Antiplatelet drugs and their use

Abstract

The present disclosure relates to compounds that exhibit activity in inhibiting platelet aggregation, as well as pharmaceutical compositions containing these compounds and methods of treating vascular disease by administering these compounds or pharmaceutical compositions.

Description

[Technical Field]

[0001] This disclosure relates, in general, to compounds that exhibit activity in inhibiting platelet aggregation, as well as pharmaceutical compositions containing these compounds and methods of treatment by administering these compounds or pharmaceutical compositions. [Background technology]

[0002] Recently, the number of patients with vascular diseases has increased significantly. Antithrombotic agents that inhibit platelet activity play an important role in preventing the onset and recurrence of these diseases, as well as in their treatment.

[0003] Clopidogrel is a well-known and widely used antithrombotic drug, a prodrug that requires biomolecular modification to become active. After absorption, 85% of clopidogrel is hydrolyzed to inactive carboxylic acids by esterases. The remaining 15% of clopidogrel undergoes a two-step oxidation process via hepatic cytochrome P450 isoenzymes, primarily CYP2C19. The transiently active thiol metabolites bind specifically and irreversibly to the platelet P2Y12 receptor.

[0004] However, clopidogrel has many drawbacks, including inter-patient variability in antithrombotic effects and clopidogrel resistance in certain patients due to different levels of CYP2C19 expression in different individuals, a low conversion rate to active metabolites and the resulting high loading dose (600 mg), a slow onset of action (2 hours after loading dose), low solubility in aqueous solutions, the lack of an injectable formulation available for emergency use, and drug-drug interactions. [Overview of the project] [Problems that the invention aims to solve]

[0005] Therefore, there is a need in this field to develop improved compounds that exhibit activity in inhibiting platelet aggregation without having the drawbacks listed above. [Means for solving the problem]

[0006] This disclosure provides compounds capable of inhibiting platelet aggregation, pharmaceutical compositions comprising these compounds, and methods for the use of such compounds or pharmaceutical compositions for the treatment of vascular diseases.

[0007] In one embodiment, the present disclosure relates to a compound having formula (I):

[0008] [ka] or a pharmaceutically acceptable salt thereof (In the formula,

[0009] [ka] This indicates a double bond in a Z or E configuration; R 1 The group is selected from hydrogen, halogen, nitro, cyano, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl is one or more R a It is replaced by an optional choice; R 2 is -C(O)R b and; R 3 This is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, where each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl; L is selected from the group consisting of direct bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R f ; W is

[0010]

Chemical formula

[0011] In some embodiments, this disclosure is,

[0012] [ka] [ka] The present invention provides compounds having a formula selected from the group consisting of the following, or pharmaceutically acceptable salts thereof.

[0013] In another embodiment, the Disclosure provides a pharmaceutical composition comprising a compound of the Disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0014] In a further embodiment, the Disclosure provides a method for treating a vascular disease in a subject requiring such treatment, comprising administering to the subject an effective amount of the compound of the Disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the Disclosure.

[0015] In a further embodiment, the Disclosure provides a method for inhibiting platelet aggregation in a subject requiring such inhibition, comprising administering to the subject requiring such inhibition an effective amount of the compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure.

[0016] In a further embodiment, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof or pharmaceutical compositions of the Disclosure in the manufacture of a medicament for treating vascular diseases.

[0017] In a further embodiment, the Disclosure provides a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, for treating vascular diseases.

[0018] In another aspect, this disclosure is:

[0019] [ka] The present invention provides a compound having the formula [formula].

[0020] In a further aspect, this disclosure may include:

[0021] [ka] The present invention provides a compound having the formula [formula]. [Brief explanation of the drawing]

[0022] [Figure 1] The concentrations of active metabolites in rat plasma after oral administration of (a) clopidogrel, compound 1a and compound 1b, and (b) clopidogrel, compound 2a and compound 2b at a dose level of 10 mg / kg are shown. [Figure 2] The concentrations of the active metabolites 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 are shown. [Figure 3] This shows the inhibition (%) of aggregation of the test compounds after oral administration in rats at dose levels of 10 mg / kg (clopidogrel), 0.5 mg / kg (compound 1a), and 2 mg / kg (compound 1b). [Modes for carrying out the invention]

[0023] Herein, specific embodiments of the Disclosure are referenced in detail, examples of which are shown in the attached Structures and Formulas. While the Disclosure is described in conjunction with the listed embodiments, it will be understood that they are not intended to limit the Disclosure to those embodiments. Rather, the Disclosure is intended to encompass all substitutes, modifications, and equivalents that may fall within the scope of the Disclosure as defined by the claims. Those skilled in the art will recognize a number of methods and materials similar to or equivalent to those described herein that can be used in the practice of the Disclosure. The Disclosure is by no means limited to the methods and materials described herein. If one or more of the incorporated documents and similar materials differ from or conflict with this application, including, but not limited to, defined terms, usage of terms, and the techniques described herein, this application shall prevail. All documents, patents, and patent applications referenced in this Disclosure are incorporated herein by reference in their entirety.

[0024] For clarity, it is understood that certain characteristics of the Disclosure described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various characteristics of the Disclosure described in the context of a single embodiment may also be provided separately or in any preferred partial combination. It should be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include their plural forms unless otherwise clearly indicated by the context. For example, a reference to “compound” includes multiple compounds.

[0025] definition 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 edition, and the inside cover of the Handbook of Chemistry and Physics, 75th edition, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional groups and reactivity, are described in Organic Chemistry, Thomas Sorrell, 2nd edition, University Science Books, Sausalito, 2006; Smith and March March's Advanced Organic Chemistry, 6th edition, John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3rd edition, VCH Publishers, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 4th edition, Cambridge University Press, Cambridge, 2004, the entire contents of each of these works are incorporated herein by reference.

[0026] Linked substituents are described in various places in this disclosure. Each linked substituent is particularly intended to include both the pre- and post-linked forms. For example, -NR(CR'R”)- includes both -NR(CR'R”)- and -(CR'R”)NR-. Where a structure clearly requires a linking group, the Markush variable enumerated for that group is understood to be the linking group. For example, where a structure requires a linking group and the definition of the Markush group for that variable enumerates "alkyl", it is understood that "alkyl" refers to a linked alkylene group.

[0027] If the bond to a substituent is shown to traverse a bond connecting two atoms in the ring, such substituent can bond to any atom in the ring. If substituents are enumerated without indicating the atom to which such substituent bonds with the rest of the compound in a given formula, such substituent can bond to any atom in such formula. Combinations of substituents and / or variable elements are permitted, but only if such combinations result in a stable compound.

[0028] " * When the symbol " is shown adjacent to an atom of a compound, it indicates that the compound contains such an atom as a chiral center with either a (R) or (S) stereoconfiguration.

[0029] Any variable (e.g., R i If a compound occurs more than once in any component or formula, its definition in each occurrence is independent of its definition in all other occurrences. For example, if a compound has 0 to 2 R groups... i If it is indicated that it is partially replaced, the base has up to two R i The part can be arbitrarily replaced, and R at each occurrence i R i The selection is independent of the definition. Furthermore, combinations of substituents and / or variable elements are permitted, but only if such combinations result in stable compounds.

[0030] When used herein, "C i~j The term "C" indicates a range of carbon atoms, where i and j are integers, and the range of carbon atoms includes the endpoints (i.e., i and j) and each integer point between them, where j is greater than i. For example, C 1~6 This refers to a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. In some embodiments, "C 1~12 The term "1 to 12, especially 1 to 10, especially 1 to 8, especially 1 to 6, especially 1 to 5, especially 1 to 4, especially 1 to 3, or especially 1 to 2 sets of monomers.

[0031] As used herein, the term “alkyl” refers to a saturated linear or branched hydrocarbon group that may be independently and optionally substituted by one or more substituents listed below, whether used as part of another term or independently. i~j The term "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. 1~10 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 1~6 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-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.

[0032] As used herein, the term “alkenyl” refers to a linear or branched hydrocarbon group having at least one carbon-carbon double bond and which may be optionally and independently substituted with one or more substituents described herein, and which have a “cis” and “trans” orientation, or instead an “E” and “Z” orientation. 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 (or vinyl), propenyl (allyl), butenyl, pentenyl, 1-methyl-2-buten-1-yl, and 5-hexenyl.

[0033] As used herein, the term "alkynyl" refers to a linear or branched hydrocarbon group having at least one carbon-carbon triple bond and which may be optionally and independently substituted with one or more substituents described herein. 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 alkynyl group contains 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, and 2-propynyl.

[0034] As used herein, the term "amino" refers to the -NH2 group. The amino group may also be substituted with one or more groups, such as alkyl, aryl, carbonyl, or other amino groups.

[0035] As used herein, the term “aryl” refers to monocyclic and polycyclic systems having a total of 5 to 20 ring members, where at least one ring in the system is aromatic, and each ring in the system contains 3 to 12 ring members, either as part of another term or independently. Examples of “aryl” include, but are not limited to, phenyl, biphenyl, naphthyl, anthrasyl, etc., which may have one or more substituents. Also included within the scope of the term “aryl” as used herein are groups in which an aromatic ring is condensed with one or more further rings. In the case of polycyclic systems, only one of the rings needs to be aromatic (e.g., 2,3-dihydroindole), but all rings may be aromatic (e.g., quinoline). The second ring may also be condensed or crosslinked. Examples of polycyclic aryls include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthoimidyl, phenantridinyl, or tetrahydronaphthyl. The aryl group may be substituted with one or more substituents as described above at one or more ring positions.

[0036] As used herein, the term “cycloalkyl,” whether used as part of another term or independently, refers to monovalent, non-aromatic, saturated or partially unsaturated monocyclic and polycyclic ring systems in which the entire ring is carbon and which contain at least three ring-forming carbon atoms. In some embodiments, cycloalkyls may contain 3 to 12 ring-forming carbon atoms, 3 to 10 ring-forming carbon atoms, 3 to 9 ring-forming carbon atoms, 3 to 8 ring-forming carbon atoms, 3 to 7 ring-forming carbon atoms, 3 to 6 ring-forming carbon atoms, 3 to 5 ring-forming carbon atoms, 4 to 12 ring-forming carbon atoms, 4 to 10 ring-forming carbon atoms, 4 to 9 ring-forming carbon atoms, 4 to 8 ring-forming carbon atoms, 4 to 7 ring-forming carbon atoms, 4 to 6 ring-forming carbon atoms, or 4 to 5 ring-forming carbon atoms. Cycloalkyls may be saturated or partially unsaturated. Cycloalkyls may be substituted. In some embodiments, cycloalkyls may be saturated cyclic alkyl groups. In some embodiments, the cycloalkyl group may be a partially unsaturated cyclic alkyl group containing at least one double or triple bond in its ring system. In some embodiments, the cycloalkyl group may be monocyclic or polycyclic. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, 1-cyclopenta-2-enyl, 1-cyclopenta-3-enyl, cyclohexyl, 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, 1-cyclohexa-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, adamantyl, norbornyl, fluorenyl, spiropentadienyl, spiro[3,6]-decanyl, bicyclo[1,1,1]pentenyl, and bicyclo[2,2,1]heptenyl.

[0037] As used herein, the term "cyano" refers to -CN.

[0038] As used herein, the term "halogen" refers to an atom selected from fluorine (or fluoro), chlorine (or chloro), bromine (or bromo), and iodine (or iod).

[0039] As used herein, the term “heteroatom” means nitrogen, oxygen, sulfur, or phosphorus, and includes all oxidized forms of nitrogen or sulfur and all quaternized forms of basic nitrogen (including N-oxides).

[0040] As used herein, the term “heteroalkenyl” refers to an alkenyl in which at least one of its carbon atoms is replaced by a heteroatom selected from N, O, or S. A heteroalkenyl can be a carbon group or a heteroatom group (i.e., the heteroatom may appear in the middle or at the end of the group) and may be optionally and independently substituted with one or more substituents described herein.

[0041] As used herein, the term “heteroalkynyl” means an alkynyl in which at least one of its carbon atoms is replaced by a heteroatom selected from N, O, or S. A heteroalkynyl can be a carbon group or a heteroatom group (i.e., the heteroatom may appear in the middle or at the end of the group) and may be optionally and independently substituted with one or more substituents described herein.

[0042] As used herein, the term “heteroaryl” refers to an aryl group having one or more heteroatoms in addition to a carbon atom, either as part of another term or independently. Heteroaryl groups can be monocyclic. Examples of monocyclic heteroaryls include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazole, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthylidinyl, benzofuranyl, and pteridinyl. Heteroaryl groups also include polycyclic groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and the bonded group or dot lies on the heteroaromatic ring. Examples of polycyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranil, benzo[1,3]dioxolyl, dibenzofuranil, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, sinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.

[0043] As used herein, the term “heterocyclyl” refers to a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, etc., the remaining ring atoms are carbon, and one or more ring atoms may be optionally and independently substituted with one or more substituents. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, the heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system. In some embodiments, the heterocyclyl may contain any oxidized form of carbon, nitrogen, or sulfur, and any quaternized form of basic nitrogen. “Heterocyclyl” also includes groups in which the heterocyclyl group is fused with a saturated, partially unsaturated, or fully saturated (i.e., aromatic) carbocycle or heterocycle. The heterocyclyl group may be carbon-bonded or nitrogen-bonded, where possible. In some embodiments, the heterocycle is carbon-bonded. In some embodiments, the heterocycle is nitrogen-bonded. For example, a group derived from pyrrole may be pyrrole-1-yl (nitrogen bond) or pyrrole-3-yl (carbon bond). Furthermore, a group derived from imidazole may be imidazole-1-yl (nitrogen bond) or imidazole-3-yl (carbon bond).

[0044] In some embodiments, the term “3- to 12-membered heterocyclil” refers to a 3- to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Condensed, spiro, and bridging ring systems are also included within this definition. Examples of monocyclic heterocyclils include, but are not limited to, oxetanyl, 1,1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, piperidinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and others. Examples of condensed heterocyclyls include, but are not limited to, phenyl condensed rings or pyridinyl condensed rings such as quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinolidinyl, quinazolinyl, azaindridinyl, pteridinyl, clomenyl, isoclomenyl, indolyl, isoindolyl, indazolyl, purinyl, benzofuranil, isobenzofuranil, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenadinyl, phenothiazinyl, phenanthiazinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, and [1,2,3]triazolo[4,3-a]pyridinyl groups. Examples of spiroheterocyclils include, but are not limited to, spiropyranil and spirooxazinil. Examples of cross-linked heterocyclils include, but are not limited to, morphanyl, hexamethylenetetraminyl, 3-azabicyclo[3.1.0]hexane, 8-azabicyclo[3.2.1]octane, 1-azabicyclo[2.2.2]octane, and 1,4-diazabicyclo[2.2.2]octane (DABCO).

[0045] As used herein, the term "hydroxyl" refers to -OH.

[0046] As used herein, the term “partially unsaturated” refers to a group containing at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple unsaturated moieties, but not aromatic (i.e., fully saturated) moieties.

[0047] Where used herein, the term “substituted” means that one or more hydrogens of a specified part are replaced by a preferred substituent, whether preceded by the term “optionally.” “Substituted” or “substituted with” should be understood to imply that such substitutions result in a stable or chemically feasible compound that does not spontaneously undergo deformation, such as rearrangement, cyclization, or elimination, according to the permitted valence of the substituted atom. Unless otherwise specified, a group “optionally substituted” may have preferred substitutions at each substituted position of the group, and the substituents may be the same or different at each position if more than one position in any given structure can be replaced by more than one substituent selected from a particular group. Where appropriate, substituents may be substituted themselves, as will be understood by those skilled in the art. Unless specifically indicated as “unsubstituted,” references to chemical parts herein should be understood to include substituted variants. For example, references to an “aryl” group or part implicitly include both substituted and unsubstituted variants.

