Small-molecule drug for treating CGRP-related disorder

Abstract

The present invention relates to a novel compound as shown in formula (I) and a pharmaceutically acceptable salt thereof, the compound is a CGRP receptor antagonist. The present invention further relates to a pharmaceutical composition of the compound, a preparation method therefor and the therapeutic use thereof.

Description

A small molecule drug for treating CGRP-related disorders Technical Field

[0001] The present invention belongs to the field of biomedicine.

[0002] The present invention relates to novel compounds of Formula I, including pharmaceutically acceptable salts. These compounds are CGRP receptor antagonists. The present invention relates to compounds and pharmaceutical compositions thereof for use in treating CGRP-related disorders, including migraine, neurogenic vasodilation, neurogenic inflammation, and respiratory inflammatory diseases such as asthma and chronic obstructive pulmonary disease. Background Art

[0003] Migraine is the second most common disabling neurological disorder. Its clinical characteristics are recurrent, mostly unilateral, moderate to severe throbbing headaches, often accompanied by nausea, vomiting, photophobia, and phonophobia. Migraine is comorbid with anxiety, depression, and sleep disorders, and may increase the risk of cognitive impairment and cardiovascular and cerebrovascular diseases.

[0004] The World Health Organization lists migraine as one of the 10 most disabling diseases, affecting over 1 billion people worldwide. The number of female sufferers is approximately three times that of male sufferers. China has a migraine prevalence of over 10%, with approximately 132 million sufferers, ranking first globally. However, significant deficiencies remain in the diagnosis and treatment of migraine in my country, with only 52.9% of patients seeking medical attention and only 13.8% of physicians making accurate diagnoses. Furthermore, insufficient preventive treatment and overuse of analgesics are common (see: 2022 Guidelines for the Diagnosis and Treatment of Migraine in China).

[0005] Traditional therapies are diverse and affordable, but they offer poor efficacy, low response rates, significant side effects, and low patient compliance, with satisfaction rates as low as 40%. There is an urgent need for more novel, specific drugs, especially for patients who are intolerant to, have contraindications for, or are unresponsive to current treatments. In recent years, with the successful launch of multiple drugs targeting the novel therapeutic target calcitonin gene-related peptide (CGRP), CGRP-targeted therapies have become breakthroughs in this field. These drugs offer advantages such as greater safety, effectiveness, and the absence of cardiovascular risks, and can address clinical problems that current traditional therapies cannot.

[0006] CGRP is a highly potent vasoactive peptide released from sensory nerves. It contains 37 amino acids and is the most potent endogenous vasodilator peptide known to date, with protective effects in several cardiovascular diseases. CGRP belongs to a family of peptides that includes calcitonin, adrenomedullin, and amylin. In humans, two forms of CGRP exist (a-CGRP and β-CGRP) and have similar activities. CGRP receptors are located in pain signaling pathways, intracranial arteries, and mast cells, and their activation is thought to play a causal role in the pathophysiology of migraine.

[0007] CGRP-targeted therapies work primarily through three mechanisms: 1) Blocking neurogenic inflammation: inhibiting inflammation caused by the release of CGRP from the trigeminal nerve to mast cells in the brain's hard outer shell, or meninges; 2) Reducing arterial dilation: inhibiting pathological dilation of intracranial arteries by blocking CGRP receptors located in smooth muscle cells within the blood vessel walls without producing undesirable vasoconstriction; 3) Inhibiting pain transmission: inhibiting pain transmission by inhibiting the central transmission of pain signals from the trigeminal nerve to the caudate nucleus of the trigeminal nerve.

[0008] Published patent applications related to small-molecule CGRP inhibitors include CN102656159A, CN104136437A, CN117466893A, and CN117624191A. Currently, four CGRP monoclonal antibodies (Erenumab, Fremanezumab, Galcanezumab, and Eptinezumab) and four CGRP small-molecule antagonists (Ubrogepant, Rimegepant, Atogepant, and Zavegepant) are marketed internationally. Due to their long half-lives, monoclonal antibodies are primarily used for prevention. Their high cost and injection-only nature limit their widespread application. In contrast, small-molecule drugs, generally due to their rapid metabolism, are primarily used for acute treatment. Among all marketed CGRP drugs, oral small-molecule drugs have seen the fastest sales growth and the highest satisfaction ratings. Rimegepant is currently the only oral CGRP receptor antagonist approved for both the treatment and prevention of migraines, potentially enabling physicians to prescribe a single medication for both the treatment and prevention of migraine attacks. Since its launch in 2020, Rimegepant has achieved the fastest sales growth, with annual sales reaching US$526 million in 2021; according to the forecast of the original research company Biohaven, Rimegepant's sales in 2028 can reach US$3.3 billion, far exceeding other CGRP antibodies and small molecule drugs.

[0009] While rimegepant is highly regarded, it also has inherent drawbacks, such as poor solubility and permeability. Its clinical onset of action is at least 1.5 hours, leaving room for improvement for acute clinical patients. The present invention relates to a novel class of small-molecule CGRP receptor antagonists with enhanced efficacy, improved permeability, or faster onset of action, as well as pharmaceutical compositions containing them and their use in the treatment of CGRP-related disorders.

[0010] Summary of the Invention

[0011] The present invention relates to a class of novel compounds and pharmaceutically acceptable salts thereof. The compounds are CGRP receptor antagonists. The present invention relates to the use of the compounds and pharmaceutical compositions thereof in treating CGRP-related disorders, including migraine, neurogenic vasodilation, neurogenic inflammation, and respiratory inflammatory diseases such as asthma and chronic obstructive pulmonary disease.

[0012] The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0013] in:

[0014] R 1 is hydrogen, cyano, halogen, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl;

[0015] R 2 is hydrogen, hydroxy, azido or -NR 2a R 2b , where R 2a or R 2b are each independently selected from hydrogen or alkyl, or R 2a and R 2b Together with the atoms to which they are attached, they form a heterocyclic group, which may be optionally substituted by 0-3 identical or different halogen or alkyl groups; preferably hydrogen, hydroxy, azido, amino, alkylamino, dialkylamino, N-pyrrolidinyl, N-piperidinyl or N-piperazinyl; more preferably hydrogen, hydroxy, amino, or N-piperazinyl;

[0016] R 3 is a piperidinyl or piperazinyl substituted with one substituent selected from the group consisting of:

[0017] R 3a is a five-membered or six-membered monocyclic aromatic or heteroaromatic group which may be optionally substituted by 0-2 identical or different halogen or alkyl groups, wherein the heteroaromatic group contains at least one nitrogen atom;

[0018] R3b is alkoxy, alkanoyl, alkyl-S(O)2- or alkyl-S(O)-;

[0019] R 4 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy;

[0020] R 5 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy;

[0021] Ar is phenyl substituted with 0 to 3 substituents selected from the group consisting of cyano, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkyl-S(O)2-;

[0022] P is NH, O or S;

[0023] Q is O or S;

[0024] X is N or CR 6 ;

[0025] R 6 is hydrogen, alkyl or alkoxy;

[0026] Y is O, S or Se;

[0027] Z is NH, CH2, O or S;

[0028] In addition, when Q is O and Y is O, R 3 is piperazinyl substituted with one substituent selected from the group consisting of:

[0029] The alkyl portion of the alkyl or halogenated alkyl, alkoxy, alkylamino, dialkylamino, halogenated alkoxy, alkyl-S(O)2- and alkyl-S(O)- is a straight or branched chain alkyl consisting of 1 to 6 carbon atoms.

[0030] In some embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0031] R 1 is hydrogen, cyano, halogen, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, or piperidinyl;

[0032] R 2 is hydrogen, hydroxy, azido, amino, alkylamino or dialkylamino;

[0033] R 3 is a piperidinyl or piperazinyl substituted with one substituent selected from the group consisting of:

[0034] R4 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy;

[0035] R 5 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy;

[0036] Ar is phenyl substituted with 0 to 3 substituents selected from the group consisting of cyano, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkyl-S(O)2-;

[0037] P is NH, O or S;

[0038] Q is O or S;

[0039] X is N or CR 6 ;

[0040] R 6 is hydrogen, alkyl or alkoxy;

[0041] Y is O, S or Se;

[0042] Z is NH, CH2, O or S;

[0043] In addition, when Q is S and Y is O, R 3 is a piperidinyl or piperazinyl substituted with one substituent selected from the group consisting of:

[0044] When Q is O and Y is O, R 3 is piperazinyl substituted with one substituent selected from the group consisting of:

[0045] The alkyl or halogenated alkyl, alkoxy, alkylamino, dialkylamino, halogenated alkoxy and alkyl-S(O)2- alkyl moiety is a straight chain or branched chain alkyl consisting of 1 to 6 carbon atoms.

[0046] In some embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof having the specified stereochemical structure of formula (I')

[0047] Among them, R 1 、R 2 , Ar, P, Q and R 3 As defined in claim 1 or claim 2.

[0048] In some embodiments, there is provided a compound of formula (I') or a pharmaceutically acceptable salt thereof, wherein:

[0049] R 1is hydrogen, cyano, halogen, alkyl, haloalkyl, amino, alkylamino, dialkylamino;

[0050] R 2 is hydrogen, hydroxy, azido, amino, alkylamino or dialkylamino;

[0051] R 3 is a piperidinyl or piperazinyl substituted with one substituent selected from the group consisting of:

[0052] R 4 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy;

[0053] R 5 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy;

[0054] Ar is phenyl substituted with 0 to 2 halogen substituents;

[0055] P is NH, O or S;

[0056] Q is O or S;

[0057] X is N or CR 6 ;

[0058] R 6 is hydrogen, alkyl or alkoxy;

[0059] Y is O, S or Se;

[0060] Z is NH or CH2;

[0061] In addition, when Q is S and Y is O, R 3 is a piperidinyl or piperazinyl substituted with one substituent selected from the group consisting of:

[0062] When Q is O and Y is O, R 3 is piperazinyl substituted with one substituent selected from the group consisting of:

[0063] In some embodiments, there is provided a compound of formula (I') or a pharmaceutically acceptable salt thereof, wherein R 1 It's hydrogen.

