Small molecule medicine for treating CGRP related disorders

Abstract

The invention relates to a novel compound as shown in a formula (I) and pharmaceutically acceptable salts thereof. # imgabs0, wherein the compound is a CGRP receptor antagonist; the invention also relates to a pharmaceutical composition of the compound, a preparation method and a therapeutic use thereof.

Description

Technical Field

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

[0002] The present invention relates to a novel compound of formula I comprising a pharmaceutically acceptable salt. The compound is a CGRP receptor antagonist. The present invention relates to the compound and its pharmaceutical composition for treating CGRP-related disorders, including migraine, neurogenic vasodilation, neurogenic inflammation, respiratory inflammatory diseases such as asthma and chronic obstructive pulmonary disease, etc. Background Art

[0003] Migraine is the second most common disabling neurological disease, with clinical features of 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 dysfunction and cardiovascular and cerebrovascular diseases.

[0004] The World Health Organization lists migraine as one of the 10 most disabling diseases, affecting more than 1 billion people worldwide. The number of female patients is about three times that of male patients. The incidence of migraine in China exceeds 10%, with about 132 million patients, ranking first in the world. However, there are still major deficiencies in the diagnosis and treatment of migraine in my country. The patient consultation rate is only 52.9%, and the correct diagnosis rate of doctors is only 13.8%. In addition, there are widespread problems such as insufficient preventive treatment and excessive use of analgesics (reference: 2022 edition of the Chinese Migraine Diagnosis and Treatment Guidelines).

[0005] Traditional therapies are of various types and inexpensive, but they have poor efficacy, low response rate, large side effects, and low patient compliance! The satisfaction rate is only 40%. More new specific drugs are urgently needed in the clinic, especially for patients who are intolerant, contraindicated, or unresponsive to current treatments. In recent years, with the successful launch of a number of drugs related to the new therapeutic target calcitonin gene-related peptide (CGRP), CGRP-targeted therapeutic drugs have become a breakthrough therapy in this field. Due to its advantages such as being safer, more effective, and free of cardiovascular risks, it can solve clinical problems that current traditional therapies cannot solve.

[0006] CGRP is a highly potent vasoactive peptide released from sensory nerves, containing 37 amino acids. It is the strongest endogenous vasodilator peptide known to date and has a protective effect in several cardiovascular diseases. CGRP belongs to a family of peptides that includes calcitonin, adrenomedullin, and amylin. In humans, there are two forms of CGRP (a-CGRP and β-CGRP) and they 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 therapy works 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 in smooth muscle cells within the blood vessel wall 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] The patent applications related to the disclosed small molecule CGRP inhibitors include CN102656159A, CN104136437A, CN117466893A and CN117624191A. At present, there are 4 CGRP monoclonal antibodies (Erenumab, Fremanezumab, Galcanezumab and Eptinezumab) and 4 CGRP small molecule antagonists (Ubrogepant, Rimegepant, Atogepant and Zavegepant) on the market abroad. Monoclonal antibody drugs are mainly used for prevention due to their long half-life, and they are expensive and can only be injected, which limits their wide application. In contrast, small molecule drugs are mainly used for acute treatment due to their generally rapid metabolism. Among all the CGRP drugs on the market, oral small molecule drugs have the fastest sales growth and the highest satisfaction. Among them, Rimegepant is currently the only oral CGRP receptor antagonist approved for the treatment and prevention of migraines. Doctors are expected to prescribe a single drug to treat and prevent migraine attacks. Since its launch in 2020, Rimegepant's sales have grown the fastest, with full-year 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] Although Rimegepant is favored by everyone, it also has its inherent disadvantages, such as poor solubility and poor permeability; its clinical onset time is at least 1.5 hours, and there is still room for improvement for clinical acute patients. The present invention relates to a class of small molecule CGRP receptor antagonists with novel structures, better efficacy, better permeability or faster onset, pharmaceutical compositions containing them, and their use in treating CGRP-related disorders. Summary of the invention

[0010] The present invention relates to a class of novel compounds and pharmaceutically acceptable salts thereof. The compounds of the present invention are CGRP receptor antagonists. The present invention relates to the compounds and pharmaceutical compositions thereof for treating diseases associated with CGRP disorders, including migraine, neurogenic vasodilation, neurogenic inflammation, respiratory inflammatory diseases such as asthma and chronic obstructive pulmonary disease, etc.

[0011] The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0012]

[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, 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;

[0016] R 3 is piperidinyl or piperazinyl substituted with 1 substituent selected from the following:

[0017]

[0018]

[0019] 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;

[0020] R 3b is alkoxy, alkanoyl, alkyl-S(O) 2 - or alkyl-S(O)-;

[0021] R 4 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy;

[0022] R 5 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy;

[0023] 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 -;

[0024] P is NH, O or S;

[0025] Q is O or S;

[0026] X is N or CR 6 ;

[0027] R 6 is hydrogen, alkyl or alkoxy;

[0028] Y is O, S or Se;

[0029] Z is NH, CH 2 , O or S;

[0030] In addition, when Q is O and Y is O, R 3 is piperazinyl substituted with 1 substituent selected from the following:

[0031]

[0032] wherein the alkyl or halogenated alkyl, alkoxy, alkylamino, dialkylamino, halogenated alkoxy, alkyl-S(O) 2 The alkyl portion in - and alkyl-S(O)- is a straight or branched chain alkyl consisting of 1 to 6 carbon atoms.

[0033] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein:

[0034] R 1 is hydrogen, cyano, halogen, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl or piperidinyl;

[0035] R 2 is hydrogen, hydroxy, azido, amino, alkylamino or dialkylamino;

[0036] R 3 is piperidinyl or piperazinyl substituted with 1 substituent selected from the following:

[0037]

[0038] R 4is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy;

[0039] R 5 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy;

[0040] 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 -;

[0041] P is NH, O or S;

[0042] Q is O or S;

[0043] X is N or CR 6 ;

[0044] R 6 is hydrogen, alkyl or alkoxy;

[0045] Y is O, S or Se;

[0046] Z is NH, CH 2 , O or S;

[0047] In addition, when Q is S and Y is O, R 3 is piperidinyl or piperazinyl substituted with 1 substituent selected from the following:

[0048]

[0049] When Q is O and Y is O, R 3 is piperazinyl substituted with 1 substituent selected from the following:

[0050]

[0051] wherein the alkyl or halogenated alkyl, alkoxy, alkylamino, dialkylamino, halogenated alkoxy and alkyl-S(O) 2 The alkyl portion in - is a straight or branched chain alkyl consisting of 1 to 6 carbon atoms.

