Novel spiro compound as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a novel spiro compound as well as a pharmaceutical composition and application thereof, the novel spiro compound is shown as a formula (I), and the definition of each substituent is shown in the specification. The compound can be used for preparing medicines for preventing or treating head pain diseases.

Description

Technical Field

[0001] This invention relates to, but is not limited to, the field of pharmaceutical chemistry, and particularly to a novel spirocyclic compound, tautomer, stereoisomer, prodrug, pharmaceutically acceptable salt thereof, pharmaceutical composition thereof, and uses. Background Technology

[0002] Migraine is a recurrent chronic neurological disorder whose pathogenesis is not fully understood. It manifests as reversible neurological and systemic symptoms, lasting 4–72 hours, mostly in moderate to severe attacks, affecting any part of the head. It is typically unilateral and throbbing, and can be exacerbated by daily activities. It is often accompanied by nausea and / or vomiting. Some patients also experience non-headache symptoms such as photophobia, phonophobia, anxiety, and depression. The peak incidence is between 25 and 55 years of age, with women being more frequently affected than men. The World Health Organization lists migraine as the third most common disease and the second leading cause of neurological disability worldwide, ranking third in the global disease burden. Due to its high incidence, recurrence rate, and disabling effect, migraine severely impacts patients' quality of life and places a heavy burden on families and society.

[0003] With the deepening of research on migraines, calcitonin gene-related peptide (CGRP) has been found to play an important role in the pathogenesis of migraines. CGRP has functions such as vasodilation, promoting inflammation, regulating neuronal sensitization, and enhancing somatic pain. Its receptor is located in almost all sites potentially involved in migraine pathogenesis; therefore, further exploration of this target could lead to the development of more effective drugs in the field of migraine treatment. Summary of the Invention

[0004] The inventors have developed a novel spirocyclic compound that has the potential to be developed into a drug for treating headaches.

[0005] In one aspect, this invention provides a novel spirocyclic compound, tautomer, stereoisomer, prodrug, and pharmaceutically acceptable salt thereof as shown in (I):

[0006]

[0007] In formula (I),

[0008] W represents O or S;

[0009] R1, R2, and R3 are independently selected from hydrogen, deuterium, halogen, and cyano groups, respectively;

[0010] R 4a R 4b R 5a and R 5b They are selected independently from hydrogen and deuterium, respectively;

[0011] R6 and R7 are independently selected from hydrogen and deuterium, respectively;

[0012] R8 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Carbon cyclo group; among which,

[0013] The above C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The carbocyclic group may be independently replaced by one or more of the following groups: deuterium, halogen, hydroxyl, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto, mercaptomethyl, mercaptoethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl;

[0014] R 9a R 9b R 9c They are selected independently from hydrogen and deuterium, respectively;

[0015] R 10a and R 10b They are selected independently from hydrogen and deuterium, respectively;

[0016] R 11 R 12 R 13 R 14 and R 15 Each element is independently selected from hydrogen, deuterium, and halogens;

[0017] G1 and G2 independently select hydrogen,

[0018] in,

[0019] The above R a1 and R a2 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkylamine group, or R a1 R a2 Connect them in a loop in any reasonable way;

[0020] R b Selected from hydrogen, C 1-6 Alkyl, C 3-10 carbon cyclo group, C 2-8 Heterocyclic group, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-15 Aromatic ring group, C 3-10 Heterocyclic aryl; the above-mentioned C 1-6 Alkyl, C1-6 alkylamine group, C 3-10 carbon cyclo group, C 2-8 Heterocyclic group, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-15 Aromatic ring group, C 3-10 The heterocyclic aryl group may optionally be substituted with one or more of the following groups: deuterium, halogen, hydroxyl, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto, mercaptomethyl, mercaptoethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl, C 1-6 Alkoxy, C 1-6 Alkylamine group;

[0021] R c Selected from hydrogen, C 1-6 Alkyl, C 1-6 alkylamine group, C 3-10 carbon cyclo group, C 2-8 Heterocyclic groups; the above-mentioned C 1-6 Alkyl, C 1-6 alkylamine group, C 3-10 carbon cyclo group, C 2-8 The heterocyclic group may optionally be replaced by one or more of the following groups: deuterium, halogen, hydroxyl, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto, mercaptomethyl, mercaptoethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl;

[0022] R d1 and R d2 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, or R d1 R d2 Connect them in a loop in any reasonable way;

[0023] R e1 and R e2 Each is independently selected from hydrogen, metal ions, and C. 1-6 Alkyl, C 1-6 alkylamine group, C 3-10 carbon cyclo group, C 2-8 Heterocyclic group, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-15 Aromatic ring group, C 3-10 Heterocyclic aryl, or R e1 R e2 Connected in any reasonable way to form a loop; the above C 1-6 Alkyl, C 1-6alkylamine group, C 3-10 carbon cyclo group, C 2-8 Heterocyclic group, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-15 Aromatic ring group, C 3-10 The heterocyclic aryl group may optionally be substituted by one or more of the following groups: deuterium, halogen, hydroxyl, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto, mercaptomethyl, mercaptoethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl;

[0024] In particular,

[0025] When G1 and G2 are both hydrogen, and R8 is not substituted with deuterium, then R1, R2, R3, R 4a R 4b R 5a R 5b R6, R7, R 9a R 9b R 9c R 10a R 10b R 11 R 12 R 13 R 14 and R 15 One of them must be deuterium; or,

[0026] When G1 is not hydrogen, G2 is hydrogen, and R8 is not replaced by deuterium, and R... 11 R 12 and R 15 When all are halogens, then R1, R2, R3, R 4a R 4b R 5a R 5b R6, R7, R 9a R 9b R 9c R 10a R 10b R 13 and R 14 One of them must be deuterium.

[0027] In some implementations, W in the above formula (I) is O or S, preferably W is O.

[0028] In some embodiments, in the above formula (I), R1 is selected from hydrogen, deuterium, halogen and cyano, preferably, R1 is hydrogen and deuterium.

[0029] In some embodiments, in formula (I) above, R2 is selected from hydrogen, deuterium, halogen and cyano, preferably, R2 is hydrogen and deuterium.

[0030] In some embodiments, in formula (I) above, R3 is selected from hydrogen, deuterium, halogen and cyano, preferably, R3 is hydrogen and deuterium.

[0031] In some implementations, in equation (I) above, R 4a Selected from hydrogen and deuterium.

[0032] In some implementations, in equation (I) above, R 4b Selected from hydrogen and deuterium.

[0033] In some implementations, in equation (I) above, R 5a Selected from hydrogen and deuterium.

[0034] In some implementations, in equation (I) above, R 5b Selected from hydrogen and deuterium.

[0035] In some implementations, R6 in formula (I) above is selected from hydrogen and deuterium.

[0036] In some implementations, R7 in formula (I) above is selected from hydrogen and deuterium.

[0037] In some implementations, in formula (I) above, R8 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Carbocyclic group, preferably, R8 is selected from C 1-6 Alkyl; wherein,

[0038] The above C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The carbocyclic group may be independently substituted by one or more of the following groups: deuterium, halogen, hydroxyl, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto, mercaptomethyl, mercaptoethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl. Preferably, the alkyl group may be independently substituted by one or more of deuterium and halogen. More preferably, the alkyl group may be independently substituted by one or more of deuterium and F.

[0039] In some implementations, in equation (I) above, R 9a Selected from hydrogen and deuterium.

[0040] In some implementations, in equation (I) above, R 9b Selected from hydrogen and deuterium.

[0041] In some implementations, in equation (I) above, R 9c Selected from hydrogen and deuterium.

[0042] In some implementations, in equation (I) above, R 10a Selected from hydrogen and deuterium.

[0043] In some implementations, in equation (I) above, R 10b Selected from hydrogen and deuterium.

[0044] In some implementations, in equation (I) above, R 11 Selected from hydrogen, deuterium, and halogens.

[0045] In some implementations, in equation (I) above, R 12 Selected from hydrogen, deuterium, and halogens.

[0046] In some implementations, in equation (I) above, R 13 Selected from hydrogen, deuterium, and halogens.

[0047] In some implementations, in equation (I) above, R 14 Selected from hydrogen, deuterium, and halogens.

[0048] In some implementations, in equation (I) above, R 15 Selected from hydrogen, deuterium, and halogens.

[0049] In some implementations, in formula (I) above, G1 is selected from hydrogen, in,

[0050] The above R a1 and R a2 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, or R a1 R a2 Connected in a loop in any reasonable manner, preferably R a1 and R a2 All are hydrogen, or R a1 and R a2 One is hydrogen and the other is methyl;

[0051] R b Selected from hydrogen, C 1-6 Alkyl, C 3-10 carbon cyclo group, C 2-8 Heterocyclic group, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-15 Aromatic ring group, C 3-10 Heterocyclic aryl, preferably, R b Selected from C 1-6 Alkyl; wherein,

[0052] The above C 1-6Alkyl, C 3-10 carbon cyclo group, C 2-8 Heterocyclic group, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-15 Aromatic ring group, C 3-10 The heterocyclic aryl group may optionally be substituted with one or more of the following groups: deuterium, halogen, hydroxyl, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto, mercaptomethyl, mercaptoethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl, C 1-6 Alkoxy, C 1-6 Alkylamine substitution, preferably, the alkyl group may optionally be replaced by one or more deuterium groups;

[0053] R c Selected from hydrogen, C 1-6 Alkyl, C 1-6 alkylamine group, C 3-10 carbon cyclo group, C 2-8 Heterocyclic group, preferably, R c Selected from C 1-6 Alkyl; wherein,

[0054] The above C 1-6 Alkyl, C 1-6 alkylamine group, C 3-10 carbon cyclo group, C 2-8 The heterocyclic group may optionally be substituted with one or more of the following groups: deuterium, halogen, hydroxyl, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto, mercaptomethyl, mercaptoethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl, preferably.

