WO2024099404A1 - 一种含氮螺环类化合物、药物组合物以及其用途 - Google Patents

一种含氮螺环类化合物、药物组合物以及其用途 Download PDF

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WO2024099404A1
WO2024099404A1 PCT/CN2023/130831 CN2023130831W WO2024099404A1 WO 2024099404 A1 WO2024099404 A1 WO 2024099404A1 CN 2023130831 W CN2023130831 W CN 2023130831W WO 2024099404 A1 WO2024099404 A1 WO 2024099404A1
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substituted
ring
independently selected
alkyl
nitrogen
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PCT/CN2023/130831
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English (en)
French (fr)
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杨艳青
祝力
李雨亮
张慧
杜云龙
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北京普祺医药科技股份有限公司
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Publication of WO2024099404A1 publication Critical patent/WO2024099404A1/zh

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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
    • A61K31/495—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
    • A61K31/499—Spiro-condensed pyrazines or piperazines
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D471/10—Spiro-condensed systems

Definitions

  • the present invention relates to the field of medicine, and in particular to a nitrogen-containing spirocyclic compound, stereoisomers and deuterated substances of the compound, a pharmaceutical composition, and uses of the compound and the pharmaceutical composition.
  • TRP Transient receptor potential
  • TRPV Transient receptor potential vanilloid receptor subfamily
  • TRPV3 is a pathogenic gene of Olmsted syndrome, a rare skin disease (Am. J. Hum. Genet. 2012, 90, 558). TRPV3 inhibitors have potential therapeutic prospects in keratotic skin diseases, pruritic skin diseases, inflammation, abnormal hair growth and painful skin diseases. TRPV3 is mainly expressed in skin keratinocytes, as well as in tissues such as the tongue, dorsal root ganglia, trigeminal ganglia, spinal cord and brain, and mainly senses warm stimulation (32-39°C).
  • TRPV3's thermal sensitivity is also regulated by calcium in the extracellular fluid. When subjected to repeated thermal stimulation, the channel current continues to increase. Free nerve endings under the skin may sense and conduct thermal stimulation through similar signal molecules present in thermoreceptor neurons. Therefore, TRPV3 has potential therapeutic prospects in painful diseases.
  • TRPV3 can be activated by monoterpenoid compounds (such as camphor, borneol, mint, etc.), and studies have found that it works by increasing the level of intracellular divalent calcium ions (Ca 2+ ). These aromatic compounds have anti-inflammatory, analgesic, antipruritic effects, and have been widely used in the fields of medicine and cosmetics.
  • monoterpenoid compounds such as camphor, borneol, mint, etc.
  • these aromatic compounds have anti-inflammatory, analgesic, antipruritic effects, and have been widely used in the fields of medicine and cosmetics.
  • these early TRPV3 inhibitors are mostly natural products with poor specificity and large effective doses, which may cause serious side effects, or the molecular skeleton activity is general, and most of the research and development is stagnant.
  • Existing TRPV3 inhibitors have the problem of few structural types and slow development. It is very necessary to develop molecules with novel skeletons and clinical value.
  • Ring A is selected from a monocyclic or polycyclic ring system containing 3 to 12 ring atoms
  • R 1 is each independently selected from H, halogen, hydroxyl, mercapto, nitro, cyano, oxo, C 1 -C 6 alkyl substituted with 0-2 R f , C 1 -C 6 haloalkyl substituted with 0-2 R f , C 1 -C 6 alkoxy substituted with 0-2 R f , C 1 -C 6 haloalkoxy substituted with 0-2 R f , C 3 -C 6 cycloalkyl substituted with 0-2 R f , C 3 -C 6 halocycloalkyl substituted with 0-2 R f , C 3 -C 6 cycloalkyloxy substituted with 0-2 R f , C 3 -C 6 halocycloalkyloxy substituted with 0-2 R f , aryl substituted with 0-2 R f , aralkyl substituted with 0-2 R f , alkaryl substituted with
  • R2 is each independently selected from H, halogen, hydroxyl, mercapto, nitro, cyano, oxo, C1 - C6 alkyl substituted with 0-2 Rf , C1- C6 haloalkyl substituted with 0-2 Rf , C1 - C6 alkoxy substituted with 0-2 Rf , C1 - C6 haloalkoxy substituted with 0-2 Rf, C3-C6 cycloalkyl substituted with 0-2 Rf , C3 - C6 halocycloalkyl substituted with 0-2 Rf , C3 - C6 cycloalkyloxy substituted with 0-2 Rf , C3 - C6 halocycloalkyl substituted with 0-2 Rf , aryl substituted with 0-2 Rf , aralkyl substituted with 0-2 Rf , alkaryl substituted with 0-2 Rf , heteroaryl substituted with
  • L 1 is selected from a bond, or the following structural formula:
  • X1 is independently selected at each occurrence from C, O or N;
  • X2 is independently selected at each occurrence from C, O, B or N;
  • XA , XB , and XC are each independently CRx or N;
  • Rx is each independently selected from H, halogen, hydroxyl, mercapto, nitro, cyano, C1 - C6 alkyl substituted with 0-2 Rf , C1 - C6 haloalkyl substituted with 0-2 Rf , C1 - C6 alkoxy substituted with 0-2 Rf , C1- C6 haloalkoxy substituted with 0-2 Rf, C3-C6 cycloalkyl substituted with 0-2 Rf , C3 - C6 halocycloalkyl substituted with 0-2 Rf , C3 - C6 cycloalkyloxy substituted with 0-2 Rf , C3 -C6 halocycloalkyl substituted with 0-2 Rf , aryl substituted with 0-2 Rf , aralkyl substituted with 0-2 Rf , alkaryl substituted with 0-2 Rf , heteroaryl substituted with 0-2 Rf
  • R 0 is independently selected from H, halogen or the structural formula II
  • L 2 is each independently selected from a bond, -O-, -S-, -N(R 20 )-, -C(O)-, -C(R 20 R 21 )-, -S(O)-, and -S(O 2 )-;
  • Ring C is independently selected from a monocyclic or polycyclic ring system containing 3-12 ring atoms
  • R3 is each independently selected from H, halogen, hydroxyl, mercapto, nitro, cyano, oxo, C1 - C6 alkyl substituted with 0-2 Rf , C1- C6 haloalkyl substituted with 0-2 Rf , C1 - C6 alkoxy substituted with 0-2 Rf , C1 - C6 haloalkoxy substituted with 0-2 Rf, C3-C6 cycloalkyl substituted with 0-2 Rf , C3 - C6 halocycloalkyl substituted with 0-2 Rf , C3 - C6 cycloalkyloxy substituted with 0-2 Rf , C3 - C6 halocycloalkyloxy substituted with 0-2 Rf , aryl substituted with 0-2 Rf , aralkyl substituted with 0-2 Rf , alkaryl substituted with 0-2 Rf , heteroaryl substituted with
  • R 11 is each independently selected from C 1 -C 6 alkylene substituted with 0-2 R f ;
  • R 12 is each independently selected from H, C 1 -C 6 alkyl substituted with 0-2 R f , C 1 -C 6 haloalkyl substituted with 0-2 R f , C 3 -C 6 cycloalkyl substituted with 0-2 R f , and C 3 -C 6 halocycloalkyl substituted with 0-2 R f ;
  • Ra and Rb are each independently selected from H, C1 - C6 alkyl substituted with 0-2 Rf , aryl substituted with 0-2 Rf , aralkyl substituted with 0-2 Rf , -C(O) Rc and -C(O) ORd ;
  • R c is independently selected from H, halogen, C 1 -C 6 alkyl substituted with 0-2 R f , aryl substituted with 0-2 R f and aralkyl substituted with 0-2 R f ;
  • R d is each independently selected from H, C 1 -C 6 alkyl substituted with 0-2 R f , aryl substituted with 0-2 R f and aralkyl substituted with 0-2 R f ;
  • R 20 and R 21 are each independently selected from H, hydroxyl, C 1 -C 6 alkyl, aryl and aralkyl;
  • Rf is each independently selected from halogen, hydroxyl, amino , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1 - C6 haloalkoxy , C3 - C6 cycloalkyl and C3 -C6 halocycloalkyl ;
  • n 0, 1, 2 or 3;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2, or 3;
  • n 1 or 2;
  • r is 1 or 2.
  • the present application also relates to a pharmaceutical composition, which comprises the compound of the present application or its stereoisomer, tautomer, solvate, hydrate, active metabolite, isotope-labeled substance or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.
  • the present application also relates to the use of the compound of the present application or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope labels or pharmaceutically acceptable salts, and the pharmaceutical composition of the present application in the preparation of drugs for inhibiting TRPV3 activity.
  • the present application also relates to the use of the compound of the present application or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope labels or pharmaceutically acceptable salts, and the pharmaceutical composition of the present application in the preparation of a medicament for treating a TRPV3-mediated disorder in a subject.
  • the present invention further provides the use of the TRPV3 inhibitor in the preparation of a reagent for inhibiting TRPV3 ion channels.
  • the TRPV3 inhibitor is used in the preparation of a drug for inhibiting skin itching, pain, hair loss or inflammation caused by overexpression of TRPV3.
  • the present application relates to a method for treating a TRPV3-mediated disease, comprising administering a therapeutically effective amount of a compound of the present application or its stereoisomers, tautomers, solvates, hydrates, active metabolites, or the like.
  • the metabolite, isotope label or pharmaceutically acceptable salt, or the pharmaceutical composition of the present application is administered to a patient in need of administration.
  • the compounds of the present invention have the ability to inhibit TRPV3 activity and can be used as TRPV3 antagonists or inhibitors, which have a great role in promoting the study of the properties and characteristics of TRPV3 ion channels.
  • drugs for treating diseases related to enhanced TRPV3 ion channel activity can also be prepared. Therefore, the TRPV3 antagonists or inhibitors provided by the present invention are of great value to scientific research and clinical research.
  • antagonist and “inhibitor” are used interchangeably and refer to an agent that reduces or inhibits a biological activity, such as inhibiting the activity of an ion channel such as TRPV3.
  • an "effective amount" of a TRPV3 antagonist refers to an amount of the antagonist in a formulation that, when administered as part of a desired dosing regimen, results in a desired clinical or functional outcome.
  • an effective amount of a TRPV3 antagonist for use in the present invention includes an amount of a TRPV3 antagonist that effectively reduces one or more in vitro or in vivo functions of a TRPV3 channel.
  • Exemplary functions include, but are not limited to, intracellular calcium levels, membrane polarization (e.g., antagonists can promote cell hyperpolarization), phase I outward current, phase II outward current, phase I inward current, and phase II inward current.
  • Compounds that antagonize TRPV3 function include compounds that antagonize TRPV3 functional activity in vitro or in vivo. When a specific functional activity is only readily observable in an in vitro assay, the ability of a compound to inhibit TRPV3 function is a reasonable surrogate for the activity of the compound as used in an in vitro assay.
  • prevent is art-recognized and when applied to a condition, such as a local recurrence (e.g., pain), a disease, such as cancer, a syndrome, such as heart failure, or other medical condition, is art-recognized and includes the administration of a composition that reduces the incidence of a medical condition in a subject relative to a subject not receiving the composition.
  • a condition such as a local recurrence (e.g., pain)
  • a disease such as cancer
  • a syndrome such as heart failure
  • other medical condition is art-recognized and includes the administration of a composition that reduces the incidence of a medical condition in a subject relative to a subject not receiving the composition.
  • the frequency of symptoms of a medical condition or delaying the onset of symptoms of a medical condition.
  • preventing cancer includes, for example, reducing the number of detectable cancer growths in a patient population receiving a preventive treatment relative to an untreated control population by a statistically and/or clinically significant amount, and/or delaying the onset of detectable cancer growths in a treated population relative to an untreated control population.
  • Preventing infection includes, for example, reducing the number of infection diagnoses in a treated population relative to an untreated control population, and/or delaying the onset of symptoms of infection in a treated population relative to an untreated control population.
  • Preventing pain includes, for example, reducing the magnitude of pain experienced by a subject or delaying the pain experienced by a subject in a treated population relative to an untreated control population.
  • the present invention provides compounds in the form of prodrugs.
  • prodrug is intended to encompass compounds that are converted into therapeutic agents of the present invention under physiological conditions. Common methods for preparing prodrugs include displaying selected portions of the desired molecule after hydrolysis under physiological conditions. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal. In addition, the prodrug is converted into the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, the prodrug can be slowly converted into the compounds of the present invention.
  • oxidative metabolite is intended to encompass compounds obtained by metabolism of the parent compound under normal physiological conditions. Specifically, the oxidative metabolite is formed by oxidation of the parent compound during metabolism. For example, oxidation of a thioether group may give the corresponding sulfoxide or sulfone.
  • solvate refers to a compound formed by solvation (eg, a compound formed by combining solvent molecules with solute molecules or ions).
  • hydrate refers to a compound formed by the combination of water and a parent compound.
  • treatment includes preventive and/or therapeutic treatment.
  • preventive or therapeutic treatment are art-recognized and include administering one or more compositions of the present invention to a host. If the administration is prior to clinical manifestation of an undesirable condition (e.g., a host animal disease or other undesirable state), the treatment is preventive, (i.e., it prevents the host from developing the undesirable condition), while if the administration is after manifestation of the undesirable condition, the treatment is therapeutic, (i.e., intended to reduce, alleviate or stabilize an existing undesirable condition or its side effects).
  • an undesirable condition e.g., a host animal disease or other undesirable state
  • the treatment is preventive, (i.e., it prevents the host from developing the undesirable condition)
  • the treatment is therapeutic, (i.e., intended to reduce, alleviate or stabilize an existing undesirable condition or its side effects).
  • TRPV3 TRPV3 protein
  • TRPV3 channel TRPV3 channel
  • ion channel e.g., a polypeptide
  • TRPV3 amino acid sequence such as described in any patent application cited herein, or consisting of, or consisting essentially of.
  • TRPV3 proteins may also include orthologous orthologs, such as TRPV3 from mouse, rat, horse, or fruit fly.
  • TRPV3 includes polypeptides that maintain TRPV3 function and include (i) all or part of a TRPV3 amino acid sequence; (ii) a TRPV3 amino acid sequence having 1 to about 2, 3, 5, 7, 10, 15, 20, 30, 50, 75, or more conservative amino acid substitutions; (iii) an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to a TRPV3 amino acid sequence; and (iv) a functional fragment thereof.
  • the polypeptides of the present invention also include homologs of human TRPV3 polypeptides, for example, orthologs and intraspecific homologs.
  • TRPV3 polypeptides and amino acid sequences include, for example, sequences described in any patent application cited herein.
  • TRPV3 also refers to a nucleic acid encoding a polypeptide of the present invention, such as a nucleic acid comprising a sequence consisting of, or consisting essentially of, a TRPV3 polynucleotide sequence.
  • the nucleic acid of the present invention may comprise all or part of the following nucleotide sequences: (i) a TRPV3 nucleotide sequence; (ii) a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to a TRPV3 nucleotide sequence; (iii) a nucleotide sequence that hybridizes to a TRPV3 nucleotide sequence under stringent conditions; (iv) a nucleotide sequence encoding a polypeptide that is functionally equivalent to a polypeptide of the present invention; (v) a nucleotide sequence encoding a polypeptide that is at least about 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% homologous or identical to a TRPV3 polypeptide sequence; (vi) ) a nucleotide sequence encoding a polypeptide having
  • the nucleic acids of the invention also include homologs of TRPV3 nucleic acid sequences, such as orthologs and intraspecific homologous genes, and variants after codon optimization for expression in a specific organism (e.g., a host cell).
  • TRPV3 nucleic acid sequences include, for example, sequences described in any patent application cited herein. If not specifically stated, a person skilled in the art can easily evaluate whether TRPV3 refers to a nucleic acid or a protein.
  • aliphatic group refers to a straight-chain, branched-chain, or cyclic aliphatic hydrocarbon group, and includes saturated and unsaturated aliphatic groups such as alkyl, alkenyl, and alkynyl groups.
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possibly substituted to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • alkoxy refers to an alkyl group as defined below to which is attached an oxygen group. Alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, etc. "Ether” is two hydrocarbons covalently linked by oxygen.
  • the substituent of the alkyl group that makes the alkyl group an ether is an alkoxy group or an alkoxy-like group, for example, it can be represented by one of the following groups: -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(CH 2 ) t -R 8 , wherein R 8 is selected from hydrogen, halogen, lower alkyl, lower alkoxy, amino, or -NHSO 2 NH 2 , and t is an integer from 0 to 6.
  • alkyl refers to a saturated aliphatic group, including straight chain alkyl and branched chain alkyl.
  • the straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., straight chain C1 - C30 , branched chain C3 - C30 ), more preferably 20 or fewer, and most preferably 10 or fewer.
  • cycloalkyl includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, more preferably 3 to 6 carbons, wherein the cycloalkyl is additionally optionally substituted.
  • Preferred cycloalkyl groups have 3-12, and more preferably 5, 6, 7 or 8 carbon atoms in their ring structure.
  • Preferred cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • cycloalkyl also includes bridged ring groups, including, but not limited to, bicyclo[2.2.2]octyl, bicyclo[1.1.1]pentyl, bicyclo[3.2.1]octyl, bicyclo[2.1.1]hexyl.
  • alkyl (or “lower alkyl”) is intended to include both “unsubstituted alkyl” and “substituted alkyl”, wherein the latter refers to an alkyl moiety having a substituent replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents may include, for example, halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., 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 an aromatic or heteroaromatic moiety.
  • carbonyl e.g., carboxyl, alkoxycarbonyl, formyl, or acyl
  • thiocarbonyl e.g., thioester, thioacetate,
  • substituents of substituted alkyl groups may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl, as well as ether, alkylthio, carbonyl (including ketone, aldehyde, carboxylate, and ester), -CF 3 , -CN, and the like.
  • Exemplary substituted alkyl groups are described below. Cycloalkyl groups may be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF 3 , -CN, and the like.
  • Alkenyl and alkynyl groups may be similarly substituted to provide, for example, aminoalkenyl, aminoalkynyl, Amidoalkenyl, amidoalkynyl, iminoalkenyl, iminoalkynyl, thioalkenyl, thioalkynyl, carbonyl-substituted alkenyl or alkynyl.
  • lower alkyl as used herein means an alkyl as defined above, but having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout this application, preferred alkyl groups are lower alkyl groups. In preferred embodiments, the substituents referred to herein as alkyl groups are lower alkyl groups.
  • alkylthio refers to an alkyl group as defined above, to which a sulfur group is attached.
  • the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH 2 ) t -R 8 , wherein t and R 8 are as defined above.
  • Representative alkylthio groups include methylthio, ethylthio, and the like.
  • aralkyl refers to an alkyl group substituted with an aryl group (eg, an aromatic or heteroaromatic group).
  • aryl includes 5-, 6-, and 7-membered monocyclic aromatic groups containing 0-4 heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine.
  • aryl heterocycles or "heteroaromatic compounds”.
  • the aromatic ring may be substituted at one or more ring positions with substituents such as those described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, alkoxy, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphite, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3 , -CN, etc.
  • substituents such as those described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, alkoxy, amino, nitro, sulfhydryl, imin
  • aryl also includes polycyclic ring systems having two or more rings in which two or more carbons are common to two adjacent rings (such rings are "fused rings"), wherein at least one of the rings is aromatic, e.g., the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and/or heterocyclyl.
  • Carbocycle refers to an aromatic or non-aromatic ring in which every atom in the ring is carbon.
  • electron withdrawing group refers to a chemical group that attracts electron density from an atom or group of atoms to which the electron withdrawing group is attached. Attracting electron density includes attraction through an inductive effect or through a delocalized/resonance effect.
  • electron withdrawing groups attached to aromatic rings include perfluoroalkyl groups such as trifluoromethyl, halogens, azides, carbonyl-containing groups such as acyl, cyano, and imine-containing groups.
  • heteroatom refers to an atom of any element other than carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
  • heterocyclyl or “heterocyclic group” refers to a 3- to 10-membered ring structure, more preferably a 3- to 7-membered ring, Its ring structure includes 1 to 4 heteroatoms.
  • the heterocycle can also be polycyclic.
  • Heterocyclic groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, 2,3-diazine, 1,5-diazine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenpyrazine, phenothiazine, furazan, phenoxazine, pyrrolidine,
  • the heterocycle may be substituted at one or more positions with substituents as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphite, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3 , -CN, etc.
  • substituents as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphite, carbonyl, carboxyl, si
  • nitro means -NO2 ;
  • halogen refers to -F, -Cl, -Br or -I;
  • mercapto means -SH;
  • hydroxy means -OH; and
  • sulfonyl means -SO2- .
  • polycyclic group refers to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and/or heterocyclic groups) wherein two adjacent rings share one, two or more ring atoms, e.g., the rings are "fused rings” or "spirocycles".
  • bridged rings e.g., C5 - C12 bridged carbocycles, including but not limited to bicyclo[2.2.2]octyl, bicyclo[1.1.1]pentyl, bicyclo[3.2.1]octyl, bicyclo[2.1.1]hexyl.
  • Each ring in the polycyclic ring may be substituted with the above-mentioned substituents, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, thiol, imino, amide, phosphate, phosphonate, phosphite, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3 , -CN and the like.
  • substituents for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, thiol, imino, amide, phosphate, phosphonate, phosphite, carbonyl, carboxyl, sily
  • protecting group refers to a temporary substituent that protects a potentially reactive functional group from unwanted chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991).
  • permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroaralkyl, any of which substituents may themselves be further substituted), as well as halogen, carbonyl (e.g., ester, carboxyl, or formyl), thiocarbonyl (e.g., thioester, thiocarboxylate, or thioformate), ketone, aldehyde, amino, amido, amide, amidino, cyano, nitro, azi
  • Illustrative substituents include, for example, those described above.
  • the permissible substituents may be one or more and the same or different for appropriate organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible organic compound substituents described herein that satisfy the valence of the heteroatoms.
  • the present invention is not intended to be limited in any way to the permissible organic compound substituents.
  • substituted or “substituted with” includes the implicit proviso that such substitution is based on the valence allowed by the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., it does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc.
  • Substituted with 0-2 R f means that the corresponding group carries 0, 1 or 2 R f .
  • each expression when it occurs more than once in any construction, is intended to represent an independent definition unless in the same construction.
  • Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and mesyl, respectively.
  • a more comprehensive list of abbreviations used by those of ordinary skill in the field of organic chemistry appears in the first issue of each volume of the Journal of Organic Chemistry; the list is presented in the form of a table entitled Standard List of Abbreviations .
  • the abbreviations contained in the list and all abbreviations used by those of ordinary skill in the field of organic chemistry are hereby incorporated by reference.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates that all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, also fall within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents, such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be included in the present invention.
  • a specific enantiomer of a compound of the invention may be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary groups are cleaved to provide the pure desired enantiomer.
  • the enantiomer may be purified by a chiral auxiliary.
  • a group such as a carboxyl group can form diastereomeric salts with an appropriate optically active acid or base, followed by separation of the diastereomers thus formed by fractional crystallization or chromatographic methods known in the art, and subsequent recovery of the pure enantiomers.
  • enantiomerically enriched mixtures and pure enantiomer compounds can be prepared by using enantiomerically pure synthetic intermediates in combination with reactions that leave the stereochemistry of the chiral center unchanged or result in its complete inversion. Techniques for inverting a particular stereocenter or leaving it unchanged, as well as those for resolving stereoisomer mixtures, are well known in the art and are well within the ability of one of ordinary skill in the art to screen the appropriate method for a particular situation.
  • Equivalents of the compounds described above include compounds that correspond to them and have the same general properties (e.g., ability to inhibit TRPV3 activity) as them, wherein one or more simple variations of the substituents do not negatively affect the efficacy of the compound.
  • the compounds of the present invention are prepared by methods such as those described in the following general reaction schemes, or by modifications thereof, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, variants known per se but not mentioned herein may also be used.
  • hydrocarbon is intended to include all permissible compounds having at least one hydrogen and one carbon atom.
  • permissible hydrocarbons include acyclic and cyclic hydrocarbons, branched and unbranched hydrocarbons, carbocyclic and heterocyclic hydrocarbons, aromatic and nonaromatic hydrocarbon organic compounds that may be substituted or unsubstituted.
  • the compounds of the present invention may also contain non-natural ratios of isotopic atoms at one or more atoms constituting the compound.
  • the compound may be isotopically labeled with a radioactive isotope, such as deuterium ( 2H ), tritium ( 3H ), iodine-125 ( 125I ) or carbon-14 ( 14C ). All isotopic variants of the compounds of the present invention, whether radioactive or non-radioactive, are intended to be included within the scope of the present invention.
  • hydrogen or “H” may include all isotopes of the element hydrogen, protium ( 1H ), deuterium ( 2H ) and tritium ( 3H ), when not present simultaneously with protium ( 1H ), deuterium ( 2H ) and tritium ( 3H ).
  • Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrates. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, All physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • Substituents are defined by their conventional chemical formula, written left to right, and they equally encompass chemically identical substituents writing the structure from right to left, e.g., -CH2O- is intended to also represent -OCH2- ; -NHS(O) 2- is also intended to represent -S(O) 2HN- , and so forth.
  • pharmaceutically acceptable salt includes salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or the like.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphoric acid, and the like, and salts derived from relatively nontoxic organic acids such as acetic acid, trifluoroacetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen
  • salts of amino acids such as arginine salts and the like, and organic acids such as glucuronic acid or galacturonic acid and the like (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for purposes of the present invention, the salts are equivalent to the parent form of the compound.
  • the term "sufficiently low pyrogenic activity” means that the amount of pyrogens in the preparation does not result in adverse effects (e.g., irritation, fever, inflammation, diarrhea, respiratory distress, endotoxic shock, etc.) in a subject to whom the preparation has been administered.
  • the term includes preparations that are free or substantially free of endotoxins, such as lipopolysaccharide (LPS).
  • LPS lipopolysaccharide
  • the drug administered is a drug that modulates TRPV3 protein levels and/or activity.
  • the compound inhibits the expression and/or activity of TRPV3 protein.
  • the compound selectively inhibits the expression of TRPV3 protein.
  • the compound preferentially inhibits the activity of TRPV3 protein compared to one or more other ion channels.
  • the disease or condition can be, for example, contact pain or sensitivity, such as pain associated with a disease or condition, such as cancer pain, skin diseases or conditions, such as psoriasis and basal cell carcinoma and squamous cell carcinoma, neurodegenerative diseases or conditions, such as Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and other brain diseases caused by trauma or other damage, the damage includes aging, inflammatory diseases (e.g., asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases, multiple sclerosis, and immune system disorders), cancer or other proliferative diseases, kidney and liver diseases, metabolic disorders, such as diabetes.
  • Other diseases and conditions include postoperative pain, postherpetic neuralgia, fibromyalgia, and herpes zo
  • diseases and disorders include skin diseases and disorders; neurological and neurodegenerative diseases and disorders; fever associated with a variety of diseases, disorders, or conditions; incontinence; inflammatory diseases and disorders, such as inflammatory bowel disease and Crohn's disease; respiratory diseases and disorders, such as chronic cough, asthma, and chronic obstructive pulmonary disease (COPD); digestive diseases, such as ulcers and acid reflux; metabolic diseases and disorders, including obesity and diabetes; liver and kidney diseases and disorders; malignant diseases, including cancer; age-related diseases; and sensitivity to pain and touch.
  • diseases and disorders include skin diseases and disorders; neurological and neurodegenerative diseases and disorders; fever associated with a variety of diseases, disorders, or conditions; incontinence; inflammatory diseases and disorders, such as inflammatory bowel disease and Crohn's disease; respiratory diseases and disorders, such as chronic cough, asthma, and chronic obstructive pulmonary disease (COPD); digestive diseases, such as ulcers and acid reflux; metabolic diseases and disorders, including obesity and diabetes; liver and kidney diseases and disorders; malignant diseases, including cancer; age-related
  • Additional diseases or conditions that may be treated include ATP-related diseases or conditions, including epilepsy, cognition, vomiting, pain (e.g., migraine), asthma, peripheral vascular disease, hypertension, immune and inflammatory disorders, irritable bowel syndrome, cystitis, depression, age-related degenerative diseases, urinary incontinence, premature ejaculation, cystic fibrosis, diabetes, birth control and infertility, and wound healing (see, e.g., Foresta et al. (1992) J. Biol. Chem. 257: 19443-19447; Wang et al. (1990) Biochim. Biophys. Res. Commun. 166: 251-258; Burnstock and Williams, (2000) J. Pharmacol. Exp. Ther. 295: 862-869; and Burnstock, Pharmacol Rev (2006) 58: 58-86).
  • the TRPV3 inhibitors described herein can be used to treat any of the above and below described diseases or conditions, including the treatment of pain associated with any of the above or below described diseases or conditions.
  • the inhibitor can be selected and formulated based on the intended route of administration.
  • the compounds and compositions provided herein can be used to prevent or treat pain or sensitivity to pain and touch. Pain or sensitivity to pain and touch can manifest in a variety of different diseases, patients or conditions, including, but not limited to, diabetic neuropathy, chest pain, psoriasis, eczema, dermatitis, burns, post-herpetic neuralgia (shingles), nociceptive pain, peripheral and central nerve pain, chronic pain, cancer and tumor pain, spinal cord injury, crushing injury and trauma-induced pain, migraine, cerebrovascular pain and vascular pain, sickle cell disease pain, rheumatoid arthritis pain, musculoskeletal pain, including treatment of osteoarthritis and rheumatoid arthritis signs and symptoms, oral and facial pain, including dental and cancer-related lower back or pelvic pain, surgical incision-related pain, inflammatory and non-inflammatory pain, visceral pain, psychological pain and soft tissue inflammatory pain, fibromyalgia-related pain, and reflex sympathetic dystrophy.
  • N-type calcium channels are involved in synaptic transmission, which transmits pain signals from sensory afferent nerve cells to the central nervous system.
  • Certain naturally occurring peptide neurotoxins that specifically block N-type calcium channels have been shown to act as extremely powerful and effective analgesics in a wide range of animal pain models, including models of inflammatory and neuropathic pain.
  • Available evidence suggests that N-type calcium channel blockers are at least as effective as opioids, lack numerous typical opioid side effects (e.g., respiratory weakness), and that the analgesic effect does not undergo tolerance development.
  • TRPV3 is expressed in pain-sensitive neurons, and the expression is upregulated after injury. In addition, TRPV3 is strongly expressed in the skin. Therefore, methods for treating pain include administering: (i) an antagonist of TRPV3 function; (ii) a combination of selective antagonists of TRPV3 and TRPV1 and/or TRPV4 function; or (iii) a pan-TRP inhibitor that inhibits the function of TRPV3, TRPV1, and TRPV4.
  • the methods of the present invention include administering (i) a combination of a selective TRPV3 antagonist and a selective TRPM8 antagonist; (ii) a combination of a selective TRPV3 antagonist, a selective TRPM8 antagonist, and one or more selective TRPV1 and/or TRPV4 antagonists; (iii) a cross-TRP inhibitor that antagonizes the function of TRPV3 and TRPM8; or (iv) an antagonist of TRPV3, TRPM8, and pan-inhibitors of one or more TRPV1 and TRPV4 functions for treating pain.
  • Modulating or regulating the calcium entry pathway, and therefore the key control point of skin cell growth may treat or prevent skin diseases or conditions characterized by epidermal hyperplasia, a condition in which skin cells both proliferate too rapidly and differentiate poorly.
  • skin diseases include psoriasis, basal cell carcinoma, and squamous cell carcinoma.
  • BCC Basal cell carcinoma
  • SCC squamous cell carcinoma
  • Pruritus and pain share many mechanistic similarities. Both are associated with C-fiber activation, both are enhanced by temperature increases and increases in inflammatory transmitters, and both are eliminated by opioids. Reducing neuronal excitability, especially C-fiber excitability, may relieve pruritus associated with dialysis, dermatitis, pregnancy, poison ivy, allergies, dry skin, chemotherapy, and eczema.
  • Acne is a skin disease of complex etiology.
  • oil secretion from the sebaceous glands contributes to the development of acne, and since TRPV3 is also expressed in sebaceous glands and has been shown to regulate secretion in other skin cells, antagonizing TRPV3 function may reduce the signs and symptoms of acne.
  • the TRPV3 antagonist is administered to prevent, treat or ameliorate signs and symptoms of acute pain, chronic pain, contact sensitivity, itch sensitivity, or as part of the treatment of burns, e.g., post-operative pain, cancer pain or neuropathic pain.
  • the TRPV3 antagonist is administered to prevent, treat or ameliorate the signs and symptoms of migraine.
  • the TRPV3 antagonist is administered to prevent, treat or ameliorate the signs and symptoms of a condition or disorder selected from diabetic neuropathy, inflammation, psoriasis, eczema, dermatitis, post-herpetic neuralgia (shingles), incontinence, bladder incontinence, fever, hot flashes and cough.
  • a condition or disorder selected from diabetic neuropathy, inflammation, psoriasis, eczema, dermatitis, post-herpetic neuralgia (shingles), incontinence, bladder incontinence, fever, hot flashes and cough.
  • the TRPV3 antagonist is administered to prevent, treat or improve Signs and symptoms of osteoarthritis.
  • the TRPV3 antagonist is administered to prevent, treat or ameliorate the signs and symptoms of rheumatoid arthritis.
  • the TRPV3 antagonist is administered to prevent, treat or ameliorate the signs and symptoms of oral mucositis.
  • the TRPV3 antagonist is administered to promote hair loss or inhibit hair growth in a patient.
  • Another aspect of the invention relates to the use of a TRPV3 antagonist in the manufacture of a medicament for preventing, treating or ameliorating in a patient a symptom of a disease, disorder or condition involving activation of TRPV3 or for which decreased TRPV3 activity reduces severity.
  • the present application relates to a method for treating TRPV3-mediated diseases, comprising administering a therapeutically effective amount of a compound of the present application or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope labels or pharmaceutically acceptable salts, or a pharmaceutical composition of the present application to a patient in need of administration.
