WO2024099403A1 - 一种具有软药性质的硫醚类化合物、药物组合物及其用途 - Google Patents

一种具有软药性质的硫醚类化合物、药物组合物及其用途 Download PDF

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WO2024099403A1
WO2024099403A1 PCT/CN2023/130830 CN2023130830W WO2024099403A1 WO 2024099403 A1 WO2024099403 A1 WO 2024099403A1 CN 2023130830 W CN2023130830 W CN 2023130830W WO 2024099403 A1 WO2024099403 A1 WO 2024099403A1
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substituted
ring
independently selected
alkyl
compound according
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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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  • the present invention relates to the field of medicine, and in particular to a TRPV3 antagonist compound, a stereoisomer comprising 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 and Ring B are each independently 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
  • R 0 is independently selected from H, halogen or the structural formula II
  • L 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 ;
  • X is selected from -S-, -S(O)- and -S(O 2 )-;
  • n 0, 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2, or 3.
  • 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 application also relates to a method for treating TRPV3-mediated diseases, comprising administering a therapeutically effective amount of the compound of the present application or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope labels or pharmaceutically acceptable salts, or the pharmaceutical composition of the present application to a patient in need of administration.
  • the thioether structures in the compounds of the present invention have pharmacological activity and are rapidly converted into pharmacologically inactive sulfoxide and sulfone metabolites according to established metabolic pathways after exerting their pharmacological effects, thereby achieving the goal of avoiding the toxicity of the prototype drug, active metabolites, and reactive metabolites to the body while exerting their pharmacological effects, and having relatively higher safety.
  • 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, for example, a TRPV3 antagonist refers to that amount of the antagonist in a formulation which, when administered as part of a desired dosing regimen, results in the desired clinical or functional outcome. Able to result.
  • 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 in vitro or in vivo functional activity. When a specific functional activity can only be easily observed in an in vitro assay, the ability of a compound to inhibit TRPV3 function is a reasonable surrogate for the activity of the compound in an in vitro assay.
  • prevention is art-recognized and is well known in the art when used for conditions, such as local recurrences (e.g., pain), diseases, such as cancer, syndromes, such as heart failure or other medical conditions, and includes the administration of a composition that reduces the frequency of symptoms of a medical condition in a subject, or delays the onset of symptoms of a medical condition, relative to a subject that does not receive the composition.
  • preventing cancer includes, for example, reducing the number of detectable cancer growths in a patient population receiving a prophylactic treatment relative to an untreated control population by a statistically and/or clinically significant amount, and/or delaying the appearance 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 prophylactic and/or therapeutic treatment.
  • Treatments are art-recognized and include administering one or more compositions of the invention to a host. If administered prior to clinical manifestation of an undesirable condition (e.g., a disease or other undesirable condition in the host animal), the treatment is preventive, (i.e., it prevents the host from developing the undesirable condition), while if administered 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 disease or other undesirable condition in the host animal
  • 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 the amino acid sequence of a human TRPV3 protein, or an equivalent polypeptide or functional biologically active fragment thereof.
  • the term refers to a TRPV3 amino acid sequence comprising, consisting of, or consisting essentially of, such as described in any patent application cited herein.
  • TRPV3 proteins may also include orthologs, such as TRPV3 of 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 that encodes a polypeptide that is at least about 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% identical to a TRPV3 polypeptide sequence.
  • nucleotide sequence encoding a polypeptide having the activity of a polypeptide of the present invention and having at least about 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or more homology or identity with a TRPV3 polypeptide sequence;
  • the nucleic acids of the present invention also include homologs of the TRPV3 nucleic acid sequences, for example, orthologs and intraspecific homologous genes, and variants after codon optimization for expression in a specific organism (e.g., a host cell).
  • the TRPV3 nucleic acid sequence includes, 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 an oxygen group is attached.
  • Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.
  • An “ether” is two hydrocarbons covalently linked by an oxygen.
  • the substituent of an alkyl group that makes an alkyl group an ether is an alkoxy group or an alkoxy-like group, for example, 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, hydroxy, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, Phosphonates, phosphinates, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfates, sulfonates, sulfamoyl, sulfonamido, sulfonyl, heterocyclic, aralkyl, or aromatic or heteroaromatic moieties.
  • carbonyl e.g., carboxyl, alkoxycarbonyl, formyl, or acyl
  • thiocarbonyl e.g., thioester, thioacetate, or thi
  • the moieties substituted on the hydrocarbon chain may themselves be substituted if appropriate.
  • the substituents of the substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamido, sulfamoyl and sulfonates), and silyl, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates, and esters), -CF 3 , -CN, etc. Exemplary substituted alkyls are described below.
  • Cycloalkyls may be further substituted by alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF 3 , -CN, etc.
  • Alkenyl and alkynyl groups may be similarly substituted to yield, for example, aminoalkenyl, aminoalkynyl, amidoalkenyl, amidoalkynyl, iminoalkenyl, iminoalkynyl, thioalkenyl, thioalkynyl, carbonyl-substituted alkenyl or alkynyl groups.
  • 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,
  • 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, which 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 radical refers to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and/or heterocyclic radicals) 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, e.g., halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, 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 e.g., halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amide, phosphate, Phosphonate, phosphite,
  • 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 non-aromatic substituents (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroaralkyl, any of which can be further substituted), and halogen, carbonyl (e.g., ester, carboxyl, or formyl), thiocarbonyl (e.g., thioester, thiocarboxylate, or thioformate), ketone, aldehyde, amino, amido, amide, amidino, cyano, nitro, azido, sulfon
  • aromatic and non-aromatic substituents e.g., alkyl, alkenyl, alkynyl,
  • Illustrated substituents include, for example, those described above.
  • Permissible substituents may be one or more, and the same or different, to a suitable organic compound.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner to the permissible substituents of organic compounds.
  • 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.
  • 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 diastereomeric salt may be formed with a suitable optically active acid or base, followed by fractional crystallization or chromatographic separation of the diastereomers thus formed, and subsequent recovery of the pure enantiomer.
  • enantiomerically enriched mixtures and pure enantiomer compounds may 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.
  • 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 unnatural moieties at one or more atoms constituting the compounds.
  • 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 variations of the compounds of the invention, whether radioactive or non-radioactive, are intended to be encompassed within the scope of the invention.
  • Some compounds of the present invention can exist in unsolvated form as well as solvated form, including hydrate form.
  • the solvated form is the equivalent of the unsolvated form and is included within the scope of the present invention.
  • Some compounds of the present invention can exist in polycrystalline or amorphous form. In general, all physical forms are equivalent to the intended applications of the present invention and are intended to fall 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 forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the 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 the purposes of this invention, the salts are equivalent to the compounds.
  • the parent form of things are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the 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 the purposes of this invention, the salts are equivalent to the compounds.
  • the parent form of things are regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • 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 the level and/or activity of a TRPV3 protein.
  • the compound inhibits the expression and/or activity of a TRPV3 protein.
  • the compound selectively inhibits the expression of a TRPV3 protein.
  • the compound preferentially inhibits the activity of a 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 (such as migraine), asthma, peripheral vascular disease, hypertension, immunity and inflammation.
  • sexual disorders include 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).
  • TRPV3 inhibitors described herein can be used to treat any of the diseases or conditions described above or below, including the treatment of pain associated with any of the diseases or conditions described above or below.
  • 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.
  • a method of treating pain comprises 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 treating pain by 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 functions of TRPV3 and TRPM8; or (iv) a pan-inhibitor that antagonizes the functions of TRPV3, TRPM8, and one or more TRPV1 and TRPV4.
  • 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 the signs and symptoms of acute pain, chronic pain, contact sensitivity, itch sensitivity, or as a treatment for burns. pain caused by an injury, such as postoperative 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 ameliorate the 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 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.
  • another aspect of the present invention provides a pharmaceutical composition
  • 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 (containing water or The invention can be administered in any of the following forms: (a) a non-aqueous solution or suspension); (b) a tablet; (c) a pill; (d) a powder; (e) a granule; (e) a paste for application to the tongue, teeth, lips, or gums; (e) a mouthwash; (f) a gel; (g) (i) parenteral administration, for example, as a sterile solution or suspension, by subcutaneous, intramuscular, or intravenous injection; (g) topical administration, for example, as a cream, oint
  • 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.
  • pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, that participates in carrying or transporting a pharmaceutically acceptable to deliver 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, that participates in carrying or transporting a pharmaceutically acceptable to deliver 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 can be used 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 sodium carboxymethylcellulose, 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) 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
  • 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 thus be capable of
  • pharmaceutically acceptable salt refers to the addition salts of relatively non-toxic inorganic and organic bases of the compounds of the invention.
  • the above-mentioned base addition salts can also be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in the form of a free acid with a suitable base, ammonium, or a pharmaceutically acceptable organic primary, secondary or tertiary amine separately, wherein the base is, for example, a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation.
  • Representative alkali salts or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, etc.
  • Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc.
  • 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 and Ring B are each independently 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
  • R 0 is independently selected from H, halogen or the structural formula II
  • L 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 ;
  • X is selected from -S-, -S(O)- and -S(O 2 )-;
  • n 0, 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2, or 3.
  • the compound has the structural formula I-1
  • ring A, ring B, ring C, X, R 1 , R 2 , R 3 , L, n, p, m and q are as defined in formula I.
  • ring A is selected from a benzene 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 A is selected from the following structural formulas:
  • ring B is selected from a benzene 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 B is selected from the following structural formulas:
  • 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 .
  • n 0, 1 or 2.
  • m is 0, ie, X is directly attached to ring A.
  • R 1 is located at the ortho or para position to X on ring A.
  • one R 1 is located para to X on ring A.
  • R2 is each independently selected from H, cyano, hydroxyl, C1- C6 alkyl, C1 -C6 haloalkyl, C3 - C6 cycloalkyl substituted with 0-2 Rf , C1 - C6 alkoxy, C1 - C6 haloalkoxy, -R11OR12 , -R11SR12 , -C(O) ORd and -C(O)N(R a ) (R b ) ; wherein, R11 is each independently selected from C1 - C6 alkylene; R12 is each independently selected from H, C1 - C6 alkyl, C1 - C6 haloalkyl, C3 - C6 cycloalkyl and C3 - C6 halocycloalkyl; R a and R b are each independently selected from H and C1 - C6 alkyl; R d is each independently selected from H and C1 - C6 alkyl;
  • each R 2 is independently selected from H, -CH 3 , -OH, -CH 2 OH, -CH 2 OCH 3 , -CH 2 CH 2 OH, -CH(CH 3 ) OH, -C(CH 3 ) 2 OH, -CH 2 SH, -OCH 2 CH 3 , -OCF 3 , -OCH 3 , -OCH(CH 3 ) 2 , -COOH, -COOCH 3 , -CONH 2 , -CH 2 NH 2 , -CH 2 CHF 2 , -CN, -CHF 2 , Preferably, R 2 is -CH 2 OH.
  • p is 1, ie, only one R 2 as defined above is substituted on ring B.
  • the R 2 is located in the ortho position to the pyrrolidinyl group.
  • each L is independently selected from a bond, -O-, -S-, -N-, -C(O)-, -CH2- , -C(OH)-, -S(O)-, and -S( O2 )-.
  • L is -S-, or L is -S(O)-, or L is -S(O 2 )-.
  • L is -S-.
  • 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, hydroxy, 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 are connected to them.
  • the ring C atoms together 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, ethyl, methyl, methylcarbonyl, methoxymethyl.
  • the present application relates to a compound of formula (I-2):
  • Ring A is independently selected from a monocyclic or polycyclic ring system containing 3-12 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 , R f is a hetero
  • R 0 is independently selected from H, halogen or the structural formula II
  • L 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 ;
  • X is selected from -S-, -S(O)- and -S(O 2 )-;
  • XA , XB , XC , XD , and XE are each independently CH or N;
  • XF is CH
  • n 0, 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2, or 3.
  • XA , XB , XC , XD , XE are each independently CH;
  • XA , XB , XC , and XE are each independently CH, and XD is N;
  • XA , XB , XC , and XD are each independently CH, and XE is N;
  • XA , XC , and XD are each independently CH, and XB and XE are N.
  • m may be zero.
  • n may be 1 or 2, that is, ring A is substituted with 1 or 2 R 1 .
  • p may be 1, that is, one R 2 is substituted on ring B or the six-membered ring composed of X A , X B , X C , X D , X E , and X F.
  • the R 2 is located at the ortho position of the pyrrolidinyl group.
  • 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 present application also relates to a method for treating TRPV3-mediated diseases, comprising administering a therapeutically effective amount of the compound of the present application or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope labels or pharmaceutically acceptable salts, or the pharmaceutical composition of the present application to a patient in need of administration.
  • 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, and 3 Representative procedures for preparing compounds of the invention are outlined in Schemes 1, 2, and 3.
  • the (R)-1-BOC-3-hydroxypyrrolidine starting material can be purchased or prepared using methods known in the art, with representative procedures providing intermediates.
  • Scheme 1 highlights the fully detailed synthesis of (2-(3-(pyridin-2-ylthio)pyrrolidin-1-yl)phenyl)methanol.
  • intermediate thioether 3 is obtained by reaction of (R)-1-BOC-3-methanesulfonyloxypyrrolidine 2 with the desired aromatic thiol in alkaline solution to produce intermediate 3, which is deprotected under acidic conditions to produce intermediate Form 4, 4 reacts with 5-bromo-2-fluorobenzaldehyde in an alkaline solution to generate intermediate 5, which is further reduced under a reducing agent to generate 6.
  • Intermediate 6 can be coupled to 7 by reacting 5 with a desired boronic acid under Suzuki conditions.
  • Scheme 2 shows the synthesis of the desired compounds, where 5 is generated in the fourth step via a catalytic coupling reaction, intermediate 4 is prepared in the same manner as in Scheme 1, and intermediate 5 is reacted with the desired boronic acid under Suzuki conditions to produce coupling to give 6.
  • Scheme 3 shows the synthesis of the desired compound, except that intermediate 5 is first prepared by purchasing or using methods known in the art.
  • the preparation of intermediate 4 is the same as in Scheme 1, and intermediates 4 and 5 are catalyzed by coupling reaction to generate 6.
  • Step A (R)-tert-butyl 3-(methylsulfonyl)oxy)pyrrolidine-1-carboxylate
  • the aqueous phase was extracted once with 150mL of dichloromethane, and the organic phases were combined. The organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness.
  • Step B (S)-tert-butyl 3-(5-chloropyridin-2-yl)thio)pyrrolidine-1-carboxylate
  • the aqueous phase was extracted twice with ethyl acetate (2*100mL), and the organic phases were combined.
  • the organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product.
  • Step A (S)-4-(3-(5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-carbaldehyde
  • Step B ((S)-(4-(3-(5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-yl)methanol
  • Step A (S)-4-(3-(5-chloropyridin-2-yl)sulfonyl)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-carbaldehyde
  • Step B (S)-(4-(3-(5-chloropyridin-2-yl)sulfonyl)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-yl)methanol
  • Step A 4-(S)-3-(S)-(5-chloropyridin-2-yl)sulfoxide)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-carbaldehyde
  • Step B (4-(S)-3-(S)-(5-chloropyridin-2-yl)sulfoxide)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-yl)methanol
  • Step A (S)-4-(3-(5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-cyclopropyl-[1,1'-biphenyl]-3-carbaldehyde
  • the LC-MS results confirmed the formation of the target product.
  • the reaction solution was cooled to room temperature, quenched with water, and extracted three times with ethyl acetate.
  • Step B ((S)-(4-(3-(5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-cyclopropyl-[1,1'-biphenyl]-3-yl)methanol
  • the reaction solution was cooled to 0°C, quenched by adding saturated aqueous ammonium chloride solution, extracted twice by adding ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness.
  • the experimental operation refers to the synthesis steps of Example 2, replacing the reagent (2-isopropylphenyl)boric acid with (2-cyclopropylphenyl)boric acid, and Example 5 is synthesized.
  • the experimental operation refers to the synthesis steps of Example 3, replacing the reagent (2-isopropylphenyl)boric acid with (2-cyclopropylphenyl)boric acid, and synthesizing Example 6.
  • Step A (S)-tert-butyl 3-(5-(trifluoromethyl)pyridin-2-yl)thio)pyrrolidine-1-carboxylate
  • the aqueous phase was extracted three times with ethyl acetate (2*100mL), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product.
  • Step B (S)-2-(Pyrrolidin-3-ylthio)-5-(trifluoromethyl)pyridine hydrochloride
  • Step C (S)-5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yl)thio)pyrrolidin-1-yl)benzaldehyde
  • Step D (S)-2'-Isopropyl-4-(3-(5-(trifluoromethyl)pyridin-2-yl)thio)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-carbaldehyde
  • the LC-MS results confirmed the formation of the target product.
  • Step E ((S)-(2'-isopropyl-4-(3-(5-(trifluoromethyl)pyridin-2-yl)thio)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-yl)methanol
  • the reaction solution was cooled to 0°C, quenched by adding saturated aqueous ammonium chloride solution, extracted three times with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness.
  • Step A (S)-2'-isopropyl-4-(3-(5-(trifluoromethyl)pyridin-2-yl)sulfonyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-carbaldehyde
  • Step B (S)-(2'-isopropyl-4-(3-(5-(trifluoromethyl)pyridin-2-yl)sulfonyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-yl)methanol
  • the reaction solution is cooled to 0°C, quenched by adding saturated ammonium chloride aqueous solution, and extracted twice with ethyl acetate.
  • the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness.
  • Step A 2'-isopropyl-4-(S)-3-(S)-(5-(trifluoromethyl)pyridin-2-yl)sulfoxide)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-carbaldehyde
  • Step B (2'-isopropyl-4-(S)-3-(S)-(5-(trifluoromethyl)pyridin-2-yl)sulfoxide)pyrrolidine-1-yl 1,1'-Biphenyl-3-yl)methanol
  • the reaction solution was cooled to 0°C, quenched by adding saturated aqueous ammonium chloride solution, extracted twice by adding ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness.
  • Step B (S)-tert-butyl 3-(5-fluoropyridin-2-yl)thio)pyrrolidine-1-carboxylate
  • Step D (S)-5-Bromo-2-(3-(5-fluoropyridin-2-yl)thio)pyrrolidin-1-yl)benzaldehyde
  • reaction solution was cooled to room temperature, water was added to quench the reaction, and ethyl acetate was added to extract three times.
  • Step E (S)-2'-cyclopropyl-4-(3-((5-fluoropyridin-2-yl)thio)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-carbaldehyde
  • Step F ((S)-(4-(3-(5-fluoropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-cyclopropyl-[1,1'- Benzene]-3-yl)methanol
  • Table 1 The examples in Table 1 were prepared by the method of Example 1 described above, with the starting materials being replaced by (S)-1-BOC-3-hydroxypyrrolidine, 1-BOC-3-hydroxypyrrolidine and other required materials, respectively.
  • Step A (S)-4-bromo-2-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)benzaldehyde
  • Step B (S)-3-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-4-carbaldehyde
  • the product was confirmed to be generated by LC-MS, 5mL of water was added, and then extracted with ethyl acetate three times, the organic layer was washed with 5mL of saturated saline solution, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 48.0mg of light yellow oily liquid, which was directly used in the next reaction without purification.
  • Step C (S)-3-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-4-methanol
  • Step A (S)-2-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-5-((2-isopropylphenyl)amino)benzaldehyde
  • Step B (S)-(2-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-5-((2-isopropylphenyl)amino)phenyl)methanol
  • 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, mix well; add 3 ⁇ g plasmid to the other tube, mix well, and then add 6 ⁇ L P3000, 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 pre-placed, 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 current peak. The experimental data are collected by an EPC10 amplifier (HEKA) and stored in the PatchMaster (HEKA) software.
  • HEKA EPC10 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 then 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.
  • the prepared compounds were tested using the above analytical process, and the results obtained are shown in Table 5.
  • the inhibition rate (%) at a concentration of 0.3 ⁇ M is shown in the table.
  • the sulfide compounds of the present invention have soft drug properties, and the sulfoxide and sulfone metabolites have no pharmacological activity (Table 5), thereby achieving the effect of the drug while avoiding the toxicity of the prototype drug, active metabolites, and reactive metabolites to the body.
  • the patented compounds of the present invention also have good selectivity (Table 6).
  • Table 5 Inhibition rate (%) of the compounds of the present invention on hTRPV3 at a single concentration (0.3 ⁇ M) a Note: Example compound KM-001 in patent WO2021154966A1.
  • the selectivity ratio refers to the ratio of the compound's inhibition rate on TRPV3 ion channel to the inhibition rate on other ion channels.
  • NADPH 10 ⁇ L of 20 mg/mL liver microsomes and 40 ⁇ L of 10 mM NADPH was added to the culture medium. The final concentrations of microsomes and NADPH were 0.5 mg/mL and 1 mM, respectively.
  • Without NADPH 10 ⁇ L of 20 mg/mL liver microsomes and 40 ⁇ L of ultrapure H 2 O were added to the culture medium. The final concentration of microsomes was 0.5 mg/mL.