[0055] The alkyl group described above may optionally be substituted with one or more deuterium groups;

[0056] R d1 and R d2 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkylamine group, or R d1 R d2 Preferably connected in a ring in any reasonable manner, R a1 and R a2 All are hydrogen, or R a1 and R a2 One is hydrogen and the other is methyl;

[0057] R e1 and R e2 Each is independently selected from hydrogen, metal ions, and C. 1-6 Alkyl, C1-6 alkylamine group, C 3-10 carbon cyclo group, C 2-8 Heterocyclic group, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-15 Aromatic rings and C 3-10 Heterocyclic aryl, or R e1 R e2 Connected in a loop in any reasonable manner, preferably, R e1 and R e2 Each is independently selected from hydrogen, metal ions, and C. 1-6 Alkyl; wherein,

[0058] The above C 1-6 Alkyl, C 1-6 alkylamine group, C 3-10 carbon cyclo group, C 2-8 Heterocyclic group, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-15 Aromatic rings and C 3-10 The heterocyclic aryl group may optionally be substituted by one or more of the following groups: deuterium, halogen, hydroxyl, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto, mercaptomethyl, mercaptoethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl.

[0059] In some implementations, in formula (I) above, G2 is selected from hydrogen, Preferably, G2 is hydrogen; wherein,

[0060] The above R a1 and R a2 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkylamine group, or R a1 R a2 Connected in a loop in any reasonable manner, preferably R a1 and R a2 All are hydrogen, or R a1 and R a2 One is hydrogen and the other is methyl;

[0061] R b Selected from hydrogen, C 1-6 Alkyl, C 3-10 carbon cyclo group, C 2-8 Heterocyclic group, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-15 Aromatic rings and C 3-10Heterocyclic aryl, preferably, R b Selected from C 1-6 Alkyl; wherein,

[0062] The above C 1-6 Alkyl, C 3-10 carbon cyclo group, C 2-8 Heterocyclic group, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-15 Aromatic rings and C 3-10 The heterocyclic aryl group may optionally be substituted with one or more of the following groups: deuterium, halogen, hydroxyl, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto, mercaptomethyl, mercaptoethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl, C 1-6 Alkoxy, C 1-6 Alkylamine group, preferably, the above-mentioned alkyl group may optionally be substituted with one or more deuterium groups;

[0063] R c Selected from hydrogen, C 1-6 Alkyl, C 1-6 alkylamine group, C 3-10 Carbocyclic group and C 2-8 Heterocyclic group, preferably, R c Selected from C 1-6 Alkyl; wherein,

[0064] The above C 1-6 Alkyl, C 1-6 alkylamine group, C 3-10 Carbocyclic group and C 2-8 The heterocyclic group may optionally be substituted with one or more of the following groups: deuterium, halogen, hydroxyl, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto, mercaptomethyl, mercaptoethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl; preferably, the alkyl group may optionally be substituted with one or more deuterium groups.

[0065] R d1 and R d2 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkylamine group, or R d1 R d2 Connected in a loop in any reasonable manner, preferably R a1 and R a2 All are hydrogen, or R a1 and R a2 One is hydrogen and the other is methyl;

[0066] R e1 and R e2 Each is independently selected from hydrogen, metal ions, and C. 1-6 Alkyl, C 1-6 alkylamine group, C 3-10 carbon cyclo group, C 2-8 Heterocyclic group, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-15 Aromatic ring group, C 3-10 Heterocyclic aryl, or R e1 R e2 Connected in a loop in any reasonable manner, preferably, R e1 and R e2 Each is independently selected from hydrogen, metal ions, and C. 1-6 Alkyl, more preferably,; wherein,

[0067] The above C 1-6 Alkyl, C 1-6 alkylamine group, C 3-10 carbon cyclo group, C 2-8 Heterocyclic group, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-15 Aromatic ring group, C 3-10 The heterocyclic aryl group may optionally be substituted by one or more of the following groups: deuterium, halogen, hydroxyl, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto, mercaptomethyl, mercaptoethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl.

[0068] In particular,

[0069] When G1 and G2 are both hydrogen, and R8 is not substituted with deuterium, then R1, R2, R3, R 4a R 4b R 5a R 5b R6, R7, R 9a R 9b R 9c R 10a R 10b R 11 R 12 R 13 R 14 and R 15 One of them must be deuterium; or,

[0070] When G1 is not hydrogen, G2 is hydrogen, and R8 is not replaced by deuterium, and R... 11 R 12 and R 15 When all are halogens, then R1, R2, R3, R4a R 4b R 5a R 5b R6, R7, R 9a R 9b R 9c R 10a R 10b R 13 and R 14 One of them must be deuterium.

[0071] In some embodiments, the novel spirocyclic compounds, tautomers, stereoisomers, prodrugs, and pharmaceutically acceptable salts provided by the present invention are selected from the following compounds:

[0072]

[0073]

[0074]

[0075] On the other hand, the present invention provides a pharmaceutical composition comprising the above-mentioned novel spirocyclic compound, tautomer, stereoisomer, prodrug, and pharmaceutically acceptable salt thereof.

[0076] This invention discloses a pharmaceutical composition comprising the compounds, tautomers, stereoisomers, prodrugs and their pharmaceutically acceptable salts described in this invention as active ingredients or main active ingredients, supplemented by a pharmaceutically acceptable carrier.

[0077] In another aspect, the present invention provides the use of the above-mentioned novel spirocyclic compounds, tautomers, stereoisomers, prodrugs and their pharmaceutically acceptable salts or the above-mentioned pharmaceutical compositions in the preparation of medicaments for diseases mediated by the Calcitonin gene-related peptide (CGRP) receptor.

[0078] The present invention provides the use of the above-described pharmaceutical composition in the preparation of CGRP receptor-mediated disease drugs, wherein the CGRP receptor-mediated disease drugs are for the treatment of cardiovascular diseases, hypertension, diabetes, autoimmune diseases, organ pain, headache, bone diseases, and chronic obstructive pulmonary disease.

[0079] The present invention provides a drug that can be used to treat headaches, wherein the headache is a migraine.

[0080] In some embodiments, the novel compounds of the present invention can be formulated as pharmaceutical compositions and administered to patients via a variety of suitable routes of administration, including systemic (e.g., oral or parenteral), intravenous, intramuscular, transdermal, or subcutaneous routes.

[0081] The compounds disclosed in this invention have stronger CGRP receptor antagonistic activity, better efficacy against rat migraines, and unexpectedly exhibit pharmacokinetic advantages such as higher peak concentration, faster onset of action, longer half-life, and greater exposure, significantly improving efficacy and ease of administration.

[0082] definition:

[0083] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0084] Some compounds of this invention can exist in either a solvated or a solvent-based form, such as hydrates or ethanolates. Generally, the solvent-based and the solvent-based forms are equivalent and are both included within the scope of this invention.

[0085] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0086] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include aluminum, sodium, potassium, calcium, manganese, iron, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0087] In this article, "amino" refers to a functional group having one nitrogen atom and 0 to 2 hydrogen atoms.

[0088] In this article, halogen refers to fluorine, chlorine, bromine, or iodine atoms.

[0089] The "C" in this article 1-6 "Alkyl" refers to a straight-chain, branched, or unbranched saturated aliphatic hydrocarbon group containing up to 6 carbon atoms. Specific examples of alkyl groups include methyl, ethyl, isopropyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 2,2-dimethylpropyl, etc.

[0090] The "C" in this article 1-6 "Alkoxy" refers to an alkyl group containing up to 6 carbon atoms with -O- or -OH groups inserted at any reasonable position. This group can be straight-chain, branched, or unbranched. Specific examples include methoxy, ethoxy, isopropoxy, tert-butoxy, isopentoxy, cyclopentoxy, 2-methoxybutyl, 2-ethoxypropyl, 2-hydroxybutyl, etc.

[0091] The "C" in this article 1-6"Alkylamino" refers to an alkyl group containing up to 6 carbon atoms with -N-, -NH, or -NH2 groups inserted at any reasonable position. This group can be straight-chain, branched, or unbranched. Specific examples include methylamino, ethylamino, isopropylamino, tert-butylamino, cyclopentanamino, 2-methylaminobutyl, 2-ethylaminopropyl, 2-aminobutyl, etc.

[0092] The "C" in this article 2-8 "Alkenyl" indicates a straight-chain, branched, or unbranched hydrocarbon group containing up to 8 carbon atoms and at least one carbon-carbon double bond. Specific examples include vinyl, allyl, cis-2-pentenyl, 3-methyl-2-pentenyl, 2-methyl-2-pentenyl, etc.

[0093] The "C" in this article 2-8 "Alynyl" indicates a straight-chain, branched, or unbranched hydrocarbon group containing up to 8 carbon atoms and at least one carbon-carbon triple bond. Specific examples include ethynyl, propynyl, methylisopropylethynyl, prop-1-ynylcyclopropane, 1-pentynyl, 5-methyl-3-hexynyl, etc.

[0094] The "C" in this article 3-10 "Carbocyclic group" refers to a saturated or unsaturated aliphatic cyclic hydrocarbon group containing 3 to 10 carbon atoms in the molecule. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, cyclohexenyl, cyclopentenyl, 1,3-cyclohexadienyl, etc.

[0095] The "C" in this article 2-8 "Heterocyclic group" refers to a saturated or unsaturated aliphatic cyclic group containing 2 to 8 carbon atoms and 1 to 6 heteroatoms in a molecule. It may contain one or more rings. The rings of such polycyclic heterocyclic alkyl groups may have different linkages, such as fused, bridged, spirocyclic, etc. Specific examples include ethylene oxide, pyrrolidinyl, furanyl, piperidinyl, piperazinyl, pyrazinyl, pyranyl, tetrahydro-3-thiophenolyl, sulfide cyclopentyl, etc.