[0064] In some embodiments, a compound of formula (I') or a pharmaceutically acceptable salt thereof is provided, wherein Ar is phenyl substituted with 2 halogen substituents.

[0065] In some embodiments, a compound of formula (I') or a pharmaceutically acceptable salt thereof is provided, wherein Ar is 2,3-difluorophenyl.

[0066] In some embodiments, there is provided a compound of formula (I') or a pharmaceutically acceptable salt thereof, wherein P is O, R 2 is hydrogen, hydroxy or amino.

[0067] In some embodiments, there is provided a compound of formula (I') or a pharmaceutically acceptable salt thereof, wherein R 3 is N-piperidinyl and is 4-substituted, or is N-piperazinyl and is 4-substituted.

[0068] In some embodiments, there is provided a compound of formula (I') or a pharmaceutically acceptable salt thereof, wherein R 2 is amino, R 3 is N-piperidinyl and is 4-substituted.

[0069] In some embodiments, there is provided a compound of formula (I') or a pharmaceutically acceptable salt thereof, wherein R 2 is hydroxyl, R 3 is N-piperidinyl and is 4-substituted.

[0070] In some embodiments, there is provided a compound of formula (I') or a pharmaceutically acceptable salt thereof, wherein R 4 is a hydrogen or halogen substituent; R 5 is a hydrogen or halogen substituent; R 6 is hydrogen; Z is NH.

[0071] In some embodiments, there is provided a compound of formula (I') or a pharmaceutically acceptable salt thereof, wherein:

[0072] R 1 It is hydrogen;

[0073] R 2 is an amino group or a hydroxyl group;

[0074] R 4 is hydrogen or a halogen;

[0075] R 5 It is hydrogen;

[0076] Ar is 2,3-difluorophenyl;

[0077] P is O;

[0078] Q is O or S;

[0079] X is N;

[0080] Y is O, S or Se;

[0081] Z is NH.

[0082] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein X is N; and Z is NH.

[0083] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the compound has a structure of formula (Ia),

[0084] in:

[0085] A is N or CH;

[0086] Ring B is selected from the following groups:

[0087] R 1 is hydrogen, cyano, halogen, alkyl, haloalkyl, amino, alkylamino, dialkylamino;

[0088] R 2 is hydrogen, hydroxy, azido, amino, alkylamino, dialkylamino, N-pyrrolidinyl, N-piperidinyl or N-piperazinyl;

[0089] R 4 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy;

[0090] R 5 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy;

[0091] Ar is a phenyl group substituted with two halogen substituents;

[0092] P is O;

[0093] Q is O or S;

[0094] Y is O, S or Se;

[0095] Preferably, R 1 is hydrogen; R 2 is hydrogen, hydroxy, amino or N-piperazinyl; R 4 is hydrogen or halogen; R 5 is hydrogen or halogen; Ar is 2,3-difluorophenyl;

[0096] Furthermore, when Q is O and Y is O: A is N.

[0097] In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt thereof is provided, wherein:

[0098] A is N or CH;

[0099] Selected from the following groups:

[0100] R 1 It is hydrogen;

[0101] R 2 is hydrogen, hydroxy, amino or N-piperazinyl;

[0102] R 4 is hydrogen or a halogen;

[0103] Ar is a phenyl group substituted with two halogen substituents, preferably a 2,3-difluorophenyl group;

[0104] P is O;

[0105] Q is O or S;

[0106] Y is O, S or Se.

[0107] In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt thereof is provided, wherein the compound has a structure of formula (IVa) or formula (IVb),

[0108] in:

[0109] Selected from the following groups:

[0110] R 1 It is hydrogen;

[0111] R 2 is hydrogen, hydroxy, amino or N-piperazinyl;

[0112] R 4 is hydrogen or a halogen;

[0113] Ar is a phenyl group substituted with two halogen substituents;

[0114] P is O;

[0115] Q is O or S;

[0116] Y is O, S or Se;

[0117] Preferably, R 2 is hydroxy or amino; R 4 is hydrogen, fluorine or chlorine; Ar is 2,3-difluorophenyl.

[0118] In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt thereof is provided, wherein the compound has the structure of formula (V):

[0119] in:

[0120] A is N or CH;

[0121] R 1 It is hydrogen;

[0122] R 2 is hydrogen, hydroxy, amino or N-piperazinyl;

[0123] Q is O or S;

[0124] Y is O, S or Se;

[0125] Preferably, R 2 is amino; Q is O; and Y is S or Se.

[0126] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the compound has a structure of formula (IIa),

[0127] in:

[0128] A is N or CH;

[0129] R 1 is hydrogen, cyano, halogen, alkyl, haloalkyl, amino, alkylamino, dialkylamino;

[0130] R 2 is hydrogen, hydroxy, amino or N-piperazinyl;

[0131] Ar is a phenyl group substituted with two halogen substituents;

[0132] P is O;

[0133] Q is O or S;

[0134] Y is O, S or Se;

[0135] R 3a is a six-membered monocyclic heteroaryl group containing 1-2 nitrogen atoms which may be optionally substituted by 0-2 identical or different halogen or alkyl groups;

[0136] Preferably, A is CH; R 1 is hydrogen; R 2 is amino; Ar is 2,3-difluorophenyl; Q is O; Y is S; R 3a is pyridinyl or pyrimidinyl which may be optionally substituted by 0-2 identical or different halogen or alkyl groups.

[0137] In some embodiments, a compound of formula (IIa) or a pharmaceutically acceptable salt thereof is provided, wherein the compound has a structure of formula (IIc) or formula (IId),

[0138] Among them, A, R 1、R 2 , Ar, P, Q and Y are as defined in claim 21.

[0139] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the compound has a structure of formula (IIIa),

[0140] in:

[0141] A is N or CH;

[0142] R 1 is hydrogen, cyano, halogen, alkyl, haloalkyl, amino, alkylamino, dialkylamino;

[0143] R 2 is hydrogen, hydroxy, azido, amino, alkylamino, dialkylamino, N-pyrrolidinyl, N-piperidinyl or N-piperazinyl;

[0144] Ar is a phenyl group substituted with two halogen substituents;

[0145] P is O;

[0146] Q is O or S;

[0147] R 3b is alkyl-S(O)2- or alkyl-S(O)-;

[0148] R 4 is hydrogen or a halogen;

[0149] R 5 is hydrogen or a halogen;

[0150] Preferably, A is CH; R 1 is hydrogen; R 2 is amino; Ar is 2,3-difluorophenyl; Q is O; R 3b is alkyl-S(O)-; R 4 is hydrogen; R 5 It's hydrogen.

[0151] The present invention includes all pharmaceutically acceptable salt forms of the compounds. Such salts can be prepared using commercially available reagents by conventional organic chemical methods, and specifically include hydrochlorides, hydrobromides, hydroiodides, phosphates, sulfates, nitrates, formates, acetates, succinates, benzenesulfonates, citrates, glucuronates, lactates, methanesulfonates, toluenesulfonates, pamoates, and tartrates.

[0152] The present invention is intended to include all isotopes of atoms in all compounds. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known in the art or by methods analogous to those described herein, and these compounds have the potential to improve pharmacological or pharmacokinetic properties.

[0153] The compounds of the present invention include but are not limited to:

[0154] On the other hand, the present invention provides a method for preparing a compound of formula (I), characterized in that the reaction steps are as shown in Reaction Scheme 1:

[0155] Reaction 1

[0156] In Reaction Scheme 1, compound A is deprotected, and the resulting intermediate B reacts with carbonyldiimidazole or 1,1-thiocarbonyldiimidazole to obtain intermediate C; intermediate C is connected with intermediate D and then deprotected to obtain a general compound as shown in Formula II (wherein, X is O or S; Y is O, S or Se; V is N or CH; Ar is an optionally substituted heteroaryl or aryl group).

[0157] On the other hand, the present invention provides a method for preparing a compound of formula (I), characterized in that the reaction steps are as shown in Reaction Scheme 2:

[0158] Reaction 2

[0159] In Reaction Scheme 2, compound A is deprotected, and the resulting intermediate B reacts with carbonyldiimidazole or 1,1-thiocarbonyldiimidazole to obtain intermediate C; intermediate C is connected with intermediate F and then deprotected to obtain a general compound as shown in Formula III (wherein, X is O or S; Y is O, S or Se; V is N or CH; Ar is an optionally substituted heteroaryl or aryl group).

[0160] On the other hand, the present invention is intended to include all isotopes of atoms in all compounds. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known in the art or by methods analogous to those described herein, and these compounds have the potential to improve pharmacological or pharmacokinetic properties.

[0161] On the other hand, the present invention is intended to include tautomers of all compounds unless otherwise specified. Tautomers refer to a proton shift from one atom of a molecule to another atom of the same molecule, examples of which include keto-enol pairs, amide-imino acid pairs, lactam-lactim pairs, amide-imino acid pairs, enamine-imine pairs, and the like.

[0162] On the other hand, the present invention is intended to include all stereoisomers of the compounds, such as enantiomers and diastereomers, unless otherwise indicated. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolution of racemic mixtures or by stereospecific synthesis. Various geometric isomers of alkenes, C=N double bonds, etc. may also be present in the compounds described herein, and all such stable isomers are intended to be included in the present invention.

[0163] In another aspect, the present invention provides pharmaceutical formulations suitable for use in human patients, comprising any of the compounds shown above (e.g., compounds of the present invention, such as compounds of formula (I)) and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical formulations can be used to treat or prevent the conditions or diseases described herein.

[0164] In another aspect, the present invention discloses methods for treating conditions associated with abnormal CGRP levels, including but not limited to migraine, neurogenic vasodilation, neurogenic inflammation, asthma, and chronic obstructive pulmonary disease.