[0048] compound This disclosure provides novel compounds of formula (I) and pharmaceutically acceptable salts thereof, methods for synthesizing the compounds, pharmaceutical compositions containing them, and various uses of the disclosed compounds.

[0049] In one embodiment, the present disclosure relates to a compound having formula (I):

[0050] [ka] or a pharmaceutically acceptable salt thereof (In the formula,

[0051] [ka] This indicates a double bond in a Z or E configuration; R 1 The group is selected from hydrogen, halogen, nitro, cyano, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl is one or more R a It is replaced by an optional choice; R 2 is -C(O)R b and; R 3 This is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, where each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl; L is selected from the group consisting of direct bonds, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, and each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R f It is replaced by an optional choice; W is

[0052] [ka] Selected from the group consisting of W * The ends are joined to L; R 4 This is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, where each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl; R a Each of these is hydrogen, halogen, hydroxyl, amino, cyano, nitro, or -NR c R d Independently selected from the group consisting of; R b This includes hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, heteroaryl, -NR c R d and -OR e Selected from the group consisting of; R c and R d Each of these is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, or amino; R eThis is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, where each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl; R f Each of these is independently selected from the group consisting of hydrogen, cyano, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl; or Two R's f They both form saturated or partially unsaturated cycloalkyl or saturated or partially unsaturated heterocyclines with the atoms to which they are bonded, and each of the cycloalkyl and heterocyclines is optionally substituted with cyano, halogen, hydroxyl, amino, and alkyl atoms; R g This is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, or saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, where each of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxy, or amino; n is 0, 1, 2, 3, 4, or 5. To provide.

[0053] In some embodiments, R 1The group is selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, alkyl, and heteroalkyl, and each alkyl and heteroalkyl is one or more R a It is being replaced by an optional choice.

[0054] In a particular embodiment, R a Each of these is independently selected from the group consisting of halogens, hydroxyls, cyanos, and nitros.

[0055] In some embodiments, R 1 is one or more R a The halogen, cyano, hydroxyl, amino, or alkyl elements are optionally substituted.

[0056] In a particular embodiment, R 1 is one or more R a The halogen, cyano, or alkyl group is optionally substituted.

[0057] In a particular embodiment, R 1 These are fluoro, chloro, bromo, cyano, methyl, or trifluoromethyl.

[0058] In some embodiments, n is 1, 2, or 3. In certain embodiments, n is 1 or 2. In certain embodiments, n is 1.

[0059] In some embodiments, R 2 is -C(O)R b And R b This includes hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocycloalkyl, -NR c R d and -OR e It is selected from the group consisting of the following.

[0060] In a particular embodiment, Rc and R d Each of which is independently selected from the group consisting of hydrogen, alkyl, and alkenyl, and each of the alkyl and alkenyl is optionally substituted with halogen or hydroxyl.

[0061] In certain embodiments, R e is selected from the group consisting of alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, and heteroaryl, and each of the alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, and heteroaryl is optionally substituted with cyano, halogen, hydroxy, amino, or alkyl.

[0062] In some embodiments, R 2 is -C(O)R b where R b is hydrogen, hydroxyl, alkyl, saturated or partially unsaturated cycloalkyl, or -OR e where R

[0063] In certain embodiments, R 2 is -C(O)R b where R b is saturated cycloalkyl or -OR e where R e is alkyl.

[0064] In certain embodiments, R 2 is -C(O)R b where R b is saturated C 3~6 cycloalkyl or -OR e where R e is C 1~6 alkyl.

[0065] In certain embodiments, R 2 is -C(O)R b where R b is cyclopropyl or -OR e where R eis methyl, ethyl, n-propyl or isopropyl.

[0066] In some embodiments, R 2 is -C(O)-cyclopropyl or -C(O)OCH3.

[0067] In some embodiments, R 3 is hydrogen, or alkyl optionally substituted with halogen, hydroxyl, cyano or amino.

[0068] In some embodiments, R 3 is hydrogen.

[0069] In some embodiments, R 3 is alkyl optionally substituted with halogen, hydroxyl, cyano or amino.

[0070] In certain embodiments, R 3 is C 1~6 alkyl optionally substituted with halogen, hydroxyl, cyano or amino. <​​​​​​​​​​​​​​​​​​​​In a particular embodiment, two R f These, along with the atoms to which they are bonded, form saturated or partially unsaturated cycloalkyl groups that are optionally substituted with cyano, halogen, hydroxyl, amino, and alkyl atoms.

[0075] In some embodiments, L is a direct bond.

[0076] In some embodiments, L is one or more R f This is an alkyl group that has been optionally substituted.

[0077] In a particular embodiment, L is one or more R f C is replaced by an optional choice. 1~6 It is alkyl.

[0078] In a particular embodiment, L is one or more R f C is replaced by an optional choice. 1~6 It is alkyl, R f Each of these is independently selected from the group consisting of hydrogen, halogen, hydroxyl, methyl, and ethyl.

[0079] In some embodiments, L is -CH2-, -CH(CH3)-, or -C(CH3)2-.

[0080] In some embodiments, W is

[0081] [ka] That is the case.

[0082] In some embodiments, W is

[0083] [ka] That is the case.

[0084] In some embodiments, W is

[0085] [ka] That is the case.

[0086] In some embodiments, W is

[0087] [ka] That is the case.

[0088] In some embodiments, W is

[0089] [ka] That is the case.

[0090] In some embodiments, W is

[0091] [ka] That is the case.

[0092] In some embodiments, R g The group is selected from hydrogen, alkyl, and heteroalkyl, and each alkyl and heteroalkyl is optionally substituted with a halogen, hydroxyl, cyano, or amino.

[0093] In a particular embodiment, W is

[0094] [ka] (In the formula, R g is hydrogen or C 1~6 (It is alkyl.) In a particular embodiment, R g It is hydrogen, methyl, or ethyl.

[0095] In some embodiments, R 4The elements are hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, or aryl, and each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and aryl elements is optionally substituted with cyano, halogen, hydroxyl, amino, or alkyl.

[0096] In a particular embodiment, R 4 This is an alkyl or aryl atom optionally substituted with hydrogen, or a halogen, hydroxyl, cyano, or amino.

[0097] In a particular embodiment, R 4 C is optionally substituted with hydrogen, halogen, hydroxyl, cyano, or amino. 1~6 C is optionally substituted with alkyl, halogen, hydroxyl, cyano, or amino. 6~12 It is Ariel.

[0098] In a particular embodiment, R 4 These are hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH(CH3)(NH2), or phenyl.

[0099] In some embodiments,

[0100] [ka] This is a double bond in an E configuration.

[0101] In some embodiments,

[0102] [ka] This is a double bond in a Z configuration.

[0103] In a further aspect, this disclosure may include:

[0104] [ka] [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R g (L and n are defined as above) The present invention provides compounds having a formula selected from the group consisting of the following, or pharmaceutically acceptable salts thereof.

[0105] In some embodiments, R 1 is a halogen. In a particular embodiment, R 1 These are fluoro, chloro, or bromo.

[0106] In some embodiments, n is 1, 2, or 3. In certain embodiments, n is 1 or 2. In certain embodiments, n is 1.

[0107] In some embodiments, R 2 is -C(O)R b And R b This includes hydrogen, hydroxyl, alkyl, saturated cycloalkyl or -OR e In a particular embodiment, R 2 is -C(O)R b And R b is saturated cycloalkyl or -OR e And R e is alkyl. In a particular embodiment, R 2 is -C(O)R b And R b is saturated C 3~6 Cycloalkyl or -OR e And R e C 1~6 It is alkyl. In a particular embodiment, R 2 is -C(O)R b And R b is cyclopropyl or -OR e And Re is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, R 2 It is -C(O)-cyclopropyl or -C(O)OCH3.

[0108] In some embodiments, R 3 It is hydrogen.

[0109] In some embodiments, R 3 is alkyl. In a particular embodiment, R 3 C 1~6 It is alkyl. In a particular embodiment, R 3 These are methyl, ethyl, n-propyl, or isopropyl.

[0110] In some embodiments, L is a direct bond.

[0111] In some embodiments, L is one or more R independently selected from hydrogen, halogen, hydroxyl, methyl, and ethyl. f The alkyl is optionally substituted. In certain embodiments, L is one or more R independently selected from hydrogen, halogen, hydroxyl, methyl and ethyl. f C is replaced by an optional choice. 1~6 It is alkyl. In certain embodiments, L is -CH2-, -CH(CH3)-, or -C(CH3)2-.

[0112] In some embodiments, R 4 is an alkyl group optionally substituted with hydrogen, or a halogen, hydroxyl, cyano, or amino. In certain embodiments, R 4 C is optionally substituted with hydrogen, or halogen, hydroxyl, cyano, or amino. 1~6 It is alkyl. In a particular embodiment, R 4 These are hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, or -CH(CH3)(NH2).

[0113] In some embodiments, R g is hydrogen or alkyl. In certain embodiments, R g is hydrogen or C 1~6 It is alkyl. In a particular embodiment, R g is hydrogen, methyl, or ethyl. In certain embodiments, R g It is hydrogen.

[0114] In some embodiments,

[0115] [ka] This is a double bond in an E configuration.

[0116] In some embodiments,

[0117] [ka] This is a double bond in a Z configuration.

[0118] In a further aspect, this disclosure may include:

[0119] [ka] [ka] (In the formula, R 1 , R 2 , R 4 , R g (L and n are defined as above) The present invention provides compounds having a formula selected from the group consisting of the following, or pharmaceutically acceptable salts thereof.

[0120] In some embodiments,

[0121] [ka] This is a double bond in an E configuration.

[0122] In some embodiments,

[0123]

Chem.

[0124] In a further aspect, the present disclosure

[0125]

Chem.

Chem.

[0126] In some embodiments,

[0127]

Chem.

[0128] In some embodiments,

[0129]

Chem.

[0130] In a further aspect, the present disclosure

[0131]

Chem.

Chem.

[0132] The compounds provided herein are described by reference to both general formulae and specific compounds. In addition, the compounds of the present disclosure may exist in several different forms or derivatives all within the scope of the present disclosure. These include, for example, tautomers, stereoisomers, racemic mixtures, positional isomers, salts, solvate forms, amorphous forms, different crystalline forms or polymorphs.

[0133] The compounds of the present disclosure may contain one or more asymmetric centers depending on the substituent selection and may thus exist in various stereoisomeric forms, for example, enantiomers and / or diastereomers. For example, the compounds provided herein may have an asymmetric carbon center and thus the compounds provided herein may have the (R) or (S) configuration at the carbon asymmetric center. Accordingly, the compounds of the present disclosure may be in the form of individual enantiomers, diastereomers, or geometric isomers or in the form of mixtures of stereoisomers.

[0134] As used herein, the term "enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. The term "diastereomer" refers to a pair of optical isomers that are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity.

[0135] Where a particular enantiomer is preferred, in some embodiments this may be provided substantially without a pair of enantiomers and may be referred to as “optically concentrated.” “Optical concentrated,” as used herein, means that the compound consists of a significantly larger proportion of one enantiomer. In certain embodiments, the compound consists of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound consists of at least about 95% by weight, 98% by weight, or 99% by weight of the preferred enantiomer. The preferred enantiomer can be isolated from the racemic mixture by any method known to those skilled in the art, for example, by chromatography or crystallization, by the use of stereochemically homogeneous starting materials for synthesis, or by stereoselective synthesis. Optionally, derivatization can be carried out before the separation of stereoisomers. Separation of the mixture of stereoisomers can be carried out as an intermediate step during the synthesis of the compounds provided herein, or it can be carried out against the final racemic product. Absolute stereochemistry can, if necessary, be determined by X-ray crystallography of crystalline products or intermediates derivatized with reagents containing stereogenic centers of known configurations. 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, SH et al., Tetrahedron Vol. 33: p. 2725 (1977); Eliel, E., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL, edited by Eliel, Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0136] In some embodiments, a mixture of diastereomers is provided, for example, a mixture of diastereomers rich in 51% or more of one diastereomer, which includes, for example, 60% or more, 70% or more, 80% or more, or 90% or more of one diastereomer.

[0137] In some embodiments, the compounds provided herein may have one or more double bonds that can exist as either Z or E isomers, unless otherwise specified. The disclosure also includes compounds as individual isomers substantially devoid of other isomers, or as mixtures of various isomers, such as a racemic mixture of enantiomers.

[0138] The compounds of this disclosure may also exist in different tautomer forms, and all such forms are encompassed within the scope of this disclosure. The terms “tautomer” or “tautomer form” refer to structural isomers of different energies that are interconvertible over a low energy barrier. Examples include proton tautomers (also known as prototropic tautomers) which are interconverted by proton transfer, e.g., keto-enols, amide-imido acids, lactam-lactims, imine-enamine isomerizations, and cyclic forms in which protons may occupy two or more positions in a heterocyclic system (e.g., 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles). Valence tautomers which are interconverted by rearrangement of some of the bonding electrons. Tautomers may be in equilibrium or sterically fixed into a single form by appropriate substitution. Compounds of this disclosure identified by name or structure as a specific tautomer form are intended to include other tautomer forms unless otherwise specified.

[0139] This disclosure is also intended to include all isotopes of atoms in a compound. An isotope of an element includes atoms that have the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromide, or iodine in the compounds of this disclosure include their isotopes, for example, but not limited to: 1 H, 2 H, 3 H, 11 C, 12 C, 13 C, 14 C, 14 N, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I, 127 I and 131 This also means that it includes I. In some embodiments, hydrogen includes protium, deuterium and tritium. In some embodiments, carbon is 12 C and 13 Contains C. Isotopically-enriched compounds of formula (I) can be prepared without excessive experimentation by conventional techniques well known to those skilled in the art, or by processes similar to those described herein in schemes and examples, using suitable isotopically enriched reagents and / or intermediates.

[0140] The compounds of this disclosure may be formulated as pharmaceutically acceptable salts or in that form. Unless otherwise specified, the compounds provided herein include pharmaceutically acceptable salts of such compounds.

[0141] As used herein, the term “pharmaceutically acceptable” means that a substance or composition is chemically and / or toxicologically compatible with other components, including the formulation, and / or the subject being treated with it.

[0142] As used herein, the term “pharmaceutically acceptable salt” includes, unless otherwise specified, salts that retain the biological efficacy of the free acids and bases of a particular compound and are not biologically or otherwise undesirable. Intended pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, and tetrakis. pharmaceutically acceptable salts are nontoxic at the amounts and concentrations in which they are administered. Preparation of such salts can facilitate pharmacological use by altering the physical properties of a compound without interfering with the exertion of 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 concentrations of the drug.

[0143] Pharmaceutically acceptable salts include those containing acid addition salts, such as sulfates, chlorides, hydrochlorides, fumarates, maleates, phosphates, sulfamates, acetic acids, citrates, lactates, tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, and quinates. Pharmaceutically acceptable salts can be obtained from acids, such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.

[0144] Pharmaceutically acceptable salts include those containing acidic functional groups, such as carboxylic acids or phenols, and those containing base addition salts, such as benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-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” by Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using appropriate corresponding bases.

[0145] Pharmacopoeia-acidic salts can be prepared by standard techniques. The free base form of a compound can be isolated by dissolving it in a suitable solvent, such as an aqueous or aqueous alcohol solution containing a suitable acid, and then evaporating the solution. Thus, if a particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by treatment of the free base using any suitable method available in the art, such as inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidylic acid, such as glucuronic acid or galacturonic acid, alpha-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.

[0146] Similarly, when a particular compound is an acid, the desired pharmaceutically acceptable salts can be prepared by any suitable method, for example, treatment of 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 and the like. Representative examples of suitable salts include amino acids such as L-glycine, L-lysine and L-arginine, ammonia, primary, secondary or tertiary amines, and cyclic amines such as organic salts derived from hydroxyethylpyrrolidone, piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0147] The compounds of the present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms) and solid forms (e.g., crystalline or polymorphic forms), and it is understood that the present disclosure is intended to encompass all such forms.

