Thioether compound with soft drug property, pharmaceutical composition and application of thioether compound

Abstract

A thioether compound with soft drug properties, a pharmaceutical composition and uses thereof, the compound has a structural formula of formula I, the thioether structure in the compound has pharmacological activity, and the thioether structure is rapidly converted into sulfoxide and sulfone metabolites without pharmacological activity according to a set metabolic pathway after the drug effect is exerted, so that the thioether compound can be used for preparing a medicine for treating or preventing or treating diseases caused by the pharmacological activity of the sulfoxide and sulfone metabolites. Therefore, toxicity of prototype drugs, active metabolites and reactive metabolites to an organism is avoided while the drug effect is exerted, and the safety is relatively higher. # imgabs0 #

Description

Sulfide compound with soft drug properties, pharmaceutical composition and use thereof Technical Field

[0001] 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. Background Art

[0002] Transient receptor potential (TRP) is a class of ion channel proteins present on cell membranes or intracellular organelle membranes. It is composed of seven subfamilies: TRPC, TRPV, TRPM, TRPML, TRPP, TRPA, and TRPN. The mammalian transient receptor potential vanilloid receptor (TRPV) subfamily is comprised of TRPV1-6. ​​Recent studies have revealed that TRPV3 is primarily expressed in human skin keratinocytes, playing a crucial role in mediating skin sensation, influencing epidermal keratinocyte proliferation and differentiation, hair growth, participating in inflammatory responses, and maintaining skin homeostasis and normal function. This ion channel can be regulated by numerous factors, such as temperature, osmotic pressure, pH, mechanical forces, and intracellular signaling molecules. Research has shown that TRPV3 is the causative gene for the rare skin disorder Olmsted syndrome (Am. J. Hum. Genet. 2012, 90, 558). TRPV3 inhibitors have potential therapeutic potential in keratotic skin disorders, pruritic skin disorders, inflammatory conditions, hair growth disorders, and painful skin disorders. TRPV3 is primarily expressed in skin keratinocytes, as well as in tissues such as the tongue, dorsal root ganglia, trigeminal ganglia, spinal cord, and brain. It primarily senses heat (32-39°C). TRPV3's thermal sensitivity is also regulated by calcium in the extracellular fluid. Repeated heat stimulation increases the channel current. Free nerve endings in the skin may sense and transmit heat stimuli through signaling molecules similar to those present in thermoreceptor neurons. Therefore, TRPV3-mediated pain disorders have potential therapeutic potential.

[0003] TRPV3 can be activated by monoterpenoid compounds (such as camphor, borneol, mint, etc.). Studies have found that it is activated by increasing the intracellular divalent calcium ions (Ca 2+) levels to exert their effects. These aromatic compounds have anti-inflammatory, analgesic, and antipruritic effects and have been widely used in the fields of medicine, cosmetics, etc. However, these early TRPV3 inhibitors are mostly natural products with poor specificity, large effective doses, and the potential for serious side effects, or their molecular skeletons have general activity, and their research and development has mostly stagnated. Existing TRPV3 inhibitors have the problem of a small number of structural types and relatively slow development. It is very necessary to develop molecules with novel skeletons and clinical value.

[0004] Summary of the Invention

[0005] The present application relates to compounds of formula (I):

[0006] or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances, or pharmaceutically acceptable salts,

[0007] wherein Ring A and Ring B are each independently selected from a monocyclic or polycyclic ring system containing 3-12 ring atoms;

[0008] R 1 Each independently selected from H, halogen, hydroxyl, thiol, nitro, cyano, oxo, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C1-C6 alkoxy, substituted with 0-2 R f C1-C6 haloalkoxy, substituted with 0-2 R f C3-C6 cycloalkyl, substituted with 0-2 R f C3-C6 halocycloalkyl, substituted with 0-2 R f C3-C6 cycloalkoxy, substituted with 0-2 R f C3-C6 halocycloalkoxy, substituted with 0-2 R f Aryl, substituted with 0-2 R f Arylalkyl, substituted with 0-2 R f Alkaryl, substituted with 0-2 R f heteroaryl, -R 11 OR 12 、-R 11 SR 12 、-N(R a )(R b ),-C(O)R c 、-C(O)N(R a )(R b ) and -SO2N(R a )(R b) or -SOR c , or two R 1 Together with the ring A atoms to which they are attached, they form a 3-10 membered ring structure;

[0009] R 2 Each independently selected from H, halogen, hydroxyl, thiol, nitro, cyano, oxo, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C1-C6 alkoxy, substituted with 0-2 R f C1-C6 haloalkoxy, substituted with 0-2 R f C3-C6 cycloalkyl, substituted with 0-2 R f C3-C6 halocycloalkyl, substituted with 0-2 R f C3-C6 cycloalkoxy, substituted with 0-2 R f C3-C6 halocycloalkoxy, substituted with 0-2 R f Aryl, substituted with 0-2 R f Arylalkyl, substituted with 0-2 R f Alkaryl, substituted with 0-2 R f heteroaryl, -R 11 OR 12 、-R 11 SR 12 、-N(R a )(R b ),-C(O)R c 、-C(O)OR d 、-C(O)N(R a )(R b ) and -SO2N(R a )(R b ) or -SOR c , or two R 2 Together with the ring B atoms to which they are attached, they form a 3-10 membered ring structure;

[0010] R 0 Each independently selected from H, halogen or the structural formula II

[0011] in,

[0012] L is independently selected from a bond, -O-, -S-, -N(R 20 )-、-C(O)-、-C(R 20 R 21 )-, -S(O)- and -S(O2)-;

[0013] Ring C is independently selected from a monocyclic or polycyclic ring system containing 3-12 ring atoms;

[0014] R 3 Each independently selected from H, halogen, hydroxyl, thiol, nitro, cyano, oxo, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C1-C6 alkoxy, substituted with 0-2 R f C1-C6 haloalkoxy, substituted with 0-2 R f C3-C6 cycloalkyl, substituted with 0-2 R f C3-C6 halocycloalkyl, substituted with 0-2 R f C3-C6 cycloalkoxy, substituted with 0-2 R f C3-C6 halocycloalkoxy, substituted with 0-2 R f Aryl, substituted with 0-2 R f Arylalkyl, substituted with 0-2 R f Alkaryl, substituted with 0-2 R f heteroaryl, -R 11 OR 12 、-R 11 SR 12 、-N(R a )(R b ),-C(O)R c 、-C(O)OR d 、-C(O)N(R a )(R b ) and -SO2N(R a )(R b ) or -SOR c , or two R 3 Together with the ring C atoms to which they are attached, they form a 3-10 membered ring structure;

[0015] R 11 Each independently selected from substituted with 0-2 R f C1-C6 alkylene;

[0016] R 12 Each independently selected from H, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C3-C6 cycloalkyl and substituted with 0-2 R f C3-C6 halocycloalkyl;

[0017] R a and R b Each independently selected from H, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f Aryl, substituted with 0-2 R f Aralkyl, -C(O)R c and -C(O)OR d ;

[0018] R c Each independently selected from H, halogen, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f The aryl group and the substituent have 0-2 R f Aralkyl;

[0019] R d Each independently selected from H, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f The aryl group and the substituent have 0-2 R f Aralkyl;

[0020] R 20 and R 21 Each is independently selected from H, hydroxy, C1-C6 alkyl, aryl and aralkyl;

[0021] R f Each is independently selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl and C3-C6 halocycloalkyl;

[0022] X is selected from -S-, -S(O)- and -S(O2)-;

[0023] n is 0, 1, 2, or 3;

[0024] m is 0, 1, 2, or 3;

[0025] p is 0, 1, 2, or 3;

[0026] q is 0, 1, 2, or 3.

[0027] The present application also relates to a pharmaceutical composition comprising the compound of the present application or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier.

[0028] 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, as well as the pharmaceutical composition of the present application in the preparation of drugs for inhibiting TRPV3 activity.

[0029] 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 preparing a medicament for treating a TRPV3-mediated disorder in a subject.

[0030] 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.

[0031] The sulfide 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. This allows the compounds to exert their pharmacological effects while avoiding the toxicity of the parent drug, active metabolites, and reactive metabolites to the body, resulting in relatively higher safety. DETAILED DESCRIPTION

[0032] The present invention will be further described in detail below through the following examples, through which the features and advantages of the present invention will become more clearly understood.

[0033] The word “exemplary” is used exclusively herein to mean “serving as an example, example, or illustration.” Any embodiment described herein as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments.

[0034] In addition, the technical features involved in different embodiments of the present application described below can be combined with each other as long as they do not conflict with each other.

[0035] definition

[0036] The terms "antagonist" and "inhibitor" are used interchangeably and refer to an agent that reduces or inhibits a biological activity, eg, inhibits the activity of an ion channel such as TRPV3.

[0037] For purposes of the present invention, an "effective amount" of, for example, a TRPV3 antagonist refers to an amount of the antagonist in a formulation that, when administered as part of a desired dosing regimen, results in a desired clinical or functional outcome. Without being bound by theory, 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., an antagonist 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 the functional activity of TRPV3 in vitro or in vivo. When a specific functional activity is readily observable only in an in vitro assay, the ability of a compound to inhibit TRPV3 function is a reasonable surrogate for the activity of the compound as used in an in vitro assay. The term "prevention" is art-recognized and, when used for conditions such as local recurrence (e.g., pain), diseases such as cancer, syndromes such as heart failure or other medical conditions, is well known in the art 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. Thus, preventing cancer includes, for example, reducing the number of detectable cancer growths in a patient population receiving prophylactic treatment relative to an untreated control population, and / or delaying the appearance of detectable cancer growth in a treatment population relative to an untreated control population. Preventing infection includes, for example, reducing the number of infection diagnoses in a treatment population relative to an untreated control population, and / or delaying the onset of infection symptoms in a treatment population relative to an untreated control population. Preventing pain includes, for example, reducing the amplitude of pain experienced by a subject or delaying the pain experienced by a subject in a treatment population relative to an untreated control population.

[0038] The present invention provides compounds in the form of prodrugs. The term "prodrug" is intended to encompass compounds that are converted to therapeutically active agents of the present invention under physiological conditions. Common methods for preparing prodrugs include revealing selected portions of the desired molecule upon hydrolysis under physiological conditions. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. Alternatively, the prodrug can be converted to the compounds of the present invention by chemical or biochemical methods in an in vitro environment. For example, when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, the prodrug can be slowly converted to the compounds of the present invention.

[0039] The term "oxidative metabolite" is intended to encompass compounds that are derived from the metabolism of a parent compound under normal physiological conditions. Specifically, oxidative metabolites are formed by oxidation of the parent compound during metabolism. For example, oxidation of a thioether group can yield the corresponding sulfoxide or sulfone.

[0040] As used herein, the term "solvate" refers to a compound formed by solvation (eg, a compound formed by combining solvent molecules with solute molecules or ions).

[0041] As used herein, the term "hydrate" refers to a compound formed by the combination of water and a parent compound.

[0042] The term "treatment" includes both preventative and / or therapeutic treatment. The terms "preventative or therapeutic" treatment are art-recognized and include administering one or more compositions of the present invention to a host. If administered prior to clinical manifestation of an undesirable condition (e.g., a disease or other undesirable condition in a host animal), the treatment is preventative (i.e., it prevents the host from developing the undesirable condition), whereas 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).

[0043] The terms "TRPV3," "TRPV3 protein," and "TRPV3 channel" are used interchangeably throughout this application. These terms refer to an ion channel (e.g., a polypeptide) comprising an amino acid sequence, such as that of a human TRPV3 protein, or an equivalent polypeptide or functional, biologically active fragment thereof. In certain embodiments, the terms refer to a protein comprising, consisting of, or consisting essentially of a TRPV3 amino acid sequence, such as that described in any of the patent applications cited herein. TRPV3 proteins may also include orthologs, such as mouse, rat, horse, or fruit fly TRPV3.

[0044] 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) functional fragments thereof. The polypeptides of the present invention also include homologs of human TRPV3 polypeptides, e.g., orthologs and intraspecific homologs. Exemplary TRPV3 polypeptides and amino acid sequences include those described in any of the patent applications cited herein.

[0045] The term "TRPV3" also refers to a nucleic acid encoding a polypeptide of the present invention, for example, a nucleic acid comprising a sequence consisting of, or consisting essentially of, a TRPV3 polynucleotide sequence. A nucleic acid of the present invention may comprise all or part of the following nucleotide sequences: (i) a TRPV3 nucleotide sequence; (ii) a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to a TRPV3 nucleotide sequence; (iii) a nucleotide sequence that hybridizes to a TRPV3 nucleotide sequence under stringent conditions; (iv) a nucleotide sequence encoding a polypeptide that is functionally equivalent to a polypeptide of the present invention; (v) a nucleotide sequence encoding a polypeptide that is at least about 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% homologous or identical to a TRPV3 polypeptide sequence; (vi) a nucleotide sequence encoding a polypeptide that is at least about 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% homologous or identical to a TRPV3 polypeptide sequence; ) a nucleotide sequence encoding a polypeptide having an activity of a polypeptide of the invention and having at least about 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or more homology or identity to a TRPV3 polypeptide sequence; (vii) a nucleotide sequence that differs from a TRPV3 nucleotide sequence by 1 to about 2, 3, 5, 7, 10, 15, 20, 30, 50, 75 or more nucleotide substitutions, additions or deletions, such as allelic variants; (viii) a nucleic acid derived from a TRPV3 nucleotide sequence and evolutionarily related thereto; and (ix) complementary sequences of all the foregoing nucleic acids and other nucleic acids of the invention, and nucleotide sequences resulting from the degeneracy of the genetic code. The nucleic acids of the invention also include homologs of the TRPV3 nucleic acid sequence, such as orthologs and intraspecific homologs, and include variants that have been codon-optimized for expression in a particular organism (e.g., a host cell). TRPV3 nucleic acid sequences include, for example, those described in any of the patent applications cited herein. If not specifically stated, one skilled in the art can readily assess whether TRPV3 refers to a nucleic acid or a protein.