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Abstract

一种具有软药性质的硫醚类化合物、药物组合物及其用途，该化合物具有式I的结构式，化合物中的硫醚类结构具有药理活性，在发挥药效后按照既定的代谢途径迅速地被转化为不具有药理活性的亚砜、砜类代谢产物，从而实现在发挥药效的同时，避免原型药物、活性代谢物、反应性代谢物对机体造成毒性，安全性相对更高。

Description

一种具有软药性质的硫醚类化合物、药物组合物及其用途 技术领域
本发明涉及医药领域，具体涉及一种TRPV3拮抗剂类化合物、包含所述化合物的立体异构体、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
本申请涉及式(I)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、药学上可接受的盐，
其中，环A和环B各自独立地选自含有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B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，
L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；
X选自-S-、-S(O)-和-S(O2)-；
n为0、1、2或3；
m为0、1、2或3；
p为0、1、2或3；
q为0、1、2或3。
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。
本申请还涉及一种治疗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。
本发明化合物中的硫醚类结构具有药理活性，在发挥药效后按照既定的代谢途径迅速地被转化为不具有药理活性的亚砜、砜类代谢产物，从而实现在发挥药效的同时，避免原型药物、活性代谢物、反应性代谢物对机体造成毒性，安全性相对更高。
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。
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。
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。
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。
本申请涉及式(I)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、药学上可接受的盐，
其中，环A和环B各自独立地选自含有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B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，
L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；
X选自-S-、-S(O)-和-S(O2)-；
n为0、1、2或3；
m为0、1、2或3；
p为0、1、2或3；
q为0、1、2或3。
在一种实施方案中，所述化合物具有I-1的结构式
其中，环A、环B、环C、X、R1、R2、R3、L、n、p、m和q定义如式I。
在一种实施方案中，环A选自苯环、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A选自以下结构式：
在一种实施方案中，环B选自苯环、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B选自以下结构式：
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，n为0、1或者2。
在一种实施方案中，m为0，即X直接连接在环A上。
在一种实施方案中，当n为1且m为0时，在环A上该R1位于X的邻位或者对位。
在一种实施方案中，当n为2且m为0时，在环A上一个R1位于X的对位。
在一种实施方案中，R2各自独立地选自H、氰基、羟基、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、-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H、-CH3、-OH、-CH2OH、-CH2OCH3、-CH2CH2OH、-CH(CH3)OH、-C(CH3)2OH、-CH2SH、-OCH2CH3、-OCF3、-OCH3、-OCH(CH3)2、-COOH、-COOCH3、-CONH2、-CH2NH2、-CH2CHF2、-CN、-CHF2、优选地，R2为-CH2OH。
在一种实施方案中，p为1，即环B上仅取代有1个如上定义的R2。在p为1的实施方案中，在环B上该R2位于吡咯烷基的邻位。
在一种实施方案中，L各自独立地选自键、-O-、-S-、-N-、-C(O)-、-CH2-、-C(OH)-、-S(O)-和-S(O2)-。
在一种实施方案中，L为-S-，或者L为-S(O)-，或者L为-S(O2)-。优选地，L为-S-。
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、乙基、甲基、甲基羰基、甲氧基甲基。
本申请涉及式(I-2)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、药学上可接受的盐，
其中，环A各自独立地选自含有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；
R0各自独立地选自H、卤素或者式II的结构式
其中，
L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；
X选自-S-、-S(O)-和-S(O2)-；
XA、XB、XC、XD、XE各自独立地为CH或N；
XF为CH；
n为0、1、2或3；
m为0、1、2或3；
p为0、1、2或3；
q为0、1、2或3。
在一种实施方案中，XA、XB、XC、XD、XE各自独立地为CH；
或者，XA、XB、XC、XE各自独立地为CH，XD为N；
或者，XA、XB、XC、XD各自独立地为CH，XE为N；
或者，XA、XC、XD各自独立地为CH，XB、XE为N。
需要说明的是，以上关于化合物I以及化合物I-1中各基团的限定同样适用于化合物I-2。
在以上化合物的实施方案中，m可以为0。
在以上化合物的实施方案中，n可以为1或者2，也即环A上取代有1或2个R1。
在以上化合物的实施方案中，p可以为1，也即环B或者XA、XB、XC、XD、XE、XF构成的六元环上取代有1个R2。在一种实施方案中，该R2位于吡咯烷基的邻位。
在一种实施方案中，所述化合物选自以下化合物：

