HK40090099A - Antiplatelet drugs and uses thereof - Google Patents

Description

Antiplatelet drugs and their uses

Invention Field

This disclosure generally relates to compounds that exhibit activity in inhibiting platelet aggregation and pharmaceutical compositions comprising such compounds, as well as methods of treatment by administering such compounds or said pharmaceutical compositions.

Background Technology

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

Clopidogrel is a globally known and widely used antithrombotic drug, and it is a prodrug that requires biotransformation to become active. After absorption, 85% of clopidogrel is hydrolyzed into an inactive carboxylic acid by esterases. The remaining 15% of clopidogrel undergoes a two-step oxidation process via hepatic cytochrome P450 isoenzymes (mainly CYP2C19). The transiently active thiol metabolite specifically and irreversibly binds to platelet P2Y12 receptors.

However, clopidogrel has many drawbacks, including patient-to-patient variability in antithrombotic effects and resistance in some patients due to differences in CYP2C19 expression levels among individuals; low conversion rate to the active metabolite and therefore a high loading dose (600 mg); slow onset of action (2 hours after the loading dose); low solubility in aqueous solution; and the lack of injectable formulations available for acute treatment; drug-drug interactions, etc.

Therefore, there is a need in the art to develop improved compounds that exhibit activity in inhibiting platelet aggregation without the disadvantages listed above.

Summary of the Invention

This disclosure provides compounds capable of inhibiting platelet aggregation, pharmaceutical compositions comprising these compounds, and methods of treating vascular diseases using said compounds or pharmaceutical compositions.

In one aspect, this disclosure provides a compound having formula (I):

Or its pharmaceutically acceptable salt.

in

Indicates a double bond with a Z or E configuration;

R ¹ is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, amino, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, and heteroynyl, wherein each of the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, and heteroynyl groups is optionally substituted by one or more ^Ra .

^R2 is -C(O) ^Rb ;

R ³ is 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.

L is selected from the group consisting of: straight, 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 substituted by one or more R ^f ;

W is selected from the following group:

Where the * end of W is connected to L;

R ⁴ is 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.

Each of ^Ra is independently selected from the group consisting of: hydrogen, halogen, hydroxyl, amino, cyano, nitro, or ^{-NRcRd ;}

^Rb is 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 , ^-NRcRd and ^-ORe ;

Each of ^Rc and ^Rd 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.

^Re is 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.

Each of ^Rf is independently selected from the group consisting of: hydrogen, cyano, halogen, hydroxyl, amino, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclic, aryl, and heteroaryl; or

The two R ^f groups together with the atoms they are attached to form a saturated or partially unsaturated cycloalkyl group or a saturated or partially unsaturated heterocyclic group, wherein each of the cycloalkyl group and the heterocyclic group is optionally substituted with a cyano group, a halogen group, a hydroxyl group, an amino group or an alkyl group.

R ^g is 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 hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocyclic, aryl and heteroaryl is optionally substituted by cyano, halogen, hydroxyl or amino.

n can be 0, 1, 2, 3, 4, or 5.

In some embodiments, this disclosure provides compounds having a formula selected from the group consisting of:

Or its pharmaceutically acceptable salt.

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

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

In another aspect, this disclosure provides a method for inhibiting platelet aggregation in an individual in need, comprising administering to the individual in need an effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

In another aspect, this disclosure provides for the use of the disclosed compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof in the manufacture of medicaments for the treatment of vascular diseases.

In another aspect, this disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure for the treatment of vascular diseases.

On the other hand, this disclosure provides compounds having the following formula:

In another aspect, this disclosure provides compounds having the following formula:

Attached Figure Description

Figure 1 shows the concentrations of the active metabolites in rat plasma after oral administration of (a) clopidogrel, compound 1a and compound 1b, and (b) clopidogrel, compound 2a and compound 2b at a dose level of 10 mg/kg.

Figure 2 shows the concentrations of the active metabolite in rat plasma 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.

Figure 3 shows the inhibition (%) of agglutination after oral administration of the test compounds to rats at dose levels of 10 mg/kg (clopidogrel), 0.5 mg/kg (compound 1a), and 2 mg/kg (compound 1b).

Detailed Implementation

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.

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.

definition

The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this disclosure, chemical elements are identified according to the periodic table, CAS version, *Handbook of Chemistry and Physics*, 75th edition, inner cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional groups and reactivity, are described in *Organic Chemistry*, Thomas Sorrell, 2nd edition, University Science Books, Sausalito, 2006; Smith and March, *March's Advanced Organic Chemistry*, 6th edition, John Wiley & Sons, Inc., New York, 2007; Lar ock, Comprehensive Organic Transformations, 3rd ed., VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4th ed., Cambridge University Press, Cambridge, 2004; the entire contents of each of these are incorporated herein by reference.

Linking substituents are described in several places in this disclosure. In particular, each linking substituent is intended to include both the forward and reverse forms of the linking substituent. For example, -NR(CR'R")- includes both -NR(CR'R")- and -(CR'R")NR-. Where the structure explicitly requires a linking group, the Markush variable listed with respect to said group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition of said variable lists "alkyl", then it should be understood that said "alkyl" means linked alkylene.

When the bond to a substituent is shown to be an intersecting bond with two atoms in the connecting ring, then the substituent may be bonded to any atom in the ring. When the listed substituents do not indicate that the substituent is bonded to atoms of the remainder of the given compound, then the substituent may be bonded via any atom in the formula. Combinations of substituents and/or variables are permissible, but only if the combination produces a stable compound.

When an asterisk (*) is displayed adjacent to an atom of a compound, it indicates that the compound contains the atom as an asymmetric center of an (R) or (S) stereoconfiguration.

When any variable (e.g., ^Ri ) appears more than once in any component or formula of a compound, its definition for each occurrence is independent of its definition for every other occurrence. Thus, for example, if a group appears to be partially substituted by 0-2 ^Ri , then the group may optionally be partially substituted by up to two ^Ri , and ^Ri is selected independently from the definition of ^Ri for each occurrence. Furthermore, combinations of substituents and/or variables are permissible, but only if such combinations produce a stable compound.

As used herein, the term "C_{_ij}" indicates a range of carbon atoms, where i and j are integers, and the range includes the endpoints (i.e., i and j) and every integer point in between, where j is greater than i. For example, C _{_1-6} indicates a range of one to six carbon atoms, including one, two, three, four, five, and six carbon atoms. In some embodiments, the term "C _{_1-12} " indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3, or particularly 1 to 2 carbon atoms.

Whether used as part of another term or independently, as used herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon group that may optionally be substituted independently by one or more substituents as described below. The term "C_{_ij}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. Examples of "C _1-6 alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, etc.

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

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

As used herein, the term "amino" refers to the _-NH₂ group. Amino groups can also be substituted by one or more groups, such as alkyl, aryl, carbonyl, or other amino groups.

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

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

As used in this article, the term "cyano" refers to -CN.

As used herein, the term "halogen" refers to an atom selected from fluorine, chlorine, bromine, and iodine.

As used herein, the term “heteroatom” refers to nitrogen, oxygen, sulfur, or phosphorus, and includes any oxidized form of nitrogen or sulfur, as well as any quaternized form of basic nitrogen (including N-oxides).

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

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

Whether used as part of another term or independently, as used herein, the term "heteroaryl" refers to an aryl group having one or more heteroatoms in addition to a carbon atom. Heteroaryl groups can be monocyclic. Examples of monocyclic heteroaryl groups include (but are not limited to) thiophene, furanyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, indoleazinyl, purine, naphridinyl, benzofuranyl, and pteridinyl. Heteroaryl groups also include polycyclic groups fused with one or more aryl, cycloaliphatic, or heterocyclic rings, wherein the linking group or linking point is located on the heteroaryl ring. Examples of polycyclic heteroaryl groups include (but are not limited to) indolyl, isoindolyl, benzothiophene, benzofuranyl, benzo[1,3]dioxacyclopentenyl, dibenzofuranyl, indazole, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, terolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinazinyl, carbazolyl, acridineyl, phenazinyl, phenothiazinyl, phenotoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

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

In some embodiments, the term "3- to 12-membered heterocyclic group" refers to a 3- to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having one to three heteroatoms independently selected from nitrogen, oxygen, or sulfur. Fused, spirocyclic, and bridging ring systems are also included within the scope of this definition. Examples of monocyclic heterocyclic groups include (but are not limited to) oxobutyranyl, 1,1-dioxothiobutyranylpyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, piperidinyl, morpholinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazonyl, triazinyl, pyridoneyl, pyrazinonyl, pyridazonyl, pyrrolidinyl, triazinonyl, etc. Examples of fused heterocyclic groups include (but are not limited to) phenyl fused rings or pyridyl fused rings, such as quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinazinyl, quinazolinyl, azaindolazinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolazinyl, indazole, purine, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothiopheneyl, benzothiazolyl, carbazole, phenazinyl, phenthiazolyl, phenidinyl, imidazole[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[4,3-a]pyridinyl, etc. Examples of spiroheterocyclic groups include (but are not limited to) spiropyranyl, spiroxazinyl, etc. Examples of bridging heterocyclic groups include (but are not limited to) morphanyl, hexamethylenetetramine, 3-azabicyclo[3.1.0]hexane, 8-azabicyclo[3.2.1]octane, 1-azabicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane (DABCO), etc.

As used in this article, the term "hydroxyl group" refers to -OH.

As used herein, the term "partially unsaturated" refers to a group comprising at least one double or triple bond. The term "partially unsaturated" is intended to cover rings having multiple unsaturated sites, but is not intended to include aromatic (i.e., completely unsaturated) moieties.

As used herein, the term “substituted,” whether or not preceded by the term “optionally,” means that one or more hydrogen atoms of the specified moiety are replaced by suitable substituents. It should be understood that “substituted” or “substituted” includes the implied limitation that the substitution is consistent with the permissible valence state of the substituted atom, and that the substitution produces a stable or chemically viable compound, such as a compound that does not spontaneously transform through rearrangement, cyclization, elimination, etc. Unless otherwise specified, a “optionally substituted” group may have suitable substituents at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure can be substituted by more than one substituent selected from the specified group. Those skilled in the art will understand that, where appropriate, the substituent itself may be substituted. Unless specifically stated as “unsubstituted,” references to the chemical moiety herein should be understood to include substituted variants. For example, references to “aryl” or the “aryl” moiety implicitly include both substituted and unsubstituted variants.

compound

This disclosure provides novel compounds of formula (I) and pharmaceutically acceptable salts thereof, synthetic methods for manufacturing said compounds, pharmaceutical compositions containing them, and various uses of the disclosed compounds.

In one aspect, this disclosure provides a compound having formula (I):

Or its pharmaceutically acceptable salt.

in

Indicates a double bond with a Z or E configuration;

R ¹ is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, amino, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, and heteroynyl, wherein each of the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, and heteroynyl groups is optionally substituted by one or more ^Ra .

^R2 is -C(O) ^Rb ;

R ³ is 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.

L is selected from the group consisting of: straight, 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 substituted by one or more R ^f ;

W is selected from the following group:

Where the * end of W is connected to L;

R ⁴ is 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.

Each of ^Ra is independently selected from the group consisting of: hydrogen, halogen, hydroxyl, amino, cyano, nitro, or ^{-NRcRd ;}

^Rb is 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 , ^-NRcRd and ^-ORe ;

Each of ^Rc and ^Rd 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.

^Re is 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.

Each of ^Rf is independently selected from the group consisting of: hydrogen, cyano, halogen, hydroxyl, amino, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclic, aryl, and heteroaryl; or

The two R ^f groups together with the atoms they are attached to form a saturated or partially unsaturated cycloalkyl group or a saturated or partially unsaturated heterocyclic group, wherein each of the cycloalkyl group and the heterocyclic group is optionally substituted with a cyano group, a halogen group, a hydroxyl group, an amino group or an alkyl group.

R ^g is 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 hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocyclic, aryl and heteroaryl is optionally substituted by cyano, halogen, hydroxyl or amino.

n can be 0, 1, 2, 3, 4, or 5.

In some embodiments, ^R1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, amino, alkyl, and heteroalkyl, wherein each of the alkyl and heteroalkyl groups is optionally substituted by one or more ^Ra .

In some embodiments, each of ^Ra is independently selected from the group consisting of halogen, hydroxyl, cyano, and nitro.

In some embodiments, ^R1 is a halogen, cyano, hydroxyl, amino, or an alkyl group optionally substituted with one or more ^Ra .

In some embodiments, ^R1 is a halogen, a cyano group, or an alkyl group optionally substituted with one or more Ra ^groups .

In some embodiments, ^R1 is fluorine, chlorine, bromine, cyano, methyl, or trifluoromethyl.

In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1.

In some embodiments, ^R2 is -C(O) ^Rb , wherein ^Rb 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, ^-NRcRd and ^{-ORe .}

In some embodiments, each of ^Rc and ^Rd is independently selected from the group consisting of hydrogen, alkyl, and alkenyl, wherein each of the alkyl and alkenyl groups is optionally substituted with a halogen or a hydroxyl group.