[0046] As used herein, the term "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.

[0047] The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possibility of substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.

[0048] As used herein, the term "alkoxy" refers to an alkyl group as defined below to which is attached an oxygen group. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Thus, 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-(CH2) t-R8, wherein R8 is selected from hydrogen, halogen, lower alkyl, lower alkoxy, amino, or -NHSO2NH2, and t is an integer from 0 to 6.

[0049] The term "alkyl" refers to a saturated aliphatic group, including straight chain alkyl groups and branched chain alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl group has 30 or fewer carbon atoms in its backbone (e.g., a straight chain C1-C1 30 , branched C3-C 30 ), and more preferably 20 or less, and most preferably 10 or less.

[0050] The term "cycloalkyl" includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms, wherein the cycloalkyl group is additionally optionally substituted. Preferred cycloalkyl groups have 3 to 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. The term "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, and bicyclo[2.1.1]hexyl.

[0051] In addition, as used throughout the specification, examples, and claims, the term "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. These substituents can include, for example, halogen, hydroxy, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For example, the substituents of substituted alkyl groups may include substituted and unsubstituted amino, azido, imino, amide, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl, as well as ether, alkylthio, carbonyl (including ketone, aldehyde, carboxylate, and ester), -CF , -CN, etc. Exemplary substituted alkyl groups are described below. Cycloalkyl groups may be further substituted by alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF , -CN, etc.

[0052] Alkenyl and alkynyl groups can be similarly substituted to provide, for example, aminoalkenyl, aminoalkynyl, amidoalkenyl, amidoalkynyl, iminoalkenyl, iminoalkynyl, thioalkenyl, thioalkynyl, carbonyl-substituted alkenyl or alkynyl groups.

[0053] Unless the carbon number is otherwise explicitly stated, "lower alkyl" as used herein means an alkyl group as defined above, but having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, in its backbone structure. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout this application, preferred alkyl groups are lower alkyl groups. In preferred embodiments, substituents referred to herein as alkyl groups are lower alkyl groups.

[0054] The term "alkylthio" refers to an alkyl group as defined above to which is attached a sulfur group. In preferred embodiments, the "alkylthio" moiety consists of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2) t -R8 represents one of: wherein t and R8 are as defined above. Representative alkylthio groups include methylthio, ethylthio, and the like.

[0055] The term "aralkyl," as used herein, refers to an alkyl group substituted with an aryl group (eg, an aromatic or heteroaromatic group).

[0056] As used herein, the term "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. Those aryl groups having heteroatoms in the ring structure may also be referred to as "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, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3, -CN, and the like. The term "aryl" also includes polycyclic ring systems having two or more rings in which two or more carbons are common to two adjacent rings (such rings are "fused rings"), wherein at least one of the rings is aromatic, e.g., the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and / or heterocyclyl.

[0057] As used herein, the term "carbocycle" refers to an aromatic or non-aromatic ring in which every atom in the ring is carbon.

[0058] The term "electron withdrawing group" refers to a chemical group that attracts electron density from the atom or group of atoms to which the electron withdrawing group is attached. Attraction of electron density includes attraction via inductive effects or via delocalization / resonance effects. Examples of electron withdrawing groups attached to aromatic rings include perfluoroalkyl groups such as trifluoromethyl, halogens, azides, carbonyl-containing groups such as acyl groups, cyano groups, and imine-containing groups.

[0059] As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium.

[0060] The term "heterocyclyl" or "heterocyclic group" refers to a 3 to 10-membered ring structure, more preferably a 3 to 7-membered ring structure, which includes 1-4 heteroatoms. The heterocycle can also be polycyclic. Heterocyclyl includes, 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-naphthyridine, 1,5-naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine,

[0066] The heterocycles may be substituted at one or more positions with substituents such as halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3, -CN, etc.

[0061] As used herein, the term "nitro" refers to -NO2; the term "halogen" refers to -F, -Cl, -Br or -I; the term "mercapto" refers to -SH; the term "hydroxy" refers to -OH; and the term "sulfonyl" refers to -SO2-.

[0062] The term "polycyclic group", "polycyclic radical" or "polycyclic ring system" refers to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and / or heterocyclyl) wherein two adjacent rings share one, two or more ring atoms, e.g., the rings are "fused rings" or "spirocycles". Rings connected by non-adjacent atoms are called "bridged" rings, e.g., C5-C 12Bridged carbocyclic rings include, but are not limited to, bicyclo[2.2.2]octyl, bicyclo[1.1.1]pentyl, bicyclo[3.2.1]octyl, and bicyclo[2.1.1]hexyl. Each ring in the polycyclic ring may be substituted with substituents as described above, such as halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3, -CN, and the like.

[0063] As used herein, the term "protecting group" refers to a temporary substituent that protects a potentially reactive functional group from unwanted chemical transformations. Examples of such 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, TW; Wuts, PGM Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991).

[0064] The term "substituted" as used herein is intended to include all permissible substituents of an organic compound. In a broad sense, 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, sulfonyl, sulfoxide, sulfate, sulfonate, sulfamoyl, sulfonamido, and phosphoryl. Illustrative substituents include, for example, those described above. Permissible substituents may be one or more, and the same or different, for a suitable organic compound. For purposes of this invention, 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.

[0065] It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is based on the valences allowed by the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., one that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. "Substituted with 0-2 R f " indicates that the corresponding group has 0, 1 or 2 R f.

[0066] As used herein, the definition of each expression, when it occurs more than once in any structure, is intended to represent an independent definition unless in the same structure.

[0067] The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl, and methanesulfonyl, respectively. A more comprehensive list of abbreviations used by those skilled in the art of organic chemistry appears in the first issue of each volume of the Journal of Organic Chemistry; this list is presented in the form of a table entitled "Standard List of Abbreviations." The abbreviations contained in this list, as well as all abbreviations used by those skilled in the art of organic chemistry, are incorporated herein by reference.

[0068] 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 further mixtures thereof, 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 encompassed by the present invention.

[0069] Methods for preparing substantially isomerically pure compounds are well known in the art. For example, if a specific enantiomer of a compound of the invention is desired, its preparation can be accomplished by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary groups are cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as an amino group, or an acidic functional group such as a carboxyl group, diastereomeric salts can be formed with a suitable optically active acid or base, followed by resolution of the resulting diastereomers by fractional crystallization or chromatographic methods known in the art, and subsequent recovery of the pure enantiomers. Alternatively, enantiomerically enriched mixtures and enantiomerically pure compounds can be prepared by employing enantiomerically pure synthetic intermediates in combination with reactions that either leave the stereochemistry of the chiral center unchanged or result in its complete inversion. Techniques for inverting or preserving a specific stereocenter, as well as those for resolving mixtures of stereoisomers, are well known in the art and are well within the capabilities of those skilled in the art to screen for the appropriate method for a particular situation. See generally, Furniss et al. (eds.), Vogel's Encyclopedia of Practical Organic Chemistry 5th ed., Longman Scientific and Technical Ltd., Essex, 1991, pp. 809-816; and Heller, Ace. Chem. Res. 23: 128 (1990).

[0070] Equivalents of the compounds described above include compounds that correspond to the compounds described above and have the same general properties (e.g., ability to inhibit TRPV3 activity) as the compounds described above, wherein simple variations of one or more substituents do not negatively affect the efficacy of the compounds. In general, the compounds of the present invention are prepared by methods such as those described in the following general reaction schemes, or modifications thereof, using readily available starting materials, reagents, and conventional synthetic procedures. In these reactions, variations known per se but not described herein may also be utilized.

[0071] For purposes of this invention, the definition of chemical elements is based on the Periodic Table of the Elements. Also for purposes of this invention, the term "hydrocarbon" is intended to include all permissible compounds having at least one hydrogen and one carbon atom. Broadly speaking, the permissible hydrocarbons include acyclic and cyclic hydrocarbons, branched and unbranched hydrocarbons, carbocyclic and heterocyclic hydrocarbons, aromatic and non-aromatic hydrocarbon organic compounds that may be substituted or unsubstituted.

[0072] The compounds of the present invention may also contain unnatural proportions of isotopes of atoms at one or more of the atoms that constitute the compound. For example, the compounds may be treated with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3H), iodine-125( 125 I) or carbon-14 ( 14 C) Isotopic Labeling: All isotopic variations of the compounds of the present invention, whether radioactive or non-radioactive, are intended to be encompassed within the scope of the present invention.

[0073] symbol Whether used as a bond or shown perpendicular to a bond, it indicates the point at which the shown moiety is attached to the rest of the molecule, a solid support, or the like.

[0074] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrates. In general, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention.

[0075] Substituents are defined by their conventional chemical formula, written left to right, and they equally encompass chemically identical substituents as the structure is written right to left, e.g., -CH2O- is intended to also represent -OCH2-; -NHS(O)2- is also intended to represent -S(O)2HN-, etc.

[0076] The term "pharmaceutically acceptable salt" includes salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, 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. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When compounds of the present invention contain relatively basic functionalities, 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, as well as salts derived from relatively non-toxic 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. Also included are salts of amino acids such as arginine salts and the like, and salts of organic acids such as glucuronic acid or galacturonic acid and the like (see, for example, 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.

[0077] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for purposes of the present invention, the salts are equivalent to the parent form of the compound.

[0078] With respect to pharmaceutical preparations, 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. For example, the term includes preparations that are free or substantially free of endotoxins, such as lipopolysaccharide (LPS).

[0079] Diseases, conditions or disorders related to TRPV3 function

[0080] In embodiments of the methods for preventing or treating a disease, condition, or disorder, the administered agent is an agent that modulates the level and / or activity of a TRPV3 protein. In certain embodiments, the compound inhibits the expression and / or activity of a TRPV3 protein. In other embodiments, the compound selectively inhibits the expression of a TRPV3 protein. In other words, in certain embodiments, the compound preferentially inhibits the activity of a TRPV3 protein over one or more other ion channels.

[0081] In specific embodiments of the methods provided herein for preventing or treating diseases and conditions, 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 insults, such as 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 zoster.

[0082] Because calcium regulation plays an important role in many cellular processes, including cell activation, gene expression, cell trafficking, and apoptotic cell death, imbalances in calcium homeostasis are implicated in many diseases and conditions involving such cellular activities. These diseases and conditions include skin diseases and conditions; neurological and neurodegenerative diseases and conditions; fever associated with a variety of diseases, conditions, or disorders; incontinence; inflammatory diseases and conditions, such as inflammatory bowel disease and Crohn's disease; respiratory diseases and conditions, such as chronic cough, asthma, and chronic obstructive pulmonary disease (COPD); digestive diseases, such as ulcers and acid reflux; metabolic diseases and conditions, including obesity and diabetes; liver and kidney diseases and conditions; malignant diseases, including cancer; age-related diseases; and sensitivity to pain and touch.

[0083] Additional diseases or conditions that can be treated include ATP-related diseases or conditions, including epilepsy, cognition, vomiting, pain (such as migraine), asthma, peripheral vascular disease, hypertension, immune and inflammatory disorders, irritable bowel syndrome, cystitis, depression, age-related degenerative diseases, urinary incontinence, premature ejaculation, cystic fibrosis, diabetes, birth control and infertility, and wound healing (see, e.g., Foresta et al. (1992) J. Biol. Chem. 257: 19443-19447; Wang et al. (1990) Biochim. Biophys. Res. Commun. 166: 251-258; Burnstock and Williams, (2000) J. Pharmacol. Exp. Ther. 295: 862-869; and Burnstock, Pharmacol Rev (2006) 58: 58-86).

[0084] The 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. When used in a therapeutic method, the inhibitor can be selected and formulated based on the intended route of administration.

[0085] 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 the signs and symptoms of osteoarthritis and rheumatoid arthritis, orofacial 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. The compounds and methods of the present invention can be used to treat chronic and acute pain. Chronic or acute pain can be the result of injury, age, or disease.

[0086] Other ion channels have been implicated in the reception or transmission of pain. For example, it is well established that N-type calcium channels are involved in synaptic transmission, which transmits pain signals from sensory afferent neurons to the central nervous system. Certain naturally occurring peptide neurotoxins that specifically block N-type calcium channels have been shown to act as extremely potent 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 many typical opioid side effects (e.g., respiratory weakness), and that the analgesic effect does not develop tolerance.

[0087] The pattern of expression of TRPV3, as well as TRPV1 and TRPV4, is consistent with involvement in pain. TRPV3 is expressed in pain-sensitive neurons, and this expression is upregulated after injury. In addition, TRPV3 is strongly expressed in the skin. Therefore, methods for treating pain include administering: (i) an antagonist of TRPV3 function; (ii) a combination of selective antagonists of TRPV3 and TRPV1 and / or TRPV4 function; or (iii) a pan-TRP inhibitor that inhibits the function of TRPV3, TRPV1, and TRPV4.