[0148] As used herein, the terms "solvate" or "solvated form" refer to a solvate addition form containing either a stoichiometric or non-stoichiometric amount of a solvent. Some compounds have a tendency to trap solvent molecules in a crystalline solid phase in a certain molar ratio, thereby forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more moles of water with one of the substances, where the water retains its molecular state as H2O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine.

[0149] As used herein, the terms “crystal form,” “crystalline form,” “polymorph,” and “polymorph” are interchangeable and refer to crystalline structures in which a compound (or its salt or solvate) can crystallize in different crystal packing arrangements, all having the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability, and solubility. One crystalline form may become dominant depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors. Crystalline polymorphs of a compound can be prepared by recrystallization under different conditions.

[0150] This disclosure is intended to include all isotopes of atoms in a compound. An isotope of an element includes atoms that have 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 are, non-limitingly, 1 H, 2 H, 3 H, 11 C, 12 C, 13 C, 14 C, 14 N, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I, 127 I, and 131 It shall also include those isotopes such as 1. In some embodiments, hydrogen includes protium, deuterium and tritium. In some embodiments, carbon 12 C and13 Includes C.

[0151] Compound synthesis The synthesis of the compounds provided herein, including their pharmaceutically acceptable salts, is illustrated in the synthesis schemes in the Examples. The compounds provided herein can be prepared using any known organic synthesis technique and can be synthesized according to any of the countless possible synthesis routes; therefore, these schemes are illustrative only and do not mean to limit other possible methods that can be used to prepare the compounds provided herein. In addition, the steps in the schemes are for better illustration and can be appropriately modified. The embodiments of the compounds in the Examples were synthesized for the purpose of investigation and potential submission to regulatory authorities.

[0152] The reactions for preparing the compounds of this disclosure can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents can be substantially inactive with the starting materials (reactants), intermediates, or products at the temperature in which the reaction takes place, for example, a temperature ranging from the freezing temperature to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of one or more solvents. Depending on the specific reaction step, a suitable solvent for a particular reaction step can be selected by those skilled in the art.

[0153] The preparation of the compounds of this disclosure may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemical properties of protecting groups are, for example, all incorporated herein by reference in their entirety, TW. Greene and PGMWuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003, and Peter GMWuts, Greene's Protective Groups in Organic Synthesis, 5 th This can be found in Edition, Wiley, 2014.

[0154] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic methods, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) The compounds can be monitored by infrared spectroscopy, spectrophotometric methods (e.g., ultraviolet-visible), or mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC). Compounds can be purified by various methods, including high-performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization," Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs, J. Combi. Chem. 2004, Vol. 6 (No. 6), pp. 874-883, which is incorporated herein by reference in its entirety) and normal-phase silica gel chromatography, as can be described by those skilled in the art.

[0155] The known starting materials of this disclosure may be synthesized by using or in accordance with methods known in the art, or purchased from commercial suppliers. Unless otherwise specified, analytical-grade solvents and commercially available reagents were used without further purification.

[0156] Unless otherwise specified, all reactions in this disclosure were carried out under positive pressure of nitrogen or argon, or in anhydrous solvent, with drying tubes, and the reaction flasks were typically equipped with rubber septums for the introduction of substrates and reagents by syringe. Glassware was oven-dried and / or heat-dried.

[0157] For illustrative purposes, the following Examples section illustrates synthetic routes for preparing the compounds of the Disclosure and key intermediates. Those skilled in the art will understand that other synthetic routes may be used to synthesize the compounds of the present invention. While specific starting materials and reagents are described in the scheme and discussed below, other starting materials and reagents can be readily substituted to produce various derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified using conventional chemistry well known to those skilled in the art in light of the Disclosure.

[0158] In one aspect, this disclosure is,

[0159] [ka] The present invention provides a compound having the formula [formula].

[0160] In some embodiments, the above-mentioned compounds can be used as intermediates to prepare the compounds of the present disclosure.

[0161] In another aspect, this disclosure is:

[0162] [ka] The present invention provides a compound having the formula [formula].

[0163] In some embodiments, the above-mentioned compounds can be used as intermediates to prepare the compounds of the present disclosure.

[0164] Use of compounds In one embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof that is capable of inhibiting platelet aggregation. Thus, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are useful as pharmaceuticals and are particularly useful as therapeutic or prophylactic agents for various thrombotic diseases.

[0165] As used herein, the term “therapy” has its usual meaning, meaning addressing a disease in order to completely or partially alleviate one, some or all of its symptoms, or correct or supplement the underlying condition, 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 the severity of the disease, a stable (i.e., non-worsening) state of the disease, delay or slowing of disease progression, improvement or reduction of the condition, and remission (whether partial or complete), whether detectable or undetectable. “Therapy” may also mean a longer survival than the expected survival without it. People who need therapy include those who already have a condition or disease, as well as those who are prone to developing a condition or disease, or those for whom prevention of a condition or disease is desirable. The term “therapy” also includes prevention unless specifically indicated otherwise. The terms “therapeutic” and “therapeutic” should be interpreted in their corresponding ways.

[0166] The term “treatment” is used synonymously with “therapy.” Similarly, the term “to treat” can be considered as “to utilize therapy,” in which case “therapy” is as defined herein.

[0167] As used herein, the term “prevention” has its ordinary meaning and includes primary prevention, which prevents the onset of disease, and secondary prevention, which protects a patient, temporarily or permanently, from exacerbation or worsening of the disease or the onset of new symptoms associated with the disease, once the disease has already occurred.

[0168] In some embodiments, the compounds of the Disclosure can be converted to active thiol metabolites after administration. In some embodiments, the compounds of the Disclosure can be converted to active thiol metabolites after oral administration. In some embodiments, the compounds of the Disclosure can be converted to active thiol metabolites after intravenous injection.

[0169] For prodrugs of active thiol metabolites, it is desirable that the prodrug remains stable (environmentally resistant) and converts to the active thiol metabolite in the target tissue with a high conversion rate. Furthermore, it is desirable that the prodrug be formulated as an aqueous solution for injection in emergency and surgical use, has a rapid onset of action, and therefore requires a low loading dose, fewer side effects, and high solubility.

[0170] In some embodiments, the compounds provided herein can form active thiol metabolites through hydrolysis via hydrolase. Due to their high in vivo activity and broad hydrolase range in the intestine, liver, and plasma, the compounds provided herein can be converted to active thiol metabolites in vivo with higher conversion rates and lower patient-to-patient variability, thereby resulting in a rapid onset of antiplatelet activity without the need for high loading doses. In addition, since the metabolites of the compounds provided herein are mediated by hydrolase rather than CYP enzymes, the use of these compounds is not limited by potential interactions with other CYP-targeted drugs.

[0171] In some embodiments, the compounds provided herein exhibit a faster onset of antiplatelet activity than clopidogrel at the same dose. In some embodiments, the compounds provided herein exhibit a smaller onset of antiplatelet activity than clopidogrel at a lower dose. In some embodiments, the compounds provided herein exhibit a smaller onset of antiplatelet activity than clopidogrel at half the dose of clopidogrel. In some embodiments, the compounds provided herein exhibit a smaller onset of antiplatelet activity than clopidogrel at one-third the dose of clopidogrel. In some embodiments, the compounds provided herein exhibit a smaller onset of antiplatelet activity than clopidogrel at one-quarter the dose of clopidogrel. In some embodiments, the compounds provided herein exhibit a smaller onset of antiplatelet activity than clopidogrel at one-fifth the dose of clopidogrel.

[0172] In some embodiments, at a dose one-fifth that of clopidogrel, the compounds provided herein exhibit antiplatelet activity in less than 120 minutes, less than 110 minutes, less than 100 minutes, less than 90 minutes, less than 80 minutes, less than 70 minutes, less than 60 minutes, less than 50 minutes, less than 40 minutes, or less than 30 minutes.

[0173] In some embodiments, the compounds provided herein exhibit improved water solubility compared to clopidogrel as measured with a phosphate buffer. In some embodiments, the compounds provided herein exhibit water solubility as measured in buffered aqueous solutions of 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.

[0174] The improved solubility of the compounds provided herein offers an opportunity to broaden the use of these compounds in inhibiting platelet aggregation. In some embodiments, the compounds provided herein may be formulated for injectable administration for use in emergency and surgical settings. In some embodiments, the compounds provided herein may be formulated for oral administration for long-term inhibition of platelet aggregation.

[0175] In a further embodiment, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof for the treatment of vascular diseases.

[0176] In a further embodiment, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof or pharmaceutical compositions of the Disclosure in the manufacture of a medicament for treating vascular diseases.

[0177] Pharmaceutical composition For the purpose of administration, in some embodiments, the compounds provided herein are administered as raw chemical substances or formulated as pharmaceutical compositions.

[0178] Accordingly, in further embodiments, pharmaceutical compositions comprising one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof are provided.

[0179] In some embodiments, the pharmaceutical compositions of the 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 the Disclosure comprise a first compound selected from any one of formulas (I) to (VII) or a pharmaceutically acceptable salt thereof, and one or more further compounds of the same formula, wherein the first compound and the further compounds are not the same molecule.

[0180] As used herein, the term “pharmaceutical composition” refers to a formulation containing the molecules or compounds of the Disclosure in a form suitable for administration to a subject.

[0181] In some embodiments, the pharmaceutical compositions of the present disclosure comprise one or more compounds of formulas (I) to (VII) or pharmaceutically acceptable salts thereof in a therapeutically effective amount.

[0182] As used herein, the term “therapeutic dose” means the amount of a molecule, compound, or composition containing a molecule or compound that treats, improves, or prevents a specified disease or condition, or exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective dose for a subject will depend on the subject’s weight, size, and health status; the nature and severity of the condition; the rate of administration; the treatment or combination of treatments selected for administration; and the judgment of the prescribing physician. The therapeutic dose in a given situation can be determined by routine experiments that are within the clinician’s skill and judgment.

[0183] In another embodiment, a pharmaceutical composition is provided comprising one or more molecules or compounds of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0184] As used herein, the term “pharmaceutically acceptable excipient” refers to an excipient that is generally safe, non-toxic, and free from any biological or other undesirable aspects, and is useful for preparing a pharmaceutical composition, and includes excipients that are acceptable for veterinary and human pharmaceutical use. As used herein, “pharmaceutically acceptable excipient” includes both one and more such excipients. The term “pharmaceutically acceptable excipient” also includes “pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent.”

[0185] The specific excipients used will depend on the means and purpose to which the compounds of this disclosure are applied. Solvents are generally selected based on those recognized by those skilled in the art as safe for administration to mammals, including humans. Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and mixtures thereof.

[0186] In some embodiments, suitable excipients include buffers such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkylparabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; and tamethionine such as serum albumin, gelatin, or immunoglobulin. It may contain proteins; 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; counterions that form salts such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as TWEEN®, PLURONIC®, or polyethylene glycol (PEG).

[0187] In some embodiments, suitable excipients may include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, flow enhancers, processing aids, colorants, sweeteners, fragrances, and other known additives that give a pleasing appearance to a drug (i.e., the compounds of the Disclosure or their pharmaceutical compositions) or assist in the manufacture of a pharmaceutical product (i.e., a drug). The pharmacoactive ingredient may also be encapsulated in microcapsules prepared, for example, by coacervation techniques or interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in macroemulsions, respectively. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). Liposomes are small vesicles composed of various types of lipids, phospholipids, and / or surfactants that are useful for delivering drugs (compounds disclosed herein and optionally chemotherapeutic agents, etc.) to mammals, including humans. The components of liposomes are typically arranged in a bilayer formation similar to the lipid arrangement of biological membranes.

[0188] The pharmaceutical compositions provided herein may be in any form that enables the composition to be administered to subjects including but not limited to humans, and may be formulated to be compatible with the intended route of administration.

[0189] Various routes are intended for the pharmaceutical compositions provided herein, and therefore, the pharmaceutical compositions provided herein may be supplied in bulk or in unit dosage forms, depending on the intended route of administration. For example, for oral, intraoral, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gel caps, and caplets may be accepted as solid dosage forms, and emulsions, syrups, elixirs, suspensions, and solutions may be accepted as liquid dosage forms. For injectable administration, emulsions and suspensions may be accepted as liquid dosage forms, and powders suitable for reconstitution with appropriate solutions may be accepted as solid dosage forms. For inhalation administration, solutions, sprays, dry powders, and aerosols may be accepted dosage forms. For topical (including intraoral and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be accepted dosage forms. For vaginal administration, acceptable dosage forms may include pessaries, tampons, creams, gels, pastes, foams, and sprays.

[0190] The amount of the active ingredient in a unit dosage form of a composition is the therapeutically effective dose and varies according to the specific treatment being treated. As used herein, the term “therapeutically effective dose” refers to the amount of a molecule, compound, or composition containing a molecule or compound that treats, improves, or prevents a specific disease or condition, or exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective dose for a subject will depend on the subject’s weight, size, and health status; the nature and severity of the condition; the rate of administration; the treatment or combination of treatments selected for administration; and the judgment of the prescribing physician. The therapeutically effective dose in a given situation can be determined by routine experiments within the clinician’s skill and judgment.

[0191] In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of formulations for oral administration.

[0192] In certain embodiments, the pharmaceutical compositions of this disclosure may be in the form of tablet formulations. Suitable pharmaceutically acceptable excipients for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate, or calcium carbonate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid, or talc; preservatives such as ethyl or propyl p-hydroxybenzoate; and antioxidants such as ascorbic acid. Tablet formulations may be left uncoated or coated using conventional coating agents and procedures known in the art, either to modulate their disintegration in the gastrointestinal tract and subsequent absorption of the active ingredient, or to improve their stability and / or appearance.

[0193] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.

[0194] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of aqueous suspensions, which generally comprise an active ingredient in the form of a fine powder, together with one or more suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; or a dispersing or wetting agent such as a condensation product of lecithin or alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), or a condensation product of ethylene oxide with a long-chain aliphatic alcohol, such as heptadecaethyleneoxycetanol, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol, such as polyoxyethylene sorbitol monooleate, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol anhydride, such as polyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate), antioxidants (such as ascorbic acid), colorants, flavorings, and / or sweeteners (such as sucrose, saccharin, or aspartame).

[0195] In certain embodiments, the pharmaceutical compositions of this disclosure may generally be in the form of an oily suspension containing an active ingredient suspended 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 include thickeners such as beeswax, solid paraffin, or cetyl alcohol. Sweeteners and flavorings, such as those mentioned above, may be added to give a palatable oral preparation. These compositions may be preserved by the addition of antioxidants such as ascorbic acid.

[0196] In certain 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 a mixture thereof. Suitable emulsifiers may be natural gums such as gum arabic or gum tragacanth, natural phosphatides such as soybeans and lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners, flavorings, and preservatives.

[0197] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweeteners, lubricants, preservatives, flavorings, and / or colorings such as glycerol, propylene glycol, sorbitol, aspartame, or sucrose.

[0198] In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of formulations for administration by injection.

[0199] In certain embodiments, the pharmaceutical compositions of this disclosure may be in the form of sterile injectable preparations, such as sterile aqueous or oily suspensions for injection. These suspensions may be formulated according to known techniques using the preferred dispersants or wetting agents and suspensions described above. The sterile injectable preparations may be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as a solution in 1,3-butanediol, or they may be prepared as lyophilized powders. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils may conventionally be used as solvents or suspension media. For this purpose, any non-irritating non-volatile oils, including synthetic mono- or diglycerides, may be used. Furthermore, fatty acids such as oleic acid may also be used in the preparation of injectable preparations.

[0200] In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of formulations for inhalation administration.

[0201] In certain 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, optionally, other compounds such as stabilizers, antimicrobial agents, antioxidants, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof. The carriers and stabilizers vary depending on the requirements of the particular compound, but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, amino acids such as oleic acid, lecithin, and glycine, buffers, salts, sugars, or sugar alcohols.

[0202] In some embodiments, the pharmaceutical compositions of this disclosure may be in the form of formulations for topical or transdermal administration.