[0096] The "C" in this article 6-15 "Aromatic ring group" refers to a group containing 6 to 15 carbon atoms and at least one aromatic ring. Besides covalent groups, the rings of a polycyclic aryl group can have different linkages, such as fusion or bridging, and the fused rings can be saturated or unsaturated. Specific examples include phenyl, naphthyl, diphenyl, α-tetrahydronaphthyl, indenyl, indenyl, benzopyrazine, and 3,4-dihydro-1H-benzopyranyl.

[0097] The "C" in this article 3-10"Heterocyclic aryl" refers to an aromatic heterocyclic group containing 3 to 10 carbon atoms and 1 to 6 heteroatoms. Besides the covalent groups, the rings of the polycyclic aryl group can have different linkages, such as fusion or bridging, and the fused rings can be saturated or unsaturated. Specific examples include thiophene, imidazolyl, ethazolyl, isethazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, quinolinyl, isoquinolinyl, quinoxalinyl, thiazolyl, purine, and 5,6,7,8-tetrahydroquinolinyl.

[0098] In this article, heteroatoms refer to oxygen atoms, nitrogen atoms, sulfur atoms, phosphorus atoms, boron atoms, selenium atoms, etc.

[0099] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of this invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, transdermal penetration enhancers, etc.

[0100] The term "stereoisomer" refers to compounds that have the same chemical composition but different spatial arrangements of atoms or groups. Detailed Implementation

[0101] The following examples provide numerous exemplary methods for preparing the compounds of the present invention. The invention is described in detail below through examples, but this does not imply any adverse limitation thereof. The invention has been described in detail herein, and specific embodiments thereof are also disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope thereof. Some compounds of the present invention can be used as intermediates for preparing other compounds of the present invention; the structures of all compounds have been determined by liquid chromatography-mass spectrometry.

[0102] Unless otherwise specified, all materials used in the embodiments of this application were purchased commercially.

[0103] Example 1: Synthesis of compound ZJT-1

[0104] Reaction formula:

[0105]

[0106] Preparation method:

[0107] Step 1: Preparation of ZJT-1-1

[0108] Under nitrogen atmosphere, ZJT-1-SM (17.16 g, 0.05 mol) was added to DMF (100 mL), followed by 1-phenylpropanone (6.71 g, 0.05 mol) and cesium carbonate (16.29 g, 0.05 mol). The system was reacted at 60 °C for 10 hours.

[0109] Thin-layer chromatography showed the reaction was complete. The mixture was filtered, concentrated, diluted with water (100 mL), and the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was recrystallized from ethanol / water to give ZJT-1-1, 9.28 g (yield: 53.1%). ESI-MS(+): m / z = 350.47 [M+1].

[0110] Step 2: Preparation of ZJT-1

[0111] Under nitrogen atmosphere, ZJT-1-1 (6.99 g, 0.02 mol) was added to tetrahydrofuran (90 mL), followed by 2,2,2-trifluoroethylamine (1.98 g, 0.02 mol) and acetic acid (3 mL). After reacting at room temperature for 5 hours, sodium cyanoborohydride (2.51 g, 0.04 mol) was added, and the reaction continued for another 3 hours.

[0112] Thin-layer chromatography showed that the reaction was complete. The system was neutralized and concentrated with potassium carbonate, diluted with water (100 mL), and the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by preparative liquid chromatography to give ZJT-1, 1.45 g (yield: 18.7%). ESI-MS(+): m / z = 387.37 [M+1].

[0113] Example 2: Synthesis of compound ZJT-2

[0114] Reaction formula:

[0115]

[0116] Preparation method:

[0117] Step 1: Preparation of ZJT-2-1

[0118] Under nitrogen protection, ZJT-2-SM (66.74 g, 0.3 mol) was added to dichloromethane (500 mL), followed by trimethylchlorosilane (32.59 g, 0.3 mol) and triethylamine (60.71 g, 0.6 mol). The system was reacted at room temperature for 4 hours.

[0119] Thin-layer chromatography showed that the reaction was complete. The system was poured into water (500 mL), separated, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to obtain ZJT-2-1, 47.20 g (yield: 53.4%). ESI-MS(+): m / z = 293.31 [M+1].

[0120] Step 2: Preparation of ZJT-2-2

[0121] Under nitrogen protection, ZJT-2-1 (44.20 g, 0.15 mol) was added to tetrahydrofuran (300 mL), followed by lithium chloride (7.63 g, 0.18 mol). The system was cooled to -40 °C, and a tetrahydrofuran solution of diisopropylmagnesium chloride (2.0 M / 90 mL) was slowly added dropwise. After the addition was complete, the system was heated to room temperature and reacted for 3 hours. Then, the temperature was lowered to -40 °C, and DMF (30 mL) was slowly added dropwise. After the addition was complete, the system was heated to room temperature and the reaction continued for 10 hours.

[0122] Thin-layer chromatography showed that the reaction was complete. The system was poured into a saturated ammonium chloride solution (300 mL), filtered, concentrated, and the aqueous phase was extracted with dichloromethane (300 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to obtain ZJT-2-2, 26.14 g (yield: 71.5%). ESI-MS(+): m / z = 244.41 [M+1].

[0123] Step 3: Preparation of ZJT-2-3

[0124] Under nitrogen protection, 7-aza-indole-2-one (13.41 g, 0.1 mol) was added to tetrahydrofuran (200 mL), followed by sodium ethoxide (13.61 g, 0.2 mol). The mixture was stirred at room temperature for 2 hours, and then ZJT-2-2 (24.38 g, 0.1 mol) was added in portions. After the addition was complete, the reaction was continued for 12 hours.

[0125] The mixture was filtered, and the system was quenched in a saturated ammonium chloride solution (200 mL). The solution was concentrated, and the residue was recrystallized from ethanol / water. The resulting solid was added to methanol (150 mL), followed by sodium borohydride (15.13 g, 0.4 mol), and the reaction was continued at room temperature for 10 hours. Thin-layer chromatography showed the reaction was complete. The mixture was filtered, concentrated, and the residue was separated by column chromatography to obtain ZJT-2-3, 14.66 g (yield: 40.5%). ESI-MS(+): m / z = 362.31 [M+1].

[0126] Step 4: Preparation of ZJT-2-4

[0127] Under nitrogen protection, ZJT-2-3 (10.86 g, 0.03 mol) was added to dichloromethane (100 mL), followed by hydrochloric acid solution (0.01 M / 30 mL). The reaction was carried out at room temperature for 1 hour. The system was separated, the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue.

[0128] Under nitrogen protection, the residue was added to DMF (50 mL), followed by the slow addition of phosphorus tribromooxyphosphate (12.90 g, 0.045 mol), keeping the system temperature below 5 °C. After the addition was complete, the system was allowed to rise to room temperature and react for 4 hours. Thin-layer chromatography showed that the reaction was complete. The system was poured into ice water (500 mL), filtered, and the filter cake was dried to give ZJT-2-4, 6.69 g (yield: 63.2%). ESI-MS(+): m / z = 351.87 [M+1].

[0129] Step 5: Preparation of ZJT-2-5

[0130] Under nitrogen protection, ZJT-2-4 (5.29 g, 0.015 mol) was added to tetrahydrofuran (80 mL), followed by sodium hydroxide (1.20 g, 0.03 mol). The system was stirred at room temperature for 24 hours.

[0131] Thin-layer chromatography showed that the reaction was complete. The mixture was filtered, the filtrate was concentrated, and the residue was recrystallized from ethanol / water to give ZJT-2-5, 1.57 g (yield: 38.5%). ESI-MS(+): m / z = 272.41 [M+1].

[0132] Step 6: Preparation of ZJT-2

[0133] Under nitrogen protection, ZJT-2-5 (1.36 g, 5 mmol) was added to ethanol (30 mL), and then carbon monoxide gas at 30 psi was introduced. The reaction was carried out at 100 °C for 12 hours. After the reaction was completed, 50% sodium hydroxide aqueous solution was added to adjust the pH of the system to 11-12, and the system was heated to 80 °C for 4 hours.

[0134] Thin-layer chromatography showed the reaction was complete. The system was adjusted to pH 3.0 with hydrochloric acid solution (2.0 M), filtered, concentrated, and the aqueous phase was extracted with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography to give ZJT-2, 0.59 g (yield: 42.0%). ESI-MS(+): m / z = 282.3 [M+1]

[0135] Example 3: Synthesis of compound ZJT-3

[0136] Reaction formula:

[0137]

[0138] Under nitrogen protection, ZJT-1 (1.16 g, 3 mmol) was added to tetrahydrofuran (20 mL), followed by hydrochloric acid solution (1 M / 3 mL). After the addition was complete, the system was reacted at room temperature for 1 hour. The pH was then adjusted to 8-9 with triethylamine, concentrated, and the aqueous phase was extracted with dichloromethane (40 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was reserved for later use.

[0139] Under nitrogen protection, ZJT-2 (0.84 g, 3 mmol) was added to tetrahydrofuran (20 mL), followed by thionyl chloride (0.71 g, 6 mmol). After the addition was complete, the system was reacted at room temperature for 3 hours. The above-mentioned prepared residue was then added to the system, followed by triethylamine (0.91 g, 9 mmol). The system was then reacted for another 4 hours.

[0140] Thin-layer chromatography showed that the reaction was complete. The residue was concentrated and separated by column chromatography to obtain ZJT-3, 0.46 g (yield: 27.9%). ESI-MS(+): m / z = 550.41 [M+1].