[0088] In addition to TRPV family members, other TRP channels have also been involved in pain reception and / or sensation. For example, certain TRPM channels, including TRPM8, have been involved in pain reception and / or sensation. Therefore, in certain embodiments, 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.

[0089] Calcium influx across the plasma membrane of skin cells is a key signaling element involved in cell differentiation in the epidermis (Dotto, 1999 Crit Rev Oral Biol Med 10:442-457). Modulating or regulating calcium entry pathways, and therefore key control points in skin cell growth, could treat or prevent skin diseases or conditions characterized by epidermal hyperplasia, a condition in which skin cells both proliferate excessively and differentiate poorly. Such diseases include psoriasis, basal cell carcinoma, and squamous cell carcinoma. Psoriasis, estimated to affect up to 7 million Americans, causes mild to severe symptoms, increased susceptibility to secondary infections, and psychological consequences due to the disfiguring appearance of the affected areas (Lebwohl and Ali, 2001 J Am Acad Dermatol 45:487-498). Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin account for at least one-third of all cancers diagnosed annually in the United States. Over one million new cases are reported annually, and the incidence is increasing. Despite being a relatively non-aggressive, slow-growing cancer, BCC can cause significant local tissue destruction and deformity. SCC is more aggressive and presents with more complications. Furthermore, with 80% of lesions located on the head and neck, and another 15% on the shoulders, back, or chest, BCC and SCC of the skin have a significant impact on the appearance and quality of life of affected patients.

[0090] Many skin conditions are accompanied by itching (pruritus). Pruritus and pain share many mechanistic similarities. Both are associated with C-fiber activation, are potentiated by elevated temperature and inflammatory mediators, and are eliminated by opioids. Reducing neuronal excitability, particularly C-fiber excitability, may alleviate pruritus associated with dialysis, dermatitis, pregnancy, poison ivy, allergies, dry skin, chemotherapy, and eczema.

[0091] Acne is a skin disease with a complex etiology. Among other factors, oil secretion from the sebaceous glands contributes to the development of acne. 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.

[0092] In certain preferred embodiments, 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 part of the treatment of burns, e.g., post-operative pain, cancer pain or neuropathic pain.

[0093] In certain preferred embodiments, the TRPV3 antagonist is administered to prevent, treat, or ameliorate the signs and symptoms of migraine.

[0094] In certain preferred embodiments, 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, postherpetic neuralgia (shingles), incontinence, bladder incontinence, fever, hot flashes, and cough.

[0095] In certain preferred embodiments, the TRPV3 antagonist is administered to prevent, treat, or ameliorate the signs and symptoms of osteoarthritis.

[0096] In certain preferred embodiments, the TRPV3 antagonist is administered to prevent, treat, or ameliorate the signs and symptoms of rheumatoid arthritis.

[0097] In certain preferred embodiments, the TRPV3 antagonist is administered to prevent, treat, or ameliorate the signs and symptoms of oral mucositis.

[0098] In certain preferred embodiments, the TRPV3 antagonist is administered to promote hair loss or inhibit hair growth in a patient.

[0099] Another aspect of the invention relates to the use of a TRPV3 antagonist in the preparation of a medicament for preventing, treating or ameliorating the symptoms of a disease, disorder or condition in a patient that involves activation of TRPV3 or for which decreased TRPV3 activity reduces severity.

[0100] Pharmaceutical composition

[0101] Although the compounds of the present invention can be administered alone, it is preferred that the compounds be administered as pharmaceutical preparations (compositions). The compounds of the present invention can be formulated into preparations in a convenient manner for human or veterinary use. In certain embodiments, 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.

[0102] Regardless of the route of administration selected, 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.

[0103] Therefore, another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. As described in detail below, the pharmaceutical compositions of the present invention are particularly formulated into solid or liquid administration forms, including administration forms suitable for the following modes: (1) oral administration, for example, as a dip (aqueous or non-aqueous solution or suspension); tablets; pills; powders; granules; pastes for application to the tongue, teeth, lips, gums; mouthwashes; gels; (2) parenteral administration, for example, as a sterile solution or suspension, by subcutaneous, intramuscular or intravenous injection; (3) topical administration, for example, as a cream, ointment or spray applied to the skin; (4) intravaginal or intrarectal administration, for example, as a vaginal suppository, cream or foam; or (5) inhalation. However, in certain embodiments, the compounds of the present invention can be readily dissolved or suspended in sterile water. In certain embodiments, the pharmaceutical formulation is non-pyrogenic, that is, it does not increase the patient's body temperature.

[0104] The TRPV3 antagonist can be administered alone or in combination with other therapeutic agents. For example, the TRPV3 antagonist can be 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 antifungal agent, an antiviral agent, an antiseptic, an anti-migraine agent, a keratolytic agent, or a hair growth inhibitor.

[0105] 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.

[0106] In certain preferred embodiments, the TRPV3 antagonist is administered topically.

[0107] In certain preferred embodiments, the TRPV3 antagonist is administered orally.

[0108] In certain preferred embodiments, the TRPV3 antagonist is administered parenterally.

[0109] As used herein, the term "therapeutically effective amount" means an amount of a compound, material, or composition comprising a compound of the invention that is effective to produce some desired therapeutic effect by inhibiting TRPV3 function in at least a subpopulation of cells in an animal, and thereby blocking the biological consequences of that function in the treated cells, at a reasonable benefit / risk ratio applicable to any drug treatment.

[0110] As used herein, the terms "systemic administration" and "peripheral administration" refer to administration of a compound, drug or other material other than directly to the central nervous system so that it enters the patient's system and is metabolized and otherwise processed there, such as subcutaneous administration.

[0111] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms that 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.

[0112] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, e.g., a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting the antagonist 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. Some examples of materials that serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, 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; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other nontoxic compatible substances used in pharmaceutical formulations.

[0113] As mentioned above, some embodiments of the compounds of the present invention can contain basic functional groups, such as amino or alkylamino, and therefore can form pharmaceutically acceptable salts with pharmaceutically acceptable acids. In this respect, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of the compounds of the present invention. During final separation and purification of the compounds of the present invention, or by reacting the purified compounds of the present invention in free alkali form with suitable organic or inorganic acids alone, and then separating the salt formed, the above-mentioned addition salts can be prepared in situ. 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, e.g., Berge et al. (1977) "Pharmaceutical Salts", J Pharm. Sci. 66: 1-19).

[0114] Pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts or quaternary ammonium salts of the compounds, such as those derived from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic 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, ethanedisulfonic acid, oxalic acid, isothionic acid, and the like.

[0115] In other cases, the compounds of the present invention may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these cases refers to the addition salts of relatively non-toxic inorganic and organic bases of the compounds of the present 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 free acid form with a suitable base, ammonium, or a pharmaceutically acceptable organic primary, secondary or tertiary amine, such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, among others. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

[0116] Examples of pharmaceutically acceptable antioxidants 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, α-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0117] The formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. Oral formulations include those that are delivered to the mouth and maintained in the mouth without swallowing, as well as formulations that are used as part or swallowed after use. The formulations can be conveniently presented in unit dosage form and can be prepared by any method known in the art 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. Typically, based on 100%, this 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.

[0118] 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. In general, 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.

[0119] Formulations 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 an oil-in-water or water-in-oil liquid emulsion, 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 the active ingredient. The compounds of the present invention may also be administered in the form of boluses, electuaries or pastes.

[0120] The present application relates to compounds of formula (I):

[0121] or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances, or pharmaceutically acceptable salts,

[0122] wherein Ring A and Ring B are each independently selected from a monocyclic or polycyclic ring system containing 3-12 ring atoms;

[0123] R 1 Each independently selected from H, halogen, hydroxyl, thiol, nitro, cyano, oxo, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C1-C6 alkoxy, substituted with 0-2 R f C1-C6 haloalkoxy, substituted with 0-2 R f C3-C6 cycloalkyl, substituted with 0-2 R f C3-C6 halocycloalkyl, substituted with 0-2 R f C3-C6 cycloalkoxy, substituted with 0-2 R f C3-C6 halocycloalkoxy, substituted with 0-2 R f Aryl, substituted with 0-2 R f Arylalkyl, substituted with 0-2 R f Alkaryl, substituted with 0-2 R f heteroaryl, -R 11 OR 12 、-R 11 SR 12 、-N(R a )(R b ),-C(O)R c 、-C(O)N(R a )(R b ) and -SO2N(R a )(R b ) or -SOR c , or two R 1 Together with the ring A atoms to which they are attached, they form a 3-10 membered ring structure;

[0124] R 2 Each independently selected from H, halogen, hydroxyl, thiol, nitro, cyano, oxo, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C1-C6 alkoxy, substituted with 0-2 R f C1-C6 haloalkoxy, substituted with 0-2 R f C3-C6 cycloalkyl, substituted with 0-2 R f C3-C6 halocycloalkyl, substituted with 0-2 R fC3-C6 cycloalkoxy, substituted with 0-2 R f C3-C6 halocycloalkoxy, substituted with 0-2 R f Aryl, substituted with 0-2 R f Arylalkyl, substituted with 0-2 R f Alkaryl, substituted with 0-2 R f heteroaryl, -R 11 OR 12 、-R 11 SR 12 、-N(R a )(R b ),-C(O)R c 、-C(O)OR d 、-C(O)N(R a )(R b ) and -SO2N(R a )(R b ) or -SOR c , or two R 2 Together with the ring B atoms to which they are attached, they form a 3-10 membered ring structure;

[0125] R 0 Each independently selected from H, halogen or the structural formula II

[0126] in,

[0127] L is independently selected from a bond, -O-, -S-, -N(R 20 )-、-C(O)-、-C(R 20 R 21 )-, -S(O)- and -S(O2)-;

[0128] Ring C is independently selected from a monocyclic or polycyclic ring system containing 3-12 ring atoms;

[0129] R 3 Each independently selected from H, halogen, hydroxyl, thiol, nitro, cyano, oxo, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C1-C6 alkoxy, substituted with 0-2 R f C1-C6 haloalkoxy, substituted with 0-2 R f C3-C6 cycloalkyl, substituted with 0-2 R f C3-C6 halocycloalkyl, substituted with 0-2 R f C3-C6 cycloalkoxy, substituted with 0-2 Rf C3-C6 halocycloalkoxy, substituted with 0-2 R f Aryl, substituted with 0-2 R f Arylalkyl, substituted with 0-2 R f Alkaryl, substituted with 0-2 R f heteroaryl, -R 11 OR 12 、-R 11 SR 12 、-N(R a )(R b ),-C(O)R c 、-C(O)OR d 、-C(O)N(R a )(R b ) and -SO2N(R a )(R b ) or -SOR c , or two R 3 Together with the ring C atoms to which they are attached, they form a 3-10 membered ring structure;

[0130] R 11 Each independently selected from substituted with 0-2 R f C1-C6 alkylene;

[0131] R 12 Each independently selected from H, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C3-C6 cycloalkyl and substituted with 0-2 R f C3-C6 halocycloalkyl;

[0132] R a and R b Each independently selected from H, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f Aryl, substituted with 0-2 R f Aralkyl, -C(O)R c and -C(O)OR d ;

[0133] R c Each independently selected from H, halogen, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f The aryl group and the substituent have 0-2 R f Aralkyl;

[0134] Rd Each independently selected from H, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f The aryl group and the substituent have 0-2 R f Aralkyl;

[0135] R 20 and R 21 Each is independently selected from H, hydroxy, C1-C6 alkyl, aryl and aralkyl;

[0136] R f Each is independently selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl and C3-C6 halocycloalkyl;

[0137] X is selected from -S-, -S(O)- and -S(O2)-;

[0138] n is 0, 1, 2, or 3;

[0139] m is 0, 1, 2, or 3;

[0140] p is 0, 1, 2, or 3;

[0141] q is 0, 1, 2, or 3.

[0142] In one embodiment, the compound has the structural formula I-1

[0143] Among them, ring A, ring B, ring C, X, R 1 、R 2 、R 3 , L, n, p, m and q are defined as in Formula I.

[0144] In one embodiment, 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.

[0145] In one embodiment, Ring A is selected from the following structural formulas:

[0146] In one embodiment, 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.

[0147] In one embodiment, Ring B is selected from the following structural formulas:

[0148] In one embodiment, R 1 Each is independently selected from H, halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -N(R a )(R b ) and -R 11 OR 12 , where R a and R b are each independently selected from H and C1-C6 alkyl; R 11 Each independently selected from C1-C6 alkylene; R 12 Each is independently selected from H and C1-C6 alkyl.

[0149] In one embodiment, R 1 Each is independently selected from H, Cl, F, -CF3, -CN, -CH3, -OH, -OCH3, -CH2OCH3.

[0150] In one embodiment, n is 0, 1 or 2.

[0151] In one embodiment, m is 0, ie, X is directly attached to ring A.

[0152] In one embodiment, when n is 1 and m is 0, on ring A the R 1 Located at the ortho or para position of X.

[0153] In one embodiment, when n is 2 and m is 0, one R 1 Located opposite to X.