In some embodiments, ^Re is selected from the group consisting of alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, and heteroaryl groups is optionally substituted with a cyano, halogen, hydroxyl, amino, or alkyl group.

In some embodiments, ^R2 is -C(O) ^Rb , wherein ^Rb is hydrogen, hydroxyl, alkyl, saturated or partially unsaturated cycloalkyl or ^-ORe .

In some embodiments, ^R2 is -C(O) ^Rb , where ^Rb is a saturated cycloalkyl or ^-ORe , and ^Re is an alkyl group.

In some embodiments, ^R2 is -C(O) ^Rb , wherein ^Rb is a saturated _C3-6 cycloalkyl or ^-ORe , and ^Re is a _C1-6 alkyl.

In some embodiments, ^R2 is -C(O) ^Rb , where ^Rb is cyclopropyl or ^-ORe , and ^Re is methyl, ethyl, n-propyl, or isopropyl.

In some embodiments, ^R2 is -C(O)-cyclopropyl or -C(O) _OCH3 .

In some embodiments, ^R3 is hydrogen or an alkyl group optionally substituted with halogen, hydroxyl, cyano or amino groups.

In some embodiments, ^R3 is hydrogen.

In some embodiments, ^R3 is an alkyl group optionally substituted with halogen, hydroxyl, cyano or amino groups.

In some embodiments, ^R3 is a _C1-6 alkyl group optionally substituted with halogen, hydroxyl, cyano or amino groups.

In some embodiments, ^R3 is methyl, ethyl, n-propyl, or isopropyl.

In some embodiments, L is selected from the group consisting of straight bonds, alkyl groups, heteroalkyl groups, saturated or partially unsaturated cycloalkyl groups, and saturated or partially unsaturated heterocyclic groups, wherein each of the alkyl, heteroalkyl, cycloalkyl, and heterocyclic groups is optionally substituted by one or more R ^f groups.

In some embodiments, each of ^Rf is independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, alkyl, and heteroalkyl.

In some embodiments, the two ^Rf atoms together with the atoms they are attached to form a saturated or partially unsaturated cycloalkyl group optionally substituted with a cyano, halogen, hydroxyl, amino, or alkyl group.

In some embodiments, L is a straight key.

In some embodiments, L is an alkyl group optionally substituted with one or more R ^f .

In some embodiments, L is a _C1-6 alkyl group optionally substituted with one or more ^Rf .

In some embodiments, L is a _C1-6 alkyl group optionally substituted with one or more ^Rf , wherein each of ^Rf is independently selected from the group consisting of hydrogen, halogen, hydroxyl, methyl, and ethyl.

In some embodiments, L is _-CH2- , -CH( _CH3 )-, or -C( _CH3 ) _2- .

In some embodiments, W is

In some embodiments, W is

In some embodiments, W is

In some embodiments, W is

In some embodiments, W is

In some embodiments, W is

In some embodiments, ^Rg is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, wherein each of the alkyl and heteroalkyl groups is optionally substituted with a halogen, hydroxyl, cyano, or amino group.

In some embodiments, W is where ^Rg is hydrogen or a _C1-6 alkyl group. In some embodiments, ^Rg is hydrogen, methyl, or ethyl.

In some embodiments, ^R4 is hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, or aryl, wherein each of the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, and aryl groups is optionally substituted with a cyano, halogen, hydroxyl, amino, or alkyl group.

In some embodiments, ^R4 is hydrogen, or optionally an alkyl or aryl group substituted with halogen, hydroxyl, cyano or amino groups.

In some embodiments, ^R4 is hydrogen, a _C1-6 alkyl group optionally substituted with halogen, hydroxyl, cyano or amino, or a _C6-12 aryl group optionally substituted with halogen, hydroxyl, cyano or amino.

In some embodiments, ^R4 is hydrogen, _-CH3 , _-CH2CH3 , _-CH ( _CH3 ) ₂ , -C( _CH3 ) ₃ , -CH( _CH3 )( _NH2 ) or phenyl.

In some embodiments, the double bond is of the E configuration.

In some embodiments, the double bond is Z-shaped.

In another aspect, this disclosure provides a compound having a formula selected from the group consisting of:

Or a pharmaceutically acceptable salt thereof, wherein ^R1 , ^R2 , ^R3 , ^R4 , ^Rg , L, and n are as defined above. In some embodiments, ^R1 is a halogen. In some embodiments, ^R1 is fluorine, chlorine, or bromine.

In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1.

In some embodiments, ^R2 is -C(O) ^Rb , wherein ^Rb is hydrogen, hydroxyl, alkyl, saturated cycloalkyl, or ^-ORe . In some embodiments, ^R2 is -C(O) ^Rb , wherein ^Rb is saturated cycloalkyl or ^-ORe , and ^Re is alkyl. In some embodiments, ^R2 is -C(O) ^Rb , wherein ^Rb is saturated _C3-6 cycloalkyl or ^-ORe , and ^Re is _C1-6 alkyl. In some embodiments, ^R2 is -C(O) ^Rb , wherein ^Rb is cyclopropyl or ^-ORe , and ^Re is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, ^R2 is -C(O)-cyclopropyl or -C(O) _OCH3 .

In some embodiments, ^R3 is hydrogen.

In some embodiments, ^R3 is an alkyl group. In some embodiments, ^R3 is a _C1-6 alkyl group. In some embodiments, ^R3 is methyl, ethyl, n-propyl, or isopropyl.

In some embodiments, L is a straight key.

In some embodiments, L is an alkyl group optionally substituted with one or more Rf ^groups , wherein the Rf ^groups are independently selected from hydrogen, halogen, hydroxyl, methyl, and ethyl. In some embodiments, L is a _C1-6 alkyl group optionally substituted with one or more ^Rf groups, wherein the Rf ^groups are independently selected from hydrogen, halogen, hydroxyl, methyl, and ethyl. In some embodiments, L is _-CH2- , -CH( _CH3 )-, or -C( _CH3 ) _2- .

In some embodiments, ^R4 is hydrogen or an alkyl group optionally substituted with a halogen, hydroxyl, cyano, or amino group. In some embodiments, ^R4 is hydrogen or a _C1-6 alkyl group optionally substituted with a halogen, hydroxyl, cyano, or amino group. In some embodiments, ^R4 is hydrogen, _-CH3 , _-CH2CH3 , _-CH ( _CH3 ) ₂ , -C( _CH3 ) ₃ , or -CH( _CH3 )( _NH2 ).

In some embodiments, ^Rg is hydrogen or an alkyl group. In some embodiments, ^Rg is hydrogen or a _C1-6 alkyl group. In some embodiments, ^Rg is hydrogen, methyl, or ethyl. In some embodiments, ^Rg is hydrogen.

In some embodiments, the double bond is of the E configuration.

In some embodiments, the double bond is Z-shaped.

In another aspect, this disclosure provides a compound having a formula selected from the group consisting of:

Or a pharmaceutically acceptable salt thereof, wherein ^R1 , ^R2 , ^R4 , ^Rg , L and n are as defined above. In some embodiments, they are double bonds in an E configuration.

In some embodiments, the double bond is Z-shaped.

In another aspect, this disclosure provides a compound having a formula selected from the group consisting of:

Or a pharmaceutically acceptable salt thereof, wherein ^R1 , ^R4 , ^Rg , L and n are as defined above. In some embodiments, they are double bonds in an E configuration.

In some embodiments, the double bond is Z-shaped.

In another aspect, this disclosure provides a compound having a formula selected from the group consisting of:

Or its pharmaceutically acceptable salt.

The compounds described herein are illustrated with reference to general chemical formulas and specific compounds. Furthermore, the compounds disclosed herein may exist in many different forms or derivatives, all of which are within the scope of this disclosure. These include, for example, tautomers, stereoisomers, racemic mixtures, regioisomers, salts, solvated forms, amorphous forms, various crystalline forms, or polymorphs.

Depending on the choice of substituents, the compounds disclosed herein may contain one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and/or diastereomers. For example, the compounds provided herein may have an asymmetric carbon center, and therefore the compounds provided herein may have (R) or (S) stereoconfigurations at the carbon asymmetric center. Thus, the compounds disclosed herein may be in individual enantiomeric, diastereomeric, or geometrical isomeric forms, or may be in mixtures of stereoisomers.

As used herein, the term "enantiomer" refers to two stereoisomers of a compound that are non-overlapping 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 point, boiling point, spectral characteristics, and reactivity.

When a particular enantiomer is preferred, in some embodiments it may be provided substantially free of the relative enantiomer and may also be referred to as “optical enrichment.” As used herein, “optical enrichment” means that the compound consists of a significantly larger proportion of one enantiomer. In some embodiments, the compound consists of at least about 90 wt% of the preferred enantiomer. In other embodiments, the compound consists of at least about 95 wt%, 98 wt%, or 99 wt% of the preferred enantiomer. The preferred enantiomer can be isolated from the racemic mixture by any method known to those skilled in the art, such as by chromatography or crystallization, by synthesis using stereochemically homogeneous starting materials, or by stereoselective synthesis. Optionally, derivatization may be performed prior to the separation of the stereoisomers. The separation of the mixture of stereoisomers may be performed as an intermediate step during the synthesis of the compound provided herein or may be performed on the final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of the crystalline product or crystalline intermediate, which, if necessary, is derivatized with a reagent containing a stereocenter of known configuration. 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, p. 268 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

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

In some embodiments, unless otherwise specified, the compounds provided herein may have one or more double bonds present as Z or E isomers. Additionally, this disclosure also covers compounds in individual isomer forms substantially free of other isomers, and alternatively, compounds in the form of mixtures of multiple isomers (e.g., racemic mixtures of enantiomers).

The compounds disclosed herein may also exist in different tautomeric forms, and all such forms are covered within the scope of this disclosure. The terms "tautomer" or "tautomeric form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also called proton transfer tautomers) include interconversions via proton migration, such as keto-enol, amide-imino, lactam-lactamimide, imine-enamine isomerization, and cyclic forms, wherein a proton can occupy two or more positions in a heterocyclic system (e.g., 1H-imidazolium and 3H-imidazolium, 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 via rearrangement of some bonding electrons. Tautomers may be in equilibrium or spatially locked into a form by appropriate substitution. Unless otherwise specified, the compounds disclosed herein that are identified by name or structure as a particular tautomer form are intended to include other tautomer forms.

This disclosure also intends to include all isotopes of atoms in the compounds. Isotopes of atoms include atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the compounds of this disclosure also means to include their isotopes, such as (but not limited to) ^¹H , ^²H , ^³H , ^¹¹C , ^¹²C , ^¹³C , ^¹⁴C , ^¹⁴N , ^¹⁵N , ^¹⁶O , ^¹⁷O , ^¹⁸O , ^³¹P , ^³²P , ^³²S , ^³³S , ^³⁴S , ^³⁶S , ^¹⁷F , ^¹⁸F , ¹⁹F, ^³⁵Cl , ^³⁷Cl , ^⁷⁹Br , ^⁸¹Br , ^¹²⁴I , ^{¹²⁷I ,} and ^¹³¹I . In some embodiments, hydrogen comprises protium, deuterium, and tritium. In some embodiments, carbon comprises ^¹²C and ^¹³C . Isotope-enriched compounds of formula (I) can be prepared without excessive experimentation using conventional techniques well known to those skilled in the art or by methods similar to those described in the schemes and examples herein, using appropriate isotope-enriching reagents and/or intermediates.

The compounds disclosed herein can be formulated into pharmaceutically acceptable salts or in the form of pharmaceutically acceptable salts. Unless otherwise stated, the compounds provided herein include pharmaceutically acceptable salts of such compounds.

As used herein, the term "pharmaceutically acceptable" indicates that the substance or composition is chemically and/or toxicologically compatible with the other components constituting the formulation and/or the individual treated with it.

As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" includes salts that retain the bioavailability of the specified compound as a free acid and base and are not biologically or otherwise undesirable. Considered pharmaceutically acceptable salt forms include (but are not limited to) single, double, triple, and tetrasalts. Pharmaceutically acceptable salts are non-toxic at the amount and concentration at which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical characteristics of the compound without impairing its physiological effects. Useful alterations to physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher drug concentrations.

Pharmaceutically acceptable salts include acid addition salts, such as those containing: sulfates, chlorides, hydrochlorides, fumarates, maleates, phosphates, aminosulfonates, acetates, citrates, lactates, tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylaminosulfonates, and quinates. Pharmaceutically acceptable salts can be obtained from acids such as: hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, aminosulfonic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylaminosulfonic acid, fumaric acid, and quinic acid.

Pharmaceutically acceptable salts, when acidic functional groups (such as carboxylic acids or phenols) are present, also include base addition salts, such as those containing: benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines, and zinc. See, for example, *Remington's Pharmaceutical Sciences*, 19th edition, Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; and *Handbook of Pharmaceutical Salts: Properties, Selection, and Use*, Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. These salts can be prepared using appropriate corresponding bases.

