Nitrogen-containing spiro compound, pharmaceutical composition and application thereof

Abstract

The invention relates to a nitrogen-containing spiro compound, a pharmaceutical composition and application of the nitrogen-containing spiro compound, the nitrogen-containing spiro compound has the structural formula shown in the formula (I), and the nitrogen-containing spiro compound has the TRPV3 inhibiting activity and can serve as a TRPV3 antagonist or inhibitor. # imgabs0 #

Description

A nitrogen-containing spirocyclic compound, a pharmaceutical composition and uses thereof Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a nitrogen-containing spirocyclic compound, stereoisomers and deuterated products of 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 provides a nitrogen-containing spiro compound of formula (I)

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

[0007] wherein Ring A is selected from a monocyclic or polycyclic ring system containing 3 to 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 atoms to which they are attached, they form a 3-10 membered ring structure;

[0010] L1 is selected from a bond, or the following structural formula:

[0011] X 1 are independently selected at each occurrence from C, O or N;

[0012] X 2 is independently selected at each occurrence from C, O, B or N;

[0013] X A 、X B 、XC Each independently CR x or N;

[0014] R x Each independently selected from H, halogen, hydroxyl, thiol, nitro, cyano, 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 x Together with the ring atoms to which they are attached, they form a 3-10 membered ring structure;

[0015] R 0 Each independently selected from H, halogen or the structural formula II

[0016] Wherein, L2 is independently selected from a bond, -O-, -S-, -N(R 20 )-、-C(O)-、-C(R 20 R 21 )-, -S(O)- and -S(O2)-;

[0017] Ring C is independently selected from a monocyclic or polycyclic ring system containing 3-12 ring atoms;

[0018] 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;

[0019] R 11 Each independently selected from substituted with 0-2 R f C1-C6 alkylene;

[0020] 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;

[0021] R a and R bEach 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 ;

[0022] 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;

[0023] 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;

[0024] R 20 and R 21 Each is independently selected from H, hydroxy, C1-C6 alkyl, aryl and aralkyl;

[0025] 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;

[0026] n is 0, 1, 2, or 3;

[0027] p is 0, 1, 2, or 3;

[0028] q is 0, 1, 2, or 3;

[0029] m is 1 or 2;

[0030] r is 1 or 2.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] The present invention further provides the use of the TRPV3 inhibitor in the preparation of a reagent for inhibiting TRPV3 ion channels. Preferably, the TRPV3 inhibitor is used in the preparation of a medicament for inhibiting skin itching, pain, hair loss or inflammation caused by overexpression of TRPV3.

[0035] The present application relates to a method for treating TRPV3-mediated diseases, comprising administering a therapeutically effective amount of a compound of the present application or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances or pharmaceutically acceptable salts, or a pharmaceutical composition of the present application to a patient in need of administration.

[0036] The compounds of the present invention inhibit TRPV3 activity and can be used as TRPV3 antagonists or inhibitors, significantly advancing research into the properties and characteristics of TRPV3 ion channels. Furthermore, they can be used to prepare drugs for treating diseases associated with increased TRPV3 ion channel activity. Therefore, the TRPV3 antagonists or inhibitors provided by the present invention are of great value to both scientific research and clinical studies. DETAILED DESCRIPTION

[0037] 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.

[0038] 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.

[0039] 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.

[0040] definition

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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).

[0046] As used herein, the term "hydrate" refers to a compound formed by the combination of water and a parent compound.

[0047] 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).

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] The term "aralkyl," as used herein, refers to an alkyl group substituted with an aryl group (eg, an aromatic or heteroaromatic group).

[0061] 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.

[0062] As used herein, the term "carbocycle" refers to an aromatic or non-aromatic ring in which every atom in the ring is carbon.

[0063] 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.

[0064] 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.

[0065] The term "heterocyclyl" or "heterocyclic group" refers to a 3 to 10-membered ring structure, more preferably a 3 to 7-membered ring, wherein the ring structure includes 1 to 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.

[0066] 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-.

[0067] 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, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3, -CN, and the like.

[0068] 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).

[0069] 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 of an organic compound (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroaralkyl, any of which can be further substituted), as well as halogen, carbonyl (e.g., ester, carboxyl, or formyl), thiocarbonyl (e.g., thioester, thiocarboxylate, or thioformate), ketone, aldehyde, amino, amido, amide, amidino, cyano, nitro, 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 the appropriate 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.

[0070] 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 Rf .

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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 a chiral center unchanged or result in its complete inversion. Techniques for inverting or preserving a specific stereocenter, as well as those for resolving stereoisomeric mixtures, 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).

[0075] 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.

[0076] 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.

[0077] 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) isotopically labeled. All isotopic variants of the compounds of the present invention, whether radioactive or non-radioactive, are intended to be included within the scope of the present invention. In this application, when not labeled with protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H) appear together, "hydrogen" or "H" may include all isotopes of hydrogen, protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H).

[0078] 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.

[0079] 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 applications contemplated herein and are intended to be within the scope of the present invention.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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).

[0084] Diseases, conditions or disorders related to TRPV3 function

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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).

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] In certain preferred embodiments, the TRPV3 antagonist is administered to prevent, treat, or ameliorate the signs and symptoms of migraine.

[0099] 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.

[0100] In certain preferred embodiments, the TRPV3 antagonist is administered to prevent, treat, or ameliorate the signs and symptoms of osteoarthritis.

[0101] In certain preferred embodiments, the TRPV3 antagonist is administered to prevent, treat, or ameliorate the signs and symptoms of rheumatoid arthritis.

[0102] In certain preferred embodiments, the TRPV3 antagonist is administered to prevent, treat, or ameliorate the signs and symptoms of oral mucositis.

[0103] In certain preferred embodiments, the TRPV3 antagonist is administered to promote hair loss or inhibit hair growth in a patient.

[0104] 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.

[0105] The present application relates to a method for treating TRPV3-mediated diseases, comprising administering a therapeutically effective amount of a compound of the present application or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances or pharmaceutically acceptable salts, or a pharmaceutical composition of the present application to a patient in need of administration.