[0154] In one embodiment, R 2 Each independently selected from H, cyano, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, substituted with 0-2 R f C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -R 11 OR 12 、-R 11 SR 12 、-C(O)OR d and -C(O)N(R a )(R b ); where R 11 Each independently selected from C1-C6 alkylene; R 12 R is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl and C3-C6 halocycloalkyl; a and R bare each independently selected from H and C1-C6 alkyl; R d are each independently selected from H and C1-C6 alkyl; R f Each is independently selected from halogen, hydroxy, amino and C1-C6 alkyl.

[0155] In one embodiment, R 2 Each independently selected from 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, Preferably, R 2 It is -CH2OH.

[0156] In one embodiment, p is 1, that is, ring B is substituted with only one R as defined above. 2 In the embodiment where p is 1, on ring B, the R 2 Located in the ortho position of the pyrrolidinyl group.

[0157] In one embodiment, each L is independently selected from a bond, -O-, -S-, -N-, -C(O)-, -CH2-, -C(OH)-, -S(O)-, and -S(O2)-.

[0158] In one embodiment, L is -S-, or L is -S(O)-, or L is -S(O2)-. Preferably, L is -S-.

[0159] In one embodiment, Ring C is selected from a C3-C6 cycloalkane ring, a benzene ring, a benzoC3-C6 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.

[0160] In one embodiment, Ring C is selected from the following structural formulas:

[0161] In one embodiment, R 3 Each is independently selected from H, cyano, hydroxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -R 11 OR 12 、-R 11 SR 12 、-C(O)R c、-C(O)OR d and -C(O)N(R a )(R b ), or two R 3 Together with the ring C atoms to which they are attached, they form a 3-10 membered ring structure;

[0162] Among them, R 11 Each independently selected from C1-C6 alkylene; R 12 R is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl and C3-C6 halocycloalkyl; a and R b are each independently selected from H and C1-C6 alkyl; R c are each independently selected from H, halogen and C1-C6 alkyl; R d Each is independently selected from H and C1-C6 alkyl.

[0163] In one embodiment, R 3 Each is independently selected from H, cyclopropyl, isopropyl, tert-butyl, F, Cl, ethyl, methyl, methylcarbonyl, and methoxymethyl.

[0164] The present application relates to a compound of formula (I-2):

[0165] or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances, or pharmaceutically acceptable salts,

[0166] wherein Ring A is each independently selected from a monocyclic or polycyclic ring system containing 3-12 ring atoms;

[0167] R 1 Each independently selected from H, halogen, hydroxyl, thiol, nitro, cyano, oxo, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C1-C6 alkoxy, substituted with 0-2 R f C1-C6 haloalkoxy, substituted with 0-2 R f C3-C6 cycloalkyl, substituted with 0-2 R f C3-C6 halocycloalkyl, substituted with 0-2 R f C3-C6 cycloalkoxy, substituted with 0-2 R f C3-C6 halocycloalkoxy, substituted with 0-2 R f Aryl, substituted with 0-2 R f Arylalkyl, substituted with 0-2 Rf Alkaryl, substituted with 0-2 R f heteroaryl, -R 11 OR 12 、-R 11 SR 12 、-N(R a )(R b ),-C(O)R c 、-C(O)N(R a )(R b ) and -SO2N(R a )(R b ) or -SOR c , or two R 1 Together with the ring A atoms to which they are attached, they form a 3-10 membered ring structure;

[0168] R 2 Each independently selected from H, halogen, hydroxyl, thiol, nitro, cyano, oxo, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C1-C6 alkoxy, substituted with 0-2 R f C1-C6 haloalkoxy, substituted with 0-2 R f C3-C6 cycloalkyl, substituted with 0-2 R f C3-C6 halocycloalkyl, substituted with 0-2 R f C3-C6 cycloalkoxy, substituted with 0-2 R f C3-C6 halocycloalkoxy, substituted with 0-2 R f Aryl, substituted with 0-2 R f Arylalkyl, substituted with 0-2 R f Alkaryl, substituted with 0-2 R f heteroaryl, -R 11 OR 12 、-R 11 SR 12 、-N(R a )(R b ),-C(O)R c 、-C(O)OR d 、-C(O)N(R a )(R b ) and -SO2N(R a )(R b ) or -SOR c , or two R 2 Together with the ring atoms to which they are attached, they form a 3-10 membered ring structure;

[0169] R 0 Each independently selected from H, halogen or the structural formula II

[0170] in,

[0171] L is independently selected from a bond, -O-, -S-, -N(R 20 )-、-C(O)-、-C(R 20 R 21 )-, -S(O)- and -S(O2)-;

[0172] Ring C is independently selected from a monocyclic or polycyclic ring system containing 3-12 ring atoms;

[0173] R 3 Each independently selected from H, halogen, hydroxyl, thiol, nitro, cyano, oxo, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C1-C6 alkoxy, substituted with 0-2 R f C1-C6 haloalkoxy, substituted with 0-2 R f C3-C6 cycloalkyl, substituted with 0-2 R f C3-C6 halocycloalkyl, substituted with 0-2 R f C3-C6 cycloalkoxy, substituted with 0-2 R f C3-C6 halocycloalkoxy, substituted with 0-2 R f Aryl, substituted with 0-2 R f Arylalkyl, substituted with 0-2 R f Alkaryl, substituted with 0-2 R f heteroaryl, -R 11 OR 12 、-R 11 SR 12 、-N(R a )(R b ),-C(O)R c 、-C(O)OR d 、-C(O)N(R a )(R b ) and -SO2N(R a )(R b ) or -SOR c , or two R 3 Together with the ring C atoms to which they are attached, they form a 3-10 membered ring structure;

[0174] R 11 Each independently selected from substituted with 0-2 R f C1-C6 alkylene;

[0175] R 12 Each independently selected from H, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C3-C6 cycloalkyl and substituted with 0-2 R f C3-C6 halocycloalkyl;

[0176] R a and R b Each independently selected from H, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f Aryl, substituted with 0-2 R f Aralkyl, -C(O)R c and -C(O)OR d ;

[0177] R c Each independently selected from H, halogen, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f The aryl group and the substituent have 0-2 R f Aralkyl;

[0178] R d Each independently selected from H, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f The aryl group and the substituent have 0-2 R f Aralkyl;

[0179] R 20 and R 21 Each is independently selected from H, hydroxy, C1-C6 alkyl, aryl and aralkyl;

[0180] R f Each is independently selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl and C3-C6 halocycloalkyl;

[0181] X is selected from -S-, -S(O)- and -S(O2)-;

[0182] X A 、X B 、X C 、XD 、X E are each independently CH or N;

[0183] X F for CH;

[0184] n is 0, 1, 2, or 3;

[0185] m is 0, 1, 2, or 3;

[0186] p is 0, 1, 2, or 3;

[0187] q is 0, 1, 2, or 3.

[0188] In one embodiment, X A 、X B 、X C 、X D 、X E Each independently is CH;

[0189] Or, X A 、X B 、X C 、X E are independently CH, X D is N;

[0190] Or, X A 、X B 、X C 、X D are independently CH, X E is N;

[0191] Or, X A 、X C 、X D are independently CH, X B 、X E is N.

[0192] It should be noted that the above limitations on the groups in compound I and compound I-1 are also applicable to compound I-2.

[0193] In the above compound embodiments, m may be zero.

[0194] In the embodiments of the above compounds, n can be 1 or 2, that is, ring A is substituted with 1 or 2 R 1 .

[0195] In the above embodiments of the compounds, p can be 1, that is, ring B or X A 、X B 、X C 、X D 、X E 、XF The six-membered ring is substituted with one R 2 In one embodiment, the R 2 Located in the ortho position of the pyrrolidinyl group.

[0196] In one embodiment, the compound is selected from the group consisting of:

[0197] The present application relates to a pharmaceutical composition comprising the compound of the present application or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier.

[0198] 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, as well as the pharmaceutical composition of the present application in the preparation of drugs for inhibiting TRPV3 activity.

[0199] 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 preparing a medicament for treating a TRPV3-mediated disorder in a subject.

[0200] 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.

[0201] In one embodiment, the condition is selected from pain, itching, skin disorders, inflammation, abnormal hair growth, incontinence, fever, hot flashes, cystitis, irritable bowel syndrome, and / or cough symptoms.

[0202] In one embodiment, the pain is cancer pain and skin pain.

[0203] In one embodiment, it is used to prepare a medicament for inhibiting proliferation, thereby preventing, treating or ameliorating symptoms of cancer.

[0204] In one embodiment, the cancer is liposarcoma.

[0205] In one embodiment, the hair growth disorder is alopecia.

[0206] In one embodiment, the skin disorder is selected from keratosis pilaris, ichthyosis, pruritus.

[0207] In one embodiment, the skin keratosis is Olmsted syndrome.

[0208] In one embodiment, the ichthyosis is harlequin ichtyosis.

[0209] General synthetic scheme

[0210] 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 starting materials used to prepare the compounds of the present invention are commercially available or can be prepared using conventional methods known in the art.

[0211] Representative procedures for preparing compounds of the present 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. The synthesis of (R)-1-BOC-3-methanesulfonyloxypyrrolidine 2 can be achieved by reacting (R)-1-BOC-3-hydroxypyrrolidine 1 and methanesulfonyl chloride in a solvent such as dichloromethane. The intermediate thioether 3 is reacted with the desired aromatic thiol group in an alkaline solution to produce intermediate 3. Intermediate 3 is deprotected under acidic conditions to produce intermediate 4. 4 reacts with 5-bromo-2-fluorobenzaldehyde in an alkaline solution to produce intermediate 5, which is further reduced under reducing agent conditions to produce 6. Intermediate 6 can be reacted with the desired boronic acid under Suzuki conditions to produce 7.

[0212] Solution 1

[0213] Scheme 2 shows the synthesis of the desired compound, wherein 5 is generated in the fourth step via a catalytic coupling reaction. The preparation of intermediate 4 is the same as in Scheme 1, and intermediate 5 is reacted with the desired boronic acid under Suzuki conditions to produce 6.

[0214] Option 2

[0215] 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 catalytically coupled to produce 6.

[0216] Option 3

[0217] For the sake of clarity, the present invention is further illustrated by examples, but the examples are not intended to limit the scope of this application. All reagents used in this application are commercially available and can be used without further purification.

[0218] Specific implementation plan

[0219] Preparation of intermediates

[0220] Preparation Example 1 (S)-5-chloro-2-(pyrrolidin-3-ylthio)pyridine hydrochloride (Compound I1)

[0221] Step A: (R)-tert-Butyl 3-(methylsulfonyl)oxy)pyrrolidine-1-carboxylate

[0222] Dissolve 18.0 g (96.1 mmol, 1.0 eq) of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate and 40 mL (288 mmol, 3.0 eq) of triethylamine in 60 mL of anhydrous tetrahydrofuran. Cool to 0°C, then add 13.2 g (115 mmol, 1.2 eq) of methanesulfonyl chloride dropwise to the reaction system. Allow to warm to room temperature and stir for 2 hours. TLC confirms complete reaction. Add 150 mL of water and 100 mL of dichloromethane to separate the organic phase. Extract the aqueous phase once with 150 mL of dichloromethane. Combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, and concentrate to dryness. The crude product is purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 30:1) to afford a light yellow oil (18.2 g, yield = 71%).

[0223] LC-MS: (M+23) + ; m / z = 288.06;

[0224] 1 H 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).

[0225] Step B: (S)-tert-Butyl 3-(5-chloropyridin-2-yl)thio)pyrrolidine-1-carboxylate

[0226] 4.00 g (15.1 mmol, 1.0 eq) of tert-butyl (R)-3-(methylsulfonyl)oxy)pyrrolidine-1-carboxylate was dissolved in 90 mL of anhydrous N,N-dimethylformamide, followed by the addition of 3.30 g (22.6 mmol, 1.5 eq) of 5-chloropyridine-2-thiol and 3.13 g (22.6 mmol, 1.5 eq) of potassium carbonate. The reaction mixture was stirred at 70°C under nitrogen for 18 h. The mixture was cooled to room temperature, and 50 mL of water and 150 mL of ethyl acetate were added. The organic phase was separated and extracted twice with ethyl acetate (2 x 100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated to yield a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 20:1) to afford an oil (4.00 g, yield = 84%).

[0227] LC-MS:(M-100) + ; m / z = 215.06;

[0228] 1 H 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, 1 H),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).

[0229] Step C: (S)-5-chloro-2-(pyrrolidin-3-ylthio)pyridine hydrochloride

[0230] 4.30 g (13.7 mmol, 1.0 eq) of tert-butyl (S)-3-(5-chloropyridin-2-yl)thio)pyrrolidine-1-carboxylate was dissolved in 50 mL of dichloromethane. 5.7 mL (68.3 mmol, 5.0 eq) of concentrated hydrochloric acid was added to the reaction mixture. The mixture was stirred at room temperature under nitrogen for 1 hour. LC-MS confirmed complete reaction of the starting materials. The reaction mixture was then concentrated under reduced pressure to yield an off-white solid (2.56 g, yield = 88%).

[0231] LC-MS: (M+H) + ; m / z = 415.06.