[0203] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels, and aqueous or oily solutions or suspensions, which can generally be obtained by formulating the active ingredient together with conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0204] In certain embodiments, the pharmaceutical compositions provided herein may be formulated in the form of transdermal patches, which are well known to those skilled in the art.

[0205] In addition to the representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in this disclosure. Such excipients and carriers are, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference, and “Remington: The Science and Practice of Pharmacy”, Ed. University of the Sciences in Philadelphia, 21 st This is described in Edition, LWW (2005).

[0206] In some embodiments, the pharmaceutical compositions of this disclosure can be formulated as unit dosage forms. The term “unit dosage form” refers to a physically distinct unit suitable as a single-unit administration for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in conjunction with a suitable pharmaceutical excipient. The amount of the compound provided herein in a unit dosage form will vary depending on the condition being treated, the subject being treated (e.g., age, weight, and response of the individual subject), the specific route of administration, the actual compound administered and its relative activity, and the severity of the subject’s condition.

[0207] In some embodiments, the dosage ranges of the pharmaceutical compositions of this disclosure are 0.001 to 1000 mg / kg body weight / day, for example, 0.001 to 1000 mg / kg body weight / day, 0.001 to 900 mg / kg body weight / day, 0.001 to 800 mg / kg body weight / day, 0.001 to 700 mg / kg body weight / day, 0.001 to 600 mg / kg body weight / day, 0.001 to 500 mg / kg body weight / day. / day, 0.001~400mg / kg body weight / day, 0.001~300mg / kg body weight / day, 0.001~200mg / kg body weight / day, 0.001~100mg / kg body weight / day, 0. 001~50mg / kg body weight / day, 0.001~40mg / kg body weight / day, 0.001~30mg / kg body weight / day, 0.001~20mg / kg body weight / day, 0.001~10mg / k g body weight / day, 0.001-5 mg / kg body weight / day, 0.001-1 mg / kg body weight / day, 0.001-0.5 mg / kg body weight / day, 0.001-0.4 mg / kg body weight / day, 0.001-0.3 mg / kg body weight / day, 0.001-0.2 mg / kg body weight / day, 0.001-0.1 mg / kg body weight / day, 0.005-0.1 mg / kg body weight / day, 0.01-0.1 The dose may be between 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, dose levels below the lower limit of the above range may be more than sufficient, while in other cases, even higher doses may be used without causing any adverse side effects, provided that such higher doses are first divided into several smaller doses for administration throughout the day. For further information on the route of administration and the regimen, please refer to Chapter 25.3 of Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, which is explicitly incorporated herein by reference.

[0208] In some embodiments, the pharmaceutical compositions of this disclosure are formulated for oral administration. In some embodiments, the unit dose for oral administration is approximately 1 mg to approximately 1000 mg, for example, approximately 5 mg to approximately 1000 mg, approximately 10 mg to approximately 1000 mg, approximately 15 mg to approximately 1000 mg, approximately 20 mg to approximately 1000 mg, approximately 25 mg to approximately 1000 mg, approximately 30 mg to approximately 1000 mg, approximately 40 mg to approximately 1000 mg, approximately 50 mg to approximately 1000 mg, approximately 60 mg to approximately 1000 mg, approximately 70 mg to approximately 1000 mg, approximately 80 mg to approximately 1000 mg, approximately 90 mg to approximately 1000 mg, approximately 100 mg to approximately 1000 mg, approximately 200 mg to approximately 1000 mg, approximately 300 mg to approximately 1000 mg, approximately 400 mg to approximately 1000 mg, and approximately 500 mg. The formulation contains one or more of the compounds provided herein in amounts such as approximately 1000 mg, approximately 1 mg to 500 mg, approximately 10 mg to approximately 500 mg, approximately 50 mg to approximately 500 mg, approximately 100 mg to approximately 500 mg, approximately 200 mg to approximately 500 mg, approximately 300 mg to approximately 500 mg, approximately 400 mg to approximately 500 mg, for example, approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 225 mg, approximately 250 mg, approximately 275 mg, and approximately 300 mg. In some embodiments, the dose unit can be administered to the subject once to six times per day depending on the severity of the subject's symptoms.

[0209] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for oral administration in treatments having a duration of longer than one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, or even longer.

[0210] In some embodiments, the pharmaceutical compositions of this disclosure are formulated for parenteral administration, for example, by intravenous, subcutaneous, or intramuscular injection. In some embodiments, the unit dose for parenteral administration is approximately 0.1 mg to approximately 500 mg, for example, approximately 0.2 mg to approximately 500 mg, approximately 0.3 mg to approximately 500 mg, approximately 0.4 mg to approximately 500 mg, approximately 0.5 mg to approximately 500 mg, approximately 1 mg to approximately 500 mg, approximately 5 mg to approximately 500 mg, approximately 10 mg to approximately 500 mg, approximately 20 mg to approximately 500 mg, approximately 30 mg to approximately 500 mg, approximately 40 mg to approximately 500 mg, approximately 50 mg to approximately 500 mg, approximately 0.5 mg to approximately 400 mg, approximately 0.5 mg to approximately 300 mg, approximately 0.5 mg to approximately 200 mg, approximately 0.5 mg to approximately 100 mg, approximately 0.5 mg to approximately 90 mg, approximately 0.5 mg to approximately 80 mg, approximately 0.5 mg to approximately 70 mg, approximately 0.5 mg to approximately 60 mg. The material contains one or more of the compounds provided herein in amounts such as approximately 0.5 mg to approximately 50 mg, approximately 0.5 mg to approximately 40 mg, approximately 1 mg to approximately 90 mg, approximately 5 mg to approximately 90 mg, approximately 10 mg to approximately 80 mg, approximately 20 mg to approximately 70 mg, approximately 30 mg to approximately 60 mg, or approximately 40 mg to approximately 50 mg, for example, approximately 0.1 mg, approximately 0.2 mg, approximately 0.3 mg, approximately 0.4 mg, approximately 0.5 mg, approximately 0.6 mg, approximately 0.7 mg, approximately 0.8 mg, approximately 0.9 mg, approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 6 mg, approximately 7 mg, approximately 8 mg, approximately 9 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, etc.

[0211] In some embodiments, a pharmaceutical composition intended to be administered by injection may be prepared by combining one or more compounds of the present disclosure with sterile distilled water, sesame or peanut oil, or aqueous propylene glycol to form a solution. In some embodiments, the pharmaceutical composition may include a surfactant or other solubilizing excipient added to facilitate the formation of a homogeneous solution or suspension. In some embodiments, the pharmaceutical composition may further include one or more further agents selected from the group consisting of wetting agents, suspending agents, preservatives, buffering agents, and isotonic agents.

[0212] In some embodiments, pharmaceutical compositions intended to be administered by injection may be administered by 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.

[0213] In further embodiments, veterinary compositions are also provided, comprising one or more molecules or compounds of the present disclosure or pharmaceutically acceptable salts thereof and a veterinary carrier. The veterinary carrier is a material useful for administering the composition and may be otherwise inert or a solid, liquid, or gaseous material that is acceptable in the veterinary field and compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally, or by any other desired route.

[0214] Pharmaceutical or veterinary compositions may be packaged in various ways depending on the method used to administer the drug. For example, articles for distribution may include containers in which the composition is placed in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, and metal cylinders. Containers may also include tamper-proof assemblies to prevent unauthorized access to the contents of the packaging. Furthermore, a label describing the contents of the container may be placed on top of the container. The label may also include appropriate warnings. Compositions may also be packaged in unit-dose or multi-dose containers, such as sealed ampoules and vials, and stored in a freeze-dried state requiring only the addition of a sterile liquid carrier, such as water, for injection immediately before use. Prescription-based injections and suspensions are prepared from the types of sterile powders, granules, and tablets described above.

[0215] In further embodiments, pharmaceutical compositions are also provided that include one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof as a first active ingredient and a second active ingredient.

[0216] In some embodiments, the second active ingredient has complementary activity to the compound provided herein, such that the second active ingredient and the compound provided herein do not adversely affect each other. Such ingredients are preferably present in combination in amounts effective for the intended purpose.

[0217] Methods of treating diseases

[0218] In a further embodiment, the present disclosure provides a method for treating a vascular disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition provided herein.

[0219] In some embodiments, the vascular disease is selected from atherothrombosis, ischemia, stroke, cerebral thrombosis, arterial thrombosis, thrombotic cerebrovascular disease, cardiovascular disease, and blood clots.

[0220] In a further embodiment, the Disclosure provides a method for inhibiting platelet aggregation in a subject requiring such inhibition, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition provided herein. [Examples]

[0221] For illustrative purposes, the following examples are included. However, it should be understood that these examples are not intended to limit the disclosure and are intended only to suggest ways of carrying out the disclosure. Those skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare several other compounds of the disclosure, and that alternative methods for preparing the compounds of the disclosure are within the scope of the disclosure. For example, the synthesis of compounds not illustrated by the disclosure may be successfully carried out by modifications obvious to those skilled in the art, for example, by using other suitable reagents and building blocks known in the art other than those described, by appropriately protecting interfering groups, and / or by making standard modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as applicable to preparing other compounds of the disclosure.

[0222] [Example 1] [ka] [ka] [ka]

[0223] Step 1.1-2 Synthesis

[0224] [ka]

[0225] 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 gradually added to the above solution. After the addition, the resulting mixture was stirred at 20°C for 4 hours. The mixture was poured into a solution of Na2S2O3 (90.0 g) and NaHCO3 (45.0 g) in water (300 mL) while stirring. The resulting mixture was extracted with DCM (300 mL x 2). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography (petroleum ether / siRNA = 100 / 1 to 5 / 1) to obtain 1-2 (67.0 g, 98% yield) as a yellow oily substance.

[0226] Step 2.1-3 Synthesis

[0227] [ka]

[0228] A mixture of 1-2 (67.0 g, 337 mmol), thiobenzoic acid (56.7 g, 370 mmol), and tetrabutylammonium chloride (4.67 g, 17 mmol) in toluene (300 mL) was stirred at room temperature for 20 minutes, then at 40°C overnight. The reaction mixture was then concentrated under vacuum. Saturated Na2CO3 (400 mL) was added to the residue with stirring, and then extracted with siRNA (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 / siRNA = 10 / 1 to 5 / 1) to obtain 1-3 (87.5 g, 77% yield) as a white solid.

[0229] LC-MS [M+1-100] + = 238.1 1H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J = 7.2 Hz, 2H), 7.59 (s, 1H), 7.46 (t, J = 7.7 Hz, 2H), 4.24 (d, J = 16.3 Hz, 1H), 4.17-3.81 (m, 1H), 3.73 (s, 1H), 3.60 (s, 1H), 2.92 (t, J = 24.3 Hz, 2H), 2.72 (s, 1H), 2.12 (d, J = 16.8 Hz, 1H), 1.71 (d, J = 11.6 Hz, 1H), 1.46 (s, 9H).

[0230] Step 3.1-4 Synthesis

[0231] [ka]

[0232] To a solution of 1-3 (157.0 g, 467.3 mmol) in DCM (1.5 L), TBSCl (141.2 g, 935 mmol) and imidazole (159.0 g, 2.34 mol) were 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 / SiO₂ = 10 / 1) to obtain 1-4 (273.0 g, 94% yield) as a white solid. LC-MS [M+1-100] + = 352.1.

[0233] Steps 4.1-5: Synthesis

[0234] [ka]

[0235] 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 / siRNA = 20 / 1) to obtain 1-5 (210.0 g, 100% yield) as a pale yellow oily substance.

[0236] Step 5.1-6 Synthesis

[0237] [ka]

[0238] To a solution of NaBH4 (1.1 g, 28.8 mmol) in DMF (1.0 L), NaH (20.7 g, 864.6 mmol) was added under N2 at 0°C with stirring. 1-5 (200.0 g, 576.4 mmol) was added dropwise at 0°C, and the mixture was stirred at 0°C for 1 hour. Next, isopropylchloromethyl carbonate (100.7 g, 662.8 mmol) was added at 0°C, and the resulting mixture was stirred at room temperature for 1 hour. H2O (1.0 L) was added to the mixture, and then extracted with SiO2 (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 / SiO2 = 20 / 1) to obtain 1-6 (135.0 g, 50% yield) as a colorless oil.

[0239] 1 H NMR (400 MHz, Chloroform-d) δ 5.25 (q, J = 12.0 Hz, 2H), 4.92-4.79 (m, 1H), 3.85 (d, J = 58.8 Hz, 2H), 3.45 (s, 1 H), 2.97-2.74 (m, 3H), 2.13-2.02 (m, 1H), 1.59-1.47 (m, 1H), 1.41 (s, 9H), 1.25 (dd, J = 15.5, 4.6 Hz, 6H), 0.89 (s, 9H), 0.19-0.01 (m, 6H).

[0240] Synthesis in Steps 6.1-7

[0241] [ka]

[0242] To a solution of 1-6 (129.0 g, 278.6 mmol) in THF (1.1 L), Et3N.3HF (135.0 g, 835.9 mmol) was added and the mixture was stirred under reflux for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / SiO7 = 3 / 1) to obtain 1-7 (80.0 g, 82% yield) as a pale yellow oily substance.

[0243] Synthesis in Steps 7.1-8

[0244] [ka]

[0245] To a solution of 1-7 (30.0 g, 86.9 mmol) in DCM (300 mL), Dess-Martin periodinane (72.9 g, 171.9 mmol) was added, and the resulting mixture was stirred at 25°C for 4 hours. After completion, the reaction mixture was added to a mixed solution of saturated Na2S2O3 / saturated NaHCO3 (600 mL / 600 mL), and then extracted with siRNA (400 mL x 2). 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 silica gel chromatography (petroleum ether / siRNA = 20 / 1~8 / 1) to obtain 1-8 (22.0 g, 73% yield) as a colorless oil.

[0246] Steps 8.1-9 and 1-10: Synthesis

[0247] [ka]

[0248] To a solution of tert-butyl 2-(diethoxyphosphoryl) acetate (11.4 g, 43.2 mmol) in THF (100 mL), LiHMDS (37.4 mL, 37.4 mmol) was added under N2 at -60°C and the mixture was stirred at -60°C for 30 minutes. Then, 1-8 (10.0 g, 28.8 mmol) was added dropwise at -60°C and the resulting mixture was stirred at 0-10°C for 1 hour. The reaction mixture was then added to saturated NH4Cl (300 mL) and extracted with siRNA (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 / SiO₂ = 60 / 1) to obtain pale yellow oily substances 1-9 (2.5 g, 19% yield) and pale yellow oily substances 1-10 (1.3 g, 10% yield).

[0249] 1-9: 1 H NMR (400 MHz, chloroform-d) δ 5.68 (s, 1H), 5.47 (d, J = 15.2 Hz, 1H), 5.24 (s, 1H), 4.89-4.94 (m, 2H), 3.95 (s, 1H), 3.87-3.92 (m, 1H), 3.79 (s, 1H), 3.17-3.19 (m, 1H), 2.15-2.16 (m, 1H), 1.87-1.90 (m, 1H), 1.48 (s, 9H), 1.43 (s, 9H), 1.29 (d, J = 4 Hz, 6H).

[0250] 1-10: 1HNMR (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).

[0251] Synthesis in Steps 9.1-11

[0252] [ka]

[0253] To a solution of 1-9 (3.0 g, 6.7 mmol) in DCM (20 mL), TFA (10 mL) was added at 0°C, and the reaction mixture was stirred at 0°C for 30 minutes. After completion, the reaction mixture was added to a solution of saturated NaHCO3 (100 mL), and then extracted with DCM (100 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain crude 1-11 (3.0 g, >100% yield) as a yellow oily substance, which was used in the next step without further purification. LC-MS [M+1] + = 346.1

[0254] Step 10.1-13 Synthesis

[0255] [ka]

[0256] To a solution of 1-11 (3.0 g, crude) in CH3CN (15 mL), 1-12 (2.6 g, 6.7 mmol) and KHCO3 (1.35 g, 13.5 mmol) were added. The resulting mixture was stirred at 40°C for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (C18, CH3CN / H2O=80 / 20) to obtain 1-13 (1.8 g, 51% yield) as a white solid. LC-MS [M+1] + = 528.2.