  • the compounds of the present invention can be administered alone, it is preferred to administer the compound as a pharmaceutical preparation (composition).
  • composition can be formulated into preparations in a convenient manner for human or veterinary use.
  • the compound contained in the pharmaceutical preparation can be an active agent itself, or can be, for example, a prodrug that can be converted into an active compound under physiological conditions.
  • the compounds of the present invention in suitable hydrated form, and/or the pharmaceutical compositions of the present invention can be formulated into the following pharmaceutically acceptable dosage forms by other conventional methods known to those skilled in the art.
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more of the above compounds, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • the pharmaceutical composition of the present invention is particularly formulated into a solid or liquid administration form, including an administration form suitable for the following modes: (1) oral administration, for example, an immersion (aqueous or non-aqueous solution or suspension); tablets; pills; powders; granules; pastes for application to the tongue, teeth, lips, gums; mouthwashes; gels; (2) parenteral administration, for example, as a sterile solution or suspension, by subcutaneous, intramuscular or intravenous injection; (3) topical administration, for example, as a cream, ointment or spray applied to the skin; (4) intravaginal or rectal administration, for example, in the form of a vaginal suppository, cream or or (5) inhalation.
  • the TRPV3 antagonist can be administered alone or in combination with other therapeutic agents.
  • the TRPV3 antagonist is administered in combination with one or more of the following therapeutic agents: an anti-inflammatory agent, an anti-acne agent, an anti-wrinkle agent, an anti-scar agent, an anti-psoriatic agent, an anti-proliferative agent, an anti-fungal agent, an anti-viral agent, an antiseptic, an anti-migraine agent, a keratolytic agent, or a hair growth inhibitor.
  • the TRPV3 antagonist can be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intraorbitally, intracardially, intradermally, intraperitoneally, transtracheally, subcutaneously, subcutaneously, intraarticularly, subcapsularly, subarachnoidally, intraspinally, intrasternally, or by inhalation.
  • the TRPV3 antagonist is administered topically.
  • the TRPV3 antagonist is administered orally.
  • the TRPV3 antagonist is administered parenterally.
  • the term "therapeutically effective amount” means an amount of a compound, material, or composition comprising a compound of the invention, which is effective to produce some desired therapeutic effect by inhibiting TRPV3 function in at least a subpopulation of cells in an animal, thereby blocking the biological consequences of that function in the treated cells, at a reasonable benefit/risk ratio applicable to any drug treatment.
  • systemic administration and “peripheral administration” refer to administration of a compound, drug or other material not directly to the central nervous system so that it enters the patient's system and is metabolized and otherwise processed therefrom, such as subcutaneous administration.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and are commensurate with a reasonable benefit/risk ratio.
  • the term "pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, which is involved in carrying or transporting the antagonists of the invention from one organ or part of the body to another.
  • a pharmaceutically acceptable material, composition, or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, which is involved in carrying or transporting the antagonists of the invention from one organ or part of the body to another.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials that serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as carboxymethyl Sodium cellulose, ethyl cellulose and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) star
  • some embodiments of the compounds of the present invention may contain basic functional groups, such as amino or alkylamino, and therefore can form pharmaceutically acceptable salts with pharmaceutically acceptable acids.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of the compounds of the present invention.
  • Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfonate etc. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J Pharm. Sci. 66: 1-19).
  • compositions of the compounds of the invention include conventional non-toxic salts or quaternary ammonium salts of the compounds, such as those derived from non-toxic organic or inorganic acids.
  • such conventional non-toxic salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethaned
  • the compounds of the invention may contain one or more acidic functional groups and are thus capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts refers to relatively non-toxic inorganic and organic base addition salts of the compounds of the invention.
  • Such base addition salts can also be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, ammonium, or a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • a suitable base ammonium, or a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • hydroxides, carbonates or bicarbonates of pharmaceutically acceptable metal cations include lithium, sodium, potassium, calcium, magnesium, and aluminum salts.
  • Organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. (See, for example, Berge et al., supra).
  • antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, ⁇ -tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, prop
  • the preparations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • Oral preparations include those that are delivered to the mouth and maintained in the mouth without swallowing, as well as preparations that are used as part or swallowed after use.
  • the preparations can be conveniently presented in unit dosage form and can be prepared by any method known in the field of pharmacology.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form varies depending on the host being treated and the specific mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of the compound that produces a therapeutic effect. Usually, based on 100%, the amount ranges from about 1% to about 99%, preferably about 5% to about 70%, and most preferably about 10% to about 30% of the active ingredient.
  • the method for preparing these preparations or compositions comprises the step of bringing the compound of the present invention into association with the carrier, and optionally one or more accessory ingredients.
  • the preparations are prepared by uniformly and intimately bringing into association the compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • the preparations of the present invention suitable for oral administration may be in the form of capsules, sachets, pills, tablets, lozenges (using a flavoring base, usually sucrose and gum arabic or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as a liquid emulsion of the oil-in-water or water-in-oil type, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and gum arabic) and/or as a mouthwash, etc., each containing a predetermined amount of the compound of the present invention as an active ingredient.
  • the compounds of the present invention may also be administered in the form of a bolus, an electuary or a paste.
  • Ring A is selected from a monocyclic or polycyclic ring system containing 3 to 12 ring atoms
  • R 1 is each independently selected from H, halogen, hydroxyl, mercapto, nitro, cyano, oxo, C 1 -C 6 alkyl substituted with 0-2 R f , C 1 -C 6 haloalkyl substituted with 0-2 R f , C 1 -C 6 alkoxy substituted with 0-2 R f , C 1 -C 6 haloalkoxy substituted with 0-2 R f , C 3 -C 6 cycloalkyl substituted with 0-2 R f , C 3 -C 6 halocycloalkyl substituted with 0-2 R f , C 3 -C 6 cycloalkyloxy substituted with 0-2 R f , C 3 -C 6 halocycloalkyloxy substituted with 0-2 R f , aryl substituted with 0-2 R f , aralkyl substituted with 0-2 R f , alkaryl substituted with
  • R2 is each independently selected from H, halogen, hydroxyl, mercapto, nitro, cyano, oxo, C1 - C6 alkyl substituted with 0-2 Rf , C1- C6 haloalkyl substituted with 0-2 Rf , C1 - C6 alkoxy substituted with 0-2 Rf , C1 - C6 haloalkoxy substituted with 0-2 Rf, C3-C6 cycloalkyl substituted with 0-2 Rf , C3 - C6 halocycloalkyl substituted with 0-2 Rf , C3 - C6 cycloalkyloxy substituted with 0-2 Rf , C3 - C6 halocycloalkyl substituted with 0-2 Rf , aryl substituted with 0-2 Rf , aralkyl substituted with 0-2 Rf , alkaryl substituted with 0-2 Rf , heteroaryl substituted with
  • L 1 is selected from a bond, or the following structural formula:
  • X1 is independently selected at each occurrence from C, O or N;
  • X2 is independently selected at each occurrence from C, O, B or N;
  • XA , XB , and XC are each independently CRx or N;
  • Rx is each independently selected from H, halogen, hydroxyl, mercapto, nitro, cyano, C1 - C6 alkyl substituted with 0-2 Rf , C1 - C6 haloalkyl substituted with 0-2 Rf , C1 - C6 alkoxy substituted with 0-2 Rf , C1- C6 haloalkoxy substituted with 0-2 Rf, C3-C6 cycloalkyl substituted with 0-2 Rf , C3 - C6 halocycloalkyl substituted with 0-2 Rf , C3 - C6 cycloalkyloxy substituted with 0-2 Rf , C3 -C6 halocycloalkyl substituted with 0-2 Rf , aryl substituted with 0-2 Rf , aralkyl substituted with 0-2 Rf , alkaryl substituted with 0-2 Rf , heteroaryl substituted with 0-2 Rf
  • R 0 is independently selected from H, halogen or the structural formula II
  • L 2 is each independently selected from a bond, -O-, -S-, -N(R 20 )-, -C(O)-, -C(R 20 R 21 )-, -S(O)-, and -S(O 2 )-;
  • Ring C is independently selected from a monocyclic or polycyclic ring system containing 3-12 ring atoms
  • R3 is each independently selected from H, halogen, hydroxyl, mercapto, nitro, cyano, oxo, C1 - C6 alkyl substituted with 0-2 Rf , C1- C6 haloalkyl substituted with 0-2 Rf , C1 - C6 alkoxy substituted with 0-2 Rf , C1 - C6 haloalkoxy substituted with 0-2 Rf, C3-C6 cycloalkyl substituted with 0-2 Rf , C3 - C6 halocycloalkyl substituted with 0-2 Rf , C3 - C6 cycloalkyloxy substituted with 0-2 Rf , C3 - C6 halocycloalkyloxy substituted with 0-2 Rf , aryl substituted with 0-2 Rf , aralkyl substituted with 0-2 Rf , alkaryl substituted with 0-2 Rf , heteroaryl substituted with
  • R 11 is each independently selected from C 1 -C 6 alkylene substituted with 0-2 R f ;
  • R 12 is each independently selected from H, C 1 -C 6 alkyl substituted with 0-2 R f , C 1 -C 6 haloalkyl substituted with 0-2 R f , C 3 -C 6 cycloalkyl substituted with 0-2 R f , and C 3 -C 6 halocycloalkyl substituted with 0-2 R f ;
  • Ra and Rb are each independently selected from H, C1 - C6 alkyl substituted with 0-2 Rf , aryl substituted with 0-2 Rf , aralkyl substituted with 0-2 Rf , -C(O) Rc and -C(O) ORd ;
  • R c is independently selected from H, halogen, C 1 -C 6 alkyl substituted with 0-2 R f , aryl substituted with 0-2 R f and aralkyl substituted with 0-2 R f ;
  • R d is each independently selected from H, C 1 -C 6 alkyl substituted with 0-2 R f , aryl substituted with 0-2 R f and aralkyl substituted with 0-2 R f ;
  • R 20 and R 21 are each independently selected from H, hydroxyl, C 1 -C 6 alkyl, aryl and aralkyl;
  • Rf is each independently selected from halogen, hydroxyl, amino , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1 - C6 haloalkoxy , C3 - C6 cycloalkyl and C3 -C6 halocycloalkyl ;
  • n 0, 1, 2 or 3;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2, or 3;
  • n 1 or 2;
  • r is 1 or 2.
  • ring A is selected from a benzene ring, a pyridine ring, a quinoline ring, a piperidine ring, a C 3 -C 6 cycloalkyl ring, an isoquinoline ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, a thiazole ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, an isothiazole ring, an indole ring, a benzimidazole ring, a furan ring, an oxazole ring, an oxadiazole ring, a quinoxaline ring and a purine ring.
  • Ring A is selected from the following structural formula:
  • R 1 is each independently selected from H, halogen, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, -N(R a )(R b ) and -R 11 OR 12 , wherein R a and R b are each independently selected from H and C 1 -C 6 alkyl; R 11 is each independently selected from C 1 -C 6 alkylene; R 12 is each independently selected from H and C 1 -C 6 alkyl.
  • each R 1 is independently selected from H, Cl, F, -CF 3 , -CN, -CH 3 , -OH, -OCH 3 , -CH 2 OCH 3 .
  • R 2 is each independently selected from H, cyano, hydroxy, mercapto, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl , C 3 -C 6 cycloalkyl substituted with 0-2 R f, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -R 11 OR 12 , -R 11 SR 12 , -CH ( O ), -C(O)OR d and -C(O)N( R a )(R b ); wherein, R 11 is each independently selected from C 1 -C 6 alkylene; R 12 is each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl and C 3 -C 6 halocycloalkyl; R a and R b are each independently selected from H and C 1 -C 6 alkyl
  • each R 2 is independently selected from protium, deuterium, tritium, -SH, -OH, -OCF 3 , -CH 3 , -NH 2 , -CN, -CONH 2 , -CH 2 OH, -CH(O), -CHF 2 , -COOH, -COOCH 3 , oxo, and
  • each L 2 is independently selected from a bond, -O-, -S-, -N-, -C(O)-, -CH 2 -, -CF 2 -, -C(OH)-, -S(O)-, and -S(O 2 )-.
  • Ring C is selected from a C 3 -C 6 cycloalkane ring, a benzene ring, a benzoC 3 -C 6 cycloalkane ring, a pyridine ring, a quinoline ring, an isoquinoline ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, a thiazole ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, an isothiazole ring, an indole ring, a benzimidazole ring, a furan ring, an oxazole ring, a quinoxaline ring and a purine ring.
  • Ring C is selected from the following structural formulas:
  • R 3 is each independently selected from H, cyano, hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 6 cycloalkyl, -R 11 OR 12 , -R 11 SR 12 , -C(O)R c , -C(O)OR d and -C(O)N(R a )(R b ), or two R 3 together with the ring C atoms to which they are attached form a 3-10 membered ring structure;
  • R 11 is each independently selected from C 1 -C 6 alkylene
  • R 12 is each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl and C 3 -C 6 halocycloalkyl
  • R a and R b are each independently selected from H and C 1 -C 6 alkyl
  • R c is each independently selected from H, halogen and C 1 -C 6 alkyl
  • R d is each independently selected from H and C 1 -C 6 alkyl.
  • each R 3 is independently selected from H, cyclopropyl, isopropyl, tert-butyl, F, Cl, CN, ethyl, methyl, trifluoromethoxy, methylcarbonyl, methoxymethyl, -C(CH 3 ) 2 OH.
  • R 2 , X A , X B , X C and p are as defined in Formula I.
  • R 2 is each independently selected from protium, deuterium, tritium, halogen, oxo, -SH, -OH, -CH 3 , -CN, -CONH 2 , -COOH, -COH, -COOCH 3 , -CF 3 , -OCH 3 , -CH 2 OH, -OCF 3 , -CHF 2 , and -NH 2 .
  • R2 groups may be optionally substituted on one or both ring parts of the spirocyclic structure.
  • the definition of R2 groups may be as described above.
  • at least one R2 is -OH.
  • R 2 is each independently selected from protium, deuterium, tritium, halogen, -CH 3 and -CF 3 .
  • R2 is independently selected from oxo, -SH, -CN, -CONH2 , -COOH, -COH, -COOCH3 , -OCH3, -CH2OH , -CHF2 , -OCF3 and -NH2 .
  • L 1 is
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • ring A is
  • ring A is
  • the compound is selected from the group consisting of:
  • the present application relates to a pharmaceutical composition, which comprises the compound of the present application or its stereoisomer, tautomer, solvate, hydrate, active metabolite, isotope-labeled substance or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.
  • the present application also relates to the use of the compound of the present application or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope labels or pharmaceutically acceptable salts, and the pharmaceutical composition of the present application in the preparation of drugs for inhibiting TRPV3 activity.
  • the present application also relates to the use of the compound of the present application or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope labels or pharmaceutically acceptable salts, and the pharmaceutical composition of the present application in the preparation of a medicament for treating a TRPV3-mediated disorder in a subject.
  • the condition is selected from pain, itching, skin disorders, inflammation, abnormal hair growth, incontinence, fever, hot flashes, cystitis, irritable bowel syndrome, and/or a coughing symptom.
  • the pain is cancer pain and skin pain.
  • it is used to prepare a medicament for inhibiting proliferation, thereby preventing, treating or ameliorating symptoms of cancer.
  • the cancer is liposarcoma.
  • the hair growth disorder is alopecia.
  • the skin disorder is selected from keratosis pilaris, ichthyosis, pruritus.
  • the skin keratosis is Olmsted syndrome.
  • the ichthyosis is harlequin ichtyosis.
  • the compounds of the present invention can be prepared using the methods exemplified in the general synthesis schemes and experimental procedures described in detail below. These general synthesis schemes and experimental procedures are presented for illustrative purposes and are not intended to be limiting.
  • the raw materials used to prepare the compounds of the present invention are commercially available or can be prepared using conventional methods known in the art.
  • Schemes 1, 2, 3, 4 and 5 Representative procedures for preparing compounds of the invention are outlined in Schemes 1, 2, 3, 4 and 5.
  • the p-halophenylacetonitrile and ethyl bromoacetate starting materials can be purchased or prepared using methods known in the art, with representative procedures providing intermediates.
  • Scheme 1 highlights a fully detailed synthesis of 1-(3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1-one.
  • diethyl 3-(4-halophenyl)-3-cyanoglutarate 2 can be achieved by reaction of p-halophenylacetonitrile and ethyl bromoacetate in a solvent such as tetrahydrofuran, the cyano and ester groups of 2 under a reducing agent to produce cyclized 3, the ester 3 is hydrolyzed to the carboxylic acid 4 under alkaline conditions, 4 undergoes cyclization with itself under acidic conditions to produce 5, 5 is reacted with the desired boronic acid under Suzuki conditions to produce the coupling intermediate 6, 6 is reduced under reducing agent conditions to produce intermediate 7, which is then reacted with a carboxylic acid under condensing agent conditions to produce 8, 8 is resolved by supercritical fluid to produce 8a, 8b, 8c and 8d.
  • a solvent such as tetrahydrofuran
  • Scheme 2 shows the synthesis of the desired compounds, where the last step is a Suzuki reaction to produce 8.
  • the synthesis of intermediate 5 is described in Scheme 1.
  • Intermediate 5a is generated by intermediate 5 under reducing conditions, 5a is reacted with a carboxylic acid to produce 5b, 5b is reacted with the desired boronic acid under Suzuki conditions to produce 8, and further resolved by supercritical separation to give 8a, 8b, 8c and 8d.
  • Scheme 3 shows the synthesis of the desired compound, which is a semi-chiral synthesis.
  • the synthesis of intermediate 6 is described in Scheme 1.
  • the intermediate is catalytically reduced in the presence of a chiral ligand to give chiral alcohol 6a, which is then reduced to amide 6b, which is condensed with the desired carboxylic acid to give 8, which is further resolved by supercritical separation to give 8a and 8b.
  • Scheme 4 shows the synthesis of the desired compound, which is also a semi-chiral synthesis.
  • the synthesis of intermediate 5 is described in Scheme 1.
  • Intermediate 5 is reduced by chiral ligand catalysis to obtain 5a, which is then reacted with the desired boronic acid under Suzuki conditions to produce 5b, 5b is reduced under reducing agent conditions to produce 5c, 5c is condensed with the desired carboxylic acid to obtain 8, and further supercritical separation is performed to obtain 8a and 8b.
  • Scheme 5 shows the synthesis of the desired compound, which is also a semi-chiral synthesis.
  • the synthesis of intermediate 5 is described in Scheme 1.
  • Intermediate 5 is catalyzed by chiral ligand reduction to give 5a, which is further reduced to lactam to give intermediate 5b.
  • the carboxylic acid required for 5b is condensed to give 5c, which is then reacted with the required boronic acid under Suzuki conditions to produce 8, which is further resolved by supercritical separation to give 8a and 8b.
  • Step B Ethyl 2-(3-(4-bromophenyl)-5-oxopyrrolidin-3-yl)acetate
  • Step B 5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3-ol
  • reaction solution was cooled to -10°C and slowly added dropwise
  • the reaction was quenched with 2 mL of water, and 20 mL of tetrahydrofuran was added to the reaction system, filtered with diatomaceous earth, and the filter cake was washed with tetrahydrofuran (20 mL x 3) until the product was completely dissolved.
  • the filtrate was concentrated to dryness to obtain 350 mg of a yellow oily liquid crude product. The next step of the reaction was carried out directly.
  • Step B (5-Bromo-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl)(5-fluoropyridin-2-yl)methanone
  • Step A 2-(4-bromophenyl)-4-(1,3-dioxolan-2-yl)butanenitrile
  • 2-(4-bromophenyl)acetonitrile (20.0 g, 102 mmol, 1.0 eq) was dissolved in 100 mL of tetrahydrofuran, and then LiHMDS (122 mL, 1.0 mol/L, 1.2 eq) was slowly added at -78 °C. After the addition was complete, the temperature was raised to room temperature and stirred for 3 hours, then lowered to -78 °C, and then 2-(2-bromoethyl)-1,3-dioxane (22.0 g, 122 mmol, 1.2 eq) was slowly added. After the addition was complete, the temperature was slowly raised to room temperature and stirred overnight.
  • Step B Ethyl 3-(4-bromophenyl)-3-cyano-5-(1,3-dioxolan-2-yl)pentanoate
  • TLC confirmed the formation of new products and some raw materials remained.
  • 100 mL of ice water was slowly added dropwise to quench the reaction, and then extracted with ethyl acetate three times (100 mL x 3), and the organic layer was washed with 100 mL of saturated saline solution.
  • the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to obtain a crude product.
  • Step C 3-cyano-3-(2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-5-(1,3-dioxane-2-yl)pentanoic acid ethyl ester
  • Step D 4-(2-(1,3-dioxan-2-yl)ethyl)-4-(2'-cyclopropyl-[1,1'-biphenyl]-4-yl)pyrrolidin-2-one
  • Step E 3-(3-(2-(2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-5-oxopyrrolidin-3-yl)propanal
  • Step F 3-(3-(2-(2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-5-oxopyrrolidin-3-yl)propanoic acid
  • Step G 6-(2-Cyclopropylphenyl)-2,3-dihydro-4H-spiro[naphthalene-1,3'-pyrrolidine]-4,5'-dione
  • Step H 6-(2-Cyclopropylphenyl)-3,4-dihydro-2H-spiro[naphthalene-1,3'-pyrrolidino]-4-ol
  • Step I (6-(2-cyclopropylphenyl)-4-hydroxy-3,4-dihydro-2H-spiro[naphthalene-1,3'-pyrrolidine]-1'-yl)(5-fluoropyridin-2yl)methanone
  • Example 2 The experimental operation was carried out by referring to step I in Example 1, except that the reagent 5-fluoropyridine-2-carboxylic acid was replaced with 5-chloropyridine-2-carboxylic acid to obtain Example 2.
  • Step B tert-Butyl 5-bromo[indene-1,4'-piperidinyl]-1'-carboxylate
  • Step C tert-Butyl 5-bromo-3-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate
  • Step E (5-Bromo-3-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)(5-fluoropyridin-2-yl)methanone
  • Step F (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)(5-fluoropyridin-2-yl)methanone
  • Step A 5-(2-Cyclopropylphenyl)-3-hydroxy-3-methyl-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-2'-one
  • Step B 5-(2-Cyclopropylphenyl)-3-methyl-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3-ol
  • Step C (5-(2-cyclopropylphenyl)-3-hydroxy-3-methyl-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl)(5-fluoropyridin-2-yl)methanone
  • the formation of the product was confirmed by LCMS, and 50 mL of brine was added thereto, followed by extraction with ethyl acetate three times, drying over anhydrous sodium sulfate, and evaporation under reduced pressure.
  • Step A 5-(2-cyclopropylphenyl)-3-hydroxy-3-(trifluoromethyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-5'-one
  • Step B 5-(2-cyclopropylphenyl)-3-(trifluoromethyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol
  • Step C (5-(2-cyclopropylphenyl)-3-hydroxy-3-(trifluoromethyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl)(5-fluoropyridin-2-yl)methanone
  • Step A tert-Butyl 3-(2-bromophenyl)-3-hydroxypyrrolidine-1-carboxylate
  • Step B tert-Butyl 1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolan-3,3'-pyrrolidine]-1'-carboxylate
  • Step D (5-Fluoropyridin-2-yl)(1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolan-3,3'-pyrrolidine]-1'-yl)methanone
  • Step A 3-Bromo-2'-cyclopropyl-[1,1'-biphenyl]-4-amine
  • Step B 3'-Bromo-2-cyclopropyl-4'-iodo-1,1'-biphenyl
  • Step C tert-Butyl 3-(3-bromo-2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-3-hydroxypyrrolidine-1-carboxylate
  • Step D tert-Butyl 6-(2-cyclopropylphenyl)-1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolane-3,3'-pyrrolidine]-1'-carboxylate
  • Step E 6-(2-Cyclopropylphenyl)-1H-spiro[benzo[c][1,2]oxaborolan-3,3'-pyrrolidine]-1-ol
  • Step F (6-(2-Cyclopropylphenyl)-1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolan-3,3'-pyrrolidine]-1'-yl)(5-fluoropyridin-2-yl)methanone
  • Example 11 (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl-3,5',5'-d 3 )(5-fluoropyridin-2-yl)methanone
  • Step A 5-(2-Cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3,5',5'-d 3 -3-ol
  • Step B (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl -3,5',5'-d 3 )(5-fluoropyridin-2-yl)methanone
  • Step A 5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-5'-one-3-d
  • Step B 5-(2-Cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3-d-3-ol
  • Step C (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl-3-d)(5-fluoropyridin-2-yl)methanone
  • Step B (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl)(5-hydroxy-6-methylpyridin-2-yl)methanone
  • 6-cyclopropylpicolinic acid 0.24 mL N,N-diisopropylethyl Amine and 279 mg (0.72 mmol, 1.5 eq) 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 5 mL tetrahydrofuran and stirred at room temperature for 0.5 h.
  • Table 1 The examples in Table 1 were prepared by subjecting compound examples 15, 16, 17, 18, 19 and 20 to separation of stereoisomers by supercritical fluid chromatography (SFC).
  • SFC supercritical fluid chromatography
  • Step A (3R)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-5'-one
  • Step B (3R)-5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3-ol
  • Step C ((3R)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl)(5-fluoropyridin-2-yl)methanone
  • Step A (3S)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-5'-one
  • Step B (3S)-5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3-ol
  • Step C ((3S)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl)(5-fluoropyridin-2-yl)methanone
  • Step C (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl)(6-(methoxymethyl)pyridin-2-yl)methanone
  • Example 48 (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl)(6-(methylamino)pyrazin-2-yl)methanone
  • Example 78 (5-fluoropyridin-2-yl)(3-hydroxy-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl)methanone
  • Step A 5-(Imidazolo[1,2-a]pyridin-6-yl)spiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione
  • the target product was confirmed to be generated by LCMS.
  • the reaction solution was quenched by adding 10 mL of water, and then extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried, and concentrated.
  • Step B 5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3-ol
  • reaction solution was cooled to -10°C, 3 mL of water was slowly added dropwise to quench the reaction, and 20 mL of tetrahydrofuran was added to the reaction system, filtered through diatomaceous earth, and the filter cake was washed with tetrahydrofuran (20 mL x 3). The filtrate was concentrated to obtain 158 mg of a yellow oily liquid crude product. The next step of the reaction was carried out directly.
  • Step C (5-fluoropyridin-2-yl)(3-hydroxy-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl)methanone
  • reaction solution was stirred at room temperature for 10 minutes, and then 120 mg (0.39 mmol, 1.0 eq) 5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3-ol dissolved in 4 mL tetrahydrofuran was added to the reaction solution, and stirred at room temperature for 2 hours. LCMS confirmed the formation of the target product.
  • Step B 5-(2-ethylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3-ol
  • Step C (5-(2-ethylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl)(5-fluoropyridin-2-yl)methanone
  • Example 79 or Example 80 were prepared by the method of Example 79 or Example 80 described above, substituting different boronic acids or boronic esters as required to prepare the examples by Suzuki reaction or the like.
  • Example 103 (5-fluoropyridin-2-yl)(3-hydroxy-6-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl)methanone
  • Step B Ethyl 2-(3-(3-bromophenyl)-5-oxopyrrolidin-3-yl)acetate
  • Step C 2-(3-(3-bromophenyl)-5-oxopyrrolidin-3-yl)acetic acid
  • Step E 6-(2-Isopropylphenyl)spiro[indene-1,3'-pyrrolidine]-3,5'-2H-dione
  • Step F 6-(2-Isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol
  • Step G (6-(2-isopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone
  • Example 104 (5-fluoropyridin-2-yl)(3-hydroxy-5-(2-isopropylphenoxy)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl)methanone
  • Table 5 The examples in Table 5 were prepared by the method of Example 15 described above, using the general intermediate I1 and the desired different phenols, thiophenols, aromatic amines or aromatic Grignard reagents, followed by reduction and condensation.
  • Example 135 1'-((5-chloropyridin-2-yl)sulfonyl)-5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3-ol
  • Example 147 was prepared by synthesis.
  • Example 150 5-(2-Cyclopropylphenyl)-1'-(6-fluorobenzo[c]isothiazol-3-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol
  • Example 151 1'-(5-chlorobenzo[d]thiazol-2-yl)-5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3-ol
  • Example 149 The experimental operation was carried out with reference to Example 149, and compound Example 151 was prepared by synthesis.
  • Example 152 5-(2-cyclopropylphenyl)-1'-(7-chloroimidazole[1,2-a]pyridin-3-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3-ol
  • Example 160 was prepared by synthesis.
  • Example 161 (5-fluoropyridin-2-yl)(1-hydroxy-6-(2-isopropylphenyl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)methanone
  • Step A 1-(tert-Butyl)4-ethyl-4-(4-bromobenzyl)piperidine-1,4-dicarboxylate
  • reaction solution was temperature controlled at 10-25°C and saturated ammonium chloride solution (60 mL) was added dropwise to quench, ethyl acetate (100 mL) was added, stirred for 10 minutes, allowed to stand for 5 minutes, separated, the aqueous phase was extracted twice with ethyl acetate (50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product (13.8 g), which was directly used in the next reaction without purification.
  • Step B 4-(4-bromobenzyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid
  • Step C tert-Butyl 6-bromo-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate
  • reaction solution was slowly poured into 200g of ice water in a hot state to quench (quenching temperature was 25-35°C), and then the pH value of the system was adjusted to 9-10 with sodium hydroxide aqueous solution, and 3.70g (17.0mmol, 1.5eq) of di-tert-butyl dicarbonate was added, and stirred at room temperature for 3 hours.
  • Step D tert-Butyl 6-(2-isopropylphenyl)-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate
  • Step E tert-Butyl 1-hydroxy-6-(2-isopropylphenyl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate
  • Step F 6-(2-Isopropylphenyl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-ol hydrochloride
  • Step G 6-(2-isopropylphenyl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-ol(5-fluoropyridin-2-yl)(1-hydroxy-6-(2-isopropenylphenyl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)methanone
  • reaction was confirmed to be complete by LC-MS results, and the system was diluted with 5 mL of saturated sodium bicarbonate solution, then extracted three times with 10 mL of ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure.
  • Example 164 2-(2-(1'-(5-fluoropyridyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-5-yl)phenyl)-2-methylpropionitrile
  • the aqueous phase was extracted twice with ethyl acetate (10 mL). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product.
  • Example 165 2-(3-(1'-(5-fluoropyridyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-5-yl)phenyl)-2-methylpropionitrile
  • HEK-293 cells transiently expressing TRPV3 were used for experimental detection.
  • the cells were cultured in DMEM medium containing 10% fetal bovine serum at 37°C and a carbon dioxide concentration of 5%.
  • Day 1 Seed cells into 6-well plates, 5 ⁇ 10 5 cells per well.
  • Lipofectamine 3000 transfection reagent for transfection, the ratio of plasmid to transfection reagent is 1 ⁇ g:2 ⁇ L. The total amount of plasmid per well is 3 ⁇ g.
  • the details are as follows: Take two sterile centrifuge tubes, add 100 ⁇ L Opti-MEM to each, add 6 ⁇ L Lipofectamine 3000 to one tube and mix well; add 3 ⁇ g plasmid to the other tube, mix well, and then add 6 ⁇ L P3000 and mix well; then add the diluted plasmid DNA to the diluted Lipofectamine 3000 and incubate at room temperature for 10-15min. Add the DNA-liposome complex dropwise to the cells, shake gently to mix, and place in the incubator for culture. Change the solution after 4-6 hours.
  • Day 3 Digest the cells and seed them into 24-well plates with coverslips placed in advance, with 8 ⁇ 10 3 cells per well.
  • the voltage stimulation scheme for whole-cell patch clamp recording of TRPV3 current is as follows: After the whole-cell seal is formed, the cell membrane voltage is clamped at -80mV. First, the membrane potential is recorded at 0mV, and then the voltage is commanded to start from -100mV, depolarize to 100mV in 100ms in the form of a ramp, and finally return to 0mV. Data is collected repeatedly every 5s to observe the inhibitory effect of the drug on the peak current. The experimental data are collected by an EPC 10 amplifier (HEKA) and stored in the PatchMaster (HEKA) software.
  • HEKA EPC 10 amplifier
  • HEKA PatchMaster
  • a microelectrode puller to pull a capillary glass tube into a recording electrode. Place the electrode filled with intracellular fluid into the microelectrode holder, and manipulate the microelectrode manipulator under an inverted microscope to immerse the electrode in the extracellular fluid and record the electrode resistance (Rpip). Contact the electrode to the cell surface, apply negative pressure to form a high-resistance seal (G ⁇ ). At this time, perform fast capacitance compensation, and continue to apply negative pressure to break the cell membrane and form a whole-cell recording mode. Then perform slow capacitance compensation and record experimental parameters such as membrane capacitance (Cm) and series resistance (Rs). No leakage compensation is given.
  • Cm membrane capacitance
  • Rs series resistance
  • the drug is administered. After each drug concentration acts for 5 minutes (or the current stabilizes), the next concentration is detected. Multiple concentrations are detected for each test compound.
  • the coverslip with cells is placed in a recording bath under an inverted microscope.
  • the blank control external solution and the working solution of the test compound flow through the recording bath from low concentration to high concentration in sequence by gravity perfusion to act on the cells.
  • a peristaltic pump is used for liquid exchange during recording.
  • the current detected by each cell in the external solution without the compound serves as its own control group. At least two cells are used for each concentration and the test is repeated twice independently. All electrophysiological experiments are performed at room temperature.
  • NADPH 10 ⁇ L of 20 mg/mL liver microsomes and 40 ⁇ L of 10 mM NADPH were added to the culture. The final concentrations of microsomes and NADPH were 0.5 mg/mL and 1 mM, respectively.
  • NADPH 10 ⁇ L of 20 mg/mL liver microsomes and 40 ⁇ L of ultrapure H 2 O were added to the culture. The final concentration of microsomes was 0.5 mg/mL.
  • Preheat the Transwell plate Before laying cells, add 100 ⁇ L of culture medium to the upper layer of the Transwell plate and 600 ⁇ L of culture medium to the lower layer, and pre-incubate at 37°C, 5% CO 2 for 1 hour. 2. Treat Caco-2 cells, add 100 ⁇ L of cell suspension (4 ⁇ 105 cells/mL) to each well, and culture in a 37°C, 5% CO 2 incubator for 14-21 days. 3. Replace the cell culture medium every other day for 7 days, and replace it every day after 7 days. 4. Use EVOM3 to measure the electrical resistance (TEER) of the monolayer epithelial cells.
  • TEER electrical resistance
  • HBSS (10mM HEPES, pH 7.4) buffer
  • Working solution 1mM DMSO dilute the test compound to 5 ⁇ M in HBSS buffer.
  • AB direction add 200 ⁇ L 5 ⁇ M working solution to the upper layer and 600 ⁇ L HBSS buffer to the lower layer; 4.
  • BA direction add 600 ⁇ L 5 ⁇ M working solution to the lower layer and 200 ⁇ L HBSS buffer to the upper layer, incubate for 2 hours 5.
  • C0 sample take 100 ⁇ L of working solution to the sample plate containing 400 ⁇ L methanol (internal standard). 6.
  • 0.3 mL of whole blood was collected through the fundus venous plexus after isoflurane anesthesia using a small animal anesthesia machine, placed in a heparin anticoagulation tube, and the sample was centrifuged at 4°C and 4000rpm for 5 minutes.
  • the plasma was transferred to a centrifuge tube and stored at -80°C until analysis.
  • the sample in the plasma was extracted using protein precipitation, and the extract was analyzed by LC-MS/MS.
  • Table 15 Pharmacokinetic parameters of different compounds after oral administration to rats at 10 mg/kg
  • Compound Example 21 and KM-001-E1 were accurately weighed and placed in vials, respectively, and placed at room temperature and 92.5% humidity (open) for 5-10 days to examine the stability of the compounds.
  • Mobile phase A 0.05% formic acid in water
  • Mobile phase B 0.05% formic acid in acetonitrile
  • Gradient 30% B 0-1.2 minutes, 95% B 1.2-3.3 minutes, 30% B 3.3-4.5 minutes
  • the main impurity produced in Example 21 is ketone, while the main impurities produced by KM-001-E1 are aldehydes and carboxylic acids.
  • the specific structure is as follows:
  • the above-mentioned compound 21 in this case has a secondary alcohol structure and has better chemical stability than the primary alcohol compound in WO2021154966A1: as alcohols, the former can only be oxidized to ketones; the latter can be oxidized to aldehydes and further oxidized to carboxylic acids, and the number and level of oxidized impurities are greater than those of the above-mentioned compound 21 in this case.
  • the stability of the compounds in the embodiments of the present application with the same secondary alcohol structure is better than that of the compounds in WO2021154966A1.