[0232] Intermediate I2(S)-5-bromo-2-(3-(5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)benzaldehyde

[0233] 1.50 g (6.99 mmol, 1.0 eq) (S)-5-chloro-2-(pyrrolidin-3-ylthio)pyridine was dissolved in 20 mL of anhydrous N,N-dimethylformamide. 3.55 g (17.5 mmol, 2.5 eq) of 5-bromo-2-fluorobenzaldehyde and 2.90 g (21.0 mmol, 3.0 eq) of anhydrous potassium carbonate were added to the reaction system. The reaction system was allowed to react overnight at 90°C under a nitrogen atmosphere. LC-MS results confirmed the formation of the desired product. The reaction solution was cooled to room temperature, quenched with water, and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 30:1) to afford a light yellow oil (1.40 g, yield = 50%).

[0234] LC-MS: (M+H) + ; m / z = 398.98;

[0235] 1 H 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).

[0236] Intermediate I3 (S)-(5-bromo-2-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)phenyl)methanol

[0237] Dissolve 2.0 g (5.03 mmol, 1.0 eq) (S)-5-bromo-2-(3-(5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)benzaldehyde in 10 mL of methanol. The reaction mixture was cooled to 0°C. Under nitrogen, 761 mg (20.12 mmol, 4.0 eq) of solid sodium borohydride was added to the reaction mixture. After addition, the mixture was allowed to warm to room temperature and react for 1.5 hours. LC-MS confirmed the formation of the desired product. The reaction mixture was cooled to 0°C and quenched with saturated aqueous ammonium chloride. The mixture was extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated to dryness, and then evaporated under reduced pressure to obtain the desired product (1.73 g, yield = 86%).

[0238] LC-MS: (M+H) +; m / z = 400.98;

[0239] Example 1: ((S)-(4-(3-(5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-yl)methanol

[0240] Step A: (S)-4-(3-(5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-carbaldehyde

[0241] 900 mg (2.26 mmol, 1.0 eq) (S)-5-bromo-2-(3-(5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)benzaldehyde was dissolved in 20 mL of dioxane and 5 mL of water. 445 mg (2.72 mmol, 1.2 eq) (2-isopropylphenyl)boric acid and 626 mg (4.53 mmol, 2.0 eq) of anhydrous potassium carbonate were added to the above reaction system. Under nitrogen protection, 185 mg (0.23 mmol, 0.1 eq) of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride was added and the mixture was reacted at 100°C for 4 h. LC-MS results confirmed the formation of the target product. The reaction solution was cooled to room temperature, quenched with water, and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated to dryness, and then purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 30:1) to give a light yellow oil (710 mg, yield = 71%).

[0242] LC-MS: (M+H) + ; m / z = 437.16;

[0243] 1 H 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),3.67-3.6 0(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).

[0244] Step B: ((S)-(4-(3-(5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-yl)methanol

[0245] Dissolve 150 mg (0.34 mmol, 1.0 eq) ((S)-4-(3-(5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-carbaldehyde in 10 mL of methanol. Cool the system to 0°C. Add 51.9 mg (1.37 mmol, 4.0 eq) of solid sodium borohydride to the reaction system under nitrogen protection. After the addition, naturally raise the temperature to room temperature and react for 1.5 h. The formation of the target product was confirmed by LC-MS results. The reaction solution was cooled to 0°C and quenched by adding saturated aqueous ammonium chloride solution. The product was extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The sample was sent for preparative purification (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) and lyophilized to give the target product (80.0 mg, yield = 53%).

[0246] LC-MS: (M+H) + ; m / z = 439.18;

[0247] 1 H 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),3.0 9-3.03(m,1H),2.63-2.54(m,1H),2.11-2.03(m,1H),1.15(d,J=4.0Hz,6H).

[0248] Example 2: (S)-(4-(3-(5-chloropyridin-2-yl)sulfonyl)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-yl)methanol

[0249] Step A: (S)-4-(3-(5-chloropyridin-2-yl)sulfonyl)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-carbaldehyde

[0250] 240 mg (0.55 mmol, 1.0 eq) of (S)-4-(3-(5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-carbaldehyde was dissolved in 6 mL of methanol and 3 mL of tetrahydrofuran. 124 mg (0.55 mmol, 1.0 eq) of sodium tungstate and 0.5 mL (5.5 mmol, 10.0 eq) of hydrogen peroxide were added to the reaction system. The temperature was raised to 40°C and the reaction was allowed to react for 2 h. LC-MS confirmed the formation of the target product. The reaction solution was cooled to room temperature, quenched with water, and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 3:1) to afford a light yellow oil (180 mg, yield = 69%).

[0251] LC-MS: (M+H) + ; m / z = 471.17;

[0252] Step B: (S)-(4-(3-(5-chloropyridin-2-yl)sulfonyl)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-yl)methanol

[0253] Dissolve 180 mg (0.38 mmol, 1.0 eq) (S)-4-(3-(5-chloropyridin-2-yl)sulfonyl)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-carbaldehyde in 5 mL of methanol. Cool the system to 0°C. Add 72.6 mg (1.37 mmol, 5.0 eq) of solid sodium borohydride to the reaction system under nitrogen protection. After the addition, naturally raise the temperature to room temperature and react for 1.5 hours. The formation of the target product was confirmed by LC-MS results. The reaction solution was cooled to 0°C and quenched by adding saturated aqueous ammonium chloride solution. The product was extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The sample was sent for preparative purification (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) and lyophilized to obtain the target product (81.8 mg, yield = 45%).

[0254] LC-MS: (M+H) + ; m / z = 471.18;

[0255] 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=16.0 Hz,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).

[0256] Example 3: (4-(S)-3-(S)-(5-chloropyridin-2-yl)sulfoxide)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-yl)methanol

[0257] Step A: 4-(S)-3-(S)-(5-chloropyridin-2-yl)sulfoxide)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-carbaldehyde

[0258] 230 mg (0.53 mmol, 1.0 eq) of (S)-4-(3-(5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-carboxaldehyde was dissolved in 5 mL of dichloromethane. The reaction mixture was cooled to 0°C under nitrogen. 145 mg (0.84 mmol, 1.6 eq) of m-chloroperbenzoic acid was then added to the reaction mixture, and the reaction was allowed to proceed at 0°C for 2 h. LC-MS confirmed the formation of the desired product. The reaction mixture was quenched with water and extracted twice with dichloromethane. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated to dryness, and purified by column chromatography (petroleum ether:ethyl acetate = 80:1 to 1:1) to afford a light yellow oil (180 mg, yield = 75%).

[0259] LC-MS: (M+H) + ; m / z = 453.17;

[0260] Step B: (4-(S)-3-(S)-(5-chloropyridin-2-yl)sulfoxide)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-yl)methanol

[0261] Dissolve 170 mg (0.38 mmol, 1.0 eq) (4-(S)-3-(S)-(5-chloropyridin-2-yl)sulfoxide)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-carboxaldehyde in 5 mL of methanol. Cool the system to 0°C. Add 42.6 mg (1.13 mmol, 3.0 eq) of solid sodium borohydride to the reaction system under nitrogen protection. After the addition, naturally raise the temperature to room temperature and react for 1.5 hours. The formation of the target product was confirmed by LC-MS results. The reaction solution was cooled to 0°C and quenched by adding saturated aqueous ammonium chloride solution. The product was extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The sample was sent for preparative purification (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) and lyophilized to obtain the target product as a white solid (68.5 mg, yield = 40%).

[0262] LC-MS: (M+H) + ; m / z = 455.16;

[0263] 1 H 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).

[0264] Example 4: ((S)-(4-(3-(5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-cyclopropyl-[1,1'-biphenyl]-3-yl)methanol

[0265] Step A: (S)-4-(3-(5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-cyclopropyl-[1,1'-biphenyl]-3-carbaldehyde

[0266] 600 mg (1.50 mmol, 1.0 eq) (S)-5-bromo-2-(3-(5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)benzaldehyde was dissolved in 20 mL of dioxane and 5 mL of water. 293 mg (1.81 mmol, 1.2 eq) (2-cyclopropylphenyl)boric acid and 626 mg (4.53 mmol, 3.0 eq) of anhydrous potassium carbonate were added to the above reaction system. Under nitrogen protection, 221 mg (0.23 mmol, 0.2 eq) [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride was added and the reaction was carried out at 100°C for 4 h. 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. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated to dryness, and then purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 30:1) to give a light yellow oil (450 mg, yield = 68%).

[0267] LC-MS: (M+H) + ; m / z = 435.12;

[0268] Step B: ((S)-(4-(3-(5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-cyclopropyl-[1,1'-biphenyl]-3-yl)methanol

[0269] Dissolve 480 mg (1.10 mmol, 1.0 eq) ((S)-4-(3-(5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-cyclopropyl-[1,1'-biphenyl]-3-carboxaldehyde in 10 mL of methanol. Cool the system to 0°C. Add 209 mg (5.52 mmol, 4.0 eq) of solid sodium borohydride to the reaction system under nitrogen protection. After the addition, naturally raise the temperature to room temperature and react for 1.5 hours. The formation of the target product was confirmed by LC-MS results. The reaction solution was cooled to 0°C and quenched by adding saturated aqueous ammonium chloride solution. The product was extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The sample was sent for preparative purification (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) and lyophilized to obtain the target product as a light yellow oily liquid (360 mg, yield = 74%).

[0270] LC-MS: (M+H) + ; m / z = 437.30;

[0271] 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).

[0272] Example 5: (S)-(4-(3-((5-chloropyridin-2-yl)sulfonyl)pyrrolidin-1-yl)-2'-cyclopropyl-[1,1'-biphenyl]-3-yl)methanol

[0273] The experimental operation refers to the synthesis steps of Example 2, replacing the reagent (2-isopropylphenyl)boric acid with (2-cyclopropylphenyl)boric acid to synthesize Example 5.

[0274] LC-MS: (M+H) + ; m / z = 469.11;

[0275] 1 H 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),3.68-3.6 6(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).

[0276] Example 6: (4-(S)-3-((S)-(5-chloropyridin-2-yl)sulfoxide)pyrrolidin-1-yl)-2'-cyclopropyl-[1,1'-biphenyl]-3-yl)methanol

[0277] The experimental operation refers to the synthesis steps of Example 3, replacing the reagent (2-isopropylphenyl)boric acid with (2-cyclopropylphenyl)boric acid to synthesize Example 6.

[0278] LC-MS: (M+H) + ; m / z = 453.10;

[0279] 1 H 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).

[0280] Example 7: ((S)-(2'-Isopropyl-4-(3-(5-(trifluoromethyl)pyridin-2-yl)thio)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-yl)methanol

[0281] Step A: (S)-tert-Butyl 3-(5-(trifluoromethyl)pyridin-2-yl)thio)pyrrolidine-1-carboxylate

[0282] 5.00 g (18.9 mmol, 1.0 eq) of tert-butyl (R)-3-(methylsulfonyl)oxy)pyrrolidine-1-carboxylate was dissolved in 90 mL of anhydrous N,N-dimethylformamide. 5.06 g (28.3 mmol, 1.5 eq) of 5-(trifluoromethyl)pyridine-2-thiol and 3.91 g (28.3 mmol, 1.5 eq) of potassium carbonate were added to the reaction system. The reaction was stirred at 70°C under nitrogen for 18 hours. The mixture was cooled to room temperature, and 50 mL of water and 150 mL of ethyl acetate were added. The organic phase was separated and extracted three times with ethyl acetate (2 x 100 mL). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain an oil (5.80 g, yield = 87%).

[0283] LC-MS:(M-56) + ; m / z = 293.03;

[0284] Step B: (S)-2-(Pyrrolidin-3-ylthio)-5-(trifluoromethyl)pyridine hydrochloride

[0285] 4.20 g (12.1 mmol, 1.0 eq.) of (S)-tert-butyl 3-(5-(trifluoromethyl)pyridin-2-yl)thio)pyrrolidine-1-carboxylate was dissolved in 50 mL of dichloromethane. 5.7 mL (68.3 mmol, 5.0 eq.) of concentrated hydrochloric acid was added to the reaction mixture. The reaction mixture was stirred at room temperature under nitrogen for 1 hour. LC-MS confirmed complete reaction of the starting materials. The reaction solution was then concentrated under reduced pressure to yield an off-white solid (3.10 g, yield = 99%).

[0286] LC-MS: (M+H) + ; m / z = 249.09;

[0287] Step C: (S)-5-Bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yl)thio)pyrrolidin-1-yl)benzaldehyde

[0288] 2.50 g (10.1 mmol, 1.0 eq.) (S)-2-(pyrrolidin-3-ylthio)-5-(trifluoromethyl)pyridine hydrochloride was dissolved in 30 mL of anhydrous N,N-dimethylformamide. 5.11 g (25.2 mmol, 2.5 eq.) 5-bromo-2-fluorobenzaldehyde and 3.20 g (30.2 mmol, 3.0 eq.) anhydrous sodium carbonate were added to the reaction system. The reaction system was allowed to react overnight at 100°C under nitrogen. LC-MS results confirmed the formation of the desired product. The reaction solution was cooled to room temperature, quenched with water, and extracted three times with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 20:1) to afford a light yellow oil (3.14 g, yield = 72%).

[0289] LC-MS: (M+H) + ; m / z = 432.94;

[0290] 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).

[0291] 19 F NMR (376MHz,CDCl3)δ-62.21.

