Et3N.3HF (4.5 g, 28.0 mmol) and the resulting mixture was stirred at 50 °C for 16 h. Upon 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] 1H NMR (400 MHz, CDC13) δ 4.29 (dd, J = 8.2, 5.2 Hz, 1H), 4.10 (m, 1H), 3.50-3.31 (m, 2H), 2.99 (s, 6H), 2.75 (s, 1H), 2.64 (dd, J = 13.2, 9.7 Hz, 1H), 1.96 (ddd, J = 13.2, 6.6, 2.9 Hz, 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. Upon completion, the reaction mixture was poured into a mixture of saturated Na2S203 / saturated NaHC03(40 mL, 1:1). The resulting mixture was extracted with DCM (20 mL*2). The combined organic layers were washed with brine, dried over Na2S04, 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] 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) at -60 °C under N2, and stirred at -60 °C for 30 min. To the resulting mixture was added 8-5 (1.6 g, 5.3 mmol) dropwise at -60 °C. After the addition, the reaction mixture was stirred at 0-10 °C for 1 h. Then the reaction mixture was poured into a saturated NH4Cl (20 mL) solution, and the resulting mixture was extracted with EtOAc (20 mL*2). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo. The reaction was repeated 5 times, and 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, CDC13) δ 5.90 (s, 1H), 5.18 (d, J = 14.0 Hz, 1H), 4.41 (s, 1H), 4.19 (d, J = 16.1 Hz, 1H), 3.77 (s, 1H), 3.33 (s, 1H), 2.98 (s, 6H), 2.13 (s, 1H), 2.01 - 1.80 (m, 1H), 1.44 (d, J = 10.3 Hz, 18H).

[0522] Step 5. Synthesis of 8-8

[0523]

[0524] A mixture of 8-7 (50 mg, 0.125 mmol) and TsOH.H20 (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 a saturated NaHC03solution (2 mL), and the resulting mixture was extracted with DCM (2 mL*2). The combined organic layers were dried over Na2S04, and filtered. The filtrate was concentrated in vacuo to give crude 8-8 (crude, >100% yield) as a light yellow oil.

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

[0526] Step 6. Synthesis of 8-10

[0527]

[0528] ​​To a solution of 8-8 (crude, 0.125 mmol) in CH3CN (1 mL) was added 8-9 (38.1 mg, 0.100 mmol) and KHCO3 (50 mg, 0.500 mmol). The resulting mixture was stirred at 40 °C for 3 h 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 yellow solid.

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

[0530] 1 H NMR (400 MHz, CDC13) δ 7.63 - 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 = 5.0 Hz, 1H), 3.69 (d, J = 1.1 Hz, 3H), 3.29 - 3.08 (m, 1H), 3.07 - 2.98 (m, 1H), 2.93 (d, J = 19.1 Hz, 6H), 2.89 (d, J = 11.8 Hz, 0.5H), 2.76 (td, J = 12.0, 2.5 Hz, 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 of 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 h. The resulting mixture was poured into a saturated NaHCO3 (3 mL) solution and extracted with DCM (2 mL*2). The combined organic layers were washed with brine, dried over Na2SO4, 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, CDC13) δ 7.64-7.52 (m, 1H), 7.41-7.35 (m, 1H), 7.32-7.18 (m, 2H), 5.71 (d, J = 39.7 Hz, 1H), 5.42-5.31 (m, 1H), 4.76 (d, J = 2.6 Hz, 1H). 3.69 (d, J = 5.0 Hz, 3H), 3.36 (d, J = 12.1 Hz, 0.5H), 3.27 (d, J = 12.2 Hz, 0.5H), 3.18 (d, J = 12.1 Hz, 0.5H), 2.98 (s, 6H), 2.89 (d, J = 11.7 Hz, 0.5H), 2.79-2.62 (m, 2H), 2.33-2.11 (m, 1H), 1.91 (t, J = 15.9 Hz, 1H).

[0536] Example 9

[0537]

[0538] Step 1: Synthesis of 9-2

[0539]

[0540] To compound 9-SM (11.0 g, 85.3 mmol) was added dimethylamine (1.76 g, 18.7 mmol) portion-wise at 20 °C. 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 9-2 (7.8 g, 69% yield) as a colorless oil.

[0541] Step 2: Synthesis of 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) portion-wise at 0 °C. After addition, the mixture was stirred at 0 °C for 1 h. 9-2 (2.37 g, 17.3 mmol) was added at 0 °C and stirred at 0 °C for 0.5 h. The mixture was poured into a saturated NH4Cl (100 mL) solution, extracted with EA (50 mL), the organic layer was washed with brine, dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure, 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, CDC13) δ 5.25 (s, 2H), 3.90 (d, J = 3.6 Hz, 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 = 2.0 Hz, 9H), 0.97 - 0.73 (m, 9H), 0.14 - 0.02 (m, 6H).