[0106] Pharmaceutical composition

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] In certain preferred embodiments, the TRPV3 antagonist is administered topically.

[0113] In certain preferred embodiments, the TRPV3 antagonist is administered orally.

[0114] In certain preferred embodiments, the TRPV3 antagonist is administered parenterally.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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).

[0120] 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.

[0121] 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 salt" in these cases refers to the addition salts of relatively non-toxic inorganic and organic bases of the compounds of the present invention. 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, the base can also be prepared in situ, 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. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (See, for example, Berge et al., supra).

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] The present application provides a nitrogen-containing spiro compound of formula (I)

[0127] or its stereoisomers, tautomers, solvates, hydrates, oxides, active metabolites, isotope-labeled substances, or pharmaceutically acceptable salts,

[0128] wherein Ring A is selected from a monocyclic or polycyclic ring system containing 3 to 12 ring atoms;

[0129] 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;

[0130] 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 atoms to which they are attached, they form a 3-10 membered ring structure;

[0131] L1 is selected from a bond, or the following structural formula:

[0132] X 1 are independently selected at each occurrence from C, O or N;

[0133] X 2 is independently selected at each occurrence from C, O, B or N;

[0134] X A 、X B 、X C Each independently CR x or N;

[0135] R x Each independently selected from H, halogen, hydroxyl, thiol, nitro, cyano, 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 fC3-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 x Together with the ring atoms to which they are attached, they form a 3-10 membered ring structure;

[0136] R 0 Each independently selected from H, halogen or the structural formula II

[0137] Wherein, L2 is independently selected from a bond, -O-, -S-, -N(R 20 )-、-C(O)-、-C(R 20 R 21 )-, -S(O)- and -S(O2)-;

[0138] Ring C is independently selected from a monocyclic or polycyclic ring system containing 3-12 ring atoms;

[0139] 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 Rf 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;

[0140] R 11 Each independently selected from substituted with 0-2 R f C1-C6 alkylene;

[0141] 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;

[0142] 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 ;

[0143] 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;

[0144] R d Each independently selected from H, substituted with 0-2 R fC1-C6 alkyl, substituted with 0-2 R f The aryl group and the substituent have 0-2 R f Aralkyl;

[0145] R 20 and R 21 Each is independently selected from H, hydroxy, C1-C6 alkyl, aryl and aralkyl;

[0146] 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;

[0147] n is 0, 1, 2, or 3;

[0148] p is 0, 1, 2, or 3;

[0149] q is 0, 1, 2, or 3;

[0150] m is 1 or 2;

[0151] r is 1 or 2.

[0152] In one embodiment, ring A is selected from a benzene ring, a pyridine ring, a quinoline ring, a piperidine ring, a C3-C6 cycloalkyl ring, an isoquinoline ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, a thiazole ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, an isothiazole ring, an indole ring, a benzimidazole ring, a furan ring, an oxazole ring, an oxadiazole ring, a quinoxaline ring and a purine ring.

[0153] In one embodiment, Ring A is selected from the following structural formulas:

[0154] 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.

[0155] In one embodiment, R 1 Each is independently selected from H, Cl, F, -CF3, -CN, -CH3, -OH, -OCH3, -CH2OCH3.

[0156] In one embodiment, R 2 Each independently selected from H, cyano, hydroxyl, mercapto, oxo, 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 、-CH(O)、-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.

[0157] In one embodiment, R 2 Each independently selected from protium, deuterium, tritium, -SH, -OH, -OCF3, -CH3, -NH2, -CN, -CONH2, -CH2OH, -CH(O), -CHF2, -COOH, -COOCH3, oxo and

[0158] In one embodiment, each L2 is independently selected from a bond, -O-, -S-, -N-, -C(O)-, -CH2-, -CF2-, -C(OH)-, -S(O)-, and -S(O2)-.

[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 3Each 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, CN, ethyl, methyl, trifluoromethoxy, methylcarbonyl, methoxymethyl, -C(CH3)2OH.

[0164] In one embodiment, in Formula I

[0165] Selected from the following structural formula:

[0166] Among them, R 2 、X A 、X B 、X C And p is defined as in Formula I.

[0167] In one embodiment, in Formula I

[0168] Selected from the following structural formula:

[0169] Among them, R 2Each is independently selected from protium, deuterium, tritium, halogen, oxo, -SH, -OH, -CH3, -CN, -CONH2, -COOH, -COH, -COOCH3, -CF3, -OCH3, -CH2OH, -OCF3, -CHF2, and -NH2.

[0170] In these structural formulas, p R can be optionally substituted in one or two ring parts of the spirocyclic structure. 2 Group. R 2 The definition of the group may be as described above. In one embodiment, at least one R 2 It is -OH.

[0171] In one embodiment, in Formula I

[0172] Select one of the following structural formulas:

[0173] Among them, R 2 Each is independently selected from protium, deuterium, tritium, halogen, -CH3 and -CF3.

[0174] In one embodiment, in Formula I

[0175] Selected from the following structural formula:

[0176] Among them, R 2 independently selected from oxo, -SH, -CN, -CONH2, -COOH, -COH, -COOCH3, -OCH3, -CH2OH, -CHF2, -OCF3 and -NH2.

[0177] In one embodiment, in Formula I

[0178] Selected from the following structural formula:

[0179] In one embodiment, L1 is

[0180] In one embodiment, Ring A is

[0181] Alternatively, Ring A is

[0182] Alternatively, Ring A is

[0183] In one embodiment, the compound is selected from the group consisting of:

[0184] 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.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] In one embodiment, the pain is cancer pain and skin pain.

[0189] In one embodiment, it is used to prepare a medicament for inhibiting proliferation, thereby preventing, treating or ameliorating symptoms of cancer.

[0190] In one embodiment, the cancer is liposarcoma.

[0191] In one embodiment, the hair growth disorder is alopecia.

[0192] In one embodiment, the skin disorder is selected from keratosis pilaris, ichthyosis, pruritus.

[0193] In one embodiment, the skin keratosis is Olmsted syndrome.

[0194] In one embodiment, the ichthyosis is harlequin ichtyosis.

[0195] General synthetic scheme

[0196] 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.