[0292] Step D: (S)-2'-Isopropyl-4-(3-(5-(trifluoromethyl)pyridin-2-yl)thio)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-carbaldehyde

[0293] 1.55 g (3.60 mmol, 1.0 eq) (S)-5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yl)thio)pyrrolidin-1-yl)benzaldehyde was dissolved in 30 mL 1,4-dioxane and 6 mL water. Then, 707 mg (4.31 mmol, 1.2 eq) (2-isopropylphenyl)boric acid and 993 mg (7.19 mmol, 2.0 eq) anhydrous potassium carbonate were added to the above reaction system. Under nitrogen protection, 263 mg (0.36 mmol, 0.1 eq) [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride was added and the reaction was carried out at 100°C for 3 h. LC-MS results confirmed the formation of the target product. The reaction solution was cooled to room temperature, quenched with water, and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated to dryness, and then purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 20:1) to give a light yellow oil (1.30 g, yield = 77%).

[0294] LC-MS: (M+H) + ; m / z = 471.20;

[0295] Step E: ((S)-(2'-Isopropyl-4-(3-(5-(trifluoromethyl)pyridin-2-yl)thio)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-yl)methanol

[0296] Dissolve 300 mg (0.64 mmol, 1.0 eq) ((S)-2'-isopropyl-4-(3-(5-(trifluoromethyl)pyridin-2-yl)thio)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-carbaldehyde in 6 mL of methanol. Cool the system to 0°C. Add 121 mg (3.19 mmol, 5.0 eq) of solid sodium borohydride to the reaction system under nitrogen protection. After the addition, naturally raise the temperature to room temperature and react for 1 h. The formation of the target product was confirmed by LC-MS results. The reaction solution was cooled to 0°C and quenched by adding saturated aqueous ammonium chloride solution. The product was extracted three times with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The sample was sent for preparative purification (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) and lyophilized to obtain the target product as a light yellow oily liquid (75.2 mg, yield = 25%).

[0297] LC-MS: (M+H) + ; m / z = 473.23;

[0298] 1 H 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).

[0299] 19 F NMR (376 MHz, CDCl3) δ-62.17.

[0300] Example 8: (S)-(2'-Isopropyl-4-(3-(5-(trifluoromethyl)pyridin-2-yl)sulfonyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-yl)methanol

[0301] Step A: (S)-2'-Isopropyl-4-(3-(5-(trifluoromethyl)pyridin-2-yl)sulfonyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-carbaldehyde

[0302] 200 mg (0.43 mmol, 1.0 eq) of (S)-2'-isopropyl-4-(3-(5-(trifluoromethyl)pyridin-2-yl)thio)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-carbaldehyde was dissolved in 4 mL of methanol and 2 mL of tetrahydrofuran. 96.0 mg (0.43 mmol, 1.0 eq) of sodium tungstate and 0.5 mL (4.3 mmol, 10.0 eq) of hydrogen peroxide were added to the reaction system. The temperature was raised to 40°C and the reaction was allowed to react for 2 h. LC-MS 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. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to afford a light yellow oil (115 mg, yield = 54%).

[0303] LC-MS: (M+H) + ; m / z = 503.17;

[0304] Step B: (S)-(2'-Isopropyl-4-(3-(5-(trifluoromethyl)pyridin-2-yl)sulfonyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-yl)methanol

[0305] Dissolve 115 mg (0.23 mmol, 1.0 eq) (S)-2'-isopropyl-4-(3-(5-(trifluoromethyl)pyridin-2-yl)sulfonyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-carbaldehyde in 5 mL of methanol. Cool the system to 0°C. Add 43.3 mg (1.14 mmol, 5.0 eq) of solid sodium borohydride to the reaction system under nitrogen protection. After the addition, naturally raise the temperature to room temperature and react for 1.5 hours. LC-MS results confirmed the formation of the target product. The reaction solution was cooled to 0°C and quenched by adding saturated aqueous ammonium chloride. The product was extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The sample was sent for preparative purification (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B over 55 minutes; flow rate: 70 mL / min) and lyophilized to obtain the target product as a white solid (42.6 mg, yield = 37%).

[0306] LC-MS: (M+H) + ; m / z = 505.22;

[0307] 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,1 H),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).

[0308] 19 F NMR (376MHz,CDCl3)δ-62.65.

[0309] Example 9: (2'-Isopropyl-4-(S)-3-(S)-(5-(trifluoromethyl)pyridin-2-yl)sulfoxide)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-yl)methanol

[0310] Step A: 2'-Isopropyl-4-(S)-3-(S)-(5-(trifluoromethyl)pyridin-2-yl)sulfoxide)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-carbaldehyde

[0311] 390 mg (0.83 mmol, 1.0 eq) of ((S)-2'-isopropyl-4-(3-(5-(trifluoromethyl)pyridin-2-yl)thio)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-carbaldehyde was dissolved in 5 mL of dichloromethane. The reaction mixture was cooled to 0°C under nitrogen. 215 mg (1.24 mmol, 1.5 eq) of m-chloroperbenzoic acid was then added to the reaction mixture, and the mixture was allowed to react at 0°C for 2 h. LC-MS confirmed the formation of the desired product. The reaction mixture was quenched with water and extracted three times with dichloromethane. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated to dryness, and purified by column chromatography (petroleum ether:ethyl acetate = 50:1 to 1:1) to afford a light yellow oil (300 mg, yield = 74%).

[0312] LC-MS: (M+H) + ; m / z = 487.37;

[0313] Step B: (2'-Isopropyl-4-(S)-3-(S)-(5-(trifluoromethyl)pyridin-2-yl)sulfoxyl)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-yl)methanol

[0314] Dissolve 300 mg (0.62 mmol, 1.0 eq) of 2'-isopropyl-4-(S)-3-(S)-(5-(trifluoromethyl)pyridin-2-yl)sulfoxide)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-carbaldehyde in 5 mL of methanol. Cool the system to 0°C. Add 70.0 mg (1.85 mmol, 3.0 eq) of solid sodium borohydride to the reaction system under nitrogen protection. After the addition, naturally raise the temperature to room temperature and react for 1.5 hours. The formation of the target product was confirmed by LC-MS results. The reaction solution was cooled to 0°C and quenched by adding saturated aqueous ammonium chloride solution. The product was extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The sample was sent for preparative purification (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) and lyophilized to obtain the target product as a white solid (92.3 mg, yield = 31%).

[0315] LC-MS: (M+H) + ;m / z=489.20;

[0316] 1 H NMR (400MHz, CDCl3) δ8.93 (d, J = 8.0Hz, 1H), 8.23-8.21 (m, 2H), 7.41-7.32 (m, 2H), 7.2 4-7.13(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,2 H),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).

[0317] 19 F NMR(376MHz, CDCl3)δ-62.32--62.35.

[0318] Example 10: ((S)-(4-(3-(5-fluoropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-cyclopropyl-[1,1'-biphenyl]-3-yl)methanol

[0319] Step A: 5-Fluoropyridine-2-thiol

[0320] Dissolve 50 mL (125.00 mmol, 1.1 eq) of n-butyllithium in 300 mL of toluene and cool to -78°C. Dissolve 20 g (113.64 mmol, 1.0 eq) of 2-bromo-5-fluoropyridine in 50 mL of toluene and add dropwise to the reaction flask. Incubate for 1 hour. Weigh 3.64 g (114 mmol, 1.0 eq) of sulfur powder and add portionwise to the reaction mixture. Incubate at -78°C for 30 minutes, then allow the mixture to warm to room temperature and react for 1 hour. Completeness of the reaction was confirmed by a plate-blot (petroleum ether:ethyl acetate = 1:1). Quench the mixture with 20 mL of water, adjust the pH to 3-4 with 1N dilute hydrochloric acid, and extract the mixture five times with dichloromethane (200 mL). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to yield the crude product. The crude product was slurried with ethyl acetate and filtered to yield the pure yellow solid (6.5 g, yield = 44%).

[0321] 1 H NMR (400MHz, CDCl3) δ7.68 (d, J = 4.0Hz, 1H), 7.50 (d, J = 4.0Hz, 1H), 7.29-7.34 (m, 1H).

[0322] Step B: (S)-tert-Butyl 3-(5-fluoropyridin-2-yl)thio)pyrrolidine-1-carboxylate

[0323] 1.00 g (4.01 mmol, 1.0 eq) of tert-butyl (R)-3-(methylsulfonyl)oxy)pyrrolidine-1-carboxylate was dissolved in 10 mL of anhydrous N,N-dimethylformamide, followed by the addition of 0.52 g (4.01 mmol, 1.0 eq) of 5-fluoropyridine-2-thiol and 1.66 g (12.0 mmol, 3.0 eq) of potassium carbonate. The reaction mixture was stirred at 70°C under nitrogen for 18 h. The mixture was cooled to room temperature, and 50 mL of water and 150 mL of ethyl acetate were added. The organic phase was separated and extracted twice with ethyl acetate (2 x 100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated to yield a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford an oil (1.00 g, yield = 83%).

[0324] LC-MS: (M+H) + ; m / z = 299.22;

[0325] 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).

[0326] Step C: (S)-5-Fluoro-2-(pyrrolidin-3-ylthio)pyridine hydrochloride

[0327] 1.00 g (3.35 mmol, 1.0 eq) of tert-butyl (S)-3-(5-fluoropyridin-2-yl)thio)pyrrolidine-1-carboxylate was dissolved in 20 mL of dichloromethane. 8.4 mL (33.5 mmol, 10.0 eq) of a 4M hydrochloric acid solution in 1,4-dioxane was added to the reaction system. The reaction system was stirred at room temperature under nitrogen for 1 hour. Complete reaction was confirmed by a microplate reader (petroleum ether:ethyl acetate = 10:1). The reaction solution was then concentrated under reduced pressure to yield an off-white solid (0.66 g, yield = 99%).

[0328] Step D: (S)-5-Bromo-2-(3-(5-fluoropyridin-2-yl)thio)pyrrolidin-1-yl)benzaldehyde

[0329] 0.66 g (3.32 mmol, 1.0 eq) (S)-5-fluoro-2-(pyrrolidin-3-ylthio)pyridine hydrochloride was dissolved in 10 mL of anhydrous N,N-dimethylformamide. 0.67 g (3.32 mmol, 1.0 eq) of 5-bromo-2-fluorobenzaldehyde and 1.38 g (9.98 mmol, 3.0 eq) of anhydrous potassium carbonate were added to the reaction system. The reaction system was allowed to react overnight at 90°C under a nitrogen atmosphere. LC-MS confirmed complete conversion of the starting material and formation of the desired product. The reaction solution was cooled to room temperature, quenched with water, and extracted three times with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The mixture was then purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford a pale yellow oil (0.99 g, yield = 78%).

[0330] LC-MS: (M+H) + ; m / z = 381.08;

[0331] Step E: (S)-2'-cyclopropyl-4-(3-((5-fluoropyridin-2-yl)thio)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-carbaldehyde

[0332] 0.99 g (2.60 mmol, 1.0 eq) (S)-5-bromo-2-(3-(5-fluoropyridin-2-yl)thio)pyrrolidin-1-yl)benzaldehyde was dissolved in 20 mL of dioxane and 5 mL of water. 0.50 g (3.11 mmol, 1.2 eq) (2-cyclopropylphenyl)boric acid and 2.20 g (10.4 mmol, 4.0 eq) of anhydrous potassium phosphate were added to the above reaction system. Under nitrogen protection, 20 mg (0.026 mmol, 0.01 eq.) [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride was added and the mixture was reacted at 100°C for 4 h. LC-MS results confirmed the formation of the target product. The reaction solution was cooled to room temperature, quenched with water, and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated to dryness, and then purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give a light yellow oil (900 mg, yield = 82%).

[0333] LC-MS: (M+H) + ; m / z = 419.10;

[0334] 1 H 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).

[0335] Step F: ((S)-(4-(3-(5-fluoropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-cyclopropyl-[1,1'-biphenyl]-3-yl)methanol

[0336] 900 mg (2.15 mmol, 1.0 eq) ((S)-2'-cyclopropyl-4-(3-((5-fluoropyridin-2-yl)thio)pyrrolidin-1-yl)-[1,1'-biphenyl]-3-carbaldehyde was dissolved in 10 mL of methanol. The system was cooled to 0°C. Under nitrogen protection, 163 mg (4.30 mmol, 2.0 eq) of sodium borohydride solid was added to the above reaction system. After the addition, the temperature was naturally raised to room temperature for 1.5 minutes. h. LC-MS results confirmed the formation of the target product. The reaction solution was cooled to 0°C and quenched with saturated aqueous ammonium chloride. Ethyl acetate was then added for extraction three times. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The sample was then sent for preparative purification (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B over 55 minutes; flow rate: 70 mL / min) and lyophilized to afford the product as a yellow oil (667 mg, yield = 73%).

[0337] LC-MS: (M+H) + ; m / z = 421.16;

[0338] 1 H 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),2.0 5-2.13(m,1H),1.88-1.95(m,1H),0.84-0.89(m,2H),0.70-0.74(m,2H).

[0339] 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.

[0340] Table 1: Examples 11-14

[0341] The examples in Table 2 were prepared by the method described above for Example 1, substituting the different substituted thiol starting materials as desired.

[0342] Table 2: Examples 15-33

[0343] The examples in Table 3 were prepared by the method described above for Example 1. Intermediate I3 and the desired boronic acid or boronic ester were prepared by Suzuki reaction.