[0545] Step 3: Synthesis of 9-4

[0546]

[0547] To a solution of 9-3 (4.7 g, 10.5 mmol) in THF (50 mL) was added Et3N.3HF (5.0 g, 31.5 mmol) and the resulting mixture was stirred at 50 °C for 16 h. Upon 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, CDC13) δ 5.34 (d, J = 12.1 Hz, 1H), 5.18 (d, J = 12.1 Hz, 1H), 4.25 (d, J = 10.8 Hz, 1H), 4.10 - 3.70 (m, 1H), 3.42 (s, 1H), 3.10 (s, 1H), 2.90 (d, J = 7.7 Hz, 6H), 2.86 - 2.68 (m, 2H), 2.66 (dd, J = 13.1, 9.7 Hz, 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. Upon completion, the reaction mixture was poured into a mixture of saturated Na2S203 / saturated NaHC03(100 mL, 1:1). The resulting mixture was extracted with DCM (50 mL*2). The combined organic layers were washed with brine, dried over Na2S04and 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, CDC13) δ 5.22 (d, J = 12.1 Hz, 1H), 5.12 (d, J = 12.1 Hz, 1H), 4.24 (d, J = 17.5 Hz, 1H), δ 4.16 - 4.06 (m, 1H), 3.72 (t, J = 5.3 Hz, 2H), 3.48 (ddd, J = 13.7, 9.5, 4.1 Hz, 1H), 2.90 (d, J = 10.3 Hz, 6H), 2.34 (dd, J = 9.5, 5.0 Hz, 1H), 2.15 - 1.96 (m, 1H), 1.44 (s, 9H).

[0553] Step 5. Synthesis of 9-7

[0554]

[0555] To a solution of 9-6 (1.7 g, 6.6 mmol) in THF (20 mL) was added LiHMDS (6.6 mL, 1M in THF, 6.6 mmol) at -60 °C under N2and stirred at -60 °C for 30 min. To the resulting mixture was added 9-5 (2.0 g, 6.0 mmol) dropwise at -60 °C. After addition, the reaction mixture was stirred at 0-10 °C for 1 h. Then the reaction mixture was poured into a saturated NH4Cl (50 mL) solution and the resulting mixture was extracted with EtOAc (30 mL*2). The combined organic layers were washed with brine, dried over Na2S04and filtered. The filtrate was concentrated in vacuo. The reaction was repeated 5 times and 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] 1H NMR (400 MHz, CDC13) δ 5.72 (s, 1H), 5.51 (s, 1H), 5.29 (s, 0.5H), 5.26 (s, 0.5H), 5.07 (d, J = 12.0 Hz, 1H), 4.40 - 4.04 (m, 1H), 3.97 (d, J = 20.3 Hz, 2H), 3.15 (s, 1H), 2.88 (d, J = 5.3 Hz, 6H), 2.03 (dd, J = 16.7, 10.0 Hz, 1H), 1.86 (d, J = 13.9 Hz, 1H), 1.45 (dd, J = 12.1, 5.8 Hz, 18H).

[0557] Step 6. Synthesis of 9-8

[0558]

[0559] A mixture of 9-7 (800 mg, 1.8 mmol) and TsOH.H20 (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 NaHC03solution (30 mL), and the resulting mixture was extracted with DCM (10 mL*2). The combined organic layers were dried over Na2S04and 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 a solution of 9-8 (185 mg, 0.56 mmol) in CH3CN (2 mL) was added 9-9 (194 mg, 0.50 mmol) and KHCO3(224 mg, 2.24 mmol). The resulting mixture was stirred at 40 °C for 3 h and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by Prep-TLC (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 (CDCI3 (400 MHz,) δ 7.61-7.57 (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 = 4.4 Hz, 1H), 5.28-5.21 (m, 1H), 5.06 (dd, J = 12.0, 7.8 Hz, 1H), 4.75 (s, 1H), 3.68 (d, J = 3.8 Hz, 3H), 3.53-3.47 (m, 0.5H), 3.40 (d, J = 11.4 Hz, 0.5H), 3.08 (d, J = 12.1 Hz, 0.5H), 2.92-2.79 (m, 6.5H), 2.71 (dt, J = 11.9, 6.0 Hz, 1H), 2.59 (dd, J = 10.2, 2.5 Hz, 1H), 2.29-2.11 (m, 1H), 1.89 (dd, J = 14.3, 2.2 Hz, 1H), 1.43 (d, J = 6.6 Hz, 9H).