[0257] Steps 11 and 12.1a-1 and 1a-2 synthesis

[0258] [ka]

[0259] A solution of 1-13 (1.8 g, 3.4 mmol) in TFA (10 mL) was stirred at room temperature for 30 minutes. After completion, the reaction mixture was added to a solution of saturated NaHCO3 (100 mL) and then extracted with RINKAN (100 mL x 3). The combined organic layers were washed with saturated NaHCO3, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (C18, CH3CN / H2O=80 / 20) to obtain 1a (550 mg, 34% yield). 1a was purified by chiral column chromatography to obtain 1a-1 and 1a-2.

[0260] 1a: LC-MS [M+1] + = 472.1 1H NMR (400 MHz, Chloroform-d) δ 7.59 (s, 1H), 7.38 (d, J = 4 Hz, 1H), 7.32-7.26 (m, 2H), 5.86 (s, 1H), 5.22 (dd, J = 12.2, 2.6 Hz, 1H), 5.00-4.83 (m, 3H), 4.50 (dd, J = 66.2, 11.9 Hz, 1H), 3.82 (s, 1H), 3.70 (d, J = 4.9 Hz, 3H), 3.52 (dd, J = 37.9, 12.9 Hz, 1H), 2.92-2.64 (m, 2H), 2.45-2.30 (m, 1 H), 1.95-1.84 (m, 1H), 1.30 (d, J = 6.2 Hz, 6H).

[0261] 1a-1: 1 H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.46 - 7.43 (m, 1H), 7.33 (dd, J = 6.3, 2.7 Hz, 2H), 5.91 (s, 1H), 5.27 (d, J = 12.3 Hz, 1H), 5.04 - 4.87 (m, 3H), 4.49 (d, J = 13.7 Hz, 1H), 3.88 (s, 1H), 3.75 (s, 3H), 3.58 (d, J = 14.0 Hz, 1H), 2.87 (s, 2H), 2.44 (s, 1H), 1.95 (dd, J = 14.2, 3.3 Hz, 1H), 1.35 (d, J = 6.2 Hz, 6H).

[0262] 1a-2: 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.44 (dt, J = 8.2, 3.1 Hz, 1H), 7.35 - 7.31 (m, 2H), 5.92 (s, 1H), 5.25 (d, J = 12.3 Hz, 1H), 5.07 (s, 1H), 4.94 (td, J = 12.5, 6.5 Hz, 2H), 4.68 (d, J = 13.4 Hz, 1H), 3.87 (s, 1H), 3.76 (s, 3H), 3.50 (d, J = 13.4 Hz, 1H), 2.90 (s, 1H), 2.75 (d, J = 12.3 Hz, 1H), 2.44 (s, 1H), 1.96 (d, J = 13.2 Hz, 1H), 1.34 (d, J = 6.3 Hz, 6H).

[0263] Synthesis in Steps 13.1-14

[0264] [ka]

[0265] To a solution of 1-10 (1.8 g, 4.0 mmol) in DCM (10 mL), TFA (5 mL) was added at 0°C and the mixture was stirred at 0°C for 1 hour. After completion, the reaction mixture was added to a solution of saturated NaHCO3 (100 mL) and then extracted with DCM (100 mL x 3). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain crude 1-14 (2.0 g, >100% yield) as a yellow oily substance, which was used in the next step without further purification. LC-MS [M+1] + = 346.1

[0266] Synthesis in Steps 14.1-15

[0267] [ka]

[0268] To a solution of 1-14 (2.0 g, crude) in CH3CN (20 mL), 1-12 (1.5 g, 4.0 mmol) and KHCO3 (800 mg, 8.0 mmol) were added. The resulting mixture was stirred at 40°C for 2 hours and then concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18, CH3CN / H2O=80 / 20) to obtain 1-15 (500 mg, 24% yield) as a white solid. LC-MS [M+1] + = 528.2

[0269] Steps 15 and 16. Synthesis of 1b-1 and 1b-2

[0270] [ka]

[0271] To a solution of 1-15 (500 mg, 0.95 mmol) in DCM (2 mL), TFA (3 mL) was added at 0°C and the mixture was stirred at 0°C for 30 minutes. After completion, the reaction mixture was added to a solution of saturated NaHCO3 (30 mL) and then extracted with ₹ (30 mL x 3). The combined organic layer was washed with saturated NaHCO3, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (C18, CH3CN / H2O=80 / 20), followed by preparative HPLC (mobile phase: A(H2O) / B(MeCN); ratio range: A / B(80% / 20%) to A / B(55% / 45%) for 10 minutes and A / B(20% / 80%) for 35 minutes; peak Rt: (67% of B); V=80 mL / min, wavelength 214 nm), and preparative TLC (DCM / MeOH=10 / 1) to obtain 1b (50 mg, 11% yield). 1b was purified by chiral column chromatography to obtain 1b-1 and 1b-2.

[0272] 1b: LC-MS [M+1] + = 472.1 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 5.6 Hz, 1H), 7.44-7.36 (m, 1H), 7.27 (s, 2H), 5.77-5.65 (m, 1H), 5.41 (s, 1H), 5.25 (dd, J = 12.0, 6.3 Hz, 1H), 5.19-5.11 (m, 1H), 4.92-4.83 (m, 1H), 4.80 (s, 1H), 3.70 (d, J = 4.6 Hz, 3H), 3.52 (dd, J = 34.3, 12.2 Hz, 1H), 3.19 (d, J = 12.9 Hz, 0.5H), 2.98 (d, J = 12.5 Hz, 0.5H), 2.90-2.84 (m, 0.5 H), 2.78-2.61 (m, 1.5 H), 2.31-2.16 (m, 1 H), 1.97-1.82 (m, 1H), 1.28 (d, J = 5.4 Hz, 6H).

[0273] 1b-1: 1 H NMR (400 MHz, CDCl3) δ 7.60-7.57 (m, 1H), 7.41-7.39 (m, 1H), 7.33 - 7.26 (m, 2H), 5.64 (s, 1H), 5.41 (s, 1H), 5.25 (d, J = 12.1 Hz, 1H), 5.14 (d, J = 12.0 Hz, 1H), 4.91 - 4.81 (m, 1H), 4.79 (s, 1H), 3.69 (s, 3H), 3.47 (d, J = 12.4 Hz, 1H), 2.97 (d, J = 12.5 Hz, 1H), 2.86 (d, J = 10.6 Hz, 1H), 2.72 (dd, J = 22.5, 10.6 Hz, 1H), 2.29-2.20 (m, 1H), 1.92 (d, J = 14.3 Hz, 1H), 1.27 (d, J = 6.2 Hz, 6H).

[0274] 1b-2: 1H NMR (400 MHz, CDCl3) δ 7.62 - 7.56 (m, 1H), 7.41-7.38 (m, 1H), 7.30 - 7.26 (m, 2H), 5.77 (s, 1H), 5.43 (s, 1H), δ 5.27 (d, J = 12.1 Hz, 1H), 5.17 (d, J = 12.0 Hz, 1H), 4.91-4.86 (m, 1H), 4.80 (s, 1H), 3.71 (s, 3H), 3.56 (d, J = 12.4 Hz, 1H), 3.17 (d, J = 12.4 Hz, 1H), 2.66 (d, J = 8.0 Hz, 2H), 2.20-2.17 (m, 1H), 1.87 (d, J = 14.4 Hz, 1H), 1.29 (dd, J = 6.2, 2.5 Hz, 6H).

[0275] [Example 2]

change

[0276] Synthesis of ステップ1.2-2および2-3

[0277]

change

[0278] To a solution of ethyl 2-(diethoxyphosphoryl)acetate (20.6 g, 86.5 mmol) in THF (300 mL), KHMDS (75 mL, 74.9 mmol) was added under N2 at -60°C and the mixture was stirred at -60°C for 1 hour. Then, 2-1 (20.0 g, 57.6 mmol) was added dropwise at -60°C and the resulting mixture was stirred at -10°C for 0.5 hours. The reaction mixture was then added to saturated NH4Cl (1000 mL). The resulting mixture was extracted with ethyl phosphate (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 / ethyl phosphate = 60 / 1) to obtain 2-3 (7.5 g, 30% yield) and 2-2 (4.5 g, 18% yield) as pale yellow oils.

[0279] 2-2: 1 H NMR (400 MHz, CDCl3) δ 5.76 (s, 1H), 5.50 (d, J = 15.8 Hz, 1H), 5.23 (d, J = 12.1 Hz, 1H), 4.97-4.83 (m, 2H), 4.23-4.06 (m, 3H), 4.01-3.91 (m, 1H), 3.91-3.77 (m, 2H), 3.28-3.12 (m, H,), 2.23- 2.10 (m, 1H), 1.88 (dd, J = 23.1, 11.5 Hz, 1H), 1.42 (s, 9H), 1.31-1.24 (m, 9 H).

[0280] 2-3: 1H NMR (400 MHz, CDCl3) δ 5.83 (s, 1H), 5.48 (s, 1H), 5.28 (d, J = 12.1 Hz, 1H), 5.16 (d, J = 12.1 Hz, 1H), 4.94-4.82 (m, 1H), 4.32-4.09 (m, 3H), 4.03-3.85 (m, 2H), 3.23-3.05 (m, 1H), 2.08-1.98 (m, 1H), 1.89 (dd, J = 14.2, 1.9 Hz, 1H), 1.44 (s, 10H), 1.31-1.23 (m, 10H).

[0281] Synthesis in Steps 2.2-4

[0282] [ka]

[0283] To a solution of 2-3 (3.0 g, 7.2 mmol) in DCM (20 mL), TFA (9 mL) was added at 0°C, and the reaction mixture was stirred at 0°C for 30 minutes. After completion, the resulting mixture was added to a solution of saturated NaHCO3 (200 mL). The resulting mixture was then extracted with DCM (200 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain crude 2-4 (3.0 g, >100% yield) as a yellow oily substance, which was used in the next step without further purification.

[0284] LC-MS [M+1-100] + = 318.1

[0285] Synthesis in Step 3.2a

[0286] [ka]

[0287] To a solution of 2-4 (3.0 g, crude) in CH3CN (15 mL), 1-12 (2.8 g, 7.2 mmol) and KHCO3 (1.4 g, 14.4 mmol) were added. The resulting mixture was stirred at 40°C for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (C18, CH3CN / H2O = 80 / 20) to obtain 2a (1.7 g, 47% yield).

[0288] LC-MS [M+1] + = 500.1 1 H NMR (400 MHz, CDCl3) δ 7.66-7.52 (m, 1H), 7.43-7.32 (m, 1H), 7.25 (s, 2H), 5.80 (s, 1H), 5.22 (d, J = 12.2 Hz, 1H), 4.97-4.79 (m, 3H), 4.49 (dd, J = 63.7, 12.8 Hz, 1H), 4.18-3.99 (m, 2H), 3.78 (s, 1H), 3.71 (d, J = 7.6 Hz, 3H), 3.47 (dd, J = 38.1, 13.2 Hz, 1H), 2.72 (dd, J = 45.3, 17.4 Hz, 2H), 2.32 (s, 1H), 1.87 (d, J = 13.7 Hz, 1H), 1.30 (d, J = 6.1 Hz, 6H), 1.24 (t, J = 7.2 Hz, 3H).

[0289] Synthesis in Steps 4.2-5

[0290] [ka]

[0291] To a solution of 2-2 (100 mg, 0.26 mmol) in DCM (3 mL), TFA (0.6 mL) was added at 0°C, and the reaction mixture was stirred at 0°C for 30 minutes. After completion, the reaction mixture was added to a solution of saturated NaHCO3 (20 mL). The resulting mixture was then extracted with DCM (20 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain crude 2-5 (120.0 mg, >100% yield) as a yellow oily substance, which was used in the next step without further purification.

[0292] LC-MS [M+1-100] + = 318.1

[0293] Step 5.2b Synthesis

[0294] [ka]

[0295] To a solution of 2-5 (120.0 mg, crude) in CH3CN (3 mL), 1-12 (88 mg, 0.23 mmol) and KHCO3 (92 mg, 0.92 mmol) were added. The resulting mixture was stirred at 40°C for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (C18, CH3CN / H2O = 80 / 20) to obtain 2b (23 mg, 20% yield).

[0296] LC-MS [M+1] + = 500.1. 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J= 5.1 Hz, 1H), 7.38 (d, J = 6.4 Hz, 1H), 7.32-7.25 (m, 2H), 5.74 (s, 0.5H), 5.61 (s, 0.5H), 5.43 (s, 1H), 5.25 (dd, J = 11.9, 5.4 Hz, 1H), 5.15 (dd, J = 11.9, 4.6 Hz, 1H), 4.93-4.81 (m, 1H), 4.77 (s, 1H), 4.23-4.06 (m, 2H), 3.69 (d, J = 3.9 Hz, 3H), 3.51 (d, J = 11.9 Hz, 0.5H), 3.42 (d, J = 12.1 Hz, 0.5H), 3.14 (d, J = 12.3 Hz, 0.5H), 2.97-2.80 (m, 1H), 2.77-2.67 (m, 0.5H), 2.63 (d, J = 7.5 Hz, 1H), 2.31-2.10 (m, 1H), 1.88 (dd, J = 21.5, 15.1 Hz, 1H), 1.26 (s, 9H).

[0297] [Example 3]

change

[0298] Synthesis of ステップ1.3-3

[0299]

change

[0300] 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 the addition, the mixture was stirred at 16°C for 2 hours. The reaction mixture was diluted with water (3 L) and extracted with HCl (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 / HCl = 20 / 1) to obtain 3-3 (79.0 g, 28% yield) as a colorless oil.

[0301] 1 H NMR (400 MHz, Chloroform-d) δ 5.36-5.25 (m, 2H), 4.02-3.91 (m, 1H), 3.88-3.83 (m, 1H), 3.80 (s, 3H), 3.52-3.41 (m, 1H), 2.98-2.84 (m, 2H), 2.84-2.74 (m, 1H), 2.14-2.06 (m, 1H), 1.44 (s, 9H), 0.89 (s, 9H), 0.12 (s, 6H).

[0302] Synthesis in Steps 2, 3, and 4

[0303] [ka]

[0304] Solutions of 3-3 (79.0 g, 0.18 mol) and Et3N.3HF (90.4 g, 0.54 mol) in THF (800 mL) were 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 / SiO7 = 3 / 1) to obtain 3-4 (41.0 g, 68% yield) as a colorless oil.

[0305] Step 3.3-5 Synthesis

[0306] [ka]

[0307] Dess-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 minutes. 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 / alkyl=3 / 1) to obtain 3-5 (37.0 g, 92% yield) as a yellow oily substance.

[0308] Step 4. Synthesis of 3-7-Z and 3-7-E

[0309] [ka]

[0310] To a solution of 3-6 (37.9 g, 0.15 mol) in dry THF (500 mL), LiHMDS (151 mL, 0.15 mol) was added under N2 at -60°C. The resulting mixture was stirred at -60°C for 30 minutes, and then 3-5 (37.0 g, 0.11 mol) was added dropwise at -60°C. The reaction mixture was heated to 0°C and stirred at 0-10°C for 1 hour. The resulting mixture was then added to saturated NH4Cl (100 mL, aqueous solution), and the resulting mixture was extracted with HCl (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 / HCl = 50 / 1) to obtain 3-7-Z (7.0 g, 14% yield) and 3-7-E (14 g, 28% yield).