Pharmaceutically acceptable salts can be prepared using standard techniques. For example, the free base form of a compound can be dissolved in a suitable solvent (such as an aqueous solution or a water-alcohol solution containing a suitable acid) and subsequently separated by evaporation of the solution. Therefore, if a particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, by treating the free base with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranoic acids (such as glucuronic acid or galacturonic acid), α-hydroxy acids (such as citric acid or tartaric acid), amino acids (such as aspartic acid or glutamic acid), aromatic acids (such as benzoic acid or cinnamic acid), sulfonic acids (such as p-toluenesulfonic acid or ethanesulfonic acid), etc.

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

It should also be understood that the compounds disclosed herein may exist in non-solventized, solvated (e.g., hydrated) and solid (e.g., crystalline or polycrystalline) forms, and this disclosure is intended to cover all such forms.

As used herein, the term "solvent" or "solventized form" refers to a solvation form containing stoichiometric or non-stoichiometric amounts of a solvent. Some compounds have a tendency to form solvates by retaining a fixed molar ratio of solvent molecules in a crystalline solid state. If the solvent is water, the formed solvate is a hydrate; and if the solvent is an alcohol, the formed solvate is an alcohol. Hydrates are formed by a combination of one or more water molecules with a molecule of another substance, 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.

As used herein, the terms “crystalline form,” “polycrystalline form,” “polymorph,” and “polymorph” are used interchangeably and refer to crystal structures in which a compound (or its salts or solvates) can crystallize in different crystalline arrangements, all of which have the same elemental composition. Different crystalline forms typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can cause one crystalline form to dominate. Crystalline polymorphs of a compound can be prepared by crystallization under different conditions.

This disclosure also intends to include all isotopes of atoms in the compounds. Isotopes of atoms include atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the compounds of this disclosure also means to include their isotopes, such as (but not limited to) ^¹H , ^²H , ^³H , ^¹¹C , ^¹²C , ^¹³C , ^¹⁴C , ^¹⁴N , ^¹⁵N , ^¹⁶O , ^¹⁷O , ^¹⁸O , ^³¹P , ^³²P , ^³²S , ^³³S , ^³⁴S , ^³⁶S , ^¹⁷F , ^¹⁸F , ¹⁹F, ^³⁵Cl , ^³⁷Cl , ^⁷⁹Br , ^⁸¹Br , ^¹²⁴I , ^{¹²⁷I ,} and ^¹³¹I . In some embodiments, hydrogen comprises protium, deuterium, and tritium. In some embodiments, carbon includes ^12C and ^13C .

Compound Synthesis

The synthetic schemes described herein illustrate the synthesis of the compounds (including their pharmaceutically acceptable salts). The compounds provided herein can be prepared using any known organic synthetic technique and can be synthesized according to any of a variety of possible synthetic routes; therefore, these 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 for better illustration and may be modified where appropriate. Examples of synthesizing the compounds in the examples are provided for research purposes and possibly for submission to regulatory authorities.

The reactions used to prepare the compounds disclosed herein can be carried out in a suitable solvent, which can be readily selected by those skilled in the art of organic synthesis. A suitable solvent is one that does not substantially react with the starting material (reactant), intermediate, or product at the temperature at which the reaction takes place, for example, at a temperature in the range of the solvent's freezing temperature to its boiling temperature. The specified reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, a suitable solvent for that specific reaction step can be selected by those skilled in the art.

The preparation of the compounds disclosed herein may 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 those skilled in the art. The chemical properties of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, *Protective Groups in Organic Synthesis*, 3rd ed., 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*, 5th ed., Wiley, 2014, all of which are incorporated herein by reference in their entirety.

The reaction can be monitored using 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 or ^¹³C ), infrared spectroscopy (IR), spectrophotometry (e.g., UV-Vis), mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC). Those skilled in the art can purify compounds using 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.

The known starting materials disclosed herein can be synthesized using or according to methods known in the art, or can be purchased from commercial suppliers. Unless otherwise indicated, analytical grade solvents and commercially available reagents are used without further purification.

Unless otherwise specified, all reactions disclosed herein are carried out under positive pressure of nitrogen or argon or in anhydrous solvent using dry tubes, and the reaction flasks are typically fitted with rubber septa for introduction of the reactants and reagents via syringe. Glassware is dried and/or heat-dried.

For illustrative purposes, the following examples partially illustrate synthetic routes and key intermediates used to prepare the compounds of this disclosure. Those skilled in the art will understand that other synthetic routes can be used to synthesize the compounds of this invention. Although specific starting materials and reagents are described, other starting materials and reagents can be readily substituted to provide a variety of derivatives and/or reaction conditions. Furthermore, many compounds prepared by the methods described below can be further modified according to this disclosure using conventional chemical reactions well known to those skilled in the art.

In one aspect, this disclosure provides compounds having the following formula:

In some embodiments, the above-described compounds may be used as intermediates in the preparation of the compounds disclosed herein.

On the other hand, this disclosure provides compounds having the following formula:

In some embodiments, the above-described compounds may be used as intermediates in the preparation of the compounds disclosed herein.

Uses of compounds

In one aspect, this disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof capable of inhibiting platelet aggregation. Therefore, the compounds of this disclosure or pharmaceutically acceptable salts thereof are suitable as medical agents, and particularly as therapeutic or preventative agents for various thrombotic diseases.

As used herein, the term "therapy" is intended to have its general meaning as the treatment of a disease in order to completely or partially alleviate one, some, or all of its symptoms, or to correct or counteract the underlying pathology, thereby achieving a beneficial or desired clinical outcome. For the purposes of this disclosure, beneficial or desired clinical outcomes include (but are not limited to): symptom relief, reduction of disease severity, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or mitigation of the disease condition, and remission (partial or complete remission), whether detectable or undetectable. "Therapy" may also mean prolonged survival compared to expected survival without therapy. Situations requiring therapy include pre-existing conditions or symptoms, susceptibility to conditions or symptoms, or situations requiring prevention of conditions or symptoms. Unless specifically indicated to the contrary, the term "therapy" also encompasses prevention. The terms "therapeutic" and "therapeutically" should be interpreted accordingly.

The term “treatment” is used synonymously with “therapeutic therapy.” Similarly, the term “treatment” can be considered as “the application of a therapeutic therapy,” where “therapeutic therapy” is as defined herein.

As used herein, the term “prevention” is intended to have its usual meaning and includes primary prevention for preventing the development of disease, as well as secondary prevention for temporarily or permanently protecting patients from disease exacerbation or worsening or the development of new disease-related symptoms once the disease has developed.

In some embodiments, the disclosed compound may be converted into an active thiol metabolite after administration. In some embodiments, the disclosed compound may be converted into an active thiol metabolite after oral administration. In some embodiments, the disclosed compound may be converted into an active thiol metabolite after intravenous injection.

For prodrugs containing active thiol metabolites, the prodrug needs to remain stable (resistant to environmental factors) while being converted to the active thiol metabolite at a high rate in the target tissue. Furthermore, the prodrug needs to have a rapid onset of action and therefore a low loading dose and few side effects, and high solubility in aqueous solution to allow for formulation into injectable solutions for emergency and surgical use.

In some embodiments, the compounds described herein can be hydrolyzed via hydrolytic enzymes to form active thiol metabolites. Because hydrolytic enzymes have high in vivo activity and wide distribution in the intestine, liver, and plasma, the compounds described herein can be converted into active thiol metabolites in vivo with high conversion rates and low inter-patient variability, thereby providing rapid onset of antiplatelet action without the need for high loading doses. Furthermore, because the metabolism of the compounds described herein is mediated by hydrolytic enzymes rather than CYP enzymes, the use of these compounds is not limited by potential interactions with other CYP-targeting drugs.

In some embodiments, the compounds provided herein exhibit a faster onset of antiplatelet action than clopidogrel at the same dose. In some embodiments, the compounds provided herein exhibit a shorter onset of antiplatelet action than clopidogrel at lower doses. In some embodiments, at a dose of 1/2 the clopidogrel dose, the compounds provided herein exhibit a shorter onset of antiplatelet action than clopidogrel. In some embodiments, at a dose of 1/3 the clopidogrel dose, the compounds provided herein exhibit a shorter onset of antiplatelet action than clopidogrel. In some embodiments, at a dose of 1/4 the clopidogrel dose, the compounds provided herein exhibit a shorter onset of antiplatelet action than clopidogrel. In some embodiments, at a dose of 1/5 the clopidogrel dose, the compounds provided herein exhibit a shorter onset of antiplatelet action than clopidogrel.

In some embodiments, at a dose of 1/5 of the clopidogrel dose, the compounds provided herein exhibit an onset time of less than 120 minutes, less than 110 minutes, less than 100 minutes, less than 90 minutes, less than 80 minutes, less than 70 minutes, less than 60 minutes, less than 50 minutes, less than 40 minutes, or even less than 30 minutes of antiplatelet activity.

In some embodiments, such as when measured in phosphate buffer, the compounds provided herein exhibit improved water solubility compared to clopidogrel. In some embodiments, such as when measured in buffered aqueous solutions, the compounds provided herein exhibit water solubility greater than 0.2 mg/ml, greater than 0.3 mg/ml, greater than 0.4 mg/ml, greater than 0.5 mg/ml, greater than 0.6 mg/ml, greater than 0.7 mg/ml, greater than 0.8 mg/ml, greater than 0.9 mg/ml, greater than 1 mg/ml, or even greater.

The improved solubility of the compounds provided herein offers opportunities to expand their use in inhibiting platelet aggregation. In some embodiments, the compounds provided herein may be formulated for injection administration for emergency and surgical purposes. In some embodiments, the compounds provided herein may be formulated for oral administration to provide long-term inhibition of platelet aggregation.

In another aspect, this disclosure provides for the use of the disclosed compounds or pharmaceutically acceptable salts thereof for the treatment of vascular diseases.

In another aspect, this disclosure provides for the use of the disclosed compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof in the manufacture of medicaments for the treatment of vascular diseases.

Pharmaceutical Composition

For administration purposes, in some embodiments the compounds provided herein are administered in their original chemical form or formulated into pharmaceutical compositions.

Therefore, in another aspect, pharmaceutical compositions comprising one or more of the compounds disclosed herein or pharmaceutically acceptable salts thereof are provided.

In some embodiments, the pharmaceutical compositions of this disclosure comprise a compound selected from any one of formulas (I) to (VII) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions of this disclosure comprise a first compound selected from any one of formulas (I) to (VII) or a pharmaceutically acceptable salt thereof and one or more other compounds of the same formula, wherein the first compound and the other compounds are not the same molecule.

As used herein, the term "pharmaceutical composition" refers to a formulation containing molecules or compounds of the present disclosure in a form suitable for individual administration.

In some embodiments, the pharmaceutical compositions disclosed herein comprise a therapeutically effective amount of one or more compounds of formulas (I) to (VII) or a pharmaceutically acceptable salt thereof.

As used herein, the term "therapeutic effective amount" refers to the amount of a molecule, compound, or composition comprising said molecule or compound that treats, improves, or prevents an identified disease or condition or exhibits detectable therapeutic or inhibitory effects. Effectiveness can be detected by any analytical method known in the art. The precise effective amount for an individual will depend on the individual's weight, build, and health status; the nature and severity of the condition; the rate of administration; the chosen therapeutic agent or combination of agents for administration; and the prescribing physician's judgment. Therapeutic effective amount for a given condition can be determined through routine laboratory testing within the skill and judgment of a clinician.

On the other hand, a pharmaceutical composition comprising one or more molecules or compounds disclosed herein or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient is provided.

As used herein, the term "pharmaceuticalally acceptable excipient" means an excipient suitable for the preparation of pharmaceutical compositions that are generally safe and non-toxic and biologically and otherwise desirable, and includes excipients acceptable for veterinary and human use. As used herein, "pharmaceuticalally acceptable excipient" includes one or more such excipients. The term "pharmaceuticalally acceptable excipient" also covers "pharmaceuticalally acceptable carriers" and "pharmaceuticalally acceptable diluents."

The specific excipients used will depend on the means and purpose for which the compounds of this disclosure are to be applied. Solvents are generally selected based on those known to be safe for use on mammals (including humans). Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), and mixtures thereof.

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

In some embodiments, suitable excipients may include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, slip agents, processing aids, colorants, sweeteners, flavoring agents, and other known additives to provide optimal presentation of the drug (i.e., the compounds disclosed herein or pharmaceutical compositions thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a pharmaceutical preparation). The active pharmaceutical ingredient may also be encapsulated in microcapsules, for example, prepared by coagulation techniques or by interfacial polymerization, such as hydroxymethyl cellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in crude emulsions. Such techniques are disclosed in Remington’s Pharmaceutical Sciences, 16th edition, Osol, A. (1980). “Liposomes” are small vesicles containing various types of lipids, phospholipids, and/or surfactants, suitable for delivering drugs (such as the compounds disclosed herein and optional chemotherapeutic agents) to mammals, including humans. The components of liposomes are usually arranged in a bilayer, similar to the lipid arrangement of biological membranes.