[0052] In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, which has a specified stereochemical structure of formula (I'):

[0053]

[0054] Among them, R 1 , R 2 , Ar, P, Q and R 3 As defined in claim 1 or claim 2.

[0055] In some embodiments, a compound of formula (I') or a pharmaceutically acceptable salt thereof is provided, wherein:

[0056] R 1 is hydrogen, cyano, halogen, alkyl, haloalkyl, amino, alkylamino, dialkylamino;

[0057] R 2 is hydrogen, hydroxy, azido, amino, alkylamino or dialkylamino;

[0058] R 3 is piperidinyl or piperazinyl substituted with 1 substituent selected from the following:

[0059]

[0060] R 4 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy;

[0061] R 5 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy;

[0062] Ar is phenyl substituted with 0 to 2 halogen substituents;

[0063] P is NH, O or S;

[0064] Q is O or S;

[0065] X is N or CR 6 ;

[0066] R 6 is hydrogen, alkyl or alkoxy;

[0067] Y is O, S or Se;

[0068] Z is NH or CH 2 ;

[0069] In addition, when Q is S and Y is O, R 3 is piperidinyl or piperazinyl substituted with 1 substituent selected from the following:

[0070]

[0071] When Q is O and Y is O, R 3 is piperazinyl substituted with 1 substituent selected from the following:

[0072]

[0073] In some embodiments, a compound of formula (I') or a pharmaceutically acceptable salt thereof is provided, wherein R 1 It's hydrogen.

[0074] 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.

[0075] In some embodiments, a compound of formula (I') or a pharmaceutically acceptable salt thereof is provided, wherein Ar is 2,3-difluorophenyl.

[0076] In some embodiments, a compound of formula (I') or a pharmaceutically acceptable salt thereof is provided, wherein P is O, R 2 is hydrogen, hydroxy or amino.

[0077] In some embodiments, a compound of formula (I') or a pharmaceutically acceptable salt thereof is provided, wherein R 3 is N-piperidinyl and is 4-substituted, or is N-piperazinyl and is 4-substituted.

[0078] In some embodiments, a compound of formula (I') or a pharmaceutically acceptable salt thereof is provided, wherein R 2 is amino, R 3 is N-piperidinyl and is 4-substituted.

[0079] In some embodiments, a compound of formula (I') or a pharmaceutically acceptable salt thereof is provided, wherein R 2 is hydroxyl, R 3 is N-piperidinyl and is 4-substituted.

[0080] In some embodiments, a compound of formula (I') or a pharmaceutically acceptable salt thereof is provided, wherein R 4 is hydrogen or a halogen substituent; R 5 is hydrogen or a halogen substituent; R 6 is hydrogen; Z is NH.

[0081] In some embodiments, a compound of formula (I') or a pharmaceutically acceptable salt thereof is provided, wherein:

[0082] R 1 It is hydrogen;

[0083] R 2 is an amino group or a hydroxyl group;

[0084] R 4 is hydrogen or a halogen;

[0085] R 5 It is hydrogen;

[0086] Ar is 2,3-difluorophenyl;

[0087] P is O;

[0088] Q is O or S;

[0089] X is N;

[0090] Y is O, S or Se;

[0091] Z is NH.

[0092] In some embodiments, provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is N; and Z is NH.

[0093] 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),

[0094]

[0095] in:

[0096] A is N or CH;

[0097] Ring B is selected from the following groups:

[0098]

[0099] R 1 is hydrogen, cyano, halogen, alkyl, haloalkyl, amino, alkylamino, dialkylamino;

[0100] R 2 is hydrogen, hydroxy, azido, amino, alkylamino, dialkylamino, N-pyrrolidinyl, N-piperidinyl or N-piperazinyl;

[0101] R 4 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy;

[0102] R 5 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy;

[0103] Ar is a phenyl group substituted with two halogen substituents;

[0104] P is O;

[0105] Q is O or S;

[0106] Y is O, S or Se;

[0107] 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;

[0108] Furthermore, when Q is O and Y is O: A is N.

[0109] In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt thereof is provided, wherein:

[0110] A is N or CH;

[0111] Selected from the following groups:

[0112]

[0113] R 1 It is hydrogen;

[0114] R 2 is hydrogen, hydroxy, amino or N-piperazinyl;

[0115] R 4 is hydrogen or a halogen;

[0116] Ar is phenyl substituted with 2 halogen substituents, preferably 2,3-difluorophenyl;

[0117] P is O;

[0118] Q is O or S;

[0119] Y is O, S or Se.

[0120] 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),

[0121]

[0122] in:

[0123] Selected from the following groups:

[0124]

[0125] R 1 It is hydrogen;

[0126] R 2 is hydrogen, hydroxy, amino or N-piperazinyl;

[0127] R 4 is hydrogen or a halogen;

[0128] Ar is a phenyl group substituted with two halogen substituents;

[0129] P is O;

[0130] Q is O or S;

[0131] Y is O, S or Se;

[0132] Preferably, R 2 is hydroxyl or amino; R 4 is hydrogen, fluorine or chlorine; Ar is 2,3-difluorophenyl.

[0133] In some embodiments, a compound of formula (Ia) or a pharmaceutically acceptable salt thereof is provided, wherein the compound has a structure of formula (V):

[0134]

[0135] in:

[0136] A is N or CH;

[0137] R 1 It is hydrogen;

[0138] R 2 is hydrogen, hydroxy, amino or N-piperazinyl;

[0139] Q is O or S;

[0140] Y is O, S or Se;

[0141] Preferably, R 2 is amino; Q is O; Y is S or Se.

[0142] 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),

[0143]

[0144] in:

[0145] A is N or CH;

[0146] R 1 is hydrogen, cyano, halogen, alkyl, haloalkyl, amino, alkylamino, dialkylamino;

[0147] R 2 is hydrogen, hydroxy, amino or N-piperazinyl;

[0148] Ar is a phenyl group substituted with two halogen substituents;

[0149] P is O;

[0150] Q is O or S;

[0151] Y is O, S or Se;

[0152] R 3ais 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;

[0153] 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.

[0154] 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),

[0155]

[0156] Among them, A, R 1 , R 2 , Ar, P, Q and Y are as defined in claim 21.

[0157] 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),

[0158]

[0159] in:

[0160] A is N or CH;

[0161] R 1 is hydrogen, cyano, halogen, alkyl, haloalkyl, amino, alkylamino, dialkylamino;

[0162] R 2 is hydrogen, hydroxy, azido, amino, alkylamino, dialkylamino, N-pyrrolidinyl, N-piperidinyl or N-piperazinyl;

[0163] Ar is a phenyl group substituted with two halogen substituents;

[0164] P is O;

[0165] Q is O or S;

[0166] R 3b is alkyl-S(O) 2 - or alkyl-S(O)-;

[0167] R 4 is hydrogen or a halogen;

[0168] R 5 is hydrogen or a halogen;

[0169] 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.

[0170] The present invention includes all pharmaceutically acceptable salt forms of the compounds. Such salts can be prepared by conventional organic chemical methods using commercially available reagents, and specifically include hydrochlorides, hydrobromides, hydroiodides, phosphates, sulfates, nitrates, formates, acetates, succinates, benzenesulfonates, citrates, glucuronates, lactates, methanesulfonates, toluenesulfonates, pamoates and tartrates, etc.

[0171] The present invention is intended to include all isotopes of atoms in all compounds. Isotope-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.

[0172] The compounds described in the present invention include but are not limited to:

[0173]

[0174]

[0175]

[0176] 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:

[0177]

[0178] Reaction 1

[0179] 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).

[0180] 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:

[0181]

[0182] Reaction 2

[0183] In Reaction Scheme 2, 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 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).

[0184] On the other hand, the present invention is intended to include all isotopes of atoms in all compounds. Isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known in the art or by methods analogous to the present application, and these compounds have the potential to improve pharmacological or pharmacokinetic properties.

[0185] On the other hand, the present invention is intended to include tautomers of all compounds unless otherwise specified. Tautomers refer to proton shifts from one atom of a molecule to another atom of the same molecule, examples include keto-enol pairs, amide-imido pairs, lactam-lactim pairs, amide-imido pairs, enamine-imine pairs, etc.

[0186] On the other hand, the present invention is intended to include all stereoisomers of the compounds, such as enantiomers and diastereomers, unless otherwise specified. The compounds of the present invention containing asymmetrically substituted carbon atoms can be separated in optically active forms or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolving racemic mixtures or by stereoselective synthesis. Various geometric isomers of olefins, C=N double bonds, etc. may also be present in the compounds described herein, and all such stable isomers should be included in the present invention.

[0187] On the other hand, the present invention provides a pharmaceutical preparation suitable for use in a human patient, the pharmaceutical preparation comprising any compound shown above (e.g., a compound of the present invention, such as a compound of formula (I)) and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparation can be used to treat or prevent a condition or disease described herein.

[0188] In another aspect, the present invention discloses methods for treating conditions associated with abnormal CGRP levels. These diseases or disorders include, but are not limited to, migraine, neurogenic vasodilation, neurogenic inflammation, asthma, and chronic obstructive pulmonary disease.

[0189] In another aspect, the present invention discloses methods for treating or preventing migraine, including but not limited to the treatment of acute attacks of migraine and / or the long-term prevention of migraine.

[0190] In another aspect, the present invention discloses combination therapy of a compound of formula (I) and a migraine therapeutic agent, which can enhance the clinical benefit of migraine prevention or treatment beyond the ability of monotherapy.

[0191] Terminology

[0192] Alkyl or alkane is a completely saturated straight or branched chain non-aromatic hydrocarbon. Typically, unless otherwise defined, a straight or branched chain alkyl has 1 to about 20 carbon atoms, preferably 1 to about 10 carbon atoms, more preferably 1 to about 6 carbon atoms, and most preferably 1 to about 3 carbon atoms. Non-limiting examples of straight and branched chain alkyls include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, amyl, and octyl. 1 -C 6 A straight chain or branched chain alkyl group is also referred to as a "lower alkyl group".

[0193] Moreover, 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 an alkyl moiety having a substituent replacing a 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, phosphite, 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 appreciate 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, amide, phosphoryl (including phosphonate and phosphite), sulfonyl (including sulfate, sulfonamide, sulfamoyl and sulfonate), and silyl, as well as ether, alkylthio, carbonyl (including ketone, aldehyde, carboxylate and ester), -CF 3 , -CN, etc., substituted and unsubstituted forms.

[0194] Cycloalkyl groups preferably have 3 to about 20 ring carbon atoms and can be substituted and unsubstituted. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl or methylcyclopentyl, etc. Cycloalkyl groups can be further substituted by alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aminoalkyl, carbonyl substituted alkyl, -CF 3 , -CN, etc.

[0195] Aryl refers to a cyclic aromatic group having 5 to about 20 ring carbon atoms. Typically, unless otherwise defined, heteroaryl has a monocyclic or bicyclic ring. Non-limiting examples of aryl include phenyl, 1-naphthyl or 2-naphthyl, or a bicyclic fused derivative containing phenyl, such as indanyl, dihydro or tetrahydronaphthyl, etc.

[0196] Heteroaryl represents an aromatic group containing at least one heteroatom selected from nitrogen, oxygen and sulfur. Usually, unless otherwise defined, heteroaryl has a monocyclic or bicyclic ring. Monocyclic heteroaryl includes 5 or 6 yuan 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 condensed derivatives containing monocyclic heteroaryl, such as indolyl, benzimidazolyl, benzofuranyl, quinolyl, isoquinolyl, quinazolinyl, purinyl, etc.

[0197] 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, dioxolanyl or tetrahydropyranyl, or bicyclic fused derivatives containing monocyclic heterocyclic radicals, such as benzopyrrolidinyl, benzopiperidinyl, etc.

[0198] 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 carbon atom or hydrogen on heteroatom. In the aryl, heteroaryl or heterocyclic radical that are optionally substituted, 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.

[0199] 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.

[0200] Alkynyl is preferably a lower alkynyl group such as propargyl or ethynyl.

[0201] In the optionally substituted alkenyl or alkynyl group, the substituent is preferably lower alkyl, lower alkoxy, halo or di(lower alkyl)amino and is attached to a saturated carbon atom of the alkenyl or alkynyl group or to an unsaturated carbon atom of the alkenyl group.

[0202] Acyl represents, for example, alkylcarbonyl, cyclohexylcarbonyl, arylcarbonyl, aryl-lower alkylcarbonyl or heteroarylcarbonyl. Lower acyl is preferably lower alkylcarbonyl, in particular propionyl or acetyl.

[0203] 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.

[0204] 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.

[0205] The haloalkyl group refers to an alkyl group substituted by at least one halogen, preferably a halogen-lower alkyl group, such as monofluoromethyl, difluoromethyl, trifluoromethyl, 3,3,3-trifluoroethyl or pentafluoroethyl.

[0206] Halogen is fluorine, chlorine, bromine or iodine.

[0207] Lower alkoxy is especially methoxy, ethoxy, isopropoxy or tert-butoxy.

[0208] Arylalkyl includes aryl and alkyl as defined above and is, for example, benzyl, 1-phenethyl or 2-phenethyl.

[0209] 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.

[0210] 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-oxypropylene, 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-oxypropylene, 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

[0211] Figure 1 Results of blood drug concentrations of RIMEGEPANT, compounds 1, 5, and 21 at different time points after oral administration

[0212] Figure 2 Results of blood drug concentrations of RIMEGEPANT, compounds 1, 5, and 21 at different time points after intravenous administration

[0213] Figure 3 Effects of oral administration (PO) of RIMEGEPANT and compound 5 on the comprehensive blood flow growth rate (%) of model animals DETAILED DESCRIPTION

[0214] 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; "N 3 " indicates azide; "NO 2 " " represents nitro; "Ar" represents aryl; "Boc" represents tert-butyloxycarbonyl; "DMSO" represents dimethyl sulfoxide; "EtOAc" represents ethyl acetate; "THF" represents tetrahydrofuran; "DCM" represents dichloromethane; "ACN" represents acetonitrile; "DIPEA" represents diisopropylethylamine; "NaHMDS" represents sodium bis(trimethylsilyl)amide; "LDA" represents lithium diisopropylamide; and "NCS" represents N-chlorosuccinimide.

[0215] The structures of the compounds described in the following examples are determined by nuclear magnetic resonance spectroscopy ( 1 H-NMR) or mass spectrometry (MS).

[0216] 1 The H-NMR was measured using a Bruker 400 MHz nuclear magnetic resonance spectrometer, the measuring solvent was deuterated methanol (CD3OD), deuterated chloroform (CDCl3) or hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard was tetramethylsilane (TMS). The chemical shift (δ) was given in parts per million (ppm).

[0217] The mass spectrometry (MS) was performed using an Agilent (ESI) mass spectrometer, model Agilent 6120B.

[0218] 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.

[0219] The reaction is monitored by thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS), and the developing solvent systems used include dichloromethane and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system. 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.).

[0220] The instrument model used for the preparative high performance liquid chromatography method is: Agilent 1260, chromatographic column: Waters XBridgePrep C18OBD (19mm×150mm×5.0μm); chromatographic column temperature: 25°C; flow rate: 20.0mL / min; detection wavelength: 214nm; elution gradient: (0min: 10% A, 90% B; 16.0min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% ammonium bicarbonate aqueous solution.

[0221] Unless otherwise specified, the reaction temperature is room temperature (20°C to 30°C).

[0222] The reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company, etc.

[0223] Synthesis method

[0224] The present invention provides the following synthetic methods to synthesize all the compounds involved.

[0225] Ar in the synthesis methods refers to an aryl group or a heteroaryl group.

[0226] Scenario 1:

[0227]

[0228] 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 shown in formula (II) and formula (III), respectively.

[0229] 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.

[0230] The synthesis of intermediate D and intermediate F refers to the method of J. Med. Chem. 2012, 55, 23, 10644.

[0231] The key intermediates of this scheme can be synthesized by the following route:

[0232] Synthesis of intermediate A:

[0233]

[0234] First, intermediate A1 reacts with S to undergo a nucleophilic substitution reaction, and the nitro group of the obtained intermediate A2 is reduced to an amino group to generate intermediate A3, and 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 A.

[0235] This method is applicable to target compounds where Y is O or S.

[0236] Synthesis of intermediate A-5:

[0237]

[0238] The first two steps are the same as described above. In the third step, intermediate A6 and methyl orthoformate are dehydrated and cyclized under Lewis acid catalysis to obtain intermediate A7; A7 is subjected to LDA hydrogen extraction and then reacts with NCS to obtain chlorinated intermediate A8; finally, A8 reacts with sodium borohydride and selenium to obtain intermediate A-5.

[0239] This method is applicable to target compounds where Y is Se.

[0240] The present invention also provides a method for synthesizing the following intermediates:

[0241]

[0242] Intermediate A-1 is used as a reaction raw material and methylated 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.

[0243]

[0244] 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.

[0245]

[0246] 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.

[0247] Synthesis of intermediates

[0248] Synthesis Example 1 Synthesis of Intermediate A-1:

[0249]

[0250] 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 completion of the reaction. The reaction solution was concentrated under reduced pressure, quenched with water (500 mL), and extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with saturated brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give intermediate I-3b.

[0251] MS (ESI) m / z = 323.1 [M + 1] +

[0252] 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 passed with hydrogen (15 Psi) for 3 hours. The reaction mixture was then stirred at 20°C for 16 hours under hydrogen. LCMS confirmed the completion of the reaction. The reaction solution was filtered and concentrated under reduced pressure to obtain intermediate I-4b.

[0253] MS (ESI) m / z = 293.2 [M + 1] +

[0254] 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 mixture was stirred at 80 °C for 12 hours. LCMS confirmed the completion of the reaction. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column chromatography to obtain intermediate A-1.

[0255] MS (ESI) m / z = 335.3 [M + 1] +

[0256] 1 H NMR:DMSO-d 6δ13.42(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).

[0257] Synthesis Example 2 Synthesis of Intermediate A-3:

[0258]

[0259] 4-Amino-2-chloro-3-nitropyridine A1'-3 (3.00 g, 17.2 mmol) was dissolved in ethanol (15 mL), 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.

[0260] MS (ESI) m / z = 338.2 [M+1] +;

[0261] 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).

[0262] The above crude product (3.00 g, 8.89 mmol) was dissolved in acetonitrile (30 mL), tert-butyl nitrite (916 mg, 8.89 mmol, 1.06 m) was added, stirred at 25 ° C for 30 minutes, then cooled to 0 ° C, cuprous bromide (1.28 g, 8.89 mmol, 270 μL) was added, and the reaction continued at 25 ° C for 12 hours. The mixture was filtered and concentrated under reduced pressure. The obtained crude product was dissolved in N, N-dimethylformamide (20 mL), and potassium fluoride (738 mg, 12.7 mmol) was added, and the reaction was carried out at 100 ° C for 12 hours, then poured into water, extracted with ethyl acetate 3 times, and 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.

[0263] MS (ESI) m / z = 341.2 [M+1] +;

[0264] 1 HNMR: (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).

[0265] Palladium carbon (0.25 g, 234 μmol, 10% purity) was added to a methanol (15 mL) solution of intermediate A2-3, and the mixture was reacted at 20 ° C in a hydrogen (50 Psi) atmosphere for 12 hours. The reaction mixture was then filtered and concentrated under reduced pressure to obtain intermediate A3-3 (brown solid, 1.1 g, crude product). A3-3 was dissolved in tetrahydrofuran (10 mL), 1,1-thiocarbonyldiimidazole (1.15 g, 6.44 mmol) was added, and the mixture was reacted at 50 ° C for 12 hours. The reaction solution was then filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to obtain intermediate A-3.

[0266] MS (ESI) m / z = 353.2 [M+1] +.

[0267] Synthesis Example 3 Synthesis of Intermediate A-5:

[0268]

[0269] Potassium carbonate (19.5 g, 140.8 mmol, 2 eq) and 1-Boc-4-aminopiperidine (15.5 g, 77.4 mmol, 1.1 eq) were added to a solution of A4 (10 g, 70.38 mmol, 1 eq) in N,N-dimethylformamide (100 mL). The reaction mixture was stirred at 80 ° C for 12 hours, and then concentrated under reduced pressure to remove the solvent. The residue was diluted with water and extracted with ethyl acetate three times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain intermediate A5.

[0270] MS (ESI) m / z = 323.1 [M+1] +.

[0271] A5 (15.0 g, 46.5 mmol, 1.00 eq) was dissolved in methanol (400 mL), palladium carbon (3.00 g, 2.82 mmol, 10% purity, 6.06e-2 eq) was added, and the mixture was reacted at 20° C. for 16 hours under a hydrogen atmosphere (15 Psi). The reaction mixture was filtered and concentrated to obtain A6.

[0272] MS (ESI) m / z = 293.2 [M+1] +.

[0273] To a toluene (100 mL) solution of A6 (7.20 g, 24.6 mmol, 1.00 eq), 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) were added 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 condition) to obtain A7.

[0274] MS (ESI) m / z = 331.2 [M+1] +.

[0275] 1 H NMR:CDCl 3 δ8.56(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).

[0276] At -78°C, lithium diisopropylamide (2M, 1.98mL, 1.20eq) was slowly added dropwise to a tetrahydrofuran (10mL) solution of A7 (1.00g, 3.31mmol, 1.00eq). After the addition, the reaction was continued at the same temperature for 1 hour, and then N-chlorosuccinimide (529mg, 3.97mmol, 1.20eq) was added dropwise. The mixture was returned to 20°C for reaction 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 combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by reverse phase high performance liquid chromatography (0.1% FA condition) to obtain A8.

[0277] MS (ESI) m / z = 337.2 [M+1] +.

[0278] 1 HNMR:CDCl 3 δ8.54(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),4.69-4.6 2(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).

[0279] At 20°C, 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), and the temperature was maintained for 0.5 hours. Then, A8 (1.00 g, 2.97 mmol, 1.00 eq) was 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 obtain A-5.

[0280] MS (ESI) m / z = 383.1 [M+1] +.

[0281] Synthesis Example 4 Synthesis of Intermediate H-4:

[0282]

[0283] Ozone (15 Psi) was ventilated to a mixture of intermediate H1 (10 g, 59.09 mmol, 1 eq) in dichloromethane (200 mL) at -78 ° C for 1 hour. N2 (15 psi) was then ventilated for half an hour to remove ozone. Thin layer chromatography (petroleum ether / ethyl acetate = 10:1) confirmed that the reaction was complete. The reaction mixture was not treated and was directly used in the next step. Intermediate D2 was obtained in dichloromethane (200 mL) as a nearly white oil.

[0284] Under nitrogen protection, NaBH(OAc)3 (1.10 g, 5.17 mmol, 3 eq) was added 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). The reaction mixture was stirred at 25 ° C for 12 hours. LCMS showed that the reaction was complete. Under nitrogen protection, saturated ammonium chloride solution (100 mL) was added at 0 ° C to quench the reaction, and extracted with ethyl acetate (20 mL * 3). The organic layers were combined, washed with saturated brine (20 mL * 2), dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to obtain intermediate H-4.

[0285] MS (ESI) m / z = 460.2 [M + 1] + .

[0286] 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).

[0287] Synthesis Example 5 Synthesis of Intermediate C':

[0288]

[0289] 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). The reaction mixture was stirred at 25 °C for 12 hours. LCMS confirmed the completion of the reaction. The reaction mixture was concentrated under reduced pressure to give intermediate I-7b.

[0290] MS (ESI) m / z = 235.0 [M + 1] +

[0291] 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 completion of the reaction. The reaction mixture was concentrated, acetonitrile (5 mL) was added and filtered, and the filter cake was concentrated under reduced pressure to obtain intermediate C'.

[0292] MS (ESI) m / z = 329.1 [M + 1] +

[0293] 1 H NMR:DMSO-d 6 δ13.47(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).

[0294] Synthesis Example 6 Synthesis of Intermediate C-6:

[0295]

[0296] 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 solution was stirred at 20 ° C for 1 hour. LCMS confirmed the completion of the reaction. 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.

[0297] MS (ESI) m / z = 349.2 [M + 1] +

[0298] 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 mixture was stirred at 25 °C for 12 hours. LCMS confirmed the completion of the reaction. The reaction mixture was concentrated under reduced pressure to give intermediate I-8.

[0299] MS (ESI) m / z = 249.1 [M + 1] +

[0300] 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 solution was stirred at 25 ° C for 12 hours. LCMS confirmed that 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 (0.1% NH3·H2O) to obtain intermediate C-6.

[0301] MS (ESI) m / z = 343.1 [M + 1] +

[0302] Synthesis Example 7 Synthesis of Intermediate C-a5:

[0303]

[0304] To a solution of intermediate C-a1 (1 g, 4.99 mmol, 1 eq) in tetrahydrofuran (15 mL) was added thiocarbonyldiimidazole (961.02 mg, 5.39 mmol, 1.08 eq) at -15 °C. The reaction solution was stirred at -15-20 °C for 14 hours. LCMS confirmed the completion of the reaction. The reaction mixture was concentrated under reduced pressure and quenched with water (100 mL), extracted with ethyl acetate (100 mL*3), the organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain intermediate C-a2.

[0305] MS (ESI) m / z = 243.1 [M + 1] +

[0306] 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 that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove the solvent, and quenched with water (100 mL), extracted with ethyl acetate (100 mL*3), and 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 high performance liquid chromatography (0.1% FA condition) to obtain intermediate C-a3.

[0307] MS (ESI) m / z = 359.1 [M + 23] +

[0308] 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 completion of the reaction. The reaction mixture was concentrated under reduced pressure to give intermediate C-a4.

[0309] MS (ESI) m / z = 237.1 [M + 23] +

[0310] C-a4 (1 g, 4.23 mmol, 1 eq) was dissolved in tetrahydrofuran (10 mL), and N,N'-carbonyldiimidazole (2.06 g, 12.69 mmol, 3 eq) and diisopropylethylamine (1.64 g, 12.69 mmol, 2.21 mL, 3 eq) were added. The reaction was carried out at room temperature of 25°C for 14 hours. LCMS confirmed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was ground in acetonitrile for 30 min. The mixture was filtered, the solid was collected, and it was concentrated under reduced pressure to obtain the intermediate C-a5.

[0311] MS (ESI) m / z = 353.0 [M + 23] +

[0312] Example 1, (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloheptyl[b]pyridin-9-yl 4-(2-sulfoxy-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (Compound 1)

[0313]

[0314] The 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 a hydrochloric acid dioxane solution (4 mol / L, 10 mL), and reacted at room temperature 25°C for 3 hours. After the reaction, the mixture was directly concentrated to dryness to obtain an oily intermediate B-1;

[0315] Dissolve B-1 in dichloromethane (10 mL), slowly add N,N'-carbonyldiimidazole (534.7 mg, 3.0 mmol) and diisopropylethylamine (775.4 mg, 6.0 mmol) at 0°C, return to room temperature 25°C and react for 5 hours, wash the reaction mixture with 0.5 mol / L dilute hydrochloric acid solution and saturated sodium bicarbonate solution, and dry over anhydrous sodium sulfate, and purify the concentrated crude product by flash column chromatography (silica gel, dichloromethane / methanol = 10 / 1) to obtain intermediate C-1 (625 mg, total yield of two steps 63%);

[0316] Under nitrogen protection, the intermediate C-1 (200.0 mg, 0.61 mmol) and the 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 the reaction was maintained at this temperature for 1 hour, the reverse system was restored 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 with ethyl acetate 3 times. The combined organic phase was 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);

[0317] 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.

[0318] Compounds 2-4, 6-13, and 18 were synthesized by referring to the method of Example 1.

[0319] The characterization data of compounds 1-4, 6-13, and 18 are as follows:

[0320]

[0321]

[0322]

[0323] 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)

[0324]

[0325] Intermediate A-5 (0.94 g, 2.47 mmol, 1.00 eq) was dissolved in dioxane hydrochloride solution (4 mol / L, 10 mL).

[0326] The mixture was 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 a yellow solid intermediate B-5 (0.9 g, crude);

[0327] Dissolve B-5 (0.9 g, 3.20 mmol, 1.00 eq) in tetrahydrofuran (10 mL), add 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). After adding, return to 50 ° C for 1 hour, and LC-MS confirms that the reaction is complete. The reaction mixture is concentrated under reduced pressure to obtain a residue. The crude product is ground with cerium ammonium nitrate (CAN) at 25 ° C for 30 minutes to obtain a yellow solid compound C-5 (1.00 g, crude);

[0328] Potassium tert-butoxide (1M, 5mL, 1.88eq) was added to a solution of intermediate C-5 (1.00g, 2.66mmol, 1.00eq) and intermediate D' (520mg, 1.33mmol, 0.5eq) in tetrahydrofuran (10mL) at -78°C. Under nitrogen protection, the reaction solution was warmed to 20°C and stirred for 12 hours. LCMS confirmed that the reaction was complete. The reaction mixture was diluted with 5mL of water and extracted with ethyl acetate (2mL*3). The organic layers were combined, washed with saturated brine (2mL*3), dried with sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue to obtain a yellow solid intermediate E-5 (1.00g, crude).

[0329] Under nitrogen protection, the intermediate E-5 (1.00 g, 1.43 mmol, 1.00 eq) was dissolved in a solution of dioxane methanol (1 mL) at -78 °C, and then stirred at 20 °C for 12 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative high performance liquid chromatography to obtain the target compound 5.

[0330] Compound 21 was synthesized according to the method of Example 2.

[0331] The characterization data of compounds 5 and 21 are as follows:

[0332]

[0333]

[0334] 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)

[0335]

[0336] Potassium tert-butoxide (1M, 640.36μL, 2eq) was added to a solution of intermediate C'6 (100mg, 320.18μmol, 1eq) and intermediate D' (125mg, 320.18μmol, 1eq) in tetrahydrofuran (2mL) at -20°C. The reaction solution was stirred at -20°C for 0.5 hours and then at 25°C for 0.5 hours. LCMS confirmed that the reaction was complete. The reaction mixture was poured into a saturated ammonium chloride solution (100mL) for quenching and extracted with ethyl acetate (30mL*3). The organic layers were combined, washed with saturated brine (20mL), dried with sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to obtain a brown solid intermediate E'7 (15mg, 23.63μmol, 7.38% yield).

[0337] 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 showed that the target product was obtained. The reaction mixture was poured into a saturated sodium bicarbonate (100 mL) solution for quenching and extracted with ethyl acetate (30 mL*3). The organic layers were combined, 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 high performance liquid chromatography to obtain the target compound 14.

[0338] Compound 15 was synthesized according to the method of Example 3.

[0339] The characterization data of compounds 14-15 are as follows:

[0340]

[0341]

[0342] Example 4, (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloheptyl[b]pyridin-9-yl 4-(2-thioxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperazine-1-carboxylate (Compound 16)

[0343]

[0344] To a solution of intermediate E-10 (3.00 g, 4.29 mmol, 1 eq)i dissolved 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 showed that the target product was obtained. The reaction mixture was poured into a saturated sodium bicarbonate (500 mL) solution for quenching and extracted with ethyl acetate (100 mL*2). The organic layers were combined, 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 high performance liquid chromatography to obtain the target compound 16.

[0345] Compound 20 was synthesized according to the method of Example 4.

[0346] The characterization data of compounds 16 and 20 are as follows:

[0347]

[0348]

[0349] Example 5, (5S,6S,9R)-5-N-piperazinyl-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloheptyl[b]pyridin-9-yl 4-(2-sulfoxy-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (Compound 17)

[0350]

[0351] 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 target product was obtained (MS (ESI) m / z = 720.2 [M+1] +The reaction mixture was poured into a saturated ammonium chloride solution (100 mL) for quenching and extracted with ethyl acetate (30 mL*3). The organic layers were combined, washed with saturated brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a light yellow oily intermediate H-5 (0.1 g, 138.92 μmol, 70.93% yield).

[0352] 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 showed that the target product was obtained. The reaction mixture was poured into a saturated sodium bicarbonate (100 mL) solution for quenching and extracted with ethyl acetate (30 mL*3). The organic layers were combined, 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 high performance liquid chromatography to obtain the target compound 17.

[0353] The characterization data of compound 17 are as follows:

[0354]

[0355] Example 6, (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloheptyl[b]pyridin-9-yl 4-(2-methylsulfinyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (Compound 19)

[0356]

[0357] Potassium tert-butoxide (1M, 512.27 μL, 2 eq) was added 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) at 0°C. The reaction solution was stirred at 25°C for 0.5 hours. LCMS showed 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, 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 meta-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 solution was quenched by adding saturated sodium bicarbonate solution (50 mL) at 0°C under nitrogen protection, and extracted with ethyl acetate (20 mL*2). The organic layers were combined, washed with saturated brine (30 mL*2), dried with sodium sulfate, filtered and concentrated under reduced pressure to obtain yellow oily intermediate C-9 (0.1 g, crude).

[0358] Trifluoroacetic acid (1.54 g, 13.46 mmol, 1 mL, 223.74 eq) was added to a solution of intermediate C-9 (40.96 mg, 60.17 μmol, 1 eq) in dichloromethane (4 mL) at 0°C. The reaction solution was stirred at 25°C for 12 hours. LCMS showed that the target product was obtained. The reaction solution was poured into a saturated sodium bicarbonate solution (50 mL) at 0°C under nitrogen protection and quenched, and extracted with ethyl acetate (20 mL*2). The organic layers were combined, washed with saturated brine (30 mL*2), dried with sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative high performance liquid chromatography to obtain the target compound 19.

[0359] The characterization data of compound 19 are as follows:

[0360]

[0361] Example 7, (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloheptyl[b]pyridin-9-yl 4-(2-pyridylaminomethylthioylamino)piperidine-1-carboxylate (Compound 22)

[0362]

[0363] Potassium tert-butoxide (129.34 mg, 1.15 mmol, 3 eq) was added 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) at -20°C. The reaction solution was reacted at -20°C for 0.5 hour and then at 25°C for 0.5 hour. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain intermediate C-a6 (0.25 g, crude) as a white solid.

[0364] 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 mixture was stirred at 25 °C for 12 hours. LCMS confirmed the completion of the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC to obtain the target compound 22.

[0365] Compound 23 was synthesized according to the method of Example 7.

[0366] The characterization data of compounds 22-23 are as follows:

[0367]

[0368] RIMEGEPANT was synthesized with reference to Example 8 of patent CN102656159A.

[0369] Example 8: In vitro human CGRP receptor antagonist activity test

[0370] Cell culture and reagent configuration:

[0371] 1) Cell line: SK-N-MC;

[0372] 2) Complete culture medium: MEM + 10% fetal bovine serum + 1* penicillin-streptomycin;

[0373] 3) Experimental buffer: 1*HBSS+20mM HEPES+0.1% BSA+500μM IBMX.

[0374] Determination of the activity of the test compound on CGRP receptor:

[0375] After TrypLE digestion, cells were resuspended in assay buffer and seeded into 384 cell culture plates at a density of 2000 per well. Compounds were diluted in assay buffer, 2.5 μl of compound was added to each well, and incubated at 37°C for 10 minutes. α-CGRP was diluted to 8*α-CGRP (80 nM) in assay buffer, 2.5 μl of 8*α-CGRP diluted in the previous step was added, and incubated at 37°C for 30 minutes. Freeze-thaw Eu-cAMP tracer and Ulight-anti-cAMP and dilute them with lysis buffer. 10 μl Eu-cAMPtracer was added to the experimental wells, and then 10 μl Ulight-anti-cAMP was added to the experimental wells. The reaction plate was centrifuged at 200 g for 30 seconds at room temperature, and after standing at 25°C for 1 hour, data were collected using Envision.

[0376] Data Analysis:

[0377] 1) %Inhibition calculation:

[0378] %inhibition=(Signalcmpd-SignalAve_VC) / (SignalAve_PC-SignalAve_VC)×100.

[0379] 2) Calculate the IC50 of the compound using the GraphPad nonlinear fitting formula:

[0380] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0381] X: log value of compound concentration; Y: Inhibition%

[0382] The human CGRP receptor antagonist IC50 values ​​of each compound are shown in the following table:

[0383] Table 1

[0384] Compound Human CGRP receptor antagonist activity IC50 (nM) RIMEGEPANT 0.577 1 0.058 2 0.384 3 2.911 4 2.306 5 1.118 6 28.59 7 2.176 8 5.92 9 1.287 10 2.387 11 28.99 12 7.347 13 7.211 16 0.158 17 0.441 18 0.536 19 6.894 20 0.661 21 0.441 22 0.892 23 0.182

[0385] Example 9, MDR1-MDCKII cell permeability test

[0386] 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.

[0387] 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) in 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 direction or B to A direction was determined in duplicate wells. At the same time, the permeation of digoxin from A to B direction or B to A direction at 10.0 μM, and the permeation of nadolol and metoprolol from A to B direction at 2.00 μM were tested in duplicate wells. 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 compounds and reference compounds were quantified by LC-MS / MS analysis based on the peak area ratio of analyte / standard.

[0388] After the transport assay, the Lucifer Yellow exclusion assay was applied to determine the cell monolayer integrity. Remove the buffer from the apical and basolateral chambers, and then add 75 μL of 100 μM Lucifer Yellow to the transfer buffer and 250 μL of transfer buffer to the apical and basolateral chambers, respectively. Incubate the plate at 37.0°C, 5.0% CO 2 and saturated humidity for 30 minutes without shaking. After incubation for 30 minutes, remove 20 μL of the Lucifer Yellow sample from the apical side and then add 60 μL of transfer buffer. Then take 80 μL of the Lucifer Yellow sample from the basolateral side. The relative fluorescence units (RFU) of Lucifer Yellow were measured at 425 / 528nm (excitation / emission) wavelengths using an Envision plate reader.

[0389] Data Analysis:

[0390] The calculation formula of apparent permeability coefficient Papp (cm / s) is:

[0391] P app =(dC r / d t )x V r / (Ax C0)

[0392] where dC r / d t is 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 transmission, for example, the area of ​​a single layer is 0.143 cm 2 ; C 0 is the initial concentration in the donor compartment (μM).