[0165] In another aspect, the present invention discloses methods for treating or preventing migraine, including but not limited to the treatment of acute migraine attacks and / or the long-term prevention of migraine.

[0166] In another aspect, the present invention discloses combination therapies of a compound of formula (I) and a migraine therapeutic agent that may enhance clinical benefit in the prevention or treatment of migraine beyond the ability of either therapy alone.

[0167] Terminology

[0168] Alkyl or alkane is a completely saturated straight or branched non-aromatic hydrocarbon. Usually, unless otherwise defined, straight or branched alkyl has 1 to about 20 carbon atoms, preferably 1 to about 10 carbon atoms, more preferably 1 to about 6 carbon atoms, most preferably 1 to about 3 carbon atoms. Non-limiting examples of straight and branched alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, amyl, hexyl, amyl and octyl. C1-C6 straight or branched alkyl is also referred to as "low alkyl".

[0169] Furthermore, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include "unsubstituted alkyl" and "substituted alkyl," the latter referring to alkyl moieties having substituents replacing hydrogen on one or more carbons of the hydrocarbon backbone. If not otherwise specified, non-limiting examples of such substituents include, for example, halogen, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that the moieties substituted on the hydrocarbon chain may themselves be substituted, if appropriate. For example, non-limiting examples of substituents of substituted alkyl groups include amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl, as well as substituted and unsubstituted forms of ether, alkylthio, carbonyl (including ketone, aldehyde, carboxylate and ester), -CF3, -CN, and the like.

[0170] Cycloalkyl preferably has 3 to about 20 ring carbon atoms and can be substituted and unsubstituted. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl or methylcyclopentyl, etc. Cycloalkyl can be further substituted by alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF , -CN, etc.

[0171] Aryl refers to a cyclic aromatic group having 5 to about 20 ring carbon atoms. Typically, unless otherwise defined, heteroaryl groups have a monocyclic or bicyclic ring. Non-limiting examples of aryl include phenyl, 1-naphthyl or 2-naphthyl, or bicyclic fused derivatives containing phenyl, such as indanyl, dihydro- or tetrahydro-naphthyl, etc.

[0172] Heteroaryl represents an aromatic group containing at least one heteroatom selected from nitrogen, oxygen and sulfur. Typically, unless otherwise defined, heteroaryl has a monocyclic or bicyclic ring. Monocyclic heteroaryl includes 5 or 6 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur and oxygen. Non-limiting examples of heteroaryl include pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl etc., or bicyclic fused derivatives containing monocyclic heteroaryl, such as indolyl, benzimidazolyl, benzofuranyl, quinolyl, isoquinolyl, quinazolinyl, purinyl etc.

[0173] Heterocyclic radical represents a saturated, partially saturated or unsaturated monocyclic or bicyclic ring containing at least one heteroatom selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclic radicals include pyrrolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, dioxolane or tetrahydropyranyl, or bicyclic fused derivatives containing monocyclic heterocyclic radicals, such as benzopyrrolidinyl, benzopiperidinyl, etc.

[0174] Aryl, heteroaryl or heterocyclic radical can be optionally substituted or unsubstituted. "Substitution" means that one or more hydrogens on aryl, heteroaryl or heterocyclic radical are substituted, and the hydrogen can be hydrogen on a carbon atom or hydrogen on a heteroatom. In the optionally substituted aryl, heteroaryl or heterocyclic radical, substituent is preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl, sulfo, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, amino, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl, oxo or carboxylate etc.

[0175] Alkenyl contains one or more, for example two or three, double bonds and is preferably lower alkenyl, for example 1- or 2-butenyl, 1-propenyl, allyl or vinyl.

[0176] Alkynyl is preferably a lower alkynyl group such as propargyl or ethynyl.

[0177] In optionally substituted alkenyl or alkynyl groups, the substituents are preferably lower alkyl, lower alkoxy, halo or di(lower alkyl)amino and are attached to a saturated carbon atom of the alkenyl or alkynyl group or to an unsaturated carbon atom of the alkenyl group.

[0178] Acyl represents, for example, alkylcarbonyl, cyclohexylcarbonyl, arylcarbonyl, aryl-lower alkylcarbonyl or heteroarylcarbonyl. Lower acyl is preferably lower alkylcarbonyl, in particular propionyl or acetyl.

[0179] The hydroxyalkyl group refers to an alkyl group substituted with at least one hydroxy group, preferably a hydroxy-lower alkyl group, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-n-propyl, and hydroxyisopropyl.

[0180] The cyanoalkyl group refers to an alkyl group substituted by at least one cyano group, preferably a cyano-lower alkyl group, such as cyanomethyl or cyanoethyl.

[0181] The haloalkyl group refers to an alkyl group substituted by at least one halogen, preferably a halo-lower alkyl group, such as monofluoromethyl, difluoromethyl, trifluoromethyl, 3,3,3-trifluoroethyl or pentafluoroethyl.

[0182] Halogen is fluorine, chlorine, bromine or iodine.

[0183] Lower alkoxy is especially methoxy, ethoxy, isopropoxy or tert-butoxy.

[0184] Arylalkyl includes aryl and alkyl as defined above and is, for example, benzyl, 1-phenylethyl or 2-phenylethyl.

[0185] Heteroarylalkyl includes heteroaryl and alkyl as defined above and is, for example, 2-, 3- or 4-pyridylmethyl, 1- or 2-pyrrolylmethyl, 1-pyrazolylmethyl, 1-imidazolylmethyl, 2-(1-imidazolyl)ethyl or 3-(1-imidazolyl)propyl.

[0186] Two adjacent substituents which, together with the atoms of the aryl or heteroaryl radicals, can form a 5- or 6-membered carbocyclic or heterocyclic ring are, for example, propylene, 1- or 2-oxopropylene, 1- or 2-oxapropylene, 1-oxapropylidene, methylenedioxy, difluoro-methylenedioxy, 1- or 2-azapropylene, 1- or 2-azapropylidene, 1,2- or 1,3-diaza-propylidene, 1,3-diaza-2-oxopropylene, butylene, 1- or 2-oxabutylene, ethylenedioxy, 1- or 2-azetidinyl or 1- or 2-azabutadienyl or such radicals which carry further substituents as defined above. BRIEF DESCRIPTION OF THE DRAWINGS

[0187] Figure 1. Blood drug concentrations of RIMEGEPANT, compounds 1, 5, and 21 at different time points after oral administration.

[0188] Figure 2 Blood drug concentration results of RIMEGEPANT, compounds 1, 5, and 21 at different time points after intravenous administration

[0189] Figure 3 Effects of oral administration (PO) of RIMEGEPANT and compound 5 on the comprehensive growth rate of blood flow in model animals DETAILED DESCRIPTION

[0190] The chemical abbreviations used in the present specification and examples generally follow the conventions used in the art and are defined as follows: "CDI" means carbonyldiimidazole; "TCDI" means 1,1-thiocarbonyldiimidazole; "DMF" means N,N-dimethylformamide; "MeOH" means methanol; "N3" means azide; "NO2" means nitro; "Ar" means aryl; "Boc" means tert-butyloxycarbonyl; "DMSO" means dimethyl sulfoxide; "EtOAc" means ethyl acetate; "THF" means tetrahydrofuran; "DCM" means dichloromethane; "ACN" means acetonitrile; "DIPEA" means diisopropylethylamine; "NaHMDS" means sodium bis(trimethylsilyl)amide; "LDA" means lithium diisopropylamide; and "NCS" means N-chlorosuccinimide.

[0191] The structures of the compounds described in the following examples were determined by H NMR spectroscopy ( 1 H-NMR) or mass spectrometry (MS).

[0192] 1 H-NMR measurements were performed on a Bruker 400 MHz nuclear magnetic resonance instrument. The solvents used were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeuterated dimethyl sulfoxide (DMSO-d6), and tetramethylsilane (TMS) was used as the internal standard. Chemical shifts (δ) are given in parts per million (ppm).

[0193] The mass spectrometry (MS) was performed using an Agilent (ESI) mass spectrometer, model Agilent 6120B.

[0194] Thin layer chromatography (TLC) was performed using aluminum plates (20×20 cm) manufactured by Merck, and preparative thin layer chromatography was performed using GF254 (0.4-0.5 mm) silica gel plates.

[0195] The reaction is monitored by thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS), using developing solvents including dichloromethane and methanol, n-hexane and ethyl acetate, and petroleum ether and ethyl acetate. The developing solvent system is adjusted according to the polarity of the compound to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc.).

[0196] The instrument model used for preparative high-performance liquid chromatography was Agilent 1260, and the chromatographic column was Waters XBridge Prep C18 OBD (19 mm × 150 mm × 5.0 μm). The column temperature was 25° C., the flow rate was 20.0 mL / min, and the detection wavelength was 214 nm. The elution gradient was (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B). The mobile phase A was 100% acetonitrile, and the mobile phase B was 0.05% aqueous ammonium bicarbonate solution.

[0197] Unless otherwise specified, the reaction temperature is room temperature (20°C to 30°C).

[0198] The reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company, etc.

[0199] Synthesis method

[0200] The present invention provides the following synthetic methods to synthesize all the compounds involved.

[0201] Ar in the synthesis methods refers to an aryl group or a heteroaryl group.

[0202] Option 1:

[0203] First, the intermediate A is deprotected, and the obtained intermediate B is reacted with carbonyldiimidazole or 1,1-thiocarbonyldiimidazole to obtain intermediate C; intermediate C is connected with intermediate D or F, respectively, and then deprotected to obtain a series of compounds represented by formula (II) and formula (III), respectively.

[0204] Among them, by replacing the piperidinyl group with a piperazinyl group in the substrate, a similar compound with a piperazinyl group in the middle can be obtained.

[0205] The synthesis of intermediate D and intermediate F was based on the method of J. Med. Chem. 2012, 55, 23, 10644.