The pharmaceutical compositions described herein may be in any form that allows the composition to be administered to an individual (including, but not limited to, a person) and formulated to be compatible with the intended route of administration.

Multiple routes of administration are considered for the pharmaceutical compositions provided herein, and therefore the pharmaceutical compositions provided herein may be supplied in bulk or unit dosage forms depending on the intended route of administration. For example, for oral, buccal, and sublingual administration, powders, suspensions, granules, lozenges, pills, capsules, soft capsules, and tablets 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 are acceptable dosage forms. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches are acceptable dosage forms. For vaginal administration, vaginal suppositories, tampons, creams, gels, pastes, foams, and sprays are acceptable dosage forms.

The amount of active ingredient in a unit dosage form of a composition is a therapeutically effective amount and varies depending on the specific treatment involved. As used herein, the term "therapeuticly effective amount" refers to the amount of a molecule, compound, or composition containing said molecule or compound that treats, improves, or prevents an identified disease or condition or exhibits detectable therapeutic or inhibitory effects. These effects can be detected by any analytical method known in the art. The precise effective amount for an individual will depend on the individual's weight, build, and health status; the nature and severity of the condition; the rate of administration; the chosen therapeutic agent or combination of therapeutic agents for administration; and the prescribing physician's judgment. The therapeutically effective amount for a given condition can be determined through routine laboratory testing within the skill and judgment of a clinician.

In some embodiments, the pharmaceutical compositions disclosed herein may be in the form of an oral administration formulation.

In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of tablet formulations. Pharmaceutically acceptable excipients suitable for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate, or calcium carbonate; granulating and disintegrants such as corn starch or alginate; binders such as starch; lubricants such as magnesium stearate, stearic acid, or talc; preservatives such as ethylparaben or propylparaben; and antioxidants such as ascorbic acid. Tablet formulations may be uncoated or coated to modulate their disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability and/or appearance. In either case, conventional coating agents and procedures well known in the art are used.

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

In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of an aqueous suspension, which generally contains an active ingredient in fine powder form and one or more suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, astragalus gum, and gum arabic; dispersants or wetting agents, such as lecithin, or condensation products of alkyl esters and fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecanethoxylated cetyl alcohol), or condensation products of ethylene oxide and esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitan monooleate), or condensation products of ethylene oxide and esters derived from fatty acids and hexitols (e.g., polyvinyl sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives (such as ethylparaben or propylparaben), antioxidants (such as ascorbic acid), colorants, flavorings and/or sweeteners (such as sucrose, saccharin or aspartame).

In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of an oily suspension, typically containing a suspended active ingredient in a vegetable oil (such as peanut oil, castor oil, olive oil, sesame oil, or coconut oil) or a mineral oil (such as liquid paraffin). The oily suspension may also contain a thickener, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (such as those described above) and flavoring agents may be added to provide a palatable oral formulation. These compositions may be preserved by adding antioxidants (such as ascorbic acid).

In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil; or a mineral oil, such as liquid paraffin; or any mixture of these oils. Suitable emulsifiers may be, for example, naturally occurring gums, such as gum arabic or astragalus gum; naturally occurring phospholipids, such as soybean, lecithin, esters or metaesters derived from fatty acids and hexadiol anhydrides (e.g., sorbitan monooleate), and condensation products of said metaesters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The emulsion may also contain sweeteners, flavoring agents, and preservatives.

In some embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, and may contain sweeteners such as glycerin, propylene glycol, sorbitol, aspartame, or sucrose; modifiers; preservatives; flavoring agents and/or coloring agents.

In some embodiments, the pharmaceutical compositions disclosed herein may be in the form of an injection formulation.

In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of a sterile injectable formulation, such as a sterile injectable aqueous or oily suspension. This suspension may be formulated using suitable dispersants or wetting agents and suspending agents mentioned above, according to known techniques. The sterile injectable formulation may also be a sterile injectable solution or suspension in a non-toxic, parenteral-acceptable diluent or solvent, such as a solution in 1,3-butanediol, or prepared as a lyophilized powder. Acceptable mediators and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any mild non-volatile oil may be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid may also be used in the preparation of injectable formulations.

In some embodiments, the pharmaceutical compositions disclosed herein may be in the form of an inhalation formulation.

In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of aqueous and non-aqueous (e.g., in fluorocarbon propellants) aerosols containing any suitable solvent and optional other compounds, such as (but not limited to) stabilizers, antimicrobial agents, antioxidants, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof. The carrier and stabilizer vary depending on the requirements of the specific compound, but generally include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), harmless proteins (such as serum albumin), sorbitol esters, oleic acid, lecithin, amino acids (such as glycine), buffers, salts, sugars, or sugar alcohols.

In some embodiments, the pharmaceutical compositions disclosed herein may be in the form of a topical or transdermal formulation.

In some embodiments, the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels, and aqueous or oily solutions or suspensions, which may generally be obtained by formulating an active ingredient and conventional, locally acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, astragalus gum, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

In some embodiments, the pharmaceutical compositions provided herein may be formulated in the form of transdermal patches, as is well known to those skilled in the art.

In addition to the representative dosage forms mentioned above, pharmaceutically acceptable excipients and carriers are commonly known to those skilled in the art and are therefore included in this disclosure. Such excipients and carriers are described, for example, in Remington's Pharmaceutical Sciences, Mark Publishing, NJ (1991), and Remington: The Science and Practice of Pharmacy, University of the Sciences in Philadelphia, ed., 21st ed., LWW (2005), which are incorporated herein by reference.

In some embodiments, the pharmaceutical compositions disclosed herein may be formulated into unit dosage forms. The term "unit dosage form" refers to a physically discrete unit suitable for single-dose administration to an individual human or other mammal, each unit containing a predetermined amount of active substance calculated to bind with a suitable pharmaceutical excipient to produce the desired therapeutic effect. The amount of compounds provided herein in unit dosage forms will vary depending on the condition to be treated, the individual to be treated (e.g., age, weight, and response), the specific route of administration, the actual compound administered and its relative activity, and the severity of the individual's symptoms.

In some embodiments, the dosage of the pharmaceutical composition disclosed herein may be 0.001-1000 mg/kg body weight/day, for example, 0.001-1000 mg/kg body weight/day, 0.001-900 mg/kg body weight/day, 0.001-800 mg/kg body weight/day, 0.001-700 mg/kg body weight/day, 0.001-600 mg/kg body weight/day, 0.001-500 mg/kg body weight/day. 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 The dosage ranges are: -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, dosages below the lower limit of the foregoing ranges may be sufficient, while in other cases, larger doses may be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day. For further information regarding the route of administration and dosing regimen, see Volume 5, Chapter 25.3 of *Comprehensive Medicinal Chemistry* (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press, 1990, which is specifically incorporated herein by reference.

In some embodiments, the pharmaceutical compositions disclosed herein are formulated for oral administration. In some embodiments, a unit dose for oral administration contains one or more of the compounds provided herein in amounts of: about 1 mg to about 1000 mg, for example, about 5 mg to about 1000 mg, about 10 mg to about 1000 mg, about 15 mg to about 1000 mg, about 20 mg to about 1000 mg, about 25 mg to about 1000 mg, about 30 mg to about 1000 mg, about 40 mg to about 1000 mg, about 50 mg to about 1000 mg, about 60 mg to about 1000 mg, about 70 mg to about 1000 mg, about 80 mg to about 1000 mg, about 90 mg to about 1000 mg, about 100 mg to about 1000 mg, about 200 mg to 1000 mg, about 300 mg to about 1000 mg. 00 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, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, etc. In some embodiments, depending on the severity of individual symptoms, the dosage unit may be administered to the individual 1 to 6 times daily.

In some embodiments, the pharmaceutical compositions disclosed herein are formulated for oral administration in treatment lasting longer than 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, or even longer.

In some embodiments, the pharmaceutical compositions disclosed herein are formulated for parenteral administration, such as via intravenous, subcutaneous, or intramuscular injection. In some embodiments, a unit dose for parenteral administration contains one or more of the compounds provided herein, in amounts from about 0.1 mg to about 500 mg, such as about 0.2 mg to about 500 mg, about 0.3 mg to about 500 mg, about 0.4 mg to about 500 mg, about 0.5 mg to about 500 mg, about 1 mg to about 500 mg, about 5 mg to about 500 mg, about 10 mg to about 500 mg, about 20 mg to about 500 mg, about 30 mg to about 500 mg, about 40 mg to about 500 mg, about 50 mg to about 500 mg, about 0.5 mg to about 400 mg, about 0.5 mg to about 300 mg, about 0.5 mg to about 200 mg, about 0.5 mg to about 100 mg, about 0.5 mg to about 90 mg, about 0.5 mg to about 80mg, about 0.5mg to about 70mg, about 0.5mg to about 60mg, about 0.5mg to about 50mg, about 0.5mg to about 40mg, about 1mg to about 90mg, about 5mg to about 90mg, about 10mg to about 80mg, about 20mg to about 70mg, about 30mg to about 60mg or about 40mg to about 50mg, such as about 0.1mg, about 0.2mg, about 0.3mg, about 0.4mg, about 0.5mg, about 0.6mg, about 0.7mg, about 0.8mg, about 0.9mg, about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, etc.

In some embodiments, a pharmaceutical composition intended for injection may be prepared by combining one or more of the disclosed compounds with sterile distilled water, sesame oil, peanut oil, or an aqueous solution of propylene glycol to form a solution. In some embodiments, the pharmaceutical composition may contain a surfactant or other dissolving excipient added to promote the formation of a homogeneous solution or suspension. In some embodiments, the pharmaceutical composition may further contain one or more additional agents selected from the group consisting of wetting agents, suspending agents, preservatives, buffers, and isotonic agents.

In some embodiments, the pharmaceutical composition intended for injection may be administered using 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 the pharmaceutical composition provided herein.

In another aspect, a veterinary composition is also provided, comprising one or more molecules or compounds disclosed herein, or pharmaceutically acceptable salts thereof, and a veterinary carrier. The veterinary carrier is a substance suitable for the purpose of administering the composition and may be an inert or veterinarily acceptable solid, liquid, or gaseous substance, compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally, or via any other desired route.

Pharmaceutical or veterinary compositions may be packaged in various ways depending on the method of administration. For example, articles for dispensing may include containers in which a suitable form of composition is deposited. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), capsules, ampoules, plastic bags, metal tubes, etc. Containers may also include tamper-evident assemblies to prevent easy access to the contents of the package. Additionally, the container is affixed with a label describing the contents. The label may also include appropriate warnings. Compositions may be packaged in single-dose or multi-dose containers (e.g., sealed ampoules and vials) and can be stored under lyophilized (freeze-dried) conditions, requiring only the immediate addition of a sterile liquid carrier (e.g., water) for injection before use. Ready-to-use injectable solutions and suspensions are prepared from sterile powders, granules, and tablets of the types described above.

In another aspect, pharmaceutical compositions comprising one or more of the disclosed compounds or their pharmaceutically acceptable salts as a first active ingredient and a second active ingredient are also provided.

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

Treatment methods for diseases

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

In some embodiments, vascular disease is selected from atherosclerotic thrombosis, ischemia, stroke, cerebral thrombosis, arterial thrombosis, thrombotic cerebrovascular disease, cardiovascular disease, and thrombosis.

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

Example

For illustrative purposes, the following examples are included. However, it should be understood that these examples do not limit this disclosure and are intended only to illustrate the methods of practicing this disclosure. Those skilled in the art will recognize that the described chemical reactions are readily applicable to the preparation of many other compounds of this disclosure, and alternative methods for preparing the compounds of this disclosure are considered to be within the scope of this disclosure. For example, non-exemplary compounds according to this disclosure can be successfully synthesized by modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks known in the art besides the described reagents and building blocks, and/or by conventionally changing the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered suitable for the preparation of other compounds of this disclosure.

Example 1

Step 1. Synthesize 1-2

A solution of 1-1 (56.7 g, 310 mmol) in DCM (500 mL) was stirred in an ice bath (T < ₅ °C) under _N2 protection. mCPBA (107.0 g, 620 mmol) was added fractionally to the above solution. After addition, the mixture was stirred at 20 °C for 4 hours. The mixture was then poured into a solution of _Na2S2O3 (90.0 _g ) and _NaHCO3 (45.0 g) in water (300 mL) while stirring. The mixture was extracted with DCM (300 mL * ₂ ). The combined organic layers were dried over _Na2SO4 and filtered. The filtrate was concentrated and the residue 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.

Step 2. Synthesize 1-3

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 for 20 minutes at room temperature, followed by stirring overnight at 40 _° C. The reaction mixture was then concentrated under vacuum. _{Saturated Na₂CO₃} (400 mL) was added to the residue with stirring, followed by extraction with EtOAc (400 mL x 2). The organic layer was dried over _Na₂SO₄ and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (petroleum ether/EtOAc = 10/1 to 5/1) to give 1-3 (87.5 g, 77% yield) as a white solid.