[0197] Representative procedures for preparing compounds of the present invention are outlined in Schemes 1, 2, 3, 4, and 5. The p-halogenated benzyl acetonitrile and ethyl bromoacetate starting materials can be purchased or prepared using methods known in the art, with representative procedures providing intermediates. Scheme 1 highlights a fully detailed synthesis of 1-(3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1-one. The synthesis of diethyl 3-(4-halophenyl)-3-cyanoglutarate 2 can be achieved by reacting p-halophenylacetonitrile with ethyl bromoacetate in a solvent such as tetrahydrofuran. The cyano and ester groups of 2 react in the presence of a reducing agent to produce cyclized 3. The ester 3 is hydrolyzed to the carboxylic acid 4 under alkaline conditions. 4 itself undergoes cyclization under acidic conditions to produce 5. 5 is reacted with the desired boronic acid under Suzuki conditions to produce the coupling intermediate 6. 6 is reduced under reducing conditions to produce intermediate 7. This is then reacted with a carboxylic acid under condensing conditions to produce 8. 8 is resolved by supercritical fluid to give 8a, 8b, 8c, and 8d.

[0198] Option 1:

[0199] Scheme 2 shows the synthesis of the desired compound, wherein a Suzuki reaction is performed in the final step to produce 8. The synthesis of intermediate 5 is described in Scheme 1. Intermediate 5a is generated by treating intermediate 5 with a reducing agent, reacting 5a with a carboxylic acid to produce 5b, and reacting 5b with the desired boronic acid under Suzuki conditions to produce 8, which is then further resolved by supercritical carbonylation to give 8a, 8b, 8c, and 8d.

[0200] Option 2

[0201] Scheme 3 shows the synthesis of the desired compound, which is a semichiral synthesis. The synthesis of intermediate 6 is described in Scheme 1. The intermediate is catalytically reduced in the presence of a chiral ligand to give the chiral alcohol 6a. The amide 6b is further reduced to 6b. 6b is condensed with the desired carboxylic acid to give 8, which is further resolved by supercritical fluid to afford 8a and 8b.

[0202] Option 3

[0203] Scheme 4 shows the synthesis of the desired compound, also a semichiral synthesis. The synthesis of intermediate 5 is described in Scheme 1. Intermediate 5 is catalytically reduced using a chiral ligand to yield 5a, which then reacts with the desired boronic acid under Suzuki conditions to produce 5b. 5b is reduced with a reducing agent to yield 5c, which is then condensed with the desired carboxylic acid to yield 8. Further supercritical separation affords 8a and 8b.

[0204] Option 4

[0205] Scheme 5 shows the synthesis of the desired compound, which is also a semichiral synthesis. The synthesis of intermediate 5 is described in Scheme 1. Intermediate 5 is catalyzed by chiral ligand reduction to give 5a. Further reduction of the lactam produces intermediate 5b. The carboxylic acid required for 5b is condensed to give 5c. 5c is then reacted with the desired boronic acid under Suzuki conditions to produce 8. Further supercritical separation yields 8a and 8b.

[0206] Option 5

[0207] Specific implementation plan

[0208] Preparation of intermediates

[0209] Preparation Example 1: 5-bromospiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione (Compound I1)

[0210] Step A: Diethyl 3-(4-bromophenyl)-3-cyanoglutarate

[0211] Dissolve 20.0 g (102 mmol, 1.0 eq) of 2-(4-bromophenyl)acetonitrile in 100 mL of tetrahydrofuran and replace the atmosphere with nitrogen three times. Cool to -60°C with dry ice. Add 224 mL (224 mmol, 2.2 eq) of lithium bistrimethylsilylamide dropwise at -60°C and stir at room temperature for 3 hours. Then, add 34.1 g (204 mmol, 2.0 eq) of ethyl bromoacetate dropwise below -60°C and stir at room temperature overnight. LCMS confirms complete reaction of the starting material. Quench with 200 mL of water, extract three times with ethyl acetate, wash the organic layer with 100 mL of saturated brine, dry over anhydrous sodium sulfate, and evaporate to dryness under reduced pressure. The residue is purified by column chromatography (PE / EA = 0-10:1) to obtain the product (37.4 g, yield = 99%).

[0212] 1H NMR (400MHz, CDCl3) δ7.54 (dd, J=8.7, 2.7Hz, 2H), 7.39 (dd, J=8.7, 2.7Hz, 2H), 4.12 -4.10(m,4H),3.25(d,J=16.3Hz,2H),3.08(d,J=16.3Hz,2H),1.19(t,J=7.1Hz,6H).

[0213] Step B: Ethyl 2-(3-(4-bromophenyl)-5-oxopyrrolidin-3-yl)acetate

[0214] 5.00 g (13.8 mmol, 1.0 eq) of diethyl 3-(4-bromophenyl)-3-cyanoglutarate was dissolved in 50 mL of methanol, and 3.70 g (28.5 mmol, 2.1 eq) of anhydrous cobalt chloride was added. 5.39 g (142 mmol, 10.5 eq) of sodium borohydride was slowly added at 0°C and stirred at room temperature for 1 hour. LCMS confirmed the formation of the product, and the mixture was diluted with 50 mL of 2 mol / L hydrochloric acid solution. The mixture was then extracted three times with dichloromethane, and the organic layer was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 0-15:1) to obtain the product (3.29 g, yield = 59%).

[0215] LC-MS: (M+H) + ;m / z=326.05,327.17;

[0216] Step C: 2-(3-(4-bromophenyl)-5-oxopyrrolidin-3-yl)acetic acid

[0217] 1.0 g (3.07 mmol, 1.0 eq) of ethyl 2-(3-(4-bromophenyl)-5-oxopyrrolidin-3-yl)acetate was dissolved in 20 mL of methanol. 12.5 mL of 1.0 mol / L sodium hydroxide solution was slowly added at 0°C, and the mixture was stirred at 40°C for 1 h. LCMS confirmed the formation of the product. The reaction solution was diluted with 1.0 mol / L hydrochloric acid solution until acidic, then extracted three times with dichloromethane. The organic layer was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain a crude product (0.75 g, yield = 82%).