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。
本申请还涉及一种治疗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。
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和方案3中。(R)-1-BOC-3-羟基吡咯烷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(2-(3-(吡啶-2-基硫代)吡咯烷-1-基)苯基)甲醇的合成。(R)-1-BOC-3-甲磺酰氧基吡咯烷2的合成可通过(R)-1-BOC-3-羟基吡咯烷1和甲基磺酰氯在诸如二氯甲烷的溶剂中的反应而实现，中间体硫醚3通过(R)-1-BOC-3-甲磺酰氧基吡咯烷2与所需的芳香巯基在碱性溶液中反应生成中间体3，中间体3在酸性条件下脱保护生成中间 体4，4与5-溴-2-氟苯甲醛在碱性溶液中反应生成中间体5，进一步在还原剂的条件下还原生成6，中间体6可通过5与所需的硼酸在Suzuki条件下反应以产生偶联得到7。
方案1
方案2显示了所需化合物的合成，其中在第四步通过催化偶联反应生成5，中间体4的制备与方案1相同，中间体5与所需的硼酸在Suzuki条件下反应以产生偶联得到6。
方案2
方案3显示了所需化合物的合成，只是购买或使用本领域已知的方法先制备中间体5，中间体4的制备与方案1相同，中间体4和5通过催化偶联反应生成6。
方案3
为清楚起见，进一步用实施例来阐述本发明，但是实施例并非限制本申请的范围。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。
具体实施方案
中间体的制备
制备例1(S)-5-氯-2-(吡咯烷-3-基硫代)吡啶盐酸盐(化合物I1)
步骤A:(R)-3-(甲磺酰基)氧基)吡咯烷-1-羧酸叔丁酯
将18.0g(96.1mmol,1.0eq)(R)-3-羟基吡咯烷-1-羧酸叔丁酯和40mL(288mmol,3.0eq)三乙胺溶解在60mL无水四氢呋喃中，降温到0℃，再将13.2g(115mmol,1.2eq)甲磺酰氯滴加至该反应体系，滴完自然升温到室温搅拌2小时。经TLC确认原料反应完，加入水150mL，二氯甲烷100mL，分得有机相，水相加入二氯甲烷150mL萃取一遍，合并有机相，有机相经过盐水洗涤，无水硫酸钠干燥后浓缩干，粗品经柱层析(石油醚:乙酸乙酯＝100:1～30:1)得到淡黄色油状物(18.2g，收率＝71％)。
LC-MS:(M+23)+；m/z＝288.06；
1H NMR(400MHz,CDCl3)δ5.18-5.13(m,1H),3.60-3.32(m,4H),2.93(s,3H),2.16-2.02(m,2H),1.35(s,9H).
步骤B:(S)-3-(5-氯吡啶-2-基)硫代)吡咯烷-1-羧酸叔丁酯
4.00g(15.1mmol,1.0eq)(R)-3-(甲磺酰基)氧基)吡咯烷-1-羧酸叔丁酯溶解在90mL无水N,N-二甲基甲酰胺中，再将3.30g(22.6mmol,1.5eq)5-氯吡啶-2-硫醇和3.13g(22.6mmol,1.5eq)碳酸钾加至该反应体系，氮气保护下在70℃搅拌反应18h。降温到室温，加入水50mL和乙酸乙酯150mL，分得有机相，水相用乙酸乙酯(2*100mL)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(4.00g，收率＝84％)。
LC-MS:(M-100)+；m/z＝215.06；
1H NMR(400MHz,CDCl3)δ8.38(s,1H),7.47-7.44(m,1H),7.10(d,J＝8.0Hz,1H),4.32-4.27(m,1H),3.93-3.84(m,1H),3.59-3.27(m,3H),2.37-2.32(m,1H),1.99-1.92(m,1H),1.46(s,9H).
步骤C:(S)-5-氯-2-(吡咯烷-3-基硫代)吡啶盐酸盐
4.30g(13.7mmol,1.0eq)(S)-3-(5-氯吡啶-2-基)硫代)吡咯烷-1-羧酸叔丁酯溶解在50mL二氯甲烷中，再将5.7mL(68.3mmol,5.0eq)浓盐酸加到上述反应体系中，该反应体系在氮气保护条件下常温搅拌1h。经LC-MS结果确认原料反应完全，将反应液直接减压浓缩得到类白色固体(2.56g，收率＝88％)。
LC-MS:(M+H)+；m/z＝415.06。
中间体I2(S)-5-溴-2-(3-(5-氯吡啶-2-基)硫代)吡咯烷-1-基)苯甲醛
1.50g(6.99mmol,1.0eq)(S)-5-氯-2-(吡咯烷-3-基硫代)吡啶溶解在20mL无水N,N-二甲基甲酰胺中，再将3.55g(17.5mmol,2.5eq)5-溴-2-氟苯甲醛和2.90g(21.0mmol,3.0eq)无水碳酸钾加到上述反应体系中，该反应体系在氮气保护条件下于90℃反应过夜。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(石油醚:乙酸乙酯＝100:1～30:1)得到淡黄色油状物(1.40g,收率＝50％)。
LC-MS:(M+H)+；m/z＝398.98；
1H NMR(400MHz,CDCl3)δ10.00(s,1H),8.37-8.36(m,1H),7.79(d,J＝4.0Hz,1H),7.48-7.44(m,2H),7.10(d,J＝8.0Hz,1H),6.74(d,J＝8.0Hz,1H),4.46-4.40(m,1H),3.93-3.90(m,1H),3.58-3.48(m,2H),3.34-3.33(m,1H),2.56-2.48(m,1H),2.18-2.10(m,1H)。
中间体I3(S)-(5-溴-2-(3-((5-氯吡啶-2-基)硫代)吡咯烷-1-基)苯基)甲醇
将2.0g(5.03mmol,1.0eq)(S)-5-溴-2-(3-(5-氯吡啶-2-基)硫代)吡咯烷-1-基)苯甲醛溶解在10mL甲醇中，体系降温到0℃，氮气保护条件下再将761mg(20.12mmol,4.0eq)硼氢化钠固体加到上述反应体系中，加完自然升温到室温反应1.5h。经LC-MS结果确认有目标产物生成，将反应液降到0℃，加入饱和氯化铵水溶液淬灭，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，减压蒸馏浓缩得到目标产物(1.73g，收率＝86％)。
LC-MS:(M+H)+；m/z＝400.98；
实施例1：((S)-(4-(3-(5-氯吡啶-2-基)硫代)吡咯烷-1-基)-2’-异丙基-[1,1’-联苯]-3-基)甲醇
步骤A:(S)-4-(3-(5-氯吡啶-2-基)硫代)吡咯烷-1-基)-2’-异丙基-[1,1'-联苯]-3-甲醛
将900mg(2.26mmol,1.0eq)(S)-5-溴-2-(3-(5-氯吡啶-2-基)硫代)吡咯烷-1-基)苯甲醛溶解在20mL二氧六环和5mL水中，再将445mg(2.72mmol,1.2eq)(2-异丙基苯基)硼酸和626mg(4.53mmol,2.0eq)无水碳酸钾加到上述反应体系中，氮气保护条件下加入185mg(0.23mmol,0.1eq)[1,1'-双(二苯基膦)二茂铁]二氯化钯于100℃反应4h。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(石油醚:乙酸乙酯＝100:1～30:1)得到淡黄色油状物(710mg，收率＝71％)。
LC-MS:(M+H)+；m/z＝437.16；
1H NMR(400MHz,CDCl3)δ10.13(s,1H),8.41-8.40(m,1H),7.66(d,J＝4.0Hz,1H),7.50(dd,J＝8.0Hz,4.0Hz,1H),7.42-7.34(m,3H),7.25-7.14(m,3H),6.93(d,J＝8.0Hz,1H),4.53-4.46(m,1H),4.01-3.99(m,1H),3.67-3.60(m,2H),3.46-3.45(m,1H),3.13-3.04(m,1H),2.63-2.55(m,1H),2.26- 2.15(m,1H),1.20(d,J＝8.0Hz,6H).
步骤B:((S)-(4-(3-(5-氯吡啶-2-基)硫代)吡咯烷-1-基)-2’-异丙基-[1,1’-联苯]-3-基)甲醇
将150mg(0.34mmol,1.0eq)((S)-4-(3-(5-氯吡啶-2-基)硫代)吡咯烷-1-基)-2’-异丙基-[1,1’-联苯]-3-甲醛溶解在10mL甲醇中，体系降温到0℃，氮气保护条件下再将51.9mg(1.37mmol,4.0eq)硼氢化钠固体加到上述反应体系中，加完自然升温到室温反应1.5h。经LC-MS结果确认有目标产物生成，将反应液降到0℃，加入饱和氯化铵水溶液淬灭，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)，冻干得到目标产物(80.0mg，收率＝53％)。
LC-MS:(M+H)+；m/z＝439.18；
1H NMR(400MHz,CDCl3)δ8.39(d,J＝4.0Hz,1H),7.46(dd,J＝8.0Hz,4.0Hz,1H),7.38-7.30(m,2H),7.21-7.12(m,6H),4.82-4.78(m,2H),4.46-4.40(m,1H),4.20(s,1H),3.76-3.75(m,1H),3.49-3.44(m,1H),3.32-3.25(m,2H),3.09-3.03(m,1H),2.63-2.54(m,1H),2.11-2.03(m,1H),1.15(d,J＝4.0Hz,6H).
实施例2：(S)-(4-(3-(5-氯吡啶-2-基)磺酰基)吡咯烷-1-基)-2’-异丙基-[1,1’-联苯]-3-基)甲醇
步骤A:(S)-4-(3-(5-氯吡啶-2-基)磺酰基)吡咯烷-1-基)-2’-异丙基-[1,1’-联苯]-3-甲醛
240mg(0.55mmol,1.0eq)(S)-4-(3-(5-氯吡啶-2-基)硫代)吡咯烷-1-基)-2’-异丙基-[1,1’-联苯]-3-甲醛溶解在6mL甲醇和3mL四氢呋喃中，再将124mg(0.55mmol,1.0eq)钨酸钠和0.5mL(5.5mmol,10.0eq)双氧水加入反应体系中。升温到40℃反应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(石油醚:乙酸乙酯＝100:1～3:1)得到淡黄色油状物(180mg,收率＝69％)。
LC-MS:(M+H)+；m/z＝471.17；
步骤B:(S)-(4-(3-(5-氯吡啶-2-基)磺酰基)吡咯烷-1-基)-2’-异丙基-[1,1’-联苯]-3-基)甲醇
将180mg(0.38mmol,1.0eq)(S)-4-(3-(5-氯吡啶-2-基)磺酰基)吡咯烷-1-基)-2’-异丙基-[1,1’-联苯]-3-甲醛溶解在5mL甲醇中，体系降温到0℃，氮气保护条件下再将72.6mg(1.37mmol,5.0eq)硼氢化钠固体加到上述反应体系中，加完自然升温到室温反应1.5h。经LC-MS结果确认有目标产物生成，将反应液降到0℃，加入饱和氯化铵水溶液淬灭，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)，冻干得到目标产物(81.8mg,收率＝45％)。
LC-MS:(M+H)+；m/z＝471.18；
1H NMR(400MHz,CDCl3)δ8.70(d,J＝2.0Hz,1H),8.12(d,J＝8.0Hz,1H),7.96(dd,J＝8.0Hz,4.0Hz,1H),7.38-7.30(m,2H),7.20-7.11(m,5H),4.83(d,J＝12.0Hz,1H),4.70(d,J＝16.0Hz,1H),4.50-4.40(m,1H),4.0(s,1H),3.68-3.66(m,1H),3.49-3.43(m,2H),3.24-3.18(m,1H),3.07-3.00(m,1H),2.64-2.55(m,1H),2.42-2.33(m,1H),1.15(d,J＝6.8Hz,6H).
实施例3：(4-(S)-3-(S)-(5-氯吡啶-2-基)亚砜基)吡咯烷-1-基)-2’-异丙基-[1,1’-联苯]-3-基)甲醇
步骤A:4-(S)-3-(S)-(5-氯吡啶-2-基)亚砜基)吡咯烷-1-基)-2’-异丙基-[1,1’-联苯]-3-甲醛