LC-MS[M+1-100] ⁺ ＝238.1

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

Step 3. Synthesize 1-4

TBSCl (141.2 g, 935 mmol) and imidazole (159.0 g, 2.34 mol) were added to a solution of 1-3 (157.0 g, 467.3 mmol) in DCM (1.5 L). The resulting mixture was stirred overnight at room temperature 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.

Step 4. Synthesize 1-5

To a solution of 1-4 (263.0 g, 583.1 mmol) in _NH3 /MeOH (7 M, 2.0 L), _NaBH4 (222 mg, 5.8 mmol) was added. The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 20/1) to give 1-5 (210.0 g, 100% yield) as a pale yellow oil.

Step 5. Synthesize 1-6

NaH (20.7 g, 864.6 mmol) was added to a solution of _NaBH4 (1.1 g, 28.8 mmol) in DMF (1.0 L) under stirring at 0 °C and _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, isopropyl chloromethyl carbonate (100.7 g, 662.8 mmol) was added at 0 °C, and the 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 _Na2SO4 , and filtered. The filtrate was concentrated under vacuum, and the residue was purified by silica gel chromatography (petroleum/EtOAc = 20/1) to give 1-6 (135.0 g, 50% yield) as a colorless oil.

^1H NMR (400MHz, chloroform-d) δ 5.25 (q, J = 12.0Hz, 2H), 4.92–4.79 (m, 1H), 3.85 (d, J = 58.8Hz, 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, 4.6Hz, 6H), 0.89 (s, 9H), 0.19–0.01 (m, 6H).

Step 6. Synthesize 1-7

Add Et ₃ N.3HF (135.0 g, 835.9 mmol) to a solution of 1-6 (129.0 g, 278.6 mmol) in THF (1.1 L), and stir under reflux for 16 hours. After completion, concentrate the reaction mixture under reduced pressure and purify the residue by silica gel chromatography (petroleum ether/EtOAc = 3/1) to give 1-7 (80.0 g, 82% yield) as a pale yellow oil.

Step 7. Synthesize 1-8

Add Dess-Martin periodinane (72.9 g, 171.9 mmol) to a solution of 1-7 (30.0 g, 86.9 mmol) in DCM (300 mL), and stir the resulting mixture at 25 °C for 4 hours. After completion, add the above reaction mixture to _{a saturated Na₂S₂O₃ / saturated NaHCO₃} mixture (600 mL/600 mL), followed by extraction with EtOAc (400 mL x 2). Wash the combined organic layers with saturated _NaHCO₃ , _dry over _Na₂SO₄ , and filter. Concentrate the filtrate under reduced pressure and purify the residue 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.

Step 8. Synthesize 1-9 and 1-10

LiHMDS (37.4 mL, 37.4 mmol) was added to a solution of tert-butyl 2-(diethoxyphosphoryl)acetate (11.4 g, 43.2 mmol) in 100 mL of THF at -60 °C under _N2 , and the mixture was stirred at -60 °C for 30 min. Subsequently, 1–8 (10.0 g, 28.8 mmol) was added dropwise at -60 °C, and the mixture was stirred at 0–10 °C for 1 h. The reaction mixture was then added to saturated _NH4Cl (300 mL), followed by extraction with EtOAc (150 mL x 2). The combined organic layers were washed with brine, dried over _{Na2SO4 ,} and filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel chromatography (petroleum ether/EtOAc = 60/1) to give 1-9 (2.5 g, 19% yield) and 1-10 (1.3 g, 10% yield) as pale yellow oil.

1-9: ^1H NMR (400MHz, chloroform-d) δ 5.68 (s, 1H), 5.47 (d, J = 15.2Hz, 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 = 4Hz, 6H).

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).

Step 9. Synthesize 1-11

TFA (10 mL) was added to a solution of 1-9 (3.0 g, 6.7 mmol) in DCM (20 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. Afterward, the reaction mixture was added to a saturated _NaHCO3 solution (100 mL) and then extracted with DCM ( ₁₀₀ mL). The organic layer was dried over _Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give crude 1-11 (3.0 g, >100% yield) as a yellow oil, which was used in the next step without further purification. LC-MS [M+1] ⁺ = 346.1

Step 10. Synthesize 1-13

Add 1-12 (2.6 g, 6.7 mmol) and _KHCO3 (1.35 g, 13.5 mmol) to a solution of 1-11 (3.0 g, crude) in _CH3CN (15 mL). Stir the resulting mixture at 40 °C for 2 hours. After completion, concentrate the reaction mixture under reduced pressure and purify the residue by reversed-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.

Steps 11 and 12. Synthesize 1a-1 and 1a-2

The solution of 1-13 (1.8 g, 3.4 mmol) in TFA (10 mL) was stirred for 30 minutes at room temperature. After stirring, 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 reversed-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.

1a:

LC-MS[M+1] ⁺ ＝472.1

¹ H NMR (400MHz, chloroform-d) δ7.59 (s, 1H), 7.38 (d, J = 4Hz, 1H), 7.32-7.26 (m, 2H), 5.86 (s,1H),5.22(dd,J＝12.2,2.6Hz,1H),5.00-4.83(m,3H),4.50(dd,J＝66.2,11. 9Hz,1H),3.82(s,1H),3.70(d,J＝4.9Hz,3H),3.52(dd,J＝37.9,12.9Hz,1H),2 .92-2.64(m,2H),2.45-2.30(m,1H),1.95-1.84(m,1H),1.30(d,J＝6.2Hz,6H).

1a-1:

¹ H NMR (400MHz, CDCl ₃ )δ7.65(s,1H),7.46–7.43(m,1H),7.33(dd,J＝6.3,2.7Hz,2H),5.91(s,1H),5.27(d,J＝12.3Hz,1H),5.04–4.87(m,3H),4.49(d,J＝13.7H z,1H),3.88(s,1H),3.75(s,3H),3.58(d,J＝14.0Hz,1H),2.87(s,2H),2.44(s,1H),1.95(dd,J＝14.2,3.3Hz,1H),1.35(d,J＝6.2Hz,6H).

1a-2:

^1H NMR (400MHz, CDCl3 ₎ )δ7.63(s,1H),7.44(dt,J＝8.2,3.1Hz,1H),7.35–7.31(m,2H),5.92(s,1H),5 .25(d,J＝12.3Hz,1H),5.07(s,1H),4.94(td,J＝12.5,6.5Hz,2H),4.68(d,J＝13 .4Hz,1H),3.87(s,1H),3.76(s,3H),3.50(d,J＝13.4Hz,1H),2.90(s,1H),2.75 (d,J=12.3Hz,1H),2.44(s,1H),1.96(d,J=13.2Hz,1H),1.34(d,J=6.3Hz,6H).

Step 13. Synthesize 1-14

TFA (5 mL) was added to a solution of 1-10 (1.8 g, 4.0 mmol) in DCM (10 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 hour. Afterward, the reaction mixture was added to a saturated _NaHCO3 solution (100 mL), followed by extraction with DCM (100 mL * ₃ ). The combined organic layers were dried over _Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give crude 1-14 (2.0 g, >100% yield) as a yellow oil, which was used directly in the next step without further purification. LC-MS [M+1] ⁺ = 346.1

Step 14. Synthesize 1-15

Add 1-12 (1.5 g, 4.0 mmol) and _KHCO3 (800 mg, 8.0 mmol) to a solution of 1-14 (2.0 g, crude) in _CH3CN (20 mL). Stir the resulting mixture at 40 °C for 2 hours, followed by concentration under reduced pressure. Purify the residue by reversed-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

Steps 15 and 16. Synthesize 1b-1 and 1b-2

TFA (3 mL) was added to a solution of 1-15 (500 mg, 0.95 mmol) in DCM (2 mL) at 0 °C, and the mixture was stirred at 0 °C for 30 minutes. After completion, the reactants were added to a saturated _NaHCO3 solution (30 mL), followed by extraction 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 purified by reversed-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 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.

1b:

LC-MS[M+1] ⁺ ＝472.1

¹ H NMR (400MHz, CDCl ₃ )δ7.58(d,J＝5.6Hz,1H),7.44-7.36(m,1H),7.27(s,2H),5.77-5.65(m,1H),5.41(s,1H),5.25 (dd,J＝12.0,6.3Hz,1H),5.19-5.11(m,1H),4.92-4.83(m,1H),4.80(s,1H),3.70(d,J＝4.6Hz,3 H),3.52(dd,J＝34.3,12.2Hz,1H),3.19(d,J＝12.9Hz,0.5H),2.98(d,J＝12.5Hz,0.5H),2.90-2. 84(m,0.5H),2.78-2.61(m,1.5H),2.31-2.16(m,1H),1.97-1.82(m,1H),1.28(d,J＝5.4Hz,6H).

1b-1:

¹ H NMR (400MHz, CDCl ₃ )δ7.60-7.57(m,1H),7.41-7.39(m,1H),7.33–7.26(m,2H),5.64(s,1H),5.41(s,1H), 5.25(d,J＝12.1Hz,1H),5.14(d,J＝12.0Hz,1H),4.91–4.81(m,1H),4.79(s,1H),3.69(s ,3H),3.47(d,J＝12.4Hz,1H),2.97(d,J＝12.5Hz,1H),2.86(d,J＝10.6Hz,1H),2.72(dd, J＝22.5,10.6Hz,1H),2.29-2.20(m,1H),1.92(d,J＝14.3Hz,1H),1.27(d,J＝6.2Hz,6H).

1b-2:

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

Example 2

Step 1. Synthesize 2-2 and 2-3

KHMDS (75 mL, 74.9 mmol) was added to a solution of ethyl 2-(diethoxyphosphoryl)ethyl acetate (20.6 g, 86.5 mmol) in THF (300 mL) at -60 °C under _N2 , and the mixture was stirred at -60 °C for 1 h. Then, 2-1 (20.0 g, 57.6 mmol) was added dropwise at -60 °C, and the mixture was stirred at -10 °C for 0.5 h. The reaction mixture was then added to saturated _NH4Cl (1000 mL). The mixture was extracted with EtOAc (500 mL x 2). The combined organic layers were washed with brine, _dried over _Na2SO4 , and filtered. The filtrate was concentrated under vacuum, and the residue was purified by silica gel chromatography (petroleum ether/EtOAc = 60/1) to give 2-3 (7.5 g, 30% yield) and 2-2 (4.5 g, 18% yield) as pale yellow oil.

2-2: ¹ H NMR (400MHz, CDCl ₃ )δ5.76(s,1H),5.50(d,J＝15.8Hz,1H),5.23(d,J＝12.1Hz,1H),4.97-4.83(m,2H),4.23-4.06(m,3H),4.01-3.91(m,1H), 3.91-3.77(m,2H),3.28-3.12(m,H,),2.23-2.10(m,1H),1.88(dd,J＝23.1,11.5Hz,1H),1.42(s,9H),1.31-1.24(m,9H).

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

Step 2. Synthesize 2-4

TFA (9 mL) was added to a solution of 2-3 (3.0 g, 7.2 mmol) in DCM (20 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 30 minutes. After completion, the resulting mixture was added to a saturated _NaHCO3 solution (200 mL). The mixture was then extracted with DCM (200 mL). The _organic layer was dried over _Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give crude 2-4 (3.0 g, >100% yield) as a yellow oil, which could be used in the next step without further purification.

LC-MS[M+1-100] ⁺ ＝318.1

Step 3. Synthesize 2a

Add 1-12 (2.8 g, 7.2 mmol) and _KHCO3 (1.4 g, 14.4 mmol) to a solution of 2-4 (3.0 g, crude material) in _CH3CN (15 mL). Stir the resulting mixture at 40 °C for 1 hour. After completion, concentrate the reaction mixture under reduced pressure and purify the residue by reversed-phase column chromatography (C18, _CH3CN / _H2O = 80/20) to give 2a (1.7 g, 47% yield).

LC-MS[M+1] ⁺ ＝500.1

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

Step 4. Synthesize 2-5

TFA (0.6 mL) was added to a solution of 2-2 (100 mg, 0.26 mmol) in DCM (3 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 30 minutes. After stirring, the reaction mixture was added to a saturated _NaHCO3 solution ( ₂₀ mL). The resulting mixture was then extracted with DCM (20 mL). The organic layer was dried over _Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give crude 2-5 (120.0 mg, >100% yield) as a yellow oil, which could be used in the next step without further purification.

LC-MS[M+1-100] ⁺ ＝318.1

Step 5. Synthesize 2b

Add 1-12 (88 mg, 0.23 mmol) and _KHCO3 (92 mg, 0.92 mmol) to a solution of 2-5 (120.0 mg, crude matter) in _CH3CN (3 mL). Stir the resulting mixture at 40 °C for 1 hour. After completion, concentrate the reaction mixture under reduced pressure and purify the residue by reversed-phase column chromatography (C18, _CH3CN / _H2O = 80/20) to give 2b (23 mg, 20% yield).