[0344] Table 3: Examples 34-40

[0345] Example 41: (S)-(3-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-4-yl)methanol

[0346] Step A: (S)-4-Bromo-2-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)benzaldehyde

[0347] 140 mg (652 umol, 1.0 eq) (S)-5-chloro-2-(pyrrolidin-3-ylthio)pyridine was dissolved in 5 mL of N,N-dimethylformamide, and 198 mg (978 umol, 1.5 eq) of 4-bromo-2-fluorobenzaldehyde and 180 mg (1.3 mmol, 2.0 eq) of potassium carbonate were added. The atmosphere was purged with nitrogen three times, and the mixture was stirred at 100°C overnight. LC-MS confirmed the formation of the product. 5 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with 5 mL of saturated saline solution, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 0-15:1) to obtain the product (190 mg, yield = 73%).

[0348] LC-MS: (M+H) + ; m / z = 398.84;

[0349] Step B: (S)-3-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-4-carbaldehyde

[0350] 50.0 mg (126 μmol, 1.0 eq) of (S)-4-bromo-2-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)benzaldehyde was dissolved in 4 mL of dioxane and 1 mL of water. Then, 24.7 mg (151 μmol, 1.2 eq) of 2-isopropylphenylboronic acid, 9.20 mg (13 μmol, 0.1 eq) of 1,1-bis(diphenylphosphino)diboraneferronichloridopalladium, and 52.1 mg (377 μmol, 3.0 eq) of potassium carbonate were added. The atmosphere was purged with nitrogen three times, and the mixture was stirred at 100°C for 2 hours. LC-MS confirmed the formation of the product. 5 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with 5 mL of saturated saline solution, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to yield 48.0 mg of a light yellow oily liquid, which was used directly in the next reaction without purification.

[0351] LC-MS: (M+H) + ; m / z = 437.05;

[0352] Step C: (S)-3-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-4-methanol

[0353] 48.0 mg (110 μmol, 1.0 eq) of (S)-3-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-4-carbaldehyde was dissolved in 5 mL of methanol. 8.32 mg (220 μmol, 2.0 eq) of sodium borohydride was slowly added in an ice bath, and the mixture was stirred at room temperature for 10 minutes. LC-MS confirmed the formation of the product, which was then evaporated to dryness under reduced pressure and preparatively purified (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30% to 70% B over 55 minutes; flow rate: 70 mL / min) to afford a white solid (20.9 mg, two-step yield = 38%).

[0354] LC-MS: (M+H) + ; m / z = 439.36;

[0355] 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,1 H),3.75-3.71(m,1H),3.45-3.43(m,1H),3.30-3.24(m,2H),3.05-3.0 2(m,1H),2.56-2.54(m,1H),2.05-2.03(m,1H),1.16(d,J=6.7Hz,6H).

[0356] The examples in Table 4 were prepared by either General Scheme 2 or Scheme 3 described above.

[0357] Table 4: Examples 42-76

[0358] Example 77: (S)-5-chloro-2-((1-(3-(difluoromethyl)-2'-isopropyl-[1,1'-biphenyl]-4-yl)pyrrolidin-3-yl)thiopyridine

[0359] 30.0 mg (68.7 μmol, 1.0 eq) of (S)-4-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-2'-isopropyl-[1,1'-biphenyl]-3-carbaldehyde was dissolved in 0.5 mL of anhydrous dichloromethane. After nitrogen was replaced, the system was cooled to 0°C and 16.6 mg (103 μmol, 1.5 eq) of diethylaminosulfur trifluoride was slowly added dropwise. After the addition, the mixture was allowed to return to room temperature and stirred for 18 hours. After LC-MS confirmation of the reaction completion, the reaction was quenched with 2 mL of cold saturated sodium bicarbonate solution and extracted three times with 5 mL of dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by preparative chromatography (mobile phase A: 0.1% trifluoroacetic acid; mobile phase B: acetonitrile; gradient: 30%-70% B over 55 minutes; flow rate: 70 mL / min) to give (S)-5-chloro-2-((1-(3-(difluoromethyl)-2'-isopropyl-[1,1'-biphenyl]-4-yl)pyrrolidin-3-yl)thio)pyridine (4.3 mg, yield = 14%) as a gray solid.

[0360] LC-MS: (M+H) + ; m / z = 459;

[0361] 1 H NMR (400MHz, CDCl3) δ8.39(d,J=2.5Hz,1H),7.53(d,J=2.1Hz,1H),7.47(dd,J=8.5,2.5 Hz,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),4.4 4-4.41(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).

[0362] Example 78: (S)-(2-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-5-((2-isopropylphenyl)amino)phenyl)methanol

[0363] Step A: (S)-2-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-5-((2-isopropylphenyl)amino)benzaldehyde

[0364] 30.0 mg (75.4 μmol, 1.0 eq) of (S)-5-bromo-2-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)benzaldehyde was dissolved in 2 mL of 1,4-dioxane, and then 11.2 mg (83.0 μmol, 1.1 eq) of 2-isopropylaniline, 3.50 mg (3.77 μmol, 0.05 eq) of tris(dibenzylideneacetone)dipalladium, 4.4 mg (7.54 μmol, 0.1 eq) of 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) and 24.6 mg (75.4 μmol, 1.0 eq) of cesium carbonate were added to the reaction system. After nitrogen was replaced, the temperature was raised to 100°C and the reaction was carried out for 5 hours. LC-MS results confirmed the completion of the reaction. The system was cooled to room temperature and diluted with 5 mL of saturated sodium chloride solution. The mixture was then extracted three times with 10 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 1:10) to afford (S)-2-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-5-((2-isopropylphenyl)amino)benzaldehyde (8.30 mg, yield = 24%) as a yellow oil.

[0365] LC-MS: (M+H) + ; m / z = 452;

[0366] Step B: (S)-(2-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-5-((2-isopropylphenyl)amino)phenyl)methanol

[0367] 8.30 mg (18.4 μmol, 1.0 eq) of (S)-2-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-5-((2-isopropylphenyl)amino)benzaldehyde was dissolved in 0.5 mL of methanol. After nitrogen was replaced, the system was cooled to 0°C and 0.80 mg (22.0 μmol, 1.2 eq) of sodium borohydride was slowly added. After the addition was complete, the mixture was allowed to return to room temperature and the reaction was continued for 30 minutes. After LC-MS results confirmed the reaction was complete, the mixture was quenched with 1 mL of saturated ammonium chloride solution and extracted three times with 5 mL of ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by preparative chromatography (mobile phase A: 0.1% trifluoroacetic acid; mobile phase B: acetonitrile; gradient: 30%-70% B over 55 min; flow rate: 70 mL / min) to give (S)-(2-(3-((5-chloropyridin-2-yl)thio)pyrrolidin-1-yl)-5-((2-isopropylphenyl)amino)phenyl)methanol (1.0 mg, yield = 12%) as a yellow solid.

[0368] LC-MS: (M+H) +; m / z = 454.30;

[0369] 1 H NMR (400MHz, CDCl3) δ8.37 (d, J=2.5Hz, 1H), 7.45 (dd, J=8.4, 2.4Hz, 1H), 7.2 9(d,J=8.5Hz,1H),7.23-6.98(m,5H),6.82-6.69(m,2H),5.34(brs,1H),4.7 8-4.65(m,2H),4.41-4.34(m,1H),3.64-3.58(m,1H),3.34-3.27(m,1H),3.2 1-3.02(m,3H),2.61-2.53(m,1H),2.10-1.87(m,2H),1.24(d,J=6.9Hz,6H).

[0370] Biological activity test of the compound of the present invention

[0371] In this study, HEK-293 cells transiently expressing TRPV3 were used for experimental detection.

[0372] The steps are as follows:

[0373] The cells were cultured in DMEM medium containing 10% fetal bovine serum at 37°C and a carbon dioxide concentration of 5%.

[0374] Day 1: Seed cells into 6-well plates, 5×10 cells per well 5 cell.

[0375] Day 2: Transfect cells using Lipofectamine 3000 transfection reagent at a ratio of 1 μg plasmid to 2 μL transfection reagent. Use 3 μg of plasmid per well. To do this, add 100 μL of Opti-MEM to each of two sterile centrifuge tubes. Add 6 μL of Lipofectamine 3000 to one tube and mix thoroughly. Add 3 μg of plasmid to the other tube and mix thoroughly. Then, add 6 μL of P3000 and mix thoroughly. Add the diluted plasmid DNA to the diluted Lipofectamine 3000 and incubate at room temperature for 10-15 minutes. Add the DNA-liposome complex dropwise to the cells, gently shake to mix, and place in an incubator. Change the medium after 4-6 hours.

[0376] Day 3: Digest the cells and seed them into a 24-well plate with a cover slip placed on it, with 8×10 cells per well. 3 cells.

[0377] Day 4: Patch clamp assay was performed.

[0378] The voltage stimulation protocol for whole-cell patch-clamp recording of TRPV3 currents was as follows: after whole-cell patch clamping, the cell membrane voltage was clamped at -80 mV. The membrane potential was first recorded at 0 mV. The voltage was then ramped from -100 mV to 100 mV over 100 ms, and finally returned to 0 mV. Data were collected repeatedly every 5 s to observe the inhibitory effect of the drug on the peak current. The experimental data were acquired using an EPC10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0379] A recording electrode is formed from a capillary glass tube using a microelectrode puller. The electrode, filled with intracellular fluid, is placed in a microelectrode holder. Under an inverted microscope, the microelectrode manipulator is used to immerse the electrode in extracellular fluid and record the electrode resistance (Rpip). The electrode is brought into contact with the cell surface and negative pressure is applied to create a high-resistance seal (GΩ). Fast capacitance compensation is then performed, and negative pressure is continued to rupture the cell membrane, establishing whole-cell recording mode. Slow capacitance compensation is then performed, and experimental parameters such as membrane capacitance (Cm) and series resistance (Rs) are recorded. No leakage compensation is performed.

[0380] Drug administration was started after the TRPV3 current recorded in the whole cell was stable. The next concentration was detected after each drug concentration was applied for 5 minutes (or the current was stable). Multiple concentrations were tested for each test compound. The coverslip with cells was placed in a recording bath under an inverted microscope. The blank control external solution and the working solution of the test compound were flowed through the recording bath from low concentration to high concentration by gravity perfusion to act on the cells. A peristaltic pump was used for liquid exchange during the recording. The current detected for each cell in the external solution without the compound served as its own control group. At least two cells were used for each concentration and the test was repeated twice independently. All electrophysiological experiments were performed at room temperature.

[0381] The prepared compounds were tested using the above analytical process, and the results are shown in Table 5. Details of the inhibition rate (%) at a concentration of 0.3 μM for selected examples are also shown in the table. The thioether compounds of this invention exhibit soft drug properties, while their sulfoxide and sulfone metabolites are pharmacologically inactive (Table 5). This allows them to achieve efficacy while avoiding the toxic effects of the parent drug, active metabolites, and reactive metabolites. Furthermore, the compounds of this invention exhibit good selectivity (Table 6).

[0382] Table 5: Inhibitory rate (%) of the compounds of the present invention on hTRPV3 at a single concentration (0.3 μM) a Note: Example compound KM-001 in patent WO2021154966A1.

[0383] Table 6: Inhibition rate of Example 4 on different hTRP (0.3 μM) Note: Selectivity ratio refers to the ratio of the compound’s inhibition rate on TRPV3 ion channel to the inhibition rate on other ion channels.

[0384] Liver microparticle metabolic stability test

[0385] Two separate experiments were performed. a) NADPH: 10 μL of 20 mg / mL liver microsomes and 40 μL of 10 mM NADPH were added to the culture medium. The final concentrations of microsomes and NADPH were 0.5 mg / mL and 1 mM, respectively. b) No NADPH: 10 μL of 20 mg / mL liver microsomes and 40 μL of ultrapure HO were added to the culture medium. The final concentration of microsomes was 0.5 mg / mL.

[0386] At the start of the reaction, 4 μL of a 100 μM test compound solution or a control compound solution having a final concentration of 1 μM was added, and the reaction was carried out at 37°C.

[0387] 50 μL aliquots were taken from the reaction solution at 0, 7, 15, 30, and 60 minutes. The reaction was stopped by adding 4 volumes of cold acetonitrile and IS (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 2 μM ketoprofen). The samples were centrifuged at 3220 g for 40 minutes. A 100 μL aliquot of the supernatant was mixed with 100 μL of ultrapure HO and then used for LC-MS / MS analysis.

[0388] Table 7: Liver microsome metabolic stability test results

[0389] Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope of the invention as defined in the accompanying claims.