[0311] 3-7-Z 1H NMR (400 MHz, Chloroform-d) δ 5.76 (s, 1H), 5.50 (s, 1H), 5.32 (d, J = 12 Hz, 1H), 5.17 (d, J = 12 Hz, 1H), 4.32-3.87 (m, 3H), 3.79 (s, 3H), 3.24-3.03 (m, 1H), 2.13-2.00 (m, 1H), 1.93-1.85 (m, 1H), 1.47 (s, 9H), 1.45 (s, 9H).

[0312] 3-7-E 1 H NMR (400 MHz, Chloroform-d) δ 5.68 (s, 1H), 5.52-5.43 (s, 1H), 5.26 (d, J = 12.4 Hz, 1H), 4.96 (d, J = 12.4 Hz, 1H), 3.97-3.85 (m, 2H), 3.80 (s, 3H), 3.79-3.75 (m, 1H), 3.27-3.13 (m, 1H), 2.21-2.09 (m, 1H), 1.93-1.83 (m, 1H), 1.48 (s, 9H), 1.43 (s, 9H).

[0313] Synthesis of Steps 5.3-8

[0314] [ka]

[0315] 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. The reaction mixture was then diluted with saturated NaHCO3 aqueous solution (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 obtain 3-8 (3 g, 71% yield) as a yellow oil, which was used in the next step without further purification. LC-MS [M+1] + = 318.1

[0316] Step 6: Synthesis of 3-10

[0317] [ka]

[0318] To a solution of 3-8 (3.0 g, 9.4 mmol) in CH3CN (10 mL), 3-9 (3.6 g, 9.4 mmol) and KHCO3 (2.8 g, 28.2 mmol) were added. The resulting mixture was stirred at 40°C for 4 hours. After completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (C18, CH3CN / H2O=90 / 10) to obtain 3-10 (2.5 g, 53% yield) as a yellow oil. LC-MS [M+1] + = 500.2

[0319] Steps 7 and 8. Synthesis of 3b-1 and 3b-2

[0320] [ka]

[0321] To a solution of 3-10 (2.5 g, 5.0 mmol) in DCM (20 mL), TFA (5 mL) was added and the mixture was stirred at 20°C for 1 hour. After completion, the reaction product was added to a solution of saturated NaHCO3 aqueous solution (50 mL) and extracted with DCM (50 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain 3 (800 mg, yield 36%). 3 was purified by chiral column chromatography to obtain 3b-1 and 3b-2.

[0322] 3: LC-MS [M+1] + = 444.1. 1H NMR (400 MHz, Chloroform-d) δ 7.60-7.54 (m, 1H), 7.41-7.36 (m, 1H), 7.31-7.22 (m, 2H), 5.77 (s, 0.5H), 5.65 (s, 0.5H), 5.43-5.37 (m, 1H), 5.30-5.23 (m, 1H), 5.19-5.12 (m, 1H), 4.81-4.77 (m, 1H), 3.76 (s, 3H), 3.69 (d, J = 4.4 Hz, 3H), 3.54 (d, J = 12.4 Hz, 0.5H), 3.45 (d, J = 12.4 Hz, 0.5H), 3.17 (d, J = 12.4 Hz, 0.5H), 2.96 (d, J = 12.4 Hz, 0.5H), 2.85 (d, J = 12.0 Hz, 0.5H), 2.73 (d, J = 12.0 Hz, 0.5H), 2.70-2.62 (m, 1H), 2.30-2.13 (m, 1H), 2.02-1.82 (m, 1H).

[0323] 3b-1: 1 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.5 Hz, 2H), 7.56 - 7.41 (m, 2H), 6.10 (s, 1H), 5.71 (s, 1H), 5.52 (s, 1H), 5.27 (q, J = 12.2 Hz, 2H), 3.98 (s, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 3.71 - 3.56 (m, 1H), 3.35 - 3.14 (m, 1H), 3.01 - 2.71 (m, 1H), 2.06 (d, J = 15.0 Hz, 1H).

[0324] 3b-2: 1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.45 (s, 2H), 6.06 (s, 1H), 5.50 (s, 1H), 5.44 (s, 1H), 5.33 (d, J = 12.0 Hz, 1H), 5.22 (d, J = 11.9 Hz, 1H), 4.02 - 3.97 (m, 1H), 3.86 (d, J = 10.8 Hz, 1H), 3.81 (s, 6H), 3.49 (d, J = 13.6 Hz, 1H), 3.12 - 3.07 (m, 1H), 2.71 - 2.66 (m, 1H), 2.03 (d, J = 14.8 Hz, 1H).

[0325] [Example 4] [ka]

[0326] Synthesis in Step 1.4-2

[0327] [ka]

[0328] 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 resulting mixture was stirred at 20°C for 2 hours. The reaction product was diluted with water (2 L) and extracted with ELISA (600 L x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 4-2 (250 g, 100% yield) as a dark oily substance, which was used in the next step without further purification.

[0329] Synthesis in Step 2.4-3

[0330] [ka]

[0331] 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 formed solution was washed with brine (500 ml x 2), the organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / SiO=3 / 1) to obtain 4-3 (108 g, 73% yield) as a white solid. LC-MS [M+1] + -100 = 246.2.

[0332] 1 H NMR (400 MHz, CDCl3) δ 4.19 (d, J = 12.1 Hz, 1H), 3.98 (s, 1H), 3.72 (s, 1H), 3.52 (d, J = 15.2 Hz, 2H), 2.90 - 2.78 (m, 1H), 2.77 - 2.67 (m, 1H), 2.66 - 2.56 (m, 1H), 2.11 (s, 3H), 2.02 (d, J = 12.0 Hz, 1H), 1.63 - 1.49 (m, 1H), 1.45 (s, 9H).

[0333] Synthesis in Step 3.4-4

[0334] [ka]

[0335] Dess-Martin (159 g, 0.375 mol) was added to a solution of 4-3 (108 g, 0.313 mol) in DCM (1 L) at 20°C. After addition, the resulting mixture was stirred at 20°C for 30 minutes. The reaction mixture was washed with saturated Na2S2O3 solution (1 L x 2), saturated NaHCO3 solution (1 L x 2), and brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum / alkyl=3 / 1) to obtain 4-4 (80.0 g, 74.5% yield) as an orange oily substance. LC-MS [M+1] + +Na=366.1.

[0336] 1 H NMR (400 MHz, CDCl3) δ 4.29 (d, J = 17.9 Hz, 1H), 4.16 (d, J = 18.4 Hz, 1H), 3.82 (s, 1H), 3.48 (d, J = 15.6 Hz, 1H), 3.44 - 3.32 (m, 2H), 3.27 (s, 1H), 2.43 - 2.29 (m, 1H), 2.16 (s, 3H), 2.09 - 2.04 (m, 1H), 1.46 (s, 9H).

[0337] Step 4. Synthesis of 4-6-Z and 4-6-E

[0338] [ka]

[0339] To a solution of 4-5 (77 g, 0.302 mol) in dry THF (800 mL), LiHMDS (303 mL, 0.303 mol) was added under N2 at -60°C. The reaction mixture was stirred at -60°C for 30 minutes, after which 4-4 (80 g, 0.233 mol) was added dropwise at -60°C. The resulting mixture was stirred at 0-10°C for 1 hour. The reaction mixture was then added to saturated NH4Cl solution (800 mL) and extracted with HCl (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 / HCl = 20 / 1) to obtain 4-6-Z (12 g, 9% yield) as a pale orange oil and 4-6-E (15 g, 11% yield) as an off-white solid. LC-MS [M+1] + +23 = 464.2.

[0340] 4-6-Z 1 H NMR (400 MHz, CDCl3) δ 5.74 (s, 1H), 4.27 (s, 1H), 4.07 - 3.83 (s, 2H), 3.68 (d, J = 15.1 Hz, 1H), 3.44 (d, J = 15.2 Hz, 1H), 3.25 - 3.10 (m,1H), 2.09 (s, 3H), 2.02 (d, J = 14.6 Hz, 1H), 1.85 (d, J = 13.7 Hz, 1H), 1.54 - 1.32 (m, 18H).

[0341] 4-6-E 1 H NMR (400 MHz, CDCl3) δ 5.59 (s, 1H), 5.49 (d, J = 15.6 Hz, 1H), 4.00 (d, J = 15.7 Hz, 1H), 3.95- 3.80 (m, 1H), 3.61 (s, 1H), 3.40 - 3.14 (m, 3H), 2.21- 2.11 (m, 1H), 2.08 (s, 3H), 1.89 (d, J = 11.4 Hz, 1H), 1.52- 1.42 (m,18H).

[0342] Step 5: Synthesis of 4-7

[0343] [ka]

[0344] A solution of 4-6-Z (10 g, 0.023 mol) and TFA (20 ml) in DCM (80 mL) was stirred at 20°C for 2 hours. The resulting mixture was concentrated under vacuum to obtain 4-7 (15 g, 100% yield) as a dark oily substance, which was used in the next step without further purification. LC-MS [M+1] + = 286.2.

[0345] Steps 6 and 7: Synthesis of 4b-1 and 4b-2

[0346] [ka]

[0347] Solutions of 4-7 (15 g, crude, 0.023 mol) and 4-8 (5 mL) in DCM were added dropwise to Et3N 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 reverse-phase column chromatography (C18, ACN / H2O=70 / 30) to obtain 4 (1.8 g, 16.7% yield). 4 was purified by chiral column chromatography to obtain 4b-1 and 4b-2.

[0348] 4: LC-MS [M+1]+ = 468.1. 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 6.7 Hz, 1H), 7.40 (d, J = 6.2 Hz, 1H), 7.32-7.23 (m, 2H), 5.79 (s, 0.5H), 5.67 (s, 0.5H), 5.23 (s, 1H), 4.77 - 4.67 (m, 1H), 3.71 (d, J = 4.5 Hz, 3H), 3.60- 3.52 (m, 1.5H), 3.50 - 3.36 (m, 1.5H), 3.17 (d, J = 12.3 Hz, 0.5H), 2.97 (d, J = 12.4 Hz, 0.5H), 2.90- 2.82 (m, 0.5H), 2.80- 2.70 (m, 0.5H), 2.66 (d, J = 8.6 Hz, 1H), 2.30- 2.13 (m, 1H), 2.06 (s, 3H), 1.93- 1.81 (m, 1H).

[0349] 4b-1: 1 H NMR (400 MHz, CDCl3) δ 7.71 - 7.63 (m, 1H), 7.50 - 7.43 (m, 1H), 7.38 - 7.32 (m, 2H), 5.89 (s, 1H), 5.29 (d, J = 4.0 Hz, 1H), 4.94 (s, 1H), 3.77 (s, 3H), 3.67 (dd, J = 21.5, 13.7 Hz, 2H), 3.48 (d, J = 15.2 Hz, 1H), 3.35 (d, J = 12.4 Hz, 1H), 2.79 (t, J = 13.1 Hz, 2H), 2.37 - 2.32 (m, 1H), 2.12 (s, 3H), 1.90 (d, J = 14.3 Hz, 1H).

[0350] 4b-2: 1H NMR (400 MHz, CDCl3) δ 7.69 - 7.62 (m, 1H), 7.52 - 7.44 (m, 1H), 7.41 - 7.31 (m, 2H), 5.78 (s, 1H), 5.28 (d, J = 4.3 Hz, 1H), 4.95 (s, 1H), 3.76 (s, 3H), 3.62 (t, J = 15.4 Hz, 2H), 3.46 (d, J = 15.3 Hz, 1H), 3.17 (d, J = 12.4 Hz, 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 = 14.3 Hz, 1H).

[0351] [Example 5] [ka]

[0352] Step 1: Synthesis of 5-3

[0353] [ka]

[0354] To a mixture of 5-1 (10 g, 28.8 mmol) and K2CO3 (4.8 g, 34.6 mmol) in DMF (100 ml), 5-2 (7.6 g, 31.6 mmol) was gradually added at 20°C. After the 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 / siRNA = 10 / 1) to obtain 5-3 (4.4 g, 33% yield) as a colorless oil.

[0355] 1H NMR (400 MHz, CDCl3) δ 5.21 (s, 2H), 3.89 (d, J = 15.2 Hz, 1H), 3.74 (s, 1H), 3.49 (s, 1H), 3.03 (ddd, J = 13.1, 9.8, 3.1 Hz, 1H), 2.97 - 2.77 (m, 2H), 2.19 - 2.02 (m, 1H), δ 1.60 - 1.49 (m, 1H),1.44 (s, 9H), 1.20 (s, 9H), 0.89 (s, 9H), 0.11 (s, 6H).

[0356] Synthesis in Steps 2.5-4

[0357] [ka]

[0358] To a solution of 5-3 (4.4 g, 9.5 mmol) in THF (40 mL), Et3N.3HF (4.6 g, 28.6 mmol) was added, and the resulting mixture was stirred at 50°C for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / siRNA = 5 / 1) to obtain 5-4 (2.5 g, 76% yield) as a colorless oil.

[0359] Synthesis in Step 3.5-5

[0360] [ka]

[0361] To a solution of 5-4 (2.5 g, 7.2 mmol) in DCM (25 mL), Dess-Martin periodinane (3.9 g, 9.4 mmol) was added, and the resulting mixture was stirred at 25°C for 30 minutes. After completion, the reaction mixture was poured into a solution of saturated Na2S2O3 / saturated NaHCO3 (50 mL, 1:1). The resulting mixture was extracted with DCM (20 mL x 2). 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 silica gel chromatography (petroleum ether / siRNA = 3 / 1) to obtain 5-5 (2.0 g, 80% yield) as a colorless oil.

[0362] Synthesis in Steps 4.5-7

[0363] [ka]

[0364] To a solution of 5-6 (1.2 g, 4.8 mmol) in THF (15 mL), LiHMDS (4.8 mL, 1 M in THF, 4.8 mmol) was added under N2 at -60°C and the mixture was stirred at -60°C for 30 minutes. 5-5 (1.5 g, 4.4 mmol) was added to the resulting mixture at -60°C. After the 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 resulting mixture was extracted with HCl (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 / HCl = 20 / 1) to obtain 5-7 (310 mg, 16% yield) as a colorless oil.

[0365] 1H NMR (400 MHz, CDCl3) δ 5.75 (s, 1H), 5.58 (s, 1H), 5.29 (d, J = 12.0 Hz, 1H), 5.18 (d, J = 12.0 Hz, 1H), 4.39 - 4.10 (m, 1H), 4.00 (s, 2H), 3.18 (s, 1H), 2.08 (dd, J = 16.1, 9.9 Hz, 1H), 1.91 (d, J = 13.8 Hz, 1H), 1.49 (d, J = 12.7 Hz, 18H), 1.21 (s, 9H).

[0366] Synthesis in Steps 5.5-8

[0367] [ka]

[0368] A solution 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 solution of saturated NaHCO3 (20 mL), and the resulting mixture was extracted with DCM (20 mL x 2). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum to obtain crude 5-8 (450 mg, yield >100%) as a colorless oil.

[0369] LC-MS [M+1] + = 344.3

[0370] Synthesis in Steps 6.5-10

[0371] [ka]

[0372] To a solution of 5-8 (crude, 1.01 mmol) in CH3CN (5 mL), 5-9 (389 mg, 1.01 mmol) and KHCO3 (400 mg, 4.04 mmol) were added. The resulting mixture was stirred at 40°C for 3 hours and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / Â=20 / 1) to obtain 5-10 (50 mg, 9% yield) as a pale yellow oily substance.

[0373] LC-MS [M+1] + = 526.3 1 H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 6.4 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 11.8 Hz, 2H), 5.68 (s, 1H), 5.51 (d, J = 3.7 Hz, 1H), 5.26 (d, J = 12.1 Hz, 1H), 5.14 (d, J = 12.0 Hz, 1H), 4.77 (s, 1H), 3.70 (s, 3H), 3.52 (d, J = 11.9 Hz, 1H), 3.10 (d, J = 12.0 Hz, 1H), 2.59 (d, J = 8.5 Hz, 2H), 2.28 - 2.09 (m, 1H), 1.84 (d, J = 14.3 Hz, 1H), 1.47 (s, 9H), 1.18 (s, 9H).