LC-MS[M+1] ⁺ ＝500.1.

¹ H NMR (400MHz, CDCl ₃ )δ7.59(d,J＝5.1Hz,1H),7.38(d,J＝6.4Hz,1H),7.32-7.25(m,2H),5.74(s,0.5H),5.61(s,0.5H),5.43(s,1H),5 .25(dd,J＝11.9,5.4Hz,1H),5.15(dd,J＝11.9,4.6Hz,1H),4.93-4.81(m,1H),4.77(s,1H),4.23-4.06(m,2H),3. 69(d,J＝3.9Hz,3H),3.51(d,J＝11.9Hz,0.5H),3.42(d,J＝12.1Hz,0.5H),3.14(d,J＝12.3Hz,0.5H),2.97-2.80(m ,1H),2.77-2.67(m,0.5H),2.63(d,J＝7.5Hz,1H),2.31-2.10(m,1H),1.88(dd,J＝21.5,15.1Hz,1H),1.26(s,9H).

Example 3

Step 1. Synthesize 3-3

A solution of 3-2 (79.98 g, 0.64 mol) and KI (142.76 g, 0.86 mol) in acetone (1.5 L) was stirred at 16 °C for 16 hours. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in DMF (1.5 L), and 3-1 (150.0 g, 0.43 mol) and _K₂CO₃ (88.32 g, 0.64 mol) were added to the solution. After addition, the mixture was stirred at 16 ° _C for 2 hours. The reactants were diluted with water (3 L) and extracted with EtOAc (1 L x 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.

^1H NMR (400MHz, 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).

Step 2. Synthesize 3-4

A solution of 3-3 (79.0 g, 0.18 mol) and Et ₃ N.3HF (90.4 g, 0.54 mol) in THF (800 mL) was refluxed for 16 hours with stirring. 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 as a colorless oil (41.0 g, 68% yield).

Step 3. Synthesize 3-5

Des Martin (64.9 g, 0.15 _mol ) was added to a solution of 3-4 (41.0 g, 0.12 mol) in DCM (500 mL) at 20 °C. After addition, the mixture was stirred at 20 °C for 30 min. The resulting mixture was washed with saturated _Na₂SO₃ aqueous solution (500 mL), saturated _NaHCO₃ aqueous solution (500 mL x 2), and brine. The organic layer was separated, _dried over _Na₂SO₄ , and filtered. The filtrate was concentrated under vacuum, and the residue was purified by silica gel chromatography (petroleum/EtOAc = 3/1) to give 3-5 (37.0 g, 92% yield) as a yellow oil.

Step 4. Synthesize 3-7-Z and 3-7-E

LiHMDS (151 mL, 0.15 mol) was added to a solution of 3-6 (37.9 g, 0.15 mol) in anhydrous THF (500 mL) at -60 °C under _N2 atmosphere. The resulting mixture was stirred at -60 °C for 30 min, followed by dropwise addition of 3-5 (37.0 g, 0.11 mol) at -60 °C. The reaction mixture was heated to 0 °C and stirred at 0–10 °C for 1 h. The resulting mixture was then added to saturated _NH4Cl (100 mL, aqueous solution) and extracted with EtOAc (500 mL x 2). The combined organic layers were washed with brine, _dried over _Na2SO4 , and filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel chromatography (petroleum ether/EtOAc = 50/1) to give 3-7-Z (7.0 g, 14% yield) and 3-7-E (14 g, 28% yield).

3-7-Z

^1H NMR (400MHz, chloroform-d) δ 5.76 (s, 1H), 5.50 (s, 1H), 5.32 (d, J = 12Hz, 1H), 5.17 (d, J = 12Hz, 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).

3-7-E

^1H NMR (400MHz, 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).

Step 5. Synthesize 3-8

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 hours. Subsequently, the reaction mixture was diluted with a saturated aqueous solution of _NaHCO₃ (100 mL) and extracted with DCM (50 mL x ₂ ). The combined organic layers were washed with brine, dried over _Na₂SO₄ , and filtered. The filtrate was concentrated under vacuum to give 3-8 (3 g, 71% yield) as a yellow oil, which was used directly in the next step without further purification. LC-MS [M+1] ^⁺ = 318.1

Step 6: Synthesize 3-10

Add 3-9 (3.6 g, 9.4 mmol) and _KHCO₃ (2.8 g, 28.2 mmol) to a solution of 3-8 (3.0 g, 9.4 mmol) in _CH₃CN (10 mL). Stir the resulting mixture at 40 °C for 4 hours. After completion, concentrate the reaction mixture under reduced pressure and purify the residue by reversed-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

Steps 7 and 8. Synthesize 3b-1 and 3b-2

TFA (5 mL) was added to a solution of 3-10 (2.5 g, 5.0 mmol) in DCM (20 mL), and the mixture was stirred at 20 °C for 1 hour. Afterward, the reaction mixture was added to a saturated _NaHCO3 aqueous solution (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine, _dried over _Na2SO4 , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by 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:

LC-MS[M+1] ⁺ ＝444.1.

^¹H NMR (400MHz, 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 = 4.4Hz, 3 H),3.54(d,J＝12.4Hz,0.5H),3.45(d,J＝12.4Hz,0.5H),3.17(d,J＝12.4Hz,0.5H),2.96(d,J＝12.4Hz,0.5H), 2.85(d,J＝12.0Hz,0.5H),2.73(d,J＝12.0Hz,0.5H),2.70-2.62(m,1H),2.30-2.13(m,1H),2.02-1.82(m,1H).

3b-1:

¹ H NMR (400MHz, CDCl ₃ )δ7.61(d,J＝7.5Hz,2H),7.56–7.41(m,2H),6.10(s,1H),5.71(s,1H),5.52(s,1H),5.27(q,J＝12.2Hz,2H),3.98( s,2H),3.83(s,3H),3.80(s,3H),3.71–3.56(m,1H),3.35–3.14(m,1H),3.01–2.71(m,1H),2.06(d,J＝15.0Hz,1H).

3b-2:

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

Example 4

Step 1. Synthesize 4-2

A solution of 4-1 (64 g, 0.43 mol) and KI (96.3 g, 0.86 mol) in acetone (0.8 L) was stirred at 20 °C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMF (1 L). 1-5 (150.0 g, 0.43 mol) and _K₂CO₃ (120 g, 0.864 mol) were added to the above solution. After the addition, the mixture was stirred at 20 ° _C for 2 hours. The reactants were diluted with water (2 L) and extracted with 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), a dark oil, which was used in the next step without further purification.

Step 2. Synthesize 4-3

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 hours. The resulting mixture was concentrated under reduced pressure, and the residue was diluted with EA (1.5 L). The solution was washed with brine (500 ml * 2) and the organic layer was separated. The residue was 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 as a white solid (108 g, 73% yield). LC-MS [M+1] ⁺ -100 = 246.2.

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

Step 3. Synthesize 4-4

A solution of 4-3 (108 g, 0.313 mol) in DCM (1 L) was added to a solution _of 4-3 at 20 °C. The mixture was stirred at 20 °C for 30 min. The reaction mixture was washed with saturated _{Na₂S₂O₃} solution ( ₁ L), saturated _NaHCO₃ solution (1 L x 2), and brine. The mixture was dried _{over Na₂SO₄} and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum/EtOAc = 3/1) to give 4-4 (80.0 g, 74.5% yield) as an orange oil. LC-MS [M+1] ^⁺ +Na = 366.1.

¹ H NMR (400MHz, CDCl ₃ )δ4.29(d,J＝17.9Hz,1H),4.16(d,J＝18.4Hz,1H),3.82(s,1H),3.48(d,J＝15.6Hz,1H),3.44 -3.32(m,2H),3.27(s,1H),2.43-2.29(m,1H),2.16(s,3H),2.09-2.04(m,1H),1.46(s,9H).

Step 4. Synthesize 4-6-Z and 4-6-E

LiHMDS (303 mL, 0.303 mol) was added to a solution of 4-5 (77 g, 0.302 mol) in anhydrous THF (800 mL) at -60 °C in a _N₂ environment. The reaction mixture was stirred at -60 °C for 30 min, followed by dropwise addition of 4-4 (80 g, 0.233 mol) at -60 °C. The mixture was stirred at 0–10 °C for 1 h. The reaction mixture was then added to a saturated _NH₄Cl solution (800 mL) and extracted with EtOAc (700 mL x 2). The combined organic layers were washed with brine, dried over _{Na₂SO₄ ,} and filtered. The filtrate was concentrated under vacuum, and the residue was purified by silica gel chromatography (petroleum ether/EtOAc = 20/1) to give 4-6-Z (12 g, 9% yield) as a pale orange oil and 4-6-E (15 g, 11% yield) as a grayish-white solid. LC-MS[M+1] ⁺ +23 = 464.2.

4-6-Z

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

4-6-E

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

Step 5: Synthesize 4-7

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

Steps 6 and 7. Synthesize 4b-1 and 4b-2

Et ₃ N was added dropwise to a solution of 4-7 (15 g, crude material, 0.023 mol) and 4-8 (5 mL) in DCM at 20 °C. After addition, the mixture was stirred at 20 °C for 4 hours. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EA (200 mL) and water (300 mL). The pH was adjusted to ₃ with HCl (1 M, aqueous solution). The organic layer was separated, washed with brine, dried over _Na₂SO₄ , and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18, ACN/ _H₂O = 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:

LC-MS[M+1]+＝468.1.

¹ H NMR (400MHz, CDCl ₃ )δ7.57(d,J＝6.7Hz,1H),7.40(d,J＝6.2Hz,1H),7.32-7.23(m,2H),5.79(s,0.5H),5.67(s, 0.5H),5.23(s,1H),4.77-4.67(m,1H),3.71(d,J＝4.5Hz,3H),3.60-3.52(m,1.5H),3.50-3. 36(m,1.5H),3.17(d,J＝12.3Hz,0.5H),2.97(d,J＝12.4Hz,0.5H),2.90-2.82(m,0.5H),2.8 0-2.70(m,0.5H),2.66(d,J＝8.6Hz,1H),2.30-2.13(m,1H),2.06(s,3H),1.93-1.81(m,1H).

4b-1:

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

4b-2:

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

Example 5

Step 1: Synthesize 5-3

5-2 (7.6 g, 31.6 mmol) was added in portions to a mixture of _5-1 (10 g, 28.8 mmol) and _K₂CO₃ (4.8 g, 34.6 mmol) in DMF (100 mL) at 20 °C. After addition, the mixture was stirred at 20 °C for 2 hours. The mixture was poured into water (300 mL), extracted with EA (200 mL), 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 a colorless oil.

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

Step 2. Synthesize 5-4

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

Step 3. Synthesize 5-5

Add Dess-Martin Periodinane (3.9 g, 9.4 mmol) to a 25 mL solution of 5-4 (2.5 g, 7.2 mmol) of DCM, and stir the mixture at 25 °C for 30 minutes. Afterward, pour the reaction mixture into a ₅₀ mL 1: ₁ mixture of saturated _{Na₂S₂O₃ and} saturated NaHCO₃. Extract the mixture with DCM (20 mL x 2). Wash the combined organic layers with brine, dry over _{Na₂SO₄ ,} and filter. Concentrate the filtrate under reduced pressure, and purify the residue by silica gel chromatography (petroleum ether/EtOAc = 3/1) to give 5-5 (2.0 g, 80% yield) as a colorless oil.

Step 4. Synthesize 5-7

LiHMDS (4.8 mL, 1 M, 4.8 mmol in THF) was added to a 15 mL solution of 5-6 (1.2 g, 4.8 mmol) at -60 °C under N₂ _conditions , and the mixture was stirred for 30 minutes at -60 °C. 5-5 (1.5 g, 4.4 mmol) was then added to the resulting mixture at -60 °C. After addition, the reaction mixture was stirred at _0–10 °C for 1 hour. The reaction mixture was then poured into a saturated _NH₄Cl (20 mL) solution, and the mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over _Na₂SO₄ , and filtered. The filtrate was concentrated under vacuum. 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.

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

Step 5. Synthesize 5-8

The 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 hours. 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 under vacuum to give crude 5-8 (450 mg, yield >100%) as a colorless oil.

LC-MS[M+1] ⁺ ＝344.3

Step 6. Synthesize 5-10

Add 5-9 (389 mg, 1.01 mmol) and _KHCO3 (400 mg, 4.04 mmol) to a 5 mL solution of _CH3CN (crude matter) containing 5-8. Stir the mixture at 40 °C for 3 hours and filter. Concentrate the filtrate under reduced pressure and purify the residue by silica gel chromatography (petroleum ether/EtOAc = 20/1) to give 5-10 (50 mg, 9% yield) as a pale yellow oil.