[0206] The key intermediates of this scheme can be synthesized by the following route:

[0207] Synthesis of intermediate A:

[0208] First, intermediate A1 undergoes a nucleophilic substitution reaction with S, and the nitro group of the obtained intermediate A2 is reduced to an amino group to generate intermediate A3. A3 reacts with carbonyldiimidazole or 1,1-thiocarbonyldiimidazole to obtain the target intermediate A. For intermediate A2, A1' can also react with S' to generate intermediate A2', and then the amino group of A2' is converted to W to obtain the target intermediate.

[0209] This method is applicable to target compounds where Y is O or S.

[0210] Synthesis of intermediate A-5:

[0211] The first two steps are identical to those described above. In the third step, intermediate A6 undergoes Lewis acid-catalyzed dehydration and ring closure with methyl orthoformate to produce intermediate A7. A7 is then subjected to LDA hydrogenation followed by reaction with NCS to produce the chlorinated intermediate A8. Finally, A8 reacts with sodium borohydride and selenium to yield intermediate A-5.

[0212] This method is applicable to target compounds where Y is Se.

[0213] The present invention also provides a method for synthesizing the following intermediates:

[0214] Intermediate A-1 is used as the reaction raw material and undergoes methylation with iodomethane to obtain intermediate I-7; intermediate I-7 is deprotected under acidic conditions to obtain intermediate I-8; intermediate I-8 is condensed with carbonyldiimidazole or thiocarbonyldiimidazole to obtain intermediate C-6.

[0215] Intermediate C-a1 is condensed with thiocarbonyldiimidazole to obtain intermediate C-a2; intermediate C-a2 is condensed with aminopyridine to obtain intermediate C-a3; intermediate C-a3 is deprotected under acidic conditions to obtain intermediate C-a4; intermediate C-a4 is condensed with carbonyldiimidazole or thiocarbonyldiimidazole to obtain intermediate C-a5.

[0216] Intermediate A-b1 is condensed with thiocarbonyl chloride to obtain intermediate A-b2; intermediate A-b2 is condensed with intermediate A-a1 to obtain intermediate A-b3; intermediate A-b3 is deprotected under acidic conditions to obtain intermediate B-b4; intermediate B-b4 is condensed with carbonyldiimidazole or thiocarbonyldiimidazole to obtain intermediate C-b5.

[0217] Synthesis of intermediates

[0218] Synthesis Example 1 Synthesis of Intermediate A-1:

[0219] To a solution of intermediate 2b (10 g, 70.38 mmol, 1 eq) in N,N-dimethylformamide (100 mL) was added potassium carbonate (19.5 g, 140.8 mmol, 2 eq) and intermediate I-1b (15.5 g, 77.4 mmol, 1.1 eq). The reaction mixture was stirred at 80°C for 12 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, quenched with water (500 mL), and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide intermediate I-3b.

[0220] MS (ESI) m / z = 323.1 [M + 1] +

[0221] To a solution of intermediate I-3b (15.0 g, 46.5 mmol, 1.00 eq) in methanol (400 mL) was added palladium carbon (3.00 g, 2.82 mmol, 10% purity, 6.06 eq) under nitrogen protection. -2 eq). The suspension was purged with hydrogen (15 psi) for 3 hours. The reaction mixture was then stirred at 20°C under hydrogen for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure to provide Intermediate I-4b.

[0222] MS (ESI) m / z = 293.2 [M + 1] +

[0223] To a solution of Intermediate I-4b (2 g, 6.84 mmol, 1 eq) in anhydrous tetrahydrofuran (20 mL) was added Intermediate 5b (2.44 g, 13.68 mmol, 2 eq). The reaction was stirred at 80°C for 12 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield Intermediate A-1.

[0224] MS (ESI) m / z = 335.3 [M + 1] +

[0225] 1 H NMR: DMSO-d6δ13.42(brs,1H),8.16(d,J=0.8Hz,1H),7.90(dd,J=8.0,0.8Hz,1H),7.16(dd,J=8.0,0.8Hz,1H),5.28-5.12(m,1H),4.16(br d,J=12.0Hz,2H),2.90(brs,2H),2.30-2.10(m,2H),1.75(br d,J=10.4Hz,2H),1.44(s,9H).

[0226] Synthesis Example 2 Synthesis of Intermediate A-3:

[0227] 4-Amino-2-chloro-3-nitropyridine A1'-3 (3.00 g, 17.2 mmol) was dissolved in ethanol (15 mL), and triethylamine (3.50 g, 34.5 mmol, 4.81 mL) and 1-Boc-4-aminopiperidine (3.46 g, 17.29 mmol) were added. The mixture was reacted at 80 ° C for 12 hours and concentrated under reduced pressure to dryness to obtain A2'-3.

[0228] MS (ESI) m / z = 338.2 [M + 1] +;

[0229] 1 H NMR: (DMSO-d6)δ8.64(br d,J=7.24Hz,1H),8.15(br s,2H),7.65(d,J=5.88Hz,1H),6.12(d,J=5.88Hz,1H),4.16-4.28(m,1H),3.76-3.98(m,2H),3.34-3.50(m,2H),2.91(br d,J=1.63Hz,2H)1.90(br d,J=9.64Hz,2H)1.40(s,9H).

[0230] The crude product (3.00 g, 8.89 mmol) was dissolved in acetonitrile (30 mL), and tert-butyl nitrite (916 mg, 8.89 mmol, 1.06 mL) was added. The mixture was stirred at 25°C for 30 minutes, then cooled to 0°C and cuprous bromide (1.28 g, 8.89 mmol, 270 μL) was added. The reaction was continued at 25°C for 12 hours. The mixture was filtered and concentrated under reduced pressure. The crude product was dissolved in N,N-dimethylformamide (20 mL), and potassium fluoride (738 mg, 12.7 mmol) was added. The reaction was continued at 100°C for 12 hours, then poured into water and extracted three times with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained after decompression and filtration was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 8 / 1 to 3 / 1) to obtain Intermediate A2-3.

[0231] MS (ESI) m / z = 341.2 [M+1] +;

[0232] 1 H NMR: (CDCl3)δ8.00(d,J=5.13Hz,1H),6.90(d,J=5.13Hz,1H),6.64-6.78(m, 1H),4.22(dtd,J=10.8,7.06,7.06,3.63Hz,1H),3.97-4.14(m,2H),2.96(br t,J=11.76Hz,2H),1.96-2.10(m,2H),1.38-1.53(m,11H).

[0233] To a solution of intermediate A2-3 in methanol (15 mL) was added palladium on carbon (0.25 g, 234 μmol, 10% purity), and the mixture was allowed to react at 20°C under a hydrogen atmosphere (50 psi) for 12 hours. The reaction mixture was then filtered and concentrated under reduced pressure to yield intermediate A3-3 (brown solid, 1.1 g, crude product). A3-3 was dissolved in tetrahydrofuran (10 mL), and 1,1-thiocarbonyldiimidazole (1.15 g, 6.44 mmol) was added. The mixture was allowed to react at 50°C for 12 hours. The reaction mixture was then filtered and concentrated under reduced pressure to yield the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to yield intermediate A-3.

[0234] MS (ESI) m / z = 353.2 [M+1] +.

[0235] Synthesis Example 3 Synthesis of Intermediate A-5:

[0236] To a solution of A4 (10 g, 70.38 mmol, 1 eq) in N,N-dimethylformamide (100 mL) were added potassium carbonate (19.5 g, 140.8 mmol, 2 eq) and 1-Boc-4-aminopiperidine (15.5 g, 77.4 mmol, 1.1 eq). The reaction mixture was stirred at 80°C for 12 hours, then concentrated under reduced pressure to remove the solvent. The residue was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield Intermediate A5.

[0237] MS (ESI) m / z = 323.1 [M+1] +.

[0238] A5 (15.0 g, 46.5 mmol, 1.00 eq) was dissolved in methanol (400 mL), palladium on carbon (3.00 g, 2.82 mmol, 10% purity, 6.06 e-2 eq) was added, and the mixture was reacted at 20°C under a hydrogen atmosphere (15 psi) for 16 hours. The reaction mixture was filtered and concentrated to obtain A6.

[0239] MS (ESI) m / z = 293.2 [M+1] +.

[0240] To a solution of A6 (7.20 g, 24.6 mmol, 1.00 eq) in toluene (100 mL) were added p-toluenesulfonic acid (424 mg, 2.46 mmol, 0.1 eq) and triethyl orthoformate (7.30 g, 49.2 mmol, 8.19 mL, 2.00 eq) in sequence. The mixture was reacted at 110°C for 16 hours. The reaction mixture was filtered and concentrated, and the crude product was purified by reverse-phase HPLC (0.1% FA) to yield A7.

[0241] MS (ESI) m / z = 331.2 [M+1] +.

[0242] 1 H NMR: CDCl3δ8.56(dd,J=7.6,4.0Hz,1H),8.18(s,1H),7.77(dd,J=8.0,1.2Hz,1H),7.22(dd,J=8.00, 4.4Hz,1H),4.50-4.32(m,3H),3.00-2.90(m,2H),2.11-2.19(m,2H),1.96-2.09(m,2H),1.48(s,9H).

[0243] To a solution of A7 (1.00 g, 3.31 mmol, 1.00 eq) in tetrahydrofuran (10 mL) at -78°C was slowly added lithium diisopropylamide (2 M, 1.98 mL, 1.20 eq). After the addition was complete, the reaction was continued at this temperature for 1 hour, followed by the dropwise addition of N-chlorosuccinimide (529 mg, 3.97 mmol, 1.20 eq). The mixture was returned to 20°C for 16 hours, then cooled to 0°C and quenched with ammonium chloride solution. The mixture was extracted three times with ethyl acetate, and the resulting organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. This crude product was purified by reverse-phase HPLC (0.1% FA) to yield A8.