[0393] The efflux ratio was calculated using the following formula:

[0394] Efflux Ratio=Papp(BA) / Papp(AB)

[0395] 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 for the relevant efflux transporter and has a higher potential blood-brain barrier permeability, which facilitates drug entry into the brain and leads to a higher brain exposure level.

[0396] Table 2

[0397] Compound <![CDATA[P app (10-6cm / s)_A-B]]> <![CDATA[P app (10-6cm / s)_B-A]]> Efflux Ratio(ER) RIMEGEPANT 0.38 22.52 59.98 1 2.62 6.47 2.47 2 2.40 6.56 2.74 3 3.94 6.38 1.62 4 5.37 8.41 1.57 5 2.59 6.98 2.70 7 0.847 1.08 1.28 9 2.02 7.88 3.90 16 2.83 7.96 2.81 21 2.44 8.29 3.40

[0398] Example 10. Oral pharmacokinetic study in cynomolgus monkeys

[0399] Using cynomolgus monkeys as test animals, the UPLC-MS / MS method was used to determine the compound concentration in plasma at different times after a single oral administration of the disclosed compound to cynomolgus monkeys, so as to study the pharmacokinetics of the disclosed compound in cynomolgus monkeys.

[0400] Experimental animals: Cynomolgus monkeys (male, about 3 to 5 years old, weighing 5 to 9 kg).

[0401] Drug preparation: The solvent was DMSO / HS-15 / normal saline (5:5:90, v:v:v).

[0402] Administration: single oral gavage administration; 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.

[0403] Sample collection: The collection site was the inner saphenous vein of the right forelimb; plasma was collected before administration and 15min, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after administration; 0.5mL of whole blood was collected from each blood collection point and plasma was separated; the plasma separation method was centrifugation at 4°C and 1800g centrifugal force for 10min, and the supernatant was taken; then UPLC-MS / MS analysis method was used to quantitatively analyze the blood drug concentration.

[0404] The results of blood drug concentrations of RIMEGEPANT, compounds 1, 5, and 21 at different time points after oral administration are shown in the attached figure. Figure 1 As shown, the exposure AUC of compounds 1, 5, and 21 at different time points was significantly higher than that of RIMEGEPANT.

[0405] Example 11. Intravenous pharmacokinetic study in cynomolgus monkeys

[0406] Using cynomolgus monkeys as test animals, the UPLC-MS / MS method was used to determine the concentration of the compound in the plasma at different times after a single intravenous administration of the disclosed compound to the cynomolgus monkeys, so as to study the pharmacokinetics of the disclosed compound in cynomolgus monkeys.

[0407] Experimental animals: Cynomolgus monkeys (male, about 3 to 5 years old, weighing 5 to 9 kg).

[0408] Drug preparation: The solvent was DMSO / HS-15 / normal saline (5:5:90, v:v:v).

[0409] Administration: Single intravenous injection; the dosage of RIMEGEPANT and compounds 1, 5, and 21 was 1 mg / kg.

[0410] Sample collection: The collection site was the inner saphenous vein of the right forelimb; plasma was collected before administration and 15min, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after administration; 0.5mL of whole blood was collected from each blood collection point and plasma was separated; the plasma separation method was centrifugation at 4°C and 1800g centrifugal force for 10min, and the supernatant was taken; then UPLC-MS / MS analysis method was used to quantitatively analyze the blood drug concentration.

[0411] The results of blood drug concentrations of RIMEGEPANT, compounds 1, 5, and 21 at different time points after intravenous administration are shown in the attached figure. Figure 2 As shown, the exposure AUC of compounds 1, 5, and 21 at different time points was significantly higher than that of RIMEGEPANT.

[0412] Example 12: Oral pharmacodynamics study in cynomolgus monkeys

[0413] Cynomolgus monkeys were used as test animals, and the hCGRP local injection model was used to study the effect of a single oral (PO) administration of the disclosed compounds on blood flow.

[0414] PO grouping: RIMEGEPANT group (Yang Shen); Compound 5 group; Model group (blank control)

[0415] Experimental animals: Cynomolgus monkeys (male, about 3 to 5 years old, weighing 5 to 9 kg).

[0416] Drug preparation: The solvent was DMSO / HS-15 / normal saline (5:5:90, v:v:v).

[0417] 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 at -20°C. When used, PBS was used to dilute it to a working solution with a concentration of 5 μg / mL.

[0418] Modeling: The day before hCGRP modeling, the forearm modeling site of the animal to be modeled was depilated. Animals in the PO group fasted but not watered for 12 hours before surgery; animals in the IV group had a normal diet and were given 0.04 mg / kg atropine sulfate injection about half an hour before anesthesia to reduce glandular secretion. After anesthesia with an intramuscular injection of 0.1 mL / kg of Shutai 50, the animals were transferred to the operating room. 0.1 μg CGRP was injected intradermally in the forearm without obvious visible blood vessels, and the injection volume was 20 μL; the same volume of solvent was injected in the vehicle control; the injection time points of hCGRP and vehicle control in the PO group were 0 min, 30 min, and 60 min.

[0419] Administration: Single oral gavage administration; the administration time for the PO group was 80 minutes before the first CGRP injection modeling, and the dosage of RIMEGEPANT and compound 5 was 3 mg / kg.

[0420] Sample collection: The collection site was the saphenous vein on the right forelimb; 0.5 mL of whole blood was collected at each blood collection point and plasma was separated; the plasma separation method was centrifugation at 4°C and 1800g centrifugal force for 10 minutes, and the supernatant was taken; then UPLC-MS / MS analysis method was used to quantitatively analyze the blood drug concentration; the blood collection points for the PO group were -5min, 5min, 20min, 35min, 50min, 65min and 80min.

[0421] Skin blood flow detection: Laser Doppler speckle blood flow meter was used to detect the skin blood flow data at the injection site at each time point; the skin blood flow increase percentage (%) was calculated according to the blood flow value (blood flow t) at each time point = (blood flow t-blood flow baseline) / blood flow baseline × 100%; and the blood flow comprehensive growth rate (%) = CGRP-treated side blood flow increase percentage-control side blood flow increase percentage. hCGRP can induce hemodynamic changes, leading to increased blood flow; the blood flow comprehensive growth rate % reflects the blood flow increase ratio induced by hCGRP, and a lower blood flow comprehensive growth rate % indicates that the compound has a better inhibitory effect on the increase in blood flow caused by hCGRP.

[0422] 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 the attached figure. Figure 3 shown.

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: 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: 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.

Images