230mg(0.53mmol,1.0eq)(S)-4-(3-(5-氯吡啶-2-基)硫代)吡咯烷-1-基)-2’-异丙基-[1,1’-联苯]-3-碳醛溶解在5mL二氯甲烷中，氮气保护下将体系降温到0℃，再将145mg(0.84mmol,1.6eq)间氯过氧苯甲酸加入反应体系中，0℃反应2h。经LC-MS结果确认有目标产物生成，将反应液加入水淬灭，加入二氯甲烷萃取两遍，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(石油醚:乙酸乙酯＝80:1～1:1)得到淡黄色油状物(180mg,收率＝75％)。
LC-MS:(M+H)+；m/z＝453.17；
步骤B:(4-(S)-3-(S)-(5-氯吡啶-2-基)亚砜基)吡咯烷-1-基)-2’-异丙基-[1,1’-联苯]-3-基)甲醇
将170mg(0.38mmol,1.0eq)(4-(S)-3-(S)-(5-氯吡啶-2-基)亚砜基)吡咯烷-1-基)-2’-异丙基-[1,1’-联苯]-3-碳醛溶解在5mL甲醇中，体系降温到0℃，氮气保护条件下再将42.6mg(1.13mmol,3.0eq)硼氢化钠固体加到上述反应体系中，加完自然升温到室温反应1.5h。经LC-MS结果确认有目标产物生成，将反应液降到0℃，加入饱和氯化铵水溶液淬灭，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)，冻干得到目标产物为白色固体(68.5mg,收率＝40％)。
LC-MS:(M+H)+；m/z＝455.16；
1H NMR(400MHz,CDCl3)δ8.61-8.59(m,1H),8.00(dd,J＝8.0Hz,4.0Hz,1H),7.95-7.90(m,1H),7.39-7.30(m,2H),7.21-7.10(m,5H),4.86-4.80(m,1H),4.71-4.69(m,1H),3.85-3.78(m,2H),3.66-3.52(m,1H),3.44-3.35(m,1H),3.14-3.00(m,2H),2.66-2.59(m,1H),2.56-2.39(m,1H),1.94-1.85(m,1H),1.16(d,J＝6.8Hz,6H).
实施例4：((S)-(4-(3-(5-氯吡啶-2-基)硫代)吡咯烷-1-基)-2’-环丙基-[1,1’-联苯]-3-基)甲醇
步骤A:(S)-4-(3-(5-氯吡啶-2-基)硫代)吡咯烷-1-基)-2’-环丙基-[1,1’-联苯]-3-甲醛
将600mg(1.50mmol,1.0eq)(S)-5-溴-2-(3-(5-氯吡啶-2-基)硫代)吡咯烷-1-基)苯甲醛溶解在20mL二氧六环和5mL水中，再将293mg(1.81mmol,1.2eq)(2-环丙基苯基)硼酸和626mg(4.53mmol,3.0eq)无水碳酸钾加到上述反应体系中，氮气保护条件下加入221mg(0.23mmol,0.2eq)[1,1'-双(二苯基膦)二茂铁]二氯化钯于100℃反应4h。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，加入乙酸乙酯萃取三遍，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(石油醚:乙酸乙酯＝100:1～30:1)得到淡黄色油状物(450mg,收率＝68％)。
LC-MS:(M+H)+；m/z＝435.12；
步骤B:((S)-(4-(3-(5-氯吡啶-2-基)硫代)吡咯烷-1-基)-2’-环丙基-[1,1’-联苯]-3-基)甲醇
将480mg(1.10mmol,1.0eq)((S)-4-(3-(5-氯吡啶-2-基)硫代)吡咯烷-1-基)-2’-环丙基-[1,1’-联苯]-3-碳醛溶解在10mL甲醇中，体系降温到0℃，氮气保护条件下再将209mg(5.52mmol,4.0eq)硼氢化钠固体加到上述反应体系中，加完自然升温到室温反应1.5h。经LC-MS结果确认有目标产物生成，将反应液降到0℃，加入饱和氯化铵水溶液淬灭，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)，冻干得到目标产物为淡黄色油状液体(360mg,收率＝74％)。
LC-MS:(M+H)+；m/z＝437.30；
1H NMR(400MHz,CDCl3)δ8.41(d,J＝4.0Hz,1H),7.46(dd,J＝8.0Hz,4.0Hz,1H),7.37-7.33(m,2H),7.28-7.25(m,1H),7.23-7.20(m,2H),7.18-7.15(m,2H),6.93(d,J＝8.0Hz,1H),4.86-4.80(m,2H),4.49-4.44(m,1H),4.21(s,1H),3.79-3.78(m,1H),3.52-3.46(m,1H),3.35-3.27(m,2H),2.65-2.57(m,1H),2.13-2.05(m,1H),1.95-1.88(m,1H),0.89-0.84(m,2H),0.75-0.71(m,2H).
实施例5：(S)-(4-(3-((5-氯吡啶-2-基)磺酰基)吡咯烷-1-基)-2'-环丙基-[1,1'-联苯]-3-基)甲醇
实验操作参考实施例2的合成步骤，将试剂(2-异丙基苯基)硼酸替换为(2-环丙基苯基)硼酸，经合成得实施例5。
LC-MS:(M+H)+；m/z＝469.11；
1H NMR(400MHz,CDCl3)δ8.71(d,J＝2.0Hz,1H),8.13(d,J＝8.0Hz,1H),7.98(dd,J＝8.0Hz,4.0Hz,1H),7.39-7.31(m,2H),7.22-7.11(m,5H),4.85-4.83(m,1H),4.71-4.69(m,1H),4.50-4.40(m,1H),4.0(s,1H),3.68-3.66(m,1H),3.49-3.43(m,2H),3.24-3.18(m,1H),2.66-2.57(m,1H),2.14- 2.06(m,1H),1.95-1.88(m,1H),0.89-0.85(m,2H),0.75-0.72(m,2H).
实施例6：(4-(S)-3-((S)-(5-氯吡啶-2-基)亚砜基)吡咯烷-1-基)-2'-环丙基-[1,1'-联苯]-3-基)甲醇
实验操作参考实施例3的合成步骤，将试剂(2-异丙基苯基)硼酸替换为(2-环丙基苯基)硼酸，经合成得实施例6。
LC-MS:(M+H)+；m/z＝453.10；
1H NMR(400MHz,CDCl3)δ8.63-8.59(m,1H),8.01(dd,J＝8.0Hz,4.0Hz,1H),7.95-7.90(m,1H),7.38-7.29(m,2H),7.21-7.10(m,5H),4.86-4.80(m,1H),4.71-4.69(m,1H),3.85-3.78(m,2H),3.66-3.52(m,1H),3.44-3.35(m,1H),3.26-3.20(m,1H),3.14-3.00(m,1H),2.65-2.57(m,1H),2.13-2.05(m,1H),1.95-1.88(m,1H),0.88-0.84(m,2H),0.76-0.71(m,2H).
实施例7：((S)-(2’-异丙基-4-(3-(5-(三氟甲基)吡啶-2-基)硫代)吡咯烷-1-基)-[1,1’-联苯]-3-基)甲醇
步骤A:(S)-3-(5-(三氟甲基)吡啶-2-基)硫代)吡咯烷-1-羧酸叔丁酯
5.00g(18.9mmol,1.0eq)(R)-3-(甲磺酰基)氧基)吡咯烷-1-羧酸叔丁酯溶解在90mL无水N,N-二甲基甲酰胺中,再将5.06g(28.3mmol,1.5eq)5-(三氟甲基)吡啶-2-硫醇和3.91g(28.3mmol,1.5eq)碳酸钾加至该反应体系,氮气保护下在70℃搅拌反应18h。降温到室温，加入水50mL和乙酸乙酯150mL，分得有机相，水相用乙酸乙酯(2*100mL)萃取三次,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＝100:1～10:1)得到油状物(5.80g,收率＝87％)。
LC-MS:(M-56)+；m/z＝293.03；
步骤B:(S)-2-(吡咯烷-3-基硫基)-5-(三氟甲基)吡啶盐酸盐
4.20g(12.1mmol,1.0e.)(S)-3-(5-(三氟甲基)吡啶-2-基)硫代)吡咯烷-1-羧酸叔丁酯溶解在50mL二氯甲烷中，再将5.7mL(68.3mmol,5.0eq)浓盐酸加到上述反应体系中，该反应体系在氮气保护条件下常温搅拌1h。经LC-MS结果确认原料反应完全，将反应液直接减压浓缩得到类白色固体(3.10g,收率＝99％)。
LC-MS:(M+H)+；m/z＝249.09；
步骤C:(S)-5-溴-2-(3-(5-(三氟甲基)吡啶-2-基)硫代)吡咯烷-1-基)苯甲醛
2.50g(10.1mmol,1.0eq.)(S)-2-(吡咯烷-3-基硫基)-5-(三氟甲基)吡啶盐酸盐溶解在30mL无水N,N-二甲基甲酰胺中，再将5.11g(25.2mmol,2.5eq)5-溴-2-氟苯甲醛和3.20g(30.2mmol,3.0eq)无水碳酸钠加到上述反应体系中，该反应体系在氮气保护条件下于100℃反应过夜。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，加入乙酸乙酯萃取三遍，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(石油醚:乙酸乙酯＝100:1～20:1)得到淡黄色油状物(3.14g,收率＝72％)。
LC-MS:(M+H)+；m/z＝432.94；
1H NMR(400MHz,CDCl3)δ10.00(s,1H),8.65-8.64(m,1H),7.80(d,J＝4.0Hz,1H),7.67(dd,J＝8.0Hz,4.0Hz,1H),7.46(dd,J＝8.0Hz,4.0Hz,1H),7.26-7.24(m,1H),6.76(d,J＝12.0Hz,1H),4.56-4.50(m,1H),3.94-3.93(m,1H),3.60-3.49(m,2H),3.36-3.35(m,1H),2.60-2.52(m,1H),2.22-2.12(m,1H).
19F NMR(376MHz,CDCl3)δ-62.21.
步骤D:(S)-2’-异丙基-4-(3-(5-(三氟甲基)吡啶-2-基)硫代)吡咯烷-1-基)-[1,1’-联苯]-3-甲醛
将1.55g(3.60mmol,1.0eq)(S)-5-溴-2-(3-(5-(三氟甲基)吡啶-2-基)硫代)吡咯烷-1-基)苯甲醛溶解在30mL 1,4-二氧六环和6mL水中，再将707mg(4.31mmol,1.2eq)(2-异丙基苯基)硼酸和993mg(7.19mmol,2.0eq)无水碳酸钾加到上述反应体系中，氮气保护条件下加入263mg(0.36mmol,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，再经过柱层析(石油醚:乙酸乙酯＝100:1～20:1)得到淡黄色油状物(1.30g,收率＝77％)。
LC-MS:(M+H)+；m/z＝471.20；
步骤E:((S)-(2’-异丙基-4-(3-(5-(三氟甲基)吡啶-2-基)硫代)吡咯烷-1-基)-[1,1’-联苯]-3-基)甲醇
将300mg(0.64mmol,1.0eq)((S)-2’-异丙基-4-(3-(5-(三氟甲基)吡啶-2-基)硫代)吡咯烷-1-基)-[1,1’-联苯]-3-甲醛溶解在6mL甲醇中，体系降温到0℃，氮气保护条件下再将121mg(3.19mmol,5.0eq)硼氢化钠固体加到上述反应体系中，加完自然升温到室温反应1h。经LC-MS结果确认有目标产物生成，将反应液降到0℃，加入饱和氯化铵水溶液淬灭，加入乙酸乙酯萃取三遍，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)，冻干得到目标产物为淡黄色油状液体(75.2mg,收率＝25％)。
LC-MS:(M+H)+；m/z＝473.23；
1H NMR(400MHz,CDCl3)δ8.67(s,1H),7.68(d,J＝8.0Hz,1H),7.38-7.27(m,3H),7.21-7.13(m,5H),4.82-4.75(m,2H),4.56-4.50(m,1H),4.14(s,1H),3.82-3.78(m,1H),3.51-3.45(m,1H),3.35-3.26(m,2H),3.10-3.03(m,1H),2.66-2.58(m,1H),2.14-2.05(m,1H),1.15(d,J＝4.0Hz,6H).