[0244] MS (ESI) m / z = 337.2 [M+1] +.

[0245] 1 H NMR: CDCl3δ8.54(dd,J=4.8,1.2Hz,1H),7.81(dd,J=8.00,1.2Hz,1H),7.21(dd,J=8.0,4.8Hz,1H),4.69 -4.62(m,1H),4.50-4.39(m,2H),2.94-2.87(m,2H),2.37-1.96(m,2H),1.94-2.03(m,2H),1.52(s,9H).

[0246] Sodium borohydride (0.17 g, 4.45 mmol, 1.50 eq) was added to a solution of hydrogen selenide (0.36 g, 4.45 mmol, 353 μL, 1.50 eq) in ethanol (10 mL) at 20°C and the reaction was maintained at this temperature for 0.5 hours. A8 (1.00 g, 2.97 mmol, 1.00 eq) was then added and the temperature was raised to 90°C for 12 hours. The mixture was cooled to 0°C, quenched with ammonium chloride solution (50 mL), washed with water (30 mL), and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to yield A-5.

[0247] MS (ESI) m / z = 383.1 [M+1] +.

[0248] Synthesis Example 4 Synthesis of Intermediate H-4:

[0249] A mixture of intermediate H1 (10 g, 59.09 mmol, 1 eq) in dichloromethane (200 mL) was purged with ozone (15 psi) at -78°C for 1 hour. N2 (15 psi) was then vented for half an hour to remove the ozone. Thin-layer chromatography (petroleum ether / ethyl acetate = 10:1) confirmed the completion of the reaction. The reaction mixture was used directly in the next step without treatment. Intermediate D2 was obtained in dichloromethane (200 mL) as a nearly white oil.

[0250] Under nitrogen, to a mixture of intermediate H2 (0.7 g, 3.44 mmol, 2 eq) in dichloromethane (12 mL) and intermediate 12a (500 mg, 1.72 mmol, 1 eq) in tetrahydrofuran (10 mL) was added NaBH(OAc)3 (1.10 g, 5.17 mmol, 3 eq). The reaction mixture was stirred at 25°C for 12 hours. LCMS indicated that the reaction was complete. Under nitrogen, saturated ammonium chloride solution (100 mL) was added at 0°C to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL*3). The organic layers were combined, washed with saturated brine (20 mL*2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford intermediate H-4.

[0251] MS (ESI) m / z = 460.2 [M+1] + .

[0252] 1 H NMR: CDCl3-dδ8.49(d,J=4.8Hz,1H),7.85(brs,1H),7.22(d,J=7.2Hz,1H),7.08-7.05(m,1H),7.04-6.95(m,3H),6.79-6.69(m,1H),6.45-6.40( m,1H),5.04(brs,1H),4.06(brd,J=3.6Hz,1H),3.65-3.40(m,6H),2.65 -2.50(m,2H),2.44-2.30(m,2H),2.29-2.14(m,2H),1.51-1.43(m,10H).

[0253] Synthesis Example 5 Synthesis of Intermediate C':

[0254] To a mixture of Intermediate A-1 (1 g, 2.99 mmol, 1 eq) in anhydrous dioxane (10 mL) was added dioxane hydrochloride (4 M, 30 mL, 40.13 eq) dropwise. The reaction mixture was stirred at 25°C for 12 hours. LCMS confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure to yield Intermediate I-7b.

[0255] MS (ESI) m / z = 235.0 [M+1] +

[0256] To a solution of Intermediate I-7b (700 mg, 2.28 mmol, 1 eq, 2HCl) in anhydrous tetrahydrofuran (5 mL) was added N,N'-carbonyldiimidazole (554 mg, 3.42 mmol, 1.5 eq) and diisopropylethylamine (5.01 mmol, 0.87 mL, 2.2 eq). The reaction mixture was stirred at 40°C for 3 hours. LCMS confirmed the reaction was complete. The reaction mixture was concentrated, acetonitrile (5 mL) was added, and the resulting mixture was filtered. The filter cake was concentrated under reduced pressure to yield Intermediate C'.

[0257] MS (ESI) m / z = 329.1 [M+1] +

[0258] 1 H NMR: DMSO-d6δ13.47(brs,1H),8.19(d,J=1.6Hz,1H),8.18(s,1H),8.12(s,1H) ,7.58-7.56(m,1H),7.23-7.16(m,1H),7.07(s,1H),5.44-5.33(m,1H),4.11(br d,J=12.0Hz,2H),3.31-3.22(m,2H),2.49-2.37(m,2H),1.85(br d,J=10.4Hz,2H).

[0259] Synthesis Example 6 Synthesis of Intermediate C-6:

[0260] To a solution of Intermediate A-1 (3.7 g, 11.06 mmol, 1 eq) in N,N-dimethylformamide (4 mL) was added iodomethane (1.88 g, 13.28 mmol, 826.48 μL, 1.2 eq). The reaction mixture was stirred at 20°C for 1 hour. LCMS confirmed the reaction was complete. The reaction mixture was quenched with sodium bicarbonate (100 mL) and water (100 mL), extracted with ethyl acetate (50 mL*3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain Intermediate I-7.

[0261] MS (ESI) m / z = 349.2 [M+1] +

[0262] To a solution of Intermediate I-7 (4.5 g, 12.91 mmol, 1 eq) in dioxane (1 mL) was added dioxane hydrochloride (2 M, 58.44 mL, 9.05 eq). The reaction was stirred at 25°C for 12 hours. LCMS confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure to yield Intermediate I-8.

[0263] MS (ESI) m / z = 249.1 [M+1] +

[0264] To a solution of Intermediate I-8 (3 g, 12.08 mmol, 1 eq) in tetrahydrofuran (30 mL) were added N,N'-carbonyldiimidazole (5.88 g, 36.24 mmol, 3 eq) and diisopropylethylamine (4.68 g, 36.24 mmol, 6.31 mL, 3 eq). The reaction was stirred at 25°C for 12 hours. LCMS confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified using a reverse phase column chromatography (0.1% NH3·H2O) to afford Intermediate C-6.

[0265] MS (ESI) m / z = 343.1 [M+1] +

[0266] Synthesis Example 7 Synthesis of Intermediate C-a5:

[0267] To a solution of intermediate C-a1 (1 g, 4.99 mmol, 1 eq) in tetrahydrofuran (15 mL) at -15°C was added thiocarbonyldiimidazole (961.02 mg, 5.39 mmol, 1.08 eq). The reaction mixture was stirred at -15-20°C for 14 hours. LCMS confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure and quenched with water (100 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield intermediate C-a2.

[0268] MS (ESI) m / z = 243.1 [M+1] +

[0269] To a solution of 2-aminopyridine (1.36 g, 14.44 mmol, 1 eq) in tetrahydrofuran (5 mL) was added intermediate C-a2 (3.5 g, 14.44 mmol, 1 eq). The reaction mixture was stirred at 70°C for 72 hours. LCMS confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove the solvent and quenched with water (100 mL). The mixture was extracted with ethyl acetate (100 mL*3). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified by reverse-phase HPLC (0.1% FA condition) to obtain intermediate C-a3.

[0270] MS (ESI) m / z = 359.1 [M + 23] +

[0271] To a solution of Intermediate C-a3 (1.5 g, 4.46 mmol, 1 eq) in dioxane (15 mL) was added dioxane hydrochloride (2 M, 28.98 mL, 13 eq). The mixture was stirred at 25°C for 2 hours. LCMS confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure to yield Intermediate C-a4.

[0272] MS (ESI) m / z = 237.1 [M + 23] +

[0273] Dissolve C-a4 (1 g, 4.23 mmol, 1 eq) in tetrahydrofuran (10 mL) and add N,N'-carbonyldiimidazole (2.06 g, 12.69 mmol, 3 eq) and diisopropylethylamine (1.64 g, 12.69 mmol, 2.21 mL, 3 eq). Allow to react at room temperature (25°C) for 14 hours. LCMS confirms the reaction is complete. The reaction mixture is concentrated under reduced pressure to remove the solvent. The crude product is triturated in acetonitrile for 30 min. The mixture is filtered, the solid is collected, and concentrated under reduced pressure to provide intermediate C-a5.

[0274] MS (ESI) m / z = 353.0 [M + 23] +

[0275] Example 1, (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-sulfoxy-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (Compound 1)

[0276] Intermediate A-1 (N-tert-butyloxycarbonyl-4-(2-thio-2,3-dihydro-1H-[4,5-B]pyridin-1-ylpiperidine, 1 g, 3.0 mmol) was dissolved in dioxane hydrochloride solution (4 mol / L, 10 mL), and the mixture was reacted at room temperature (25°C) for 3 hours. After the reaction, the mixture was directly concentrated to dryness to obtain intermediate B-1 as an oily substance.

[0277] B-1 was dissolved in dichloromethane (10 mL), and N,N'-carbonyldiimidazole (534.7 mg, 3.0 mmol) and diisopropylethylamine (775.4 mg, 6.0 mmol) were slowly added at 0°C. After the addition, the mixture was returned to room temperature (25°C) and reacted for 5 hours. The reaction mixture was washed with 0.5 mol / L dilute hydrochloric acid solution and saturated sodium bicarbonate solution, respectively, and dried over anhydrous sodium sulfate. The concentrated crude product was purified by flash column chromatography (silica gel, dichloromethane / methanol = 10 / 1) to obtain intermediate C-1 (625 mg, total yield of two steps 63%).