LC-MS[M+1] ⁺ ＝526.3

^1H NMR (400MHz, CDCl3 ₎ )δ7.60(d,J＝6.4Hz,1H),7.39(d,J＝7.7Hz,1H),7.25(d,J＝11.8Hz,2H),5.68(s, 1H),5.51(d,J＝3.7Hz,1H),5.26(d,J＝12.1Hz,1H),5.14(d,J＝12.0Hz,1H),4.77 (s,1H),3.70(s,3H),3.52(d,J＝11.9Hz,1H),3.10(d,J＝12.0Hz,1H),2.59(d,J＝ 8.5Hz,2H),2.28–2.09(m,1H),1.84(d,J=14.3Hz,1H),1.47(s,9H),1.18(s,9H).

Step 7. Synthesize 5

TFA (0.5 mL) was added to a 5-10 (50 mg, 0.095 mmol) solution of DCM (0.5 mL) at 0 °C. After addition, the mixture was stirred at 0 °C for 3 hours. The resulting mixture was poured into a saturated _NaHCO3 (2 mL) mixture and extracted with DCM (2 mL x 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).

LC-MS[M+1] ⁺ ＝470.1

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

Example 6

Step 1: Synthesize 6-3

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

Step 2: Synthesize 6-4

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

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

Step 3. Synthesize 6-5

Add Dess-Martin Periodinane (4.1 g, 9.82 mmol) to a 20 mL solution of 6-4 (2.2 g, 7.56 mmol) in DCM, and stir the mixture at 25 °C for 10 minutes. After stirring, pour the reaction mixture into a ₄₀ mL 1: ₁ mixture of saturated _{Na₂S₂O₃ and} saturated NaHCO₃. Extract the mixture with DCM (20 mL x 2). Wash the combined organic layers with brine, _dry over _Na₂SO₄ , and filter. Concentrate the filtrate under reduced pressure, and purify the residue by silica gel chromatography (petroleum ether/EtOAc = 5/1) to give 6-5 as a colorless oil (1.9 g, 87% yield).

Step 4. Synthesize 6-7

LiHMDS (3.8 mL, 1 M, 3.8 mmol in THF) was added to a 10 mL solution of 6-6 (1.0 g, 3.80 mmol) at -60 °C under N₂ _conditions , and the mixture was stirred for 30 minutes at -60 °C. 6-5 (1.0 g, 3.46 mmol) was added to the resulting mixture at -60 °C. After addition, the reaction mixture was stirred at _0–10 °C for 1 hour. The reaction mixture was then poured into a saturated _NH₄Cl (20 mL) solution, and the mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over _Na₂SO₄ , and filtered. The filtrate was concentrated under vacuum. 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.

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

Step 5. Synthesize 6-8

The mixture of 6-7 (30 mg, 0.0775 mmol) and TsOH· _H₂O (22 mg, 0.116 mmol) in DCM (1 mL ₎ was stirred at 40 °C for 2 hours. After completion, the reaction mixture was poured into a saturated _NaHCO₃ solution (5 mL), and the resulting mixture was extracted with DCM (2 mL x 2). The combined organic layers were dried over _Na₂SO₄ and filtered. The filtrate was concentrated under vacuum to give crude 6-8 (crude substance, yield >100%), which was a pale yellow oil.

LC-MS[M+1] ⁺ ＝288.2

Step 6. Synthesize 6-10

Add 6-9 (30 mg, 0.0775 mmol) and _KHCO3 (31 mg, 0.31 mmol) to a _CH3CN (1 mL) solution of 6-8 (crude matter, 0.0775 mmol). Stir the resulting mixture at 40 °C for 3 hours and filter. Concentrate the filtrate under reduced pressure, and purify the residue by Prep-TLC (petroleum ether/EtOAc = 10/1) to give 6-10 (10 mg, 28% yield) as a colorless oil.

LC-MS[M+1] ⁺ ＝470.2

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

Step 7. Synthesize 6

TFA (0.5 mL) was added to a DCM (0.5 mL) solution of 6-10 (10 mg, 0.032 mmol) at 0 °C. The mixture was stirred at 0 °C for 3 hours. The resulting mixture was poured into a saturated _NaHCO3 (3 mL) mixture and extracted with DCM (2 mL x 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 6 (5 mg, 38% yield).

LC-MS[M+1] ⁺ ＝414.1

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

Example 7

Step 1. Synthesize 7-2

Add Dess-Martin Periodinane (3.03 g, 7.16 mol) to a DCM (20 mL) solution of 7-1 (2 g, 5.97 mmol) and stir the mixture at 25 °C for 1 hour. After completion, pour the reaction mixture into _{a saturated Na₂S₂O₃} /saturated _NaHCO₃ (40 mL, 1:1) mixture. Extract the mixture with DCM (20 mL x 2). Wash the combined organic layers with brine, _dry over _Na₂SO₄ , and filter. Concentrate the filtrate under reduced pressure and purify the residue by silica gel chromatography (petroleum ether/EtOAc = 5/1) to give 7-2 (1.3 g, 65% yield) as a pale yellow oil.

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

Step 2. Synthesize 7-4

LiHMDS (4.3 mL, 1 M, 4.3 mmol in THF) was added to a 15 mL solution of 7-3 (1.1 g, 4.3 mmol) at -60 °C under N₂ _conditions , and the mixture was stirred at -60 °C for 30 minutes. 7-2 (1.3 g, 3.9 mmol) was added dropwise to the mixture at -60 °C. After addition, the reaction mixture was stirred at _0–10 °C for 1 hour. The reaction mixture was then poured into a saturated _NH₄Cl (30 mL) solution, and the mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over _Na₂SO₄ , and filtered. The filtrate was concentrated under vacuum. 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.

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

Step 3. Synthesize 7-5

The mixture of 7-4 (60 mg, 0.138 mmol) and TsOH· _H₂O (39 mg, 0.207 mmol) in DCM ( ₂ mL) was stirred at 40 °C for 2 hours. After completion, the reaction mixture was poured into a saturated _NaHCO₃ solution (4 mL), and the resulting mixture was extracted with DCM (2 mL * 2). The combined organic layers were dried over _Na₂SO₄ and filtered. The filtrate was concentrated under vacuum to give crude 7-5 (50 mg, yield >100%) as a pale yellow oil.

Step 4. Synthesize 7-7

Add 7-6 (53 mg, 0.138 mmol) and _KHCO3 (55 mg, 0.552 mmol) to a ₂ mL solution of 7-5 (crude material, 0.138 mmol). Stir the mixture at 40 °C for 3 hours. After cooling to room temperature, filter the mixture. Concentrate the filtrate under reduced pressure and purify the residue by silica gel chromatography (petroleum ether/EtOAc = 10/1) to give 7-7 (20 mg, 28% yield) as a white solid.

LC-MS[M+1] ⁺ ＝516.3

Step 5. Synthesize 7

TFA (1 mL) was added to a DCM (1 mL) solution of 7-7 (20 mg, 0.039 mmol) at 0 °C. The mixture was stirred at 0 °C for 3 hours. The resulting mixture was poured into a saturated _NaHCO3 (4 mL) solution and extracted with DCM (2 mL x 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 7 (10 mg, 45% yield).

LC-MS[M+1] ⁺ ＝460.1

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

Example 8

Step 1: Synthesize 8-3

NaH (0.688 g, 17.2 mmol, 60% paraffinic dispersion) was added in portions to a THF (50 mL) solution of 8-1 (5.00 g, 14.4 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. 8-2 (1.86 g, 17.2 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 0.5 hours. 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, and the residue was purified by silica gel chromatography (petroleum ether/EtOAc = 10/1) to give 8-3 (3.9 g, 65% yield) as a colorless oil.

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

LC-MS[M+1-100] ⁺ ＝319.2

Step 2: Synthesize 8-4

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

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

LC-MS[M+1-100] ⁺ ＝205.1

Step 3. Synthesize 8-5

Add Dess-Martin Periodinane (8.3 g, 19.7 mmol) to a DCM (30 mL) solution of 8-4 (2.4 g, 7.9 mmol) and stir the mixture at 25 °C for 3 hours. After stirring, pour the reaction mixture into _{a saturated Na₂S₂O₃} /saturated _NaHCO₃ (40 mL, 1:1) mixture. Extract the mixture with DCM (20 mL x 2). Wash the combined organic layers with brine, _dry over _Na₂SO₄ , and filter. Concentrate the filtrate under reduced pressure and purify the residue by silica gel chromatography (petroleum ether/EtOAc = 5/1) to give 8-5 (1.6 g, 67% yield) as a white solid.

LC-MS[M+1-56] ⁺ ＝247.1

Step 4. Synthesize 8-7

LiHMDS (5.8 mL, 1 M, 5.8 mmol in THF) was added to a 20 mL solution of 8-6 (1.5 g, 5.8 mmol) at -60 °C under N₂ _conditions , and the mixture was stirred for 30 minutes at -60 °C. 8-5 (1.6 g, 5.3 mmol) was added dropwise to the resulting mixture at -60 °C. After addition, the reaction mixture was stirred at 0–10 °C for 1 hour. The reaction mixture was then poured into a saturated _NH₄Cl (20 mL) solution, and the mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over _{Na₂SO₄ ,} and filtered. The filtrate was concentrated under vacuum. 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.

LC-MS[M+Na] ⁺ = 423.3

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

Step 5. Synthesize 8-8

The mixture of 8-7 (50 mg, 0.125 mmol) and TsOH· _H₂O (36 mg, 0.188 mmol) in DCM (1 mL ₎ was stirred at 40 °C for 2 hours. After completion, the reaction mixture was poured into a saturated _NaHCO₃ solution (2 mL), and the resulting mixture was extracted with DCM (2 mL * 2). The combined organic layers were dried over _Na₂SO₄ and filtered. The filtrate was concentrated under vacuum to give crude 8-8 (crude substance, yield >100%), which was a pale yellow oil.

LC-MS[M+1] ⁺ ＝301.1

Step 6. Synthesize 8-10

Add 8-9 (38.1 mg, 0.100 mmol) and _KHCO3 (50 mg, 0.500 mmol) to a _CH3CN (1 mL) solution of 8-8 (crude matter, 0.125 mmol). Stir the resulting mixture at 40 °C for 3 hours and filter. Concentrate the filtrate under reduced pressure, and purify the residue by Prep-TLC (petroleum ether/EtOAc = 10/1) to give 8-10 (10 mg, 16% yield) as a pale yellow solid.

LC-MS[M+1] ⁺ ＝483.2

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

Step 7. Synthesize 8

TFA (0.5 mL) was added to a DCM (0.5 mL) solution containing 8–10 (10 mg, 0.021 mmol) at 0 °C. The mixture was stirred at 0 °C for 3 hours. The resulting mixture was poured into a saturated NaHCO₃ ( ₃ mL) solution and extracted with DCM (2 mL x 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).

LC-MS[M+1] ⁺ ＝427.1

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

Example 9

Step 1: Synthesize 9-2

Dimethylamine (1.76 g, 18.7 mmol) was added in portions to compound 9-SM (11.0 g, 85.3 mmol) at 20 °C. After addition, the mixture was stirred at 20 °C for 0.5 h. The mixture was then concentrated under vacuum. 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.

Step 2: Synthesize 9-3

NaH (0.700 g, 17.3 mmol) was added in portions to a THF (50 mL) solution of 9-1 (5.00 g, 14.4 mmol) at 0 °C, and the mixture was stirred at 0 °C for 1 hour. 9-2 (2.37 g, 17.3 _mmol ) was added at 0 °C, and the mixture was stirred at 0 °C for 0.5 hours. 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 _Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether/EtOAc = 10/1) to give 9-3 (4.8 g, 65% yield) as a colorless oil.

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

Step 3: Synthesize 9-4

Add Et ₃ N.3HF (5.0 g, 31.5 mmol) to a solution of 9-3 (4.7 g, 10.5 mmol) in THF (50 mL), and stir the mixture at 50 °C for 16 hours. After completion, concentrate the reaction mixture under reduced pressure. Purify the residue by silica gel chromatography (petroleum ether/EtOAc = 3/1) to give 9-4 (3.2 g, 91% yield) as a colorless oil.

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

Step 4. Synthesize 9-5

Add Dess-Martin Periodinane (5.7 g, 13.47 mmol) to a DCM (30 mL) solution of 9-4 (3.0 g, 8.98 mmol) and stir the mixture at 25 °C for 10 min. After stirring, pour the reaction mixture into _{a saturated Na₂S₂O₃ / saturated NaHCO₃} (100 mL, 1:1) mixture. Extract the mixture with DCM (50 mL x 2). Wash the combined organic layers with brine, _dry over _Na₂SO₄ , and filter. Concentrate the filtrate under reduced pressure and purify the residue by silica gel chromatography (petroleum ether/EtOAc = 5/1) to give 9-5 (2.2 g, 74% yield) as a pale orange oil.