19F NMR(376MHz,CDCl3)δ-62.17.
实施例8：(S)-(2’-异丙基-4-(3-(5-(三氟甲基)吡啶-2-基)磺酰基)吡咯烷-1-基)-[1,1’-联苯]-3-基)甲醇
步骤A:(S)-2’-异丙基-4-(3-(5-(三氟甲基)吡啶-2-基)磺酰基)吡咯烷-1-基)-[1,1’-联苯]-3-甲醛
200mg(0.43mmol,1.0eq)(S)-2’-异丙基-4-(3-(5-(三氟甲基)吡啶-2-基)硫代)吡咯烷-1-基)-[1,1’-联苯]-3-甲醛溶解在4mL甲醇和2mL四氢呋喃中，再将96.0mg(0.43mmol,1.0eq)钨酸钠和0.5mL(4.3mmol,10.0eq)双氧水加入反应体系中。升温到40℃反应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，加入乙酸乙酯萃取三遍，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(石油醚:乙酸乙酯＝100:1～10:1)得到淡黄色油状物(115mg,收率＝54％)。
LC-MS:(M+H)+；m/z＝503.17；
步骤B:(S)-(2’-异丙基-4-(3-(5-(三氟甲基)吡啶-2-基)磺酰基)吡咯烷-1-基)-[1,1’-联苯]-3-基)甲醇
将115mg(0.23mmol,1.0eq)(S)-2’-异丙基-4-(3-(5-(三氟甲基)吡啶-2-基)磺酰基)吡咯烷-1-基)-[1,1’-联苯]-3-甲醛溶解在5mL甲醇中，体系降温到0℃，氮气保护条件下再将43.3mg(1.14mmol,5.0eq)硼氢化钠固体加到上述反应体系中，加完自然升温到室温反应1.5h。经LC-MS结果确认有目标产物生成，将反应液降到0℃，加入饱和氯化铵水溶液淬灭，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)，冻干得到目标产物为白色固体(42.6mg,收率＝37％)。
LC-MS:(M+H)+；m/z＝505.22；
1H NMR(400MHz,CDCl3)δ9.02-9.01(m,1H),8.32(d,J＝8.0Hz,1H),8.26-8.24(m,1H),7.38-7.31(m,2H),7.21-7.11(m,5H),4.83(d,J＝12.0Hz,1H),4.71-4.69(m,1H),4.55-4.48(m,1H),3.93(s,1H),3.68-3.67(m,1H),3.52-3.45(m,2H),3.25-3.20(m,1H),3.06-3.00(m,1H),2.66-2.58(m,1H),2.46-2.37(m,1H),1.15(d,J＝7.2Hz,6H).
19F NMR(376MHz,CDCl3)δ-62.65.
实施例9：(2’-异丙基-4-(S)-3-(S)-(5-(三氟甲基)吡啶-2-基)亚砜基)吡咯烷-1-基)-[1,1’-联苯]-3-基)甲醇
步骤A:2’-异丙基-4-(S)-3-(S)-(5-(三氟甲基)吡啶-2-基)亚砜基)吡咯烷-1-基)-[1,1’-联苯]-3-甲醛
390mg(0.83mmol,1.0eq)((S)-2’-异丙基-4-(3-(5-(三氟甲基)吡啶-2-基)硫代)吡咯烷-1-基)-[1,1’-联苯]-3-甲醛溶解在5mL二氯甲烷中，氮气保护下将体系降温到0℃，再将215mg(1.24mmol,1.5eq)间氯过氧苯甲酸加入反应体系中,0℃反应2h。经LC-MS结果确认有目标产物生成，将反应液加入水淬灭，加入二氯甲烷萃取三遍，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(石油醚:乙酸乙酯＝50:1～1:1)得到淡黄色油状物(300mg,收率＝74％)。
LC-MS:(M+H)+；m/z＝487.37；
步骤B:(2’-异丙基-4-(S)-3-(S)-(5-(三氟甲基)吡啶-2-基)亚砜基)吡咯烷-1- 基)-[1,1’-联苯]-3-基)甲醇
将300mg(0.62mmol,1.0eq)2’-异丙基-4-(S)-3-(S)-(5-(三氟甲基)吡啶-2-基)亚砜基)吡咯烷-1-基)-[1,1’-联苯]-3-甲醛溶解在5mL甲醇中，体系降温到0℃，氮气保护条件下再将70.0mg(1.85mmol,3.0eq)硼氢化钠固体加到上述反应体系中，加完自然升温到室温反应1.5h。经LC-MS结果确认有目标产物生成，将反应液降到0℃，加入饱和氯化铵水溶液淬灭，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)，冻干得到目标产物为白色固体(92.3mg,收率＝31％)。
LC-MS:(M+H)+；m/z＝489.20；
1H NMR(400MHz,CDCl3)δ8.93(d,J＝8.0Hz,1H),8.23-8.21(m,2H),7.41-7.32(m,2H),7.24-7.13(m,5H),4.87-4.85(m,1H),4.78-4.67(m,1H),3.94-3.86(m,2H),3.72-3.67(m,0.5H),3.58-3.54(m,0.5H),3.48-3.39(m,1H),3.30-3.24(m,0.5H),3.17-3.02(m,2H),2.74-2.67(m,0.5H),2.63-2.42(m,1H),1.96-1.87(m,1H),1.18(d,J＝6.8Hz,6H).
19F NMR(376MHz,CDCl3)δ-62.32--62.35.
实施例10：((S)-(4-(3-(5-氟吡啶-2-基)硫代)吡咯烷-1-基)-2’-环丙基-[1,1’-联苯]-3-基)甲醇
步骤A:5-氟吡啶-2-硫醇
50mL(125.00mmol,1.1eq)正丁基锂溶解在300mL甲苯中,降温至-78℃，20g(113.64mmol,1.0eq)2-溴-5-氟吡啶溶解于50mL甲苯中，滴加至反应瓶 中，保温反应1小时。称量3.64g(114mmol,1.0eq)硫粉，分批加入至反应液，在-78℃保温30分钟，自然升温至室温，反应1小时。点板(石油醚:乙酸乙酯＝1:1)确定反应完全。加入20mL水淬灭，使用1N的稀盐酸溶液调pH至3-4，使用二氯甲烷(200mL)萃取5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，粗品使用乙酸乙酯打浆，过滤得到黄色固体纯品(6.5g,收率＝44％)。
1H NMR(400MHz,CDCl3)δ7.68(d,J＝4.0Hz,1H),7.50(d,J＝4.0Hz,1H),7.29-7.34(m,1H).
步骤B:(S)-3-(5-氟吡啶-2-基)硫代)吡咯烷-1-羧酸叔丁酯
1.00g(4.01mmol,1.0eq)(R)-3-(甲磺酰基)氧基)吡咯烷-1-羧酸叔丁酯溶解在10mL无水N,N-二甲基甲酰胺中，再将0.52g(4.01mmol,1.0eq)5-氟吡啶-2-硫醇和1.66g(12.0mmol,3.0eq)碳酸钾加至该反应体系，氮气保护下在70℃搅拌反应18h。降温至室温，加入水50mL和乙酸乙酯150mL，分得有机相，水相用乙酸乙酯(2*100mL)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＝10:1)得到油状物(1.00g,收率＝83％)。
LC-MS:(M+H)+；m/z＝299.22；
1H NMR(400MHz,CDCl3)δ8.33-7.34(m,1H),7.26-7.31(m,1H),7.17-7.20(m,1H),4.29-4.32(m,1H),3.86-3.95(m,1H),3.29-3.59(m,3H),2.37-2.43(m,1H),1.94-1.99(m,1H),1.48(s,9H).
步骤C:(S)-5-氟-2-(吡咯烷-3-基硫代)吡啶盐酸盐
1.00g(3.35mmol,1.0eq)(S)-3-(5-氟吡啶-2-基)硫代)吡咯烷-1-羧酸叔丁酯溶解在20mL二氯甲烷中，再将8.4mL(33.5mmol,10.0eq)4M盐酸1,4-二氧六环溶液加到上述反应体系中，该反应体系在氮气保护条件下常温搅拌1h。经点板(石油醚:乙酸乙酯＝10:1)确认原料反应完全，将反应液直接减压浓缩得到类白色固体(0.66g,收率＝99％)。
步骤D:(S)-5-溴-2-(3-(5-氟吡啶-2-基)硫代)吡咯烷-1-基)苯甲醛
0.66g(3.32mmol,1.0eq)(S)-5-氟-2-(吡咯烷-3-基硫代)吡啶盐酸盐溶解在10mL无水N,N-二甲基甲酰胺中，再将0.67g(3.32mmol,1.0eq)5-溴-2-氟苯甲醛和1.38g(9.98mmol,3.0eq)无水碳酸钾加到上述反应体系中，该反应体系在氮气保护条件下于90℃反应过夜。经LC-MS结果确认原料转化完全有目标产物生成，将反应液降到室温，加水淬灭反应，加入乙酸乙酯萃取三遍，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(石油醚:乙酸乙酯＝10:1)得到淡黄色油状物(0.99g,收率＝78％)。
LC-MS:(M+H)+；m/z＝381.08；
步骤E:(S)-2'-环丙基-4-(3-((5-氟吡啶-2-基)硫代)吡咯烷-1-基)-[1,1'-联苯]-3-甲醛
将0.99g(2.60mmol,1.0eq)(S)-5-溴-2-(3-(5-氟吡啶-2-基)硫代)吡咯烷-1-基)苯甲醛溶解在20mL二氧六环和5mL水中，再将0.50g(3.11mmol,1.2eq)(2-环丙基苯基)硼酸和2.20g(10.4mmol,4.0eq)无水磷酸钾加到上述反应体系中，氮气保护条件下加入20mg(0.026mmol,0.01eq.)[1,1'-双(二苯基膦)二茂铁]二氯化钯于100℃反应4h。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(石油醚:乙酸乙酯＝10:1)得到淡黄色油状物(900mg,收率＝82％)。
LC-MS:(M+H)+；m/z＝419.10；
1H NMR(400MHz,CDCl3)δ10.13(s,1H),8.34(d,J＝4.0Hz,1H),7.83(d,J＝4.0Hz,1H),7.59(dd,J＝4.0Hz,4.0Hz,1H),7.32-7.18(m,5H),6.98-6.93(m,2H),4.42-4.50(m,1H),4.02(d,J＝8.0Hz,1H),3.61-3.68(m,2H),3.48(d,J＝8.0Hz,1H),2.55-2.62(m,1H),2.16-2.22(m,1H),1.90-1.94(m,1H),0.86-0.92(m,2H),0.77-0.75(m,2H).
步骤F:((S)-(4-(3-(5-氟吡啶-2-基)硫代)吡咯烷-1-基)-2’-环丙基-[1,1’-联 苯]-3-基)甲醇
将900mg(2.15mmol,1.0eq)((S)-2'-环丙基-4-(3-((5-氟吡啶-2-基)硫代)吡咯烷-1-基)-[1,1'-联苯]-3-甲醛溶解在10mL甲醇中，体系降温到0℃，氮气保护条件下再将163mg(4.30mmol,2.0eq)硼氢化钠固体加到上述反应体系中，加完自然升温到室温反应1.5h。经LC-MS结果确认有目标产物生成，将反应液降到0℃，加入饱和氯化铵水溶液淬灭，加入乙酸乙酯萃取三遍，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)，冻干得黄色油状产物(667mg,收率＝73％)。
LC-MS:(M+H)+；m/z＝421.16；
1H NMR(400MHz,CDCl3)δ8.34(d,J＝4.0Hz,1H),7.17-7.37(m,8H),6.92-6.94(m,1H),4.89-4.81(m,2H),4.41-4.47(m,1H),4.25(s,1H),3.80(d,J＝4.0Hz,1H),3.46-3.50(m,1H),3.29-3.35(m,2H),2.56-2.64(m,1H),2.05-2.13(m,1H),1.88-1.95(m,1H),0.84-0.89(m,2H),0.70-0.74(m,2H).
通过上文描述的实施例1的方法制备表1中的实施例，起始原料分别替换成(S)-1-BOC-3-羟基吡咯烷、1-BOC-3-羟基吡咯烷以及所需的其他原料。
表1:实施例11-14