[0141] Example 4: Synthesis of compound WUR-01

[0142] Reaction formula:

[0143]

[0144] Preparation method:

[0145] Under nitrogen protection, ZJT-3 (1.65 g, 3 mol) was added to DMF (20 ml), followed by 60% sodium hydroxide (0.24 g, 6 mmol). The system was stirred at room temperature for 0.5 hours. Then, dimethyl chloromethyl carbonate (0.37 g, 3 mmol) was added, and the reaction was continued for 12 hours.

[0146] Thin-layer chromatography showed that the reaction was complete. The residue was concentrated and separated by preparative liquid chromatography to give WUR-01, 0.35 g (yield: 18.5%). ESI-MS(+): m / z = 638.71 [M+1].

[0147] Example 5: Synthesis of compound WUR-04

[0148] Reaction formula:

[0149]

[0150] Preparation method:

[0151] Under nitrogen protection, ZJT-3 (2.20 g, 4 mol) was added to DMF (20 ml), followed by 60% sodium hydroxide (0.32 g, 8 mmol). The system was stirred at room temperature for 0.5 hours.

[0152] Chloromethyl isobutyrate (0.55 g, 4 mmol) was then added, and the reaction was continued for 12 hours. Thin-layer chromatography showed that the reaction was complete. The residue was concentrated and separated by preparative liquid chromatography to give WUR-04, 0.36 g (yield: 13.7%). ESI-MS(+): m / z = 650.35 [M+1].

[0153] Example 6: Synthesis of compound WUR-05

[0154] Reaction formula:

[0155]

[0156] Preparation method:

[0157] Under nitrogen protection, ZJT-3 (2.75 g, 5 mol) was added to DMF (30 ml), followed by 60% sodium hydroxide (0.4 g, 10 mmol). The system was stirred at room temperature for 0.5 hours.

[0158] Then, methyl tervastatin (0.75 g, 5 mmol) was added, and the reaction was continued for 12 hours. Thin-layer chromatography showed that the reaction was complete. The residue was concentrated and separated by preparative liquid chromatography to give WUR-005, 0.65 g (yield: 19.6%). ESI-MS(+): m / z = 664.51 [M+1].

[0159] Example 7: Synthesis of compound WUR-06

[0160] Reaction formula:

[0161]

[0162] Preparation method:

[0163] Step 1: Preparation of compound WUR-06-1

[0164] ZJT-3 (2.75 g, 5 mmol) was added to 30 ml of methanol, followed by 10 ml of 40% formaldehyde solution. The mixture was heated to reflux and reacted for 48 hours.

[0165] TLC monitoring showed that the reactants reacted completely. Concentration yielded a residue of 2.72 g (yield: 93.7%). ESI-MS(+): m / z = 580.41 [M+1]

[0166] Step 2: Preparation of compound WUR-06

[0167] Under nitrogen protection, WUR-06-1 (2.32 g, 4 mol) was added to DMF (20 ml), followed by 60% sodium hydroxide (0.32 g, 8 mmol). The mixture was stirred at room temperature for 0.5 hours. Then, dimethyl chloromethyl carbonate (0.5 g, 4 mmol) was added, and the reaction was continued for 12 hours.

[0168] Thin-layer chromatography showed the reaction was complete. The residue was concentrated and separated by preparative liquid chromatography to give WUR-06, 0.33 g (yield: 12.4%). ESI-MS(+): m / z = 668.41 [M+1]

[0169] Example 8: Synthesis of compound WUR-08

[0170] Reaction formula:

[0171]

[0172] Preparation method:

[0173] Step 1: Preparation of compound WUR-08-1

[0174] Under nitrogen protection, ZJT-3 (3.30 g, 6 mol) was added to DMF (40 ml), followed by 60% sodium hydroxide (0.48 g, 12 mmol). The system was stirred at room temperature for 0.5 hours.

[0175] Chloromethyl dibenzyl phosphate (1.96 g, 6 mmol) was then added, and the reaction was continued for 12 hours. Thin-layer chromatography showed that the reaction was complete. The mixture was concentrated, and the residue was separated by preparative liquid chromatography to give WUR-08-1, 0.94 g (yield: 18.6%). ESI-MS(+): m / z = 840.37 [M+1]

[0176] Step 2: Preparation of compound WUR-08

[0177] Under nitrogen protection, WUR-08-1 (0.9 g, 1.07 mmol) was added to methanol (30 ml), followed by palladium on carbon (0.09 g), and hydrogen was introduced. The reaction was carried out at room temperature for 2 hours.

[0178] Thin-layer chromatography showed that the reaction was complete. After filtration and concentration, 0.59 g of WUR-08 was obtained (yield 82.9%). ESI-MS (-): m / z = 658.37 [M-1].

[0179] Example 9: Synthesis of compound WUR-09

[0180] Reaction formula:

[0181]

[0182] Preparation method:

[0183] Under nitrogen protection, ZJT-3 (2.75 g, 5 mol) was added to DMF (30 ml), followed by 60% sodium hydroxide (0.4 g, 10 mmol). The system was stirred at room temperature for 0.5 hours.

[0184] Chloromethyl diethyl phosphate (1.01 g, 5 mmol) was then added, and the reaction was continued for 12 hours. Thin-layer chromatography showed that the reaction was complete. The mixture was concentrated, and the residue was separated by preparative liquid chromatography to give WUR-09, 0.49 g (yield: 13.6%). ESI-MS(+): m / z = 716.11 [M+1]

[0185] Example 10: Synthesis of compound WUR-12

[0186] Reaction formula:

[0187]

[0188] Preparation method:

[0189] Under nitrogen protection, WUR-08 (0.66 g, 1.0 mmol) was added to acetonitrile (20 mL), followed by thionyl chloride (0.36 g, 3.0 mmol). After the addition was complete, the reaction continued for 2 hours. Under ice bath conditions, triethylamine (0.40 g, 4.0 mmol) was added to the system, followed by the slow addition of propylene glycol (1 mL). After the addition was complete, the system continued to react for 1 hour.

[0190] Thin-layer chromatography showed that the reaction was complete. The system was concentrated, and the residue was preparatively isolated by liquid chromatography to give compound WUR-12, 0.17 g (yield: 23.6%). ESI-MS(+): m / z = 700.11 [M+1]

[0191] Example 11: Synthesis of compound WUR-13

[0192] Reaction formula:

[0193]

[0194] Preparation method:

[0195] Under nitrogen protection, WUR-08 (0.66 g, 1.0 mmol) was added to acetone (20 mL), followed by sodium hydroxide (0.12 g, 3.0 mmol). After the addition was complete, the reaction was continued for 2 hours.

[0196] Add ice water (30 mL) to the system, filter, and recrystallize the resulting solid with acetone / water to give compound WUR-13, 0.16 g (yield: 22.9%). ESI-MS (-): m / z = 328.52 [(M-2Na) / 2].

[0197] Example 12: Synthesis of compound WUR-14

[0198] Reaction formula:

[0199]

[0200] Preparation method:

[0201] Under nitrogen protection, WUR-06-1 (1.16 g, 2 mol) was added to DMF (20 ml), followed by 60% sodium hydroxide (0.16 g, 4 mmol). The mixture was stirred at room temperature for 0.5 hours. Then, 1-chloro-ethyl methyl carbonate (0.28 g, 2 mmol) was added, and the reaction was continued for 12 hours.

[0202] Thin-layer chromatography showed that the reaction was complete. The residue was concentrated and separated by preparative liquid chromatography to give WUR-14, 0.19 g (yield: 14.2%). ESI-MS(+): m / z = 682.31 [M+1].

[0203] Example 13: Synthesis of compound WUR-16

[0204] Reaction formula:

[0205]

[0206] Preparation method:

[0207] Step 1: Preparation of compound ZJT-4

[0208] 2,2,2-Trifluoroacetamide (3.39 g, 30 mmol) was added to tetrahydrofuran (50 mL), cooled to approximately 0 °C, and then lithium deuterated aluminum (2.52 g, 60 mmol) was added. After the addition was complete, the mixture was slowly heated to 60 °C and refluxed for 4 hours. After the reaction was complete, the mixture was cooled to 0 °C, and water (50 mL) was slowly added to the phase system, followed by 1% sodium hydroxide (50 mL) and water (150 mL) to quench the reaction. The mixture was then filtered, the filter cake was washed with ethyl acetate, and the residue ZJT-4 was concentrated to obtain 2.35 g (yield: 78.3%). ESI-MS(+): m / z = 102.1 [M+1].

[0209] Step 2: Preparation of compound WUR-16-1

[0210] Under nitrogen atmosphere, ZJT-1-1 (6.99 g, 0.02 mol) was added to tetrahydrofuran (90 mL), followed by ZJT-4 (2.02 g, 0.02 mol) and acetic acid (3 mL). After reacting at room temperature for 5 hours, sodium cyanoborohydride (2.51 g, 0.04 mol) was added, and the reaction continued for another 3 hours.

[0211] Thin-layer chromatography showed that the reaction was complete. The system was neutralized and concentrated with potassium carbonate, diluted with water (100 ml), and the aqueous phase was extracted with dichloromethane (100 ml × 3). The organic phases were combined, washed with saturated brine (300 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by preparative liquid chromatography to give ZJT-16-1, 1.52 g (yield: 19.6%). ESI-MS(+): m / z = 389.37 [M+1].

[0212] Step 3: Preparation of compound WUR-16

[0213] Under nitrogen protection, WUR-16-1 (1.16 g, 3 mmol) was added to tetrahydrofuran (30 ml), followed by hydrochloric acid solution (0.01 M / 3 ml). After the addition was complete, the system was reacted at room temperature for 1 hour. The pH was then adjusted to 8-9 with triethylamine, and the mixture was concentrated. The aqueous phase was extracted with dichloromethane (50 ml × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue for later use.