Claims

1. Compounds of formula (I): or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances, or pharmaceutically acceptable salts, in, Ring A and Ring B are each independently selected from a monocyclic or polycyclic ring system containing 3-12 ring atoms; R 1 Each independently selected from H, halogen, hydroxyl, thiol, nitro, cyano, oxo, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C1-C6 alkoxy, substituted with 0-2 R f C1-C6 haloalkoxy, substituted with 0-2 R f C3-C6 cycloalkyl, substituted with 0-2 R f C3-C6 halocycloalkyl, substituted with 0-2 R f C3-C6 cycloalkoxy, substituted with 0-2 R f C3-C6 halocycloalkoxy, substituted with 0-2 R f Aryl, substituted with 0-2 R f Arylalkyl, substituted with 0-2 R f Alkaryl, substituted with 0-2 R f heteroaryl, -R 11 OR 12 、-R 11 SR 12 、-N(R a )(R b ),-C(O)R c 、-C(O)N(R a )(R b ) and -SO2N(R a )(R b ) or -SOR c , or two R 1 Together with the ring A atoms to which they are attached, they form a 3-10 membered ring structure; R 2 Each independently selected from H, halogen, hydroxyl, thiol, nitro, cyano, oxo, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C1-C6 alkoxy, substituted with 0-2 R f C1-C6 haloalkoxy, substituted with 0-2 R f C3-C6 cycloalkyl, substituted with 0-2 R f C3-C6 halocycloalkyl, substituted with 0-2 R f C3-C6 cycloalkoxy, substituted with 0-2 R f C3-C6 halocycloalkoxy, substituted with 0-2 R f Aryl, substituted with 0-2 R f Arylalkyl, substituted with 0-2 R f Alkaryl, substituted with 0-2 R f heteroaryl, -R 11 OR 12 、-R 11 SR 12 、-N(R a )(R b ),-C(O)R c 、-C(O)OR d 、-C(O)N(R a )(R b ) and -SO2N(R a )(R b ) or -SOR c , or two R 2 Together with the ring B atoms to which they are attached, they form a 3-10 membered ring structure; R 0 Each independently selected from H, halogen or the structural formula II in, L is independently selected from a bond, -O-, -S-, -N(R 20 )-、-C(O)-、-C(R 20 R 21 )-, -S(O)- and -S(O2)-; Ring C is independently selected from a monocyclic or polycyclic ring system containing 3-12 ring atoms; R 3 Each independently selected from H, halogen, hydroxyl, thiol, nitro, cyano, oxo, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C1-C6 alkoxy, substituted with 0-2 R f C1-C6 haloalkoxy, substituted with 0-2 R f C3-C6 cycloalkyl, substituted with 0-2 R f C3-C6 halocycloalkyl, substituted with 0-2 R f C3-C6 cycloalkoxy, substituted with 0-2 R f C3-C6 halocycloalkoxy, substituted with 0-2 R f Aryl, substituted with 0-2 R f Arylalkyl, substituted with 0-2 R f Alkaryl, substituted with 0-2 R f heteroaryl, -R 11 OR 12 、-R 11 SR 12 、-N(R a )(R b ),-C(O)R c 、-C(O)OR d 、-C(O)N(R a )(R b ) and -SO2N(R a )(R b ) or -SOR c , or two R 3 Together with the ring C atoms to which they are attached, they form a 3-10 membered ring structure; R 11 Each independently selected from substituted with 0-2 R f C1-C6 alkylene; R 12 Each independently selected from H, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C3-C6 cycloalkyl and substituted with 0-2 R f C3-C6 halocycloalkyl; R a and R b Each independently selected from H, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f Aryl, substituted with 0-2 R f Aralkyl, -C(O)R c and -C(O)OR d ; R c Each independently selected from H, halogen, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f The aryl group and the substituent have 0-2 R f Aralkyl; R d Each independently selected from H, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f The aryl group and the substituent have 0-2 R f Aralkyl; R 20 and R 21 Each is independently selected from H, hydroxy, C1-C6 alkyl, aryl and aralkyl; R f Each is independently selected from halogen, hydroxy, 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(O2)-; n is 0, 1, 2, or 3; m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3.

2. The compound according to claim 1, wherein The compound has the structural formula I-1 Among them, ring A, ring B, ring C, X, R 1 、R 2 、R 3 , L, n, p, m and q are defined as in Formula I.

3. The compound according to claim 1 or 2, wherein 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.

4. The compound according to claim 3, wherein Ring A is selected from the following structural formulas:

5. The compound according to claim 1 or 2, wherein 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.

6. The compound according to claim 5, wherein Ring B is selected from the following structural formulas:

7. The compound according to claim 1 or 2, wherein R 1 Each is independently selected from H, halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -N(R a )(R b ) and -R 11 OR 12 , where R a and R b are each independently selected from H and C1-C6 alkyl; R 11 Each independently selected from C1-C6 alkylene; R 12 Each is independently selected from H and C1-C6 alkyl.

8. The compound according to claim 7, wherein R 1 Each is independently selected from H, Cl, F, -CF3, -CN, -CH3, -OH, -OCH3, -CH2OCH3.

9. The compound according to claim 1 or 2, wherein R 2 Each independently selected from H, cyano, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, substituted with 0-2 R f C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -R 11 OR 12 、-R 11 SR 12 、-C(O)OR d and -C(O)N(R a )(R b ); where R 11 Each independently selected from C1-C6 alkylene; R 12 R is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl and C3-C6 halocycloalkyl; a and R b are each independently selected from H and C1-C6 alkyl; R d are each independently selected from H and C1-C6 alkyl; R f Each is independently selected from halogen, hydroxy, amino and C1-C6 alkyl.

10. The compound according to claim 9, wherein R 2 Each independently selected from 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. The compound according to claim 2, wherein L is each independently selected from a bond, -O-, -S-, -N-, -C(O)-, -CH2-, -C(OH)-, -S(O)-, and -S(O2)-.

12. The compound according to claim 2, wherein Ring C is selected from C3-C6 cycloalkane ring, benzene ring, benzo C3-C6 cycloalkane ring, C5-C 12 bridged carbocyclic ring, pyridine ring, quinoline ring, isoquinoline ring, pyrazine ring, pyrimidine ring, pyridazine ring, thiazole ring, thiophene ring, pyrrole ring, pyrazole ring, imidazole ring, isothiazole ring, indole ring, benzimidazole ring, furan ring, oxazole ring, quinoxaline ring and purine ring.

13. The compound according to claim 12, wherein Ring C is selected from the following structural formulas:

14. The compound according to claim 2, wherein R 3 Each is independently selected from H, cyano, hydroxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -R 11 OR 12 、-R 11 SR 12 、-C(O)R c 、-C(O)OR d and -C(O)N(R a )(R b ), or two R 3 Together with the ring C atoms to which they are attached, they form a 3-10 membered ring structure; Among them, R 11 Each independently selected from C1-C6 alkylene; R 12 R is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl and C3-C6 halocycloalkyl; a and R b are each independently selected from H and C1-C6 alkyl; R c are each independently selected from H, halogen and C1-C6 alkyl; R d Each is independently selected from H and C1-C6 alkyl.

15. The compound according to claim 14, wherein R 3 Each is independently selected from H, cyclopropyl, isopropyl, tert-butyl, F, Cl, ethyl, methyl, methylcarbonyl, and methoxymethyl.

16. The compound according to claim 1 or 2, wherein m is 0.

17. The compound according to claim 1 or 2, wherein n is 0, 1 or 2.

18. The compound according to claim 1 or 2, wherein n is 1 and m is 0, and R 1 Located at the ortho or para position of X.

19. The compound according to claim 1 or 2, wherein n is 2 and m is 0, an R 1 Located opposite to X.

20. The compound according to claim 1 or 2, wherein p is 1, preferably, the R 2 Located in the ortho position of the pyrrolidinyl group.

21. The compound according to claim 1 or 2, wherein R 2 It is -CH2OH.

22. The compound according to claim 1 or 2, wherein L is -S-; Alternatively, L is -S(O)-; Alternatively, L is -S(O2)-; Preferably, L is -S-.

23. Compounds of formula (I-2): or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances, or pharmaceutically acceptable salts, in, Ring A is independently selected from a monocyclic or polycyclic ring system containing 3-12 ring atoms; R 1 Each independently selected from H, halogen, hydroxyl, thiol, nitro, cyano, oxo, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C1-C6 alkoxy, substituted with 0-2 R f C1-C6 haloalkoxy, substituted with 0-2 R f C3-C6 cycloalkyl, substituted with 0-2 R f C3-C6 halocycloalkyl, substituted with 0-2 R f C3-C6 cycloalkoxy, substituted with 0-2 R f C3-C6 halocycloalkoxy, substituted with 0-2 R f Aryl, substituted with 0-2 R f Arylalkyl, substituted with 0-2 R f Alkaryl, substituted with 0-2 R f heteroaryl, -R 11 OR 12 、-R 11 SR 12 、-N(R a )(R b ),-C(O)R c 、-C(O)N(R a )(R b ) and -SO2N(R a )(R b ) or -SOR c , or two R 1 Together with the ring A atoms to which they are attached, they form a 3-10 membered ring structure; R 2 Each independently selected from H, halogen, hydroxyl, thiol, nitro, cyano, oxo, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C1-C6 alkoxy, substituted with 0-2 R f C1-C6 haloalkoxy, substituted with 0-2 R f C3-C6 cycloalkyl, substituted with 0-2 R f C3-C6 halocycloalkyl, substituted with 0-2 R f C3-C6 cycloalkoxy, substituted with 0-2 R f C3-C6 halocycloalkoxy, substituted with 0-2 R f Aryl, substituted with 0-2 R f Arylalkyl, substituted with 0-2 R f Alkaryl, substituted with 0-2 R f heteroaryl, -R 11 OR 12 、-R 11 SR 12 、-N(R a )(R b ),-C(O)R c 、-C(O)OR d 、-C(O)N(R a )(R b ) and -SO2N(R a )(R b ) or -SOR c , or two R 2 Together with the ring atoms to which they are attached, they form a 3-10 membered ring structure; R 0 Each independently selected from H, halogen or the structural formula II in, L is independently selected from a bond, -O-, -S-, -N(R 20 )-、-C(O)-、-C(R 20 R 21 )-, -S(O)- and -S(O2)-; Ring C is independently selected from a monocyclic or polycyclic ring system containing 3-12 ring atoms; R 3 Each independently selected from H, halogen, hydroxyl, thiol, nitro, cyano, oxo, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C1-C6 alkoxy, substituted with 0-2 R f C1-C6 haloalkoxy, substituted with 0-2 R f C3-C6 cycloalkyl, substituted with 0-2 R f C3-C6 halocycloalkyl, substituted with 0-2 R f C3-C6 cycloalkoxy, substituted with 0-2 R f C3-C6 halocycloalkoxy, substituted with 0-2 R f Aryl, substituted with 0-2 R f Arylalkyl, substituted with 0-2 R f Alkaryl, substituted with 0-2 R f heteroaryl, -R 11 OR 12 、-R 11 SR 12 、-N(R a )(R b ),-C(O)R c 、-C(O)OR d 、-C(O)N(R a )(R b ) and -SO2N(R a )(R b ) or -SOR c , or two R 3 Together with the ring C atoms to which they are attached, they form a 3-10 membered ring structure; R 11 Each independently selected from substituted with 0-2 R f C1-C6 alkylene; R 12 Each independently selected from H, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f C1-C6 haloalkyl, substituted with 0-2 R f C3-C6 cycloalkyl and substituted with 0-2 R f C3-C6 halocycloalkyl; R a and R b Each independently selected from H, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f Aryl, substituted with 0-2 R f Aralkyl, -C(O)R c and -C(O)OR d ; R c Each independently selected from H, halogen, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f The aryl group and the substituent have 0-2 R f Aralkyl; R d Each independently selected from H, substituted with 0-2 R f C1-C6 alkyl, substituted with 0-2 R f The aryl group and the substituent have 0-2 R f Aralkyl; R 20 and R 21 Each is independently selected from H, hydroxy, C1-C6 alkyl, aryl and aralkyl; R f Each is independently selected from halogen, hydroxy, 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(O2)-; X A 、X B 、X C 、X D 、X E are each independently CH or N; X F for CH; n is 0, 1, 2, or 3; m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3.

24. The compound according to claim 23, wherein X A 、X B 、X C 、X D 、X E Each independently is CH; Or, X A 、X B 、X C 、X E are independently CH, X D is N; Or, X A 、X B 、X C 、X D are independently CH, X E is N; Or, X A 、X C 、X D are independently CH, X B 、X E is N.

25. The compound according to claim 1, wherein The compound is selected from the following compounds:

26. A pharmaceutical composition comprising the compound according to any one of claims 1 to 25 or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotope-labeled substance or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

27. Use of the compound of any one of claims 1 to 25 or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances or pharmaceutically acceptable salts, and the pharmaceutical composition of claim 26 in the preparation of a medicament for inhibiting TRPV3 activity.

28. Use of the compound of any one of claims 1 to 25, or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically labeled product or pharmaceutically acceptable salt thereof, and the pharmaceutical composition of claim 26, in the preparation of a medicament for treating a TRPV3-mediated disorder in a subject.

29. The use according to claim 27, wherein The condition is selected from the group consisting of pain, itching, skin disorders, inflammation, abnormal hair growth, incontinence, fever, hot flashes, cystitis, irritable bowel syndrome and / or cough symptoms.

30. The use according to claim 29, wherein The pain is cancer pain and skin pain.

31. The use according to claim 30, wherein Used for preparing drugs for inhibiting proliferation, thereby preventing, treating or alleviating cancer symptoms.

32. The method according to claim 31, wherein The cancer is liposarcoma.

33. The use according to claim 29, wherein The abnormal hair growth is alopecia.

34. The use according to claim 29, wherein The skin disorder is selected from the group consisting of keratosis pilaris, ichthyosis, and pruritus.

35. The use according to claim 34, wherein Keratosis pilaris is Olmsted syndrome.

36. The use according to claim 35, wherein The ichthyosis is harlequin ichtyosis.

37. A method for treating a TRPV3-mediated disorder, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 25, or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically labeled substance, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 26, to a patient in need thereof.

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