[0566] Step 8. Synthesis of 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 a mixture of saturated NaHC03(15 mL), extracted with DCM (5 mL*2). The combined organic layers were washed with brine, dried over Na2S04, 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] 1H NMR(CDCl3(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 =12.4Hz,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] Pharmacokinetic experiments were conducted using male Sprague-Dawley rats.

[0574] Test compounds (clopidogrel and exemplary compounds provided herein) were administered orally or intravenously to fasted rats. Blood samples were collected via jugular vein at 5, 15, 30, 60, and 120 minutes using EDTA-K2 (anticoagulant), 3'-methoxybenzoylmethyl bromide (MPBr, derivatizing agent), and phenylmethylsulfonyl fluoride (PMSF, stabilizer). Plasma samples were then collected by centrifugation at 1500 g for 10 minutes at 2–8 °C and stored at -80 °C after separation. Plasma samples were loaded into an LC-MS / MS instrument after extraction to determine the concentration of thiol active metabolites. Figure 1 and 2 The results show the concentration in rat plasma.

[0575] like Figure 1 As shown, at a dose level of 10 mg / kg, compounds 1a, 1b, and 2a presented herein reached peak concentrations of the thiol active metabolite in less than 20 minutes after administration, compared to clopidogrel, which reached peak concentrations approximately 30 minutes after administration. Furthermore, the peak concentrations of the thiol active metabolite in compounds 1a, 1b, and 2a were significantly higher than those in clopidogrel. These results indicate that compounds 1a, 1b, and 2a provide a faster and more efficient release of the active metabolite compared to clopidogrel.

[0576] As Figure 2 shown, when administered orally, Compound 3 provided herein reaches peak concentration at about 20 minutes post administration at a dose level of 2 mg / kg, compared to clopidogrel which reaches peak concentration of the thiol active metabolite at about 30 minutes post administration at a much higher dose level of 10 mg / kg. When administered intravenously, Compound 3 provided herein reaches peak concentration of the thiol active metabolite at about 6 minutes post administration at a dose level of only 1 mg / kg. These results indicate that Compound 3 provides faster and more efficient release of the active metabolite compared to clopidogrel.

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

[0578] Assay 2: Anti-aggregatory effect in rats

[0579] Male Sprague-Dawley rats were used for ex vivo 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 hour, 1 hour, and 2 hour time points using a 3.8% (w / v) sodium citrate solution as an anticoagulant (1 / 9 volume of whole blood). The citrated blood sample was centrifuged at low speed of 1000 rpm for 5 minutes to obtain platelet-rich plasma (PRP). After isolation of PRP, the remaining blood was further centrifuged at high speed of 3000 rpm for 10 minutes to obtain platelet-poor plasma (PPP). Platelet number in PRP was measured by a hematology analyzer (Siemens, ADVIA 2120) and adjusted to 4 x 10 8 / mL by PPP.

[0580] Platelet aggregation was determined by turbidimetric aggregation method using an automated platelet aggregometer (PRECIL LBY-NJ4). The aggregometer was first warmed to 37°C, and a PRP (290 μΐ^) sample was added to a cuvette and placed in the automated platelet aggregometer. After a 5-minute pre-incubation, the aggregometer was calibrated using PPP to represent 100% aggregation and PRP to represent 0% aggregation. Finally, a volume of 10 μΐ^ of ADP solution (final concentration of 10 μΜ) was added to the PRP sample to initiate platelet aggregation. Platelet aggregation was monitored for 5 minutes and the maximum platelet aggregation (%) was reported over the duration. Anti-aggregatory effect of the test compound was expressed as inhibition (%) determined by the following relationship:

[0581] Inhibition (%) = (Maximum platelet aggregation (%) of control - Maximum platelet aggregation (%) of test compound) / (Maximum platelet aggregation (%) of control) * 100

[0582] Inhibition (%) results for 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. As can be seen from Figure 2 Clopidogrel reached a maximum platelet aggregation inhibition of about 45% within about 120 minutes after administration, while compound 1b reached a maximum inhibition of about 45% within 60 minutes after administration at a much lower dose level than clopidogrel, indicating that it has a much earlier onset of action and is much more potent than clopidogrel.

[0583] Other compounds provided herein can show a faster onset and higher potency than clopidogrel.

[0584] The foregoing description is considered as illustrative only of the principles of the disclosure. Furthermore, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the application to the exact construction and process shown. Therefore, all suitable modifications and equivalents should be considered as falling within the scope of the application as defined by the claims appended hereto.

Claims

1. A compound having a formula selected from the group consisting of: or a pharmaceutically acceptable salt thereof. and ， 2. The compound of claim 1, wherein the compound has the structure: or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound has the structure: ， 4. The compound of claim 1, wherein the compound has the structure: or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein the compound has the structure: 。 6. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. ， 7. The pharmaceutical composition of claim 6, formulated for oral or injectable administration. ​ 。 ​ ​

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