[0214] Under nitrogen protection, ZJT-2 (0.84 g, 3 mmol) was added to tetrahydrofuran (20 mL), followed by thionyl chloride (0.71 g, 6 mmol). After the addition was complete, the mixture was reacted at room temperature for 3 hours. The prepared residue was then added to the mixture, followed by triethylamine (0.91 g, 9 mmol), and the reaction was continued for 4 hours. Thin-layer chromatography showed that the reaction was complete. The residue was concentrated and separated by column chromatography to obtain WUR-16, 0.42 g (yield: 25.3%). ESI-MS(+): m / z = 552.41 [M+1].

[0215] Example 14: Synthesis of compound ZJT-5

[0216] Reaction formula:

[0217]

[0218] Preparation method:

[0219] Step 1: Preparation of compound ZJT-5-1

[0220] Under nitrogen protection, ZJT-1-SM (1.72 g, 5 mmol) was added to DMF (50 mL), followed by 1-(2,3,6-trifluorophenyl)acetone (0.94 g, 5 mmol) and cesium carbonate (3.26 g, 10 mmol). The system was reacted at 60 °C for 10 hours.

[0221] Thin-layer chromatography showed the reaction was complete. The mixture was filtered, concentrated, diluted with water (100 ml), and the aqueous phase was extracted with dichloromethane (100 ml × 3). The organic phases were combined, washed with saturated brine (150 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was recrystallized from ethanol / water to give ZJT-5-1, 0.84 g (yield: 47.3%). ESI-MS(+): m / z = 355.27 [M+1].

[0222] Step 2: Preparation of compound ZJT-5

[0223] Under nitrogen atmosphere, ZJT-5-1 (0.71 g, 2 mmol) was added to tetrahydrofuran (20 mL), followed by 2,2,2-trifluoroethylamine (0.20 g, 2 mmol) and acetic acid (0.3 mL). After reacting at room temperature for 5 hours, sodium cyanoborohydride (0.25 g, 4 mol) was added, and the reaction continued for another 3 hours.

[0224] Thin-layer chromatography showed that the reaction was complete. The system was neutralized and concentrated with potassium carbonate, diluted with water (50 ml), and the aqueous phase was extracted with dichloromethane (50 ml × 3). The organic phases were combined, washed with saturated brine (150 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by preparative liquid chromatography to give ZJT-5, 0.16 g (yield: 20.7%). ESI-MS(+): m / z = 392.31 [M+1].

[0225] Example 15: Synthesis of compound WUR-17

[0226] Reaction formula:

[0227]

[0228] Preparation method:

[0229] Under nitrogen protection, ZJT-5 (1.17 g, 3 mmol) was added to tetrahydrofuran (20 ml), followed by hydrochloric acid solution (1 M / 3 ml). After the addition was complete, the system was reacted at room temperature for 1 hour. The pH was then adjusted to 8-9 with triethylamine, and the mixture was concentrated. The aqueous phase was extracted with dichloromethane (40 ml × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue for later use.

[0230] Under nitrogen protection, ZJT-2 (0.84 g, 3 mmol) was added to tetrahydrofuran (20 mL), followed by thionyl chloride (0.71 g, 6 mmol). After the addition was complete, the mixture was reacted at room temperature for 3 hours. The prepared residue was then added to the mixture, followed by triethylamine (0.91 g, 9 mmol), and the reaction was continued for 4 hours. Thin-layer chromatography showed that the reaction was complete. The residue was concentrated, and column chromatography yielded WUR-17, 0.51 g (yield: 30.9%). ESI-MS (+): m / z = 555.41 [M+1].

[0231] Example 16: Synthesis of compound WUR-19

[0232] Reaction formula:

[0233]

[0234] Preparation method:

[0235] Under nitrogen protection, WUR-16 (1.65 g, 3 mol) was added to DMF (30 ml), followed by 60% sodium hydroxide (0.24 g, 6 mmol). The system was stirred at room temperature for 0.5 hours.

[0236] Then add dimethyl chloromethyl carbonate (0.37 g, 3 mmol) and continue the reaction for 12 hours.

[0237] Thin-layer chromatography showed that the reaction was complete. The residue was concentrated and separated by preparative liquid chromatography to give WUR-19, 0.37 g (yield: 19.4%). ESI-MS(+): m / z = 640.21 [M+1].

[0238] Example 17: Synthesis of compound WUR-21

[0239] Reaction formula:

[0240]

[0241] Preparation method:

[0242] Step 1: Preparation of compound ZJT-6

[0243] Under nitrogen protection, methyl chloroformate (0.64 g, 5 mmol) was added to dichloromethane (20 ml), and the system was cooled to 0 °C. Then, deuterated methanol-4d (0.18 g, 5 mmol) and triethylamine (0.51 g, 5 mmol) were added, and the system temperature was controlled to not exceed 5 °C. After the addition was complete, the system was stirred at room temperature for 1 hour.

[0244] The system was filtered and concentrated to obtain 0.62 g of residue ZJT-6 (yield: 97.5%). ESI-MS(+): m / z = 128.51 [M+1]

[0245] Step 2: Preparation of compound WUR-21

[0246] Under nitrogen protection, ZJT-3 (1.65 g, 3 mol) was added to DMF (30 ml), followed by 60% sodium hydroxide (0.24 g, 6 mmol). The system was stirred at room temperature for 0.5 hours.

[0247] Then add ZJT-6 (0.38g, 3mmol) and continue the reaction for 12 hours.

[0248] Thin-layer chromatography showed that the reaction was complete. The residue was concentrated and separated by preparative liquid chromatography to give WUR-21, 0.32 g (yield: 16.4%). ESI-MS(+): m / z = 641.28 [M+1].

[0249] Example 18: Synthesis of compound WUR-22

[0250] Reaction formula:

[0251]

[0252] Preparation method:

[0253] Under nitrogen protection, WUR-16 (1.65 g, 3 mol) was added to DMF (30 ml), followed by 60% sodium hydroxide (0.24 g, 6 mmol). The system was stirred at room temperature for 0.5 hours.

[0254] Then add ZJT-6 (0.38g, 3mmol) and continue the reaction for 12 hours.

[0255] Thin-layer chromatography showed that the reaction was complete. The residue was concentrated and separated by preparative liquid chromatography to give WUR-22, 0.29 g (yield: 15.3%). ESI-MS(+): m / z = 643.51 [M+1].

[0256] Example 19: Synthesis of compound WUR-23

[0257] Reaction formula:

[0258]

[0259] Preparation method:

[0260] Under nitrogen protection, WUR-16 (1.65 g, 3 mol) was added to DMF (30 ml), followed by 60% sodium hydroxide (0.24 g, 6 mmol). The system was stirred at room temperature for 0.5 hours.

[0261] Then add chloromethyl isobutyrate (0.41 g, 3 mmol) and continue the reaction for 12 hours.

[0262] Thin-layer chromatography showed that the reaction was complete. The residue was concentrated and separated by preparative liquid chromatography to give WUR-23, 0.31 g (yield: 16.1%). ESI-MS(+): m / z = 652.31 [M+1].

[0263] Example 20: Synthesis of compound WUR-24

[0264] Reaction formula:

[0265]

[0266] Preparation method:

[0267] Step 1: Preparation of compound WUR-24-1

[0268] WUR-16 (1.38 g, 2.5 mmol) was added to 20 mL of methanol, followed by 5 mL of 40% formaldehyde solution. The mixture was heated to reflux and reacted for 48 hours. Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the starting material reacted completely. The solution was concentrated to obtain 1.41 g of the residue WUR-24-1 (yield: 97.3%) for later use. ESI-MS(+): m / z = 582.38 [M+1]

[0269] Step 2: Preparation of compound WUR-24

[0270] Deuterated isobutyric acid-6d (0.19 g, 2 mmol) was added to DCM (20 ml), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 0.77 g, 4 mmol), 4,4-dimethylaminopyridine (DMAP, 0.12 g, 1 mmol), and finally WUR-24-1 (1.16 g, 2 mmol). The mixture was stirred at room temperature for 24 hours.

[0271] The system was concentrated, and the residue was separated by column chromatography to give WUR-24, 0.30 g (yield: 22.8%). ESI-MS(+): m / z = 658.18 [M+1]

[0272] Example 21: Synthesis of compound WUR-26

[0273] Reaction formula:

[0274]

[0275] Preparation method:

[0276] Deuterated isobutyric acid-6d (0.19 g, 2 mmol) was added to DCM (20 ml), followed by EDCI (0.77 g, 4 mmol) and DMAP (0.12 g, 1 mmol). Finally, WUR-06-1 (1.16 g, 2 mmol) was added, and the mixture was stirred at room temperature for 24 hours.

[0277] Thin-layer chromatography showed that the reaction was complete. The system was concentrated, and the residue was separated by column chromatography to give WUR-26, 0.28 g (yield: 21.5%). ESI-MS(+): m / z = 656.51 [M+1].

[0278] Example 22: Synthesis of compound WUR-29

[0279] Reaction formula:

[0280]

[0281] Preparation method:

[0282] Step 1: Preparation of compound WUR-29-1

[0283] Under nitrogen protection, WUR-16 (3.31 g, 6 mmol) was added to DMF (60 ml), followed by 60% sodium hydroxide (0.48 g, 12 mmol). The mixture was stirred at room temperature for 0.5 hours. Then, chloromethyl dibenzyl phosphate (1.96 g, 6 mmol) was added, and the reaction was continued for 12 hours.

[0284] Thin-layer chromatography showed that the reaction was complete. The residue was concentrated and separated by preparative liquid chromatography to give WUR-08-1, 1.95 g (yield: 38.7%). ESI-MS(+): m / z = 842.59 [M+1].

[0285] Step 2: Preparation of compound WUR-29

[0286] Under nitrogen protection, WUR-29-1 (0.84 g, 1 mmol) was added to methanol (20 ml), followed by palladium on carbon (0.04 g), and hydrogen was introduced. The reaction was carried out at room temperature for 2 hours.