通过上文描述的实施例1的方法制备表2中的实施例，替换所需的不同取代巯基原料。
表2:实施例15-33





通过上文描述的实施例1的方法制备表3中的实施例，中间体I3和所需的不同硼酸或者硼酸酯通过Suzuki反应制备得到。
表3:实施例34-40


实施例41:(S)-(3-(3-((5-氯吡啶-2-基)硫代)吡咯烷-1-基)-2'-异丙基-[1,1'-联苯]-4-基)甲醇
步骤A:(S)-4-溴-2-(3-((5-氯吡啶-2-基)硫代)吡咯烷-1-基)苯甲醛
140mg(652umol,1.0eq)(S)-5-氯-2-(吡咯烷-3-基硫代)吡啶溶于5mL N,N-二甲基甲酰胺中，加入198mg(978umol,1.5eq)4-溴-2-氟苯甲醛和180mg(1.3mmol,2.0eq)碳酸钾，氮气置换3次，100℃搅拌过夜。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。残余物通过柱层析(二氯甲烷/甲醇＝0～15:1)，得产物(190mg,收率＝73％)。
LC-MS:(M+H)+；m/z＝398.84；
步骤B:(S)-3-(3-((5-氯吡啶-2-基)硫代)吡咯烷-1-基)-2'-异丙基-[1,1'-联苯]-4-甲醛
50.0mg(126umol,1.0eq)(S)-4-溴-2-(3-((5-氯吡啶-2-基)硫代)吡咯烷-1-基)苯甲醛溶解在4mL二氧六环和1mL水中，再加入24.7mg(151umol,1.2eq)2-异丙基苯硼酸、9.20mg(13umol,0.1eq)1,1-双(二苯基膦)二荗铁二氯化钯和52.1mg(377umol,3.0eq)碳酸钾。氮气置换三次，100℃搅拌2小时。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48.0mg淡黄色油状液体，无需纯化直接用于下一步反应。
LC-MS:(M+H)+；m/z＝437.05；
步骤C:(S)-3-(3-((5-氯吡啶-2-基)硫代)吡咯烷-1-基)-2'-异丙基-[1,1'-联苯]-4-甲醇
48.0mg(110umol,1.0eq)(S)-3-(3-((5-氯吡啶-2-基)硫代)吡咯烷-1-基)-2'-异丙基-[1,1'-联苯]-4-甲醛溶于5mL甲醇中，在冰浴中缓慢添加8.32mg(220umol，2.0eq)硼氢化钠，室温搅拌10分钟。经LC-MS确认有产物生成，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(20.9mg，两步收率＝38％)。
LC-MS:(M+H)+；m/z＝439.36；
1H NMR(400MHz,CDCl3)δ8.36(d,J＝2.3Hz,1H),7.45(dd,J＝8.5, 2.6Hz,1H),7.42-7.31(m,2H),7.25(d,J＝7.8Hz,1H),7.23-7.09(m,3H),7.02-6.91(m,2H),4.90-4.76(m,2H),4.41-4.40(m,1H),3.99(s,1H),3.75-3.71(m,1H),3.45-3.43(m,1H),3.30-3.24(m,2H),3.05-3.02(m,1H),2.56-2.54(m,1H),2.05-2.03(m,1H),1.16(d,J＝6.7Hz,6H).
通过上文描述的通用方案2或方案3制备表4中的实施例。
表4:实施例42-76









实施例77：(S)-5-氯-2-((1-(3-(二氟甲基)-2'-异丙基-[1,1'-联苯]-4-基)吡咯烷-3-基)硫代吡啶
30.0mg(68.7μmol,1.0eq)(S)-4-(3-((5-氯吡啶-2-基)硫代)吡咯烷-1-基)-2'-异丙基-[1,1'-联苯]-3-甲醛溶解在0.5mL无水二氯甲烷并置换氮气后将体系降温到0℃，将16.6mg(103μmol,1.5eq)二乙胺基三氟化硫缓慢滴加到前者，滴加完自然回到室温并继续搅拌18小时。经LC-MS结果确认反应完全后，用2mL冷的饱和碳酸氢钠溶液淬灭，然后用5mL二氯甲烷萃取三次，有机相用饱和氯化钠溶液洗涤后，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％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(S)-5-氯-2-((1-(3-(二氟甲基)-2'-异丙基-[1,1'-联苯]-4-基)吡咯烷-3-基)硫代)吡啶(4.3mg,收率＝14％)，灰色固体。
LC-MS:(M+H)+；m/z＝459；
1H NMR(400MHz,CDCl3)δ8.39(d,J＝2.5Hz,1H),7.53(d,J＝2.1Hz,1H),7.47(dd,J＝8.5,2.5Hz,1H),7.39-7.29(m,3H),7.22-7.16(m,2H),7.13-7.05(m,2H),6.98-6.91(m,1H),4.44-4.41(m,1H),3.85-3.85(m,1H),3.48-3.47(m,1H),3.39(t,J＝7.4Hz,1H),3.39-3.31(m,1H),3.05-3.02(m,1H),2.57-2.55(m,1H),2.11-2.03(m,1H),1.17(d,J＝6.9Hz,6H).
实施例78：(S)-(2-(3-((5-氯吡啶-2-基)硫代)吡咯烷-1-基)-5-((2-异丙基苯基)氨基)苯基)甲醇
步骤A:(S)-2-(3-((5-氯吡啶-2-基)硫代)吡咯烷-1-基)-5-((2-异丙基苯基)氨基)苯甲醛
30.0mg(75.4μmol,1.0eq)(S)-5-溴-2-(3-((5-氯吡啶-2-基)硫代)吡咯烷-1-基)苯甲醛溶解在2mL 1,4-二氧六环中，再将11.2mg(83.0μmol,1.1eq)2-异丙基苯胺、3.50mg(3.77μmol,0.05eq)三(二亚苄基丙酮)二钯、4.4mg(7.54μmol,0.1eq)4,5-双二苯基膦-9,9-二甲基氧杂蒽和24.6mg(75.4μmol,1.0eq)碳酸铯加至该反应体系，置换氮气后升温到100℃反应5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。残余物通过柱层析(乙酸乙酯:石油醚＝1:10)得(S)-2-(3-((5-氯吡啶-2-基)硫代)吡咯烷-1-基)-5-((2-异丙基苯基)氨基)苯甲醛(8.30mg,收率＝24％)为黄色油状液体。
LC-MS:(M+H)+；m/z＝452；
步骤B:(S)-(2-(3-((5-氯吡啶-2-基)硫代)吡咯烷-1-基)-5-((2-异丙基苯基)氨基)苯基)甲醇
8.30mg(18.4μmol,1.0eq)(S)-2-(3-((5-氯吡啶-2-基)硫代)吡咯烷-1-基)-5-((2-异丙基苯基)氨基)苯甲醛溶解在0.5mL甲醇并置换氮气后将体系降温到0℃，将0.80mg(22.0μmol,1.2eq)硼氢化钠缓慢加到前者，加完后自然回到室温并继续反应30分钟。经LC-MS结果确认反应完全后，用1mL饱和氯化铵溶液淬灭，然后用5mL乙酸乙酯萃取三次，有机相用饱和氯化钠溶液洗涤后，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％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(S)-(2-(3-((5-氯吡啶-2-基)硫代)吡咯烷-1-基)-5-((2-异丙基苯基)氨基)苯基)甲醇(1.0mg,收率＝12％)为黄色固体。
LC-MS:(M+H)+；m/z＝454.30；
1H NMR(400MHz,CDCl3)δ8.37(d,J＝2.5Hz,1H),7.45(dd,J＝8.4,2.4Hz,1H),7.29(d,J＝8.5Hz,1H),7.23-6.98(m,5H),6.82-6.69(m,2H),5.34(brs,1H),4.78-4.65(m,2H),4.41-4.34(m,1H),3.64-3.58(m,1H),3.34-3.27(m,1H),3.21-3.02(m,3H),2.61-2.53(m,1H),2.10-1.87(m,2H),1.24(d,J＝6.9Hz,6H).
本发明化合物生物活性测试
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，其中一管加入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EPC10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5。对于选定的实施例，浓度为0.3μM下的抑制率(％)详情示于表中。本发明专利硫醚类化合物具有软药性质，亚砜、砜类代谢产物不具有药理活性(表5)，从而实现在发挥药效的同时，避免原型药物、活性代谢物、反应性代谢物对机体造成毒性。同时，本发明专利化合物亦具有较好的选择性(表6)。
表5:本发明化合物对hTRPV3单浓度下(0.3μM)的抑制率(％)

a注：专利WO2021154966A1中的实施例化合物KM-001。
表6:实施例4对不同hTRP(0.3μM)的抑制率

注：选择性比值是指化合物对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7:肝微粒体代谢稳定性测试结果
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 (37)

  1. 式(I)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、药学上可接受的盐，
    其中，环A和环B各自独立地选自含有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B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，
    L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；
    X选自-S-、-S(O)-和-S(O2)-；
    n为0、1、2或3；
    m为0、1、2或3；
    p为0、1、2或3；
    q为0、1、2或3。
  2. 根据权利要求1所述的化合物，其中，所述化合物具有I-1的结构式
    其中，环A、环B、环C、X、R1、R2、R3、L、n、p、m和q定义如式I。
  3. 根据权利要求1或2所述的化合物，其中，环A选自苯环、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。
  4. 根据权利要求3所述的化合物，其中，环A选自以下结构式：
  5. 根据权利要求1或2所述的化合物，其中，环B选自苯环、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。
  6. 根据权利要求5所述的化合物，其中，环B选自以下结构式：
  7. 根据权利要求1或2所述的化合物，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。
  8. 根据权利要求7所述的化合物，其中，R1各自独立地选自H、Cl、F、-CF3、-CN、-CH3、-OH、-OCH3、-CH2OCH3。
  9. 根据权利要求1或2所述的化合物，其中，R2各自独立地选自H、氰基、羟基、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、-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。
  10. 根据权利要求9所述的化合物，其中，R2各自独立地选自H、-CH3、-OH、-CH2OH、-CH2OCH3、-CH2CH2OH、-CH(CH3)OH、-C(CH3)2OH、-CH2SH、-OCH2CH3、-OCF3、-OCH3、-OCH(CH3)2、-COOH、-COOCH3、-CONH2、-CH2NH2、-CH2CHF2、-CN、-CHF2、
  11. 根据权利要求2所述的化合物，其中，L各自独立地选自键、-O-、-S-、-N-、-C(O)-、-CH2-、-C(OH)-、-S(O)-和-S(O2)-。
  12. 根据权利要求2所述的化合物，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。
  13. 根据权利要求12所述的化合物，其中，环C选自以下结构式：
  14. 根据权利要求2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。
  15. 根据权利要求14所述的化合物，其中，R3各自独立地选自H、环丙基、异丙基、叔丁基、F、Cl、乙基、甲基、甲基羰基、甲氧基甲基。
  16. 根据权利要求1或2所述的化合物，其中，m为0。
  17. 根据权利要求1或2所述的化合物，其中，n为0、1或者2。
  18. 根据权利要求1或2所述的化合物，其中，n为1且m为0，并且R1位于X的邻位或者对位。
  19. 根据权利要求1或2所述的化合物，其中，n为2且m为0，一个R1位于X的对位。
  20. 根据权利要求1或2所述的化合物，其中，p为1，优选地，该R2位于吡咯烷基的邻位。
  21. 根据权利要求1或2所述的化合物，其中，R2为-CH2OH。
  22. 根据权利要求1或2所述的化合物，其中，L为-S-；
    或者，L为-S(O)-；
    或者，L为-S(O2)-；
    优选地，L为-S-。
  23. 式(I-2)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、药学上可接受的盐，
    其中，环A各自独立地选自含有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；
    R0各自独立地选自H、卤素或者式II的结构式
    其中，
    L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；
    X选自-S-、-S(O)-和-S(O2)-；
    XA、XB、XC、XD、XE各自独立地为CH或N；
    XF为CH；
    n为0、1、2或3；
    m为0、1、2或3；
    p为0、1、2或3；
    q为0、1、2或3。
  24. 根据权利要求23所述的化合物，其中，
    XA、XB、XC、XD、XE各自独立地为CH；
    或者，XA、XB、XC、XE各自独立地为CH，XD为N；
    或者，XA、XB、XC、XD各自独立地为CH，XE为N；
    或者，XA、XC、XD各自独立地为CH，XB、XE为N。
  25. 根据权利要求1所述的化合物，其中，所述化合物选自以下化合物：

  26. 一种药物组合物，其包含权利要求1-25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。
  27. 权利要求1-25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26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。
  28. 权利要求1-25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26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。
  29. 根据权利要求27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。
  30. 根据权利要求29所述的用途，其中，所述疼痛为癌性痛和皮肤疼痛。
  31. 根据权利要求30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。
  32. 根据权利要求31的用途，其中，所述癌症为脂肪肉瘤。
  33. 根据权利要求29的用途，其中，所述毛发生长异常为脱发。
  34. 根据权利要求29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。
  35. 根据权利要求34所述的用途，其中，皮肤角化病为olmsted综合征(olmsted syndrome)。
  36. 根据权利要求35所述的用途，其中，鱼鳞病为丑角样鱼鳞病(harlequin ichtyosis)。
  37. 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1-25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26所述的药物组合物，给药于需要给药的患者。
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997028128A1 (en) * 1996-02-02 1997-08-07 Zeneca Limited Heterocyclic compounds useful as pharmaceutical agents
CN1422268A (zh) * 2000-03-06 2003-06-04 沃尼尔·朗伯公司 5－烷基吡啶并[2,3－d]嘧啶酪氨酸激酶抑制剂
CN1425002A (zh) * 2000-04-20 2003-06-18 弗·哈夫曼-拉罗切有限公司 吡咯烷与哌啶衍生物和它们用于治疗神经变性疾病的用途
CN103201274A (zh) * 2010-11-05 2013-07-10 霍夫曼-拉罗奇有限公司 作为组织蛋白酶抑制剂的吡咯烷衍生物
CN106458952A (zh) * 2014-01-28 2017-02-22 Ea制药株式会社 杂环磺酰胺衍生物及含有所述杂环磺酰胺衍生物的药物
CN108602807A (zh) * 2016-02-05 2018-09-28 Ea制药株式会社 杂环磺酰胺衍生物及含有其的药物
WO2018208630A1 (en) * 2017-05-07 2018-11-15 Calygene Biotechnology Inc. Aryl-sulfonamide and aryl-sulfone derivatives as trpml modulators

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997028128A1 (en) * 1996-02-02 1997-08-07 Zeneca Limited Heterocyclic compounds useful as pharmaceutical agents
CN1422268A (zh) * 2000-03-06 2003-06-04 沃尼尔·朗伯公司 5－烷基吡啶并[2,3－d]嘧啶酪氨酸激酶抑制剂
CN1425002A (zh) * 2000-04-20 2003-06-18 弗·哈夫曼-拉罗切有限公司 吡咯烷与哌啶衍生物和它们用于治疗神经变性疾病的用途
CN103201274A (zh) * 2010-11-05 2013-07-10 霍夫曼-拉罗奇有限公司 作为组织蛋白酶抑制剂的吡咯烷衍生物
CN106458952A (zh) * 2014-01-28 2017-02-22 Ea制药株式会社 杂环磺酰胺衍生物及含有所述杂环磺酰胺衍生物的药物
CN108602807A (zh) * 2016-02-05 2018-09-28 Ea制药株式会社 杂环磺酰胺衍生物及含有其的药物
WO2018208630A1 (en) * 2017-05-07 2018-11-15 Calygene Biotechnology Inc. Aryl-sulfonamide and aryl-sulfone derivatives as trpml modulators

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
OHSAWA, TATSUSHI ET AL.: "Novel Synthesis of the Pyrrolizidine Skeleton by Sulfenocycloamination. Total Synthesis of (±)-retronecine and (±)-turneforcidine", JOURNAL OF ORGANIC CHEMISTRY, vol. 48, no. 21, 31 December 1983 (1983-12-31), pages 3644 - 3648, XP001013139, DOI: 10.1021/jo00169a005 *
VERMA, VISHAL A. ET AL.: "α-Aryl Pyrrolidine Sulfonamides as TRPA1 Sntagonists", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 26, 25 November 2015 (2015-11-25), pages 495 - 498, XP029380254, DOI: 10.1016/j.bmcl.2015.11.088 *

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