[0374] Step 7.5 Synthesis

[0375] [ka]

[0376] To a solution of 5-10 (50 mg, 0.095 mmol) in DCM (0.5 mL), TFA (0.5 mL) was added at 0°C. After addition, the mixture was stirred at 0°C for 3 hours. The resulting mixture was poured into a mixture of saturated NaHCO3 (2 mL) 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 preparative TLC (DCM / MeOH = 20 / 1) to obtain 5 (10 mg, 22% yield).

[0377] LC-MS [M+1] + = 470.1 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 6.4 Hz, 1H), 7.45 - 7.35 (m, 1H), 7.32 - 7.13 (m, 2H), 5.77 (s, 0.5H), 5.64 (s, 0.5H), 5.42 (s, 1H), 5.23 (dd, J = 12.0, 8.0 Hz, 1H), 5.13 (dd, J = 12.0, 6.4 Hz, 1H), 4.80 (s, 1H), 3.70 (d, J = 4.4 Hz, 3H), 3.55 (dd, J = 26.1, 12.2 Hz, 1H), 3.15 (d, J = 12.2 Hz, 0.5H), 2.95 (d, J = 12.5 Hz, 0.5H), 2.85 (d, J = 10.6 Hz, 0.5H), 2.73 (t, J = 11.4 Hz, 0.5H), 2.65 (d, J = 7.9 Hz, 1H), 2.32 - 2.12 (m, 1H), 1.88 (t, J = 15.8 Hz, 1H), 1.16 (d, J = 3.3 Hz, 9H).

[0378] [Example 6] [ka]

[0379] Step 1: Synthesis of 6-3

[0380] [ka]

[0381] To a mixture of 6-1 (5.00 g, 14.4 mmol) and Et3N (2.3 g, 20.0 mmol) in DCM (50 ml), 6-2 (1.76 g, 18.7 mmol) was gradually added at 20°C. After the addition, the mixture was stirred at 20°C for 0.5 hours. The mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / siRNA = 20 / 1) to obtain 63 (3.60 g, 62% yield) as a colorless oil.

[0382] Step 2: Synthesis of 6-4

[0383] [ka]

[0384] To a solution of 6-3 (3.5 g, 8.6 mmol) in THF (40 mL), Et3N.3HF (4.12 g, 25.9 mmol) was added, and the resulting mixture was stirred at 50°C for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / siRNA = 3 / 1) to obtain 6-4 (2.2 g, 88% yield) as a colorless oil.

[0385] 1 H NMR (400 MHz,CDCl3) δ 4.18 (dd, J = 13.3, 4.3 Hz, 1H), 3.91 (s, 1H), 3.82 (s, 3H), 3.53 (s, 1H), 3.33 (td, J = 11.0, 4.3 Hz, 1H), 2.91 (s, 1H), 2.87 - 2.59 (m, 2H), 2.19 - 2.03 (m, 1H), 1.45 (s, 9H).

[0386] Synthesis in Step 3.6-5

[0387] [ka]

[0388] To a solution of 6-4 (2.2 g, 7.56 mmol) in DCM (20 mL), Dess-Martin periodinane (4.1 g, 9.82 mmol) was added, and the resulting mixture was stirred at 25°C for 10 minutes. After completion, the reaction mixture was poured into a solution of saturated Na2S2O3 / saturated NaHCO3 (40 mL, 1:1). The resulting mixture was extracted with DCM (20 mL x 2). 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 silica gel chromatography (petroleum ether / siRNA = 5 / 1) to obtain 6-5 (1.9 g, 87% yield) as a colorless oil.

[0389] Synthesis in Step 4.6-7

[0390] [ka]

[0391] To a solution of 6-6 (1.0 g, 3.8 mmol) in THF (10 mL), LiHMDS (3.8 mL, 1 M in THF, 3.8 mmol) was added under N2 at -60°C and the mixture was stirred at -60°C for 30 minutes. 6-5 (1.0 g, 3.46 mmol) was added to the resulting mixture at -60°C. After the 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 resulting mixture was extracted with Depositphotos (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 five times, the residues were combined, and purified by silica gel chromatography (petroleum ether / Depositphotos = 20 / 1) to obtain 6-7 (50 mg, 3.7% yield) as a white solid.

[0392] 1 1H NMR (400 MHz, CDCl3) δ 5.74 (s, 2H), 4.36 (s, 1H), 3.98 (s, 1H), 3.92 - 3.78 (s, 3H), 3.77 - 3.48 (m, 1H), 3.21 (s, 1H), 2.24 - 1.88 (m, 2H), 1.59 - 1.38 (m, 18H).

[0393] Synthesis in Steps 5, 6-8

[0394] [ka]

[0395] A 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 solution of saturated NaHCO3 (5 mL), and the resulting mixture was extracted with DCM (2 mL x 2). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum to obtain crude 6-8 (crude, yield >100%) as a pale yellow oily substance.

[0396] LC-MS [M+1] + =288.2

[0397] Synthesis in Steps 6.6-10

[0398] [ka]

[0399] To a solution of 6-8 (crude, 0.0775 mmol) in CH3CN (1 mL), 6-9 (30 mg, 0.0775 mmol) and KHCO3 (31 mg, 0.31 mmol) were added. The resulting mixture was stirred at 40°C for 3 hours and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (petroleum ether / siRNA = 10 / 1) to obtain 6-10 (10 mg, 28% yield) as a colorless oil.

[0400] LC-MS [M+1] + = 470.2 1 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 8.0, 5.3 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.27 (d, J = 4.9 Hz, 2H), 5.71 (s, 1H), 5.61 (d, J = 54.0 Hz, 1H), 4.76 (s, 1H), 3.80 (s, 3H), 3.70 (s, 3H), 3.18 (q, J = 12.6 Hz, 1H), 3.11 - 2.86 (m, 2H), 2.78 - 2.54 (m, 1H), 2.18 (dd, J = 28.3, 12.9 Hz, 1H), 1.95 (dd, J = 22.6, 14.5 Hz, 1H), 1.46 (t, J = 11.9 Hz, 9H).

[0401] Step 7.6 Synthesis

[0402] [ka]

[0403] To a solution of 6-10 (10 mg, 0.032 mmol) in DCM (0.5 mL), TFA (0.5 mL) was added at 0°C. After addition, the mixture was stirred at 0°C for 3 hours. The resulting mixture was poured into a mixture of saturated NaHCO3 (3 mL) 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 preparative TLC (DCM / MeOH = 20 / 1) to obtain 6 (5 mg, 38% yield).

[0404] LC-MS [M+1] + = 414.1 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.40 (s, 1H), 7.27 (s, 2H), 5.70 (d, J = 31.6 Hz, 2H), 4.79 (s, 1H), 3.79 (s, 3H), 3.71 (s, 3H), 3.25 (s, 1H), 3.12 (dd, J = 48.2, 12.7 Hz, 1H), 2.91 (s, 0.5H), 2.84 - 2.56 (m, 1.5H), 2.23 (s, 1H), 1.97 (dd, J = 34.1, 17.2 Hz, 1H).

[0405] [Example 7] [ka]

[0406] Step 1.7-2 Synthesis

[0407] [ka]

[0408] To a solution of 7-1 (2 g, 5.97 mmol) in DCM (20 mL), Dess-Martin periodinane (3.03 g, 7.16 mol) was added, and the resulting mixture was stirred at 25°C for 1 hour. After completion, the reaction mixture was poured into a solution of saturated Na2S2O3 / saturated NaHCO3 (40 mL, 1:1). The resulting mixture was extracted with DCM (20 mL x 2). 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 silica gel chromatography (petroleum ether / siRNA = 5 / 1) to obtain 7-2 (1.3 g, 65% yield) as a pale yellow oily substance.

[0409] 1H NMR (400 MHz, cdcl3) δ 7.95 (d, J = 7.3 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 4.49 - 4.29 (m, 2H), 4.05 (d, J = 17.6 Hz, 2H), 3.48 (s, 1H), 2.58 - 2.33 (m, 1H), 2.25-2.11(m, 1H), 1.57 - 1.44 (s, 9H).

[0410] Synthesis in Step 2.7-4

[0411] [ka]

[0412] To a solution of 7-3 (1.1 g, 4.3 mmol) in THF (15 mL), LiHMDS (4.3 mL, 1 M in THF, 4.3 mmol) was added under N2 at -60°C, and the resulting mixture was stirred at -60°C for 30 minutes. 7-2 (1.3 g, 3.9 mmol) was added dropwise to the above mixture at -60°C. After the addition, the reaction mixture was stirred at 0-10°C for 1 hour. Next, the reaction mixture was poured into a saturated NH4Cl (30 mL) solution, and the resulting mixture was extracted with HCl (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 / HCl = 20 / 1) to obtain 7-4 (65 mg, 3.8% yield) as a white solid.

[0413] 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.4 Hz, 2H), 7.59 (d, J = 6.6 Hz, 1H), 7.47 (t, J = 7.1 Hz, 2H), 5.99 (s, 1H), 5.79 (s, 1H), 4.55 - 4.35 (m, 1H), 4.20 - 3.91 (m, 1H), 3.83 - 3.64 (m, 1H), 3.35 - 3.12(m, 1H), 2.17 (s, 1H), 2.03 (d, J = 14.0 Hz, 1H), 1.62 - 1.36 (m, 18H).

[0414] Step 3.7-5 Synthesis

[0415] [ka]

[0416] A 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 solution of saturated NaHCO3 (4 mL), and the resulting mixture was extracted with DCM (2 mL x 2). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum to obtain crude 7-5 (50 mg, yield >100%) as a pale yellow oil.

[0417] Step 4.7-7 Synthesis

[0418] [ka]

[0419] To a solution of 7-5 (crude, 0.138 mmol) in CH3CN (2 mL), 7-6 (53 mg, 0.138 mmol) and KHCO3 (55 mg, 0.552 mmol) were added. The resulting mixture was stirred at 40°C for 3 hours. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / Â=10 / 1) to obtain 7-7 (20 mg, 28% yield) as a white solid.

[0420] LC-MS [M+1] + = 516.3

[0421] Step 5.7 Synthesis

[0422] [ka]

[0423] To a solution of 7-7 (20 mg, 0.039 mmol) in DCM (1 mL), TFA (1 mL) was added at 0°C. After addition, the mixture was stirred at 0°C for 3 hours. The resulting mixture was poured into a mixture of saturated NaHCO3 (4 mL) 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 preparative TLC (DCM / MeOH = 20 / 1) to obtain 7 (10 mg, 45% yield).

[0424] LC-MS [M+1] + = 460.1 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.2 Hz, 2H), 7.58 (dd, J = 7.3, 2.1 Hz, 1H), 7.51 (dd, J = 8.9, 5.9 Hz, 1H), 7.42 - 7.35 (m, 3H), 7.29 - 7.25 (m, 2H), 6.01 (s, 1H), 5.75 (s, 0.5H), 5.64 (s, 0.5H), 4.77 (d, J = 4.5 Hz, 1H), 3.70 (d, J = 4.2 Hz, 3H), 3.28 (d, J = 12.8 Hz, 1H), 3.12 (dd, J = 34.1, 12.4 Hz, 1H), 2.93 (d, J = 12.3 Hz, 1H), 2.73 (d, J = 9.2 Hz, 0.5H), 2.68 - 2.57 (m, 1H), 2.33 - 2.14 (m, 0.5H), 1.88 (t, J = 17.4 Hz, 1H).

[0425] [Example 8]

change

[0426] Synthesis of ステップ1:8-3

[0427]

change

[0428] To a solution of 8-1 (5.00 g, 14.4 mmol) in THF (50 mL), NaH (0.688 g, 17.2 mmol, 60%, dispersed in liquid paraffin) was gradually added at 0°C. After addition, the mixture was stirred at 0°C for 1 hour. 8-2 (1.86 g, 17.2 mmol) was added at 0°C and stirred at 0°C for 0.5 hours. The reaction mixture was poured into a solution of saturated NH4Cl (100 mL), 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 / siRNA = 10 / 1) to obtain 8-3 (3.9 g, 65% yield) as a colorless oil.

[0429] 1 H NMR (400 MHz, CDCl3) δ 3.88 - 3.66 (m, 1H), 3.64 - 3.42 (m, 3H), 3.18 (d, J = 33.4 Hz, 1H), 3.15 - 3.02 (m, 1H), 3.03 - 2.90 (m, 6H), 2.28 - 2.13 (m, 1H), 1.99 (d, J = 9.4 Hz, 1H), 1.41 (d, J = 14.9 Hz, 9H), 0.91 - 0.77 (m, 9H), 0.14 - 0.02 (m, 6H). LC-MS [M+1-100] + = 319.2

[0430] Step 2: Synthesis of 8-4

[0431] [ka]

[0432] To a solution of 8-3 (3.9 g, 9.3 mmol) in THF (40 mL), Et3N.3HF (4.5 g, 28.0 mmol) was added, and the resulting mixture was stirred at 50°C for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / siRNA = 3 / 1) to obtain 8-4 (2.4 g, 85% yield) as a white solid.

[0433] 1 H NMR (400 MHz, CDCl3) δ 4.29 (dd, J = 8.2, 5.2 Hz, 1H), 4.10 (m, 1H), 3.50 - 3.31 (m, 2H), 2.99 (s, 6H), 2.75 (s, 1H), 2.64 (dd, J = 13.2, 9.7 Hz, 1H), 1.96 (ddd, J = 13.2, 6.6, 2.9 Hz, 1H), 1.67 - 1.54 (m, 1H), 1.46 - 1.37 (s, 9H). LC-MS [M+1-100] + = 205.1

[0434] Synthesis in Step 3.8-5

[0435] [ka]

[0436] Dess-Martin periodinane (8.3 g, 19.7 mmol) was added to a solution of 8-4 (2.4 g, 7.9 mmol) in DCM (30 mL), and the resulting mixture was stirred at 25°C for 3 hours. After completion, the reaction mixture was poured into a solution of saturated Na2S2O3 / saturated NaHCO3 (40 mL, 1:1). The resulting mixture was extracted with DCM (20 mL x 2). 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 silica gel chromatography (petroleum ether / siRNA=5 / 1) to obtain 8-5 (1.6 g, 67% yield) as a white solid.

[0437] LC-MS [M+1-56] + = 247.1

[0438] Synthesis in Step 4.8-7

[0439] [ka]

[0440] To a solution of 8-6 (1.5 g, 5.8 mmol) in THF (20 mL), LiHMDS (5.8 mL, 1 M in THF, 5.8 mmol) was added under N2 at -60°C and the mixture was stirred at -60°C for 30 minutes. 8-5 (1.6 g, 5.3 mmol) was added dropwise to the resulting mixture at -60°C. After the 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 resulting mixture was extracted with Depositphotos (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 five times, the residues were combined, and purified by silica gel chromatography (petroleum ether / Depositphotos = 20 / 1) to obtain 8-7 (100 mg, 4.7% yield) as a white solid.

[0441] LC-MS [M+Na] + = 423.3 1 H NMR (400 MHz, CDCl3) δ 5.90 (s, 1H), 5.18 (d, J = 14.0 Hz, 1H), 4.41 (s, 1H), 4.19 (d, J = 16.1 Hz, 1H), 3.77 (s, 1H), 3.33 (s, 1H), 2.98 (s, 6H), 2.13 (s, 1H), 2.01 - 1.80 (m, 1H), 1.44 (d, J = 10.3 Hz, 18H).

[0442] Synthesis of Step 5.8-8

[0443] [ka]

[0444] A 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 solution of saturated NaHCO3 (2 mL), and the resulting mixture was extracted with DCM (2 mL x 2). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum to obtain crude 8-8 (crude, yield >100%) as a pale yellow oily substance.