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Abstract

本申请涉及一种含氮螺环类化合物、药物组合物以及其用途，该含氮螺环类化合物具有式(I)的结构式，本发明化合物具有抑制TRPV3活性，可以作为TRPV3拮抗剂或者抑制剂。

Description

一种含氮螺环类化合物、药物组合物以及其用途 技术领域
本发明涉及医药领域，具体涉及一种含氮螺环类化合物、包含所述化合物的立体异构体、氘代物、药物组合物以及所述化合物、药物组合物的用途。
背景技术
瞬时感受器电位(transient receptor potential，TRP)是存在于细胞膜或胞内细胞器膜上的一类离子通道蛋白，由TRPC、TRPV、TRPM、TRPML、TRPP、TRPA、TRPN等7个亚家族组成。而哺乳动物的瞬时感受器电位香草素受体亚家族(transient receptor potential vanilloid，TRPV)又由TRPV1-6构成。近年研究发现，TRPV3主要在人体皮肤角质细胞表达，在介导皮肤感觉、影响表皮角质细胞增殖分化、毛发生长、参与炎症反应及维持皮肤内稳态和正常功能过程中发挥重要作用。该离子通道可被许多因素调节，如温度、渗透压、pH值、机械力以及细胞内信号分子。研究表明，TRPV3是一种罕见皮肤病Olmsted综合征的致病基因(Am.J.Hum.Genet.2012,90,558)，TRPV3抑制剂在角化性皮肤病、瘙痒性皮肤病、炎症、毛发生长异常和疼痛性皮肤病中有潜在的治疗前景。TRPV3除主要表达于皮肤角质细胞，还表达于舌、背根神经节、三叉神经节、脊髓和大脑等组织，主要感受温热刺激(32～39℃)。TRPV3的热敏感性，还受细胞外液中钙的调节，受到重复热刺激时，通道电流不断加大。皮肤下游离神经末梢有可能是通过与热感受神经元中存在的类似信号分子，来感受和传导热刺激。因此，TRPV3疼痛性疾病中有潜在的治疗前景。
TRPV3可以被单萜类化合物(如樟脑、冰片、薄荷等)激活，研究发现是通过提高细胞内二价钙离子(Ca2+)水平来发挥作用的。这些芳香族化合物有抗炎、镇痛、止痒等作用，已被广泛应用于医药、化妆品等领域。然而，这些早期的TRPV3抑制剂或者大多是天然产物，特异性差，有效剂量大，可能导致严重的副作用，或者分子骨架活性一般，研发大多停滞。现有的TRPV3抑制剂存在结构种类少，发展较为缓慢的问题，开发新颖骨架的具备临床使用价值的分子非常必要。
发明内容
本申请提供一种式(I)的含氮螺环化合物
或其立体异构体、互变异构体、溶剂化合物、水合物、氧化物、活性代谢物、同位素标记物、药学上可接受的盐，
其中，环A选自含有3-12个环原子的单环或多环环系；
R1各自独立地选自H、卤素、羟基、巯基、硝基、氰基、氧代、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的C1-C6卤代烷基、取代有0-2个Rf的C1-C6烷氧基、取代有0-2个Rf的C1-C6卤代烷氧基、取代有0-2个Rf的C3-C6环烷基、取代有0-2个Rf的C3-C6卤代环烷基、取代有0-2个Rf的C3-C6环烷氧基、取代有0-2个Rf的C3-C6卤代环烷氧基、取代有0-2个Rf的芳基、取代有0-2个Rf的芳烷基、取代有0-2个Rf的烷芳基、取代有0-2个Rf的杂芳基、-R11OR12、-R11SR12、-N(Ra)(Rb)、-C(O)Rc、-C(O)N(Ra)(Rb)和-SO2N(Ra)(Rb)或-SORc，或者两个R1与它们所连接的环A原子一起形成3-10元环结构；
R2各自独立地选自H、卤素、羟基、巯基、硝基、氰基、氧代、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的C1-C6卤代烷基、取代有0-2个Rf的C1-C6烷氧基、取代有0-2个Rf的C1-C6卤代烷氧基、取代有0-2个Rf的C3-C6环烷基、取代有0-2个Rf的C3-C6卤代环烷基、取代有0-2个Rf的C3-C6环烷氧基、取代有0-2个Rf的C3-C6卤代环烷氧基、取代有0-2个Rf的芳基、取代有0-2个Rf的芳烷基、取代有0-2个Rf的烷芳基、取代有0-2个Rf的杂芳基、-R11OR12、-R11SR12、-N(Ra)(Rb)、-C(O)Rc、-C(O)ORd、-C(O)N(Ra)(Rb)和-SO2N(Ra)(Rb)或-SORc，或者两个R2与它们所连接的环原子一起形成3-10元环结构；
L1选自键，或者如下结构式：
X1在每次出现时各自独立地选自C、O或N；
X2在每次出现时各自独立地选自C、O、B或N；
XA、XB、XC各自独立地为CRx或N；
Rx各自独立地选自H、卤素、羟基、巯基、硝基、氰基、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的C1-C6卤代烷基、取代有0-2个Rf的C1-C6烷氧基、取代有0-2个Rf的C1-C6卤代烷氧基、取代有0-2个Rf的C3-C6环烷基、取代有0-2个Rf的C3-C6卤代环烷基、取代有0-2个Rf的C3-C6环烷氧基、取代有0-2个Rf的C3-C6卤代环烷氧基、取代有0-2个Rf的芳基、取代有0-2个Rf的芳烷基、取代有0-2个Rf的烷芳基、取代有0-2个Rf的杂芳基、-R11OR12、-R11SR12、-N(Ra)(Rb)、-C(O)Rc、-C(O)ORd、-C(O)N(Ra)(Rb)和-SO2N(Ra)(Rb)或-SORc；或者两个Rx与它们所连接的环原子一起形成3-10元环结构；
R0各自独立地选自H、卤素或者式II的结构式
其中，L2各自独立地选自键、-O-、-S-、-N(R20)-、-C(O)-、-C(R20R21)-、-S(O)-和-S(O2)-；
环C各自独立地选自含有3-12个环原子的单环或多环环系；
R3各自独立地选自H、卤素、羟基、巯基、硝基、氰基、氧代、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的C1-C6卤代烷基、取代有0-2个Rf的C1-C6烷氧基、取代有0-2个Rf的C1-C6卤代烷氧基、取代有0-2个Rf的C3-C6环烷基、取代有0-2个Rf的C3-C6卤代环烷基、取代有0-2个Rf的C3-C6环烷氧基、取代有0-2个Rf的C3-C6卤代环烷氧基、取代有0-2个Rf的芳基、取代有0-2个Rf的芳烷基、取代有0-2个Rf的烷芳基、取代有0-2个Rf的杂芳基、-R11OR12、-R11SR12、-N(Ra)(Rb)、-C(O)Rc、-C(O)ORd、-C(O)N(Ra)(Rb)和-SO2N(Ra)(Rb)或-SORc，或者两个R3与它们所连接的环C原子一起形成3-10元环结构；
R11各自独立地选自取代有0-2个Rf的C1-C6亚烷基；
R12各自独立地选自H、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的C1-C6卤代烷基、取代有0-2个Rf的C3-C6环烷基和取代有0-2个Rf的C3-C6卤代环烷基；
Ra和Rb各自独立地选自H、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的芳基、取代有0-2个Rf的芳烷基、-C(O)Rc和-C(O)ORd；
Rc各自独立地选自H、卤素、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的芳基和取代有0-2个Rf的芳烷基；
Rd各自独立地选自H、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的芳基和取代有0-2个Rf的芳烷基；
R20和R21各自独立地选自H、羟基、C1-C6烷基、芳基和芳烷基；
Rf各自独立地选自卤素、羟基、氨基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、C3-C6环烷基和C3-C6卤代环烷基；
n为0、1、2或3；
p为0、1、2或3；
q为0、1、2或3；
m为1或2；
r为1或2。
本申请还涉及一种药物组合物，其包含本申请的化合物或其立体异构体、互变异构体、溶剂化合物、水合物、活性代谢物、同位素标记物或药学上可接受的盐，以及药学可接受的载体。
本申请还涉及本申请化合物或其立体异构体、互变异构体、溶剂化合物、水合物、活性代谢物、同位素标记物或药学上可接受的盐，以及本申请药物组合物在制备用于抑制TRPV3活性的药物中的用途。
本申请还涉及本申请化合物或其立体异构体、互变异构体、溶剂化合物、水合物、活性代谢物、同位素标记物或药学上可接受的盐，以及本申请药物组合物在制备用于治疗受治疗者的TRPV3介导的病症的药物中的用途。
本发明进一步提供了上述的TRPV3抑制剂在制备用于抑制TRPV3离子通道的试剂中的应用。优选地，所述TRPV3抑制剂在制备用于抑制因TRPV3过度表达引起的皮肤瘙痒、疼痛、脱发或炎症的药物中的应用。
本申请涉及一种治疗TRPV3介导的病症的方法，包括将治疗有效量的本申请化合物或其立体异构体、互变异构体、溶剂化合物、水合物、活性代 谢物、同位素标记物或药学上可接受的盐，或本申请药物组合物，给药于需要给药的患者。
本发明化合物具有抑制TRPV3活性，可以作为TRPV3拮抗剂或者抑制剂，对于TRPV3离子通道的性质及特性研究有巨大的推动作用。同时，也可以制备用于治疗与TRPV3离子通道活性增强相关的疾病的药物。因此，本发明提供的TRPV3拮抗剂或抑制剂对科研和临床研究均有巨大的价值。
具体实施方式
下面通过实施例对本申请进一步详细说明。通过这些说明，本申请的特点和优点将变得更为清楚明确。
在这里专用的词“示例性”意为“用作例子、实施例或说明性”。这里作为“示例性”所说明的任何实施例不必解释为优于或好于其它实施例。
此外，下面所描述的本申请不同实施方案中涉及的技术特征只要彼此之间未构成冲突就可以相互结合。
定义
术语“拮抗剂”和“抑制剂”互换使用，是指减少或抑制生物活性，例如抑制离子通道例如TRPV3的活性的药物。
就本发明而言，例如TRPV3拮抗剂的“有效量”是指所述拮抗剂在制剂中的量，当作为所需配药方案的部分施用时，所述量带来所需的临床或功能结果。不受理论束缚，用于本发明有效量的TRPV3拮抗剂包括有效降低TRPV3通道的一种或多种体外或体内功能的量的TRPV3拮抗剂。示例性功能包括，但不限于胞内钙水平，膜极化(例如，拮抗剂可促进细胞超极化)，第I阶段外向电流，第II阶段外向电流，第I阶段内向电流，和第II阶段内向电流。拮抗TRPV3功能的化合物包括拮抗TRPV3体外或体内功能活性的化合物。当具体功能活性只在体外分析中可容易地观察时，化合物抑制TRPV3功能的能力是体外分析用作该化合物活性的合理替代者。术语“预防”是本领域公认的，并当用于病症，例如局部复发(例如，疼痛)，疾病，例如癌症，综合征，例如心衰或其它医学病症时，是本领域公知的，并包括组合物的给药，该给药相对于不接受该组合物的对象，减少了在对象中医学 病症症状的频率，或延迟医学病症症状的发作。因此，预防癌症包括例如，以统计学和/或临床上显著量，相对未治疗的对照群体，在接受预防治疗的患者群体中减少可检测癌症生长的数目，和/或相对未治疗对照群体，在治疗群体中延迟可检测癌症生长的出现。预防感染包括，例如，相对未治疗对照群体，在治疗群体中减少感染诊断的数目，和/或相对未治疗对照群体，在治疗群体中延迟感染症状的发作。预防疼痛包括，例如，相对未治疗对照群体，在治疗群体中减少对象经历的痛感的幅度或延迟对象经历的痛感。
本发明提供前药形式的化合物。术语“前药”旨在涵盖在生理条件下转化成本发明治疗活性剂的化合物。制备前药的常用方法包括在生理条件下水解后展现所需分子的选择部分。在其它实施方案中，前药由宿主动物的酶活性转化。另外，通过化学或生化法在离体环境下将前药转化成本发明化合物。例如，当置于带有合适酶或化学试剂的透皮贴剂储库中时，前药可被缓慢转化成本发明化合物。
术语“氧化代谢物”旨在涵盖通过母体化合物在正常生理条件下被代谢而得到的化合物。具体地，通过母体化合物在代谢期间被氧化形成氧化代谢物。例如，硫醚基团被氧化可得到相应的亚砜或砜。
本文使用的术语“溶剂合物”是指通过溶剂合作用形成的化合物(例如，通过将溶剂分子与溶质分子或离子组合形成的化合物)。
本文使用的术语“水合物”是指通过水与母体化合物的结合形成的化合物。
术语“处理”包括预防性和/治疗性处理。术语“预防性或治疗性”处理是本领域公认的，并包括向宿主给药一种或多种本发明组合物。如果在不希望的病症(例如，宿主动物疾病或其它不希望的状态)的临床表现之前给药，则所述处理是预防性的，(即，其防止宿主发展所述不希望的病症)，而如果在不希望的病症表现之后给药，则所述处理就是治疗性的，(即旨在减少，缓解或稳定存在的不希望的病症或其副作用)。
术语“TRPV3”，“TRPV3蛋白”和“TRPV3通道”在本申请全文交互使用。这些术语是指含有氨基酸序列，例如人TRPV3蛋白的氨基酸序列的离子通道(例如，多肽)，或其等价多肽或功能性生物活性片段。在某些实施方案中，该术语是指包含例如本文引用的任何专利申请中所述的TRPV3氨基酸序列，或由其组成，或基本由其组成。TRPV3蛋白还可包括直向同源 物(orthologs)，例如小鼠，大鼠，马，或果蝇的TRPV3。
TRPV3包括维持TRPV3功能的多肽，并包括(i)全部或部分TRPV3氨基酸序列；(ii)具有1至约2，3，5，7，10，15，20，30，50，75，或更多个保守性氨基酸替换的TRPV3氨基酸序列；(iii)与TRPV3氨基酸序列的同一性至少70％，75％，80％，85％，90％，95％，96％，97％，98％，或99％的氨基酸序列；和(iv)其功能性片段。本发明的多肽还包括人TRPV3多肽的同系物，例如，直向同源物和种内同源基因。TRPV3多肽和氨基酸序列例如包括在本文引用的任何专利申请中所述的序列。
术语“TRPV3”还指编码本发明多肽的核酸，例如包含由TRPV3多核苷酸序列组成的，或基本由其组成的序列的核酸。本发明核酸可包含下列全部或部分核苷酸序列：(i)TRPV3核苷酸序列；(ii)与TRPV3核苷酸序列的同一性至少70％，75％，80％，85％，90％，95％，96％，97％，98％或99％的核苷酸序列；(iii)在严格条件下与TRPV3核苷酸序列杂交的核苷酸序列；(iv)编码与本发明多肽在功能上等同的多肽的核苷酸序列；(v)编码与TRPV3多肽序列的同源性或同一性为至少约70％，75％，80％，85％，90％，95％，98％，99％的多肽的核苷酸序列；(vi)编码具有本发明多肽活性并与TRPV3多肽序列具有至少约70％，75％，80％，85％，90％，95％，98％，99％或更高同源性或同一性的多肽的核苷酸序列；(vii)与TRPV3核苷酸序列有1至约2，3，5，7，10，15，20，30，50，75或更多核苷酸替换，添加或缺失差异的核苷酸序列，例如等位基因变体；(viii)源自TRPV3核苷酸序列并在进化上与其相关的核酸；以及(ix)所有前述核酸和本发明其它核酸的互补序列，和由遗传密码子的简并性引起的核苷酸序列。本发明核酸还包括TRPV3核酸序列的同系物，例如，直向同源物和种内同源基因，并包括为在特定生物体(例如，宿主细胞)中表达而对密码子进行优化后的变体。TRPV3核酸序列包括例如，本文引用的任何专利申请中所述的序列。如果不专门说明，本领域技术人员可容易地评价TRPV3是指核酸还是指蛋白。
在本文中，术语“脂肪族基”是指直链，直链，或环状脂肪族烃基，并包括饱和和不饱和脂肪族基，例如烷基，烯基和炔基。
术语“烯基”和“炔基”是指与上述烷基在长度上类似并可能取代的不饱和脂肪族基，但分别含有至少一个双键或三键。
本文所用的术语“烷氧基”是指如下定义的烷基，其上连接有氧基。代表 性烷氧基包括甲氧基，乙氧基，丙氧基，叔丁氧基等。“醚”是通过氧共价连接的两个烃。因此，使烷基成为醚的烷基的取代基，是烷氧基或类似烷氧基，例如可由下列基团之一代表：-O-烷基，-O-烯基，-O-炔基，-O-(CH2)t-R8，其中R8选自氢，卤素，低级烷基，低级烷氧基，氨基，或-NHSO2NH2，t为0至6的整数。
术语“烷基”是指饱和脂肪族基的基团，包括直链烷基以及支链烷基。在优选的实施方案中，直链或支链烷基在其骨架中具有30个或更少的碳原子(例如，直链C1-C30，支链C3-C30)，以及更优选20个或更少，和最优选10个或更少。
术语“环烷基”包括具有3～12个碳，优选3～8个碳，更优选3～6个碳的饱和的及局部不饱和的环状烃基，其中该环烷基额外地任选被取代。优选的环烷基在其环结构中具有3-12个，和更优选5，6，7或8个碳原子。优选的环烷基包括但不限于环丙基，环丁基，环戊基，环戊烯基，环己基，环己烯基，环庚基，及环辛基。术语“环烷基”还包括桥连环基团，包括但不限于二环[2.2.2]辛烷基，二环[1.1.1]戊烷基，二环[3.2.1]辛烷基，二环[2.1.1]己烷基。
此外，如整个说明书，实施例，和权利要求书中所用的，术语“烷基”(或“低级烷基”)旨在包括“未取代的烷基”和“取代的烷基”二者，其中后者是指在烃骨架的一个或多个碳上以取代基代替氢的烷基部分。这些取代基可以包括，例如，卤素，羟基，羰基(例如羧基，烷氧基羰基，甲酰基，或酰基)，硫代羰基(例如硫代酯，硫代乙酸酯，或硫代甲酸酯)，烷氧基，磷酰基，磷酸酯，膦酸酯，亚膦酸酯，氨基，酰胺基，脒，亚胺，氰基，硝基，叠氮基，巯基，烷硫基，硫酸酯，磺酸酯，氨磺酰基，亚磺酰氨基，磺酰基，杂环基，芳烷基，或芳香族或杂芳香族部分。本领域技术人员会理解，如果合适，烃链上取代的部分本身可被取代。例如，取代烷基的取代基可包括取代和未取代形式的氨基，叠氮基，亚氨基，酰胺基，磷酰基(包括膦酸酯和亚膦酸酯)，磺酰基(包括硫酸酯，亚磺酰氨基，氨磺酰基和磺酸酯)，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。示例性的取代烷基如下描述。环烷基可进一步被烷基，烯基，烷氧基，烷硫基，氨基烷基，羰基取代的烷基，-CF3，-CN等取代。
可对烯基和炔基进行类似的取代，以得到例如，氨基烯基，氨基炔基， 酰胺基烯基，酰胺基炔基，亚氨基烯基，亚氨基炔基，硫代烯基，硫代炔基，羰基-取代的烯基或炔基。
除非碳数另外明确说明，本文中所用的“低级烷基”表示如上定义的烷基，但在其骨架结构中具有1-10个碳原子，更优选1-6个碳原子。同样，“低级烯基”和“低级炔基”具有相似链长。在整个本申请中，优选的烷基是低级烷基。在优选的实施方案中，在本文中称为烷基的取代基是低级烷基。
术语“烷硫基”是指如上定义的烷基，其上连接硫基团。在优选的实施方案中，“烷硫基”部分由-S-烷基，-S-烯基，-S-炔基，和-S-(CH2)t-R8之一代表，其中t和R8如上定义。代表性烷硫基包括甲硫基，乙硫基等。
本文中所用的术语“芳烷基”，是指被芳基(例如，芳香族或杂芳香族基团)取代的烷基。
本文所用的术语“芳基”包括含0-4个杂原子的5-，6-，和7-元单环芳香族基团，例如，苯，吡咯，呋喃，噻吩，咪唑，噁唑，噻唑，三唑，吡唑，吡啶，吡嗪，哒嗪和嘧啶等。在环结构中有杂原子的那些芳基也可称作“芳基杂环”或“杂芳香族化合物”。芳香族环在一个或多个环位置处可被如上所述的那些取代基取代，所述取代基例如，卤素，叠氮，烷基，芳烷基，烯基，炔基，环烷基，羟基，烷氧基，氨基，硝基，巯基，亚氨基，酰胺基，磷酸酯，膦酸酯，亚膦酸酯，羰基，羧基，甲硅烷基，醚，烷硫基，磺酰基，亚磺酰氨基，酮，醛，酯，杂环基，芳香族或杂芳香族部分，-CF3，-CN等。术语“芳基”还包括具有两个或更多个环的多环系统，其中两个或多个碳对两个相邻环是共有的(该环为“稠合环”)，其中所述环中的至少一个是芳香族的，例如其它环可以是环烷基，环烯基，环炔基，芳基和/或杂环基。
本文所用的术语“碳环”是指芳香族或非芳香族环，其中环中每个原子是碳。
术语“吸电子基”是指从结合有吸电子基的原子或原子团吸引电子密度的化学基。吸引电子密度包括通过感应效应或通过离域/共振效应的吸引。与芳香环连接的吸电子基的例子包括全氟烷基如三氟甲基，卤素，叠氮化物，含羰基基团如酰基，氰基，和含亚胺基团。
本文中所用的术语“杂原子”指除碳或氢之外的任何元素的原子。优选的杂原子是硼，氮，氧，磷，硫和硒。
术语“杂环基”或“杂环基团”是指3至10元环结构，更优选3至7元环， 其环结构包括1-4个杂原子。杂环也可以是多环。杂环基包括例如，噻吩，噻蒽，呋喃，吡喃，异苯并呋喃，色烯，呫吨，吩噻噁(phenoxathiin)，吡咯，咪唑，吡唑，异噻唑，异噁唑，吡啶，吡嗪，嘧啶，哒嗪，中氮茚，异吲哚，吲哚，吲唑，嘌呤，喹嗪，异喹啉，喹啉，2,3-二氮杂萘，1,5-二氮杂萘，喹喔啉，喹唑啉，噌啉，蝶啶，咔唑，咔啉，菲啶，吖啶，嘧啶，菲咯啉，吩嗪，吩吡嗪，吩噻嗪，呋咱(furazan)，吩噁嗪，吡咯烷，四氢呋喃(oxolane)，四氢噻吩(thiolane)，噁唑，哌啶，哌嗪，吗啉，内酯，内酰胺，例如氮杂环丁酮(azetidinones)和吡咯烷酮，磺内酰胺，磺内酯等。所述杂环可在一个或多个位置被如上所述的取代基取代，所述取代基例如，卤素，烷基，芳烷基，烯基，炔基，环烷基，羟基，氨基，硝基，巯基，亚氨基，酰胺基，磷酸酯，膦酸酯，亚膦酸酯，羰基，羧基，甲硅烷基，醚，烷硫基，磺酰基，酮，醛，酯，杂环基，芳香族或杂芳香族部分，-CF3，-CN等。
本文中所用的术语“硝基”表示-NO2；术语“卤素”指-F，-Cl，-Br或-I；术语“巯基”表示-SH；术语“羟基”表示-OH；以及术语“磺酰基”表示-SO2-。
术语“多环基”、“多环基团”或者“多环环系”是指两个或多个环(例如，环烷基，环烯基，环炔基，芳基和/或杂环基)，其中两个相邻环共有一个、两个或多个环原子，例如，所述环是“稠合环”或者“螺环”。通过非相邻原子连接的环称为“桥连”环，例如C5-C12桥连碳环，包括但不限于二环[2.2.2]辛烷基，二环[1.1.1]戊烷基，二环[3.2.1]辛烷基，二环[2.1.1]己烷基。所述多环中的每个环可以被上述取代基取代，所述取代基例如，卤素，烷基，芳烷基，烯基，炔基，环烷基，羟基，氨基，硝基，巯基，亚氨基，酰胺基，磷酸酯，膦酸酯，亚膦酸酯，羰基，羧基，甲硅烷基，醚，烷硫基，磺酰基，酮，醛，酯，杂环基，芳香族或杂芳香族部分，-CF3，-CN等。
本文中所用的术语“保护基”表示暂时的取代基，其保护潜在反应性官能团免于不需要的化学转化。这种保护基的例子包括羧酸的酯，醇的甲硅烷基醚，以及醛和酮各自的缩醛和缩酮。保护基团化学领域已有综述(Greene，T.W.；Wuts，P.G.M.Protective Groups in Organic Synthesis，第二版；Wiley：New York，1991)。
本文所用的术语“取代的”预期包括有机化合物所有可允许的取代基。广义来说，可允许的取代基包括有机化合物的无环和有环，支链和非支链，碳环和杂环，芳香族和非芳香族取代基(例如，烷基，烯基，炔基，环烷基， 杂环基，芳基，杂芳基，环烷基烷基，杂环基烷基，芳烷基，或杂芳烷基，其中任何取代基自身可被进一步取代)，以及卤素，羰基(例如，酯，羧基，或甲酰基)，硫代羰基(例如，硫代酯，硫代羧酸酯，或硫代甲酸酯)，酮，醛，氨基，酰氨基，酰胺基，脒基，氰基，硝基，叠氮基，磺酰基，亚砜基，硫酸酯，磺酸酯，氨磺酰基，亚磺酰氨基，和磷酰基。举例说明的取代基包括例如上文所述的那些取代基。可允许的取代基对合适的有机化合物可以是一个或多个，并且相同或不同。为本发明的目的，例如氮的杂原子可以具有氢取代基和/或本文中所述的任何可允许的有机化合物取代基，该取代基满足所述杂原子的化合价。本发明并非意于以任何方式限制于所述可允许的有机化合物取代基。
将理解的是，“取代”或“取代以”包括隐含的条件，即这种取代是基于取代的原子和取代基所允许的化合价，以及该取代导致稳定的化合物，例如，其不自发地进行例如重排，环化，消除等转化。“取代有0-2个Rf”表示相应基团上带有0个、1个或者2个Rf。
本文中所用的对每个表述的定义，当其在任意结构中出现一次以上时，旨在表示独立的定义，除非在同一结构中。
缩写Me，Et，Ph，Tf，Nf，Ts，Ms分别代表甲基，乙基，苯基，三氟甲磺酰基，九氟丁磺酰基，对甲苯磺酰基和甲磺酰基。被有机化学领域普通技术人员利用的更全面缩写列表出现在Journal of Organic Chemistry(有机化学杂志)各卷第一期中；该列表通过以表格的形式呈现，表格名称为Standard List of Abbreviations(标准缩写列表)。在所述列表中所含缩写以及被有机化学领域普通技术人员利用的全部缩写在此引作参考。
本发明的某些化合物可以特定的几何或立体异构形式存在。本发明预期所有这些化合物，包括顺式-和反式-异构体，R-和S-对映体，非对映异构体，(D)-异构体，(L)-异构体，其外消旋混合物，及其另外的混合物，也落入本发明范围内。另外的不对称碳原子可出现于取代基，例如烷基中。所有这些异构体，以及其混合物，意于包含在本发明中。
制备基本上异构纯的化合物的方法在本领域是公知的。例如，如果想得到本发明化合物的特定对映体，则其制备方法可采用不对成合成，或用手性助剂衍生化，其中分离所得非对映混合物，并切除辅助基团，从而提供纯的想得到的对映体。替代地，如果分子含有碱性官能团例如氨基，或酸性官能 团例如羧基，则可与合适的光学活性酸或碱形成非对映盐，，接着通过本领域公知的分级结晶或色谱方法拆分由此形成的非对映体，以及随后回收该纯净的对映体。替代地，富含对映体的混合物和纯的对映体化合物可通过采用对映体纯的合成中间体与如下反应组合而制备，所述反应使手性中心的立体化学保持不变，或导致其完全反转。反转特定的立体中心或使其不变的技术，以及拆分立体异构体混合物的那些技术在本领域是公知的，，并充分落入本领域普通技术人员针对特殊情形筛选恰当方法的能力范围内。一般而言，可参见Furniss等(编)，Vogel’s Encyclopedia of Practical Organic Chemistry第5版，Longman Scientific and Technical Ltd.，Essex，1991，第809-816页；以及Heller，Ace.Chem.Res.23：128(1990)。
上述化合物预期的等同物包括另外与其对应，并与其具有相同的一般性质(例如，抑制TRPV3活性的能力)的化合物，其中使得取代基的一个或多个简单变体不负面影响该化合物的功效。总的来说，本发明化合物通过例如下述通用反应方案中所说明的方法，或其修改方法，利用容易获得的起始材料，试剂和常规合成程序而制备。在这些反应中，也可能利用本身已知、但未在此提及的变体。
为了本发明的目的，化学元素的定义基于元素周期表。同样为了本发明的目的，术语“烃”预期包括具有至少一个氢和一个碳原子的所有允许的化合物。广义上来说，可允许的烃包括可被取代或未取代的无环烃和有环烃，支链烃和非支链烃，碳环烃和杂环烃，芳香族烃和非芳香族烃有机化合物。
本发明化合物还可在构成该化合物的一个或多个原子处含有非天然比例的同位素原子。例如，该化合物可用放射性同位素，例如氘(2H)，氚(3H)，碘-125(125I)或碳-14(14C)进行同位素标记。本发明化合物的所有同位素变体，不管是放射性的还是非放射性的，皆意于包含在本发明范围内。在本申请中，当不与氕(1H)、氘(2H)和氚(3H)同时出现时，“氢”或者“H”可以包括氢元素的所有同位素，氕(1H)、氘(2H)和氚(3H)。
符号不管是用作键还是显示垂直于键，表示如下点，在该点处显示的部分与分子的其余部分，固相支持物等连接。
本发明的某些化合物可以未溶剂化形式以及溶剂化形式，包括水合物形式存在。总的来说，所述溶剂化形式是未溶剂化形式的等同物，并包含在本发明范围内。本发明某些化合物可以多晶体或无定形形式存在。总的来说， 所有物理形式对本发明预期的应用是等同的，并意于落入本发明范围之内。
取代基由其常规化学式规定，从左向右书写，它们同等地包含化学上相同的取代基，这些取代基从右到左书写结构，例如，-CH2O-意于还代表-OCH2-；-NHS(O)2-还意于代表-S(O)2HN-等。
术语“可药用盐”包括与相对非毒性的酸或碱制备的活性化合物的盐，这依赖于本文所述化合物上发现的具体取代基而定。当本发明化合物含有相对酸性官能团时，通过将中性形式的这种化合物与足量的期望碱，纯粹接触或在合适的惰性溶剂中接触，可获得碱加成盐。可药用碱加成盐的例子包括钠，钾，钙，铵，有机氨基，或镁盐，或类似盐。当本发明化合物含有相对碱性官能团时，通过将中性形式的这种化合物与足量的期望酸，纯粹接触或在合适的惰性溶剂中接触，可获得酸加成盐。可药用酸加成盐的例子包括那些衍生自无机酸的盐，所述无机酸如盐酸，氢溴酸，硝酸，碳酸，一氢碳酸，磷酸，一氢磷酸，二氢磷酸，硫酸，一氢硫酸，氢碘酸，或磷酸等，以及衍生自相对非毒性有机酸的盐，所述有机酸如乙酸，三氟乙酸，丙酸，异丁酸，马来酸，丙二酸，苯甲酸，琥珀酸，辛二酸，富马酸，乳酸，扁桃酸，邻苯二甲酸，苯磺酸，对甲苯磺酸，柠檬酸，酒石酸，甲磺酸等。同样包括氨基酸的盐，例如精氨酸盐等，以及有机酸，例如葡糖醛酸或半乳糖醛酸等的盐(参见，例如，Berge等，“Pharmaceutical Salts(药用盐)”，Journal of Pharmaceutical Science，1977，66，1-19)。本发明某些特定化合物含有碱性官能团和酸性官能团二者，使得该化合物可转化成碱或酸加成盐。
中性形式的化合物优选通过将盐与碱或酸接触，并以常规方式分离母体化合物而再生。母体形式的化合物在某些物理性质，例如在极性溶剂中的溶解度，区别于多种盐形式，但就本发明的目的而言，所述盐等同于所述化合物的母体形式。
对药物制剂而言，术语“足够低的热原活性”是指制剂中热原的含量不会导致在已经给药所述制剂的对象中的副作用(例如，刺激，发烧，炎症，腹泻，呼吸窘迫，内毒性休克等)。例如，该术语包括如下制剂，该制剂不含或基本不含内毒素，例如脂多糖(LPS)。
与TRPV3功能相关的疾病，病患或病症
在用于预防或治疗疾病或病患或病症的方法的实施方案中，被给药的药物是一种调节TRPV3蛋白水平和/或活性的药物。在某些实施方案中，该化 合物抑制TRPV3蛋白的表达和/或活性。在另一些实施方案中，该化合物选择性抑制TRPV3蛋白的表达。换言之，在某些实施方案中，与一种或多种其它离子通道相比，该化合物优先抑制TRPV3蛋白的活性。
在本文提供的用于预防或治疗疾病和病患的方法的具体实施方案中，所述疾病或病患可以是例如，接触疼痛或敏感性，例如与疾病或病患有关的疼痛，例如，癌性疼痛，皮肤病或病患，例如，牛皮癣和基细胞癌和扁平细胞癌，神经变性疾病或病患，例如，阿尔茨海默氏病(AD)，帕金森病，亨廷顿舞蹈病(Huntington’s disease)，肌萎缩侧索硬化(ALS)，和其它由创伤或其它损害引起的脑病，所述损害包括衰老，炎性疾病(例如，哮喘，慢性梗阻性肺病，类风湿性关节炎，骨关节炎，炎性肠病，血管球性肾炎，神经炎性疾病，多发性硬化，和免疫系统病患)，癌症或其它增殖性疾病，肾病和肝病，代谢性病患，例如糖尿病。其它疾病和病症包括手术后疼痛，疱疹后神经痛，纤维肌痛，和带状疱疹。
由于钙调节在许多细胞过程中所起的重要作用，所述细胞过程包括细胞活化，基因表达，细胞转运和凋亡细胞死亡，所以钙稳态失衡牵涉包括这种细胞活性的许多疾病和病患。这些疾病和病患包括皮肤病和病患；神经和神经变性疾病和病患；与多种疾病，病患或病症相关的发烧；失禁；炎性疾病和病患，例如炎性肠病和克隆病；呼吸疾病和病患，例如慢性咳嗽，哮喘和慢性梗阻性肺病(COPD)；消化疾病，例如溃疡和酸返流；代谢性疾病和病患，包括肥胖和糖尿病；肝和肾病和病患；恶性疾病，包括癌症；年龄相关性疾病；以及对疼痛和接触的敏感性。
可进行治疗的另外的疾病或病症包括ATP相关疾病或病患，包括癫痫症，认知，呕吐，疼痛(如偏头痛)，哮喘，周围血管病，高血压，免疫和炎性病症，肠易激综合征，膀胱炎，抑郁症，年龄相关性退行性疾病，尿失禁，早泄，囊性纤维化，糖尿病，节育和不孕，和伤口愈合(例如参见，Foresta等(1992)J.Biol.Chem.257：19443-19447；Wang等(1990)Biochim.Biophys.Res.Commun.166：251-258；Burnstock和Williams，(2000)J.Pharmacol.Exp.Ther.295：862-869；和Burnstock，Pharmacol Rev(2006)58：58-86)。
本文所述的TRPV3抑制剂可用于治疗上述和后述的任何疾病或病症，包括治疗与上述或后述的任何疾病或病症有关的疼痛。当用在治疗方法中时， 可基于预定的给药途径选择和配制抑制剂。
本文中提供的化合物和组合物可用于预防或治疗疼痛或对疼痛和接触的敏感性。疼痛或对疼痛和接触的敏感性可在多种不同的疾病，病患或病症中显现，所述疾病，病患或病症包括但不限于，糖尿病性神经病，胸疼，牛皮癣，湿疹，皮炎，烧伤，疱疹后神经痛(带状疱疹)，伤害性疼痛，外周神经和中枢神经疼痛，慢性疼痛，癌性和肿瘤疼痛，脊髓损伤，粉碎性损伤和创伤诱导的疼痛，偏头痛，脑血管疼痛和血管疼痛，镰刀细胞病疼痛，类风湿性关节炎疼痛，肌骨骼疼痛，包括治疗骨关节炎和类风湿性关节炎的征兆和症状，口面和面疼痛，包括牙齿和癌症相关的下背部或骨盆疼痛，手术切口相关疼痛，炎性和非炎性疼痛，内脏疼痛，心理性疼痛和软组织炎性疼痛，纤维肌痛-相关疼痛，以及反射性交感神经营养不良。本发明的化合物和方法可用于治疗慢性以及急性疼痛。慢性或急性疼痛可以是损伤，年龄，或疾病的结果。
其它离子通道已牵涉疼痛的接受或传输。例如，N-型钙通道参与突触传输已被公认，所述突触传输将疼痛信号从感觉传入神经细胞传送至中枢神经系统。特异性阻断N-型钙通道的某些天然形成的肽神经毒素，已显示在宽范围的动物疼痛模型中担当极其有力和有效的止痛剂，所述模型包括炎性和神经性疼痛的模型。可获得的证据说明，N-型钙通道阻断剂与阿片样物质至少一样有效，缺乏众多典型的阿片样物质副作用(例如，呼吸衰弱)，以及说明止痛效果不经历耐受性发展。
TRPV3以及TRPV1和TRPV4表达的模式与参与疼痛一致。TRPV3被表达在疼痛敏感性神经元中，并且该表达在损伤后是上调控的。此外，TRPV3在皮肤中强表达。因此，治疗疼痛的方法包括给药：(i)TRPV3功能的拮抗剂；(ii)TRPV3和TRPV1和/或TRPV4功能的选择性拮抗剂的组合；或(iii)抑制TRPV3，TRPV1，和TRPV4的功能的泛-TRP抑制剂。
除TRPV家族成员之外，其它TRP通道也已参与疼痛接受和/或感觉。例如，某些TRPM通道，包括TRPM8，已参与疼痛的接受和/或感觉。因此，在某些实施方案中，本发明方法包括通过给药(i)选择性TRPV3拮抗剂和选择性TRPM8拮抗剂的组合；(ii)选择性TRPV3拮抗剂，选择性TRPM8拮抗剂，和一种或多种选择性TRPV1和/或TRPV4拮抗剂的组合；(iii)拮抗TRPV3和TRPM8的功能的交叉-TRP抑制剂；或(iv)拮抗TRPV3，TRPM8， 和一种或多种TRPV1和TRPV4的功能的泛抑制剂而治疗疼痛。
钙跨越皮肤细胞质膜的流入是在皮肤表皮中参与细胞分化的关键信号传导要素(Dotto，1999 Crit Rev Oral Biol Med 10：442-457)。调控或调节钙的进入途径，和因此调控或调节皮肤细胞生长的关键控制点，可治疗或预防特征为表皮增生的皮肤病或病患，所述表皮增生为一种病症，其中皮肤细胞既增殖太快又分化贫乏。此种疾病包括牛皮癣，基细胞癌和扁平细胞癌。牛皮癣，估计感染多达700万美国人，病人患有轻度至重度病症，对继发性感染的易感性增强，以及由于受侵害区域的畸形带来的心里影响(Lebwohl和Ali，2001J Am Acad Dermatol 45：487-498)。皮肤的基细胞癌(BCC)和扁平细胞癌(SCC)占每年美国诊断出的所有癌症的至少1/3。每年报道100万以上新病例，并且发病率还在增加。尽管是相对非侵犯性生长缓慢的癌症，但BCC能够导致显著的局部组织破坏和畸形。SCC更具侵犯性，因而呈现更多的并发症。而且，鉴于80％的损害位于头部和颈部，另15％位于肩部，背部或胸部，皮肤的BCC和SCC对受侵害患者的外表和生活质量有显著的影响。
许多皮肤病伴随着发痒(瘙痒症)。瘙痒症和疼痛共有许多机理相似性。两者与C-纤维活化相关，两者被温度上升和炎性递质增加而加强，而且两者皆因阿片样物质消除。降低神经元兴奋性，尤其是C-纤维兴奋性，可缓解与透析，皮炎，怀孕，毒葛，过敏，皮肤干燥，化疗和湿疹相关的搔痒症。
痤疮是综合病因学的皮肤病。在其它因素中，从皮脂腺分泌油有助于痤疮的发展，由于TRPV3也在皮脂腺中表达，并已显示能够调节在其它皮肤细胞中的分泌，因此拮抗TRPV3功能可减少痤疮的征兆和症状。
在某些优选实施方案中，给药所述TRPV3拮抗剂以预防，治疗或改善急性疼痛，慢性疼痛，接触敏感性，痒敏感性的征兆和症状，或作为治疗烧伤的部分，例如，手术后疼痛，癌性疼痛或神经性疼痛。
在某些优选实施方案中，给药所述TRPV3拮抗剂以预防，治疗或改善偏头痛的征兆和症状。
在某些优选实施方案中，给药所述TRPV3拮抗剂以预防，治疗或改善如下病患或病症的征兆和症状，所述病患或病症选自糖尿病性神经病，炎症，牛皮癣，湿疹，皮炎，疱疹后神经痛(带状疱疹)，失禁，膀胱失禁，发热，潮热和咳嗽。
在某些优选实施方案中，给药所述TRPV3拮抗剂以预防，治疗或改善 骨关节炎的征兆和症状。
在某些优选实施方案中，给药所述TRPV3拮抗剂以预防，治疗或改善类风湿性关节炎的征兆和症状。
在某些优选实施方案中，给药所述TRPV3拮抗剂以预防，治疗或改善口腔粘膜炎的征兆和症状。
在某些优选实施方案中，给药所述TRPV3拮抗剂以促进患者毛发的丧失或抑制患者毛发的生长。
本发明的另一方面涉及TRPV3拮抗剂在制备在患者中预防、治疗或改善如下疾病、病患或病症的症状的药物中的应用，所述症状涉及TRPV3的活化，或对于该症状而言降低的TRPV3活性可降低严重性。
本申请涉及一种治疗TRPV3介导的病症的方法，包括将治疗有效量的本申请化合物或其立体异构体、互变异构体、溶剂化合物、水合物、活性代谢物、同位素标记物或药学上可接受的盐，或本申请药物组合物，给药于需要给药的患者。
药物组合物
尽管本发明化合物可以被单独给药，但优选作为药物制剂(组合物)给药所述化合物。本发明化合物可以方便人或兽用药的方式配制成制剂。在某些实施方案中，所述药物制剂中所含的化合物可以是活性剂本身，或可以是例如，能够在生理条件下转化成活性化合物的前药。
不管选择的给药途径如何，可将所采用合适的水合形式的本发明化合物，和/或本发明药物组合物，通过本领域技术人员公知的其它常规方法，配制成下述可药用剂型。
因此，本发明的另一方面提供可药用组合物，所述组合物包括治疗有效量的一种或多种上述化合物，与一种或多种可药用载体(添加剂)和/或稀释剂一起配制成制剂。如下详述，本发明药物组合物特别被配制成固体或液体给药形式，包括适于下列方式的给药形式：(1)经口给药，例如，浸液(含水或非含水溶液或悬浮液)；片剂；丸药；粉末剂；颗粒剂；对舌头，牙齿，嘴唇，齿龈施用的膏体；漱口剂；凝胶剂；(2)肠胃外给药，例如，作为无菌溶液或悬浮液形式，通过皮下，肌内或静脉内注射；(3)局部施用，例如作为霜剂，膏剂或喷剂施用至皮肤；(4)阴道内或直肠内，例如以阴道栓剂，霜剂或 泡沫剂施用；或(5)吸入。然而，在某些实施方案中，本发明化合物可容易溶解或悬浮于无菌水中。在某些实施方案中，药物制剂是非热原的，即，不升高患者体温。
所述TRPV3拮抗剂可单独给药或与其它治疗剂组合给药。例如，将所述TRPV3拮抗剂与下列治疗剂中的一种或多种联合给药：抗炎剂，抗痤疮剂，抗皱剂，抗疤痕剂，抗牛皮癣剂，抗增殖剂，抗真菌剂，抗病毒剂，防腐剂，抗偏头痛剂，角质层分离剂，或毛发生长抑制剂。
所述TRPV3拮抗剂可通过局部，经口，经皮，直肠，阴道，肠胃外，鼻内，眼内，静脉内，肌内，动脉内，鞘内，囊内，眼框内，心内，皮内，腹膜内，经气管，皮下，表皮下，关节内，囊下，蛛网膜下，脊柱内，胸骨内，或通过吸入给药。
在某些优选实施方案中，将所述TRPV3拮抗剂局部给药。
在某些优选实施方案中，将所述TRPV3拮抗剂经口给药。
在某些优选实施方案中，将所述TRPV3拮抗剂肠胃外给药。
本文所用的术语“治疗有效量”表示化合物，材料，或包含本发明化合物的组合物的量，其通过抑制动物中至少细胞亚群的TRPV3功能，并由此阻断该功能在受处理细胞中的生物学结果，以对任何药物治疗适用的合理的益处/风险比，有效产生某些需要的治疗效果。
本文所用的术语“全身性给药”和“外周给药”表示将化合物，药物或其它材料非直接给药至中枢神经系统，使得它进入患者的系统，并由此进行代谢和其它过程，例如皮下给药。
术语“可药用”在本文中用于指如下那些化合物，材料，组合物，和/或剂型，它们在合理的医学评判范围内，适用于接触人类和动物组织，而无过分毒性，刺激，过敏反应，或其它问题或并发症，并与合理的益处/风险比相称。
本文所用的术语“可药用载体”表示可药用的材料，组合物，或媒介物，例如，液体或固体填料，稀释剂，赋形剂，溶剂或胶囊材料，参与携带或运输本发明拮抗剂从身体的一个器官或部分到另一器官或部分。各个载体必须是“可接受的”，其意义在于与所述制剂的其它成分相容，并且不损害患者。用作可药用载体的材料的一些例子包括：(1)糖类，例如乳糖，葡萄糖和蔗糖；(2)淀粉，例如玉米淀粉和马铃薯淀粉；(3)纤维素及其衍生物，例如羧甲基 纤维素钠，乙基纤维素和乙酸纤维素；(4)黄蓍胶粉末；(5)麦芽；(6)明胶；(7)滑石；(8)赋形剂，例如可可油和栓剂蜡；(9)油，例如花生油，棉子油，红花油，芝麻油，橄榄油，玉米油和豆油；(10)二醇类，例如丙二醇；(11)多羟基化合物，例如甘油，山梨醇，甘露醇和聚乙二醇；(12)酯，例如油酸乙酯和月桂酸乙酯；(13)琼脂；(14)缓冲剂，例如氢氧化镁和氢氧化铝；(15)藻酸；(16)无热原水；(17)等渗盐水；(18)Ringer氏溶液；(19)乙醇；(20)磷酸缓冲液；和(21)药物制剂中采用的其它非毒性相容性物质。
如上所述，本发明化合物的某些实施方案可含有碱性官能团，例如氨基或烷基氨基，并因此能够与可药用酸形成可药用盐。在这方面，术语“可药用盐”是指本发明化合物的相对非毒的，无机酸和有机酸的加成盐。在最终分离和纯化本发明化合物期间，或通过将以游离碱形式的本发明纯化的化合物与合适的有机或无机酸单独反应，并然后分离形成的盐，可原位制备上述加成盐。代表性盐包括氢溴酸盐，盐酸盐，硫酸盐，硫酸氢盐，磷酸盐，硝酸盐，乙酸盐，戊酸盐，油酸盐，棕榈酸盐，硬脂酸盐，月桂酸盐，苯甲酸盐，乳酸盐，磷酸盐，甲苯磺酸盐(tosylate)，柠檬酸盐，马来酸盐，富马酸盐，琥珀酸盐，酒石酸盐，napthylate，甲磺酸盐(mesylate)，葡庚糖酸盐(glucoheptonate)，乳糖醛酸盐(lactobionate)，和月桂基磺酸盐等。(参见，例如，Berge等(1977)″Pharmaceutical Salts″，J Pharm.Sci.66：1-19)。
本发明化合物的可药用盐包括所述化合物的例如得自非毒性有机或无机酸的常规非毒性盐或季铵盐。例如，这种常规非毒性盐包括那些衍生自无机酸的盐，所述无机酸例如盐酸，氢溴酸，硫酸，氨基磺酸，磷酸，硝酸等；以及由有机酸制备的盐，所述有机酸例如乙酸，丙酸，琥珀酸，乙醇酸，硬脂酸，乳酸，苹果酸，酒石酸，柠檬酸，抗坏血酸，棕榈酸，马来酸，羟基马来酸，苯基乙酸，谷氨酸，安息香酸，水杨酸，对氨基苯磺酸，2-乙酰氧基苯甲酸，富马酸，甲苯磺酸，甲磺酸，乙二磺酸，草酸，异硫羰酸(isothionic)等。
在其它情形下，本发明化合物可含有一种或多种酸性官能团，并因此能够与可药用碱形成可药用盐。术语“可药用盐”在这些情形下是指本发明化合物的相对非毒性的无机碱和有机碱的加成盐。在所述化合物的终分离和纯化期间，或通过使以游离酸形式的纯化的化合物与合适的碱，铵，或可药用有机伯胺，仲胺或叔胺单独反应，可同样原位制备上述碱加成盐，所述碱为 例如可药用金属阳离子的氢氧化物，碳酸盐或碳酸氢盐。代表性碱盐或碱土盐包括锂，钠，钾，钙，镁，和铝盐等。可用于形成碱加成盐的代表性有机胺包括乙胺，二乙胺，乙二胺，乙醇胺，二乙醇胺，哌嗪等。(参见，例如，Berge等，同上)。
可药用抗氧化剂的例子包括：(1)水溶性抗氧化剂，例如抗坏血酸，半胱氨酸盐酸盐，硫酸氢钠，偏亚硫酸钠，亚硫酸钠等；(2)油溶性抗氧化剂，例如抗坏血酸基棕榈酸酯，丁基化的羟基茴香醚(BHA)，丁基化的羟基甲苯(BHT)，卵磷脂，没食子酸丙酯，α-生育酚等；以及(3)金属螯合剂，例如柠檬酸，乙二胺四乙酸(EDTA)，山梨醇，酒石酸，磷酸等。
本发明制剂包括那些适合口，鼻，局部(包括颊和舌下)，直肠，阴道和/或肠胃外给药的制剂。经口制剂包括那些递送至口并在口中维持无需吞咽的制剂，以及作为部分使用或用后吞咽的制剂。所述制剂可方便地以单位剂型呈现，并可通过药物学领域公知的任何方法制备。可与载体材料组合以生产单一剂型的活性成分的量取决于被治疗的宿主、具体给药方式的不同而变化。可与载体材料组合以生产单一剂型的活性成分的量一般会是化合物产生治疗效果的量。通常，以100％计，该量的范围为约1％-约99％，优选约5％-约70％，最优选约10％-约30％的活性成分。
制备这些制剂或组合物的方法包括使本发明化合物与载体，以及任选一种或多种附属成分结合的步骤。一般而言，通过使本发明化合物与液体载体，或细分固体载体，或两者均匀和紧密组合，和然后如果需要使产物成型而制备所述制剂。
适合经口给药的本发明制剂的形式可以是胶囊，药包，丸剂，片剂，锭剂(利用加香基，通常为蔗糖和阿拉伯树胶或黄蓍胶)，粉末剂，颗粒剂，或作为含水液体或非水液体中的溶液剂或悬浮剂，或作为水包油或油包水型的液体乳剂，或作为酏剂或糖浆剂，或作为香锭(pastilles)(利用惰性基，例如明胶和甘油，或蔗糖和阿拉伯树胶)和/或作为漱口剂等，各含有预定量的本发明化合物作为活性成分。本发明化合物还可以大丸药(bolus)，干药糖剂(electuary)或膏体形式给药。
本申请提供一种式(I)的含氮螺环化合物
或其立体异构体、互变异构体、溶剂化合物、水合物、氧化物、活性代谢物、同位素标记物、药学上可接受的盐，
其中，环A选自含有3-12个环原子的单环或多环环系；
R1各自独立地选自H、卤素、羟基、巯基、硝基、氰基、氧代、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的C1-C6卤代烷基、取代有0-2个Rf的C1-C6烷氧基、取代有0-2个Rf的C1-C6卤代烷氧基、取代有0-2个Rf的C3-C6环烷基、取代有0-2个Rf的C3-C6卤代环烷基、取代有0-2个Rf的C3-C6环烷氧基、取代有0-2个Rf的C3-C6卤代环烷氧基、取代有0-2个Rf的芳基、取代有0-2个Rf的芳烷基、取代有0-2个Rf的烷芳基、取代有0-2个Rf的杂芳基、-R11OR12、-R11SR12、-N(Ra)(Rb)、-C(O)Rc、-C(O)N(Ra)(Rb)和-SO2N(Ra)(Rb)或-SORc，或者两个R1与它们所连接的环A原子一起形成3-10元环结构；
R2各自独立地选自H、卤素、羟基、巯基、硝基、氰基、氧代、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的C1-C6卤代烷基、取代有0-2个Rf的C1-C6烷氧基、取代有0-2个Rf的C1-C6卤代烷氧基、取代有0-2个Rf的C3-C6环烷基、取代有0-2个Rf的C3-C6卤代环烷基、取代有0-2个Rf的C3-C6环烷氧基、取代有0-2个Rf的C3-C6卤代环烷氧基、取代有0-2个Rf的芳基、取代有0-2个Rf的芳烷基、取代有0-2个Rf的烷芳基、取代有0-2个Rf的杂芳基、-R11OR12、-R11SR12、-N(Ra)(Rb)、-C(O)Rc、-C(O)ORd、-C(O)N(Ra)(Rb)和-SO2N(Ra)(Rb)或-SORc，或者两个R2与它们所连接的环原子一起形成3-10元环结构；
L1选自键，或者如下结构式：
X1在每次出现时各自独立地选自C、O或N；
X2在每次出现时各自独立地选自C、O、B或N；
XA、XB、XC各自独立地为CRx或N；
Rx各自独立地选自H、卤素、羟基、巯基、硝基、氰基、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的C1-C6卤代烷基、取代有0-2个Rf的C1-C6烷氧基、取代有0-2个Rf的C1-C6卤代烷氧基、取代有0-2个Rf的C3-C6环烷基、取代有0-2个Rf的C3-C6卤代环烷基、取代有0-2个Rf的C3-C6环烷氧基、取代有0-2个Rf的C3-C6卤代环烷氧基、取代有0-2个Rf的芳基、取代有0-2个Rf的芳烷基、取代有0-2个Rf的烷芳基、取代有0-2个Rf的杂芳基、-R11OR12、-R11SR12、-N(Ra)(Rb)、-C(O)Rc、-C(O)ORd、-C(O)N(Ra)(Rb)和-SO2N(Ra)(Rb)或-SORc；或者两个Rx与它们所连接的环原子一起形成3-10元环结构；
R0各自独立地选自H、卤素或者式II的结构式
其中，L2各自独立地选自键、-O-、-S-、-N(R20)-、-C(O)-、-C(R20R21)-、-S(O)-和-S(O2)-；
环C各自独立地选自含有3-12个环原子的单环或多环环系；
R3各自独立地选自H、卤素、羟基、巯基、硝基、氰基、氧代、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的C1-C6卤代烷基、取代有0-2个Rf的C1-C6烷氧基、取代有0-2个Rf的C1-C6卤代烷氧基、取代有0-2个Rf的C3-C6环烷基、取代有0-2个Rf的C3-C6卤代环烷基、取代有0-2个Rf的C3-C6环烷氧基、取代有0-2个Rf的C3-C6卤代环烷氧基、取代有0-2个Rf的芳基、取代有0-2个Rf的芳烷基、取代有0-2个Rf的烷芳基、取代有0-2个Rf的杂芳基、-R11OR12、-R11SR12、-N(Ra)(Rb)、-C(O)Rc、-C(O)ORd、-C(O)N(Ra)(Rb)和-SO2N(Ra)(Rb)或-SORc，或者两个R3与它们所连接的环C原子一起形成3-10元环结构；
R11各自独立地选自取代有0-2个Rf的C1-C6亚烷基；
R12各自独立地选自H、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的C1-C6卤代烷基、取代有0-2个Rf的C3-C6环烷基和取代有0-2个Rf的C3-C6卤代环烷基；
Ra和Rb各自独立地选自H、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的芳基、取代有0-2个Rf的芳烷基、-C(O)Rc和-C(O)ORd；
Rc各自独立地选自H、卤素、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的芳基和取代有0-2个Rf的芳烷基；
Rd各自独立地选自H、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的芳基和取代有0-2个Rf的芳烷基；
R20和R21各自独立地选自H、羟基、C1-C6烷基、芳基和芳烷基；
Rf各自独立地选自卤素、羟基、氨基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、C3-C6环烷基和C3-C6卤代环烷基；
n为0、1、2或3；
p为0、1、2或3；
q为0、1、2或3；
m为1或2；
r为1或2。
在一种实施方案中，环A选自苯环、吡啶环、喹啉环、哌啶环、C3-C6环烷基环、异喹啉环、吡嗪环、嘧啶环、哒嗪环、噻唑环、噻吩环、吡咯环、吡唑环、咪唑环、异噻唑环、吲哚环、苯并咪唑环、呋喃环、恶唑环、恶二唑环、喹喔啉环和嘌呤环。
在一种实施方案中，环A选自如下结构式：
在一种实施方案中，R1各自独立地选自H、卤素、氰基、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、-N(Ra)(Rb)和-R11OR12，其中，Ra和Rb各自独立地选自H和C1-C6烷基；R11各自独立地选自C1-C6亚烷基；R12各自独立地选自H和C1-C6烷基。
在一种实施方案中，R1各自独立地选自H、Cl、F、-CF3、-CN、-CH3、 -OH、-OCH3、-CH2OCH3。
在一种实施方案中，R2各自独立地选自H、氰基、羟基、巯基、氧代、C1-C6烷基、C1-C6卤代烷基、取代有0-2个Rf的C3-C6环烷基、C1-C6烷氧基、C1-C6卤代烷氧基、-R11OR12、-R11SR12、-CH(O)、-C(O)ORd和-C(O)N(Ra)(Rb)；其中，R11各自独立地选自C1-C6亚烷基；R12各自独立地选自H、C1-C6烷基、C1-C6卤代烷基、C3-C6环烷基和C3-C6卤代环烷基；Ra和Rb各自独立地选自H和C1-C6烷基；Rd各自独立地选自H和C1-C6烷基；Rf各自独立地选自卤素、羟基、氨基和C1-C6烷基。
在一种实施方案中，R2各自独立地选自氕、氘、氚、-SH、-OH、-OCF3、-CH3、-NH2、-CN、-CONH2、-CH2OH、-CH(O)、-CHF2、-COOH、-COOCH3、氧代和
在一种实施方案中，L2各自独立地选自键、-O-、-S-、-N-、-C(O)-、-CH2-、-CF2-、-C(OH)-、-S(O)-和-S(O2)-。
在一种实施方案中，环C选自C3-C6环烷烃环、苯环、苯并C3-C6环烷烃环、吡啶环、喹啉环、异喹啉环、吡嗪环、嘧啶环、哒嗪环、噻唑环、噻吩环、吡咯环、吡唑环、咪唑环、异噻唑环、吲哚环、苯并咪唑环、呋喃环、恶唑环、喹喔啉环和嘌呤环。
在一种实施方案中，环C选自以下结构式：
在一种实施方案中，R3各自独立地选自H、氰基、羟基、卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C6环烷基、-R11OR12、-R11SR12、-C(O)Rc、-C(O)ORd和-C(O)N(Ra)(Rb)，或者两个R3与它们所连接的环C原子一起形成3-10元环结构；
其中，R11各自独立地选自C1-C6亚烷基；R12各自独立地选自H、C1-C6烷基、C1-C6卤代烷基、C3-C6环烷基和C3-C6卤代环烷基；Ra和Rb各自独立地选自H和C1-C6烷基；Rc各自独立地选自H、卤素和C1-C6烷基；Rd各自独立地选自H和C1-C6烷基。
在一种实施方案中，R3各自独立地选自H、环丙基、异丙基、叔丁基、F、Cl、CN、乙基、甲基、三氟甲氧基、甲基羰基、甲氧基甲基、-C(CH3)2OH。
在一种实施方案中，式I中的
选自以下结构式：
其中，R2、XA、XB、XC以及p定义如式I。
在一种实施方案中，式I中的
选自以下结构式：
其中，R2各自独立地选自氕、氘、氚、卤素、氧代、-SH、-OH、-CH3、-CN、-CONH2、-COOH、-COH、-COOCH3、-CF3、-OCH3、-CH2OH、-OCF3、-CHF2、和-NH2。
这些结构式中仍然可以在螺环结构的一个或者两个环部分各自任选地取代p个R2基团。R2基团的定义可以如上所述。在一种实施方案中，至少一个R2为-OH。
在一种实施方案中，式I中的
选自以下结构式之一：
其中，R2各自独立地选自氕、氘、氚、卤素、-CH3和-CF3。
在一种实施方案中，式I中的
选自以下结构式：
其中，R2独立地选自氧代、-SH、-CN、-CONH2、-COOH、-COH、-COOCH3、-OCH3、-CH2OH、-CHF2、-OCF3和-NH2。
在一种实施方案中，式I中的
选自以下结构式：
在一种实施方案中，L1为
在一种实施方案中，环A为
或者，环A为
或者，环A为
在一种实施方案中，所述化合物选自下列化合物：