[0278] Under nitrogen protection, intermediate C-1 (200.0 mg, 0.61 mmol) and intermediate D (192.0 mg, 0.61 mmol) were dissolved in dry tetrahydrofuran (5 mL) and sodium hexamethyldisilazide (NaHMDS, 1 mol / L, 1.22 mL) solution was added dropwise at -15 ° C. After maintaining the temperature for 1 hour, the system was returned to room temperature (25 ° C) and the reaction was continued for 4 hours. The reaction solution was quenched with saturated sodium bicarbonate aqueous solution and extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by flash column chromatography (silica gel, dichloromethane / methanol = 10 / 1) to obtain intermediate D-1 (yellow solid, 200 mg, 57% yield);

[0279] D-1 (0.64 g, 1.11 mmol) was dissolved in tetrahydrofuran (5 mL) and water (1 mL), and trimethylphosphine (1 mol / L, 3.33 mL) was added. The reaction solution was stirred at room temperature (25°C) for 12 hours and concentrated under reduced pressure. The crude product was purified by reverse-phase high-performance liquid chromatography to obtain the target compound 1.

[0280] Compounds 2-4, 6-13, and 18 were synthesized according to the method of Example 1.

[0281] The characterization data of compounds 1-4, 6-13, and 18 are as follows:

[0282] Example 2, (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-selenoyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (Compound 5)

[0283] Intermediate A-5 (0.94 g, 2.47 mmol, 1.00 eq) was dissolved in dioxane hydrochloride (4 mol / L, 10 mL) and reacted at 20°C for 12 hours. LC-MS confirmed the completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain intermediate B-5 (0.9 g, crude) as a yellow solid.

[0284] B-5 (0.9 g, 3.20 mmol, 1.00 eq) was dissolved in tetrahydrofuran (10 mL), and N,N'-carbonyldiimidazole (1.56 g, 9.60 mmol, 3.00 eq) and diisopropylethylamine (1.24 g, 9.60 mmol, 1.67 mL, 3.00 eq) were added. After the addition was completed, the mixture was returned to 50 ° C and reacted for 1 hour. LC-MS confirmed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain a residue. The crude product was triturated with ceric ammonium nitrate (CAN) at 25 ° C for 30 minutes to obtain compound C-5 (1.00 g, crude) as a yellow solid;

[0285] To a solution of Intermediate C-5 (1.00 g, 2.66 mmol, 1.00 eq) and Intermediate D' (520 mg, 1.33 mmol, 0.5 eq) in tetrahydrofuran (10 mL) was added potassium tert-butoxide (1 M, 5 mL, 1.88 eq) at -78°C. Under nitrogen, the reaction mixture was warmed to 20°C and stirred for 12 hours. LCMS confirmed the reaction was complete. The reaction mixture was diluted with 5 mL of water and extracted with ethyl acetate (2 mL x 3). The organic layers were combined, washed with saturated brine (2 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the residue as a yellow solid, Intermediate E-5 (1.00 g, crude).

[0286] Under nitrogen, intermediate E-5 (1.00 g, 1.43 mmol, 1.00 eq) was dissolved in dioxane methanol (1 mL) at -78°C and stirred at 20°C for 12 hours. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to yield the target compound 5.

[0287] Compound 21 was synthesized according to the method of Example 2.

[0288] The characterization data of compounds 5 and 21 are as follows:

[0289] Example 3, (5S,6S,9R)-5-N-piperazinyl-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydropyrrolo[2,3-b]pyridin-1-yl)piperazine-1-carboxylate (Compound 14)

[0290] To a solution of Intermediate C'6 (100 mg, 320.18 μmol, 1 eq) and Intermediate D' (125 mg, 320.18 μmol, 1 eq) in tetrahydrofuran (2 mL) at -20°C was added potassium tert-butoxide (1 M, 640.36 μL, 2 eq). The reaction mixture was stirred at -20°C for 0.5 hour and then at 25°C for 0.5 hour. LCMS confirmed the reaction was complete. The reaction mixture was quenched by pouring into saturated ammonium chloride (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to obtain Intermediate E'7 (15 mg, 23.63 μmol, 7.38% yield) as a brown solid.

[0291] To a solution of intermediate E'7 (15 mg, 23.63 μmol, 1 eq) in dioxane (5 mL) was added HCl / dioxane (2 M, 1.60 mL, 135.34 eq) at 0°C. The mixture was then stirred at 25°C for 1 hour. LCMS indicated the desired product. The reaction mixture was quenched by pouring it into saturated sodium bicarbonate (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a residue. The residue was purified by preparative HPLC to yield the desired compound 14.

[0292] Compound 15 was synthesized according to the method of Example 3.

[0293] The characterization data of compounds 14-15 are as follows:

[0294] Example 4, (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-thioxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperazine-1-carboxylate (Compound 16)

[0295] To a solution of intermediate E-10 (3.00 g, 4.29 mmol, 1 eq) in dioxane was added HCl / dioxane (2 M, 60.00 mL, 27.94 eq) at 25°C. The mixture was then stirred at 25°C for 1 hour. LCMS indicated the desired product. The reaction mixture was quenched by pouring it into saturated sodium bicarbonate (500 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to yield the desired compound 16.

[0296] Compound 20 was synthesized according to the method of Example 4.

[0297] The characterization data of compounds 16 and 20 are as follows:

[0298] Example 5, (5S,6S,9R)-5-N-piperazinyl-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-sulfoxy-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (Compound 17)

[0299] To a solution of intermediate H-4 (90 mg, 195.85 μmol, 1 eq) and intermediate C' (128.63 mg, 391.71 μmol, 2 eq) in tetrahydrofuran (5 mL) and dichloromethane (5 mL) was added potassium tert-butoxide (1 M, 391.71 μL, 2 eq) at 0°C. The mixture was then stirred at 0°C for 0.5 hours. LCMS showed that the desired product was obtained (MS (ESI) m / z = 720.2 [M+1] + The reaction mixture was poured into saturated ammonium chloride (100 mL) for quenching and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with saturated brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford intermediate H-5 (0.1 g, 138.92 μmol, 70.93% yield) as a light yellow oil.

[0300] To a solution of intermediate H-5 (100.00 mg, 138.92 μmol, 1 eq) in dioxane was added HCl / dioxane (2 M, 10 mL, 143.97 eq) at 0°C. The mixture was then stirred at 25°C for 0.5 hours. LCMS indicated the desired product. The reaction mixture was quenched by pouring it into a saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to yield the desired compound 17.

[0301] The characterization data of compound 17 are as follows:

[0302] Example 6, (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-methylsulfinyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (Compound 19)

[0303] To a solution of Intermediate C-6 (175.41 mg, 512.27 μmol, 2 eq) and Intermediate D' (0.1 g, 256.13 μmol, 1 eq) in tetrahydrofuran (10 mL) was added potassium tert-butoxide (1 M, 512.27 μL, 2 eq) at 0°C. The reaction was stirred at 25°C for 0.5 hours. LCMS indicated that the reaction was complete (MS (ESI) m / z = 665.3 [M+1] + ). Under nitrogen protection, saturated ammonium chloride (50 mL) solution was added to the reaction solution at 0°C to quench the reaction, and extracted with ethyl acetate (20 mL*2). The organic layers were combined, washed with saturated brine (30 mL*2), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. Dichloromethane (10 mL) and m-chloroperbenzoic acid (52.00 mg, 256.13 μmol, 85% purity, 1 eq) were added to the residue. The reaction solution was stirred at 25°C for 12 hours. LCMS showed that the target compound was obtained (MS (ESI) m / z=681.3[M+1] + The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution (50 mL) at 0°C under nitrogen and extracted with ethyl acetate (20 mL x 2). The organic layers were combined, washed with saturated brine (30 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford intermediate C-9 (0.1 g, crude) as a yellow oil.

[0304] To a solution of intermediate C-9 (40.96 mg, 60.17 μmol, 1 eq) in dichloromethane (4 mL) was added trifluoroacetic acid (1.54 g, 13.46 mmol, 1 mL, 223.74 eq) at 0°C. The reaction mixture was stirred at 25°C for 12 hours. LCMS showed that the target product was obtained. The reaction mixture was poured into a saturated sodium bicarbonate solution (50 mL) at 0°C under nitrogen protection to quench the mixture, and then extracted with ethyl acetate (20 mL*2). The organic layers were combined, washed with saturated brine (30 mL*2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to obtain the target compound 19.

[0305] The characterization data of compound 19 are as follows:

[0306] Example 7, (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloheptyl[b]pyridin-9-yl 4-(2-pyridylaminomethylthioamido)piperidine-1-carboxylate (Compound 22)

[0307] To a solution of Intermediate C-a5 (253.88 mg, 768.40 μmol, 2 eq) and Intermediate D' (150 mg, 384.20 μmol, 1 eq) in tetrahydrofuran (1 mL) was added potassium tert-butoxide (129.34 mg, 1.15 mmol, 3 eq) at -20°C. The reaction was incubated at -20°C for 0.5 h and then at 25°C for 0.5 h. LCMS indicated the reaction was complete. The reaction was concentrated under reduced pressure to afford Intermediate C-a6 (0.25 g, crude) as a white solid.

[0308] To a solution of intermediate C-a6 (0.25 g, 382.99 μmol, 1 eq) in dioxane (5 mL) was added HCl / dioxane (2 M, 20 mL, 104.44 eq). The reaction was stirred at 25°C for 12 hours. LCMS confirmed the reaction was complete. The reaction was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC to yield the target compound 22.

[0309] Compound 23 was synthesized according to the method of Example 7.

[0310] The characterization data of compounds 22-23 are as follows:

[0311] RIMEGEPANT was synthesized with reference to Example 8 of patent CN102656159A.

[0312] Example 8: In vitro human CGRP receptor antagonist activity test

[0313] Cell culture and reagent configuration:

[0314] 1) Cell line: SK-N-MC;

[0315] 2) Complete culture medium: MEM + 10% fetal bovine serum + 1% penicillin-streptomycin;

[0316] 3) Experimental buffer: 1*HBSS + 20 mM HEPES + 0.1% BSA + 500 μM IBMX.