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

Step 5. Synthesize 9-7

LiHMDS (6.6 mL, 1 M, 6.6 mmol in THF) was added to a 20 mL solution of 9-6 (1.7 g, 6.6 mmol) at -60 °C under N₂ _conditions , and the mixture was stirred for 30 minutes at -60 °C. 9-5 (2.0 g, 6.0 mmol) was added dropwise to the resulting mixture at -60 °C. After addition, the reaction mixture was stirred at 0–10 °C for 1 hour. The reaction mixture was then poured into a saturated _NH₄Cl (50 mL) solution, and the mixture was extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine, dried over _{Na₂SO₄ ,} and filtered. The filtrate was concentrated under vacuum. 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.

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

Step 6. Synthesize 9-8

A mixture of 9-7 (800 mg, 1.8 mmol) and TsOH· _H₂O (469 mg, 2.72 mmol) in DCM (8 mL ₎ was stirred at 40 °C for 2 hours. After completion, the reaction mixture was poured into a saturated _NaHCO₃ solution (30 mL), and the resulting mixture was extracted with DCM (10 mL * 2). The combined organic layers were dried over _Na₂SO₄ and filtered. The concentrated filtrate was purified by silica gel chromatography (DCM/MeOH = 20/1) to give 9-8 as a colorless oil (185 mg, 31% yield).

LC-MS[M+1] ⁺ ＝331.2

Step 7. Synthesize 9-10

Add 9-9 (194 mg, 0.50 mmol) and _KHCO3 (224 mg, 2.24 mmol) to a _CH3CN (2 mL) solution of 9-8 (185 mg, 0.56 mmol). Stir the resulting mixture at 40 °C for 3 hours and filter. Concentrate the filtrate under reduced pressure and purify the residue by Prep-TCL (petroleum ether/EtOAc = 10/1) to give 9-10 (200 mg, 69.8% yield) as a colorless oil.

LC-MS[M+1] ⁺ ＝513.2

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

Step 8. Synthesis 9

TFA (3 mL) was added to a DCM (3 mL) solution of 9-10 (200 mg, 0.39 mmol) at 0 °C. The mixture was stirred at 0 °C for 3 hours. The resulting mixture was poured into a saturated _NaHCO3 (15 mL) solution and extracted with DCM (5 mL x 2). The combined organic layers were washed with brine, _dried over _Na2SO4 , and filtered. The filtrate was concentrated under reduced pressure to give 9 (50 mg, 28% yield) as a white solid.

LC-MS[M+1] ⁺ ＝457.2

¹ H NMR (CDCl ₃ (400MHz,)δ7.61–7.54(m,1H),7.42–7.36(m,1H),7.30–7.22(m,2H),5.75(s,0.5H),5.62(s,0.5H),5. 40(s,1H),5.29–5.20(m,1H),5.09(dd,J＝12.1,7.2Hz,1H),4.79(d,J＝2.7Hz,1H),3.69(dd,J＝4.7,2.6 Hz,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

Biochemical analysis

Analysis 1: Pharmacokinetics in rats

Pharmacokinetic experiments were conducted using male Sprague-Dawley rats.

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 onto an LC-MS/MS instrument after extraction to determine the concentration of thiol active metabolites. The concentration results in rat plasma are shown in Figures 1 and 2.

As shown in Figure 1, at a dose level of 10 mg/kg, compounds 1a, 1b, and 2a presented in this paper 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.

As shown in Figure 2, when administered orally, compound 3, presented herein at a dose level of 2 mg/kg, reached peak concentration of the thiol active metabolite approximately 20 minutes after administration, compared to clopidogrel at a much higher dose level of 10 mg/kg, which reached peak concentration of the thiol active metabolite approximately 30 minutes after administration. When administered intravenously, compound 3, presented herein at a dose level of only 1 mg/kg, reached peak concentration of the thiol active metabolite approximately 6 minutes after administration. These results indicate that compound 3 provides a faster and more effective release of the active metabolite compared to clopidogrel.

Compared to clopidogrel, the other compounds presented in this paper exhibit comparable, or even faster and more effective, release of active metabolites.

Analysis 2: Antiagglutination effect in rats

Male Spög-Dolly rats were used for in vitro platelet aggregation experiments. Following oral administration of clopidogrel, the exemplary compounds and mordants provided herein (control group) to the rats, blood was collected via the jugular vein at 0.5 h, 1 h, and 2 h using 3.8% (w/v) sodium citrate solution as an anticoagulant (1/9 volume of whole blood). The citrate-containing blood samples were centrifuged at 1000 rpm for 5 min to obtain platelet-rich plasma (PRP). After PRP separation, the remaining blood was further centrifuged at 3000 rpm for 10 min to obtain platelet-free plasma (PPP). The platelet count in the PRP was measured using a hematology analyzer (Siemens, ADVIA2120) and adjusted to 4 × ^10⁸ /mL by the PPP.

Platelet aggregation was determined using a turbidimetric agglutination assay with an automated platelet agglutinator (PRECIL LBY-NJ4). The agglutinator was first heated to 37°C, and a 290 μL PRP sample was added to a cuvette and placed in the automated platelet agglutinator. After a 5-minute pre-incubation, the agglutinator was calibrated using PPP to represent 100% agglutination and PRP to represent 0% agglutination. Finally, 10 μL of ADP solution (final concentration 10 μM) 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. The antiagglutination effect of the test compound was expressed as inhibition (%) determined by the following relationship:

Inhibition (%) = (Maximum platelet aggregation in control group (%) - Maximum platelet aggregation in test compound (%)) / (Maximum platelet aggregation in control group (%)) * 100

The inhibition (%) results of the tested compounds are shown in Figure 3. The dose levels for clopidogrel, 1a, and 1b were 10 mg/kg, 0.5 mg/kg, and 2 mg/kg, respectively. As can be seen from Figure 2, clopidogrel achieved a maximum platelet aggregation inhibition of approximately 45% within approximately 120 minutes after administration, while compound 1b achieved a maximum inhibition of approximately 45% within 60 minutes at a much lower dose level than clopidogrel, indicating that it had a much earlier onset of action and was much more potent than clopidogrel.

Compared to clopidogrel, the other compounds presented in this article can show faster onset of action and higher potency.

The foregoing description is to be considered merely an illustration of the principles of this disclosure. Furthermore, since many modifications and variations will be apparent to those skilled in the art, it is not intended to limit the invention to the exact constructions and processes shown above. Therefore, all suitable modifications and equivalents can be considered to fall within the scope of the invention as defined by the appended claims.

Claims (51)

1. A compound having formula (I): Or its pharmaceutically acceptable salt. in Indicates a double bond with a Z or E configuration; R ¹ is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, amino, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, and heteroynyl, wherein each of the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, and heteroynyl groups is optionally substituted by one or more ^Ra . ^R2 is -C(O) ^Rb ; R ³ is 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. L is selected from the group consisting of: straight, 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 substituted by one or more R ^f ; W is selected from the following group: Where the * end of W is connected to L; R ⁴ is 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. Each of ^Ra is independently selected from the group consisting of: hydrogen, halogen, hydroxyl, amino, cyano, nitro, or ^{-NRcRd ; Rb} is 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 , ^-NRcRd and ^-ORe ; Each of ^Rc and ^Rd 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. ^Re is 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. Each of ^Rf is independently selected from the group consisting of: hydrogen, cyano, halogen, hydroxyl, amino, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclic, aryl, and heteroaryl; or The two R ^f groups together with the atoms they are attached to form a saturated or partially unsaturated cycloalkyl group or a saturated or partially unsaturated heterocyclic group, wherein each of the cycloalkyl group and the heterocyclic group is optionally substituted with a cyano group, a halogen group, a hydroxyl group, an amino group or an alkyl group. R ^g is 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 hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocyclic, aryl and heteroaryl is optionally substituted by cyano, halogen, hydroxyl or amino. n can be 0, 1, 2, 3, 4, or 5. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, amino, alkyl, and heteroalkyl, wherein each of the alkyl and heteroalkyl groups is optionally substituted by one or more ^Ra . 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein each of ^Ra is independently selected from the group consisting of halogen, hydroxyl, amino, cyano, and nitro. 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R1 is fluorine, chlorine, bromine, cyano, methyl, or trifluoromethyl. 5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R1 is fluorine or chlorine. 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R2 is -C(O) ^Rb , and ^Rb is selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, ^-NRcRd , and ^{-ORe .} 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein each of ^Rc and ^Rd is independently selected from the group consisting of hydrogen, alkyl, and alkenyl, wherein each of the alkyl and alkenyl groups is optionally substituted with a halogen or a hydroxyl group. 8. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein ^Re is selected from the group consisting of alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, and heteroaryl groups is optionally substituted with a cyano, halogen, hydroxyl, amino, or alkyl group. 9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R2 is -C(O) ^Rb , wherein ^Rb is hydrogen, hydroxyl, alkyl, saturated cycloalkyl, or ^-ORe . 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein ^Re is an alkyl group. 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein ^Re is methyl, ethyl, n-propyl, or isopropyl. 12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R2 is -C(O)-cyclopropyl or -C(O) _OCH3 . 13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R3 is selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, and heteroalkenyl, wherein each of the alkyl, alkenyl, heteroalkyl, and heteroalkenyl groups is optionally substituted with a cyano, halogen, hydroxyl, amino, or alkyl group. 14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R3 is hydrogen or an alkyl group optionally substituted with a halogen, hydroxyl, cyano or amino group. 15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R3 is hydrogen, methyl, ethyl, or propyl. 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein ^R3 is hydrogen. 17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of straight bonds, alkyl groups, heteroalkyl groups, saturated or partially unsaturated cycloalkyl groups, and saturated or partially unsaturated heterocyclic groups, wherein each of the alkyl, heteroalkyl, cycloalkyl, and heterocyclic groups is optionally substituted by one or more R ^{f groups} . 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein each of R ^f is independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, alkyl, and heteroalkyl. 19. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein the two ^Rf atoms together with the atoms to which they are attached form a saturated or partially unsaturated cycloalkyl group optionally substituted with a cyano, halogen, hydroxyl, amino, or alkyl group. 20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is an alkyl group optionally substituted with one or more R ^f . 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein each of R ^f is independently selected from the group consisting of hydrogen, halogen, hydroxyl, methyl, and ethyl. 22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is a straight bond, _-CH2- , -CH( _CH3 )-, or -C( _CH3 ) _2- . 23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein W is... 24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein W is... 25. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein W is... 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R ^g is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, wherein each of the alkyl and heteroalkyl groups is optionally substituted with a halogen, hydroxyl, cyano, or amino group. 27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R ^g is hydrogen, methyl, or ethyl. 28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein R ^g is hydrogen. 29. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R4 is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, or aryl, wherein each of the alkyl, alkenyl, heteroalkyl, heteroalkenyl, and aryl groups is optionally substituted with a cyano, halogen, hydroxyl, amino, or alkyl group. 30. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R4 is hydrogen, or optionally an alkyl or aryl group substituted with a halogen, hydroxyl, cyano or amino group. 31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein ^R4 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, each of which is optionally substituted with a halogen, hydroxyl, cyano, or amino group. 32. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R4 is hydrogen, _-CH3 , _-CH2CH3 , _-CH ( _CH3 ) ₂ , -C( _CH3 ) ₃ , -CH( _CH3 )( _NH2 ) or phenyl. 33. The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein the double bond is in the E configuration. 34. The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein the double bond is in a Z configuration. 35. The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein n is 1. 36. The compound according to claim 1, having the formula selected from the group consisting of: Or its pharmaceutically acceptable salt. 37. The compound according to claim 1, having the formula selected from the group consisting of: Or its pharmaceutically acceptable salt. 38. The compound according to claim 1, having the formula selected from the group consisting of: Or its pharmaceutically acceptable salt. 39. The compound according to any one of claims 36 to 38, or a pharmaceutically acceptable salt thereof, wherein the double bond is in the E configuration. 40. The compound according to any one of claims 36 to 38, or a pharmaceutically acceptable salt thereof, wherein the double bond is in a Z configuration. 41. The compound according to any one of claims 36 to 38, or a pharmaceutically acceptable salt thereof, wherein ^R1 is a halogen and n is 1. 42. The compound according to claim 1, wherein the compound has the formula selected from the group consisting of: Or its pharmaceutically acceptable salt. 43. A pharmaceutical composition comprising a compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 44. The pharmaceutical composition according to claim 43, which is formulated for oral or injectable administration. 45. A method for treating vascular disease in an individual in need, comprising administering to the individual an effective amount of a compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of claims 43 to 44. 46. The method of claim 45, wherein the vascular disease is selected from atherosclerotic thrombosis, ischemia, stroke, cerebral thrombosis, arterial thrombosis, thrombotic cerebrovascular disease, cardiovascular disease, and thrombosis. 47. A method for inhibiting platelet aggregation in an individual in need, comprising administering to the individual an effective amount of a compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of claims 43 to 44. 48. Use of the compound of any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of claims 43 to 44 in the manufacture of a medicament for treating vascular diseases. 49. The compound of any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 43 to 44, for the treatment of vascular diseases. 50. Compounds having the following formula: 51. Compounds having the following formula: