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WO2025061177A1 - 一种治疗cgrp相关障碍的小分子药物 - Google Patents

一种治疗cgrp相关障碍的小分子药物 Download PDF

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Publication number
WO2025061177A1
WO2025061177A1 PCT/CN2024/120191 CN2024120191W WO2025061177A1 WO 2025061177 A1 WO2025061177 A1 WO 2025061177A1 CN 2024120191 W CN2024120191 W CN 2024120191W WO 2025061177 A1 WO2025061177 A1 WO 2025061177A1
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hydrogen
alkyl
halogen
amino
compound
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French (fr)
Inventor
柯尊洪
柯潇
陈沛
赵伟
黄红
刘健
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Chengdu kanghong pharmaceutical co Ltd
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Chengdu kanghong pharmaceutical co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of biomedicine.
  • 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 diseases of CGRP-related disorders, including migraine, neurogenic vasodilation, neurogenic inflammation, respiratory inflammatory diseases such as asthma and chronic obstructive pulmonary disease, etc.
  • 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.
  • 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.
  • the patient consultation rate is only 52.9%, and the correct diagnosis rate of physicians is only 13.8%.
  • 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).
  • 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 ⁇ -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.
  • 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 located 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.
  • the patent applications related to the disclosed small molecule CGRP inhibitors include CN102656159A, CN104136437A, CN117466893A and CN117624191A.
  • CGRP monoclonal antibodies Epnumab, Fremanezumab, Galcanezumab and Eptinezumab
  • 4 CGRP small molecule antagonists Ubrogepant, Rimegepant, Atogepant and Zavegepant
  • 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.
  • small molecule drugs are mainly used for acute treatment due to their generally rapid metabolism.
  • 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.
  • 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.
  • 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.
  • the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is hydrogen, cyano, halogen, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl;
  • R 2 is hydrogen, hydroxy, azido or -NR 2a R 2b , wherein R 2a or R 2b is each independently selected from hydrogen or alkyl, or R 2a and R 2b together with the atoms to which they are attached form a heterocyclic group, which may be optionally substituted by 0-3 identical or different halogens 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;
  • R3 is piperidinyl or piperazinyl substituted with one substituent selected from the following:
  • R 3a is a 5-membered or 6-membered monocyclic aryl or heteroaryl group which may be optionally substituted by 0-2 identical or different halogen or alkyl groups, wherein the heteroaryl group contains at least 1 nitrogen atom;
  • R 3b is alkoxy, alkanoyl, alkyl-S(O) 2 - or alkyl-S(O)-;
  • R4 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 ;
  • R6 is hydrogen, alkyl or alkoxy
  • Y is O, S or Se
  • Z is NH, CH 2 , O or S
  • R3 is piperazinyl substituted with 1 substituent selected from:
  • alkyl part in 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.
  • R 1 is hydrogen, cyano, halogen, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl or piperidinyl;
  • R2 is hydrogen, hydroxy, azido, amino, alkylamino or dialkylamino
  • R3 is piperidinyl or piperazinyl substituted with one substituent selected from the following:
  • R4 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 ;
  • R6 is hydrogen, alkyl or alkoxy
  • Y is O, S or Se
  • Z is NH, CH 2 , O or S
  • R 3 is piperidinyl or piperazinyl substituted with 1 substituent selected from the following:
  • R3 is piperazinyl substituted with 1 substituent selected from:
  • alkyl or halogenated alkyl, alkoxy, alkylamino, dialkylamino, halogenated alkoxy and alkyl-S(O) 2 - groups are linear or branched alkyl groups consisting of 1 to 6 carbon atoms.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, which has a specified stereochemical structure of formula (I'):
  • R 1 , R 2 , Ar, P, Q and R 3 are as defined in claim 1 or claim 2.
  • R1 is hydrogen, cyano, halogen, alkyl, haloalkyl, amino, alkylamino, dialkylamino;
  • R2 is hydrogen, hydroxy, azido, amino, alkylamino or dialkylamino
  • R3 is piperidinyl or piperazinyl substituted with one substituent selected from the following:
  • R4 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 ;
  • R6 is hydrogen, alkyl or alkoxy
  • Y is O, S or Se
  • Z is NH or CH 2 ;
  • R 3 is piperidinyl or piperazinyl substituted with 1 substituent selected from the following:
  • R3 is piperazinyl substituted with 1 substituent selected from:
  • a compound of formula (I') or a pharmaceutically acceptable salt thereof is provided, wherein R 1 is hydrogen.
  • a compound of formula (I') or a pharmaceutically acceptable salt thereof is provided, wherein Ar is phenyl substituted with 2 halogen substituents.
  • a compound of formula (I') or a pharmaceutically acceptable salt thereof is provided, wherein Ar is 2,3-difluorophenyl.
  • a compound of formula (I') or a pharmaceutically acceptable salt thereof is provided, wherein R 3 is N-piperidinyl and is 4-substituted, or N-piperazinyl and is 4-substituted.
  • a compound of formula (I') or a pharmaceutically acceptable salt thereof wherein R2 is amino, R3 is N-piperidinyl and is 4-substituted.
  • a compound of formula (I') or a pharmaceutically acceptable salt thereof wherein R2 is hydroxyl, R3 is N-piperidinyl and is 4-substituted.
  • a compound of formula (I') or a pharmaceutically acceptable salt thereof is provided, wherein R4 is hydrogen or a halogen substituent; R5 is hydrogen or a halogen substituent; R6 is hydrogen; and Z is NH.
  • R1 is hydrogen
  • R2 is amino or hydroxy
  • R4 is hydrogen or halogen
  • R5 is hydrogen
  • Ar is 2,3-difluorophenyl
  • Q is O or S
  • X is N
  • Y is O, S or Se
  • Z is NH
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein X is N; and Z is NH.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the compound has a structure of formula (Ia),
  • A is N or CH
  • Ring B is selected from the following groups:
  • R1 is hydrogen, cyano, halogen, alkyl, haloalkyl, amino, alkylamino, dialkylamino;
  • R2 is hydrogen, hydroxy, azido, amino, alkylamino, dialkylamino, N-pyrrolidinyl, N-piperidinyl or N-piperazinyl;
  • R4 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
  • Q is O or S
  • Y is O, S or Se
  • 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;
  • A is N or CH
  • R1 is hydrogen
  • R2 is hydrogen, hydroxy, amino or N-piperazinyl
  • R4 is hydrogen or halogen
  • Ar is phenyl substituted with 2 halogen substituents, preferably 2,3-difluorophenyl;
  • Q is O or S
  • Y is O, S or Se.
  • 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),
  • R1 is hydrogen
  • R2 is hydrogen, hydroxy, amino or N-piperazinyl
  • R4 is hydrogen or halogen
  • Ar is a phenyl group substituted with two halogen substituents
  • Q is O or S
  • Y is O, S or Se
  • R 2 is hydroxy or amino
  • R 4 is hydrogen, fluorine or chlorine
  • Ar is 2,3-difluorophenyl
  • a compound of formula (Ia) or a pharmaceutically acceptable salt thereof is provided, wherein the compound has a structure of formula (V):
  • A is N or CH
  • R1 is hydrogen
  • R2 is hydrogen, hydroxy, amino or N-piperazinyl
  • Q is O or S
  • Y is O, S or Se
  • R2 is amino; Q is O; and Y is S or Se.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the compound has a structure of formula (IIa),
  • A is N or CH
  • R1 is hydrogen, cyano, halogen, alkyl, haloalkyl, amino, alkylamino, dialkylamino;
  • R2 is hydrogen, hydroxy, amino or N-piperazinyl
  • Ar is a phenyl group substituted with two halogen substituents
  • Q is O or S
  • Y is O, S or Se
  • R 3a is a six-membered monocyclic heteroaryl group containing 1 to 2 nitrogen atoms which may be optionally substituted by 0 to 2 identical or different halogen or alkyl groups;
  • 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.
  • 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),
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the compound has a structure of formula (IIIa),
  • A is N or CH
  • R1 is hydrogen, cyano, halogen, alkyl, haloalkyl, amino, alkylamino, dialkylamino;
  • R2 is hydrogen, hydroxy, azido, amino, alkylamino, dialkylamino, N-pyrrolidinyl, N-piperidinyl or N-piperazinyl;
  • Ar is a phenyl group substituted with two halogen substituents
  • Q is O or S
  • R 3b is alkyl-S(O) 2 - or alkyl-S(O)-;
  • R4 is hydrogen or halogen
  • R5 is hydrogen or halogen
  • 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.
  • 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.
  • the compounds described in the present invention include but are not limited to:
  • 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:
  • reaction formula 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).
  • 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:
  • 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.
  • 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.
  • the present invention is intended to include all stereoisomers of the compounds, such as enantiomers and diastereomers, unless otherwise specified.
  • 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.
  • the pharmaceutical preparation can be used to treat or prevent a condition or disease described herein.
  • the present invention discloses methods for treating conditions associated with abnormal CGRP levels.
  • diseases or disorders include, but are not limited to, migraine, neurogenic vasodilation, neurogenic inflammation, asthma, and chronic obstructive pulmonary disease.
  • 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.
  • 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.
  • Alkyl or alkane is a completely saturated straight or branched non-aromatic hydrocarbon.
  • a 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, and most preferably 1 to about 3 carbon atoms.
  • Non-limiting examples of straight and branched alkyls include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, amyl, and octyl.
  • C 1 -C 6 straight or branched alkyl is also referred to as "lower alkyl”.
  • 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.
  • 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.
  • carbonyl such as carboxyl, alkoxycarbonyl, formyl or acyl
  • thiocarbonyl such as thioester, thioacetate or thioformate
  • alkoxy phosphoryl, phosphate,
  • substituents of substituted alkyl groups include amino, azido, imino, amide, phosphoryl (including phosphonate and phosphite), 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.
  • 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 3 , -CN, etc.
  • 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.
  • 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.
  • heteroaryl examples 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.
  • Heterocyclic radical represents a saturated, partially saturated or unsaturated monocyclic or bicyclic ring containing at least one heteroatom selected from nitrogen, oxygen and sulfur.
  • 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.
  • 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.
  • 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.
  • 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.
  • Alkynyl is preferably a lower alkynyl group such as propargyl or ethynyl.
  • 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.
  • Acyl represents, for example, alkylcarbonyl, cyclohexylcarbonyl, arylcarbonyl, aryl-lower alkylcarbonyl or heteroarylcarbonyl.
  • Lower acyl is preferably lower alkylcarbonyl, in particular propionyl or acetyl.
  • 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.
  • the cyanoalkyl group refers to an alkyl group substituted with at least one cyano group, preferably a cyano-lower alkyl group, such as cyanomethyl or cyanoethyl.
  • 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.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • Lower alkoxy is especially methoxy, ethoxy, isopropoxy or tert-butoxy.
  • Arylalkyl includes aryl and alkyl as defined above and is, for example, benzyl, 1-phenethyl or 2-phenethyl.
  • 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.
  • 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.
  • CDI carbonyldiimidazole or
  • TCDI 1,1-thiocarbonyldiimidazole
  • DMF N,N-dimethylformamide
  • MeOH means methanol
  • N 3 means azide
  • NO 2 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
  • NC carbonyldiimidazole or
  • TCDI 1,1-thiocarbonyldiimidazole
  • DF means N,N-dimethylformamide
  • MeOH means methanol
  • the 1 H-NMR was measured by 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 ( ⁇ ) was given in parts per million (ppm).
  • MS mass spectrometry
  • ESI Agilent
  • TLC Thin layer chromatography
  • 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.).
  • the instrument model used for preparative high performance liquid chromatography is: Agilent 1260, chromatographic column: Waters XBridge Prep C18OBD (19mm ⁇ 150mm ⁇ 5.0 ⁇ m); 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.
  • reaction temperature is room temperature (20°C to 30°C).
  • the reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company, etc.
  • the present invention provides the following synthetic methods to synthesize all the compounds involved.
  • Ar in the synthesis methods refers to an aryl group or a heteroaryl group.
  • 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.
  • intermediate D and intermediate F refers to the method of J. Med. Chem. 2012, 55, 23, 10644.
  • intermediate A1 reacts with S to undergo nucleophilic substitution reaction, and the nitro group of intermediate A2 is reduced to amino group to generate intermediate A3, and A3 reacts with carbonyldiimidazole or 1,1-thiocarbonyldiimidazole to obtain target intermediate A.
  • 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.
  • This method is applicable to target compounds where Y is O or S.
  • 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.
  • This method is applicable to target compounds where Y is Se.
  • the present invention also provides a method for synthesizing the following intermediates:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, and the mixture was reacted at 80 ° C for 12 hours and concentrated under reduced pressure to obtain A2'-3.
  • 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.
  • 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 organic phases were combined and 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.
  • 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 ⁇ L, 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.
  • 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 ⁇ L, 1.2 eq).
  • iodomethane (1.88 g, 13.28 mmol, 826.48 ⁇ L, 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.
  • 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.
  • N,N'-carbonyldiimidazole (5.88 g, 36.24 mmol, 3 eq) and diisopropylethylamine (4.68 g, 36.24 mmol, 6.31 mL, 3 eq) were added to a solution of intermediate I-8 (3 g, 12.08 mmol, 1 eq) in tetrahydrofuran (30 mL).
  • 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.
  • 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.
  • 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 the mixture was reacted at room temperature of 25°C for 3 hours. After the reaction, the mixture was directly concentrated to dryness to obtain an oily intermediate B-1.
  • 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 temperature was maintained 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.
  • NaHMDS sodium hexamethyldisilazide
  • 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.
  • Compound 21 was synthesized according to the method of Example 2.
  • Compound 20 was synthesized according to the method of Example 4.
  • reaction mixture was poured into a saturated ammonium chloride (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 light yellow oily intermediate H-5 (0.1 g, 138.92 ⁇ mol, 70.93% yield).
  • 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).
  • 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 ⁇ mol, 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.
  • RIMEGEPANT was synthesized with reference to Example 8 of patent CN102656159A.
  • Example 8 In vitro human CGRP receptor antagonist activity test
  • %inhibition (Signalcmpd-SignalAve_VC)/(SignalAve_PC-SignalAve_VC) ⁇ 100.
  • MDR1-MDCKII obtained from Piet Borst, Netherlands Cancer Institute. cells (obtained from Piet Borst, Netherlands Cancer Institute) were seeded onto polycarbonate membranes in 96-well plates at 4.44 x 10 5 cells/mL until a confluent cell monolayer was formed within 4-7 days.
  • test compounds were diluted to a concentration of 2.00 ⁇ M (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.
  • the permeation of digoxin from A to B direction or B to A direction at 10.0 ⁇ M, and the permeation of nadolol and metoprolol from A to B direction at 2.00 ⁇ M 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.
  • 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.
  • the Lucifer Yellow exclusion assay was applied to determine the cell monolayer integrity. Remove the buffer from the apical and basolateral chambers, then add 75 ⁇ L of 100 ⁇ M Lucifer Yellow in transfer buffer and 250 ⁇ L 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 min without shaking. After 30 min of incubation, remove 20 ⁇ L of the Lucifer Yellow sample from the apical side, then add 60 ⁇ L of transfer buffer. Then take 80 ⁇ L of the Lucifer Yellow sample from the basolateral side. Measure the relative fluorescence units (RFU) of Lucifer Yellow at 425/528 nm (excitation/emission) wavelengths using an Envision plate reader.
  • REU relative fluorescence units
  • dCr / dt is the cumulative concentration of the compound in the receiving chamber over time ( ⁇ M/s);
  • Vr is the volume of the 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 for transmission, e.g., the monolayer area is 0.143 cm2 ; and
  • C0 is the initial concentration in the donor chamber ( ⁇ M).
  • the efflux ratio was calculated using the following formula:
  • 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.
  • 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.
  • Drug preparation The solvent was DMSO/HS-15/normal saline (5:5:90, v:v:v).
  • Sample collection The collection site was the saphenous vein on 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.
  • the UPLC-MS/MS method was used to determine the compound concentration in plasma at different times after a single intravenous administration of the disclosed compound to cynomolgus monkeys, so as to study the pharmacokinetics of the disclosed compound in cynomolgus monkeys.

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Abstract

涉及一种新的如式(I)的化合物及其药学上可接受的盐，所述化合物为CGRP受体拮抗剂；还涉及所述化合物的药物组合物、制备方法及其治疗用途。

Description

一种治疗CGRP相关障碍的小分子药物 技术领域
本发明属于生物医药领域。
本发明涉及一种包含药学上可接受的盐的如式I的新型化合物。该类化合物是CGRP受体拮抗剂。本发明涉及所述化合物及其药物组合物用于治疗CGRP相关障碍的疾病，包括偏头痛、神经源性血管舒张、神经源性炎症、呼吸道炎性疾病如哮喘及慢性阻塞性肺病等。
背景技术
偏头痛是第二大常见的神经系统失能性疾病，其临床特征为反复发作性的、多为单侧的中重度搏动性头痛，常同时伴恶心、呕吐、畏光和畏声等症状。偏头痛与焦虑抑郁、睡眠障碍等存在共病关系，可能增加罹患认知功能障碍和心脑血管疾病的风险。
世界卫生组织将偏头痛列为10种最致残的疾病之一，影响全球超10亿人。女性患者人数约为男性的3倍。中国偏头痛发病率超过10％，约1.32亿患者，全球第一。然而，我国偏头痛诊断和治疗仍存在较大不足，患者就诊率仅为52.9％，医师正确诊断率仅为13.8％，且普遍存在预防性治疗不足、镇痛药物使用过度等情况(参考：2022版中国偏头痛诊治指南)。
传统疗法种类繁多、价格不高，但疗效欠佳、响应率低，副作用大，患者依从性较低！满意度仅为40％。临床迫切需要更多的新型特异性药物，尤其是对当前治疗不耐受、有禁忌或无响应的患者。近年来，随着新型治疗靶点降钙素基因相关肽(calcitonin gene related peptide,CGRP)相关的多款药物成功上市，CGRP靶向治疗药物成为该领域的突破性疗法，由于其具有更安全有效、无心血管风险等优势，可以解决当下传统疗法不能解决的临床问题。
CGRP是从感觉神经释放的高效血管活性肽，含有37个氨基酸，是目前已知最强的内源性血管扩张肽，在几种心血管疾病中具有保护作用。CGRP属于包括降钙素、肾上腺髓质素和胰淀素的肽家族。在人体中，存在两种形式的CGRP(a-CGRP和β-CGRP)并且它们具有相似的活性。CGRP受体位于疼痛信号传导途径、颅内动脉和肥大细胞内，并且其激活被认为在偏头痛病理生理学中具有因果作用。
CGRP靶向疗法主要通过三重机制发挥作用：1)阻断神经源性炎症：抑制由三叉神经向大脑坚硬外壳或脑膜内的肥大细胞释放CGRP引起的炎症；2)减少动脉扩张：通过阻断位于血管壁内平滑肌细胞中的CGRP受体进而抑制颅内动脉的病理性扩张，而不会产生不希望的血管收缩作用；3)抑制疼痛传递：通过抑制疼痛信号从三叉神经到三叉尾核的中枢传递来抑制疼痛传递。
已公开的小分子CGRP抑制剂相关专利申请包括CN102656159A、CN104136437A、CN117466893A和CN117624191A等。目前国外已有4个CGRP单抗药(Erenumab、Fremanezumab、Galcanezumab和Eptinezumab)和4个CGRP小分子拮抗剂(Ubrogepant、Rimegepant、Atogepant和Zavegepant)上市。单抗类药物由于半衰期长，主要以预防为主，且价格高昂，只能注射，限制了其广泛地应用。相比之下，小分子药物由于普遍代谢较快，主要以急性治疗为主。在所有已上市CGRP类药物中，口服的小分子药物销售增长最快、满意度最高。其中，Rimegepant是目前唯一一款获批可同时用于治疗和预防偏头痛的口服CGRP受体拮抗剂，医生有望开出单一药物来治疗和预防偏头痛发作。自2020年上市以来Rimegepant销售额增速最快，2021年全年销售额达到5.26亿美元；据原研公司Biohaven的预测，Rimegepant的2028年销量可达33亿美元，远超过其他CGRP抗体和小分子药物。
Rimegepant虽然被大家所看好，但是也有其固有的缺点，如溶解性欠佳、渗透性不好等；其临床起效时间至少为1.5小时，对于临床急性患者仍有提高的空间。本发明则涉及一类药效更好、渗透性更佳或者起效更快的结构新颖的小分子CGRP受体拮抗剂、包含它们的药物组合物以及在治疗CGRP相关障碍的疾病中的用途。
发明内容
本发明涉及一类结构新颖的化合物及其药学上可接受的盐。本发明涉及的化合物是CGRP受体拮抗剂。本发明涉及所述化合物及其药物组合物用于治疗CGRP相关障碍的疾病，包括偏头痛、神经源性血管舒张、神经源性炎症、呼吸道炎性疾病如哮喘及慢性阻塞性肺病等。
本发明涉及一种如式(Ⅰ)的化合物或其药学上可接受的盐，
其中：
R1是氢、氰基、卤素、烷基、卤代烷基、烷氧基、氨基、烷基氨基、二烷基氨基、氮杂环丁烷基、吡咯烷基、哌啶基或哌嗪基；
R2是氢、羟基、叠氮基或-NR2aR2b，其中R2a或R2b各自独立地选自氢或烷基，或R2a和R2b与它们连接的原子一起形成杂环基，所述杂环基任选地可被0-3个相同或不同的卤素或烷基所取代；优选是氢、羟基、叠氮基、氨基、烷基氨基、二烷基氨基、N-吡咯烷基、N-哌啶基或N-哌嗪基；更优选是氢、羟基、氨基、或N-哌嗪基；
R3是取代有1个选自以下的取代基的哌啶基或哌嗪基：

R3a是任选地可被0-2个相同或不同的卤素或烷基所取代的五元或六元单环芳基或杂芳基，所述杂芳基含有至少1个氮原子；
R3b是烷氧基、烷酰基、烷基-S(O)2-或烷基-S(O)-；
R4是氢、卤素、氰基、烷基、卤代烷基、烷氧基或卤代烷氧基；
R5是氢、卤素、氰基、烷基、卤代烷基、烷氧基或卤代烷氧基；
Ar是取代有0至3个选自以下的取代基的苯基：氰基、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基及烷基-S(O)2-；
P是NH、O或S；
Q是O或S；
X是N或CR6；
R6是氢、烷基或烷氧基；
Y是O、S或Se；
Z是NH、CH2、O或S；
此外，当Q是O，且Y是O时，R3是取代有1个选自以下的取代基的哌嗪基：
其中所述烷基或卤代烷基、烷氧基、烷基氨基、二烷基氨基、卤代烷氧基、烷基-S(O)2-和烷基-S(O)-中的烷基部分为由1-6个碳组成的直链或支链烷基。
在一些实施方式中，提供了式(Ⅰ)的化合物或其药学上可接受的盐，其中：
R1是氢、氰基、卤素、烷基、卤代烷基、烷氧基、氨基、烷基氨基、二烷基氨基、氮杂环丁烷基、吡咯烷基或哌啶基；
R2是氢、羟基、叠氮基、氨基、烷基氨基或二烷基氨基；
R3是取代有1个选自以下的取代基的哌啶基或哌嗪基：
R4是氢、卤素、氰基、烷基、卤代烷基、烷氧基或卤代烷氧基；
R5是氢、卤素、氰基、烷基、卤代烷基、烷氧基或卤代烷氧基；
Ar是取代有0至3个选自以下的取代基的苯基：氰基、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基及烷基-S(O)2-；
P是NH、O或S；
Q是O或S；
X是N或CR6；
R6是氢、烷基或烷氧基；
Y是O、S或Se；
Z是NH、CH2、O或S；
此外，当Q是S，且Y是O时，R3是取代有1个选自以下的取代基的哌啶基或哌嗪基：
当Q是O，且Y是O时，R3是取代有1个选自以下的取代基的哌嗪基：
其中所述烷基或卤代烷基、烷氧基、烷基氨基、二烷基氨基、卤代烷氧基和烷基-S(O)2-中的烷基部分为由1-6个碳组成的直链或支链烷基。
在一些实施方式中，提供了式(Ⅰ)的化合物或其药学上可接受的盐，其具有式(I’)的指定立体化学结构
其中，R1、R2、Ar、P、Q和R3如权利要求1或权利要求2所定义。
在一些实施方式中，提供了式(Ⅰ’)的化合物或其药学上可接受的盐，其中：
R1是氢、氰基、卤素、烷基、卤代烷基、氨基、烷基氨基、二烷基氨基；
R2是氢、羟基、叠氮基、氨基、烷基氨基或二烷基氨基；
R3是取代有1个选自以下的取代基的哌啶基或哌嗪基：
R4是氢、卤素、氰基、烷基、卤代烷基、烷氧基或卤代烷氧基；
R5是氢、卤素、氰基、烷基、卤代烷基、烷氧基或卤代烷氧基；
Ar是取代有0至2个卤素取代基的苯基；
P是NH、O或S；
Q是O或S；
X是N或CR6；
R6是氢、烷基或烷氧基；
Y是O、S或Se；
Z是NH或CH2；
此外，当Q是S，且Y是O时，R3是取代有1个选自以下的取代基的哌啶基或哌嗪基：
当Q是O，且Y是O时，R3是取代有1个选自以下的取代基的哌嗪基：
在一些实施方式中，提供了式(Ⅰ’)的化合物或其药学上可接受的盐，其中R1是氢。
在一些实施方式中，提供了式(Ⅰ’)的化合物或其药学上可接受的盐，其中Ar是取代有2个卤素取代基的苯基。
在一些实施方式中，提供了式(Ⅰ’)的化合物或其药学上可接受的盐，其中Ar是2,3-二氟苯基。
在一些实施方式中，提供了式(Ⅰ’)的化合物或其药学上可接受的盐，其中P是O，R2是氢、羟基或氨基。
在一些实施方式中，提供了式(Ⅰ’)的化合物或其药学上可接受的盐，其中R3是N-哌啶基且为4-取代的，或N-哌嗪基且为4-取代的。
在一些实施方式中，提供了式(Ⅰ’)的化合物或其药学上可接受的盐，其中R2是氨基，R3是N-哌啶基且为4-取代的。
在一些实施方式中，提供了式(Ⅰ’)的化合物或其药学上可接受的盐，其中R2是羟基，R3是N-哌啶基且为4-取代的。
在一些实施方式中，提供了式(Ⅰ’)的化合物或其药学上可接受的盐，其中R4是氢或卤素取代基；R5是氢或卤素取代基；R6是氢；Z是NH。
在一些实施方式中，提供了式(Ⅰ’)的化合物或其药学上可接受的盐，其中：
R1是氢；
R2是氨基或羟基；
R4是氢或卤素；
R5是氢；
Ar是2,3-二氟苯基；
P是O；
Q是O或S；
X是N；
Y是O、S或Se；
Z是NH。
在一些实施方式中，提供了式(Ⅰ)的化合物或其药学上可接受的盐，其中X是N；Z是NH。
在一些实施方式中，提供了式(Ⅰ)的化合物或其药学上可接受的盐，其中所述化合物具有式(Ⅰa)的结构，
其中：
A是N或CH；
环B选自下述基团：
R1是氢、氰基、卤素、烷基、卤代烷基、氨基、烷基氨基、二烷基氨基；
R2是氢、羟基、叠氮基、氨基、烷基氨基、二烷基氨基、N-吡咯烷基、N-哌啶基或N-哌嗪基；
R4是氢、卤素、氰基、烷基、卤代烷基、烷氧基或卤代烷氧基；
R5是氢、卤素、氰基、烷基、卤代烷基、烷氧基或卤代烷氧基；
Ar是取代有2个卤素取代基的苯基；
P是O；
Q是O或S；
Y是O、S或Se；
优选地，R1是氢；R2是氢、羟基、氨基或N-哌嗪基；R4是氢或卤素；R5是氢或卤素；Ar是2,3-二氟苯基；
此外，当Q是O，且Y是O时：A是N。
在一些实施方式中，提供了式(Ⅰa)的化合物或其药学上可接受的盐，其中：
A是N或CH；
选自下述基团：
R1是氢；
R2是氢、羟基、氨基或N-哌嗪基；
R4是氢或卤素；
Ar是取代有2个卤素取代基的苯基，优选是2,3-二氟苯基；
P是O；
Q是O或S；
Y是O、S或Se。
在一些实施方式中，提供了式(Ⅰa)的化合物或其药学上可接受的盐，其中所述化合物具有式(Ⅳa)或式(Ⅳb)的结构，
其中：
选自下述基团：
R1是氢；
R2是氢、羟基、氨基或N-哌嗪基；
R4是氢或卤素；
Ar是取代有2个卤素取代基的苯基；
P是O；
Q是O或S；
Y是O、S或Se；
优选地，R2是羟基或氨基；R4是氢、氟或氯；Ar是2,3-二氟苯基。
在一些实施方式中，提供了式(Ⅰa)的化合物或其药学上可接受的盐，其中所述化合物具有式(Ⅴ)的结构：
其中：
A是N或CH；
R1是氢；
R2是氢、羟基、氨基或N-哌嗪基；
Q是O或S；
Y是O、S或Se；
优选地，R2是氨基；Q是O；Y是S或Se。
在一些实施方式中，提供了式(Ⅰ)的化合物或其药学上可接受的盐，其中所述化合物具有式(Ⅱa)的结构，
其中：
A是N或CH；
R1是氢、氰基、卤素、烷基、卤代烷基、氨基、烷基氨基、二烷基氨基；
R2是氢、羟基、氨基或N-哌嗪基；
Ar是取代有2个卤素取代基的苯基；
P是O；
Q是O或S；
Y是O、S或Se；
R3a是任选地可被0-2个相同或不同的卤素或烷基所取代的含有1-2个氮原子的六元单环杂芳基；
优选地，A是CH；R1是氢；R2是氨基；Ar是2,3-二氟苯基；Q是O；Y是S；R3a是任选地可被0-2个相同或不同的卤素或烷基所取代的吡啶基或嘧啶基。
在一些实施方式中，提供了式(Ⅱa)的化合物或其药学上可接受的盐，其中所述化合物具有式(Ⅱc)或式(Ⅱd)的结构，
其中，A、R1、R2、Ar、P、Q和Y如权利要求21所定义。
在一些实施方式中，提供了式(Ⅰ)的化合物或其药学上可接受的盐，其中所述化合物具有式(Ⅲa)的结构，
其中：
A是N或CH；
R1是氢、氰基、卤素、烷基、卤代烷基、氨基、烷基氨基、二烷基氨基；
R2是氢、羟基、叠氮基、氨基、烷基氨基、二烷基氨基、N-吡咯烷基、N-哌啶基或N-哌嗪基；
Ar是取代有2个卤素取代基的苯基；
P是O；
Q是O或S；
R3b是烷基-S(O)2-或烷基-S(O)-；
R4是氢或卤素；
R5是氢或卤素；
优选地，A是CH；R1是氢；R2是氨基；Ar是2,3-二氟苯基；Q是O；R3b是烷基-S(O)-；R4是氢；R5是氢。
本发明包括所述化合物的所有药学上可接受的盐形式。该类盐可采用市售试剂通过常规有机化学方法制备，具体包括盐酸盐、氢溴酸盐、氢碘酸盐、磷酸盐、硫酸盐、硝酸盐、甲酸盐、乙酸盐、丁二酸盐、苯磺酸盐、柠檬酸盐、葡萄糖醛酸盐、乳酸盐、甲磺酸盐、甲苯磺酸盐、双羟萘酸盐和酒石酸盐等。
本发明意欲包括所有化合物中原子的所有同位素。本发明的同位素标记化合物一般可通过本领域已知的常规技术或通过与本申请类似方法制备，这些化合物具有改善药理或药代性质的潜力。
本发明所述的化合物包含但不限于：


另一方面，本发明提供了式(Ⅰ)的化合物的制备方法，其特征在于反应步骤如反应式1所示：
反应式1
在反应式1中，化合物A去保护，得到的中间体B与羰基二咪唑或1,1-硫代羰基二咪唑反应得到中间体C；中间体C与中间体D连接、随后脱保护，得到如式Ⅱ所示的通式化合物(其中，X是O或S；Y是O、S或Se；V是N或CH；Ar是任选取代的杂芳基或芳基)。
另一方面，本发明提供了式(Ⅰ)的化合物的制备方法，其特征在于反应步骤如反应式2所示：
反应式2
在反应式2中，化合物A去保护，得到的中间体B与羰基二咪唑或1,1-硫代羰基二咪唑反应得到中间体C；中间体C与中间体F连接、随后脱保护，得到如式Ⅲ所示的通式化合物(其中，X是O或S；Y是O、S或Se；V是N或CH；Ar是任选取代的杂芳基或芳基)。
另一方面，本发明意欲包括所有化合物中原子的所有同位素。本发明的同位素标记化合物一般可通过本领域已知的常规技术或通过与本申请类似方法制备，这些化合物具有改善药理或药代性质的潜力。
另一方面，本发明意欲包括所有化合物的互变异构体，除非另外指明。互变异构体是指质子从分子的一个原子移位到同一分子的另一个原子，实例包括酮-烯醇对、酰胺-亚氨基酸对、内酰胺-内酰亚胺对、酰胺-亚氨基酸对、烯胺-亚胺对等。
另一方面，本发明意欲包括所有化合物的立体异构体，如对映体和非对映体，都包括在内，除非另外指明。含有不对称取代的碳原子的本发明化合物可以以旋光性形式或外消旋形式被分离。本领域中已知如何由旋光性原料制备旋光性形式的方法，例如通过拆分外消旋混合物或通过立体有择合成。烯烃的多种几何异构体、C＝N双键等也可存在于本文所述的化合物中，所有此类稳定的异构体均应包括在本发明中。
另一方面，本发明提供了适合用于人类患者的药物制剂，该药物制剂包含以上所示的任何化合物(例如，本发明的化合物，诸如具有式(I)的化合物)以及一种或多种药学上可接受的赋形剂。在某些实施例中，药物制剂可以用于治疗或预防本文所述的病症或疾病。
另一方面，本发明披露了治疗与异常CGRP含量有关的病症的方法。这些疾病或紊乱包括但不限于偏头痛、神经源性血管舒张、神经源性炎症、哮喘和慢性阻塞性肺病。
另一方面，本发明披露了治疗或预防偏头痛的方法，包括但不限于对偏头痛急性发作的治疗和/或对偏头痛的长期预防。
另一方面，本发明披露了具有式(I)的化合物与偏头痛治疗药物的组合疗法，其可以超出单独疗法的能力增强对偏头痛预防或治疗的临床益处。
术语说明
烷基或烷烃是完全饱和的直链或支链非芳族烃。通常，除非另有定义，否则直链或支链烷基具有1至约20个碳原子，优选1至约10个碳原子，更优选1至约6个碳原子，最优选1至约3个碳原子。直链和支链烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、己基、戊基和辛基。C1-C6直链或支链烷基也称为“低级烷基”。
而且，如整个说明书、实例和权利要求书中使用的术语“烷基”(或“低级烷基”)旨在包括“未取代的烷基”和“经取代的烷基”，后者是指具有置换烃主链的一个或多个碳上的氢的取代基的烷基部分。如果没有另外指定，则此类取代基的非限制性实例包括例如卤素、羟基、羰基(诸如羧基、烷氧基羰基、甲酰基或酰基)、硫代羰基(诸如硫酯、硫代乙酸根或硫代甲酸根)、烷氧基、磷酰基、磷酸根、膦酸根、亚膦酸根、氨基、酰胺基、脒、亚胺、氰基、硝基、叠氮基、巯基、烷硫基、硫酸根、磺酸根、氨磺酰基、磺酰胺基、磺酰基、杂环基、芳烷基、或芳族或杂芳族部分。本领域的技术人员将理解，如果适当，则烃链上取代的部分本身可以被取代。例如，经取代的烷基的取代的基非限制性实例包括氨基、叠氮基、亚氨基、酰胺基、磷酰基(包括膦酸根和亚膦酸根)、磺酰基(包括硫酸根、磺酰胺基、氨磺酰基和磺酸根)和甲硅烷基，以及醚、烷硫基、羰基(包括酮、醛、羧酸酯和酯)、-CF3、-CN等的经取代和未取代形式。
环烷基优选具有3至约20个环碳原子且可以是经取代和未取代形式。环烷基的非限制性实例包括环丙基、环丁基、环己基、环戊基或甲基环戊基等。环烷基可以进一步被烷基、烯基、炔基、烷氧基、烷硫基、氨基烷基、羰基取代的烷基、-CF3、-CN等取代。
芳基表示具有5至约20个环碳原子的环芳族基团。通常，除非另有定义，杂芳基具有单环或双环。芳基的非限制性实例包括苯基、1-萘基或2-萘基，或含有苯基的双环稠合衍生物，例如茚满基、二氢或四氢萘基等。
杂芳基表示含有至少一个选自氮、氧和硫的杂原子的芳族基团。通常，除非另有定义，杂芳基具有单环或双环。单环杂芳基包括含有1、2、3或4个选自氮、硫和氧的杂原子的5或6元杂芳基。杂芳基的非限制性实例包括吡咯基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、噁唑基、异噁唑基、噁二唑基、噻唑基、异噻唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基等，或含有单环杂芳基的双环稠合衍生物，例如吲哚基、苯并咪唑基、苯并呋喃基、喹啉基、异喹啉基、喹唑啉基、嘌呤基等。
杂环基表示含有至少一个选自氮、氧和硫的杂原子的饱和、部分饱和或不饱和的单环或双环。杂环基的非限制性实例包括吡咯烷基、噁唑烷基、噻唑烷基、哌啶基、吗啉基、哌嗪基、二氧戊环基或四氢吡喃基等，或含有单环杂环基的双环稠合衍生物，例如苯并吡咯烷基、苯并哌啶基等。
芳基、杂芳基或杂环基可以任选地被取代或未被取代。“取代”是指芳基、杂芳基或杂环基上的一个或多个氢被取代，所述的氢可以是碳原子上的氢，也可以是杂原子上的氢。在任选取代的芳基、杂芳基或杂环基中，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷基、硫代、烷基氨基、卤素、巯基、羟基、硝基、氨基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基、氧代基或羧酸酯基等。
烯基含有一个或多个、例如两个或三个双键且优选为低级链烯基，例如1-或2-丁烯基、1-丙烯基、烯丙基或乙烯基。
炔基优选为低级炔基，如炔丙基或乙炔基。
在任选取代的烯基或炔基中，取代基优选为低级烷基、低级烷氧基、卤代或二(低级烷基)氨基且与链烯基或炔基的饱和碳原子或与链烯基的不饱和碳原子连接。
酰基例如表示烷基羰基、环己基羰基、芳基羰基、芳基-低级烷基羰基或杂芳基羰基。低级酰基优选为低级烷基羰基，特别是丙酰基或乙酰基。
羟基烷基指至少被1个羟基取代的烷基，优选是羟基-低级烷基，例如羟甲基、2-羟基乙基、2-羟基正丙基、羟基异丙基。
氰基烷基指至少被1个氰基取代的烷基，优选是氰基-低级烷基，例如氰基甲基或氰基乙基。
卤代烷基指至少被1个卤素取代的烷基，优选是卤素-低级烷基，例如单氟甲基、二氟甲基、三氟甲基、3,3,3-三氟乙基或五氟乙基。
卤素为氟、氯、溴或碘。
低级烷氧基尤其是甲氧基、乙氧基、异丙氧基或叔丁氧基。
芳基烷基包括如上文所定义的芳基和烷基且例如为苄基、1-苯乙基或2-苯乙基。
杂芳基烷基包括如上文所定义的杂芳基和烷基且例如为2-、3-或4-吡啶基甲基、1-或2-吡咯基甲基、1-吡唑基甲基、1-咪唑基甲基、2-(1-咪唑基)乙基或3-(1-咪唑基)丙基。
可以与芳基或杂芳基的原子一起形成5或6元碳环或杂环的两个相邻取代基例如为丙烯(propylene)、1-或2-氧代丙烯、1-或2-氧杂丙烯、1-氧杂亚丙基(propylidene)、亚甲二氧基、二氟-亚甲二氧基、1-或2-氮杂丙烯、1-或2-氮杂亚丙基、1，2-或1，3-二氮杂-亚丙基、1，3-二氮杂-2-氧代丙烯、丁烯(butylene)、1-或2-氧杂丁烯、亚乙二氧基、1-或2-氮杂丁烯或1-或2-氮杂亚丁二烯基或携带如上文所定义的其它取代基的这类基团。
附图说明
图1口服给予RIMEGEPANT、化合物1、5、21的不同时间点血药浓度结果
图2静脉给予RIMEGEPANT、化合物1、5、21的不同时间点血药浓度结果
图3RIMEGEPANT和化合物5的口服给药(PO)对模型动物血流综合增长率％的影响
具体实施方式
本发明说明书和实施例中使用的化学缩写一般遵循本领域中使用的惯例，定义如下："CDI"表示羰基二咪唑或；"TCDI"表示1,1-硫代羰基二咪唑；"DMF"表示N,N-二甲基甲酰胺；"MeOH"表示甲醇；"N3"表示叠氮；"NO2"表示硝基；"Ar"表示芳基；"Boc”表示叔丁氧羰基；"DMSO"表示二甲亚砜；"EtOAc"表示乙酸乙酯；"THF”表示四氢呋喃；"DCM"表示二氯甲烷；"ACN"表示乙腈；"DIPEA"表示二异丙基乙胺；"NaHMDS"表示双(三甲基硅基)氨基钠；"LDA"表示二异丙基氨基锂；"NCS"表示N-氯代丁二酰亚胺。
以下实施例中记载的化合物的结构通过核磁共振氢谱(1H-NMR)或质谱(MS)来确证。
1H-NMR的测定仪器为Bruker 400MHz核磁共振仪，测定溶剂为氘代甲醇(CD3OD)、氘代氯仿(CDCl3)或六氘代二甲基亚砜(DMSO-d6)，内标为四甲基硅烷(TMS)。化学位移(δ)以百万分之一(ppm)为单位给出。
质谱(MS)的测定仪器为Agilent(ESI)质谱仪，型号为Agilent 6120B。
薄层色谱法(TLC)使用Merck产的铝板(20×20cm)进行，薄层制备色谱法采用GF254(0.4～0.5mm)硅胶板进行。
反应的监测采用薄层色谱法(TLC)或液相色谱-质谱联用(LC-MS)，使用的展开剂体系包括二氯甲烷和甲醇体系、正己烷和乙酸乙酯体系以及石油醚和乙酸乙酯体系。根据要分离的化合物的极性不同对展开剂体系进行调节(通过调节溶剂的体积比或者加入三乙胺等进行)。
制备高效液相色谱法所使用的仪器型号：Agilent 1260，色谱柱：Waters XBridge Prep C18OBD(19mm×150mm×5.0μm)；色谱柱温：25℃；流速：20.0mL/min；检测波长：214nm；洗脱梯度：(0min：10％A，90％B；16.0min：90％A，10％B)；流动相A：100％乙腈；流动相B：0.05％碳酸氢铵水溶液。
除非特别指出，反应温度为室温(20℃～30℃)。
实施例中所使用的试剂购自Acros Organics、Aldrich Chemical Company等。
合成方法
本发明提供了下述合成方法以合成所涉及的所有化合物。
合成方法中的Ar指代芳基或杂芳基。
方案1：
先对中间体A去保护，得到的中间体B与羰基二咪唑或1,1-硫代羰基二咪唑反应得到中间体C；中间体C分别与中间体D或F连接、随后脱保护，分别得到如式(II)式(III)所示的系列化合物。
其中，将哌啶基换为哌嗪基的底物，即可获得中间为哌嗪基的类似化合物。
其中，中间体D和中间体F的合成参考文献J.Med.Chem.2012,55,23,10644的方法。
本方案的关键中间体可通过下述方案的路线来合成：
中间体A的合成：
首先，中间体A1与S发生亲核取代反应，得到的中间体A2的硝基还原为氨基后生成中间体A3，A3与羰基二咪唑或1,1-硫代羰基二咪唑反应，得到目标中间体A；对于中间体A2，也可先由A1’与S’反应生成中间体A2’，然后通过A2’的氨基转化为W而得到。
此方法适用于Y为O或S的目标化合物。
中间体A-5的合成：
前两步与上述描述相同。第三步中，中间体A6与原甲酸甲酯在路易斯酸催化下脱水关环，得到中间体A7；A7通过LDA拔氢、再与NCS反应得到氯代的中间体A8；最后，A8与硼氢化钠和硒反应，得到中间体A-5。
此方法适用于Y为Se的目标化合物。
本发明还提供了下述中间体的合成方法：
以中间体A-1为反应原料，与碘甲烷发生甲基化得到中间体I-7；中间体I-7在酸性条件下脱保护得到中间体I-8；中间体I-8与羰基二咪唑或硫代羰基二咪唑缩合得到中间体C-6。
中间体C-a1与硫代羰基二咪唑缩合得到中间体C-a2；中间体C-a2与氨基吡啶缩合得到中间体C-a3；中间体C-a3在酸性条件下脱保护得到中间体C-a4；中间体C-a4与羰基二咪唑或硫代羰基二咪唑缩合得到中间体C-a5。
中间体A-b1与硫代碳酰氯缩合得到中间体A-b2；中间体A-b2与中间体A-a1缩合得到中间体A-b3；中间体A-b3在酸性条件下脱保护得到中间体B-b4；中间体B-b4与羰基二咪唑或硫代羰基二咪唑缩合得到中间体C-b5。
中间体的合成
合成例1中间体A-1的合成：
向中间体2b(10g,70.38mmol,1eq)在N,N-二甲基甲酰胺(100mL)的溶液中加入碳酸钾(19.5g,140.8mmol,2eq)和中间体I-1b(15.5g,77.4mmol,1.1eq)。反应混合物在80℃搅拌12小时。LCMS确认反应完成。反应液减压浓缩，以水(500mL)淬灭，乙酸乙酯(200mL*3)萃取。合并有机层饱和食盐水洗(100mL)，硫酸钠干燥，过滤并减压浓缩得到中间体I-3b。
MS(ESI)m/z＝323.1[M+1]+
在氮气保护下向中间体I-3b(15.0g,46.5mmol,1.00eq)在甲醇(400mL)的溶液中加入钯碳(3.00g,2.82mmol,10％purity,6.06e-2eq)。混悬液通氢气(15Psi)3小时。之后反应混合物在氢气下20℃搅拌16小时。LCMS确认反应完成。反应液过滤并减压浓缩得到中间体I-4b。
MS(ESI)m/z＝293.2[M+1]+
向中间体I-4b(2g,6.84mmol,1eq)在无水四氢呋喃(20mL)的溶液中加入中间体5b(2.44g,13.68mmol,2eq)。反应液在80℃搅拌12小时。LCMS确认反应完成。反应液过滤，滤液减压浓缩。残余物使用硅胶色谱柱纯化得到中间体A-1。
MS(ESI)m/z＝335.3[M+1]+
1H 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).
合成例2中间体A-3的合成：
将4-氨基-2-氯-3-硝基吡啶A1’-3(3.00g,17.2mmol)溶于乙醇(15mL)中，加入三乙胺(3.50g,34.5mmol,4.81mL)和1-Boc-4-氨基哌啶(3.46g,17.29mmol)，混合物在80℃反应12小时，减压下浓缩干，得到A2’-3。
MS(ESI)m/z＝338.2[M+1]+；
1H 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)。
将上述粗品(3.00g,8.89mmol)溶于乙腈(30mL)中，加入亚硝酸叔丁酯(916mg,8.89mmol,1.06m)，25℃下搅拌30分钟后降至0℃，加入溴化亚铜(1.28g,8.89mmol,270μL)，继续在25℃反应12小时。混合物过滤、减压浓缩。将得到的粗品溶于N,N-二甲基甲酰胺(20mL)，并加入氟化钾(738mg,12.7mmol)，于100℃反应12小时，然后倒入水中，用乙酸乙酯萃取3次，有机相分别用饱和食盐水洗涤、无水硫酸钠干燥，减压和过滤后得到的剩余物经柱层析(硅胶,石油醚/乙酸乙酯＝8/1～3/1)纯化，得到中间体A2-3。
MS(ESI)m/z＝341.2[M+1]+；
1H 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)。
向中间体A2-3的甲醇(15mL)溶液中加入钯碳(0.25g,234μmol,10％purity)，于20℃、氢气(50Psi)氛围下反应12小时。随后反应混合物过滤、减压浓缩，得到中间体A3-3(棕色固体，1.1g,粗品)。将A3-3溶于四氢呋喃(10mL)，加入1,1-硫代羰基二咪唑(1.15g,6.44mmol)，50℃反应12小时。然后反应液经过滤、减压浓缩得到粗品。粗品经柱层析(硅胶,石油醚/乙酸乙酯＝10/1～4/1)纯化，得到中间体A-3。
MS(ESI)m/z＝353.2[M+1]+。
合成例3中间体A-5的合成：
向A4(10g,70.38mmol,1eq)的N,N-二甲基甲酰胺(100mL)溶液中加入碳酸钾(19.5g,140.8mmol,2eq)和1-Boc-4-氨基哌啶(15.5g,77.4mmol,1.1eq)。反应混合物在80℃搅拌12小时后，减压下浓缩出去溶剂，剩余物用水稀释、并用乙酸乙酯萃取3次。合并所得的有机相分别用饱和食盐水洗涤、无水硫酸钠干燥，过滤和浓缩后得到中间体A5。
MS(ESI)m/z＝323.1[M+1]+。
将A5(15.0g,46.5mmol,1.00eq)溶于甲醇(400mL)中，加入钯碳(3.00g,2.82mmol,10％purity,6.06e-2eq)，氢气氛围(15Psi)下在20℃反应16小时。反应混合物过滤和浓缩得到A6。
MS(ESI)m/z＝293.2[M+1]+。
向A6(7.20g,24.6mmol,1.00eq)的甲苯(100mL)溶液中，依次加入对甲苯磺酸(424mg,2.46mmol,0.1eq)和原甲酸三乙酯(7.30g,49.2mmol,8.19mL,2.00eq)。混合物在110℃反应16小时。反应混合物过滤和浓缩，粗品经反相高效液相色谱(0.1％FAcondition)纯化得到A7。
MS(ESI)m/z＝331.2[M+1]+。
1H 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).
在-78℃下，向A7(1.00g,3.31mmol,1.00eq)的四氢呋喃(10mL)溶液中缓慢滴入二异丙基氨基锂(2M,1.98mL,1.20eq)，加完后在该温度下继续反应1小时，然后滴入N-氯代丁二酰亚胺(529mg,3.97mmol,1.20eq)。该混合物回到20℃反应16小时后，降至0℃用氯化铵溶液淬灭。混合物用乙酸乙酯萃取三次，合并所得的有机相用无水硫酸钠干燥、过滤和浓缩后得到粗品。该粗品经反相高效液相色谱(0.1％FAcondition)纯化得到A8。
MS(ESI)m/z＝337.2[M+1]+。
1H 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).
20℃下，将硼氢化钠(0.17g,4.45mmol,1.50eq)加入到硒化氢(0.36g,4.45mmol,353μL,1.50eq)的乙醇(10mL)溶液中，保持该温度反应0.5小时。然后，加入A8(1.00g,2.97mmol,1.00eq)，升温到90℃反应12小时。该混合物降到0℃，用氯化铵溶液(50mL)淬灭，并用水(30mL)洗涤、用乙酸乙酯萃取两次。合并所得的有机相用无水硫酸钠干燥、过滤和浓缩后得到A-5。
MS(ESI)m/z＝383.1[M+1]+。
合成例4中间体H-4的合成：
向中间体H1(10g,59.09mmol,1eq)在二氯甲烷(200mL)中的混合物中在-78℃下通气臭氧(15Psi)1小时。之后通气N2(15psi)半小时以除去臭氧。薄层色谱(石油醚/乙酸乙酯＝10:1)确认反应完成。反应混合物未经处理，直接用于下一步反应。得到近白色油状的二氯甲烷(200mL)中的中间体D2。
在氮气保护下，向在二氯甲烷(12mL)中的中间体H2(0.7g,3.44mmol,2eq)和四氢呋喃(10mL)中的中间体12a(500mg,1.72mmol,1eq)的混合物中加入NaBH(OAc)3(1.10g,5.17mmol,3eq)。反应混合物在25℃下搅拌12小时。LCMS显示反应已完成。在氮气保护下0℃加入饱和氯化铵溶液(100mL)淬灭反应，并用乙酸乙酯萃取(20mL*3)。合并有机层，饱和食盐水洗(20mL*2)，硫酸钠干燥，过滤并减压浓缩。残留物使用制备高效液相色谱纯化得到中间体H-4。
MS(ESI)m/z＝460.2[M+1]+。
1H 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).
合成例5中间体C’的合成：
向中间体A-1(1g,2.99mmol,1eq)在无水二氧六环(10mL)中的混合物中滴加盐酸二氧六环(4M,30mL,40.13eq)。反应混合物在25℃下搅拌12小时。LCMS确认反应完成。反应混合物减压浓缩得到中间体I-7b。
MS(ESI)m/z＝235.0[M+1]+
向中间体I-7b(700mg,2.28mmol,1eq,2HCl)在无水四氢呋喃(5mL)中的溶液中加入N,N'-羰基二咪唑(554mg,3.42mmol,1.5eq)和二异丙基乙胺(5.01mmol,0.87mL,2.2eq)。反应混合物在40℃下搅拌3小时。LCMS确认反应完成。反应混合物浓缩，加入乙腈(5mL)后过滤，滤饼经减压浓缩得到中间体C’。
MS(ESI)m/z＝329.1[M+1]+
1H 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).
合成例6中间体C-6的合成：
向中间体A-1(3.7g,11.06mmol,1eq)在N,N-二甲基甲酰胺(4mL)的溶液中加入碘甲烷(1.88g,13.28mmol,826.48μL,1.2eq)。反应液在20℃搅拌1小时。LCMS确认反应完成。反应混合物使用碳酸氢钠(100mL)和水(100mL)淬灭，乙酸乙酯(50mL*3)萃取，硫酸钠干燥，过滤并减压浓缩，得到中间体I-7。
MS(ESI)m/z＝349.2[M+1]+
向中间体I-7(4.5g,12.91mmol,1eq)在二氧六环(1mL)的溶液中加入盐酸二氧六环(2M,58.44mL,9.05eq)。反应液在25℃搅拌12小时。LCMS确认反应完成。反应混合物减压浓缩得到中间体I-8。
MS(ESI)m/z＝249.1[M+1]+
向中间体I-8(3g,12.08mmol,1eq)在四氢呋喃(30mL)的溶液中加入N,N'-羰基二咪唑(5.88g,36.24mmol,3eq)和二异丙基乙胺(4.68g,36.24mmol,6.31mL,3eq)。反应液在25℃搅拌12小时。LCMS确认反应完成。反应混合物减压浓缩除溶剂。粗产物使用反相色谱柱(0.1％NH3·H2O)纯化得到中间体C-6。
MS(ESI)m/z＝343.1[M+1]+
合成例7中间体C-a5的合成：
在-15℃下向中间体C-a1(1g,4.99mmol,1eq)在四氢呋喃(15mL)的溶液中加入硫代羰基二咪唑(961.02mg,5.39mmol,1.08eq)。反应液在-15-20℃搅拌14小时。LCMS确认反应完成。反应混合物减压浓缩并使用水(100mL)淬灭，乙酸乙酯(100mL*3)萃取，合并有机层，硫酸钠干燥，过滤并减压浓缩，得到中间体C-a2。
MS(ESI)m/z＝243.1[M+1]+
向2-氨基吡啶(1.36g,14.44mmol,1eq)在四氢呋喃(5mL)的溶液中加入中间体C-a2(3.5g,14.44mmol,1eq)。反应液在70℃搅拌72小时。LCMS确认反应完成。反应混合物减压浓缩除溶剂，并使用水(100mL)淬灭，乙酸乙酯(100mL*3)萃取，合并有机层，硫酸钠干燥，过滤并减压浓缩，得到残余物。粗产品经反相高效液相色谱(0.1％FAcondition)纯化得到中间体C-a3。
MS(ESI)m/z＝359.1[M+23]+
向中间体C-a3(1.5g,4.46mmol,1eq)在二氧六环(15mL)的溶液中加入盐酸二氧六环(2M,28.98mL,13eq)。在25℃下搅拌2小时。LCMS确认反应完成。反应混合物减压浓缩得到中间体C-a4。
MS(ESI)m/z＝237.1[M+23]+
将C-a4(1g,4.23mmol,1eq)溶解于四氢呋喃(10mL)中，加入N,N'-羰基二咪唑(2.06g,12.69mmol,3eq)和二异丙基乙胺(1.64g,12.69mmol,2.21mL,3eq)。室温25℃下反应14小时.LCMS确认反应完成。反应混合物减压浓缩除溶剂。粗产物在乙腈中研磨30min。过滤混合物，收集固体，减压浓缩得到中间体C-a5。
MS(ESI)m/z＝353.0[M+23]+
实施例1、(5S,6S,9R)-5-氨基-6-(2,3-二氟苯基)-6,7,8,9-四氢-5H-环庚[b]吡啶-9-基4-(2-硫氧基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-羧酸酯(化合物1)
将中间体A-1(N-叔丁氧羰基-4-(2-硫代-2，3-二氢-1H-[4,5-B]吡啶-1-基哌啶，1g,3.0mmol)溶于盐酸二氧六环溶液(4mol/L,10mL)中，室温25℃下反应3小时，反应完直接浓缩干，得到油状物中间体B-1；
将B-1溶解于二氯甲烷(10mL)中，于0℃下缓慢加入N,N'-羰基二咪唑(534.7mg,3.0mmol)和二异丙基乙胺(775.4mg,6.0mmol)，加完回到室温25℃下反应5小时后，反应混合物分别用0.5mol/L的稀盐酸溶液和饱和碳酸氢钠溶液洗涤、无水硫酸钠干燥，浓缩后的粗品通过快速柱层析(硅胶，二氯甲烷/甲醇＝10/1)纯化得到中间体C-1(625mg，两步总收率63％)；
氮气保护下，将中间体C-1(200.0mg,0.61mmol)和中间体D(192.0mg,0.61mmol)溶于干燥四氢呋喃(5mL)，于-15℃下滴加六甲基二硅烷重氮钠(NaHMDS，1mol/L,1.22mL)溶液，保持该温度反应1小时后，反向体系恢复到室温25℃，继续反应4小时。反应液用饱和碳酸氢钠水溶液淬灭，用乙酸乙酯萃取3次。合并的有机相分别用水和饱和食盐水洗涤、无水硫酸钠干燥，浓缩后的粗品通过快速柱层析(硅胶，二氯甲烷/甲醇＝10/1)纯化得到中间体D-1(黄色固体，200mg，57％收率)；
将D-1(0.64g,1.11mmol溶于四氢呋喃(5mL)和水(1mL)中，加入三甲基膦(1mol/L,3.33mL)，反应液在室温25℃下搅拌12小时，减压浓缩得到的粗品经反相高效液相色谱纯化，得到目标化合物1。
化合物2～4、6～13、18参照实施例1的方法合成。
化合物1～4、6～13、18的表征数据如下：


实施例2、(5S,6S,9R)-5-氨基-6-(2,3-二氟苯基)-6,7,8,9-四氢-5H-环庚[b]吡啶-9-基4-(2-硒氧基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-羧酸酯(化合物5)
将中间体A-5(0.94g,2.47mmol,1.00eq)溶于盐酸二氧六环溶液(4mol/L,10mL)中，20℃下反12小时。LC-MS确认反应完成。反应液减压浓缩，得到黄色固体中间体B-5(0.9g,crude)；
将B-5(0.9g,3.20mmol,1.00eq)溶解于四氢呋喃(10mL)中，加入N,N'-羰基二咪唑(1.56g,9.60mmol,3.00eq)和二异丙基乙胺(1.24g,9.60mmol,1.67mL,3.00eq)。加完回到50℃下反应1小时后，LC-MS确认反应完成。反应混合物减压浓缩得到残余物。粗产物与硝酸铈铵(CAN)在25℃下研磨30分钟，得到黄色固体状化合物C-5(1.00g,crude)；
在-78℃下向中间体C-5(1.00g,2.66mmol,1.00eq)和中间体D’(520mg,1.33mmol,0.5eq)溶于四氢呋喃(10mL)的溶液中加入叔丁醇钾(1M,5mL,1.88eq)。在氮气保护下，反应液回温至20℃下搅拌12小时。LCMS确认反应完成。反应混合物以5mL的水稀释，并用乙酸乙酯(2mL*3)萃取。合并有机层，饱和食盐水(2mL*3)洗，硫酸钠干燥，过滤并减压浓缩得到残余物，得到黄色固体中间体E-5(1.00g,crude)。
在氮气保护下于-78℃将中间体E-5(1.00g,1.43mmol,.1.00eq)溶于二氧六环甲醇(1mL)的溶液，之后在20℃下搅拌12小时。LCMS显示得到反应完成。反应混合物减压浓缩得到残余物。残余物通过制备高效液相色谱纯化，得到目标化合物5。
化合物21参照实施例2的方法合成。
化合物5、21的表征数据如下：

实施例3、(5S,6S,9R)-5-N-哌嗪基-6-(2,3-二氟苯基)-6,7,8,9-四氢-5H-环庚[b]吡啶-9-基4-(2-氧代-2,3-二氢吡咯并[2,3-b]吡啶-1-基)哌嗪-1-羧酸酯(化合物14)
在-20℃下向中间体C’6(100mg,320.18μmol,1eq)和中间体D’(125mg,320.18μmol,1eq)溶于四氢呋喃(2mL)的溶液中加入叔丁醇钾(1M,640.36μL,2eq)。反应液在-20℃下搅拌0.5小时，之后在25℃下搅拌0.5小时。LCMS确认反应完成。反应混合物倒入饱和氯化铵(100mL)溶液中淬灭，乙酸乙酯(30mL*3)萃取。合并有机层，饱和食盐水(20mL)洗，硫酸钠干燥，过滤并减压浓缩得到残余物。残余物使用制备高效液相色谱纯化，得到棕色固体中间体E’7(15mg,23.63μmol,7.38％收率)。
在0℃下向中间体E’7(15mg,23.63μmol,1eq)溶于二氧六环(5mL)的溶液中加入HCl/二氧六环(2M,1.60mL,135.34eq)。之后在25℃下搅拌1小时。LCMS显示得到目标产物。反应混合物倒入饱和碳酸氢钠(100mL)溶液中淬灭，乙酸乙酯(30mL*3)萃取。合并有机层，饱和食盐水(20mL)洗，硫酸钠干燥，过滤并减压浓缩，得到残余物。残余物通过制备高效液相色谱纯化，得到目标化合物14。
化合物15参照实施例3的方法合成。
化合物14～15的表征数据如下：

实施例4、(5S,6S,9R)-5-氨基-6-(2,3-二氟苯基)-6,7,8,9-四氢-5H-环庚[b]吡啶-9-基4-(2-硫代氧基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌嗪-1-羧酸酯(化合物16)
在25℃下向中间体E-10(3.00g,4.29mmol,1eq)i溶于二氧六环的溶液中加入HCl/二氧六环(2M,60.00mL,27.94eq)。之后在25℃下搅拌1小时。LCMS显示得到目标产物。反应混合物倒入饱和碳酸氢钠(500mL)溶液中淬灭，乙酸乙酯(100mL*2)萃取。合并有机层，饱和食盐水(50mL)洗，硫酸钠干燥，过滤并减压浓缩，得到残余物。残余物通过制备高效液相色谱纯化，得到目标化合物16。
化合物20参照实施例4的方法合成。
化合物16、20的表征数据如下：

实施例5、(5S,6S,9R)-5-N-哌嗪基-6-(2,3-二氟苯基)-6,7,8,9-四氢-5H-环庚[b]吡啶-9-基4-(2-硫氧基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-羧酸酯(化合物17)
在0℃下向中间体H-4(90mg,195.85μmol,1eq)和中间体C’(128.63mg,391.71μmol,2eq)溶于四氢呋喃(5mL)和二氯甲烷(5mL)的溶液中加入叔丁醇钾(1M,391.71μL,2eq)。之后在0℃下搅拌0.5小时。LCMS显示得到目标产物(MS(ESI)m/z＝720.2[M+1]+)。反应混合物倒入饱和氯化铵(100mL)溶液中淬灭，乙酸乙酯(30mL*3)萃取。合并有机层，饱和食盐水(20mL)洗，硫酸钠干燥，过滤并减压浓缩，得到浅黄色油状中间体H-5(0.1g,138.92μmol,70.93％收率)。
在0℃下向中间体H-5(100.00mg,138.92μmol,1eq)溶于二氧六环的溶液中加入HCl/二氧六环(2M,10mL,143.97eq)。之后在25℃下搅拌0.5小时。LCMS显示得到目标产物。反应混合物倒入饱和碳酸氢钠(100mL)溶液中淬灭，乙酸乙酯(30mL*3)萃取。合并有机层，饱和食盐水(20mL)洗，硫酸钠干燥，过滤并减压浓缩，得到残余物。残余物通过制备高效液相色谱纯化，得到目标化合物17。
化合物17的表征数据如下：
实施例6、(5S,6S,9R)-5-氨基-6-(2,3-二氟苯基)-6,7,8,9-四氢-5H-环庚[b]吡啶-9-基4-(2-甲基亚磺酰基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-羧酸酯(化合物19)
在0℃下向中间体C-6(175.41mg,512.27μmol,2eq)和中间体D’(0.1g,256.13μmol,1eq)溶于四氢呋喃(10mL)的溶液中加入叔丁醇钾(1M,512.27μL,2eq)。反应液在25℃下搅拌0.5小时。LCMS显示反应已完成(MS(ESI)m/z＝665.3[M+1]+)。氮气保护下在0℃向反应液中加入饱和氯化铵(50mL)溶液中淬灭，乙酸乙酯(20mL*2)萃取。合并有机层，饱和食盐水(30mL*2)洗，硫酸钠干燥，过滤并减压浓缩得到残余物。残余物加入二氯甲烷(10mL)和间氯过氧苯甲酸(52.00mg,256.13μmol,85％purity,1eq)。反应液在25℃下搅拌12小时。LCMS显示得到目标化合物(MS(ESI)m/z＝681.3[M+1]+)。反应液在氮气保护下0℃加入饱和碳酸氢钠溶液(50mL)淬灭，乙酸乙酯(20mL*2)萃取。合并有机层，饱和食盐水(30mL*2)洗，硫酸钠干燥，过滤并减压浓缩得到黄色油状中间体C-9(0.1g,crude)。
在0℃下向中间体C-9(40.96mg,60.17μmol,1eq)在二氯甲烷(4mL)的溶液中加入三氟乙酸(1.54g,13.46mmol,1mL,223.74eq)。反应液在25℃下搅拌12小时。LCMS显示得到目标产物。反应液在氮气保护下0℃倒入饱和碳酸氢钠溶液(50mL)淬灭，乙酸乙酯(20mL*2)萃取。合并有机层，饱和食盐水(30mL*2)洗，硫酸钠干燥，过滤并减压浓缩得到残余物。残余物使用制备高效液相色谱纯化，得到目标化合物19。
化合物19的表征数据如下：
实施例7、(5S,6S,9R)-5-氨基-6-(2,3-二氟苯基)-6,7,8,9-四氢-5H-环庚[b]吡啶-9-基4-(2-吡啶基氨基甲硫酰氨基)哌啶-1-羧酸酯(化合物22)
在-20℃下向中间体C-a5(253.88mg,768.40μmol,2eq)和中间体D’(150mg,384.20μmol,1eq)溶于四氢呋喃(1mL)的溶液中加入叔丁醇钾(129.34mg,1.15mmol,3eq)。反应液在-20℃下反应0.5小时，之后在25℃下反应0.5小时。LCMS显示反应已完成。反应液减压浓缩得到白色固体状中间体C-a6(0.25g,crude)。
向中间体C-a6(0.25g,382.99μmol,1eq)在二氧六环(5mL)的溶液中加入HCl/二氧六环(2M,20mL,104.44eq)。反应液在25℃下搅拌12小时。LCMS确认反应完成。反应液减压浓缩除溶剂。残余物使用制备高效液相色谱纯化，得到目标化合物22。
化合物23参照实施例7的方法合成。
化合物22～23的表征数据如下：
RIMEGEPANT参照专利CN102656159A的实施例8合成。
实施例8、体外人CGRP受体拮抗活性试验
细胞培养及试剂配置：
1)细胞株：SK-N-MC；
2)完全培养基:MEM+10％胎牛血清+1*青霉素链霉素；
3)实验缓冲液:1*HBSS+20mM HEPES+0.1％BSA+500μM IBMX。
待测化合物对CGRP受体活性测定：
TrypLE消化处理后将细胞重悬于实验缓冲液中，种到384细胞培养板中，接种密度为2000每孔。将化合物用实验缓冲液稀释，每孔加入2.5μl的化合物，37℃培养10分钟。用实验缓冲液将α-CGRP稀释至8*α-CGRP(80nM)，加入2.5μl上一步中稀释好的8*α-CGRP，于37℃孵育30分钟。冻融Eu-cAMPtracer和Ulight-anti-cAMP，用lysis buffer将其稀释。加入10μl Eu-cAMP tracer至实验孔，然后加入10μl Ulight-anti-cAMP至实验孔中。将反应板于室温200g离心30s，25℃静置1h后，利用Envision收集数据。
数据分析：
1)％Inhibition计算:
％inhibition＝(Signalcmpd-SignalAve_VC)/(SignalAve_PC-SignalAve_VC)×100.
2)利用GraphPad非线性拟合公式计算化合物IC50:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X:化合物浓度log值；Y:Inhibition％
各化合物的人CGRP受体拮抗IC50值如下表所示：
表1
实施例9、MDR1-MDCKII细胞渗透性试验
将MDR1-MDCKII.细胞(从荷兰癌症研究所的Piet Borst获得)以4.44x 105个细胞/mL接种到96孔板中的聚碳酸酯膜上，直到4-7天形成汇合细胞单层。
供试化合物用DMSO储备溶液中的转膜缓冲液(HBSS与10mM Hepes，pH7.4)稀释至浓度为2.00μM(DMSO<1.0％)，并施用于细胞单层的顶端或基底外侧。测定供试化合物从A到B方向或B到A方向的渗透，双复孔。同时，测试地高辛在10.0μM下从A到B方向或B到A方向的渗透，测试纳多洛尔和美托洛尔在2.00μM下从A到B方向的渗透，双复孔。将板在37.0℃、5.0％CO 2和饱和湿度下孵育2.5小时而不摇晃。此外，还测定了每种化合物的外排比。根据分析物/标准品的峰面积比，通过LC-MS/MS分析对测试化合物和参比化合物进行定量。
转运测定后，应用荧光黄排斥测定来确定细胞单层完整性。从顶端和基底外侧室中取出缓冲液，然后分别在转膜缓冲液中加入75μL的100μM荧光黄，在顶端和基底外侧室中分别加入250μL转膜缓冲液。将板在37.0℃、5.0％CO 2和饱和湿度下孵育30分钟而不摇晃。孵育30分钟后，从顶端侧取出20μL的荧光黄样品，然后加入60μL的转膜缓冲液。然后从基底外侧取80μL的荧光黄样品。使用Envision读板器在425/528nm(激发/发射)波长下测量荧光黄的相对荧光单位(RFU)。
数据分析：
表观渗透系数Papp(cm/s)的计算公式为：
Papp＝(dCr/dt)x Vr/(Ax C0)
其中dCr/dt是化合物在接收室中随时间变化的累积浓度(μM/s)；Vr是接收室中的溶液体积(顶端侧0.075mL，基底外侧0.25mL)；A是传输的表面积，例如单层面积为0.143cm2；C0是供体室中的初始浓度(μM)。
外排比率使用以下公式计算：
Efflux Ratio＝Papp(BA)/Papp(AB)
Papp(AB)更高提示被动扩散更好，化合物具有更好的渗透性；低外排比率提示化合物可能不是相关外排转运体的底物，具备更高的潜在血脑屏障通透性，从而利于药物入脑，脑暴露水平更高。
表2
实施例10、在食蟹猴体内的口服药代动力学试验
以食蟹猴为受试动物，应用UPLC-MS/MS法测定食蟹猴单次口服给予本公开化合物后不同时刻血浆中的化合物浓度，研究本公开化合物在食蟹猴体内的药代动力学。
试验动物：食蟹猴(雄性，约3～5岁，体重5～9kg)。
药物配制：溶媒为DMSO/HS-15/生理盐水(5:5:90，v:v:v)。
给药：单次经口灌胃给药；给药前动物禁食12h及以上、正常饮水；RIMEGEPANT和化合物1、5、21的给药剂量均为10mg/kg。
样本采集：采集部位为右前肢内测隐静脉；收集给药前和药后15min、0.5h、1h、2h、4h、6h、8h、24h的血浆；每个采血点采集0.5mL全血，分离血浆；血浆分离方法为在4℃和1800g离心力下离心10min，取上清；之后采用UPLC-MS/MS分析方法定量分析血药浓度。
口服给予RIMEGEPANT、化合物1、5、21的不同时间点血药浓度结果如附图1所示，化合物1、5、21在不同时间点的暴露量AUC显著高于RIMEGEPANT。
实施例11、在食蟹猴体内的静脉药代动力学试验
以食蟹猴为受试动物，应用UPLC-MS/MS法测定食蟹猴单次静脉给予本公开化合物后不同时刻血浆中的化合物浓度，研究本公开化合物在食蟹猴体内的药代动力学。
试验动物：食蟹猴(雄性，约3～5岁，体重5～9kg)。
药物配制：溶媒为DMSO/HS-15/生理盐水(5:5:90，v:v:v)。
给药：单次静脉注射；RIMEGEPANT和化合物1、5、21的给药剂量均为1mg/kg。
样本采集：采集部位为右前肢内测隐静脉；收集给药前和药后15min、0.5h、1h、2h、4h、6h、8h、24h的血浆；每个采血点采集0.5mL全血，分离血浆；血浆分离方法为在4℃和1800g离心力下离心10min，取上清；之后采用UPLC-MS/MS分析方法定量分析血药浓度。
静脉给予RIMEGEPANT、化合物1、5、21的不同时间点血药浓度结果如附图2所示，化合物1、5、21在不同时间点的暴露量AUC显著高于RIMEGEPANT。
实施例12、在食蟹猴体内的口服药效学试验
以食蟹猴为受试动物，采用hCGRP局部注射造模研究单次口服(PO)给予本公开化合物对血流的影响。
PO分组：RIMEGEPANT组(阳参)；化合物5组；模型组(空白对照)
试验动物：食蟹猴(雄性，约3～5岁，体重5～9kg)。
药物配制：溶媒为DMSO/HS-15/生理盐水(5:5:90，v:v:v)。
造模剂配制：5％DMSO+30％PEG300+5％Tween 80+60％ddH2O溶媒配制为浓度为20mg/mL的母液并分装保存于-20℃，使用时采用PBS稀释至浓度为5μg/mL的工作液。
造模：hCGRP造模前一天对需要进行造模的动物前臂造模位置进行脱毛处理。PO组动物手术前禁食不禁水12h；IV组动物正常饮食，麻醉前半小时左右给予0.04mg/kg硫酸阿托品注射液，以减少腺体分泌。经肌肉注射0.1mL/kg舒泰50麻醉后，动物转移至手术室。在前臂无明显可见血管区域皮内注射0.1μg CGRP，注射体积为20μL；溶媒对照注射同样体积的溶媒；PO组hCGRP和溶媒对照的注射时间点为0min、30min、和60min。
给药：单次经口灌胃给药；PO组给药时间为首次CGRP注射造模前80min，RIMEGEPANT和化合物5的给药剂量均为3mg/kg。
样本采集：采集部位为右前肢内测隐静脉；每个采血点采集0.5mL全血，分离血浆；血浆分离方法为在4℃和1800g离心力下离心10min，取上清；之后采用UPLC-MS/MS分析方法定量分析血药浓度；PO组的采血点为-5min、5min、20min、35min、50min、65min和80min。
皮肤血流检测：采用激光多普勒散斑血流仪检测各个时间点注射部位皮肤血流量数据；根据各时间点血流量值(血流量t)计算皮肤血流量上升百分率(％)＝(血流量t—血流量基线)/血流量基线×100％；及血流综合增长率(％)＝CGRP处理侧血流上升百分率-对照侧血流上升百分率。hCGRP可诱导血流动力学改变，导致血流增加；血流综合增长率％体现了hCGRP诱导的血流上升比率，更低的血流综合增长率％提示化合物对hCGRP引起的血流增加有更好的抑制效果。
数据分析：数据经Excel 2010、GraphPad Prism 7和Stata 15.0软件进行录入与统计分析。RIMEGEPANT和化合物5口服给药(PO)对模型动物血流综合增长率的影响如附图3所示。

Claims (28)

  1. 式(Ⅰ)的化合物或其药学上可接受的盐，
    其中：
    R1是氢、氰基、卤素、烷基、卤代烷基、烷氧基、氨基、烷基氨基、二烷基氨基、氮杂环丁烷基、吡咯烷基、哌啶基或哌嗪基；
    R2是氢、羟基、叠氮基或-NR2aR2b，其中R2a或R2b各自独立地选自氢或烷基，或R2a和R2b与它们连接的原子一起形成杂环基，所述杂环基任选地可被0-3个相同或不同的卤素或烷基所取代；优选是氢、羟基、叠氮基、氨基、烷基氨基、二烷基氨基、N-吡咯烷基、N-哌啶基或N-哌嗪基；更优选是氢、羟基、氨基、或N-哌嗪基；
    R3是取代有1个选自以下的取代基的哌啶基或哌嗪基：
    R3a是任选地可被0-2个相同或不同的卤素或烷基所取代的五元或六元单环芳基或杂芳基，所述杂芳基含有至少1个氮原子；
    R3b是烷氧基、烷酰基、烷基-S(O)2-或烷基-S(O)-；
    R4是氢、卤素、氰基、烷基、卤代烷基、烷氧基或卤代烷氧基；
    R5是氢、卤素、氰基、烷基、卤代烷基、烷氧基或卤代烷氧基；
    Ar是取代有0至3个选自以下的取代基的苯基：氰基、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基及烷基-S(O)2-；
    P是NH、O或S；
    Q是O或S；
    X是N或CR6；
    R6是氢、烷基或烷氧基；
    Y是O、S或Se；
    Z是NH、CH2、O或S；
    此外，当Q是O，且Y是O时，R3是取代有1个选自以下的取代基的哌嗪基：
    其中所述烷基或卤代烷基、烷氧基、烷基氨基、二烷基氨基、卤代烷氧基、烷基-S(O)2-和烷基-S(O)-中的烷基部分为由1-6个碳组成的直链或支链烷基。
  2. 根据权利要求1的化合物或其药学上可接受的盐，其中：
    R1是氢、氰基、卤素、烷基、卤代烷基、烷氧基、氨基、烷基氨基、二烷基氨基、氮杂环丁烷基、吡咯烷基或哌啶基；
    R2是氢、羟基、叠氮基、氨基、烷基氨基或二烷基氨基；
    R3是取代有1个选自以下的取代基的哌啶基或哌嗪基：
    R4是氢、卤素、氰基、烷基、卤代烷基、烷氧基或卤代烷氧基；
    R5是氢、卤素、氰基、烷基、卤代烷基、烷氧基或卤代烷氧基；
    Ar是取代有0至3个选自以下的取代基的苯基：氰基、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基及烷基-S(O)2-；
    P是NH、O或S；
    Q是O或S；
    X是N或CR6；
    R6是氢、烷基或烷氧基；
    Y是O、S或Se；
    Z是NH、CH2、O或S；
    此外，当Q是S，且Y是O时，R3是取代有1个选自以下的取代基的哌啶基或哌嗪基：
    当Q是O，且Y是O时，R3是取代有1个选自以下的取代基的哌嗪基：
    其中所述烷基或卤代烷基、烷氧基、烷基氨基、二烷基氨基、卤代烷氧基和烷基-S(O)2-中的烷基部分为由1-6个碳组成的直链或支链烷基。
  3. 根据权利要求1或2的化合物，其具有式(I’)的指定立体化学结构
    其中，R1、R2、Ar、P、Q和R3如权利要求1或权利要求2所定义。
  4. 根据权利要求3的化合物或其药学上可接受的盐，其中：
    R1是氢、氰基、卤素、烷基、卤代烷基、氨基、烷基氨基、二烷基氨基；
    R2是氢、羟基、叠氮基、氨基、烷基氨基或二烷基氨基；
    R3是取代有1个选自以下的取代基的哌啶基或哌嗪基：
    R4是氢、卤素、氰基、烷基、卤代烷基、烷氧基或卤代烷氧基；
    R5是氢、卤素、氰基、烷基、卤代烷基、烷氧基或卤代烷氧基；
    Ar是取代有0至2个卤素取代基的苯基；
    P是NH、O或S；
    Q是O或S；
    X是N或CR6；
    R6是氢、烷基或烷氧基；
    Y是O、S或Se；
    Z是NH或CH2；
    此外，当Q是S，且Y是O时，R3是取代有1个选自以下的取代基的哌啶基或哌嗪基：
    当Q是O，且Y是O时，R3是取代有1个选自以下的取代基的哌嗪基：
  5. 根据权利要求4的化合物，其中R1是氢。
  6. 根据权利要求5的化合物，其中Ar是取代有2个卤素取代基的苯基。
  7. 根据权利要求6的化合物，其中Ar是2,3-二氟苯基。
  8. 根据权利要求7的化合物，其中P是O，R2是氢、羟基或氨基。
  9. 根据权利要求8的化合物，其中R3是N-哌啶基且为4-取代的，或N-哌嗪基且为4-取代的。
  10. 根据权利要求9的化合物，其中R2是氨基，R3是N-哌啶基且为4-取代的。
  11. 根据权利要求9的化合物，其中R2是羟基，R3是N-哌啶基且为4-取代的。
  12. 根据权利要求4的化合物或其药学上可接受的盐，其中R4是氢或卤素取代基；R5是氢或卤素取代基；R6是氢；Z是NH。
  13. 根据权利要求12的化合物或其药学上可接受的盐，其中：
    R1是氢；
    R2是氨基或羟基；
    R4是氢或卤素；
    R5是氢；
    Ar是2,3-二氟苯基；
    P是O；
    Q是O或S；
    X是N；
    Y是O、S或Se；
    Z是NH。
  14. 根据权利要求1的化合物或其药学上可接受的盐，其中X是N；Z是NH。
  15. 根据权利要求14的化合物或其药学上可接受的盐，其中所述化合物具有式(Ⅰa)的结构，
    其中：
    A是N或CH；
    环B选自下述基团：
    R1是氢、氰基、卤素、烷基、卤代烷基、氨基、烷基氨基、二烷基氨基；
    R2是氢、羟基、叠氮基、氨基、烷基氨基、二烷基氨基、N-吡咯烷基、N-哌啶基或N-哌嗪基；
    R4是氢、卤素、氰基、烷基、卤代烷基、烷氧基或卤代烷氧基；
    R5是氢、卤素、氰基、烷基、卤代烷基、烷氧基或卤代烷氧基；
    Ar是取代有2个卤素取代基的苯基；
    P是O；
    Q是O或S；
    Y是O、S或Se；
    优选地，R1是氢；R2是氢、羟基、氨基或N-哌嗪基；R4是氢或卤素；R5是氢或卤素；Ar是2,3-二氟苯基；
    此外，当Q是O，且Y是O时：A是N。
  16. 根据权利要求15的化合物或其药学上可接受的盐，其中：
    A是N或CH；
    选自下述基团：
    R1是氢；
    R2是氢、羟基、氨基或N-哌嗪基；
    R4是氢或卤素；
    Ar是取代有2个卤素取代基的苯基，优选是2,3-二氟苯基；
    P是O；
    Q是O或S；
    Y是O、S或Se。
  17. 根据权利要求16的化合物或其药学上可接受的盐，其中所述化合物具有式(Ⅳa)或式(Ⅳb)的结构，
    其中：
    选自下述基团：
    R1是氢；
    R2是氢、羟基、氨基或N-哌嗪基；
    R4是氢或卤素；
    Ar是取代有2个卤素取代基的苯基；
    P是O；
    Q是O或S；
    Y是O、S或Se；
    优选地，R2是羟基或氨基；R4是氢、氟或氯；Ar是2,3-二氟苯基。
  18. 根据权利要求16的化合物或其药学上可接受的盐，其中所述化合物具有式(Ⅴ)的结构：
    其中：
    A是N或CH；
    R1是氢；
    R2是氢、羟基、氨基或N-哌嗪基；
    Q是O或S；
    Y是O、S或Se；
    优选地，R2是氨基；Q是O；Y是S或Se。
  19. 根据权利要求14的化合物或其药学上可接受的盐，其中所述化合物具有式(Ⅱa)的结构，
    其中：
    A是N或CH；
    R1是氢、氰基、卤素、烷基、卤代烷基、氨基、烷基氨基、二烷基氨基；
    R2是氢、羟基、氨基或N-哌嗪基；
    Ar是取代有2个卤素取代基的苯基；
    P是O；
    Q是O或S；
    Y是O、S或Se；
    R3a是任选地可被0-2个相同或不同的卤素或烷基所取代的含有1-2个氮原子的六元单环杂芳基；
    优选地，A是CH；R1是氢；R2是氨基；Ar是2,3-二氟苯基；Q是O；Y是S；R3a是任选地可被0-2个相同或不同的卤素或烷基所取代的吡啶基或嘧啶基。
  20. 根据权利要求19的化合物或其药学上可接受的盐，其中所述化合物具有式(Ⅱc)或式(Ⅱd)的结构，
    其中，A、R1、R2、Ar、P、Q和Y如权利要求19所定义。
  21. 根据权利要求14的化合物或其药学上可接受的盐，其中所述化合物具有式(Ⅲa)的结构，
    其中：
    A是N或CH；
    R1是氢、氰基、卤素、烷基、卤代烷基、氨基、烷基氨基、二烷基氨基；
    R2是氢、羟基、叠氮基、氨基、烷基氨基、二烷基氨基、N-吡咯烷基、N-哌啶基或N-哌嗪基；
    Ar是取代有2个卤素取代基的苯基；
    P是O；
    Q是O或S；
    R3b是烷基-S(O)2-或烷基-S(O)-；
    R4是氢或卤素；
    R5是氢或卤素；
    优选地，A是CH；R1是氢；R2是氨基；Ar是2,3-二氟苯基；Q是O；R3b是烷基-S(O)-；R4是氢；R5是氢。
  22. 根据权利要求1或2的化合物或其药学上可接受的盐、溶剂化物、立体异构体或互变异构体，其中所述化合物选自：


  23. 根据权利要求1-20中任一项的化合物的制备方法，其特征在于反应步骤如反应式1所示：
    反应式1
    在反应式1中，化合物A去保护，得到的中间体B与羰基二咪唑或1,1-硫代羰基二咪唑反应得到中间体C；中间体C与中间体D连接、随后脱保护，得到如式Ⅱ所示的通式化合物(其中，X是O或S；Y是O、S或Se；V是N或CH；Ar是任选取代的杂芳基或芳基)。
  24. 根据权利要求1-20中任一项的化合物的制备方法，其特征在于反应步骤如反应式2所示：

    反应式2
    在反应式2中，化合物A去保护，得到的中间体B与羰基二咪唑或1,1-硫代羰基二咪唑反应得到中间体C；中间体C与中间体F连接、随后脱保护，得到如式Ⅲ所示的通式化合物(其中，X是O或S；Y是O、S或Se；V是N或CH；Ar是任选取代的杂芳基或芳基)。
  25. 一种药物组合物，其包含如权利要求1-22中任一项的化合物或其药学上可接受的盐及药学上可接受的载体。
  26. 根据权利要求1-22中任一项的化合物或其药学上可接受的盐在制备用于治疗与异常CGRP含量有关的病症的药物中的用途。
  27. 根据权利要求26的用途，其中所述病症是偏头痛、神经源性血管舒张、神经源性炎症、哮喘和慢性阻塞性肺病。
  28. 根据权利要求27的用途，其中所述病症是偏头痛。
PCT/CN2024/120191 2023-09-21 2024-09-20 一种治疗cgrp相关障碍的小分子药物 Pending WO2025061177A1 (zh)

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