[0287] Thin-layer chromatography showed that the reaction was complete. Filtration and concentration yielded 0.50 g of WUR-29 (75.3% yield). ESI-MS (-): m / z = 660.15 [M-1].

[0288] Example 23: Synthesis of compound WUR-30

[0289] Reaction formula:

[0290]

[0291] Preparation method:

[0292] Under nitrogen protection, WUR-16 (1.10 g, 2 mmol) was added to DMF (20 ml), followed by 60% sodium hydroxide (0.16 g, 4 mmol). The mixture was stirred at room temperature for 0.5 hours. Then, chloromethyl diethyl phosphate (0.41 g, 2 mmol) was added, and the reaction was continued for 12 hours.

[0293] Thin-layer chromatography showed the reaction was complete. The residue was concentrated and separated by preparative liquid chromatography to give WUR-30, 0.21 g (yield: 14.5%). ESI-MS(+): m / z = 718.19 [M+1]

[0294] Example 24: Synthesis of compound WUR-34

[0295] Reaction formula:

[0296]

[0297] Preparation method:

[0298] Under nitrogen protection, WUR-29 (1.98 g, 3.0 mmol) was added to acetonitrile (30 mL), followed by thionyl chloride (0.71 g, 6.0 mmol). After the addition was complete, the reaction continued for 2 hours. Under ice bath conditions, triethylamine (0.61 g, 6.0 mmol) was added to the system, followed by the slow addition of propylene glycol (3 mL). After the addition was complete, the system continued to react for 1 hour.

[0299] Thin-layer chromatography showed that the reaction was complete. The system was concentrated, and the residue was prepared by pre-liquid chromatography to give compound WUR-34, 0.57 g (yield: 27.3%). ESI-MS(+): m / z = 702.31 [M+1].

[0300] Example 25: Synthesis of compound ZJT-7

[0301] Reaction formula:

[0302]

[0303] Preparation method:

[0304] Step 1: Preparation of ZJT-7-1

[0305] Under nitrogen protection, ZJT-1-SM (1.72 g, 5 mmol) was added to DMF (50 mL), followed by 1-(2,3,6-trifluorophenyl)acetone (0.94 g, 5 mmol) and cesium carbonate (3.26 g, 10 mmol). The system was reacted at 60 °C for 10 hours.

[0306] Thin-layer chromatography showed the reaction was complete. The mixture was filtered, concentrated, diluted with water (100 ml), and the aqueous phase was extracted with dichloromethane (100 ml × 3). The organic phases were combined, washed with saturated brine (150 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was recrystallized from ethanol / water to give ZJT-7-1, 1.18 g (yield: 58.3%). ESI-MS(+): m / z = 404.27 [M+1].

[0307] Step 2: Preparation of ZJT-7

[0308] Under nitrogen atmosphere, ZJT-7-1 (0.81 g, 2 mmol) was added to tetrahydrofuran (20 mL), followed by ZJT-4 (0.2 g, 2 mmol) and acetic acid (0.3 mL). After reacting at room temperature for 5 hours, sodium cyanoborohydride (0.25 g, 4 mmol) was added, and the reaction continued for another 3 hours.

[0309] Thin-layer chromatography showed that the reaction was complete. The system was neutralized and concentrated with potassium carbonate, diluted with water (50 ml), and the aqueous phase was extracted with dichloromethane (50 ml × 3). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by preparative liquid chromatography to give ZJT-7, 0.16 g (yield: 17.7%). ESI-MS(+): m / z = 443.37 [M+1].

[0310] Example 26: Synthesis of compound WUR-37

[0311] Reaction formula:

[0312]

[0313] Preparation method:

[0314] Under nitrogen protection, ZJT-7 (1.33 g, 3 mmol) was added to tetrahydrofuran (30 ml), followed by hydrochloric acid solution (1 M / 3 ml). After the addition was complete, the system was reacted at room temperature for 1 hour. The pH was then adjusted to 8-9 with triethylamine, and the mixture was concentrated. The aqueous phase was extracted with dichloromethane (50 ml × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue for later use.

[0315] Under nitrogen protection, ZJT-2 (0.84 g, 3 mmol) was added to tetrahydrofuran (30 ml), followed by thionyl chloride (0.71 g, 6 mmol). After the addition was complete, the system was reacted at room temperature for 3 hours. The above-mentioned prepared residue was then added to the system, followed by triethylamine (0.91 g, 9 mmol). The system was then reacted for another 4 hours.

[0316] Thin-layer chromatography showed that the reaction was complete. The residue was concentrated and separated by column chromatography to give WUR-37, 0.46 g (yield: 25.4%). ESI-MS(+): m / z = 606.43 [M+1].

[0317] Example 27: Synthesis of compound WUR-40

[0318] Reaction formula:

[0319]

[0320] Preparation method:

[0321] Under nitrogen protection, WUR-37 (1.21 g, 2 mol) was added to DMF (20 ml), followed by 60% sodium hydroxide (0.16 g, 4 mmol). The system was stirred at room temperature for 0.5 hours.

[0322] Then add dimethyl chloromethyl carbonate (0.25 g, 2 mmol) and continue the reaction for 12 hours.

[0323] Thin-layer chromatography showed that the reaction was complete. The residue was concentrated and separated by preparative liquid chromatography to give WUR-40, 0.24 g (yield: 17.3%). ESI-MS(+): m / z = 694.31 [M+1].

[0324] Example 28: Synthesis of compound ZJT-8

[0325] Reaction formula:

[0326]

[0327] Preparation method:

[0328] Step 1: Preparation of ZJT-8-1

[0329] Under nitrogen protection, ZJT-1-SM (0.69 g, 2 mmol) was added to DMF (20 mL), followed by 1-(2,3,6-trifluorophenyl)acetone (0.38 g, 2 mmol) and cesium carbonate (1.30 g, 4 mmol). The system was reacted at 60 °C for 10 hours.

[0330] Thin-layer chromatography showed the reaction was complete. The mixture was filtered, concentrated, diluted with water (50 ml), and the aqueous phase was extracted with dichloromethane (50 ml × 3). The organic phases were combined, washed with saturated brine (150 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was recrystallized from ethanol / water to give ZJT-8-1, 0.48 g (yield: 59.6%). ESI-MS(+): m / z = 404.27 [M+1].

[0331] Step 2: Preparation of ZJT-8

[0332] Under nitrogen atmosphere, ZJT-8-1 (0.40 g, 1 mmol) was added to tetrahydrofuran (20 mL), followed by 2,2,2-trifluoroethylamine (0.10 g, 1 mmol) and acetic acid (0.15 mL). After reacting at room temperature for 5 hours, sodium cyanoborohydride (0.13 g, 2 mmol) was added, and the reaction continued for another 3 hours.

[0333] Thin-layer chromatography showed that the reaction was complete. The system was neutralized and concentrated with potassium carbonate, diluted with water (50 ml), and the aqueous phase was extracted with dichloromethane (100 ml × 2). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by preparative liquid chromatography to give ZJT-8, 0.10 g (yield: 23.8%). ESI-MS(+): m / z = 441.17 [M+1].

[0334] Example 29: Synthesis of compound WUR-41

[0335] Reaction formula:

[0336]

[0337] Preparation method:

[0338] Step 1: Preparation of compound WUR-41-1

[0339] Under nitrogen protection, ZJT-8 (1.32 g, 3 mmol) was added to tetrahydrofuran (30 ml), followed by hydrochloric acid solution (1 M / 3 ml). After the addition was complete, the system was reacted at room temperature for 1 hour. The pH was then adjusted to 8-9 with triethylamine, and the mixture was concentrated. The aqueous phase was extracted with dichloromethane (40 ml × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue for later use.

[0340] Under nitrogen protection, ZJT-2 (0.84 g, 3 mmol) was added to tetrahydrofuran (30 ml), followed by thionyl chloride (0.71 g, 6 mmol). After the addition was complete, the system was reacted at room temperature for 3 hours. The above-mentioned prepared residue was then added to the system, followed by triethylamine (0.91 g, 9 mmol). The system was then reacted for another 4 hours.

[0341] Thin-layer chromatography showed the reaction was complete. Concentration yielded a residue, which was separated by column chromatography to give WUR-41-1, 0.68 g (yield: 37.5%). ESI-MS(+): m / z = 604.81 [M+1]

[0342] Step 2: Preparation of compound WUR-41

[0343] Under nitrogen protection, WUR-41-1 (0.6 g, 1 mol) was added to DMF (20 ml), followed by 60% sodium hydroxide (0.08 g, 2 mmol). The system was stirred at room temperature for 0.5 hours. Then ZJT-6 (0.13 g, 1 mmol) was added, and the reaction was continued for 12 hours.

[0344] Thin-layer chromatography showed the reaction was complete. The residue was concentrated and separated by preparative liquid chromatography to give WUR-41, 0.15 g (yield: 20.9%). ESI-MS(+): m / z = 695.51 [M+1]

[0345] Example 30: Synthesis of compound WUR-42

[0346] Reaction formula:

[0347]

[0348] Preparation method:

[0349] Under nitrogen protection, WUR-37 (1.82 g, 3 mol) was added to DMF (30 ml), followed by 60% sodium hydroxide (0.24 g, 6 mmol). The system was stirred at room temperature for 0.5 hours.

[0350] Then add ZJT-6 (0.38g, 3mmol) and continue the reaction for 12 hours.

[0351] Thin-layer chromatography showed that the reaction was complete. The residue was concentrated and separated by preparative liquid chromatography to give WUR-42, 0.32 g (yield: 15.3%). ESI-MS(+): m / z = 697.51 [M+1].

[0352] Example 31: Synthesis of compound WUR-43

[0353] Reaction formula:

[0354]

[0355] Preparation method:

[0356] Under nitrogen protection, WUR-37 (1.65 g, 2 mol) was added to DMF (20 ml), followed by 60% sodium hydroxide (0.16 g, 4 mmol). The system was stirred at room temperature for 0.5 hours.