[0317] Determination of CGRP receptor activity of test compounds:

[0318] After TrypLE digestion, cells were resuspended in assay buffer and seeded into 384-well plates at a density of 2,000 cells per well. Compounds were diluted in assay buffer and 2.5 μl of compound was added to each well. The cells were incubated at 37°C for 10 minutes. α-CGRP was diluted to 8xα-CGRP (80 nM) in assay buffer. 2.5 μl of the diluted 8xα-CGRP from the previous step was added and the cells were incubated at 37°C for 30 minutes. Eu-cAMP tracer and Ulight anti-cAMP were freeze-thawed and diluted in lysis buffer. 10 μl of Eu-cAMP tracer was added to the assay wells, followed by 10 μl of Ulight anti-cAMP. The plate was centrifuged at 200 g for 30 seconds at room temperature and allowed to stand at 25°C for 1 hour before data collection using Envision.

[0319] Data Analysis:

[0320] 1) Calculation of % Inhibition:

[0321] %inhibition=(Signalcmpd-SignalAve_VC) / (SignalAve_PC-SignalAve_VC)×100.

[0322] 2) Calculate compound IC50 using GraphPad nonlinear fitting formula:

[0323] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0324] X: log value of compound concentration; Y: Inhibition%

[0325] The human CGRP receptor antagonist IC50 values ​​of each compound are shown in the following table:

[0326] Table 1

[0327] Example 9, MDR1-MDCKII cell permeability test

[0328] MDR1-MDCKII cells (obtained from Piet Borst, Netherlands Cancer Institute) were cultured at 4.44 x 10 5 Cells / mL were seeded onto polycarbonate membranes in 96-well plates until confluent cell monolayers formed within 4-7 days.

[0329] The test compounds were diluted to a concentration of 2.00 μM (DMSO <1.0%) in transfer buffer (HBSS with 10 mM Hepes, pH 7.4) from a DMSO stock solution and applied to the apical or basolateral side of the cell monolayer. The permeation of the test compounds from A to B or B to A was determined in duplicate. Simultaneously, the permeation of digoxin from A to B or B to A at 10.0 μM and the permeation of nadolol and metoprolol from A to B at 2.00 μM were tested in duplicate. The plates were incubated at 37.0°C, 5.0% CO2, and saturated humidity for 2.5 hours without shaking. In addition, the efflux ratio of each compound was determined. The test and reference compounds were quantified by LC-MS / MS analysis based on the peak area ratio of analyte / standard.

[0330] After the transport assay, a Lucifer Yellow exclusion assay was applied to determine the integrity of the cell monolayer. Remove the buffer from the apical and basolateral chambers, and then add 75 μL of 100 μM Lucifer Yellow to the transfer buffer, and add 250 μL of transfer buffer to the apical and basolateral chambers, respectively. Incubate the plate at 37.0°C, 5.0% CO2 and saturated humidity for 30 minutes without shaking. After incubation for 30 minutes, remove 20 μL of Lucifer Yellow sample from the apical side and add 60 μL of transfer buffer. Then take 80 μL of Lucifer Yellow sample from the basolateral side. The relative fluorescence units (RFU) of Lucifer Yellow were measured using an Envision plate reader at 425 / 528 nm (excitation / emission) wavelengths.

[0331] Data Analysis:

[0332] The calculation formula of apparent permeability coefficient Papp (cm / s) is:

[0333] P app =(dC r / d t )x V r / (Ax C0)

[0334] where dC r / d tis the cumulative concentration of the compound in the receiving chamber over time (μM / s); V r is the volume of solution in the receiving chamber (0.075 mL on the apical side and 0.25 mL on the basolateral side); A is the surface area of ​​the transport, for example, the area of ​​a monolayer is 0.143 cm 2 ; C0 is the initial concentration in the donor compartment (μM).

[0335] The efflux ratio was calculated using the following formula:

[0336] Efflux Ratio=Papp(BA) / Papp(AB)

[0337] A higher Papp(AB) indicates better passive diffusion and better permeability of the compound; a low efflux ratio suggests that the compound may not be a substrate of the relevant efflux transporter and has a higher potential blood-brain barrier permeability, which facilitates drug entry into the brain and leads to higher brain exposure levels.

[0338] Table 2

[0339] Example 10: Oral pharmacokinetic study in cynomolgus monkeys

[0340] Using cynomolgus monkeys as test animals, the UPLC-MS / MS method was used to determine the compound concentration in plasma at different time points after a single oral administration of the disclosed compound to study the pharmacokinetics of the disclosed compound in cynomolgus monkeys.

[0341] Test animals: Cynomolgus monkeys (male, about 3 to 5 years old, weighing 5 to 9 kg).

[0342] Drug preparation: The solvent was DMSO / HS-15 / normal saline (5:5:90, v:v:v).

[0343] Administration: Single oral gavage; animals were fasted for 12 hours or more before administration and had normal drinking water; the dosage of RIMEGEPANT and compounds 1, 5, and 21 was 10 mg / kg.

[0344] Sample collection: The collection site was the saphenous vein on the medial side of the right forelimb; plasma was collected before administration and 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration; 0.5 mL of whole blood was collected from each blood collection point and plasma was separated; the plasma was separated by centrifugation at 4°C and 1800g for 10 minutes, and the supernatant was collected; the blood drug concentration was then quantitatively analyzed using UPLC-MS / MS analysis.

[0345] The results of blood drug concentrations of RIMEGEPANT, compounds 1, 5, and 21 at different time points after oral administration are shown in Figure 1. The exposure AUCs of compounds 1, 5, and 21 at different time points were significantly higher than that of RIMEGEPANT.

[0346] Example 11: Intravenous pharmacokinetic study in cynomolgus monkeys

[0347] Using cynomolgus monkeys as test animals, the UPLC-MS / MS method was used to determine the compound concentration in plasma at different time points after a single intravenous administration of the disclosed compound to study the pharmacokinetics of the disclosed compound in cynomolgus monkeys.

[0348] Test animals: Cynomolgus monkeys (male, about 3 to 5 years old, weighing 5 to 9 kg).

[0349] Drug preparation: The solvent was DMSO / HS-15 / normal saline (5:5:90, v:v:v).

[0350] Administration: Single intravenous injection; the dosage of RIMEGEPANT and compounds 1, 5, and 21 was 1 mg / kg.

[0351] Sample collection: The collection site was the saphenous vein on the medial side of the right forelimb; plasma was collected before administration and 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration; 0.5 mL of whole blood was collected from each blood collection point and plasma was separated; the plasma was separated by centrifugation at 4°C and 1800g for 10 minutes, and the supernatant was collected; the blood drug concentration was then quantitatively analyzed using UPLC-MS / MS analysis.

[0352] The results of plasma concentrations of RIMEGEPANT, compounds 1, 5, and 21 at different time points after intravenous administration are shown in FIG2 . The exposure AUCs of compounds 1, 5, and 21 at different time points were significantly higher than those of RIMEGEPANT.

[0353] Example 12: Oral pharmacodynamics study in cynomolgus monkeys

[0354] Cynomolgus monkeys were used as test animals to study the effect of a single oral (PO) administration of the disclosed compounds on blood flow using a hCGRP local injection model.

[0355] PO groups: RIMEGEPANT group (Yangshen); Compound 5 group; Model group (blank control)

[0356] Test animals: Cynomolgus monkeys (male, about 3 to 5 years old, weighing 5 to 9 kg).

[0357] Drug preparation: The solvent was DMSO / HS-15 / normal saline (5:5:90, v:v:v).

[0358] Preparation of modeling agent: 5% DMSO + 30% PEG300 + 5% Tween 80 + 60% ddH2O solvent was prepared into a mother solution with a concentration of 20 mg / mL and stored in aliquots at -20°C. When used, it was diluted with PBS to a working solution with a concentration of 5 μg / mL.

[0359] Modeling: The day before hCGRP modeling, the forearms of the animals undergoing modeling were depilated at the modeling site. Animals in the PO group were fasted for 12 hours prior to surgery, but not water. Animals in the IV group were fed a normal diet and received a 0.04 mg / kg injection of atropine sulfate approximately half an hour before anesthesia to reduce glandular secretion. After anesthesia with an intramuscular injection of 0.1 mL / kg of Zotai 50, the animals were transferred to the operating room. A 20 μL injection of 0.1 μg CGRP was injected intradermally into an area of ​​the forearm devoid of visible blood vessels. The same volume of vehicle was injected as a vehicle control. Injections of hCGRP and the vehicle control in the PO group were administered at 0, 30, and 60 minutes.

[0360] Administration: Single oral gavage; the PO group was administered 80 minutes before the first CGRP injection, and the dosage of RIMEGEPANT and compound 5 was 3 mg / kg.

[0361] Sample collection: The collection site was the medial saphenous vein of the right forelimb; 0.5 mL of whole blood was collected at each blood sampling point, and plasma was separated; the plasma separation method was centrifugation at 4°C and 1800g for 10 minutes, and the supernatant was collected; the blood concentration was then quantitatively analyzed by UPLC-MS / MS analysis method; the blood sampling points for the PO group were -5 minutes, 5 minutes, 20 minutes, 35 minutes, 50 minutes, 65 minutes, and 80 minutes.

[0362] Skin blood flow assessment: Laser Doppler speckle flowmetry was used to measure skin blood flow at the injection site at various time points. Based on the blood flow values ​​at each time point (blood flow t), the percentage increase in skin blood flow (%) was calculated as (blood flow t - blood flow baseline) / blood flow baseline × 100%. The integrated blood flow growth rate (%) was calculated as the percentage increase in blood flow on the CGRP-treated side - the percentage increase in blood flow on the control side. hCGRP can induce hemodynamic changes, leading to increased blood flow. The integrated blood flow growth rate (%) reflects the rate of hCGRP-induced blood flow increase. A lower integrated blood flow growth rate (%) indicates that the compound has a greater inhibitory effect on the hCGRP-induced blood flow increase.