[0218] LC-MS:(MH) - ; m / z = 297.66, 298.25;

[0219] Step D: 5-bromospiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione

[0220] Heat 7.5 g of polyphosphoric acid to 150°C, then add 0.75 g (2.52 mmol, 1.0 eq) of 2-(3-(4-bromophenyl)-5-oxopyrrolidin-3-yl)acetic acid. Stir at 150°C for 1 hour. LCMS confirms the formation of the product. While still hot, slowly pour the mixture into ice water with stirring. Extract three times with dichloromethane, wash the organic layer with 30 mL of saturated brine, dry over anhydrous sodium sulfate, and evaporate to dryness under reduced pressure. The residue is purified by column chromatography (DCM / MeOH = 0-20:1) to obtain the product (0.65 g, yield = 92%).

[0221] LC-MS: (M+H) + ; m / z=280.03,282.04.

[0222] Preparation Example 2: 5-(2-cyclopropylphenyl)spiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione (Compound I2)

[0223] 550 mg (1.96 mmol, 1.0 eq) of 5-bromospiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione and 381 mg (2.35 mmol, 1.2 eq) of (2-cyclopropylphenyl)boronic acid were dissolved in 50 mL of a dioxane / water mixture (V:V = 4:1). 116 mg (0.20 mmol, 0.1 eq) of 1,1-bis(diphenylphosphino)diphenylferric palladium chloride and 1.25 g (5.89 mmol, 3.0 eq) of tripotassium phosphate were added. The atmosphere was purged with nitrogen three times and stirred at 100°C for 1 hour. LCMS confirmed the formation of the product. 50 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 0-10:1) to give the product (620 mg, yield = 99%).

[0224] LC-MS: (M+H) + ; m / z = 318.20.

[0225] Preparation Example 3 5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3-ol (Compound I3)

[0226] 650 mg (2.05 mmol, 1.0 eq) of 5-bromospiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione was dissolved in 50 mL of anhydrous tetrahydrofuran. 1.16 g (30.7 mmol, 15.0 eq) of lithium aluminum hydride was slowly added at 0°C, and the mixture was stirred at 70°C for 2 h. LCMS confirmed complete conversion of the starting material and the formation of product. The reaction mixture was filtered through celite and washed with tetrahydrofuran. The mixture was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to obtain the crude product (420 mg, yield = 67%).

[0227] LC-MS: (M+H) + ; m / z = 306.26;

[0228] Preparation Example 4: 5-(2-Isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol (Compound I4)

[0229] Step A: 5-(2-Isopropylphenyl)spiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione

[0230] A 100 mL reaction flask was charged with 2.60 g (9.28 mmol, 1.0 eq) of 5-bromospiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione, 1.83 g (11.1 mmol, 1.2 eq) of (2-isopropylphenyl)boronic acid, 7.88 g (37.1 mmol, 4.0 eq) of potassium phosphate, 0.07 g (0.093 mmol, 0.01 eq) of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, and 40 mL of a mixed solvent (1,4-dioxane:water = 4:1). The atmosphere was purged with nitrogen three times and the reaction was carried out at 100°C for 4 hours. TLC (DCM:MeOH = 20:1) confirmed complete reaction of the starting materials. The reaction solution was added to 50 mL of water and extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried, concentrated, and loaded onto the sample. Purification by silica gel column chromatography (DCM:MeOH=20:1) afforded 2.56 g of a yellow oily product (yield=83%).

[0231] LC-MS: (M+H) + ; m / z = 320.16;

[0232] 1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.91-7.93(m,1H),7.63-7.68(m,1H),7.37-7.52(m,2H),7.23-7.31(m,2H),7 .09-7.16(m,1H),3.40-3.63(m,2H),3.17-3.25(m,2H),2.69-2.75(m,3H),1.19(d,J=4Hz,3H),1.14(d,J=8Hz,3H).

[0233] Step B: 5-(2-Isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol

[0234] 1.50 g (4.69 mmol, 1.0 eq) of 5-(2-isopropylphenyl)spiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione and 20 mL of tetrahydrofuran were added to a 100 mL reaction flask. Under nitrogen, the reaction mixture was cooled to 0°C. 2.67 g (70.4 mmol, 15.0 eq) of lithium aluminum tetrahydride was slowly added, and after stirring at 0°C for 10 minutes, the reaction mixture was refluxed for 2 hours. TLC (DCM:MeOH = 20:1) confirmed complete reaction of the starting materials. The reaction mixture was quenched by adding 2 mL of water, filtered through celite, and the filter cake was washed with tetrahydrofuran (200 mL) until the product was completely dissolved. The filtrate was concentrated to dryness to yield 1.20 g of the crude product as a yellow oil.

[0235] LC-MS: (M+H) + ; m / z = 308.14.

[0236] Preparation Example 5: (5-Bromo-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone (Compound I5)

[0237] Step A: 5-Bromo-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol

[0238] In a 50 mL Shrek tube, 300 mg (1.07 mmol, 1.0 eq) of 5-bromospiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione was dissolved in 6 mL of tetrahydrofuran. Under nitrogen, 1.1 mL (10.7 mmol, 10.0 eq) of borane in dimethyl sulfide was slowly added via syringe. After addition, the system was heated to 70°C and allowed to react for 18 hours. LCMS confirmed the formation of the desired product. The reaction mixture was cooled to -10°C and quenched by the slow addition of 2 mL of water. 20 mL of tetrahydrofuran was then added to the reaction mixture, filtered through celite, and the filter cake was washed with 3 mL of tetrahydrofuran (20 mL x 3) until the product was completely dissolved. The filtrate was concentrated to dryness to yield 350 mg of the crude yellow oily liquid. This was then carried on to the next step.