[0357] Then add chloromethyl isobutyrate (0.27 g, 2 mmol) and continue the reaction for 12 hours.

[0358] Thin-layer chromatography showed the reaction was complete. The residue was concentrated and separated by preparative liquid chromatography to give WUR-43, 0.21 g (yield: 14.7%). ESI-MS(+): m / z = 706.72 [M+1]

[0359] Example 32: Synthesis of compound WUR-46

[0360] Reaction formula:

[0361]

[0362] Preparation method:

[0363] Step 1: Preparation of compound WUR-46-1

[0364] Under nitrogen protection, WUR-37 (1.82 g, 3 mol) was added to DMF (30 ml), followed by 60% sodium hydroxide (0.24 g, 6 mmol). The system was stirred at room temperature for 0.5 hours.

[0365] Then add chloromethyl dibenzyl phosphate (0.98 g, 3 mmol) and continue the reaction for 12 hours.

[0366] Thin-layer chromatography showed the reaction was complete. The residue was concentrated and separated by preparative liquid chromatography to give WUR-46-1, 2.11 g (yield: 78.6%). ESI-MS(+): m / z = 896.17 [M+1]

[0367] Step 2: Preparation of compound WUR-46

[0368] Under nitrogen protection, WUR-46-1 (1.79 g, 2 mmol) was added to methanol (30 ml), followed by palladium on carbon (0.09 g). Hydrogen gas was then introduced, and the reaction was carried out at room temperature for 2 hours. Thin-layer chromatography showed that the reaction was complete. The mixture was filtered and concentrated to give 0.60 g of WUR-46 (yield 42.1%). ESI-MS(+): m / z = 716.17 [M+1].

[0369] Example 33: Synthesis of compound WUR-47

[0370] Reaction formula:

[0371]

[0372] Preparation method:

[0373] Under nitrogen protection, WUR-37 (1.21 g, 2 mol) was added to DMF (20 ml), followed by 60% sodium hydroxide (0.16 g, 4 mmol). The mixture was stirred at room temperature for 0.5 hours. Then, chloromethyl diethyl phosphate (0.41 g, 2 mmol) was added, and the reaction was continued for 12 hours.

[0374] Thin-layer chromatography showed that the reaction was complete. The residue was concentrated and separated by preparative liquid chromatography to give WUR-47, 0.18 g (yield: 11.6%). ESI-MS(+): m / z = 772.11 [M+1].

[0375] The compounds of the following examples were synthesized using the same method as in the above embodiments, either commercially available compounds or intermediate compounds appropriately synthesized from commercially available compounds.

[0376]

[0377]

[0378] Example 34: Determination of the antagonistic activity of the compounds of the present invention against human CGRP receptors

[0379] Cell line: SK-N-MC cells stably expressing human CGRP receptor (purchased from Guangzhou Fuerbo Biotechnology Co., Ltd., catalog number: CB310693428).

[0380] Culture medium: MEM medium containing 10% fetal bovine serum (FBS) and 1× penicillin-streptomycin. Source: Gibco TM (Thermo Fisher Scientific), FBS: #26140-079 (Premium Fetal Bovine Serum).

[0381] Experimental buffer: 1×HBSS buffer containing 20mM HEPES, 0.1% BSA and 500μM IBMX. Source: Servicebio (Wuhan Saiweier Biotechnology Co., Ltd.), G4203-500ML.

[0382] cAMP assay kit (Lysis Buffer): PerkinElmer cAMP Kit (TR-FRET method). Source: PerkinElmer, TRF0262.

[0383] Equipment: EnVision multi-functional microplate reader (PerkinElmer).

[0384] Before the experiment, SK-N-MC cells stably expressing the CGRP receptor were digested using TrypLE. The digested cells were washed three times with experimental buffer, and the washed cells were collected and resuspended in an appropriate amount of culture medium. Subsequently, the resuspended cells were seeded into 384-well plates at a density of 2 × 10⁶ cells per well. 4 The cells were inoculated with 80 μL of the solution, and after standing, pre-cultured in a 5% CO2, 37°C incubator. The experimental drugs (including the compounds of this invention and the control compounds Ubrogepant and Atogepant) were prepared as stock solutions using DMSO. The stock solutions were diluted 10-fold with culture medium to obtain intermediate stock solutions, which were then serially diluted 3-fold with culture medium to obtain 10 concentration gradients of working solutions. 2.5 μL of each of the 10 concentration gradients of working solutions were added to each well of the inoculated cells, and the cells were incubated in 5% CO2 at 37°C for 10 minutes. Subsequently, human α-CGRP was diluted with experimental buffer to a working solution with a concentration of 16 nM, and 2.5 μL of this working solution was added to each well, and the cells were incubated in 5% CO2 at 37°C for another 30 minutes. The frozen-thawed Eu-cAMP Tracer and Ulight anti-cAMP antibody were then diluted with lysis buffer, and 10 μL of Eu-cAMP Tracer and 10 μL of ULight anti-cAMP antibody were added to each well sequentially. The reaction plate was centrifuged at 200g for 30 seconds at room temperature and then incubated for 1 hour. Each concentration was tested in triplicate, with additional blank control wells (containing cells, no drug, and DMSO content less than 0.1%) and negative control wells (containing no cells, no drug, and DMSO content less than 0.1%). Finally, the TR-FRET signal was detected using the EnVision system, and the antagonistic IC50 of each compound against the human CGRP receptor was calculated using GraphPadPrism software. 50 Values. The final concentrations of the compounds used in the experiment ranged from 0.0005 to 10.000 nM. The results are shown in Table 1.

[0385] Table 1. Results of the assay of the antagonistic activity of the compounds of the present invention against human CGRP receptors

[0386]

[0387] The results showed that compounds WUR-01 to WUR-36 of the present invention had superior CGRP receptor antagonistic activity compared with the control compound Ubrogepant, with the highest reaching 30 times that of the control compound; compounds WUR-37 to WUR-48 of the present invention also had superior CGRP receptor antagonistic activity compared with the control compound Atogepant, with the highest reaching 20 times that of the control compound.

[0388] Example 35: Pharmacodynamic study of nitroglycerin-induced migraine in rats

[0389] Instruments and equipment: MuLtiskan Go full-wavelength microplate reader, Therm-Fisher, USA; TGL-16B centrifuge, Shanghai Anting Scientific Instrument Factory; TissueLyserⅡ homogenizer, Qiagen Enterprise Management (Shanghai) Co., Ltd.; OSB-2200 rotary evaporator, Xiamen Jingyi Xingye Technology Co., Ltd.; UV-8000S ultraviolet-visible spectrophotometer, Shanghai Yuanxi Instrument Co., Ltd.

[0390] Instruments and equipment: MuLtiskan Go full-wavelength microplate reader, Therm-Fisher, USA; TGL-16B centrifuge, Shanghai Anting Scientific Instrument Factory; TissueLyserⅡ homogenizer, Qiagen Enterprise Management (Shanghai) Co., Ltd.; OSB-2200 rotary evaporator, Xiamen Jingyi Xingye Technology Co., Ltd.; UV-8000S ultraviolet-visible spectrophotometer, Shanghai Yuanxi Instrument Co., Ltd.

[0391] Sixty-four healthy, male SPF-grade SD rats (6 weeks old, weighing 180±20g) (purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) were randomly divided into eight groups: blank group, model group, control group (Ubrogepant), WUR-01 group, WUR-05 group, WUR-16 group, WUR-19 group, and WUR-28 group, with eight rats in each group. All rats were acclimatized for 7 days before the experiment, followed by a 12-hour fast with unlimited water intake before the experiment. On the day of the experiment, except for the blank group and model group, all other test groups were administered the compound of this invention or the control compound by gavage at a dose of 15mg / kg. The concentration of the drug administered by gavage was 1.5mg / mL (prepared by adding 150mg of the compound to 100mL of 1% methylcellulose solution); the blank group and model group were given an equal volume of 1% methylcellulose solution. Thirty minutes after drug administration, except for the control group, rats in all other groups underwent slow subcutaneous injection of nitroglycerin (10 mg / kg) into the left side of the midline of the back to induce a migraine model. The control group received an equal volume of saline. The successful establishment of the migraine model was determined by the appearance of typical migraine symptoms in the model group, including reddening of both ears, frequent head scratching, increased cage-climbing behavior, and ultimately, fatigue and lethargy.

[0392] Observation and detection indicators

[0393] (1) Animal behavioral observation:

[0394] Following subcutaneous injection of nitroglycerin: Starting from the injection of nitroglycerin, a segmented counting method was used, with each 30-minute interval as a time period. The number of head scratches in rats within three time intervals from 0 to 90 minutes after the model was established was observed. The head scratching inhibition rate = (number of head scratches in the model group - number of head scratches in the drug treatment group) / number of head scratches in the model group.

[0395] (2) Detection of bioactive substances in rat plasma:

[0396] Four hours after modeling, rats were intraperitoneally injected with 10% chloral hydrate (3 mL·kg⁻¹). -1 Anesthesia was administered, blood was drawn from the abdominal aorta and placed in a vacuum blood collection tube containing anticoagulant, and centrifuged (3000 r·min). -1 Plasma was separated at 4℃ for 10 min and stored at -80℃ until analysis. ET and CGRP levels were determined strictly according to the kit instructions using ELISA, and NO levels were determined using the nitrate reductase method.

[0397] Statistical analysis

[0398] Experimental data were processed using SPSS 23.0 software. Mean and standard deviation were calculated using... The independent samples t-test was used for comparisons between groups, and P<0.05 or P<0.01 indicated that the difference was statistically significant.

[0399] The effects of the drug on rats scratching their heads are shown in Table 2.