[0363] Data analysis: Data were entered and statistically analyzed using Excel 2010, GraphPad Prism 7, and Stata 15.0 software. The effects of oral administration (PO) of RIMEGEPANT and Compound 5 on the comprehensive growth rate of blood flow in model animals are shown in Figure 3.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in: R 1 is hydrogen, cyano, halogen, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl; R 2 is hydrogen, hydroxyl, azido or -NR 2a R 2b , where R 2a or R 2b are each independently selected from hydrogen or alkyl, or R 2a and R 2b Together with the atoms to which they are attached, they form a heterocyclic group, which may be optionally substituted by 0-3 identical or different halogen or alkyl groups; preferably hydrogen, hydroxy, azido, amino, alkylamino, dialkylamino, N-pyrrolidinyl, N-piperidinyl or N-piperazinyl; more preferably hydrogen, hydroxy, amino, or N-piperazinyl; R 3 is piperidinyl or piperazinyl substituted with 1 substituent selected from the following: R 3a is a five-membered or six-membered monocyclic aromatic or heteroaromatic group which may be optionally substituted by 0-2 identical or different halogen or alkyl groups, wherein the heteroaromatic group contains at least one nitrogen atom; R 3b is alkoxy, alkanoyl, alkyl-S(O)2- or alkyl-S(O)-; R 4 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy; R 5 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy; Ar is phenyl substituted with 0 to 3 substituents selected from the group consisting of cyano, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkyl-S(O)2-; P is NH, O or S; Q is O or S; X is N or CR 6 ; R 6 is hydrogen, alkyl or alkoxy; Y is O, S or Se; Z is NH, CH2, O or S; In addition, when Q is O and Y is O, R 3 is piperazinyl substituted with 1 substituent selected from the following: The alkyl part in the alkyl or haloalkyl, alkoxy, alkylamino, dialkylamino, haloalkoxy, alkyl-S(O)2- and alkyl-S(O)- is a straight or branched chain alkyl consisting of 1 to 6 carbon atoms.

2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen, cyano, halogen, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl or piperidinyl; R 2 is hydrogen, hydroxy, azido, amino, alkylamino or dialkylamino; R 3 is piperidinyl or piperazinyl substituted with 1 substituent selected from the following: R 4 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy; R 5 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy; Ar is phenyl substituted with 0 to 3 substituents selected from the group consisting of cyano, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkyl-S(O)2-; P is NH, O or S; Q is O or S; X is N or CR 6 ; R 6 is hydrogen, alkyl or alkoxy; Y is O, S or Se; Z is NH, CH2, O or S; In addition, when Q is S and Y is O, R 3 is piperidinyl or piperazinyl substituted with 1 substituent selected from the following: When Q is O and Y is O, R 3 is piperazinyl substituted with 1 substituent selected from the following: The alkyl or halogenated alkyl, alkoxy, alkylamino, dialkylamino, halogenated alkoxy and alkyl-S(O)2- are linear or branched alkyl groups consisting of 1 to 6 carbon atoms.

3. A compound according to claim 1 or 2, having the specified stereochemical structure of formula (I') in, R 1 , R 2 , Ar, P, Q and R 3 As defined in claim 1 or claim 2.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen, cyano, halogen, alkyl, haloalkyl, amino, alkylamino, dialkylamino; R 2 is hydrogen, hydroxy, azido, amino, alkylamino or dialkylamino; R 3 is piperidinyl or piperazinyl substituted with 1 substituent selected from the following: R 4 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy; R 5 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy; Ar is phenyl substituted with 0 to 2 halogen substituents; P is NH, O or S; Q is O or S; X is N or CR 6 ; R 6 is hydrogen, alkyl or alkoxy; Y is O, S or Se; Z is NH or CH2; In addition, when Q is S and Y is O, R 3 is piperidinyl or piperazinyl substituted with 1 substituent selected from the following: When Q is O and Y is O, R 3 is piperazinyl substituted with 1 substituent selected from the following:

5. A compound according to claim 4, wherein R 1 It's hydrogen.

6. A compound according to claim 5, wherein Ar is phenyl substituted with 2 halogen substituents.

7. The compound according to claim 6, wherein Ar is 2,3-difluorophenyl.

8. The compound according to claim 7, wherein P is O, R 2 is hydrogen, hydroxy or amino.

9. A compound according to claim 8, wherein R 3 is N-piperidinyl and is 4-substituted, or is N-piperazinyl and is 4-substituted.

10. The compound according to claim 9, wherein R 2 is amino, R 3 is N-piperidinyl and is 4-substituted.

11. The compound according to claim 9, wherein R 2 is hydroxyl, R 3 is N-piperidinyl and is 4-substituted.

12. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen or a halogen substituent; R 5 is hydrogen or a halogen substituent; R 6 is hydrogen; Z is NH.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein: R 1 It is hydrogen; R 2 is an amino group or a hydroxyl group; R 4 is hydrogen or a halogen; R 5 It is hydrogen; Ar is 2,3-difluorophenyl; P is O; Q is O or S; X is N; Y is O, S or Se; Z is NH.

14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N; and Z is NH.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (Ia), in: A is N or CH; Ring B is selected from the following groups: R 1 is hydrogen, cyano, halogen, alkyl, haloalkyl, amino, alkylamino, dialkylamino; R 2 is hydrogen, hydroxy, azido, amino, alkylamino, dialkylamino, N-pyrrolidinyl, N-piperidinyl or N-piperazinyl; R 4 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy; R 5 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy; Ar is a phenyl group substituted with two halogen substituents; P is O; Q is O or S; Y is O, S or Se; Preferably, R 1 is hydrogen; R 2 is hydrogen, hydroxy, amino or N-piperazinyl; R 4 is hydrogen or halogen; R 5 is hydrogen or halogen; Ar is 2,3-difluorophenyl; Furthermore, when Q is O and Y is O: A is N.

16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein: A is N or CH; Selected from the following groups: R 1 It is hydrogen; R 2 is hydrogen, hydroxy, amino or N-piperazinyl; R 4 is hydrogen or a halogen; Ar is phenyl substituted with 2 halogen substituents, preferably 2,3-difluorophenyl; P is O; Q is O or S; Y is O, S or Se.

17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (IVa) or formula (IVb), in: Selected from the following groups: R 1 It is hydrogen; R 2 is hydrogen, hydroxy, amino or N-piperazinyl; R 4 is hydrogen or a halogen; Ar is a phenyl group substituted with two halogen substituents; P is O; Q is O or S; Y is O, S or Se; Preferably, R 2 is hydroxyl or amino; R 4 is hydrogen, fluorine or chlorine; Ar is 2,3-difluorophenyl.

18. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (V): in: A is N or CH; R 1 It is hydrogen; R 2 is hydrogen, hydroxy, amino or N-piperazinyl; Q is O or S; Y is O, S or Se; Preferably, R 2 is amino; Q is O; Y is S or Se.

19. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (IIa), in: A is N or CH; R 1 is hydrogen, cyano, halogen, alkyl, haloalkyl, amino, alkylamino, dialkylamino; R 2 is hydrogen, hydroxy, amino or N-piperazinyl; Ar is a phenyl group substituted with two halogen substituents; P is O; Q is O or S; Y is O, S or Se; R 3a is a six-membered monocyclic heteroaryl group containing 1-2 nitrogen atoms which may be optionally substituted by 0-2 identical or different halogen or alkyl groups; Preferably, A is CH; R 1 is hydrogen; R 2 is amino; Ar is 2,3-difluorophenyl; Q is O; Y is S; R 3a is pyridinyl or pyrimidinyl which may be optionally substituted by 0-2 identical or different halogen or alkyl groups.

20. The compound according to claim 19 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (IIc) or formula (IId), in, A.R 1 , R 2 , Ar, P, Q and Y are as defined in claim 19.

21. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (IIIa), in: A is N or CH; R 1 is hydrogen, cyano, halogen, alkyl, haloalkyl, amino, alkylamino, dialkylamino; R 2 is hydrogen, hydroxy, azido, amino, alkylamino, dialkylamino, N-pyrrolidinyl, N-piperidinyl or N-piperazinyl; Ar is a phenyl group substituted with two halogen substituents; P is O; Q is O or S; R 3b is alkyl-S(O)2- or alkyl-S(O)-; R 4 is hydrogen or a halogen; R 5 is hydrogen or a halogen; Preferably, A is CH; R 1 is hydrogen; R 2 is amino; Ar is 2,3-difluorophenyl; Q is O; R 3b is alkyl-S(O)-; R 4 is hydrogen; R 5 It's hydrogen.

22. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein the compound is selected from:

23. A process for preparing a compound according to any one of claims 1 to 20, characterized in that The reaction steps are shown in reaction formula 1: Reaction 1 In Reaction Scheme 1, compound A is deprotected, and the obtained intermediate B reacts with carbonyldiimidazole or 1,1-thiocarbonyldiimidazole to obtain intermediate C; intermediate C is connected with intermediate D and then deprotected to obtain a general compound as shown in Formula II (wherein, X is O or S; Y is O, S or Se; V is N or CH; Ar is an optionally substituted heteroaryl or aryl group).

24. A process for preparing a compound according to any one of claims 1 to 20, characterized in that The reaction steps are shown in reaction formula 2: Reaction 2 In reaction formula 2, compound A is deprotected, and the obtained intermediate B reacts with carbonyl diimidazole or 1,1-thiocarbonyl diimidazole to obtain intermediate C; intermediate C is connected with intermediate F and then deprotected to obtain a general compound as shown in formula III (wherein, X is O or S; Y is O, S or Se; V is N or CH; Ar is optionally substituted heteroaryl or aryl).

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

26. Use of a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating a condition associated with abnormal CGRP levels.

27. Use according to claim 26, wherein the condition is migraine, neurogenic vasodilation, neurogenic inflammation, asthma and chronic obstructive pulmonary disease.

28. Use according to claim 27, wherein the condition is migraine.

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