[0239] LC-MS: (M+H) + ;m / z=268.01;

[0240] Step B: (5-Bromo-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone

[0241] 145 mg (1.03 mmol, 1.2 eq) of 5-fluoropyridine-2-carboxylic acid, 391 mg (1.03 mmol, 1.2 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 665 mg (5.15 mmol, 6.0 eq) of N,N-diisopropylethylamine, and 10 mL of tetrahydrofuran were added to a 50 mL reaction bottle. Under nitrogen protection, the reaction solution was stirred at room temperature for 10 minutes. Then, a solution of 230 mg (0.86 mmol, 1.0 eq) of 5-bromo-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3-ol dissolved in 6 mL of tetrahydrofuran was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The formation of the target product was confirmed by LCMS. The reaction solution was quenched by adding 15 mL of water and then extracted three times with ethyl acetate (25 mL). The organic phases were combined, dried, and concentrated. The crude product was purified by column chromatography (PE / EA = 50:1 to 5 / 1) to give 203 mg of an oily product (yield = 70%).

[0242] LC-MS: (M+H) + ; m / z = 391.01.

[0243] Example 1: (6-(2-cyclopropylphenyl)-4-hydroxy-3,4-dihydro-2H-spiro[naphthalene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone

[0244] Step A: 2-(4-bromophenyl)-4-(1,3-dioxolan-2-yl)butanenitrile

[0245] Under nitrogen, 2-(4-bromophenyl)acetonitrile (20.0 g, 102 mmol, 1.0 eq) was dissolved in 100 mL of tetrahydrofuran. LiHMDS (122 mL, 1.0 mol / L, 1.2 eq) was then slowly added dropwise at -78°C. After the addition was complete, the temperature was raised to room temperature and stirred for 3 hours. The temperature was then lowered to -78°C, followed by the slow addition of 2-(2-bromoethyl)-1,3-dioxane (22.0 g, 122 mmol, 1.2 eq). After the addition was complete, the temperature was slowly raised to room temperature and stirred overnight. TLC confirmed the complete reaction of the starting material. The reaction was quenched by the slow addition of 200 mL of ice water, followed by extraction with ethyl acetate (200 mL x 3). The organic layer was then washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to yield the crude product. The crude product was purified by silica gel column chromatography (PE / EA=10 / 1) to give the desired product (13.0 g, yield=43%).

[0246] 1 H NMR (400MHz, CDCl3) δ7.52-7.48(m,2H),7.23-7.19(m,2H),4.89(t,J=4.0Hz,1H),3.99-3.80(m,5H),2.07-1.93(m,2H),1.85-1.78(m,2H).

[0247] Step B: Ethyl 3-(4-bromophenyl)-3-cyano-5-(1,3-dioxolan-2-yl)pentanoate

[0248] Dissolve 2-(4-bromophenyl)-4-(1,3-dioxolan-2-yl)butanenitrile (4.0 g, 13.5 mmol, 1.0 eq) in 40 mL of tetrahydrofuran. Add sodium hydride (1.62 g, 40.5 mmol, 60% in oil, 3 eq) portionwise in an ice bath. Heat to 70°C with stirring for 2 hours. Then, slowly add ethyl bromoacetate (2.70 g, 16.2 mmol, 1.2 eq) dropwise. Continue heating at 70°C with stirring overnight. TLC confirms the formation of a new product, with some starting material remaining. After cooling, slowly add 100 mL of ice water dropwise to quench the reaction. Extract the mixture three times with ethyl acetate (100 mL x 3). Wash the organic layer with 100 mL of saturated brine, dry over anhydrous sodium sulfate, and evaporate to dryness under reduced pressure to yield the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 10:1 to 5:1) to obtain the desired product (1.6 g, yield = 31%).

[0249] 1H NMR (400MHz, CDCl3) δ7.54-7.49(m,2H),7.33-7.30(m,2H),4.82(t,J=4.0Hz,1H),4.03(q,J=6.8Hz,2H),3.92-3.78(m,4 H),3.03-2.88(m,2H),2.24-2.16(m,1H),2.06-1.99(m,1H),1.48-1.39(m,1H),1.36-1.24(m,1H),1.12(t,J=7.2Hz,3H).

[0250] Step C: Ethyl 3-cyano-3-(2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-5-(1,3-dioxan-2-yl)pentanoate

[0251] 1.60 g (4.18 mmol, 1.0 eq) of ethyl 3-(4-bromophenyl)-3-cyano-5-(1,3-dioxolan-2-yl)pentanoate and 813 mg (5.02 mmol, 1.2 eq) of (2-cyclopropylphenyl)boronic acid were dissolved in 50 mL of a dioxane / water mixture (V:V = 4:1). 307 mg (0.42 mmol, 0.1 eq) of 1,1-bis(diphenylphosphino)diphenylferric palladium chloride and 2.66 g (12.5 mmol, 3.0 eq) of tripotassium phosphate were added. The atmosphere was purged with nitrogen three times and stirred at 100°C for 2 h. After cooling, 50 mL of water was added, followed by extraction three times with ethyl acetate. The organic layer was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 0-5:1) to obtain the product (1.10 g, yield = 63%).

[0252] 1 H NMR (400MHz, CDCl3) δ7.50-7.44(m,4H),7.30-7.26(m,1H),7.23-7.19(m,2H),6.94 (d,J=7.8Hz,1H),4.87(t,J=4.4Hz,1H),4.10-4.04(m,2H),3.97-3.87(m,2H),3.86 -3.80(m,2H),3.09-2.96(m,2H),2.33-2.26(m,1H),2.17-2.10(m,1H),1.95-1.79( m,2H),1.71-1.62(m,1H),1.12(t,J=7.2,3H),0.89-0.79(m,2H),0.70-0.66(m,2H).

[0253] Step D: 4-(2-(1,3-dioxan-2-yl)ethyl)-4-(2'-cyclopropyl-[1,1'-biphenyl]-4-yl)pyrrolidin-2-one

[0254] 1.10 g (2.62 mmol, 1.0 eq) of ethyl 3-cyano-3-(2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-5-(1,3-dioxan-2-yl)pentanoate was dissolved in 25 mL of methanol, and 714 mg (5.50 mmol, 2.1 eq) of anhydrous cobalt chloride was added. 1.04 g (27.5 mmol, 10.5 eq) of sodium borohydride was slowly added at 0°C and stirred at room temperature for 1 hour. LCMS confirmed the formation of the product. The reaction was quenched with 50 mL of ice water, then extracted three times with dichloromethane. The organic layer was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 0-15:1) to obtain the product (0.80 g, yield = 81%).

[0255] LC-MS: (M+H) + ; m / z = 378.26;

[0256] 1 H NMR (400MHz, CDCl3) δ7.43-7.41(m,2H),7.29-7.24(m,1H),7.22-7.17(m,4H),6.93(d,J=8.0Hz,1H),6.02(s,1H),4.76(t,J=4.4Hz,1H),3.93-3 .78(m,4H),3.74-3.61(m,2H),2.84-2.58(m,2H),2.01-1.93(m,2H),1.9 0-1.83(m,1H),1.55-1.49(m,2H),0.89-0.80(m,2H),0.71-0.64(m,2H).

[0257] Step E: 3-(3-(2-(2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-5-oxopyrrolidin-3-yl)propanal

[0258] 0.80 g (2.12 mmol, 1.0 eq) of 4-(2-(1,3-dioxan-2-yl)ethyl)-4-(2'-cyclopropyl-[1,1'-biphenyl]-4-yl)pyrrolidin-2-one was dissolved in 5 mL of 1,4-dioxane. 10.64 mL of a 4M HCl / 1,4-dioxane solution (4.24 mmol, 20 eq) was then added under ice-cooling. The reaction was stirred overnight, and LCMS confirmed complete conversion. The pH was adjusted to approximately 7-8 by adding glacial sodium bicarbonate solution under ice-cooling. The product was then extracted three times with ethyl acetate. The organic layer was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude desired product (0.50 g, yield = 71%), which was used directly in the next step without purification.

[0259] LC-MS: (M+H) + ; m / z = 334.11;

[0260] 1 H NMR(400MHz, CDCl3)δ9.63(s,1H),7.46-7.44(m,2H),7.23-7.17(m,5H),6.96-6.93(m,2H),3.79-3.62 (m,4H),2.42-2.27(m,2H),2.21-2.17(m,1H),1.91-1.82(m,2H),0.88-0.81(m,2H),0.72-0.68(m,2H).

[0261] Step F: 3-(3-(2-(2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-5-oxopyrrolidin-3-yl)propanoic acid

[0262] 3-(3-(2-(2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-5-oxopyrrolidin-3-yl)propanal (0.50 g, 1.50 mmol, 1.0 eq) was dissolved in a mixture of tert-butyl alcohol (10 mL) and 2-methyl-2-butene (1.05 g, 15.0 mmol, 10 eq). The resulting solution was stirred and cooled to 0°C. NaClO2 (80% mixture with NaCl, 237 mg, 2.1 mmol, 1.4 eq) and NaH2PO4 (1 A mixture of 1,800 mg, 1.50 mmol, 1.0 eq) was dissolved in a minimum volume of water and added to the reaction. The reaction was monitored by TLC until complete consumption of the aldehyde was observed. The reaction was acidified to pH 3 with NaHSO4 (aq), then extracted three times with ethyl acetate. The organic layer was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain the crude desired product. The crude product was purified by column chromatography (DCM / MeOH = 0-15:1) to obtain the product (300 mg, yield = 57%).

[0263] LC-MS: (M+H) + ; m / z = 350.21;

[0264] Step G: 6-(2-cyclopropylphenyl)-2,3-dihydro-4H-spiro[naphthalene-1,3'-pyrrolidine]-4,5'-dione

[0265] 6.0 g of polyphosphoric acid was heated to 150°C, and 300 mg (0.85 mmol, 1.0 eq) of 3-(3-(2-(2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-5-oxopyrrolidin-3-yl)propanoic acid was added with stirring. The mixture was then stirred at 150°C for 1 h. LCMS confirmed the formation of the product. The hot mixture was slowly poured into ice water with stirring. The mixture was then extracted three times with dichloromethane. The organic layer was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain a crude product of the desired product (120 mg, yield = 42%), which was used directly in the next reaction.

[0266] LC-MS: (M+H) + ; m / z = 332.16;

[0267] Step H: 6-(2-cyclopropylphenyl)-3,4-dihydro-2H-spiro[naphthalene-1,3'-pyrrolidino]-4-ol

[0268] 120 mg (0.36 mmol, 1.0 eq) of 6-(2-cyclopropylphenyl)-2,3-dihydro-4H-spiro[naphthalene-1,3'-pyrrolidine]-4,5'-dione was dissolved in 5 mL of anhydrous tetrahydrofuran. 205 mg (5.40 mmol, 15.0 eq) of lithium aluminum hydride was slowly added at 0°C, and the mixture was stirred at 70°C for 2 h. LCMS confirmed the formation of the product. The reaction solution was filtered through celite and washed with tetrahydrofuran. The product was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to obtain the crude product (50 mg, yield = 43%), which was used directly in the next reaction.

[0269] LC-MS: (M+H) + ; m / z = 320.22;

[0270] Step I: (6-(2-cyclopropylphenyl)-4-hydroxy-3,4-dihydro-2H-spiro[naphthalene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2yl)methanone

[0271] 33.0 mg (0.234 mmol, 1.5 eq) of 5-fluoropyridine-2-carboxylic acid, 60.5 mg (0.468 mmol, 3.0 eq) of N,N-diisopropylethylamine, and 89.0 mg (0.234 mmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 5 mL of tetrahydrofuran and stirred at room temperature for 0.5 h. 50 mg (0.156 mmol, 1.0 eq) of 6-(2-cyclopropylphenyl)-3,4-dihydro-2H-spiro[naphthalene-1,3'-pyrrolidino]-4-ol was added, and the mixture was stirred at room temperature for 1.5 h. The product was confirmed to be generated by LCMS, and 50 mL of brine was added thereto, followed by extraction with ethyl acetate three times, drying over anhydrous sodium sulfate, and evaporation to dryness under reduced pressure. The product was purified (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 a white solid (4.15 mg, yield = 6%).

[0272] LC-MS: (M+Na) + ; m / z = 465.11;

[0273] 1H NMR (400MHz, CDCl3) δ8.45-8.35(m,1H),8.02(dd,J=8.8,4.4Hz,1H),7.59-7.49(m,4H),7.36-7.26(m,4H),4.10-3.86(m ,4H),2.91-2.86(m,2H),2.44-2.37(m,1H),2.24-2.14(m,3H),2.10-2.00(m,2H),1.90-1.83(m,1H),0.63-0.50(m,4H).

[0274] Example 2: (5-chloropyridin-2-yl)(6-(2-cyclopropylphenyl)-4-hydroxy-3,4-dihydro-2H-spiro[naphthalene-1,3'-pyrrolidino]-1'-yl)methanone

[0275] The experimental procedure was carried out with reference to step I in Example 1, except that the reagent 5-fluoropyridine-2-carboxylic acid was replaced with 5-chloropyridine-2-carboxylic acid to synthesize Example 2.

[0276] LC-MS: (M+Na) + ; m / z = 481.07;

[0277] 1 H NMR (400MHz, CDCl3) δ8.48-8.39(m,1H),8.05(dd,J=8.8,4.4Hz,1H),7.61-7.50(m,4H),7.37-7.27(m,4H),4.12-3.88(m ,4H),2.93-2.88(m,2H),2.45-2.39(m,1H),2.25-2.16(m,3H),2.13-2.00(m,2H),1.92-1.86(m,1H),0.64-0.52(m,4H).

[0278] Example 3: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)(5-fluoropyridin-2-yl)methanone

[0279] Step A: 5-Bromo-1H-indene

[0280] 2.00 g (9.38 mmol, 1.0 eq) of 6-bromo-2,3-dihydro-1H-inden-1-ol was dissolved in 20 mL of toluene, and 180 mg (0.94 mmol, 0.1 eq) of p-toluenesulfonic acid monohydrate was added to the reaction system. The reaction was stirred at 65°C under nitrogen for 3 h. The mixture was cooled to room temperature, and 30 mL of water and 80 mL of ethyl acetate were added. The organic phase was separated and extracted twice with ethyl acetate (2 x 60 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) to obtain an oil (1.50 g, yield = 82%).

[0281] 1 H NMR (400MHz, CDCl3) δ7.52 (d, J = 4.0Hz, 1H), 7.33-7.27 (m, 2H), 6.83-6.80 (m, 1H), 6.61-6.58 (m, 1H), 3.35-3.34 (m, 2H).

[0282] Step B: tert-Butyl 5-bromo[indene-1,4'-piperidine]-1'-carboxylate

[0283] Dissolve 1.50 g (7.69 mmol, 1.0 eq) of 5-bromo-1H-indene in 20 mL of tetrahydrofuran, cool to 0°C, and then add 19.4 mL (19.2 mmol, 2.5 eq) of lithium bistrimethylsilylamide dropwise to the reaction system under nitrogen. Stir the reaction system at 0°C for 1 h. Then, add 2.23 g (9.23 mmol, 1.2 eq) of tert-butyl bis(2-chloroethyl)carbamate dissolved in 20 mL of tetrahydrofuran dropwise to the reaction solution. After addition, warm to room temperature and react for 16 h. LC-MS results confirmed that the reaction of the raw materials was complete. 40 mL of water and 90 mL of ethyl acetate were added to separate the organic phase. The aqueous phase was extracted twice with ethyl acetate (2×80 mL). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 20:1) to give an oil (2.40 g, yield = 86%).

[0284] LC-MS:(M-Boc) + ; m / z = 264.12;

[0285] Step C: tert-Butyl 5-bromo-3-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate

[0286] 100 mg (0.28 mmol, 1.0 eq) of tert-butyl 5-bromo[indene-1,4'-piperidinyl]-1'-carboxylate was dissolved in 5 mL of anhydrous tetrahydrofuran, and 1.1 mL (0.56 mmol, 2.0 eq) of 9-borabicyclo[3.3.1]nonane was added to the reaction system. The reaction system was reacted at 70°C for 17 h in a sealed tube. The reaction solution was cooled to room temperature, and 0.55 mL of 1 M sodium hydroxide solution was added, followed by 0.1 mL (30% wt) of hydrogen peroxide. Stirring was continued for 1 h, and the mixture was extracted twice with ethyl acetate (50 mL x 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a light yellow oil (80.0 mg, yield = 80%).

[0287] LC-MS:(M-Boc) + ;m / z=282.00;

[0288] Step D: 5-Bromo-2,3-dihydrospiro[indene-1,4'-piperidin]-3-ol

[0289] Dissolve 80.0 mg (0.21 mmol, 1.0 eq) of tert-butyl 5-bromo-3-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate in 6 mL of dichloromethane. Add 1 mL (4.31 mmol, 30 eq) of a solution of hydrogen chloride in dioxane to the reaction system. The mixture was reacted at 40°C for 1 hour under nitrogen. LC-MS confirmed the formation of the desired product. The reaction solution was concentrated to dryness to afford a light yellow oil (58.0 mg, yield = 98%).

[0290] LC-MS: (M+H) + ; m / z = 283.95;

[0291] Step E: (5-Bromo-3-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)(5-fluoropyridin-2-yl)methanone

[0292] Dissolve 48.0 mg (0.34 mmol, 1.2 eq) of 5-fluoropicolinic acid in 6 mL of tetrahydrofuran. Add 129 mg (0.34 mmol, 1.0 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and 0.28 mL (1.70 mmol, 6.0 eq) of N,N-diisopropylethylamine to the reaction system. Stir under nitrogen for 10 minutes. Then, add 80.0 mg (0.28 mmol, 1.0 eq) of 5-bromo-2,3-dihydrospiro[indene-1,4'-piperidin]-3-ol dissolved in 3 mL of tetrahydrofuran dropwise to the reaction system. After the addition was complete, the mixture was stirred at room temperature for 2 h. LC-MS results confirmed the formation of the target product. The reaction solution was cooled to room temperature and quenched with water. 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 purified by column chromatography (dichloromethane / methanol = 80 / 1 to 30 / 1) to give a light yellow solid (50.0 mg, yield = 44%).