[0400] The effects of the drug on NO, ET, and CGRP in rat plasma are shown in Table 3.

[0401] Table 2. Effects of the drug on rat head scratching

[0402]

[0403] Note: * Compared with the control group, P < 0.01; Δ Compared with the model group, P < 0.01.

[0404] Table 3. Effects of the drug on plasma NO, ET, and CGRP levels in rats (n=8)

[0405]

[0406] Note: * indicates P < 0.01 compared to the control group; Δ indicates P < 0.01 compared to the model group.

[0407] Experimental results showed that the model group exhibited typical migraine symptoms such as bilateral ear redness, frequent head scratching, and increased cage-climbing behavior, with significantly more head scratching than the control group (P < 0.01), indicating successful establishment of the migraine model. Compared with the model group, both the control group and the compound group of this invention showed significant inhibitory effects on head scratching in rats at the same dosage during the 0–90 min time period. The compound of this invention showed a significantly better inhibitory effect on nitroglycerin-induced migraine behavior in rats than the control group compound. Regarding biochemical indicators, compared with the model group, NO and CGRP were significantly decreased in both the control group and the compound group of this invention (P < 0.01), while ET was significantly increased (P < 0.01), with the compound group of this invention showing superior results compared to the control group compound. In conclusion, the compound of this invention can significantly affect the head scratching behavior and biochemical indicators of a nitroglycerin-induced migraine rat model, and has a more significant effect on improving migraine symptoms than the control group compound.

[0408] Example 36: Pharmacokinetic Study of the Compound in Rats

[0409] Experimental animals: Eighteen healthy male Sprague-Dawley (SD) rats weighing 200±20g were selected. The rats were acclimatized for 3 days at the experimental animal center before the experiment, during which time the environment was controlled with constant temperature (22±2℃), constant humidity (55%±10%), and a 12-hour light-dark cycle. Before the experiment, the rats were fasted but allowed free access to water for at least 12 hours. After drug administration, they were kept fasted for another 4 hours but allowed free access to water.

[0410] Animal grouping and drug administration: The experimental animals were randomly divided into 6 groups of 3 animals each, as follows:

[0411] Control group: Ubrogepant group (5.00 mg / kg)

[0412] Experimental groups: WUR-01 (5.80 mg / kg), WUR-05 (6.04 mg / kg), WUR-16 (5.02 mg / kg), WUR-19 (5.82 mg / kg), WUR-28 (6.06 mg / kg)

[0413] All the above dosages were administered on an equimolar basis (9.1 μmol / kg, i.e., 2.5 mL / kg) via single oral gavage. All experimental drugs were prepared and used immediately.

[0414] Preparation of drug administration solutions: Accurately weigh appropriate amounts of each test sample and place them in a clean, dry reagent bottle. Add an appropriate amount of 1% methylcellulose (CMC-Na) solution and vortex thoroughly to prepare the oral gavage solution of the required concentration. Each group should be freshly prepared before use to ensure solution stability.

[0415] Blood collection and sample processing: Approximately 300 μL of venous blood was collected via the orbital sinus at 0 h before drug administration and at 0.25 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 5 h, 10 h, and 24 h after drug administration. The samples were placed in EP tubes containing heparin anticoagulant. After incubating the samples on ice for 15 minutes, they were centrifuged at 4000 rpm for 10 minutes at 4°C to separate the plasma. 50 μL of plasma was used for subsequent drug concentration determination.

[0416] Detection methods and pharmacokinetic analysis: Liquid chromatography-tandem mass spectrometry (LC-MS / MS) was used to quantitatively analyze the drug concentration in plasma. The detection indicators for each group were as follows: Ubrogepant group, WUR-01 group, and WUR-05 group: plasma Ubrogepant concentration was detected; WUR-16 group, WUR-19 group, and WUR-28 group: plasma WUR-16 concentration was detected. The obtained concentration-time data were used to calculate the main pharmacokinetic parameters (Cmax, Tmax, AUC, t1 / 2, etc.), specifically using non-compartmental analysis (NCA). The pharmacokinetic parameters of rats administered via gavage are shown in Table 4.

[0417] Table 4. Kinetic parameters of compounds administered via gavage

[0418]

[0419] Based on the above data analysis, compared with the control compound Ubrogepant, the compounds WUR-01, WUR-05, WUR-16, WUR-19, and WUR-28 of this invention showed significant advantages in key pharmacokinetic parameters: Cmax (0.69–0.84 μM) was significantly increased compared to Ubrogepant (0.45 μM), and higher peak concentrations indicate stronger efficacy; Tmax (1.0–1.5 h) was almost half that of Ubrogepant (2.6 h), and a shorter time to peak concentration means more rapid pain relief during acute migraine attacks; AUC 0-24 The half-life (5.12–6.21 μM·h) is almost twice that of Ubrogepant (2.87 μM·h), and the increased area under the curve indicates higher systemic exposure and higher bioavailability. The half-life T1 / 2 (5.1–6.3 h) is 2–3 times that of Ubrogepant (2.1 h), and the prolonged half-life means less frequent dosing and better compliance. Overall, the compounds of this invention, at equimolar doses, offer significant advantages such as faster onset of action, better efficacy, less frequent dosing, and better user compliance.

[0420] Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications and improvements without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention shall be defined by the claims.

Claims

1. A novel spirocyclic compound, tautomer, stereoisomer, prodrug, and pharmaceutically acceptable salt thereof as shown in formula (I): In formula (I), W represents O or S; R1, R2, and R3 are independently selected from hydrogen, deuterium, halogen, and cyano groups, respectively; R 4a R 4b R 5a and R 5b They are selected independently from hydrogen and deuterium, respectively; R6 and R7 are independently selected from hydrogen and deuterium, respectively; R8 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Carbon cyclo group; among which, The above C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The carbocyclic group may be independently replaced by one or more of the following groups: deuterium, halogen, hydroxyl, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto, mercaptomethyl, mercaptoethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl; R 9a R 9b R 9c They are selected independently from hydrogen and deuterium, respectively; R 10a and R 10b They are selected independently from hydrogen and deuterium, respectively; R 11 R 12 R 13 R 14 and R 15 Each element is independently selected from hydrogen, deuterium, and halogens; G1 and G2 independently select hydrogen, in, The above R a1 and R a2 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkylamine group, or R a1 R a2 Connect them in a loop in any reasonable way; R b Selected from hydrogen, C 1-6 Alkyl, C 3-10 carbonyl group, C 2-8 Heterocyclic group, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-15 Aromatic ring group, C 3-10 Heterocyclic aryl; the above-mentioned C 1-6 Alkyl, C 1-6 alkylamine group, C 3-10 carbon cyclo group, C 2-8 Heterocyclic group, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-15 Aromatic ring group, C 3-10 The heterocyclic aryl group may optionally be substituted with one or more of the following groups: deuterium, halogen, hydroxyl, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto, mercaptomethyl, mercaptoethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl, C 1-6 Alkoxy, C 1-6 Alkylamine group; R c Selected from hydrogen, C 1-6 Alkyl, C 1-6 alkylamine group, C 3-10 carbon cyclo group, C 2-8 Heterocyclic groups; the above-mentioned C 1-6 Alkyl, C 1-6 alkylamine group, C 3-10 carbon cyclo group, C 2-8 The heterocyclic group may optionally be replaced by one or more of the following groups: deuterium, halogen, hydroxyl, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto, mercaptomethyl, mercaptoethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl; R d1 and R d2 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, or R d1 R d2 Connect them in a loop in any reasonable way; R e1 and R e2 Each is independently selected from hydrogen, metal ions, and C. 1-6 Alkyl, C 1-6 alkylamine group, C 3-10 carbon cyclo group, C 2-8 Heterocyclic group, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-15 Aromatic ring group, C 3-10 Heterocyclic aryl, or R e1 R e2 Connected in any reasonable way to form a loop; the above C 1-6 Alkyl, C 1-6 alkylamine group, C 3-10 carbon cyclo group, C 2-8 Heterocyclic group, C 2-8 alkenyl, C 2-8 alkynyl group, C 6-15 Aromatic ring group, C 3-10 The heterocyclic aryl group may optionally be substituted by one or more of the following groups: deuterium, halogen, hydroxyl, amino, nitro, methyl, ethyl, isopropyl, carboxyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, mercapto, mercaptomethyl, mercaptoethyl, acetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl; In particular, When G1 and G2 are both hydrogen, and R8 is not substituted with deuterium, then R1, R2, R3, R 4a R 4b R 5a R 5b R6, R7, R 9a R 9b R 9c R 10a R 10b R 11 R 12 R 13 R 14 and R 15 One of them must be deuterium; or, When G1 is not hydrogen, G2 is hydrogen, and R8 is not replaced by deuterium, and R... 11 R 12 and R 15 When all are halogens, then R1, R2, R3, R 4a R 4b R 5a R 5b R6, R7, R 9a R 9b R 9c R 10a R 10b R 13 and R 14 One of them must be deuterium.

2. The novel spirocyclic compound, tautomer, stereoisomer, prodrug, and pharmaceutically acceptable salt thereof as described in claim 1, wherein the compound includes, but is not limited to, the following compounds:

3. A pharmaceutical composition comprising any novel spirocyclic compound, tautomer, stereoisomer, prodrug, or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 2.

4. Use of the novel spirocyclic compound, tautomer, stereoisomer, prodrug, or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 3 in the preparation of a medicament for calcitonin gene-related peptide (CGRP) receptor-mediated disease.

5. The use according to claim 4, wherein the calcitonin gene-related peptide (CGRP) receptor-mediated disease drug is used to treat cardiovascular diseases, hypertension, diabetes, autoimmune diseases, organ pain, headache, bone diseases, and chronic obstructive pulmonary disease.

6. The medicament described in claim 5 can be used to treat headache disorders, wherein the headache is a migraine.

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