[0445] LC-MS [M+1] + = 301.1

[0446] Synthesis in Steps 6.8-10

[0447] [ka]

[0448] To a solution of 8-8 (crude, 0.125 mmol) in CH3CN (1 mL), 8-9 (38.1 mg, 0.100 mmol) and KHCO3 (50 mg, 0.500 mmol) were added. The resulting mixture was stirred at 40°C for 3 hours and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (petroleum ether / Â=10 / 1) to obtain 8-10 (10 mg, 16% yield) as a pale yellow solid.

[0449] LC-MS [M+1] + = 483.2 1H NMR (400 MHz, CDCl3) δ 7.63 - 7.55 (m, 1H), 7.40 - 7.32 (m, 1H), 7.29 - 7.18 (m, 2H), 5.63 (s, 1.5H), 5.49 (s, 0.5H), 4.73 (d, J = 5.0 Hz, 1H), 3.69 (d, J = 1.1 Hz, 3H), 3.29 - 3.08 (m, 1H), 3.07 - 2.98 (m, 1H), 2.93 (d, J = 19.1 Hz, 6H), 2.89 (d, J = 11.8 Hz, 0.5H), 2.76 (td, J = 12.0, 2.5 Hz, 0.5H), 2.70 - 2.57 (m, 1H), 2.29 - 2.04 (m, 1H), 2.04 - 1.83 (m, 1H), 1.50 - 1.41 (m, 9H).

[0450] Step 7.8 Synthesis

[0451] [ka]

[0452] To a solution of 8-10 (10 mg, 0.021 mmol) in DCM (0.5 mL), TFA (0.5 mL) was added at 0°C. After addition, the mixture was stirred at 0°C for 3 hours. The resulting mixture was poured into a solution of saturated NaHCO3 (3 mL) 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 preparative TLC (DCM / MeOH = 20 / 1) to obtain 8 (4 mg, yield 45%).

[0453] LC-MS [M+1] + = 427.1 1H NMR (400 MHz, CDCl3) δ 7.64 - 7.52 (m,1H), 7.41 - 7.35 (m, 1H), 7.32 - 7.18 (m, 2H), 5.71 (d, J = 39.7 Hz, 1H), 5.42 - 5.31 (m, 1H), δ 4.76 (d, J = 2.6 Hz, 1H).3.69 (d, J = 5.0 Hz, 3H), 3.36 (d, J = 12.1 Hz, 0.5H), 3.27 (d, J = 12.2 Hz, 0.5H), 3.18 (d, J = 12.1 Hz, 0.5H), 2.98 (s, 6H), 2.89 (d, J = 11.7 Hz, 0.5H), 2.79 - 2.62 (m, 2H), 2.33 - 2.11 (m, 1H), 1.91 (t, J = 15.9 Hz, 1H).

[0454] [Example 9] [ka]

[0455] Step 1: Synthesis of 9-2

[0456] [ka]

[0457] To the compound 9-SM (11.0 g, 85.3 mmol), dimethylamine (1.76 g, 18.7 mmol) was gradually added at 20°C. After the addition, the mixture was stirred at 20°C for 0.5 hours. The mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / dimethyl = 20 / 1) to obtain 9-2 (7.8 g, yield 69%) as a colorless oil.

[0458] Step 2: Synthesis of 9-3

[0459] [ka]

[0460] To a solution of 9-1 (5.00 g, 14.4 mmol) in THF (50 mL), NaH (0.700 g, 17.3 mmol) was gradually added at 0°C, and the mixture was stirred at 0°C for 1 hour after the addition. 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 solution of saturated NH4Cl (100 mL), 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 / siRNA = 10 / 1) to obtain 9-3 (4.8 g, yield 65%) as a colorless oil.

[0461] 1 H NMR (400 MHz, CDCl3) δ 5.25 (s, 2H), 3.90 (d, J = 3.6 Hz, 1H), 3.75 (s, 1H), 3.48 (s, 1H), 3.09 - 2.94 (m, 2H), 2.94 - 2.79 (m, 8H), 2.19 - 2.06 (m, 1H), 1.43 (d, J = 2.0 Hz, 9H), 0.97 - 0.73 (m, 9H), 0.14 - 0.02 (m, 6H).

[0462] Step 3: Synthesis of 9-4

[0463] [ka]

[0464] To a solution of 9-3 (4.7 g, 10.5 mmol) in THF (50 mL), Et3N.3HF (5.0 g, 31.5 mmol) was added, and the resulting mixture was stirred at 50°C for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / Â=3 / 1) to obtain 9-4 (3.2 g, yield 91%) as a colorless oil.

[0465] 1H NMR (400 MHz, CDCl3) δ 5.34 (d, J = 12.1 Hz, 1H), 5.18 (d, J = 12.1 Hz, 1H), 4.25 (d, J = 10.8 Hz, 1H), 4.10 - 3.70 (m, 1H), 3.42 (s, 1H), 3.10 (s, 1H), 2.90 (d, J = 7.7 Hz, 6H),2.86 - 2.68 (m, 2H), 2.66 (dd, J = 13.1, 9.7 Hz, 1H), 2.08 - 1.92 (m, 1H), 1.47 - 1.35 (m, 9H).

[0466] Synthesis in Step 4.9-5

[0467] [ka]

[0468] To a solution of 9-4 (3.0 g, 8.98 mmol) in DCM (30 mL), Dess-Martin periodinane (5.7 g, 13.47 mmol) was added, and the resulting mixture was stirred at 25°C for 10 minutes. After completion, the reaction mixture was poured into a solution of saturated Na2S2O3 / saturated NaHCO3 (100 mL, 1:1). The resulting mixture was 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 reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / siRNA = 5 / 1) to obtain 9-5 (2.2 g, yield 74%) as a pale orange oily substance.

[0469] 1H NMR (400 MHz, CDCl3) δ 5.22 (d, J = 12.1 Hz, 1H), 5.12 (d, J = 12.1 Hz, 1H), 4.24 (d, J = 17.5 Hz, 1H), δ 4.16 - 4.06 (m, 1H), 3.72 (t, J = 5.3 Hz, 2H), 3.48 (ddd, J = 13.7, 9.5, 4.1 Hz, 1H), 2.90 (d, J = 10.3 Hz, 6H), 2.34 (dd, J = 9.5, 5.0 Hz, 1H), 2.15 - 1.96 (m, 1H), 1.44 (s, 9H).

[0470] Synthesis in Step 5.9-7

[0471] [ka]

[0472] To a solution of 9-6 (1.7 g, 6.6 mmol) in THF (20 mL), LiHMDS (6.6 mL, 1 M in THF, 6.6 mmol) was added under N2 at -60°C and the mixture was stirred at -60°C for 30 minutes. 9-5 (2.0 g, 6.0 mmol) was added dropwise to the resulting mixture at -60°C. After the 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 resulting mixture was extracted with Depositphotos (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 five times, the residues were combined, and purified by silica gel chromatography (petroleum ether / Depositphotos = 20 / 1) to obtain 9-7 (1.0 g, 28.8% yield) as a yellow oily substance.

[0473] 1H NMR (400 MHz, CDCl3)δ 5.72 (s, 1H), 5.51 (s, 1H), 5.29 (s, 0.5H), 5.26 (s, 0.5H), 5.07 (d, J = 12.0 Hz, 1H), 4.40 - 4.04 (m, 1H), 3.97 (d, J = 20.3 Hz, 2H), 3.15 (s, 1H), 2.88 (d, J = 5.3 Hz, 6H), 2.03 (dd, J = 16.7, 10.0 Hz, 1H), 1.86 (d, J = 13.9 Hz, 1H), 1.45 (dd, J = 12.1, 5.8 Hz, 18H).

[0474] Synthesis of Steps 6.9-8

[0475] [ka]

[0476] 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 solution of saturated NaHCO3 (30 mL), and the resulting mixture was extracted with DCM (10 mL x 2). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated and purified over silica gel (DCM / MeOH = 20 / 1) to obtain 9-8 (185 mg, 31% yield) as a colorless oil.

[0477] LC-MS [M+1] + = 331.2

[0478] Synthesis in Steps 7.9-10

[0479] [ka]

[0480] To a solution of 9-8 (185 mg, 0.56 mmol) in CH3CN (2 mL), 9-9 (194 mg, 0.50 mmol) and KHCO3 (224 mg, 2.24 mmol) were added. The resulting mixture was stirred at 40°C for 3 hours and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified with preparative TCL (petroleum ether / siRNA = 10 / 1) to obtain 9-10 (200 mg, 69.8% yield) as a colorless oil.

[0481] LC-MS [M+1] + = 513.2 1 H NMR (CDCl3(400 MHz, )δ 7.61 - 7.57 (m, 1H), 7.37 (m, 1H), 7.28 - 7.22 (m, 2H), 5.68 (s, 0.5H), 5.51 (s, 0.5H), 5.48 (t, J = 4.4 Hz, 1H), 5.28 - 5.21 (m, 1H), 5.06 (dd, J = 12.0, 7.8 Hz, 1H), 4.75 (s, 1H), 3.68 (d, J = 3.8 Hz, 3H), 3.53 - 3.47 (m, 0.5H), 3.40 (d, J = 11.4 Hz, 0.5H), 3.08 (d, J = 12.1 Hz, 0.5H), 2.92 - 2.79 (m, 6.5H), 2.71 (dt, J = 11.9, 6.0 Hz, 1H), 2.59 (dd, J = 10.2, 2.5 Hz, 1H), 2.29 - 2.11 (m, 1H), 1.89 (dd, J = 14.3, 2.2 Hz, 1H), 1.43 (d, J = 6.6 Hz, 9H).

[0482] Synthesis in Step 8.9

[0483] [ka]

[0484] To a solution of 9-10 (200 mg, 0.39 mmol) in DCM (3 mL), TFA (3 mL) was added at 0°C. After addition, the mixture was stirred at 0°C for 3 hours. The resulting mixture was poured into a mixture of saturated NaHCO3 (15 mL) 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 obtain 9 (50 mg, 28% yield) as a white solid.

[0485] LC-MS [M+1] + = 457.2 1 H NMR (CDCl3(400 MHz, ) δ 7.61 - 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, 7.2 Hz, 1H), 4.79 (d, J = 2.7 Hz, 1H), 3.69 (dd, J = 4.7, 2.6 Hz, 3H), 3.57 (d, J = 11.8 Hz, 0.5H), 3.49 (d, J = 12.1 Hz, 0.5H), 3.15 (d, J = 12.4 Hz, 0.5H), 2.93 (d, J = 12.4 Hz, 0.5H), 2.90 - 2.80 (m, 6H), 2.72 (m, 1H), 2.64 (d, J = 7.1 Hz, 1H), 2.19 (m, 1H), 1.96 - 1.82 (m, 1H).

[0486] [Example 10] Biochemical assay Assay 1: Pharmacokinetics in rats Pharmacokinetic experiments were conducted using male Sprague-Dawley rats.

[0487] The test compounds (clopidogrel and exemplary compounds provided herein) were administered orally or intravenously to rats under fasting conditions. Blood samples were collected via the jugular vein at 5, 15, 30, 60, and 120 minutes, along with EDTA-K2 (anticoagulant), 3'-methoxyphenacyl bromide (MPBr, derivatization reagent), and phenylmethylsulfonyl fluoride (PMSF, stabilizer). Plasma samples were then collected by centrifugation at 1500 g for 10 minutes at 2–8°C and stored at -80°C after separation. Plasma samples were loaded into LC-MS / MS equipment after extraction to determine the concentrations of thiol-active metabolites. The concentration results in rat plasma are shown in Figures 1 and 2.

[0488] As shown in Figure 1, at a dose level of 10 mg / kg, compounds 1a, 1b, and 2a provided herein reached peak concentrations of the thiol-active metabolite in less than 20 minutes after administration, compared to clopidogrel, which reached peak concentrations of the thiol-active metabolite in approximately 30 minutes after administration. Furthermore, the peak concentrations of the thiol-active metabolite for compounds 1a, 1b, and 2a were significantly higher than those for clopidogrel. These results indicate that compounds 1a, 1b, and 2a provide faster and more efficient release of the active metabolite than clopidogrel.

[0489] As shown in Figure 2, when administered orally, compound 3 provided herein reached the peak concentration of the thiol active metabolite approximately 20 minutes after administration at a dose level of 2 mg / kg, compared to clopidogrel at a higher dose level of 10 mg / kg, which reached the peak concentration approximately 30 minutes after administration. When administered intravenously, compound 3 provided herein reached the peak concentration of the thiol active metabolite approximately 6 minutes after administration at a dose level of only 1 mg / kg. These results demonstrate that compound 3 provides a faster and more efficient release of the active metabolite than clopidogrel.

[0490] Other compounds provided herein exhibit release of active metabolites that are comparable to, or even faster than, clopidogrel, and more efficient.

[0491] Assay 2: Anti-aggregation activity in rats Male Sprague-Dawley rats were used for ex vivo platelet aggregation experiments. After oral administration of clopidogrel (an exemplary compound provided herein) and vehicle (control) to the rats, blood was collected via the jugular vein at 0.5 hours, 1 hour, and 2 hours using a 3.8% (w / v) sodium citrate solution as an anticoagulant (1 / 9 volume of whole blood). The blood samples with citrate were centrifuged at a low speed of 1000 rpm for 5 minutes to obtain platelet-rich plasma (PRP). After separation of PRP, the remaining blood was further centrifuged at a high speed of 3000 rpm for 10 minutes to obtain platelet-poor plasma (PPP). The number of platelets in PRP was measured using a blood analyzer (Siemens, ADVIA2120), with 4 × 10⁶ platelets in PPP. 8 The volume was adjusted to / mL.

[0492] Platelet aggregation was determined using a turbidimetric aggregation method with an automated platelet aggregation detector (PRECIL LBY-NJ4). The aggregation detector was preheated to 37°C, a PRP (290 μL) sample was added to the cuvette, and the detector was set up in the automated platelet aggregation detector. After a 5-minute pre-incubation, the aggregation detector was calibrated using PPP to show 100% aggregation and then calibrated using PRP to show 0% aggregation. Finally, a volume of 10 μL of ADP solution (final concentration 10 μM) was added to the PRP sample for initial platelet aggregation. Platelet aggregation was monitored for 5 minutes, and the maximum platelet aggregation (%) was reported within the period. The anti-aggregating effect of the test compound was: Inhibition (%) = (Maximum platelet aggregation of control (%) - Maximum platelet aggregation of test compound (%)) / (Maximum platelet aggregation of control (%)) × 100 This was expressed as an inhibition (%) determined by the relationship.

[0493] The inhibition (%) results for the test 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 reached maximum inhibition of platelet aggregation at approximately 45% at approximately 120 minutes after administration, while compound 1b showed maximum inhibition at approximately 45% at approximately 60 minutes after administration at a much lower dose level than clopidogrel, demonstrating a much faster onset of action and much higher potency than clopidogrel.

[0494] Other compounds provided herein may exhibit a faster onset of action and higher potency than clopidogrel.

[0495] The above description is intended only as an example of the principles of this disclosure. Furthermore, since countless modifications and variations are readily apparent to those skilled in the art, this is not intended to limit the invention to the precise configurations and processes described above. Accordingly, all suitable modifications and equivalents may be considered to fall within the scope of the invention as defined by the following claims.

Claims

【Request Item 1】 【Chemistry 1】 A compound having the formula or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 2, which is formulated for oral or injectable administration.

4. A pharmaceutical composition according to claim 2 or 3, to be used in a method for treating a vascular disease in a subject requiring the same, the method comprising administering to the subject the pharmaceutical composition comprising an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition according to claim 4, wherein the vascular disease is selected from atherothrombosis, ischemia, stroke, cerebral thrombosis, arterial thrombosis, thrombotic cerebrovascular disease, cardiovascular disease, and blood clots.

6. A pharmaceutical composition according to claim 2 or 3, used in a method for inhibiting platelet aggregation in a subject requiring such inhibition, the method comprising administering to the subject the pharmaceutical composition comprising an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 【Request Item 7】 【Chemistry 2】 or 【Transformation 3】 A compound having the formula.

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