本申请涉及一种药物组合物，其包含本申请的化合物或其立体异构体、互变异构体、溶剂化合物、水合物、活性代谢物、同位素标记物或药学上可接受的盐，以及药学可接受的载体。
本申请还涉及本申请化合物或其立体异构体、互变异构体、溶剂化合物、水合物、活性代谢物、同位素标记物或药学上可接受的盐，以及本申请的药物组合物在制备用于抑制TRPV3活性的药物中的用途。
本申请还涉及本申请的化合物或其立体异构体、互变异构体、溶剂化合物、水合物、活性代谢物、同位素标记物或药学上可接受的盐，以及本申请的药物组合物在制备用于治疗受治疗者的TRPV3介导的病症的药物中的用途。
在一种实施方案中，所述病症选自疼痛、瘙痒、皮肤病症、炎症、毛发生长异常、失禁、发热、热潮红、膀胱炎、肠易激综合征和/或咳嗽症状。
在一种实施方案中，所述疼痛为癌性痛和皮肤疼痛。
在一种实施方案中，用于制备抑制增殖，由此预防、治疗或缓解癌症症状的药物。
在一种实施方案中，所述癌症为脂肪肉瘤。
在一种实施方案中，所述毛发生长异常为脱发。
在一种实施方案中，所述皮肤病症选自皮肤角化病、鱼鳞病、瘙痒症。
在一种实施方案中，皮肤角化病为olmsted综合征(Olmsted syndrome)。
在一种实施方案中，鱼鳞病为丑角样鱼鳞病(harlequin ichtyosis)。
一般合成方案
本发明的化合物可使用例示于下文详述的一般合成方案和实验程序中的方法而制备。这些一般合成方案和实验程序为说明目的而呈现且并不意在限制。用于制备本发明化合物的原料为商购获得的或可使用本领域已知的常规方法制备。
制备本发明化合物的代表性程序概述在方案1、方案2、方案3、方案4和方案5中。对卤代苯乙腈和溴乙酸乙酯原料可购买或使用本领域已知的方法制备，其中代表性程序提供中间体。方案1突出了完全详尽的1-(3-羟基-2,3-二氢螺环[茚-1,3'-吡咯烷]-1-酮的合成。3-(4-卤代苯基)-3-氰基戊二酸二乙酯2的合成可通过对卤代苯乙腈和溴乙酸乙酯在诸如四氢呋喃的溶剂中的反应而实现，2的氰基和酯基在还原剂下产生了环化的3，酯3在碱性条件下水解为羧酸4，4在酸性条件下自身发生合环化产生5，将5与所需的硼酸在Suzuki条件下反应以产生偶联得中间体6，6在还原剂条件下发生还原生产中间体7，然后其在缩合剂条件下与羧酸反应以产生8，8通过超临界拆分得8a，8b,8c和8d。
方案1：
方案2显示了所需化合物的合成，其中在最后一步Suzuki反应生成8。中间体5的合成如方案1中描述。中间体5a通过中间体5在还原剂的条件下生成，5a与羧酸反应以产生5b，将5b与所需的硼酸在Suzuki条件下反应以产生偶联生成8，进一步通过超临界拆分得8a，8b,8c和8d。
方案2
方案3显示了所需化合物的合成，属于半手性合成，中间体6的合成如方案1中描述。中间体在手性配体存在的条件下通过催化还原得到手性醇6a，再次还原酰胺生成6b，6b与所需的羧酸缩合得到8，进一步通过超临界拆分得8a和8b。
方案3
方案4显示了所需化合物的合成，也属于半手性合成。中间体5的合成如方案1中描述。中间体5利用手性配体催化还原得5a，再与所需的硼酸在Suzuki条件下反应以产生偶联生成5b，5b在还原剂得条件下还原生成5c，5c与所需的羧酸缩合得到8，进一步通过超临界拆分得8a和8b。
方案4
方案5显示了所需化合物的合成，同样属于半手性合成，中间体5的合成如方案1中描述。中间体5利用手性配体催化还原得5a，进一步还原内酰胺生成中间体5b，5b所需的羧酸缩合得到5c，5c与再与所需的硼酸在Suzuki条件下反应以产生偶联生成8，进一步通过超临界拆分得8a和8b。
方案5
具体实施方案
中间体的制备
制备例1：5-溴螺[茚-1,3'-吡咯烷]-3,5'(2H)-二酮(化合物I1)
步骤A:3-(4-溴苯基)-3-氰基戊二酸二乙酯
20.0g(102mmol,1.0eq)2-(4-溴苯基)乙腈溶解在100mL四氢呋喃中，氮气置换3次。干冰降温至-60℃。在-60℃下滴加224mL(224mmol,2.2eq)双三甲基硅基胺基锂，室温搅拌3h。然后在-60℃以下滴加34.1g(204mmol,2.0eq)溴乙酸乙酯，室温搅拌过夜。经LCMS确认原料反应完，加200mL水淬灭，然后用乙酸乙酯萃取三次，用100mL饱和食盐水溶液洗涤有机层，无水硫酸钠干燥，减压蒸干。残余物通过柱层析(PE/EA＝0～10:1)得产物(37.4g,收率＝99％)。
1H NMR(400MHz,CDCl3)δ7.54(dd,J＝8.7,2.7Hz,2H),7.39(dd,J＝8.7,2.7Hz,2H),4.12-4.10(m,4H),3.25(d,J＝16.3Hz,2H),3.08(d,J＝16.3Hz,2H),1.19(t,J＝7.1Hz,6H).
步骤B:2-(3-(4-溴苯基)-5-氧代吡咯烷-3-基)乙酸乙酯
5.00g(13.8mmol,1.0eq)3-(4-溴苯基)-3-氰基戊二酸二乙酯溶解在50mL甲醇中，加入3.70g(28.5mmol,2.1eq)无水氯化钴，并在0℃下缓慢加入5.39g (142mmol,10.5eq)硼氢化钠，室温搅拌1h。经LCMS确认有产物生成，用50mL盐酸溶液(2mol/L)稀释。然后用二氯甲烷萃取三次，用50mL饱和食盐水溶液洗涤有机层，无水硫酸钠干燥，减压蒸干。残余物通过柱层析(DCM/MeOH＝0～15:1)得产物(3.29g,收率＝59％)。
LC-MS:(M+H)+；m/z＝326.05,327.17；
步骤C:2-(3-(4-溴苯基)-5-氧代吡咯烷-3-基)乙酸
1.0g(3.07mmol,1.0eq)2-(3-(4-溴苯基)-5-氧代吡咯烷-3-基)乙酸乙酯溶解在20mL甲醇中，在0℃下缓慢加入12.5mL氢氧化钠溶液(1.0mol/L)，40℃搅拌1h。经LCMS确认有产物生成，反应液用盐酸溶液(1.0mol/L)稀释至酸性，然后用二氯甲烷萃取三次，用50mL饱和食盐水溶液洗涤有机层，无水硫酸钠干燥，减压蒸干，得粗品(0.75g,收率＝82％)。
LC-MS:(M-H)-；m/z＝297.66,298.25；
步骤D:5-溴螺[茚-1,3'-吡咯烷]-3,5'(2H)-二酮
7.5g多聚磷酸加热至150℃，再加入0.75g(2.52mmol,1.0eq)2-(3-(4-溴苯基)-5-氧代吡咯烷-3-基)乙酸。然后在150℃搅拌1h。经LCMS确认有产物生成，趁热将混合物缓慢倒入冰水中，边加边搅拌。然后用二氯甲烷萃取三次，用30mL饱和食盐水溶液洗涤有机层，无水硫酸钠干燥，减压蒸干。残余物通过柱层析(DCM/MeOH＝0～20:1)得产物(0.65g,收率＝92％)。
LC-MS:(M+H)+；m/z＝280.03,282.04。
制备例2：5-(2-环丙基苯基)螺[茚-1,3'-吡咯烷]-3,5'(2H)-二酮(化合物I2)
550mg(1.96mmol,1.0eq)5-溴螺[茚-1,3’-吡咯烷]-3,5’(2H)-二酮和381mg(2.35mmol,1.2eq)(2-环丙基苯基)硼酸溶于50mL二氧六环/水混合溶液(V:V ＝4:1)，再加入116mg(0.20mmol,0.1eq)1,1-双(二苯基膦)二荗铁二氯化钯和1.25g(5.89mmol,3.0eq)磷酸三钾，氮气置换三次，100℃搅拌1h。经LCMS确认有产物生成，向其中添加50mL水，然后用乙酸乙酯萃取三次，用30mL饱和食盐水溶液洗涤有机层，无水硫酸钠干燥，减压蒸干。残余物通过柱层析(PE/EA＝0～10:1)得产物(620mg,收率＝99％)。
LC-MS:(M+H)+；m/z＝318.20。
制备例3 5-(2-环丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇(化合物I3)
650mg(2.05mmol,1.0eq)5-溴螺[茚-1,3’-吡咯烷]-3,5’(2H)-二酮溶于50mL无水四氢呋喃中，在0℃下缓慢加入1.16g(30.7mmol,15.0eq)氢化锂铝，70℃搅拌2h。经LCMS确认原料转化完全，有产物生成，反应液通过硅藻土过滤，用四氢呋喃洗涤。无水硫酸钠干燥，减压蒸干，得粗品(420mg,收率＝67％)。
LC-MS:(M+H)+；m/z＝306.26；
制备例4：5-(2-异丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇(化合物I4)
步骤A:5-(2-异丙基苯基)螺[茚-1,3'-吡咯烷]-3,5'(2H)-二酮
将2.60g(9.28mmol,1.0eq)5-溴螺[茚-1,3'-吡咯烷]-3,5'(2H)-二酮，1.83g(11.1mmol,1.2eq)(2-异丙基苯基)硼酸，7.88g(37.1mmol,4.0eq)磷酸钾，0.07g(0.093mmol,0.01eq)[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物，40mL(1,4-二氧六环:水＝4:1)混合溶剂加入100mL反应瓶，氮气置换三次，100℃反应4小时。经TLC(DCM:MeOH＝20:1)点板,确认原料完全 反应。将该反应液加入50mL水中，使用乙酸乙酯(50mL)萃取3次，合并有机相，干燥，浓缩，上样。硅胶柱层析纯化(DCM:MeOH＝20:1)得到2.56g黄色油状产物(收率＝83％)。
LC-MS:(M+H)+；m/z＝320.16；
1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.91-7.93(m,1H),7.63-7.68(m,1H),7.37-7.52(m,2H),7.23-7.31(m,2H),7.09-7.16(m,1H),3.40-3.63(m,2H),3.17-3.25(m,2H),2.69-2.75(m,3H),1.19(d,J＝4Hz,3H),1.14(d,J＝8Hz,3H)。
步骤B:5-(2-异丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇
将1.50g(4.69mmol,1.0eq)5-(2-异丙基苯基)螺[茚-1,3'-吡咯烷]-3,5'(2H)-二酮，20mL四氢呋喃加入100mL反应瓶，氮气保护下，反应液降温至0℃。缓慢加入2.67g(70.4mmol,15.0eq)四氢铝锂，0℃搅拌10分钟之后，反应液回流反应2小时。经TLC(DCM:MeOH＝20:1)点板,确认原料完全反应。反应液加入2mL水淬灭反应，硅藻土过滤，使用四氢呋喃(200mL)洗滤饼至产物完全溶解。滤液浓干，得到1.20g黄色油状液体粗品。
LC-MS:(M+H)+；m/z＝308.14。
制备例5：(5-溴-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮(化合物I5)
步骤A:5-溴-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇
50mL史莱克管中将300mg(1.07mmol,1.0eq)5-溴螺[茚-1,3'-吡咯烷]-3,5'(2H)-二酮溶解在6mL四氢呋喃中，氮气保护下，用注射器慢慢加入1.1mL(10.7mmol,10.0eq)硼烷的二甲硫醚溶液。加完将体系升温到70℃反应18小时。经LCMS确认有目标产物生成。反应液降温到-10℃，慢慢滴加 2mL水淬灭反应，再加入20mL四氢呋喃于反应体系，硅藻土过滤，使用四氢呋喃(20mLx3)洗滤饼至产物完全溶解。滤液浓干，得到350mg黄色油状液体粗品。直接进行下一步反应。
LC-MS:(M+H)+；m/z＝268.01；
步骤B:(5-溴-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮
将145mg(1.03mmol,1.2eq)5-氟吡啶-2-羧酸，391mg(1.03mmol,1.2eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，665mg(5.15mmol,6.0eq)N,N-二异丙基乙胺，10mL四氢呋喃加入50mL反应瓶，氮气保护下，反应液在室温搅拌10分钟，然后将230mg(0.86mmol,1.0eq)5-溴-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇溶于6mL四氢呋喃的溶液加入反应液，室温搅拌2小时。经LCMS确认有目标产物生成，将该反应液加入15mL水淬灭，再用乙酸乙酯(25mL)萃取3次，合并有机相，干燥，浓缩，粗品经柱层析纯化(PE/EA＝50:1～5/1)得到203mg油状产物(收率＝70％)。
LC-MS:(M+H)+；m/z＝391.01。
实施例1：(6-(2-环丙基苯基)-4-羟基-3,4-二氢-2H-螺[萘-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮
步骤A:2-(4-溴苯基)-4-(1,3-二氧戊环-2-基)丁腈
氮气保护下将2-(4-溴苯基)乙腈(20.0g,102mmol,1.0eq)溶解在100mL四氢呋喃中，然后在-78℃下缓慢滴入LiHMDS(122mL,1.0mol/L,1.2eq)，滴加完毕之后升至室温搅拌3小时，然后降至-78℃，随后缓慢滴加2-(2-溴乙基)-1,3-二恶烷(22.0g,122mmol,1.2eq)，滴加完毕之后缓慢升至室温搅拌过夜。经TLC确认原料反应完全，向其中缓慢滴加200mL冰水淬灭反应，然 后用乙酸乙酯萃取(200mLx3)，随后用200mL饱和食盐水溶液洗涤有机层，有机相用无水硫酸钠干燥，减压蒸干得到粗品。粗品通过硅胶柱层析纯化(PE/EA＝10/1)得到目标产物(13.0g,收率＝43％)。
1H NMR(400MHz,CDCl3)δ7.52-7.48(m,2H),7.23-7.19(m,2H),4.89(t,J＝4.0Hz,1H),3.99-3.80(m,5H),2.07-1.93(m,2H),1.85-1.78(m,2H).
步骤B:3-(4-溴苯基)-3-氰基-5-(1,3-二氧戊环-2-基)戊酸乙酯
将2-(4-溴苯基)-4-(1,3-二氧戊环-2-基)丁腈(4.0g,13.5mmol,1.0eq)溶解在40mL四氢呋喃中，然后在冰浴下分批加入氢化钠(1.62g,40.5mmol,60％in oil,3eq)，加完之后升至70℃加热搅拌2小时，然后缓慢滴加溴乙酸乙酯(2.70g,16.2mmol,1.2eq)，滴加完毕后继续70℃加热搅拌过夜。TLC确认新产物生成，还有部分原料剩余。降温之后缓慢滴加100mL冰水淬灭反应，然后用乙酸乙酯萃取三次(100mLx3)，用100mL饱和食盐水溶液洗涤有机层，有机相用无水硫酸钠干燥，减压蒸干得到粗品。粗品经硅胶柱层析(PE/EA＝10:1～5:1)得到目标产物(1.6g,收率＝31％)。
1H NMR(400MHz,CDCl3)δ7.54-7.49(m,2H),7.33-7.30(m,2H),4.82(t,J＝4.0Hz,1H),4.03(q,J＝6.8Hz,2H),3.92-3.78(m,4H),3.03-2.88(m,2H),2.24-2.16(m,1H),2.06-1.99(m,1H),1.48-1.39(m,1H),1.36-1.24(m,1H),1.12(t,J＝7.2Hz,3H).
步骤C:3-氰基-3-(2'-环丙基-[1,1'-联苯]-4-基)-5-(1,3-二恶烷-2-基)戊酸乙酯
1.60g(4.18mmol,1.0eq)3-(4-溴苯基)-3-氰基-5-(1,3-二氧戊环-2-基)戊酸乙酯和813mg(5.02mmol,1.2eq)(2-环丙基苯基)硼酸溶于50mL二氧六环/水混合溶液(V:V＝4:1)，再加入307mg(0.42mmol,0.1eq)1,1-双(二苯基膦)二荗铁二氯化钯和2.66g(12.5mmol,3.0eq)磷酸三钾，氮气置换三次，100℃搅拌 2h。冷却之后向其中添加50mL水，然后用乙酸乙酯萃取三次，用30mL饱和食盐水溶液洗涤有机层，无水硫酸钠干燥，减压蒸干。残余物通过柱层析(PE/EA＝0～5:1)得产物(1.10g,收率＝63％)。
1H NMR(400MHz,CDCl3)δ7.50-7.44(m,4H),7.30-7.26(m,1H),7.23-7.19(m,2H),6.94(d,J＝7.8Hz,1H),4.87(t,J＝4.4Hz,1H),4.10-4.04(m,2H),3.97-3.87(m,2H),3.86-3.80(m,2H),3.09-2.96(m,2H),2.33-2.26(m,1H),2.17-2.10(m,1H),1.95-1.79(m,2H),1.71-1.62(m,1H),1.12(t,J＝7.2,3H),0.89-0.79(m,2H),0.70-0.66(m,2H).
步骤D:4-(2-(1,3-二恶烷-2-基)乙基)-4-(2'-环丙基-[1,1'-联苯]-4-基)吡咯烷-2-酮
1.10g(2.62mmol,1.0eq)3-氰基-3-(2'-环丙基-[1,1'-联苯]-4-基)-5-(1,3-二恶烷-2-基)戊酸乙酯溶解在25mL甲醇中，加入714mg(5.50mmol,2.1eq)无水氯化钴，并在0℃下缓慢加入1.04g(27.5mmol,10.5eq)硼氢化钠，室温搅拌1h。经LCMS确认有产物生成，用50mL冰水淬灭反应，然后用二氯甲烷萃取三次，用50mL饱和食盐水溶液洗涤有机层，无水硫酸钠干燥，减压蒸干。残余物通过柱层析(DCM/MeOH＝0～15:1)得产物(0.80g,收率＝81％)。
LC-MS:(M+H)+；m/z＝378.26；
1H NMR(400MHz,CDCl3)δ7.43-7.41(m,2H),7.29-7.24(m,1H),7.22-7.17(m,4H),6.93(d,J＝8.0Hz,1H),6.02(s,1H),4.76(t,J＝4.4Hz,1H),3.93-3.78(m,4H),3.74-3.61(m,2H),2.84-2.58(m,2H),2.01-1.93(m,2H),1.90-1.83(m,1H),1.55-1.49(m,2H),0.89-0.80(m,2H),0.71-0.64(m,2H).
步骤E:3-(3-(2-(2'-环丙基-[1,1'-联苯]-4-基)-5-氧吡咯烷-3-基)丙醛
0.80g(2.12mmol,1.0eq)4-(2-(1,3-二恶烷-2-基)乙基)-4-(2'-环丙基-[1,1'-联苯]-4-基)吡咯烷-2-酮溶解在5mL 1,4-二氧六环中，随后冰浴下加入 10.64mL HCl/1,4-二氧六环溶液(4.24mmol,20eq,4M)，搅拌反应过夜之后LCMS检测转化完全。冰浴下加入冰的碳酸氢钠溶液调节pH值7-8左右，然后用乙酸乙酯萃取三次，用50mL饱和食盐水溶液洗涤有机层，无水硫酸钠干燥，减压蒸馏浓缩得目标产物的粗品(0.50g,收率＝71％)，不用纯化直接用于下一步反应。
LC-MS:(M+H)+；m/z＝334.11；
1H NMR(400MHz,CDCl3)δ9.63(s,1H),7.46-7.44(m,2H),7.23-7.17(m,5H),6.96-6.93(m,2H),3.79-3.62(m,4H),2.42-2.27(m,2H),2.21-2.17(m,1H),1.91-1.82(m,2H),0.88-0.81(m,2H),0.72-0.68(m,2H).
步骤F:3-(3-(2-(2'-环丙基-[1,1'-联苯]-4-基)-5-氧吡咯烷-3-基)丙酸
3-(3-(2-(2'-环丙基-[1,1'-联苯]-4-基)-5-氧吡咯烷-3-基)丙醛(0.50g,1.50mmol,1.0eq)溶解在叔丁醇(10mL)和2-甲基-2-丁烯(1.05g,15.0mmol,10eq)的混合物中。将所得溶液搅拌并冷却至0℃。将NaClO2(80％与NaCl的混合物，237mg,2.1mmol,1.4eq)和NaH2PO4(180mg,1.50mmol,1.0eq)的混合物溶解在最小体积的水中，然后添加到反应中。TLC监测反应液，直到观察到醛的完全消耗。用NaHSO4(aq)将反应液酸化至pH＝3，然后用乙酸乙酯萃取三次，50mL饱和食盐水溶液洗涤有机层，无水硫酸钠干燥，减压蒸干得目标产物的粗品。粗品通过柱层析(DCM/MeOH＝0～15:1)得产物(300mg,收率＝57％)。
LC-MS:(M+H)+；m/z＝350.21；
步骤G:6-(2-环丙基苯基)-2,3-二氢-4H-螺[萘-1,3'-吡咯烷]-4,5'-二酮
6.0g多聚磷酸加热至150℃，搅拌下再加入300mg(0.85mmol,1.0eq)3-(3-(2-(2'-环丙基-[1,1'-联苯]-4-基)-5-氧吡咯烷-3-基)丙酸。然后在150℃搅拌1h。经LCMS确认有产物生成，趁热将混合物缓慢倒入冰水中，边加边搅拌。然后用二氯甲烷萃取三次，用30mL饱和食盐水溶液洗涤有机层，无水硫酸钠干燥，减压蒸干得到目标产物的粗品(120mg,收率＝42％)，直接用于下一 步反应。
LC-MS:(M+H)+；m/z＝332.16；
步骤H:6-(2-环丙基苯基)-3,4-二氢-2H-螺[萘-1,3'-吡咯烷]-4-醇
120mg(0.36mmol,1.0eq)6-(2-环丙基苯基)-2,3-二氢-4H-螺[萘-1,3'-吡咯烷]-4,5'-二酮溶于5mL无水四氢呋喃中，在0℃下缓慢加入205mg(5.40mmol,15.0eq)氢化锂铝，70℃搅拌2h。经LCMS确认有产物生成，反应液通过硅藻土过滤，用四氢呋喃洗涤。无水硫酸钠干燥，减压蒸干，得粗品(50mg,收率＝43％)，直接用于下一步反应。
LC-MS:(M+H)+；m/z＝320.22；
步骤I:(6-(2-环丙基苯基)-4-羟基-3,4-二氢-2H-螺[萘-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2基)甲酮
33.0mg(0.234mmol,1.5eq)5-氟吡啶-2-羧酸、60.5mg(0.468mmol,3.0eq)N,N-二异丙基乙胺和89.0mg(0.234mmol,1.5eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯溶于5mL四氢呋喃中，室温搅拌0.5h。加入50mg(0.156mmol,1.0eq)6-(2-环丙基苯基)-3,4-二氢-2H-螺[萘-1,3'-吡咯烷]-4-醇，室温搅拌1.5h。经LCMS确认有产物生成，向其中添加50mL盐水，然后用乙酸乙酯萃取三次，无水硫酸钠干燥，减压蒸干，制备纯化(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)，冻干得白色固体(4.15mg,收率＝6％)。
LC-MS:(M+Na)+；m/z＝465.11；
1H NMR(400MHz,CDCl3)δ8.45-8.35(m,1H),8.02(dd,J＝8.8,4.4Hz,1H),7.59-7.49(m,4H),7.36-7.26(m,4H),4.10-3.86(m,4H),2.91-2.86(m,2H),2.44-2.37(m,1H),2.24-2.14(m,3H),2.10-2.00(m,2H),1.90-1.83(m,1H),0.63-0.50(m,4H)。
实施例2：(5-氯吡啶-2-基)(6-(2-环丙基苯基)-4-羟基-3,4-二氢-2H-螺[萘-1,3'-吡咯烷]-1'-基)甲酮
实验操作参考实施例1中的步骤I，将试剂5-氟吡啶-2-羧酸替换为5-氯吡啶-2-羧酸，经合成得实施例2。
LC-MS:(M+Na)+；m/z＝481.07；
1H NMR(400MHz,CDCl3)δ8.48-8.39(m,1H),8.05(dd,J＝8.8,4.4Hz,1H),7.61-7.50(m,4H),7.37-7.27(m,4H),4.12-3.88(m,4H),2.93-2.88(m,2H),2.45-2.39(m,1H),2.25-2.16(m,3H),2.13-2.00(m,2H),1.92-1.86(m,1H),0.64-0.52(m,4H)。
实施例3：(5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,4'-哌啶]-1'-基)(5-氟吡啶-2-基)甲酮
步骤A:5-溴-1H-茚
将2.00g(9.38mmol,1.0eq)6-溴-2,3-二氢-1H-茚-1-醇溶解在20mL甲苯中，再将180mg(0.94mmol,0.1eq)对甲苯磺酸一水合物加至该反应体系，氮气保护下在65℃搅拌反应3h。降温到室温，加入水30mL和乙酸乙酯80mL，分得有机相，水相用乙酸乙酯(2x60mL)萃取两次,合并有机相，有机相经过盐水洗涤，无水硫酸钠干燥浓缩得到粗品，粗品经柱层析(石油醚)得到油状物(1.50g,收率＝82％)。
1H NMR(400MHz,CDCl3)δ7.52(d,J＝4.0Hz,1H),7.33-7.27(m,2H),6.83-6.80(m,1H),6.61-6.58(m,1H),3.35-3.34(m,2H).
步骤B:5-溴酸叔丁酯[茚-1,4'-哌啶]-1'-羧酸盐
1.50g(7.69mmol,1.0eq)5-溴-1H-茚溶解在20mL四氢呋喃中，降温到 0℃，氮气保护下再将19.4mL(19.2mmol,2.5eq)双三甲基硅基胺基锂滴加加到上述反应体系中，滴完该反应体系在0℃下搅拌1h。然后将溶于20mL四氢呋喃的2.23g(9.23mmol,1.2eq)双(2-氯乙基)氨基甲酸叔丁酯溶液滴加到上述反应液中，滴完自然升温到室温反应16h。经LC-MS结果确认原料反应完全，加入水40mL和乙酸乙酯90mL，分得有机相，水相用乙酸乙酯(2x80mL)萃取两次,合并有机相，有机相经过盐水洗涤，无水硫酸钠干燥浓缩得到粗品，粗品经柱层析(石油醚:乙酸乙酯＝100:1～20:1)得到油状物(2.40g,收率＝86％)。
LC-MS:(M-Boc)+；m/z＝264.12；
步骤C:5-溴-3-羟基-2,3-二氢螺[茚-1,4'-哌啶]-1'-羧酸叔丁酯
100mg(0.28mmol,1.0eq)5-溴酸叔丁酯[茚-1,4'-哌啶]-1'-羧酸盐溶解在5mL无水四氢呋喃中，再将1.1mL(0.56mmol,2.0eq)9-硼双环[3.3.1]壬烷加到上述反应体系中，该反应体系在封管中于70℃反应17h。将反应液降到室温，加入0.55mL 1M的氢氧化钠溶液，再加入0.1mL(30％mw)双氧水，继续搅拌1h，加入乙酸乙酯(50mLx2)萃取两遍，有机相经过盐水洗涤，无水硫酸钠干燥，浓缩干，得到淡黄色油状物(80.0mg,收率＝80％)。
LC-MS:(M-Boc)+；m/z＝282.00；
步骤D:5-溴-2,3-二氢螺[茚-1,4'-哌啶]-3-醇
将80.0mg(0.21mmol,1.0eq)5-溴-3-羟基-2,3-二氢螺[茚-1,4'-哌啶]-1'-羧酸叔丁酯溶解在6mL二氯甲烷中，再将1mL(4.31mmol,30eq)氯化氢的二氧六环溶液加到上述反应体系中，氮气保护条件下于40℃反应1h。经LC-MS结果确认有目标产物生成，将反应液直接浓缩干，得到淡黄色油状物(58.0mg,收率＝98％)。
LC-MS:(M+H)+；m/z＝283.95；
步骤E:(5-溴-3-羟基-2,3-二氢螺[茚-1,4'-哌啶]-1'-基)(5-氟吡啶-2-基)甲酮
将48.0mg(0.34mmol,1.2eq)5-氟吡啶甲酸溶解在6mL四氢呋喃中，再将129mg(0.34mmol,1.0eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯和0.28mL(1.70mmol,6.0eq)N,N-二异丙基乙胺加入到反应体系中，氮气保护下搅拌10min。将80.0mg(0.28mmol,1.0eq)5-溴-2,3-二氢螺[茚-1,4'-哌啶]-3-醇溶解于3mL四氢呋喃的溶液滴加到上述反应体系中。滴完常温搅拌2h，经LC-MS结果确认有目标产物生成，将反应液降到室温，加入水淬灭，加入乙酸乙酯萃取两遍，有机相经过盐水洗涤，无水硫酸钠干燥，浓缩干，再经过柱层析(二氯甲烷/甲醇＝80/1～30/1)得到淡黄色固体(50.0mg,收率＝44％)。
LC-MS:(M+H)+；m/z＝406.89；
步骤F:(5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,4'-哌啶]-1'-基)(5-氟吡啶-2-基)甲酮
将50.0mg(0.12mmol,1.0eq)(5-溴-3-羟基-2,3-二氢螺[茚-1,4'-哌啶]-1'-基)(5-氟吡啶-2-基)甲酮溶解在6mL二氧六环和2mL水中，再将23.9mg(0.15mmol,1.2eq)(2-环丙基苯基)硼酸和78.2mg(0.15mmol,3.0eq)磷酸钾加到上述反应体系中，氮气保护条件下加入18.0mg(0.02mmol,0.1eq)[1,1'-双(二苯基膦)二茂铁]二氯化钯于100℃反应3h。经LC-MS结果确认有目标产物生成，将反应液降到室温，加入水淬灭，加入乙酸乙酯萃取两遍，有机相经过盐水洗涤，无水硫酸钠干燥，浓缩干，样品送制备纯化(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)，冻干得产物为白色固体(10.2mg,收率＝18％)。
LC-MS:(M+H)+；m/z＝443.42；
1H NMR(400MHz,CDCl3)δ8.48-8.46(m,1H),7.78(dd,J＝8.6,4.5Hz,1H),7.56-7.51(m,2H),7.45(d,J＝7.9Hz,1H),7.31-7.27(m,2H),7.26-7.19(m,2H),6.94(d,J＝7.8Hz,1H),5.38-5.37(m,1H),4.81-4.80(m,1H),4.09-4.07(m,1H),3.40-3.38(m,1H),3.13-3.11(m,1H),2.70-2.59(m,1H),2.21-1.97(m,3H),1.95-1.87(m,3H),1.77-1.67(m,1H),0.90-0.85(m,2H),0.76-0.72(m,2H).
19F NMR(376MHz,CDCl3)δ-123.84(d,J＝3.9Hz)。
实施例4：(5-氟吡啶-2-基)(3-羟基-5-(2-异丙基苯基)-2,3-二氢螺[茚-1,4'-哌啶]-1'-基)甲酮
实验操作参考实施例3中的步骤F，将(2-环丙基苯基)硼酸替换为2-异丙基苯硼酸，经合成得实施例4化合物。
LC-MS:(M+H)+；m/z＝445.17。
实施例5和6：(5-(2-环丙基苯基)-3-羟基-3-甲基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮(P1和P2)
步骤A:5-(2-环丙基苯基)-3-羟基-3-甲基-2,3-二氢螺[茚-1,3'-吡咯烷]-2'-酮
0.76g(2.4mmol,1.0eq)5-(2-环丙基苯基)螺[茚-1,3’-吡咯烷]-3,5’(2H)-二酮溶解于25mL无水四氢呋喃中，氮气置换3次。在0℃下滴加4mL(12.0mmol,5.0eq,3M)甲基氯化镁，并在室温下搅拌2h。经LCMS确认原料转化完全有产物生成，向其中添加30mL氯化铵饱和溶液淬灭反应，然后用二氯甲烷萃取三次，用30mL饱和食盐水溶液洗涤有机层，无水硫酸钠干燥，减压蒸干。残余物通过柱层析(DCM/MeOH＝0～20:1)得产物(0.60g,收率＝75％)。
LC-MS:(M+H)+；m/z＝334.21；
步骤B:5-(2-环丙基苯基)-3-甲基-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇
550mg(1.65mmol,1.0eq)5-(2-环丙基苯基)-3-羟基-3-甲基-2,3-二氢螺[茚-1,3'-吡咯烷]-2'-酮溶于50mL无水四氢呋喃中，在0℃下缓慢加入1.25g (32.99mmol,20.0eq)氢化锂铝，70℃搅拌2h。经LCMS确认原料转化完全有产物生成，反应液通过硅藻土过滤，用四氢呋喃洗涤。无水硫酸钠干燥，减压蒸馏浓缩得含产物的反应液。
LC-MS:(M+H)+；m/z＝320.23；
步骤C:(5-(2-环丙基苯基)-3-羟基-3-甲基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮
0.40g(2.82mmol,1.5eq)5-氟吡啶-2-羧酸、0.93mL N,N-二异丙基乙胺和1.07g(2.82mmol,1.5eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯溶于50mL四氢呋喃中，室温搅拌0.5h。加入含5-(2-环丙基苯基)-3-甲基-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇的反应液，室温搅拌2h。经LCMS确认有产物生成，向其中添加50mL盐水，然后用乙酸乙酯萃取三次，无水硫酸钠干燥，减压蒸干，制备纯化(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)冻干得白色固体产物P1(118mg,收率＝14％)和白色固体产物P2(135mg,收率＝16％)。
实施例5(P1)LC-MS:(M+H)+；m/z＝443.18；1H NMR(400MHz,CDCl3)δ8.50-8.40(m,1H),8.11-8.06(m,1H),7.58-7.44(m,3H),7.34-7.30(m,2H),7.26-7.22(m,2H),6.96-6.94(m,1H),4.14-3.87(m,4H),2.44-2.22(m,5H),1.93-1.83(m,1H),1.29(s,3H),0.88-0.85(m,2H),0.79-0.75(m,2H).
实施例6(P2)LC-MS:(M-OH+H)+；m/z＝425.18；1H NMR(400MHz,CDCl3)δ8.49-8.38(m,1H),8.09-8.02(m,1H),7.57-7.45(m,3H),7.33-7.29(m,2H),7.26-7.20(m,2H),6.97-6.94(m,1H),4.14-3.85(m,4H),2.42-2.04(m,4H),1.85-1.68(m,2H),1.61(s,3H),0.90-0.84(m,2H),0.78-0.73(m,2H).
实施例7：(5-(2-环丙基苯基)-3-羟基-3-(三氟甲基)-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮
步骤A:5-(2-环丙基苯基)-3-羟基-3-(三氟甲基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5'-酮
100mg(0.31mmol,1.0eq)5-(2-环丙基苯基)-3-羟基-3-(三氟甲基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5'-酮和270mg(1.86mmol,6.0eq)(三氟甲基)三甲基硅烷溶解于5mL无水四氢呋喃中，氮气置换3次。在0℃下滴加0.3mL四丁基氟化铵，并在室温下搅拌过夜。经LCMS确认有产物生成，将反应液滴加到30mL饱和碳酸氢钠溶液中淬灭，然后用乙酸乙酯萃取三次，用30mL饱和食盐水溶液洗涤有机层，无水硫酸钠干燥，减压蒸干，得粗品(103mg,收率＝86％)。
LC-MS:(M+H)+；m/z＝388.11；
步骤B:5-(2-环丙基苯基)-3-(三氟甲基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇
103mg(0.27mmol,1.0eq)5-(2-环丙基苯基)-3-羟基-3-(三氟甲基)-2,3-二氢螺[茚-1,3'-吡咯烷]-5'-酮溶于5mL无水四氢呋喃中，在0℃下缓慢加入99.0mg(2.66mmol,10.0eq)氢化锂铝，70℃搅拌3h。经LCMS确认有产物生成，反应液通过硅藻土过滤，用四氢呋喃洗涤。无水硫酸钠干燥，减压蒸干，得粗(100mg,收率＝100％)。
LC-MS:(M+H)+；m/z＝373.97；
步骤C:(5-(2-环丙基苯基)-3-羟基-3-(三氟甲基)-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮
57.0mg(0.40mmol,1.5eq)5-氟吡啶-2-羧酸、0.08mL N,N-二异丙基乙胺和153mg(0.40mmol,1.5eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟 磷酸酯溶于10mL四氢呋喃中，室温搅拌0.5h。加入100mg(0.27mmol,1.0eq)5-(2-环丙基苯基)-3-(三氟甲基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇，室温搅拌3h。经LCMS确认有产物生成，向其中添加5mL盐水，然后用乙酸乙酯萃取三次，无水硫酸钠干燥，减压蒸干，制备纯化(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)，冻干得到白色固体(7.00mg,收率＝5％)。
LC-MS:(M+H)+；m/z＝497.29；
1H NMR(400MHz,CDCl3)δ8.40-8.38(m,1H),8.10-8.02(m,1H),7.64-7.62(m,1H),7.57-7.52(m,2H),7.39-7.29(m,2H),7.23-7.20(m,2H),7.00-6.95(m,1H),4.24-3.89(m,4H),2.65-2.35(m,5H),1.80-1.78(m,1H),0.88-0.80(m,2H),0.75-0.71(m,2H).
19F NMR(376MHz,CDCl3)δ-79.51,-122.46.
实施例8：(5-氟吡啶-2-基)(1-羟基-1H-螺[苯并[c][1,2]氧杂硼杂环戊烷-3,3'-吡咯烷]-1'-基)甲酮
步骤A:3-(2-溴苯基)-3-羟基吡咯烷-1-甲酸叔丁酯
3.00g(10.6mmol,1.0eq)邻碘溴苯溶解在20mL无水四氢呋喃后加入0.50g(12.7mmol,1.2eq)氯化锂，置换氮气后将体系降温到-78℃，将6.4mL(12.7mmol,1.2eq)异丙基氯化镁(2M)缓慢滴加到前者，过程中保持体系-78℃，加完后继续在-78℃反应1小时，随后将2.00g(10.6mmol,1.0eq)1-叔丁氧碳基-3-吡咯烷酮的(10mL)无水四氢呋喃溶液缓慢加入至该反应体系，最后在自然回到室温并继续反应18小时。经LC-MS结果确认反应完全后，用10mL饱和氯化铵溶液淬灭，然后用50mL乙酸乙酯萃取三次，取有机相用氯化钠溶液洗涤后，通过无水硫酸钠干燥，减压蒸干。残余物通过柱层析(EA/PE＝0～1:6)得3-(2-溴苯基)-3-羟基吡咯烷-1-甲酸叔丁酯(1.00g,收率＝28％)。
LC-MS:(M+H-Boc)+；m/z＝242,244；
步骤B:1-羟基-1H-螺[苯并[c][1,2]氧杂硼杂环戊烷-3,3'-吡咯烷]-1'-甲酸叔丁酯
66.0mg(0.2mmol,1.0eq)3-(2-溴苯基)-3-羟基吡咯烷-1-甲酸叔丁酯溶解在5mL 1,4-二氧六环中，再将108.9mg(0.5mmol,2.5eq)联硼酸新戊二醇酯、14.1mg(0.02mmol,0.1eq)[1,1'-双(二苯基膦)二茂铁]二氯化钯、37.9mg(0.4mmol,2.0eq)醋酸钾加至该反应体系，置换氮气后升温到80℃反应3小时。经LC-MS结果确认反应完全，将体系降回室温后直接投下一步反应。
LC-MS:(M+Na)+；m/z＝312；
步骤C:1H-螺[苯并[c][1,2]氧杂硼杂环戊烷-3,3'-吡咯烷]-1-醇盐酸盐
待1-羟基-1H-螺[苯并[c][1,2]氧杂硼杂环戊烷-3,3'-吡咯烷]-1'-甲酸叔丁酯反应体系降回室温后加入1mL(12mmol,60.0eq)盐酸二氧六环溶液(4M)，随后在氮气保护条件下室温反应1小时。经LC-MS结果确认反应完全，将体系溶剂减压蒸干，得1H-螺[苯并[c][1,2]氧杂硼杂环戊烷-3,3'-吡咯烷]-1-醇盐酸盐(21.2mg,两步综合收率＝58％)。
LC-MS:(M+H)+；m/z＝190；
步骤D:(5-氟吡啶-2-基)(1-羟基-1H-螺[苯并[c][1,2]氧杂硼杂环戊烷-3,3'-吡咯烷]-1'-基)甲酮
15.8mg(0.10mmol,1.0eq)5-氟-2-吡啶羧酸溶解在1mL N,N-二甲基甲酰胺中，置换氮气后依次加入46.9mg(0.10mmol,1.1eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯和29.0mg(0.20mmol,2.0eq)N,N-二异丙基乙胺，室温下搅拌1分钟后再加入21.2mg(0.10mmol,1.0eq)1H-螺[苯并[c][1,2]氧杂硼杂环戊烷-3,3'-吡咯烷]-1-醇，然后继续搅拌30分钟。经LC-MS结果确认反应完全，用10mL饱和氯化钠溶液稀释，然后用10mL乙酸乙酯萃取三次，取有机相通过无水硫酸钠干燥，减压蒸干。残余物依次通过柱层 析(MeOH/DCM＝0～1:30)和制备色谱(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)纯化得(5-氟吡啶-2-基)(1-羟基-1H-螺[苯并[c][1,2]氧杂硼杂环戊烷-3,3'-吡咯烷]-1'-基)甲酮(15.9mg,收率＝45％)，白色固体。
LC-MS:(M+H)+；m/z＝429；
1H NMR(400MHz,CDCl3)δ8.40(dd,J＝56.3,2.9Hz,1H),8.07(ddd,J＝10.9,8.7,4.6Hz,1H),7.74(t,J＝7.3Hz,1H),7.56-7.46(m,2H),7.45-7.34(m,2H),5.32(d,J＝43.4Hz,1H),4.35-3.96(m,4H),2.50-2.39(m,1H),2.15-2.07(m,1H).
实施例9：(6-(2-环丙基苯基)-1-羟基-1H-螺[苯并[c][1,2]氧杂硼杂环戊烷-3,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮
步骤A:3-溴-2'-环丙基-[1,1'-联苯]-4-胺
1.50g(5.00mmol,1.0eq)2-溴-4-碘苯胺溶解在12.5mL 1,4-二氧六环中，再将0.80g(5.00mmol,1.0eq)2-环丙基苯硼酸、0.30g(0.30mmol,0.05eq)四(三苯基膦)钯、1.40g(10.1mmol,2.0eq)碳酸钾和2.5mL水加至该反应体系，置换氮气后升温到80℃反应2小时。经LC-MS结果确认反应完全，将体系降回室温后用20mL饱和氯化钠溶液稀释，然后用30mL乙酸乙酯萃取三次，取有机相通过无水硫酸钠干燥，减压蒸干。残余物通过柱层析(EA/PE＝0～1:10)得3-溴-2'-环丙基-[1,1'-联苯]-4-胺(791mg,收率＝55％)。
LC-MS:(M+H)+；m/z＝288；290；
步骤B:3'-溴-2-环丙基-4'-碘-1,1'-联苯
733mg(2.50mmol,1.0eq)3-溴-2'-环丙基-[1,1'-联苯]-4-胺溶解在4mL无水四氢呋喃后在搅拌下加入8mL浓盐酸，将体系降温到0℃后，将263mg (3.80mmol,1.5eq)亚硝酸钠的(0.9mL)水溶液缓慢滴加到前者，过程中保持体系0-5℃，加完后继续在0℃反应30分钟，随后将1.69g(10.2mmol,4.0eq)碘化钾缓慢加入至该反应体系，最后在0℃反应30分钟。经LC-MS结果确认反应完全后，用10mL 10％亚硫酸钠水溶液淬灭，然后用50mL乙酸乙酯萃取三次，取有机相依次用饱和碳酸钠溶液和饱和氯化钠溶液洗涤后，通过无水硫酸钠干燥，减压蒸干。残余物通过柱层析(PE)得3'-溴-2-环丙基-4'-碘-1,1'-联苯(641mg,收率＝63％)。
1H NMR(400MHz,CDCl3)δ7.79(dd,J＝7.1,3.1Hz,1H),7.64(dd,J＝7.1,2.2Hz,1H),7.22-7.07(m,3H),7.01-6.99(m,1H),6.87-6.86(m,1H),1.73-1.71(m,1H),0.80-0.74(m,2H),0.64-0.55(m,2H).
步骤C:3-(3-溴-2'-环丙基-[1,1'-联苯]-4-基)-3-羟基吡咯烷-1-甲酸叔丁酯
389mg(1.00mmol,1.0eq)3'-溴-2-环丙基-4'-碘-1,1'-联苯溶解在6mL无水四氢呋喃后加入53.7mg(1.30mmol,1.3eq)氯化锂，置换氮气后将体系降温到-78℃，将0.6mL(1.30mmol,1.3eq)异丙基氯化镁(2M)缓慢滴加到前者，过程中保持体系-78℃，加完后继续在-78℃反应1小时，随后将253mg(1.40mmol,1.4eq)1-叔丁氧碳基-3-吡咯烷酮的(4mL)无水四氢呋喃溶液缓慢加入至该反应体系，最后在自然回到室温并继续反应18小时。经LC-MS结果确认反应完全后，用5mL饱和氯化铵溶液淬灭，然后用50mL乙酸乙酯萃取三次，取有机相用氯化钠溶液洗涤后，通过无水硫酸钠干燥，减压蒸干。残余物通过柱层析(EA/PE＝0～1:6)得3-(3-溴-2'-环丙基-[1,1'-联苯]-4-基)-3-羟基吡咯烷-1-甲酸叔丁酯(107mg,收率＝24％)。
LC-MS:(M+H-Boc-OH)+；m/z＝340；342；
步骤D:6-(2-环丙基苯基)-1-羟基-1H-螺[苯并[c][1,2]氧杂硼杂环戊烷-3,3'-吡咯烷]-1'-甲酸叔丁酯
107mg(0.20mmol,1.0eq)3-(3-溴-2'-环丙基-[1,1'-联苯]-4-基)-3-羟基吡咯烷-1-羧酸叔丁酯溶解在6mL 1,4-二氧六环中，再将132mg(0.60mmol,2.5eq) 联硼酸新戊二醇酯、17.1mg(0.02mmol,0.1eq)[1,1'-双(二苯基膦)二茂铁]二氯化钯、45.7mg(0.50mmol,2.eq)醋酸钾加至该反应体系，置换氮气后升温到80℃反应3小时。经LC-MS结果确认反应完全，将体系降回室温后直接投下一步反应。
LC-MS:(M+Na)+；m/z＝428；
步骤E:6-(2-环丙基苯基)-1H-螺[苯并[c][1,2]氧杂硼杂环戊烷-3,3'-吡咯烷]-1-醇
待6-(2-环丙基苯基)-1-羟基-1H-螺[苯并[c][1,2]氧杂硼杂环戊烷-3,3'-吡咯烷]-1'-甲酸叔丁酯反应体系降回室温后加入3mL(12mmol,60.0eq)盐酸二氧六环溶液(4M)，随后在氮气保护条件下室温反应2小时。经LC-MS结果确认反应完全，将体系溶剂减压蒸干，得6-(2-环丙基苯基)-1H-螺[苯并[c][1,2]氧杂硼杂环戊烷-3,3'-吡咯烷]-1-醇(62.2mg,两步综合收率＝88％)。
LC-MS:(M+H)+；m/z＝306；
步骤F:(6-(2-环丙基苯基)-1-羟基-1H-螺[苯并[c][1,2]氧杂硼杂环戊烷-3,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮
28.8mg(0.20mmol,1.0eq)5-氟-2-吡啶羧酸溶解在1mL N,N-二甲基甲酰胺中，置换氮气后依次加入85.3mg(0.20mmol,1.1eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯和52.7mg(0.40mmol,2.0eq)N,N-二异丙基乙胺，室温下搅拌1分钟后再加入62.2mg(0.20mmol,1.0eq)6-(2-环丙基苯基)-1H-螺[苯并[c][1,2]氧杂硼杂环戊烷-3,3'-吡咯烷]-1-醇，然后继续搅拌30分钟。经LC-MS结果确认反应完全，用10mL饱和氯化钠溶液稀释，然后用10mL乙酸乙酯萃取三次，取有机相通过无水硫酸钠干燥，减压蒸干。残余物依次通过柱层析(MeOH/DCM＝0～1:50)和制备色谱(流动相A:0.1％三氟乙酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)纯化得(6-(2-环丙基苯基)-1-羟基-1H-螺[苯并[c][1,2]氧杂硼杂环戊烷-3,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮(11.9mg,收率＝14％)，白色固体。
LC-MS:(M+H)+；m/z＝429；
1H NMR(400MHz,CDCl3)δ8.54-8.27(m,1H),8.07(dd,J＝9.4,4.6Hz,1H),7.79(d,J＝7.4Hz,1H),7.64(dd,J＝7.9,1.6Hz,1H),7.55-7.47(m,1H),7.42(dd,J＝14.9,7.8Hz,1H),7.29(s,1H),7.23-7.19(m,2H),6.98-6.92(m,1H),4.40-4.01(m,4H),2.59-2.44(m,1H),2.27-2.13(m,1H),2.02-2.00(m,1H),0.88-0.83(m,2H),0.72-0.71(m,2H).
实施例10：(5-氯吡啶-2-基)(6-(2-环丙基苯基)-1-羟基-1H-螺[苯并[c][1,2]氧杂硼杂环戊烷-3,3'-吡咯烷]-1'-基)甲酮
实验操作参考实施例9中的步骤F，将5-氟-2-吡啶羧酸替换为5-氯-2-吡啶羧酸，经合成得化合物实施例10。
LC-MS:(M+H)+；m/z＝445.09。
实施例11：(5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基-3,5',5'-d3)(5-氟吡啶-2-基)甲酮
步骤A:5-(2-环丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3,5',5'-d3-3-醇
100mg(0.31mmol,1.0eq)5-(2-环丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇溶于5mL无水四氢呋喃中，在0℃下缓慢加入120mg(3.70mmol,12.0eq)氘代氢化锂铝，70℃搅拌3h。经LCMS确认有产物生成，反应液通过硅藻土过滤，用四氢呋喃洗涤。无水硫酸钠干燥，减压蒸干，得粗品(100mg,收率＝104％)。
LC-MS:(M+H)+；m/z＝309.19；
步骤B:(5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基 -3,5',5'-d3)(5-氟吡啶-2-基)甲酮
77.0mg(0.48mmol,1.5eq)5-氯吡啶-2-羧酸、0.16mL N,N-二异丙基乙胺和187mg(0.48mmol,1.5eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯溶于10mL四氢呋喃中，室温搅拌0.5h。加入100mg(0.32mmol,1.0eq)5-(2-环丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3,5',5'-d3-3-醇，室温搅拌3h。经LCMS确认有产物生成，向其中添加5mL盐水，然后用乙酸乙酯萃取三次，无水硫酸钠干燥，减压蒸干，制备纯化(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)，得到白色固体(14.0mg,收率＝10％)。
LC-MS:(M+H)+；m/z＝432.19；
1H NMR(400MHz,CDCl3)δ8.47-8.30(m,1H),8.05-8.01(m,1H),7.54-7.42(m,3H),7.32-7.25(m,2H),7.21-7.14(m,2H),6.93-6.85(m,1H),4.14-3.77(m,2H),2.66-2.00(m,5H),1.92-1.81(m,1H),0.87-0.82(m,2H),0.74-0.70(m,2H).
19F NMR(376MHz,CDCl3)δ-123.19(d,J＝24.8Hz)。
实施例12：(5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基-3-d)(5-氟吡啶-2-基)甲酮
步骤A:5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-5'-酮-3-d
150mg(0.47mmol,1.0eq)5-溴螺[茚-1,3’-吡咯烷]-3,5’(2H)-二酮溶于5mL无水四氢呋喃中，在0℃下缓慢加入110mg(0.57mmol,1.2eq.)氘代硼氢化钠，室温搅拌2h。经LCMS确认有产物生成，反应液用水淬灭，无水硫酸钠干燥，减压蒸干，得粗品(148mg,收率＝97％)。
LC-MS:(M+H)+；m/z＝321.10；
步骤B:5-(2-环丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-d-3-醇
148mg(0.46mmol,1.0eq)5-溴螺[茚-1,3’-吡咯烷]-3,5’(2H)-二酮溶于5mL无水四氢呋喃中，在0℃下缓慢加入263mg(6.92mmol,15.0eq)氢化锂铝，70℃搅拌3h。经LCMS确认有产物生成，反应液通过硅藻土过滤，用四氢呋喃洗涤。无水硫酸钠干燥，减压蒸干，得粗品(142mg,收率＝100％)。
LC-MS:(M+H)+；m/z＝307.11；
步骤C:(5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基-3-d)(5-氟吡啶-2-基)甲酮
103mg(0.73mmol,1.5eq)5-氟吡啶-2-羧酸、0.24mL N,N-二异丙基乙胺和279mg(0.73mmol,1.5eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯溶于5mL四氢呋喃中，室温搅拌0.5h。加入142mg(0.43mmol,1.0eq)5-(2-环丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇，室温搅拌1.5h。经LCMS确认有产物生成，向其中添加10mL盐水，然后用乙酸乙酯萃取三次，无水硫酸钠干燥，减压蒸干，制备纯化(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)，得到白色固体(12.0mg,收率＝5.7％)。
LC-MS:(M+H)+；m/z＝430.06；
1H NMR(400MHz,CDCl3)δ8.43(d,J＝38.7Hz,1H),8.06-8.03(m,1H),7.56-7.43(m,3H),7.32-7.26(m,2H),7.24-7.19(m,2H),6.92(dd,J＝7.9,4.2Hz,1H),4.24-3.71(m,4H),2.67-2.53(m,1H),2.31-2.01(m,4H),1.92-1.82(m,1H),0.89-0.82(m,2H),0.74-0.70(m,2H).
19F NMR(376MHz,CDCl3)δ-122.82(d,J＝10.5Hz)。
实施例13：(5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-羟基-6-甲基吡啶-2-基)甲酮
步骤A:5-羟基-6-甲基吡啶酸的合成
0.97g(5.16mmol,1.0eq)6-溴-2-甲基吡啶-3-醇溶于30mL N,N-二甲基甲酰胺中，在冰水浴下加入2.37g(51.6mmol,10.0eq)甲酸、1.57g(15.5mmol,3.0eq)三乙胺、23.2mg(0.10mmol,0.02eq)醋酸钯和0.03g(0.15mmol,0.03eq)4,5-双二苯基膦-9,9-二甲基氧杂蒽，一氧化碳置换3次，80℃搅拌过夜。萃取之后产物大部分在水相，制备纯化(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)，冻干得产物(0.78g,收率＝99％)。
LC-MS:(M-H)-；m/z＝151.87；
步骤B:(5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-羟基-6-甲基吡啶-2-基)甲酮
150mg(0.98mmol,3.0eq)5-羟基-6-甲基吡啶酸、0.16mL N,N-二异丙基乙胺和126mg(0.98mmol,3.0eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯溶于10mL四氢呋喃中，室温搅拌0.5h。加入100mg(0.33mmol,1.0eq)5-(2-环丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇，室温搅拌3h。经LCMS确认有产物生成，向其中添加5mL盐水，然后用乙酸乙酯萃取三次，无水硫酸钠干燥，减压蒸干，制备纯化(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)，冻干得白色固体(5.0mg,收率＝3.4％)。
LC-MS:(M+H)+；m/z＝441.21；
1H NMR(400MHz,CDCl3)δ7.67(dd,J＝11.2,8.3Hz,1H),7.52(d,J＝6.2Hz,1H),7.46(dd,J＝7.9,1.7Hz,1H),7.35-7.30(m,2H),7.25-7.21(m,2H),7.11(dd,J＝14.0,8.3Hz,1H),6.96-6.93(m,1H),5.40-5.36(m,2H),4.17-3.80(m,4H),2.59-2.01(m,8H),1.93-1.87(m,1H),0.90-0.85(m,2H),0.76-0.72(m,2H).
实施例14：(5-氯吡啶-2-基)(5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'- 吡咯烷]-1'-基)甲酮
77mg(0.49mmol,1.5eq)5-氟吡啶-2-羧酸、0.16mL N,N-二异丙基乙胺和187mg(0.49mmol,1.5eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯溶于10mL四氢呋喃中，室温搅拌0.5h。加入100mg(0.33mmol,1.0eq)5-(2-环丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇，室温搅拌3h。经LCMS确认原料转化完全有产物生成，向其中添加20mL盐水，然后用乙酸乙酯萃取三次，无水硫酸钠干燥，减压蒸干，制备纯化(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)，冻干得白色固体(32.0mg,收率＝22％)。
LC-MS:(M+H)+；m/z＝445.08；
1H NMR(400MHz,CDCl3)δ8.61-8.50(m,1H),7.99-7.95(m,1H),7.84-7.78(m,1H),7.55-7.51(m,1H),7.47-7.44(m,1H),7.34-7.29(m,2H),7.26-7.19(m,2H),6.94(dd,J＝7.7,4.1Hz,1H),5.41-5.35(m,1H),4.26-3.80(m,4H),2.30-2.20(m,5H),1.93-1.85(m,1H),0.89-0.84(m,2H),0.76-0.72(m,2H).
实施例15：(5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮
291mg(2.06mmol,1.5eq)5-氟吡啶-2-羧酸、0.68mL N,N-二异丙基乙胺和784mg(2.06mmol,1.5eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯溶于65mL四氢呋喃中，室温搅拌0.5h。加入420mg(1.37mmol,1.0eq)5-(2-环丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇，室温搅拌1.5h。经LCMS确认有产物生成，向其中添加50mL盐水，然后用乙酸乙酯萃取三次，无水硫酸钠干燥，减压蒸干，制备纯化(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:7mL/min)，冻干得白色固体(83.0mg,收率＝15％)。
LC-MS:(M+H)+；m/z＝429.20；
1H NMR(400MHz,CDCl3)δ8.49-8.38(m,1H),8.09-8.04(m,1H),7.56-7.44(m,3H),7.34-7.30(m,2H),7.24-7.21(m,2H),6.95(dd,J＝7.8,4.2Hz,1H),5.41-5.30(m,1H),4.17-3.83(m,4H),2.29-2.03(m,5H),1.94-1.85(m,1H),0.90-0.84(m,2H),0.76-0.72(m,2H).
实施例16：(5-氟吡啶-2-基)(3-羟基-5-(2-异丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)甲酮
将23.0mg(0.16mmol,1.0eq)5-氟吡啶-2-羧酸，74.2mg(0.41mmol,1.2eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，63.0mg(0.48mmol,3.0eq)N,N-二异丙基乙胺，3mL四氢呋喃加入25mL反应瓶，氮气保护下，反应液在室温搅拌10分钟之后，称量50.0mg(0.16mmol,1.0eq)5-(2-异丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇溶于3mL四氢呋喃，缓慢加入至反应液，室温搅拌1小时。经TLC(DCM:MeOH＝20:1)点板，确认原料完全反应。反应液浓缩干，送制备纯化(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)，冻干得白色固体纯品(11.2mg,收率＝16％)。
LC-MS:(M+H)+；m/z＝431.15；
1H NMR(400MHz,CDCl3)δ8.47-8.37(m,1H),8.07-8.03(m,1H),7.55-7.47(m,1H),7.40-7.33(m,3H),7.0-7.26(m,2H),7.21-7.13(m,2H),5.37-5.29(m,1H),4.25-3.79(m,4H),3.11-3.00(m,1H),2.69-2.37(m,2H),2.28-2.18(m,1H),2.16-2.00(m,1H),1.89-1.83(m,1H),1.19(d,J＝6.8Hz,6H).
19F NMR(376MHz,CDCl3)δ-123.29.
实施例17：(2-氯噻唑-4-基)(5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)甲酮
实验操作参考实施例15，将5-氟吡啶-2-羧酸替换为2-氯噻唑-4-甲酸，经 合成制备纯化得化合物实施例17。
LC-MS:(M+H)+；m/z＝451.08；
1H NMR(400MHz,CDCl3)δ8.08-8.04(m,1H),7.54-7.48(m,1H),7.46-7.41(m,1H),7.32-7.26(m,2H),7.25-7.21(d,J＝6.1Hz,2H),6.92(d,J＝7.9Hz,1H),5.37(s,1H),4.33-3.75(m,4H),2.66-2.04(m,4H),2.03-1.98(m,1H),1.90-1.86(m,1H),0.88-0.84(m,2H),0.75-0.71(m,2H).
实施例18：(2-氯噻唑-4-基)(3-羟基-5-(2-异丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)甲酮
将26.7mg(0.16mmol,1.0eq)2-氯噻唑-4-羧酸，74.2mg(0.41mmol,1.2eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，63.0mg(0.48mmol,3.0eq)N,N-二异丙基乙胺，3mL四氢呋喃加入25mL反应瓶，氮气保护下，反应液在室温搅拌10分钟之后，称量50.0mg(0.16mmol,1.0eq)5-(2-异丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇溶于3mL四氢呋喃，缓慢加入至反应液，室温搅拌1小时。经TLC(DCM/MeOH＝20/1)点板，确认原料完全反应。反应液浓缩干，送制备纯化(流动相A:0.1％甲酸；流动相B:乙腈；梯度：30％-70％B，55分钟；流量:70mL/min)，冻干得白色固体纯品(5.11mg,收率＝7％)。
LC-MS:(M-OH)+；m/z＝435.07；
1H NMR(400MHz,CDCl3)δ8.08-8.04(m,1H),7.45-7.28(m,4H),7.26-7.11(m,3H),5.36-5.33(m,1H),4.37-3.73(m,4H),3.12-3.00(m,1H),2.65-1.99(m,5H),1.18(d,J＝6.8Hz,6H).
实施例19：(5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(6-环丙基吡啶-2-基)甲酮
117.4mg(0.72mmol,1.5eq)6-环丙基吡啶甲酸、0.24mL N,N-二异丙基乙 胺和279mg(0.72mmol,1.5eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯溶于5mL四氢呋喃中，室温搅拌0.5h。加入150.0mg(0.48mmol,1.0eq)5-(2-环丙基苯基)-2,3-二氢螺环[茚-1,3'-吡咯烷]-3-醇，室温搅拌3h。经LC-MS确认有产物生成，向其中添加5mL盐水，然后用乙酸乙酯萃取三次，无水硫酸钠干燥，减压蒸干，制备纯化(流动相A：0.1％甲酸；流动相B：乙腈；梯度：30％-70％B，55分钟；流量：70mL/min)，冻干得到白色固体(53.0mg,收率＝24％)。
LC-MS:(M+H)+；m/z＝451.19；
1H NMR(400MHz,CDCl3)δ7.72-7.59(m,2H),7.52-7.48(m,1H),7.46-7.40(m,1H),7.34-7.27(m,1H),7.25-7.15(m,4H),6.92(dd,J＝7.8,4.0Hz,1H),5.39-5.27(m,1H),4.21-3.77(m,4H),2.68-2.51(m,1H),2.41-2.14(m,2H),2.11-2.00(m,2H),1.91-1.83(m,2H),1.08-0.99(m,2H),0.96-0.92(m,2H),0.89-0.82(m,2H),0.77-0.69(m,2H).
实施例20：(6-环丙基吡啶-2-基)(3-羟基-5-(2-异丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)甲酮
将26.6mg(0.16mmol,1.0eq)6-环丙基吡啶甲酸，74.2mg(0.41mmol,1.2eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，63.0mg(0.48mmol,3.0eq)N,N-二异丙基乙胺，3mL四氢呋喃加入25mL反应瓶，氮气保护下，反应液在室温搅拌10分钟，之后，称量50.0mg(0.16mmol,1.0eq)5-(2-异丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇溶于3mL四氢呋喃，缓慢加入至反应液，室温搅拌1小时。经TLC(DCM/MeOH＝20/1)点板，确认原料完全反应。反应液浓缩干，送制备纯化(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)，得到黄色油状纯品(7.93mg,收率＝10％)。
LC-MS:(M+H)+；m/z＝453.16；
1H NMR(400MHz,CDCl3)δ7.84-7.52(m,3H),7.41-7.28(m,4H),7.24-7.13(m,3H),5.42-5.27(m,1H),4.17-3.80(m,4H),3.07-2.97(m,1H),2.49-2.06(m,6H),1.20(d,J＝6.6Hz,6H),1.07-0.94(m,4H).
分别对化合物实施例15、16、17、18、19和20进行超临界流体色谱(SFC)方法分离立体异构体制备得表1中的实施例。
分析条件:
仪器:WATERS 150 preparative SFC(SFC-26)
柱:ChiralCel OD,250×30mm I.D.,10μm
压强:100bar
柱温:38℃
波长:220nm
流动相A:CO2；流动相B:甲醇；梯度:30％B，9.5分钟；流速:150mL/min
表1:实施例21～44




实施例45：((3R)-5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮
步骤A:(3R)-5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-5'-酮
50.0mg(0.16mmol,1.0eq)5-溴螺[茚-1,3’-吡咯烷]-3,5’(2H)-二酮溶于5mL无水四氢呋喃中，加入4.37mg(0.016mmol,0.1eq)(S)-3,3-二苯基-1-甲基吡咯烷酮[1,2-c]-1,3,2-氧杂硼杂环戊烷和4.37mg(0.096mmol,0.6eq)硼烷二甲硫醚，室温搅拌3h。经LCMS确认有产物生成，反应液用甲醇淬灭，减压蒸干，得粗品(46.0mg,收率＝91％)。
LC-MS:(M+H)+；m/z＝320.16；
步骤B:(3R)-5-(2-环丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇
46.0mg(0.14mmol,1.0eq)(3R)-5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-5'-酮溶于5mL无水四氢呋喃中，在0℃下缓慢加入55.0mg(1.40mmol,10.0eq)氢化锂铝，70℃搅拌2h。经LCMS确认有产物生成，反应液通过硅藻土过滤，用四氢呋喃洗涤。无水硫酸钠干燥，减压蒸干，得粗品(39.0mg,收率＝88％)。
LC-MS:(M+H)+；m/z＝306.17；
步骤C:((3R)-5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮
27.0mg(0.19mmol,1.5eq)5-氟吡啶-2-羧酸、0.06mL N,N-二异丙基乙胺和73.0mg(0.19mmol,1.5eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯溶于5mL四氢呋喃中，室温搅拌0.5h。加入39.0mg(0.13mmol,1.0eq)(3R)-5-(2-环丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇，室温搅拌1.5h。经LCMS确认有产物生成，向其中添加5mL盐水，然后用乙酸乙酯萃取三次，无水硫酸钠干燥，减压蒸干，制备纯化(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B,55分钟；流量:70mL/min)，得到白色固体(8.00mg,收率＝13％,dr＝86:14)。
LC-MS:(M+H)+；m/z＝429.20；
1H NMR(400MHz,CDCl3)δ8.44(dd,J＝38.5,3.2Hz,1H),8.09-8.04(m,1H),7.56-7.44(m,3H),7.34-7.19(m,4H),6.94(dd,J＝7.9,4.2Hz,1H),5.42-5.30(m,1H),4.27-3.80(m,4H),2.70-2.03(m,5H),1.94-1.85(m,1H),0.89-0.84(m,2H),0.76-0.72(m,2H).
19F NMR(376MHz,CDCl3)δ-126.50(d,J＝20.5Hz).
实施例46：((3S)-5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮
步骤A:(3S)-5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-5'-酮
50.0mg(0.164mmol,1.0eq)5-溴螺[茚-1,3’-吡咯烷]-3,5’(2H)-二酮溶于5mL无水四氢呋喃中，加入4.37mg(0.016mmol,0.1eq)(R)-3,3-二苯基-1-甲基吡咯烷酮[1,2-c]-1,3,2-氧杂硼杂环戊烷和4.37mg(0.096mmol,0.6eq)硼烷二甲硫醚，室温搅拌3h。经LCMS确认有产物生成，反应液用甲醇淬灭，减压蒸干，得粗品(48.0mg,收率＝95％)。
LC-MS:(M+H)+；m/z＝320.14；
步骤B:(3S)-5-(2-环丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇
48.0mg(0.15mmol,1.0eq)(3S)-5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-5'-酮溶于5mL无水四氢呋喃中，在0℃下缓慢加入57.0mg(1.5mmol,10.0eq)氢化锂铝，70℃搅拌2h。经LCMS确认有产物生成，反应液通过硅藻土过滤，用四氢呋喃洗涤。无水硫酸钠干燥，减压蒸干，得粗品(43.0mg,收率＝93％)。
LC-MS:(M+H)+；m/z＝306.16；
步骤C:((3S)-5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮
30.0mg(0.21mmol,1.5eq)5-氟吡啶-2-羧酸、0.07mL N,N-二异丙基乙胺和80.0mg(0.21mmol,1.5eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯溶于5mL四氢呋喃中，室温搅拌0.5h。加入43.0mg(0.14mmol,1.0eq)(3S)-5-(2-环丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇，室温搅拌1.5h。经LCMS确认有产物生成，向其中添加5mL盐水，然后用乙酸乙酯萃取三次，无水硫酸钠干燥，减压蒸干，制备纯化(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)，得到白色固体(2.20mg,收率＝4.0％,dr＝75:15)。
LC-MS:(M+H)+；m/z＝429.20；
1H NMR(400MHz,CDCl3)δ8.44(dd,J＝38.5,3.2Hz,1H),8.09-8.04(m,1H),7.56-7.44(m,3H),7.34-7.19(m,4H),6.94(dd,J＝7.9,4.2Hz,1H),5.42-5.30(m,1H),4.27-3.80(m,4H),2.70-2.03(m,5H),1.94-1.85(m,1H),0.89-0.84(m,2H),0.76-0.72(m,2H).
19F NMR(376MHz,CDCl3)δ-126.82(d,J＝22.5Hz).
实施例47：(5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(6-(甲氧基甲基)吡啶-2-基)甲酮
步骤A:6-(甲氧基甲基)吡啶甲酸甲酯
1.00g(5.98mmol,1.0eq)6-(羟甲基)吡啶甲酸甲酯溶解在30mL无水四氢呋喃中，氮气置换3次。在0℃下加入0.36g(8.97mmol,1.5eq)氢化钠，室温搅拌0.5h。然后在0℃下滴加1.70g(12.0mmol,2.0eq)碘甲烷，室温搅拌过夜。经LCMS确认原料反应完，加50mL水淬灭，然后用二氯甲烷萃取三次，用50mL饱和食盐水溶液洗涤有机层，无水硫酸钠干燥，减压蒸干。残余物通过柱层析(DCM/MeOH＝0～20:1)得产物(222mg,收率＝20％)。
LC-MS:(M+H)+；m/z＝182.04；
步骤B:6-(甲氧基甲基)吡啶甲酸
220mg(1.21mmol,1.0eq)6-(甲氧基甲基)吡啶甲酸甲酯溶解在3mL四氢呋喃中，再加入3mL氢氧化钠溶液(0.5mol/L)，室温搅拌3h。经LCMS确认有产物生成，反应液用盐酸溶液(1.0mol/L)稀释至酸性，减压蒸干，得粗品(0.15g,收率＝74％)。
LC-MS:(M-H)+；m/z＝168.05；
步骤C:(5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(6-(甲氧甲基)吡啶-2-基)甲酮
41.0mg(0.24mmol,1.5eq)6-(甲氧基甲基)吡啶-2-羧酸、0.08mL N,N-二异丙基乙胺和93mg(0.24mmol,1.5eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯溶于10mL四氢呋喃中，室温搅拌0.5h。加入50.0mg(0.16mmol,1.0eq)5-(2-环丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇，室温搅拌3h。经LCMS确认有产物生成，向其中添加5mL盐水，然后用乙酸乙酯萃取三次，无水硫酸钠干燥，减压蒸干，制备纯化(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)，得到白色固体(11.0mg,收率＝15％)。
LC-MS:(M+H)+；m/z＝455.16；
1H NMR(400MHz,CDCl3)δ7.86-7.76(m,2H),7.53-7.41(m,3H),7.32-7.26(m,2H),7.22-7.17(m,2H),6.93-6.90(m,1H),5.38-5.27(m,1H),4.63-4.55(m,2H),4.08-3.78(m,4H),3.50-3.45(m,3H),2.68-2.35(m,2H),2.26-2.17(m,1H),2.14-2.00(m,2H),1.91-1.82(m,1H),0.89-0.82(m,2H),0.74-0.69(m,2H).
实施例48：(5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(6-(甲氨基)吡嗪-2-基)甲酮
将24.5mg(0.16mmol,1.0eq)6-(甲基氨基)吡嗪-2-羧酸，74.2mg(0.41mmol,1.2eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，63.0mg(0.48mmol,3.0eq)N,N-二异丙基乙胺，3mL四氢呋喃加入25mL反应瓶，氮气保护下，反应液在室温搅拌10分钟，之后，称量50.0mg(0.16mmol,1.0eq)5-(2-异丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇溶于3mL四氢呋喃，缓慢加入至反应液，室温搅拌1小时。经TLC(DCM:MeOH＝20:1)点板，确认原料完全反应。反应液浓缩干，送制备纯化(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)，冻干得白色固体纯品(8.42mg,收率＝12％)。
LC-MS:(M+H)+；m/z＝441.14；
1H NMR(400MHz,CDCl3)δ8.29(d,J＝18.5Hz,1H),8.03-7.96(m,1H),7.53-7.49(m,1H),7.47-7.42(m,1H),7.32-7.27(m,1H),7.26-7.23(m,1H),7.22-7.19(m,2H),6.92(dd,J＝8.0,4.1Hz,1H),5.40-5.28(m,1H),4.21-4.13(m,2H),3.97-3.78(m,3H),3.04-2.94(m,3H),2.66-1.97(m,5H),1.91-1.82(m,1H),0.88-0.82(m,2H),0.74-0.69(m,2H).
通过上文描述的实施例48的方法制备表2中的实施例，中间体I3和所需的不同羧酸通过缩合反应制备得到。
表2:实施例49～56

实施例57：(3-羟基-5-(2-异丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(吡唑并[1,5-a]嘧啶-5-基)甲酮
将26.6mg(0.16mmol,1.0eq)吡唑并[1,5-a]嘧啶-5-羧酸，74.2mg(0.41mmol,1.2eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，63.0mg(0.48mmol,3.0eq)N,N-二异丙基乙胺，3mL四氢呋喃加入25mL反应瓶，氮气保护下，反应液在室温搅拌10分钟之后，称量50.0mg(0.16mmol,1.0eq)5-(2-异丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇溶于3mL四氢呋喃，缓慢加入至反应液，室温搅拌1小时。经TLC(DCM/MeOH＝20:1)点板，确认原料完全反应。反应液浓缩干，送制备纯化(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)，得到白色固体纯品(8.54mg,收率＝11％)。
LC-MS:(M+H)+；m/z＝453.37；
1H NMR(400MHz,CDCl3)δ8.79-8.74(m,1H),8.22-8.17(m,1H),7.53-7.48(m,1H),7.41-7.26(m,5H),7.23-7.13(m,2H),6.81-6.73(m,1H),5.41-5.30(m,1H),4.41-3.81(m,4H),3.09-2.99(m,1H),2.70-2.39(m,2H),2.30-2.00(m,3H),1.17(d,J＝6.8Hz,6H).
通过上文描述的实施例57的方法制备表3中的实施例，中间体I4和所需的不同羧酸通过缩合反应制备得到。
表3:实施例58～77




实施例78：(5-氟吡啶-2-基)(3-羟基-5-(5,6,7,8-四氢咪唑并[1,2-a]吡啶-6-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)甲酮
步骤A:5-(咪唑并[1,2-a]吡啶-6-基)螺[茚-1,3'-吡咯烷]-3,5'(2H)-二酮
将100mg(0.36mmol,1.0eq)5-溴螺[茚-1,3'-吡咯烷]-3,5'(2H)-二酮，105mg(0.43mmol,1.2eq)6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)咪唑并[1,2-a]吡啶，227mg(1.07mmol,3.0eq)磷酸钾，26.1mg(0.04mmol,0.1eq)[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物，8mL(1,4-二氧六环/水＝4:1)混合溶剂加入20mL史莱克管中，氮气置换三次，于100℃反应3小时。经LCMS确认有目标产物生成。将该反应液加入10mL水淬灭，再用乙酸乙酯(20mL)萃取3次，合并有机相，干燥，浓缩，粗品经柱层析纯化(PE/EA＝50:1～1/1)得到105mg棕色油状产物(收率＝93％)。
LC-MS:(M+H)+；m/z＝318.09；
步骤B:5-(5,6,7,8-四氢咪唑并[1,2-a]吡啶-6-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇
50mL史莱克管中将120mg(0.38mmol,1.0eq)5-(咪唑并[1,2-a]吡啶-6-基)螺[茚-1,3'-吡咯烷]-3,5'(2H)-二酮溶解在5mL四氢呋喃中，氮气保护下，慢慢加入144mg(3.78mmol,10.0eq)四氢锂铝。加完将体系升温到70℃反应3小 时。经LCMS确认有目标产物生成。反应液降温到-10℃，慢慢滴加3mL水淬灭反应，再加入20mL四氢呋喃于反应体系，硅藻土过滤，使用四氢呋喃(20mLx3)洗涤滤饼。滤液浓干，得到158mg黄色油状液体粗品。直接进行下一步反应。
LC-MS:(M+H)+；m/z＝310.12；
步骤C:(5-氟吡啶-2-基)(3-羟基-5-(5,6,7,8-四氢咪唑[1,2-a]吡啶-6-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)甲酮
将65.7mg(0.47mmol,1.2eq)5-氟吡啶-2-羧酸，177mg(0.47mmol,1.2eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，301mg(2.33mmol,6.0eq)N,N-二异丙基乙胺，6mL四氢呋喃加入25mL反应瓶，氮气保护下，反应液在室温搅拌10分钟，然后将120mg(0.39mmol,1.0eq)5-(5,6,7,8-四氢咪唑并[1,2-a]吡啶-6-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇溶于4mL四氢呋喃的溶液加入反应液，室温搅拌2小时。经LCMS确认有目标产物生成。反应液浓缩干，送制备纯化(流动相A:0.1％甲酸的水；流动相B:乙腈；梯度：30％-70％B，55分钟；流量：70mL/min)，得到白色固体纯品(25.2mg,收率＝15％)。
LC-MS:(M+H)+；m/z＝433.15；
1H NMR(400MHz,CDCl3)δ8.46-8.31(m,1H),8.02-7.91(m,1H),7.54-7.44(m,1H),7.22-6.83(m,5H),5.28-5.18(m,2H),4.11-3.56(m,6H),2.60-2.19(m,2H),2.13-1.94(m,5H),1.32-1.14(m,3H).
19F NMR(376MHz,CDCl3)δ-122.93(d,J＝75.2Hz).
实施例79：(5-氟吡啶-2-基)(3-羟基-5-(咪唑[1,2-a]吡啶-6-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)甲酮
将100mg(0.26mmol,1.0eq)(5-溴-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'- 基)(5-氟吡啶-2-基)甲酮，74.9mg(0.31mmol,1.2eq)6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)咪唑并[1,2-a]吡啶，163mg(0.77mmol,3.0eq)磷酸钾，18.7mg(0.03mmol,0.1eq)[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物，6mL(1,4-二氧六环/水＝4:1)混合溶剂加入20mL史莱克管中，氮气置换三次，于100℃反应3小时。经LCMS确认有目标产物生成。将该反应液加入10mL水淬灭，再用乙酸乙(20mL)萃取3次，合并有机相，干燥，浓缩，粗品送制备纯化(流动相A:0.1％甲酸的水；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)，得到白色固体纯品。
LC-MS:(M+H)+；m/z＝433.15。
1H NMR(400MHz,CDCl3)δ8.47-8.29(m,1H),8.30(d,J＝8.8Hz,1H),8.05(dd,J＝8.4,4.2Hz,1H),7.68-7.47(m,6H),7.42-7.32(m,2H),5.40-5.31(m,1H),4.25-3.75(m,4H),2.70-2.34(m,2H),2.23-2.01(m,3H).
19F NMR(376MHz,CDCl3)δ-123.10(dd,J＝18.8,7.5Hz).
实施例80：(5-(2-乙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮
步骤A:5-(2-乙基苯基)螺[茚-1,3'-吡咯烷]-3,5'(2H)-二酮
100.0mg(0.4mmol,1.0eq)5-溴螺[茚-1,3'-吡咯烷]-3,5'(2H)-二酮溶解在2mL 1,4-二氧六环中，再将53.5mg(0.4mmol,1.0eq)2-乙基苯硼酸、20.6mg(0.02mmol,0.05eq)四(三苯基膦)钯、98.7mg(0.7mmol,2.0eq)碳酸钾和0.4mL水加至该反应体系，置换氮气后升温到100℃反应2小时。经LC-MS结果确认反应完全，将体系降回室温后用5mL饱和氯化钠溶液稀释，然后用10mL乙酸乙酯萃取三次，取有机相通过无水硫酸钠干燥，减压蒸干。得5-(2-乙基苯基)螺[茚-1,3'-吡咯烷]-3,5'(2H)-二酮(109mg,收率＝100％)。
LC-MS:(M+H)+；m/z＝306；
步骤B:5-(2-乙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇
109.0mg(0.4mmol,1.0eq)5-(2-乙基苯基)螺[茚-1,3'-吡咯烷]-3,5'(2H)-二酮溶解在3mL无水四氢呋喃并置换氮气后，将体系降温到0℃，然后将40.6mg(1.1mmol,3.0eq)四氢铝锂缓慢加入到前者，加完后升温到75℃反应3小时。经LC-MS结果确认反应完全后，将体系降温到0℃，依次用10μL水、10μL 15％氢氧化钠水溶液淬灭，然后用无水硫酸镁干燥，抽滤后的滤液经减压蒸馏浓缩得5-(2-乙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇(105mg,收率＝100％)
LC-MS:(M+H)+；m/z＝294；
步骤C:(5-(2-乙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮
50.4mg(0.4mmol,1.0eq)5-氟-2-吡啶羧酸溶解在2mL N,N-二甲基甲酰胺中，置换氮气后依次加入149.3mg(0.4mmol,1.1eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯和92.2mg(0.7mmol,2.0eq)N,N-二异丙基乙胺，室温下搅拌1分钟后再加入105mg(0.4mmol,1.0eq)5-(2-乙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇，然后继续搅拌30分钟。经LC-MS结果确认反应完全，用10mL饱和氯化钠溶液稀释，然后用10mL乙酸乙酯萃取三次，取有机相通过无水硫酸钠干燥，减压蒸干。残余物依次通过柱层析(EA/PE＝0～1:1)和制备色谱(流动相A:0.1％三氟乙酸；流动相B:乙腈；梯度：30％-70％B,55分钟；流量:70mL/min)纯化得(5-(2-乙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮(76.9mg,收率＝52％)，白色固体。
LC-MS:(M+H)+；m/z＝417.14；
1H NMR(400MHz,CDCl3)δ8.51-8.33(m,1H),8.05(dd,J＝8.5,4.4Hz,1H),7.55-7.47(m,1H),7.39-7.27(m,5H),7.23-7.16(m,2H),5.35-5.32(m,1H),4.21-3.81(m,4H),2.68-2.03(m,7H),1.13(t,J＝8.0Hz,3H).
通过上文描述的实施例79或实施例80的方法制备表4中的实施例，替换所需的不同硼酸或者硼酸酯通过Suzuki反应等制备得到。
表4:实施例81～102



实施例103：(5-氟吡啶-2-基)(3-羟基-6-(2-异丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)甲酮
步骤A：3-(3-溴苯基)-3-氰基戊烷二酸二乙酯
5.00g(25.5mmol,1.0eq)2-(3-溴苯基)乙腈溶解在50mL无水四氢呋喃中，氮气置换3次。干冰降温至-60℃。在-60℃下滴加5.00g(56.1mmol,2.2eq)双三甲基硅基胺基锂，室温搅拌3h。然后在-60℃以下滴加8.94g(53.6mmol,2.0eq)溴乙酸乙酯，室温搅拌过夜。经LC-MS确认原料反应完全，加50mL水淬灭，然后用乙酸乙酯萃取三次，用50mL饱和食盐水溶液洗涤有机层，无水硫酸钠干燥，减压蒸干，得粗品(10.6g,收率＝100％)。
LC-MS:(M+Na+H)+；m/z＝391.87,393.91。
步骤B：2-(3-(3-溴苯基)-5-氧吡咯烷-3-基)乙酸乙酯
10.0g(27.2mmol,1.0eq)3-(3-溴苯基)-3-氰基戊烷二酸二乙酯溶解在50mL甲醇中，加入7.05g(54.31mmol,2.0eq)无水氯化钴，并在0℃下缓慢加入8.22g(217.3mmol,8.0eq)硼氢化钠，室温搅拌1h。经LC-MS确认有产物生成，用50mL盐酸溶液(3mol/L)稀释。然后用二氯甲烷萃取三次，用50mL饱和食盐水溶液洗涤有机层，无水硫酸钠干燥，减压蒸干,得粗品(7.66g,收率＝86％)。
LC-MS:(M+H)+；m/z＝326.08,327.95。
步骤C：2-(3-(3-溴苯基)-5-氧吡咯烷-3-基)乙酸
1.00g(3.07mmol,1.0eq)2-(3(3-溴苯基)-5-氧吡咯烷-3-基)乙酸乙酯溶解在20mL甲醇中，在0℃下缓慢加入4.9mL氢氧化钠溶液(5mmol/mL)，40℃搅拌1h。经LC-MS确认有产物生成，反应液用盐酸溶液(3.0mol/L)稀释至酸性，然后用二氯甲烷萃取三次，用10mL饱和食盐水溶液洗涤有机层，无水硫酸钠干燥，减压蒸干，得粗品(0.86g,收率＝94％)。
LC-MS:(M-H)+；m/z＝297.98,299.76。
步骤D：6-溴吡咯[茚-1,3'-吡咯烷]-3,5'-2H-二酮
4.00g多聚磷酸加热至150℃，再加入0.86g(2.88mmol，1.0eq)2-(3-(3-溴苯基)-5-氧吡咯烷-3-基)乙酸。然后在150℃搅拌1h。经LC-MS确认有产物生成，趁热将混合物缓慢倒入冰水中，边加边搅拌。然后用二氯甲烷萃取三次，用30mL饱和食盐水溶液洗涤有机层，无水硫酸钠干燥，减压蒸干。残余物通过柱层析(DCM/MeOH＝0～20:1)得产物(0.39g,收率＝48％)。
LC-MS:(M+H)+；m/z＝279.91,281.91。
步骤E：6-(2-异丙基苯基)螺[茚-1,3'-吡咯烷]-3,5'-2H-二酮
150mg(0.53mmol,1.0eq)6-溴吡咯[茚-1,3'-吡咯烷]-3,5'-2H-二酮和110mg(0.64mmol,1.2eq)(2-环丙基苯基)硼酸溶于5mL二氧六环/水混合溶液(V:V＝4:1)，再加入30mg(0.05mmol,0.1eq)1,1-双(二苯基膦)二荗铁二氯化钯和0.34g(1.6mmol,3.0eq)磷酸三钾，氮气置换三次，100℃搅拌1h。经LC-MS确认有产物生成，向其中添加5mL水，然后用乙酸乙酯萃取三次，用5mL饱和食盐水溶液洗涤有机层，无水硫酸钠干燥，减压蒸干，得粗品(162mg,收率＝93％)。
LC-MS:(M+H)+；m/z＝320.10。
步骤F：6-(2-异丙基苯基)-2,3-二氢螺环[茚-1,3'-吡咯烷]-3-醇
162mg(0.50mmol,1.0eq)5-溴吡咯[茚-1,3'-吡咯烷]-3,5'-2H-二酮溶于20mL四氢呋喃中，在0℃下缓慢加入0.29g(7.51mmol,15.0eq)氢化锂铝，70℃搅拌2h。经LC-MS确认有产物生成，反应液通过硅藻土过滤，用四氢呋喃洗涤。无水硫酸钠干燥，减压蒸干，得粗品(110mg,收率＝71％)。
LC-MS:(M+H)+；m/z＝308.20。
步骤G：(6-(2-异丙基苯基)-3-羟基-2,3-二氢螺环[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮
76.0mg(0.54mmol,1.5eq)5-氟吡啶-2-羧酸、0.17mL N,N-二异丙基乙胺和204mg(2.06mmol,1.5eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯溶于5mL四氢呋喃中，室温搅拌0.5h。加入110mg(0.36mmol，1.0eq)6-(2-异丙基苯基)-2,3-二氢螺环[茚-1,3'-吡咯烷]-3-醇，室温搅拌过夜。经LC-MS确认有产物生成，向其中添加10mL盐水，然后用乙酸乙酯萃取三次，无水硫酸钠干燥，减压蒸干，制备纯化(流动相A：0.1％甲酸；流动相B：乙腈；梯度：30％-70％B，55分钟；流量：70mL/min)，得到白色固体(16.0mg,收率＝10％)。
LC-MS:(M+H)+；m/z＝431.13；
1H NMR(400MHz,CDCl3)δ8.44-8.36(m,1H),8.04-7.98(m,1H),7.51-7.44(m,2H),7.40-7.33(m,3H),7.23-7.13(m,3H),5.42-5.31(m,1H),4.16-3.74(m,4H),3.04-2.95(m,1H),2.70-2.33(m,2H),2.28-2.17(m,1H),2.15-2.10(m,1H),2.08-2.01(m,1H),1.17-1.12(d,J＝6.8Hz,6H).
实施例104：(5-氟吡啶-2-基)(3-羟基-5-(2-异丙基苯氧基)-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)甲酮
100.0mg(0.256mmol,1.0eq)(5-溴-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮溶解在2mL 1,4-二氧六环中，再将38.3mg(0.282mmol,1.1eq)2-异丙基苯酚、4.9mg(0.0256mmol,0.1eq)碘化亚铜、7.3mg(0.0512mmol,0.2eq)反-(1R,2R)-N,N'-二甲基1,2-环己烷二胺和163.0mg(0.768mmol,3.0eq)磷酸钾加至该反应体系，置换氮气后升温到100℃反应18小时。经LC-MS结果确认反应完全，将体系降回室温后用5mL饱和氯化钠溶液稀释，然后用10mL乙酸乙酯萃取三次，取有机相通过无水硫酸钠干燥，减压蒸干。残余物通过制备色谱(流动相A：0.1％甲酸；流动相B：乙腈；梯度：30％-70％B，55分钟；流量：70mL/min)纯化得(5-氟吡啶-2-基)(3-羟基-5-(2-异丙基苯氧基)-2,3-二氢螺环[茚-1,3'-吡咯烷]-1'-基) 甲酮(2.0mg,收率＝2％)，黄色固体。
LC-MS:(M+H)+；m/z＝447.17；
1H NMR(400MHz,CDCl3)δ8.45-8.40(m,1H),8.03(s,1H),7.56-7.45(m,1H),7.38-7.33(m,1H),7.23-7.08(m,3H),7.00-6.80(m,3H),5.37-5.18(m,1H),4.17-3.97(m,2H),3.92-3.69(m,2H),3.31-3.20(m,1H),2.62-2.45(m,1H),2.38-2.21(m,1H),2.18-2.09(m,1H),2.08-1.95(m,2H),1.22(d,J＝7.0Hz,6H).
通过上文描述的实施例15的方法制备表5中的实施例，利用通用中间体I1和所需的不同酚、硫酚、芳香胺或芳香格氏试剂反应，再经还原，缩合制得。
表5:实施例105～116


通过上文描述的实施例14的方法制备表6中的实施例，通过替换反应中不同的原料及试剂制备得到。
表6:实施例116～133



实施例134：1'-((5-氟吡啶-2-基)甲基)-5-(2-异丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇
将50.0mg(0.16mmol,1.0eq)5-(2-异丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇，24.5mg(0.19mmol,1.2eq)5-氟吡啶醛，5mL甲醇加入25mL反应瓶，降温至0℃，20.5mg(0.32mmol,2.0eq)氰基硼氢化钠加入反应液，升温至室温，搅拌20分钟。经LCMS确认原料完全反应。向该反应液加入2mL水淬灭，浓缩至干，送制备。(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)，得到白色固体纯品(12.3mg,收率＝18％)。
LC-MS:(M+H)+；m/z＝417.16；
1H NMR(400MHz,CDCl3)δ8.40(d,J＝2.8Hz,1H),7.42-7.32(m,4H),7.28-7.26(m,2H),7.23-7.15(m,3H),5.29-5.21(m,1H),3.88-3.84(m,2H),3.08-2.89(m,2H),2.76-2.68(m,2H),2.37-2.33(m,1H),2.24-2.13(m,2H), 2.09-1.99(m,2H),1.17(d,J＝6.8Hz,6H).
19F NMR(376MHz,CDCl3)δ-129.86.
实施例135：1'-((5-氯吡啶-2-基)磺酰基)-5-(2-异丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇
将34.6mg(0.16mmol,1.0eq)5-氯吡啶-2-磺酰氯，49.5mg(0.48mmol,3.0eq)三乙胺，50.0mg(0.16mmol,1.0eq)5-(2-异丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇，3mL四氢呋喃加入25mL反应瓶，氮气保护下，室温搅拌1小时。经TLC(DCM/MeOH＝20:1)点板，确认原料完全反应。反应液浓缩干，送制备纯化(流动相A:0.1％甲酸；流动相B:乙腈；梯度:30％-70％B，55分钟；流量:70mL/min)，冻干得白色固体纯品(7.19mg,收率＝9％)。
LC-MS:(M+H)+；m/z＝483.05；
1H NMR(400MHz,CDCl3)δ8.71-8.70(m,1H),7.99-7.89(m,2H),7.40-7.31(m,3H),7.26-7.12(m,4H),5.36-5.26(m,1H),3.90-3.66(m,3H),3.59(m,1H),3.04-2.97(m,1H),2.52-2.30(m,2H),2.17-1.94(m,2H),1.85-1.80(m,1H),1.17(d,J＝6.6Hz,6H).
通过上文描述的实施例135的方法制备表7中的实施例，通过替换反应中不同的原料在碱性条件下制备得到。
表7:实施例136～146


实施例147：(5-氟吡啶-2-基)(3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)甲酮
实验操作参考实施例15，将起始原料对溴苯乙腈替换为苯乙腈，经合成制备得实施例147。
LC-MS:(M+H)+；m/z＝313.07
实施例148：(5-氟吡啶-2-基)(3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)甲酮
中间体制备例5中的化合物I5即为实施例148。
LC-MS:(M+H)+；m/z＝391.01。
实施例149：1'-(5-氯吡啶-2-基)-5-(2-环丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇
100mg(327μmol,1.0eq)5-(2-环丙基苯基)-2,3-二氢螺环[茚-1,3'-吡咯烷]-3-醇溶解在10mL N,N-二甲基甲酰胺中，加入94.0mg(491μmol,1.5eq)2-溴-5-氯吡啶和213mg(654μmol,2.0eq)碳酸铯。氮气置换3次，并在100℃下搅拌3h。经LC-MS确认有产物生成，向其中添加10mL盐水，然后用乙酸乙酯萃取三次，无水硫酸钠干燥，减压蒸干，制备纯化(流动相A：0.1％甲酸；流动相B：乙腈；梯度：30％-70％B，55分钟；流量：70mL/min)，得到白色固体(17.0mg,收率＝12％)。
LC-MS：(M+H)+；m/z＝417.15；
1H NMR(400MHz,CDCl3)δ8.13(dd,J＝5.9,2.5Hz,1H),7.56-7.50(m,1H),7.47-7.36(m,2H),7.30(dd,J＝6.4,2.4Hz,1H),7.27-7.19(m,3H),6.94(d,J＝7.7Hz,1H),6.43-6.32(m,1H),5.45-5.34(m,1H),3.87-3.54(m,4H),2.63-2.61(m,1H),2.49-2.41(m,1H),2.31-2.29(m,1H),2.25-2.08(m,2H),1.93-1.87(m,1H),0.92-0.80(m,2H),0.79-0.70(m,2H).
实施例150：5-(2-环丙基苯基)-1'-(6-氟苯并[c]异噻唑-3-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇
将20.0mg(65.0μmol,1.0eq)5-(2-环丙基苯基)-2,3-二氢螺环[茚-1,3'-吡咯烷]-3-醇，24.5mg(131μmol,2.0eq)3-氯-6-氟苯并[c]异噻唑，25.3mg(196μmol,3.0eq)N,N-二异丙基乙胺，3mL DMF加入25mL反应瓶，氮气置换三次，升 温至80℃搅拌过夜。经LC-MS确认原料完全反应。降温之后向反应液中加入20mL水，乙酸乙酯(20mL)萃取三次，合并有机相，无水硫酸钠干燥，抽滤之后浓缩，粗品通过制备色谱纯化(流动相A：0.1％甲酸；流动相B：乙腈；梯度：30％-70％B，55分钟；流量：70mL/min)，冻干得到白色固体(1.36mg,收率＝4％)。
LC-MS:(M+H)+；m/z＝457.12；
1H NMR(400MHz,CDCl3)δ7.76(dd,J＝9.8,5.1Hz,1H),7.54-7.51(m,1H),7.47-7.44(m,1H),7.31-7.27(m,2H),7.24-7.21(m,2H),7.07(d,J＝10.7Hz,1H),6.93(d,J＝7.7Hz,1H),6.67-6.63(m,1H),5.41(s,1H),3.98-3.76(m,4H),2.69-2.58(m,2H),2.47-2.42(m,1H),2.31-2.18(m,2H),1.90-1.83(m,1H),0.87-0.84(m,2H),0.75-0.71(m,2H).
19F NMR(376MHz,CDCl3)δ-112.83.
实施例151：1'-(5-氯苯并[d]噻唑-2-基)-5-(2-异丙基苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇
实验操作参考实施例149，经合成制备得化合物实施例151。
LC-MS:(M+H)+；m/z＝475.06
实施例152：5-(2-环丙基苯基)-1'-(7-氯咪唑[1,2-a]吡啶-3-基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇
中间体I3和3-溴-7-氯咪唑并[1,2-A]吡啶，经Buchwald-Hartwig偶联反应制备得化合物实施例152。
LC-MS:(M+H)+；m/z＝456.08
通过上文描述的实施例152的方法制备表8中的实施例，通过替换反应中不同的原料经Buchwald-Hartwig偶联反应制备得到。
表8:实施例153～158

实施例159：2-(5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-羰基)-5-氟吡啶-1-氧化物
将(5-(2-环丙基苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮溶于二氯甲烷，冰水浴下向该混合液中加间氯过氧苯甲酸，经氧化制备得实施例159。
LC-MS:(M+H)+；m/z＝445.13
实施例160：2-(3-(2'-环丙基-3-(羟甲基)-[1,1'-联苯]-4-基)吡咯烷-1-羰基)-5-氟吡啶-1-氧化物
实验操作参考实施例159，经合成制备得实施例160。
LC-MS:(M+H)+；m/z＝433.15
实施例161：(5-氟吡啶-2-基)(1-羟基-6-(2-异丙基苯基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)甲酮
步骤A:1-(叔丁基)4-乙基-4-(4-溴苄基)哌啶-1,4-二羧酸盐
氮气保护下，在250mL三口瓶中加入10.0g(38.9mmol，1.0eq)N-Boc-4-哌啶甲酸乙酯，60mL无水四氢呋喃，控制在-70～-60℃下滴加23.3mL(46.7mmol，2M,1.2eq)二异丙基氨基锂溶液，滴加的过程中放热，滴完保温反应1小时，保持在-70～-60℃下滴加9.70g(38.9mmol,1.0eq)对溴苄溴的四氢呋喃溶液(25mL)，滴完可让其自然升温，搅拌反应4小时，取样LC-MS中控，对溴苄溴残余5％以下视为反应完全。反应液控温在10-25℃下滴加饱和氯化铵溶液(60mL)淬灭，加入乙酸乙酯(100mL)，搅拌10分钟，静置5分钟，分液，水相加入乙酸乙酯(50mL)萃取2次，合并有机相，加入无水硫酸钠干燥，抽滤之后减压浓缩干有机相得到粗品(13.8g)，无需纯化直接用于下一步反应中。
LC-MS:(M-100+H)+；m/z＝325.98；327.98。
步骤B:4-(4-溴苄基)-1-(叔丁氧基羰基)哌啶-4-羧酸
将5.00g(11.7mmol,1.0eq)1-(叔丁基)4-乙基-4-(4-溴苄基)哌啶-1,4-二羧酸盐，30mL甲醇加入到250mL单口瓶中，搅拌下加入含有2.80g(70.2mmol,6.0eq)的氢氧化钠水溶液(30mL)，然后升温到85℃回流反应24小时，LC-MS检测原料转化完全。将反应液降温之后减压浓缩干甲醇，加入二氯甲烷(150mL),分得下层有机相，用6M的盐酸调节体系pH值为5-6，分 相，水相用二氯甲烷(150mL)萃取一次，合并有机相，加入无水硫酸钠干燥，过滤之后减压浓缩得到淡黄色油状物(4.50g,收率＝96％)。
LC-MS:(M-100+H)+；m/z＝297.92；299.92。
步骤C:6-溴-1-氧代-1,3-二氢螺环[茚-2,4'-哌啶]-1'-羧酸叔丁酯
将36.0g多聚磷酸加入到250mL三口瓶中，升温到120℃，将4.50g(11.34mmol,1.0eq)4-(4-溴苄基)-1-(叔丁氧基羰基)哌啶-4-羧酸溶解于二氯甲烷(20mL)中，搅拌下滴加上述溶液，滴加完搅拌反应3小时，LC-MS检测无原料剩余，结束反应。将反应液在热的状态下慢慢倒入到200g冰水中淬灭(淬灭温度在25-35℃)，然后用氢氧化钠水溶液调节体系pH值为9-10，加入3.70g(17.0mmol,1.5eq)二碳酸二叔丁酯，常温搅拌3小时，体系用乙酸乙酯萃取两次，合并有机相，无水硫酸钠干燥，抽滤减压浓缩得到淡黄色固体(4.00g,收率＝93％)。
LC-MS:(M-100+H)+；m/z＝279.91；281.90。
步骤D:6-(2-异丙基苯基)-1-氧代-1,3-二氢螺环[茚-2,4'-哌啶]-1'-羧酸叔丁酯
将1.10g(2.89mmol,1.0eq)6-溴-1-氧代-1,3-二氢螺环[茚-2,4'-哌啶]-1'-羧酸叔丁酯和569mg(3.47mmol,1.2eq)(2-异丙基苯基)硼酸溶于10mL 1,4-二氧六环/水混合溶液(V:V＝4:1)中，再加入210mg(289μmol，0.1eq)1,1-双(二苯基膦)二荗铁二氯化钯和1.84g(8.67mmol,3.0eq)磷酸三钾，氮气置换三次，100℃搅拌1小时。经LC-MS确认有产物生成，向其中添加50mL水，然后用乙酸乙酯萃取三次，用30mL饱和食盐水溶液洗涤有机层，无水硫酸钠干燥，抽滤之后减压蒸干。残余物通过柱层析(石油醚/乙酸乙酯＝0～10:1)得到淡黄色固体(780mg,收率＝65％)。
LC-MS:(M-100+H)+；m/z＝320.12；
步骤E:1-羟基-6-(2-异丙基苯基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯
将780mg(1.86mmol，1.0eq.)6-(2-异丙基苯基)-1-氧代-1,3-二氢螺环[茚-2,4'-哌啶]-1'-羧酸叔丁酯溶于10mL无水甲醇中，在0℃下缓慢加入106mg(2.79mmol，1.5eq.)硼氢化钠，冰浴下搅拌1小时后送LC-MS确认原料转化完全，有产物生成。用饱和碳酸钠水溶液淬灭反应反应液，硅藻土抽滤，用乙酸乙酯洗涤，分取有机相，无水硫酸钠干燥，抽滤减压蒸干得到淡黄色油状液体(800mg)。
LC-MS:(M-100+H)+；m/z＝322.20；
步骤F:6-(2-异丙基苯基)-1,3-二氢螺[茚-2,4'-哌啶]-1-醇盐酸盐
将800mg(1.89mmol,1.0eq)1-羟基-6-(2-异丙基苯基)-1,3-二氢螺[茚-2,4'-哌啶]-1'-羧酸叔丁酯溶解于10mL无水二氯甲烷中，冰浴下加入2.0mLHCl/1,4-二氧六环溶液(4M)，冰浴下搅拌1小时后送LC-MS检测，原料转换完全，减压浓缩得到淡黄色固体(600mg,收率＝88％)。
LC-MS:(M+H)+；m/z＝322.17；
步骤G:6-(2-异丙基苯基)-1,3-二氢螺[茚-2,4'-哌啶]-1-醇(5-氟吡啶-2-基)(1-羟基-6-(2-异丙烯基苯基)-1,3-二氢螺[茚-2,4'--哌啶]-1'-基)甲酮
将29.6mg(209.6μmol,1.5eq)5-氟吡啶-2-羧酸、90.1mg(698.5μmol,5.0eq)N,N-二异丙基乙胺和79.7mg(209.6μmol,1.5eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯溶于5mL四氢呋喃中，室温搅拌10分钟。加入50mg(139.7μmol,1.0eq)6-(2-异丙基苯基)-1,3-二氢螺[茚-2,4'-哌啶]-1-醇的盐酸盐，室温搅拌1.5h。经LC-MS确认原料转化完全有产物生成，向其中添加50mL饱和氯化钠水溶液，然后用乙酸乙酯萃取三次，无水硫酸钠干燥，抽滤之后减压蒸干，送HPLC制备纯化(流动相A：0.1％甲酸；流动相B：乙腈；梯度：30％-70％B，55分钟；流量：70mL/min)，冻干得到两个异构体(实施例161A,9.05mg,收率＝15％；实施例161A,3.11mg，收率＝5％)。
实施例161A:LC-MS:(M+H)+；m/z＝427.23；
1H NMR(400MHz,CDCl3)δ8.43(dd,J＝5.8,2.8Hz,1H),7.75-7.70(m, 1H),7.53-7.48(m,1H),7.39-7.32(m,3H),7.28-7.25(m,1H),7.22-7.14(m,3H),4.87-4.84(m,1H),4.34-4.24(m,1H),3.85-3.81(m,1H),3.52-3.42(m,2H),3.14-3.01(m,2H),2.86-2.77(m,1H),2.06-1.95(m,1H),1.87-1.78(m,1H),1.77-1.65(m,2H),1.16(d,J＝7.0Hz,6H).
19F NMR(376MHz,CDCl3)δ-123.95(d,J＝2.9Hz).
实施例161B:LC-MS:(M+H)+；m/z＝427.18；
1H NMR(400MHz,CDCl3)δ8.43(dd,J＝5.8,2.8Hz,1H),7.75-7.70(m,1H),7.56-7.51(m,1H),7.39-7.32(m,3H),7.27-7.25(m,1H),7.22-7.14(m,3H),4.87-4.84(m,1H),4.34-4.24(m,1H),3.85-3.81(m,1H),3.52-3.42(m,2H),3.14-2.99(m,2H),2.88-2.83(m,1H),2.05-1.96(m,1H),1.87-1.77(m,1H),1.74-1.65(m,2H),1.16(d,J＝7.0Hz,6H).
19F NMR(376MHz,CDCl3)δ-123.96(d,J＝3.0Hz).
实施例162：(S)-5-(2-环丙基苯基)-1'-(5-氟吡啶甲酰基)螺[茚-1,3'-吡咯烷]-3(2H)-酮
20.0mg(46.7μmol,1.0eq)((1S,3R)-5-(2-环丙基苯基)-3-羟基-2,3-二氢螺环[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮溶解在1mL二氯甲烷中，再将23.8mg(56.0μmol,1.2eq.)戴斯-马丁试剂加至该反应体系，室温下搅拌2小时。经LC-MS结果确认反应完全，将体系用5mL饱和碳酸氢钠溶液稀释，然后用10mL乙酸乙酯萃取三次，取有机相通过无水硫酸钠干燥，减压蒸干。残余物通过制备色谱(流动相A：0.1％甲酸；流动相B：乙腈；梯度：30％-70％B，55分钟；流量：70mL/min)纯化得(S)-5-(2-环丙基苯基)-1'-(5-氟吡啶甲酰基)螺[茚-1,3'-吡咯烷]-3(2H)-酮(11.7mg,收率＝58.8％)，白色固体。
LC-MS:(M+H)+；m/z＝427.17；
1H NMR(400MHz,CDCl3)δ8.42(dd,J＝44.0,2.8Hz,1H),8.09(d,J＝4.1Hz,1H),7.84(d,J＝9.9Hz,1H),7.78(d,J＝7.9Hz,1H),7.65-7.58(m,1H),7.52-7.51(m,1H),7.30-7.26(m,1H),7.25-7.17(m,2H),6.97(dd,J＝7.7,3.9Hz,1H),4.38-4.10(m,2H),4.09-3.86(m,2H),2.93-2.69(m,2H),2.45-2.43(m,1H),2.18-2.17(m,1H),1.84-1.76(m,1H),0.87-0.83(m,2H), 0.73-0.70(m,2H).
实施例163：(5-(2-环丙基-4-氟苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮
48.3mg(0.30mmol,1.0eq)5-氟-2-吡啶羧酸溶解在2mL N,N-二甲基甲酰胺中，置换氮气后依次加入143mg(0.40mmol,1.1eq)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯和88.5mg(0.70mmol,2.0eq)N,N-二异丙基乙胺，室温下搅拌1分钟后再加入111mg(0.30mmol,1.0eq)5-(2-环丙基-4-氟苯基)-2,3-二氢螺[茚-1,3'-吡咯烷]-3-醇，然后继续搅拌30分钟。经LC-MS结果确认反应完全，用10mL饱和氯化钠溶液稀释，然后用10mL乙酸乙酯萃取三次，取有机相通过无水硫酸钠干燥，减压蒸干。残余物依次通过柱层析(甲醇/二氯甲烷＝0～1:40)和制备色谱(流动相A：0.1％三氟乙酸；流动相B：乙腈；梯度：30％-70％B，55分钟；流量：70mL/min)纯化得(5-(2-环丙基-4-氟苯基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮(86.4mg,收率＝57％)，白色固体。
LC-MS:(M+H+)+；m/z＝447.14；
1H NMR(400MHz,CDCl3)δ8.46-8.35(m,1H),8.06-8.01(m,1H),7.54-7.46(m,2H),7.42-7.39(m,1H),7.32-7.28(m,1H),7.01-6.86(m,3H),5.37-5.28(m,1H),4.24-3.76(m,4H),2.68-2.46(m,1H),2.41-2.11(m,3H),2.09-2.00(m,1H),1.86-1.77(m,1H),0.85-0.79(m,2H),0.66-0.63(m,2H).
实施例164：2-(2-(1'-(5-氟吡啶酰基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-5-基)苯基)-2-甲基丙腈
100mg(256μmol,1.0eq)(5-溴-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮溶解在2mL 1,4-二氧六环中，再将130mg(511μmol,2.0eq)联硼酸频那醇酯、18.7mg(25.6μmol,0.1eq)[1,1'-双(二苯基膦)二茂铁] 二氯化钯和100mg(1.02mmol,4.0eq)乙酸钾加至该反应体系，氮气保护下在100℃搅拌反应3小时。将体系降温到室温后，把57.3mg(256μmol,1.0eq)2-(2-溴苯基)-2-甲基丙腈、23.6mg(20.4μmol,0.08eq)四(三苯基膦)钯、70.7mg(551mmol,2.0eq)碳酸钾和0.4mL水加至该反应体系，氮气保护下在100℃搅拌反应2小时。经LC-MS结果确认原料反应完全，降温到室温，加入水5mL和乙酸乙酯10mL，分得有机相，水相用乙酸乙酯(10mL)萃取两次，合并有机相，有机相经过盐水洗涤，无水硫酸钠干燥浓缩得到粗品，粗品经柱层析(甲醇/二氯甲烷＝0～1:30)和制备色谱(流动相A：0.1％甲酸；流动相B：乙腈；梯度：30％-70％B，55分钟；流量：70mL/min)纯化得白色固体(8.70mg,收率＝7％)。
LC-MS:(M+Na)+；m/z＝478.18；
1H NMR(400MHz,CDCl3)δ8.52-8.35(m,1H),8.11-7.97(m,1H),7.62-7.48(m,2H),7.48-7.37(m,2H),7.36-7.26(m,3H),7.20-7.11(m,1H),5.43-5.26(m,1H),4.24-4.02(m,2H),4.02-3.81(m,2H),2.69-2.32(m,2H),2.24-2.02(m,3H),1.79-1.59(m,6H).
实施例165：2-(3-(1'-(5-氟吡啶酰基)-3-羟基-2,3-二氢螺[茚-1,3'-吡咯烷]-5-基)苯基)-2-甲基丙腈
将180mg(952μmol,1.0eq)(3-(2-氰基丙烷-2-基)苯基)硼酸溶解在2mL 1,4-二氧六环中，再将372mg(952μmol,1.0eq)(5-溴-3-羟基-2,3-二氢螺环[茚-1,3'-吡咯烷]-1'-基)(5-氟吡啶-2-基)甲酮、34.8mg(0.026mmol,0.05eq)[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、606mg(2.85mmol,3.0eq)磷酸钾和0.4mL水加至该反应体系，置换氮气后升温到100℃反应3小时。经LC-MS结果确认反应完全，将体系降回室温后用5mL饱和氯化钠溶液稀释，然后用10mL乙酸乙酯萃取三次，无水硫酸钠干燥，抽滤之后浓缩。粗品通过制备色谱纯化(流动相A：0.1％甲酸；流动相B：乙腈；梯度：30％-70％B，55分钟；流量：70mL/min)，冻干得到白色固体(22.0mg，收率＝5％)。
LC-MS:(M+H)+；m/z＝456.23；
1H NMR(400MHz,CDCl3)δ8.41(dd,J＝47.8,2.8Hz,1H),8.06-8.04(m,1H),7.68-7.63(m,2H),7.60-7.43(m,5H),7.35(dd,J＝10.3,7.9Hz,1H),5.39-5.32(m,1H),4.08-4.08(m,1H),3.94-3.93(m,1H),3.92-3.76(m,2H),2.70-2.53(m,1H),2.46-2.34(m,1H),2.26-1.99(m,3H),1.78(s,6H).
本发明化合物抑制率活性测试
本研究中，采用瞬时表达TRPV3的HEK-293细胞进行实验检测。
操作步骤如下:
细胞在含有10％胎牛血清的DMEM培养基中培养，培养温度为37℃，二氧化碳浓度为5％。
第一天：接种细胞至6孔板中，每孔5×105细胞。
第二天：使用Lipofectamine 3000转染试剂进行转染，质粒与转染试剂比例为1μg:2μL。每孔质粒总用量为3μg。具体如下：取两个无菌离心管，各加入100μL Opti-MEM，其中1管加入6μL Lipofectamine 3000，混匀；另一管中加入3μg质粒，混匀，再加入6μL P3000，混匀；然后将稀释的质粒DNA加入到稀释的Lipofectamine 3000中，室温孵育10-15min。将DNA-脂质体复合物滴加到细胞中，轻晃混匀，放入培养箱中培养。4-6小时后换液。
第三天：消化细胞，接种到预先放好盖玻片的24孔板中，每孔8×103个细胞。
第四天：进行膜片钳检测。
全细胞膜片钳记录TRPV3电流的电压刺激方案如下：当形成全细胞封接后细胞膜电压钳制于-80mV。首先记录膜电位在0mV，然后命令电压从-100mV开始，以Ramp形式在100ms内除极至100mV，最后恢复至0mV。每隔5s重复采集数据，观察药物对该电流峰值的抑制作用。试验数据由EPC 10放大器(HEKA)进行采集并储存于PatchMaster(HEKA)软件中。
用微电极拉制仪将毛细玻璃管拉制成记录电极。将充灌细胞内液的电极装入微电极夹持器，在倒置显微镜下操控微电极操纵器使电极浸入细胞外液并记录电极电阻(Rpip)。将电极接触到细胞表面，给予负压抽吸形成高阻封接(GΩ)。此时执行快电容补偿，再继续给予负压，吸破细胞膜，形成全细胞记录模式。然后进行慢电容补偿并记录膜电容(Cm)及串联电阻(Rs)等实验参数。不给予漏电补偿。
当全细胞记录的TRPV3电流稳定后开始给药，每个药物浓度作用至5min(或者电流至稳定)后检测下一个浓度，每一个测试化合物检测多个浓度。将铺有细胞的盖玻片置于倒置显微镜下的记录浴槽中，空白对照外液以及待测化合物工作液利用重力灌流的方法从低浓度到高浓度依次流经记录浴槽从而作用于细胞，在记录中利用蠕动泵进行液体交换。每一个细胞在不含化合物的外液中检测到的电流作为自己的对照组。每个浓度至少使用两个细胞独立重复检测两次。所有电生理试验在室温下进行。
使用上述分析过程测试制备的各化合物，获得的结果示于表9。对于选定的实施例，浓度为0.3μM下的抑制率(％)详情示于表中。其中“A”是指抑制率值70％～100％，“B”是指抑制率值在50％～69.99％范围内，“C”是指抑制率值在25％～49.99％范围内，“D”是指抑制率值小于25％，“ND”表示数据未确定。
表9:本发明化合物对hTRPV3单浓度下(0.3μM)的抑制率(％)


表10:化合物对不同hTRP(0.3μM)的抑制率

注：“选择性比值”是指化合物相同测试浓度下对TRPV3离子通道抑制率与其他离子通道抑制率的比
值。
肝微粒代谢稳定性测试
进行了两个单独的实验。a)NADPH:将10μL的20mg/mL肝微粒体和40μL的10mM NADPH添加到培养液中。微粒体和NADPH的最终浓度分别为0.5mg/mL和1mM。b)不含NADPH:向培养液中添加10μL 20mg/mL肝微粒体和40μL超纯H2O。微粒体的最终浓度为0.5mg/mL。
反应开始时，添加4μL 100μM试验化合物溶液或最终浓度为1μM的对照化合物溶液，并在37℃下进行。
在0、7、15、30和60分钟时从反应溶液中取50μL等分样品。通过添加4体积的冷乙腈和IS(100nM阿普唑仑、200nM拉贝洛尔、200nM咖啡因和2μM酮洛芬)停止反应。样品在3220克下离心40分钟。将等分的100μL上清液与100μL超纯H2O混合，然后用于LC-MS/MS分析。
表11:肝微粒体代谢稳定性测试结果

平衡透析法测试血浆蛋白结合
1.浸泡透析膜(水:60分钟，20％乙醇:20分钟，透析缓冲液:20分钟)。2.将试验化合物在二甲基亚砜(工作溶液)中稀释至200μM。3.在37℃水浴中解冻血浆，在3220g下离心血浆10分钟，以清除血块。4.将上清液转移到新管中，并在37℃水浴中预热10分钟。5.按照制造商指南组装HTD透析设备。6.向597μL血浆中添加3μL 200μM试验化合物，以1000rpm的转速旋转2分钟。7.将50μL加标血浆转移至96孔板，然后添加50μL透析缓冲液和200μL甲醇，以IS*作为T0样品。8.将120μL加标血浆和120μL透析缓冲液一式两份加入HTD透析装置的腔室。9.用透气盖盖住透析设备，并在37℃(100rpm，5％CO2)下培养透析设备和剩余的加标血浆6小时。10.将50μL透析后样品从透析缓冲液和血浆室转移到分离的96孔板中，然后添加50μL空白血浆或透析缓冲液以及200μL甲醇，IS*作为B和P样品。11.将50μL剩余加标血浆(如步骤9所述)转移至96孔板，然后添加50μL透析缓冲液和200μL甲醇，IS*作为T6样品。12.在3220g下离心样品板40分钟。13.将100μL上清液转移到含有适当体积水的分析板上，用于LC-MS/MS。14.数据分析。
表12:本发明化合物对血浆蛋白结合测试结果
平行人工膜渗透性测定(脂质PAMPA)实验
1.在10mM DMSO中制备测试化合物，并用PBS稀释1000倍至10μM。2.将卵磷脂在十二烷中以18mg/ml的速度超声处理。3.将300μL/孔的10μM测试化合物溶液加入供体室(底部)，一式三份。4.将5μL/孔卵磷脂/十二烷加入受体室(顶部)，然后在10分钟内将300μL/井PBS(pH＝7.4)加入受体室。5.将50μL 10μM测试化合物转移到含有200μL冷甲醇的样品板上，IS*为C0。6.将受体室插入供体室，并在25℃下孵育16小时。7.温育 16小时后，将50μL从受体和供体室转移到含有200μL冷甲醇和IS*的样品板上。8.在4℃、3220g下离心样品板40分钟。9.将100μL上清液转移至含有适当体积H2O的分析板，用于LC-MS/MS分析。10.数据分析。
表13:本发明化合物对于平行人工膜渗透性测定结果
Caco-2细胞的渗透性实验
细胞板准备：
1.Transwell板预热：铺细胞前，将Transwell板上层加100μL，下层加600μL培养基，在37℃,5％CO2下预孵育1小时。2.处理Caco-2细胞，每孔加100μL细胞悬液(4х105cells/mL)，在37℃，5％CO2培养箱中培养14-21天。3. 7天内每隔一天更换一次细胞培养基，7天后每天更换一次。4.使用EVOM3测量单层上皮间电阻(TEER)。
实验流程：
1.HBSS(10mM HEPES,pH 7.4)缓冲液预热，清洗Transwell板上下层各两次，37℃培养箱孵育30min。2.工作液：1mM DMSO待测化合物HBSS缓冲液稀释至5μM。3.A-B方向：上层加入200μL 5μM工作液，下层加600μL HBSS缓冲液；4.B-A方向：下层加600μL 5μM工作液，上层加200μL HBSS缓冲液，孵育2小时5.C0样品：取100μL工作液中至含400μL甲醇(内标)的样品板。6.孵育2h后，从小室上层和下层分别取100μL至含400μL甲醇(内标)的样品板。7.混匀离心，上清液与一定量水混匀后，样品用于LC-MS/MS数据分析。8.在完成步骤6后，上室加入200μL 100μM的荧光黄溶液，下室加600μL的HBSS缓冲盐溶液。在37℃，5％CO2孵育30min，分别取出50μL于黑色板中，读取荧光值。9.数据分析。
表14:本发明化合物对于caco-2细胞的渗透性测定结果
药代动力学实验
将雄性SD大鼠分组，每组3只，分别口服单次灌胃给予实施例化合物(10mg/kg)，静脉注射实施例化合物(2mg/kg)。动物在实验前禁食过夜，禁食时间从给药前10小时至给药后4小时。口服组给药后0.25、0.5、1、2、4、8和24小时采血，静脉注射组注射后0.083、0.25、0.5、1、2、4、8和24小时采血。使用小动物麻醉机经异氟烷麻醉后通过眼底静脉丛采取0.3mL全血，放于肝素抗凝管中，样品于4℃、4000rpm离心5min，血浆转移至离心管中，并放于-80℃保存直到分析。血浆中样品使用蛋白质沉淀法萃取，萃取液通过LC-MS/MS分析。
表15:大鼠灌胃给予10mg/kg不同化合物后的药代动力学参数
表16:大鼠静脉给予2mg/kg化合物后的药代动力学参数
由上述结果可知，本发明的实施例化合物的注射和口服药代动力学性能优于现有化合物KM-001(专利WO2021154966A1中化合物实施例2-72，即实施例KM-001)，且实施例的口服生物利用度达到了80.6％。按照同样的方法测试本发明其余的实施例化合物，所得的药代动力学性能也优于KM-001。
化合物稳定性考察
以化合物实施例21和WO2021154966A1中化合物KM-001-E1为例，比较两者的稳定性：
精密称取化合物实施例21和KM-001-E1分别放置于西林瓶中，并于室温下放置于92.5％湿度(开口)条件下5-10天，考察化合物的稳定性。
分析条件:
仪器:Thermo U3000-ISQEC
柱:Xtimate UHPLC C18 1.8μm 4.6*50mm
柱温:35℃
波长:210nm、254nm
流动相A:0.05％甲酸水溶液；流动相B:0.05％甲酸乙腈；梯度:30％B 0-1.2分钟，95％B 1.2-3.3分钟，30％B 3.3-4.5分钟；
通过LC-MS分析开口92.5％湿度条件下各化合物的降解杂质：实施例21主要杂质的m/z＝427.17，保留时间为2.55min，放置10天峰面积占比仅为0.3％；KM-001-E1主要杂质的m/z＝431.14和m/z＝415.16，保留时间分别为2.31min和2.64min，放置5天峰面积占比分别达到2.48％和2.43％。基于LC-MS和核磁数据分析可以推断出实施例21产生的主要杂质为酮，而KM-001-E1产生的主要杂质为醛和羧酸两种。具体结构如下：
由上述结果可知，本发明的实施例化合物的稳定性优于现有化合物KM-001-E1。
本案上述化合物21为仲醇结构，比WO2021154966A1中伯醇化合物的化学稳定性更好：同为醇，前者只能氧化为酮；后者则可氧化成醛并进一步氧化成羧酸，氧化杂质的数量和水平均多于本案上述化合物21。
同样地，基于同样的结构特征，具有同样的仲醇结构的本申请实施例化合物的稳定性均优于WO2021154966A1中化合物。
虽然为了说明本发明，已经公开了本发明的优选实施方案，但是本领域 的技术人员应当理解，在不脱离权利要求书所限定的本发明构思和范围的情况下，可以对本发明做出各种修改、添加和替换。

Claims (33)

  1. 一种式(I)的含氮螺环化合物
    或其立体异构体、互变异构体、溶剂化合物、水合物、氧化物、活性代谢物、同位素标记物、药学上可接受的盐，
    其中，环A选自含有3-12个环原子的单环或多环环系；
    R1各自独立地选自H、卤素、羟基、巯基、硝基、氰基、氧代、任选取代有1-2个Rf的C1-C6烷基、取代有0-2个Rf的C1-C6卤代烷基、取代有0-2个Rf的C1-C6烷氧基、取代有0-2个Rf的C1-C6卤代烷氧基、取代有0-2个Rf的C3-C6环烷基、取代有0-2个Rf的C3-C6卤代环烷基、取代有0-2个Rf的C3-C6环烷氧基、取代有0-2个Rf的C3-C6卤代环烷氧基、取代有0-2个Rf的芳基、取代有0-2个Rf的芳烷基、取代有0-2个Rf的烷芳基、取代有0-2个Rf的杂芳基、-R11OR12、-R11SR12、-N(Ra)(Rb)、-C(O)Rc、-C(O)N(Ra)(Rb)和-SO2N(Ra)(Rb)或-SORc，或者两个R1与它们所连接的环A原子一起形成3-10元环结构；
    R2各自独立地选自H、卤素、羟基、巯基、硝基、氰基、氧代、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的C1-C6卤代烷基、取代有0-2个Rf的C1-C6烷氧基、取代有0-2个Rf的C1-C6卤代烷氧基、取代有0-2个Rf的C3-C6环烷基、取代有0-2个Rf的C3-C6卤代环烷基、取代有0-2个Rf的C3-C6环烷氧基、取代有0-2个Rf的C3-C6卤代环烷氧基、取代有0-2个Rf的芳基、取代有0-2个Rf的芳烷基、取代有0-2个Rf的烷芳基、取代有0-2个Rf的杂芳基、-R11OR12、-R11SR12、-N(Ra)(Rb)、-C(O)Rc、-C(O)ORd、-C(O)N(Ra)(Rb)和-SO2N(Ra)(Rb)或-SORc，或者两个R2与它们所连接的环原子一起形成3-10元环结构；
    L1选自键，或者如下结构式：
    X1在每次出现时各自独立地选自C、O或N；
    X2在每次出现时各自独立地选自C、O、B或N；
    XA、XB、XC各自独立地为CRx或N；
    Rx各自独立地选自H、卤素、羟基、巯基、硝基、氰基、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的C1-C6卤代烷基、取代有0-2个Rf的C1-C6烷氧基、取代有0-2个Rf的C1-C6卤代烷氧基、取代有0-2个Rf的C3-C6环烷基、取代有0-2个Rf的C3-C6卤代环烷基、取代有0-2个Rf的C3-C6环烷氧基、取代有0-2个Rf的C3-C6卤代环烷氧基、取代有0-2个Rf的芳基、取代有0-2个Rf的芳烷基、取代有0-2个Rf的烷芳基、取代有0-2个Rf的杂芳基、-R11OR12、-R11SR12、-N(Ra)(Rb)、-C(O)Rc、-C(O)ORd、-C(O)N(Ra)(Rb)和-SO2N(Ra)(Rb)或-SORc；或者两个Rx与它们所连接的环原子一起形成3-10元环结构；
    R0各自独立地选自H、卤素或者式II的结构式
    其中，L2各自独立地选自键、-O-、-S-、-N(R20)-、-C(O)-、-C(R20R21)-、-S(O)-和-S(O2)-；
    环C各自独立地选自含有3-12个环原子的单环或多环环系；
    R3各自独立地选自H、卤素、羟基、巯基、硝基、氰基、氧代、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的C1-C6卤代烷基、取代有0-2个Rf的C1-C6烷氧基、取代有0-2个Rf的C1-C6卤代烷氧基、取代有0-2个Rf的C3-C6环烷基、取代有0-2个Rf的C3-C6卤代环烷基、取代有0-2个Rf的C3-C6环烷氧基、取代有0-2个Rf的C3-C6卤代环烷氧基、取代有0-2个Rf的芳基、取代有0-2个Rf的芳烷基、取代有0-2个Rf的烷芳基、取代有0-2个Rf的杂芳基、-R11OR12、-R11SR12、-N(Ra)(Rb)、-C(O)Rc、-C(O)ORd、-C(O)N(Ra)(Rb)和-SO2N(Ra)(Rb)或-SORc，或者两个R3与它们所连接的环C原子一起形成3-10元环结构；
    R11各自独立地选自取代有0-2个Rf的C1-C6亚烷基；
    R12各自独立地选自H、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的C1-C6卤代烷基、取代有0-2个Rf的C3-C6环烷基和取代有0-2个Rf的C3-C6卤代环烷基；
    Ra和Rb各自独立地选自H、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的芳基、取代有0-2个Rf的芳烷基、-C(O)Rc和-C(O)ORd；
    Rc各自独立地选自H、卤素、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的芳基和取代有0-2个Rf的芳烷基；
    Rd各自独立地选自H、取代有0-2个Rf的C1-C6烷基、取代有0-2个Rf的芳基和取代有0-2个Rf的芳烷基；
    R20和R21各自独立地选自H、羟基、C1-C6烷基、芳基和芳烷基；
    Rf各自独立地选自卤素、羟基、氨基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、C3-C6环烷基和C3-C6卤代环烷基；
    n为0、1、2或3；
    p为0、1、2或3；
    q为0、1、2或3；
    m为1或2；
    r为1或2。
  2. 根据权利要求1所述的含氮螺环化合物，其中，环A选自苯环、吡啶环、喹啉环、哌啶环、C3-C6环烷基环、异喹啉环、吡嗪环、嘧啶环、哒嗪环、噻唑环、噻吩环、吡咯环、吡唑环、咪唑环、异噻唑环、吲哚环、苯并咪唑环、呋喃环、恶唑环、恶二唑环、喹喔啉环和嘌呤环。
  3. 根据权利要求1所述的含氮螺环化合物，其中，环A选自如下结构式：
  4. 根据权利要求1所述的含氮螺环化合物，其中，R1各自独立地选自H、卤素、氰基、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、-N(Ra)(Rb)和-R11OR12，其中，Ra和Rb各自独立地选自H和C1-C6烷基；R11各自独立地选自C1-C6亚烷基；R12各自独立地选自H和C1-C6烷基。
  5. 根据权利要求4所述的含氮螺环化合物，其中，R1各自独立地选自H、Cl、F、-CF3、-CN、-CH3、-OH、-OCH3、-CH2OCH3。
  6. 根据权利要求1所述的含氮螺环化合物，其中，R2各自独立地选自H、卤素、氰基、羟基、巯基、氧代、C1-C6烷基、C1-C6卤代烷基、取代有0-2个Rf的C3-C6环烷基、C1-C6烷氧基、C1-C6卤代烷氧基、-R11OR12、-R11SR12、-CH(O)、-C(O)ORd和-C(O)N(Ra)(Rb)；其中，R11各自独立地选自C1-C6亚烷基；R12各自独立地选自H、C1-C6烷基、C1-C6卤代烷基、C3-C6环烷基和C3-C6卤代环烷基；Ra和Rb各自独立地选自H和C1-C6烷基；Rd各自独立地选自H和C1-C6烷基；Rf各自独立地选自卤素、羟基、氨基和C1-C6烷基。
  7. 根据权利要求6所述的含氮螺环化合物，其中，R2各自独立地选自氕、氘、氚、卤素、-SH、-OH、-OCF3、-CH3、-OCH3、-CF3、-NH2、-CN、-CONH2、-CH2OH、-CH(O)、-CHF2、-COOH、-COOCH3、氧代和
  8. 根据权利要求1所述的含氮螺环化合物，其中，L2各自独立地选自键、-O-、-S-、-N-、-C(O)-、-CH2-、-CF2-、-C(OH)-、-S(O)-和-S(O2)-。
  9. 根据权利要求1所述的含氮螺环化合物，其中，环C选自C3-C6环烷烃环、苯环、苯并C3-C6环烷烃环、C5-C12桥连碳环、吡啶环、喹啉环、异喹啉环、吡嗪环、嘧啶环、哒嗪环、噻唑环、噻吩环、吡咯环、吡唑环、咪唑环、异噻唑环、吲哚环、苯并咪唑环、呋喃环、恶唑环、喹喔啉环和嘌呤 环。
  10. 根据权利要求9所述的含氮螺环化合物，其中，环C选自以下结构式：
  11. 根据权利要求1所述的化合物，其中，R3各自独立地选自H、氰基、羟基、卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C6环烷基、-R11OR12、-R11SR12、-C(O)Rc、-C(O)ORd和-C(O)N(Ra)(Rb)，或者两个R3与它们所连接的环C原子一起形成3-10元环结构；
    其中，R11各自独立地选自C1-C6亚烷基；R12各自独立地选自H、C1-C6烷基、C1-C6卤代烷基、C3-C6环烷基和C3-C6卤代环烷基；Ra和Rb各自独立地选自H和C1-C6烷基；Rc各自独立地选自H、卤素和C1-C6烷基；Rd各自独立地选自H和C1-C6烷基。
  12. 根据权利要求11所述的含氮螺环化合物，其中，R3各自独立地选自H、环丙基、异丙基、叔丁基、F、Cl、CN、乙基、甲基、三氟甲氧基、甲基羰基、甲氧基甲基、-C(CH3)2OH。
  13. 根据权利要求1所述的含氮螺环化合物，其中，式I中的
    选自以下结构式之一：

    其中，R2、XA、XB、XC以及p定义如式I。
  14. 根据权利要求1所述的含氮螺环化合物，其中，式I中的
    选自以下结构式之一：
    其中，R2各自独立地选自氕、氘、氚、卤素、氧代、-SH、-OH、-CH3、-CN、-CONH2、-COOH、-COH、-COOCH3、-CF3、-OCH3、-CH2OH、-OCF3、-CHF2、和-NH2。
  15. 根据权利要求14所述的含氮螺环化合物，其中，至少一个R2为-OH。
  16. 根据权利要求14所述的含氮螺环化合物，其中，式I中的
    选自以下结构式之一：
    其中，R2各自独立地选自氕、氘、氚、卤素、-CH3和-CF3。
  17. 根据权利要求1所述的含氮螺环化合物，其中，式I中的
    选自以下结构式：
    其中，R2独立地选自氧代、-SH、-CN、-CONH2、-COOH、-COH、-COOCH3、-OCH3、-CH2OH、-CHF2、-OCF3和-NH2。
  18. 根据权利要求1所述的含氮螺环化合物，其中，式I中的
    选自以下结构式：
  19. 根据权利要求1所述的含氮螺环化合物，其中，L1为
  20. 根据权利要求1所述的含氮螺环化合物，其中，环A为
    或者，环A为
    或者，环A为
  21. 根据权利要求1所述的含氮螺环化合物，其中，所述化合物选自下列化合物：



  22. 一种药物组合物，其包含权利要求1-21中任一项的化合物或其立体异构体、互变异构体、溶剂化合物、水合物、活性代谢物、同位素标记物或药学上可接受的盐，以及药学可接受的载体。
  23. 权利要求1-21中任一项的化合物或其立体异构体、互变异构体、溶剂化合物、水合物、活性代谢物、同位素标记物或药学上可接受的盐，以及权利要求22所述的药物组合物在制备用于抑制TRPV3活性的药物中的用途。
  24. 权利要求1-21中任一项的化合物或其立体异构体、互变异构体、溶剂化合物、水合物、活性代谢物、同位素标记物或药学上可接受的盐，以及权利要求22所述的药物组合物在制备用于治疗受治疗者的TRPV3介导的病症的药物中的用途。
  25. 根据权利要求24所述的用途，其中，所述病症选自疼痛、瘙痒、皮肤病症、炎症、毛发生长异常、失禁、发热、热潮红、膀胱炎、肠易激综合征和/或咳嗽症状。
  26. 根据权利要求24所述的用途，其中，所述疼痛为癌性痛和皮肤疼痛。
  27. 根据权利要求26的用途，其中，用于制备抑制增殖，由此预防、治疗或缓解癌症症状的药物。
  28. 根据权利要求27的用途，其中，所述癌症为脂肪肉瘤。
  29. 根据权利要求25的用途，其中，所述毛发生长异常为脱发。
  30. 根据权利要求25所述的用途，其中，所述皮肤病症选自皮肤角化病、鱼鳞病、瘙痒症。
  31. 根据权利要求30所述的用途，其中，皮肤角化病为olmsted综合征(olmsted syndrome)。
  32. 根据权利要求31所述的用途，其中，鱼鳞病为丑角样鱼鳞病(harlequin ichtyosis)。
  33. 一种治疗TRPV3介导的病症的方法，包括将治疗有效量的权利要求1-21任一项所述的化合物或其立体异构体、互变异构体、溶剂化合物、水合物、活性代谢物、同位素标记物或药学上可接受的盐，或权利要求22所述的药物组合物，给药于需要给药的患者。
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