[0293] LC-MS: (M+H) + ;m / z=406.89;

[0294] Step F: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)(5-fluoropyridin-2-yl)methanone

[0295] 50.0 mg (0.12 mmol, 1.0 eq) (5-bromo-3-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl) (5-fluoropyridin-2-yl)methanone was dissolved in 6 mL of dioxane and 2 mL of water. 23.9 mg (0.15 mmol, 1.2 eq) (2-cyclopropylphenyl)boric acid and 78.2 mg (0.15 mmol, 3.0 eq) of potassium phosphate were added to the above reaction system. Under nitrogen protection, 18.0 mg (0.02 mmol, 0.1 eq) of [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, 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 product as a white solid (10.2 mg, yield = 18%).

[0296] LC-MS: (M+H) + ; m / z = 443.42;

[0297] 1 H NMR (400MHz, CDCl3) δ8.48-8.46(m,1H),7.78(dd,J=8.6,4.5Hz,1H),7.56-7.51(m,2H),7.45(d ,J=7.9Hz,1H),7.31-7.27(m,2H),7.26-7.19(m,2H),6.94(d,J=7.8Hz,1H),5.38-5.37(m,1H), 4.81-4.80(m,1H),4.09-4.07(m,1H),3.40-3.38(m,1H),3.13-3.11(m,1H),2.70-2.59(m,1H), 2.21-1.97(m,3H),1.95-1.87(m,3H),1.77-1.67(m,1H),0.90-0.85(m,2H),0.76-0.72(m,2H).

[0298] 19 F NMR (376MHz, CDCl3) δ-123.84 (d, J=3.9Hz).

[0299] Example 4: (5-fluoropyridin-2-yl)(3-hydroxy-5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)methanone

[0300] The experimental procedure was carried out by referring to step F in Example 3, except that (2-cyclopropylphenyl)boronic acid was replaced with 2-isopropylphenylboronic acid to obtain the compound of Example 4.

[0301] LC-MS: (M+H) + ; m / z = 445.17.

[0302] Examples 5 and 6: (5-(2-cyclopropylphenyl)-3-hydroxy-3-methyl-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone (P1 and P2)

[0303] Step A: 5-(2-cyclopropylphenyl)-3-hydroxy-3-methyl-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-2'-one

[0304] 0.76 g (2.4 mmol, 1.0 eq) of 5-(2-cyclopropylphenyl)spiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione was dissolved in 25 mL of anhydrous tetrahydrofuran and the atmosphere was purged with nitrogen three times. 4 mL (12.0 mmol, 5.0 eq, 3 M) of methylmagnesium chloride was added dropwise at 0°C and stirred at room temperature for 2 h. LCMS confirmed complete conversion of the starting material and formation of the product. The reaction was quenched by adding 30 mL of saturated ammonium chloride solution, followed by extraction three times with dichloromethane. The organic layer was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 0-20:1) to afford the product (0.60 g, yield = 75%).

[0305] LC-MS: (M+H) + ; m / z = 334.21;

[0306] Step B: 5-(2-cyclopropylphenyl)-3-methyl-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol

[0307] 550 mg (1.65 mmol, 1.0 eq) of 5-(2-cyclopropylphenyl)-3-hydroxy-3-methyl-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-2'-one was dissolved in 50 mL of anhydrous tetrahydrofuran. 1.25 g (32.99 mmol, 20.0 eq) of lithium aluminum hydride was slowly added at 0°C and stirred at 70°C for 2 h. LCMS confirmed complete conversion of the starting material and formation of the product. The reaction solution was filtered through celite and washed with tetrahydrofuran. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product-containing solution.

[0308] LC-MS: (M+H) + ; m / z = 320.23;

[0309] Step C: (5-(2-cyclopropylphenyl)-3-hydroxy-3-methyl-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone

[0310] Dissolve 0.40 g (2.82 mmol, 1.5 eq) of 5-fluoropyridine-2-carboxylic acid, 0.93 mL of N,N-diisopropylethylamine, and 1.07 g (2.82 mmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate in 50 mL of tetrahydrofuran and stir at room temperature for 0.5 h. Add the reaction solution containing 5-(2-cyclopropylphenyl)-3-methyl-2,3-dihydrospiro[indene-1,3'-pyrrolidinyl]-3-ol, and stir at room temperature for 2 h. The formation of the product was confirmed by LCMS, and 50 mL of brine was added thereto, followed by extraction with ethyl acetate three times, drying over anhydrous sodium sulfate, and evaporation under reduced pressure. The product was prepared and purified (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 white solid products P1 (118 mg, yield = 14%) and P2 (135 mg, yield = 16%).

[0311] Example 5 (P1) LC-MS: (M+H) + ; m / z = 443.18; 1 H NMR (400MHz, CDCl3) δ8.50-8.40(m,1H),8.11-8.06(m,1H),7.58-7.44(m,3H),7.34-7.30(m,2H),7.26-7.22(m,2H),6.96 -6.94(m,1H),4.14-3.87(m,4H),2.44-2.22(m,5H),1.93-1.83(m,1H),1.29(s,3H),0.88-0.85(m,2H),0.79-0.75(m,2H).

[0312] Example 6 (P2) LC-MS: (M-OH+H) + ; m / z = 425.18; 1 H NMR (400MHz, CDCl3) δ8.49-8.38(m,1H),8.09-8.02(m,1H),7.57-7.45(m,3H),7.33-7.29(m,2H),7.26-7.20(m,2H),6.97 -6.94(m,1H),4.14-3.85(m,4H),2.42-2.04(m,4H),1.85-1.68(m,2H),1.61(s,3H),0.90-0.84(m,2H),0.78-0.73(m,2H).

[0313] Example 7: (5-(2-cyclopropylphenyl)-3-hydroxy-3-(trifluoromethyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone

[0314] Step A: 5-(2-cyclopropylphenyl)-3-hydroxy-3-(trifluoromethyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-5'-one

[0315] 100 mg (0.31 mmol, 1.0 eq) of 5-(2-cyclopropylphenyl)-3-hydroxy-3-(trifluoromethyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-5'-one and 270 mg (1.86 mmol, 6.0 eq) of (trifluoromethyl)trimethylsilane were dissolved in 5 mL of anhydrous tetrahydrofuran and the atmosphere was purged with nitrogen three times. 0.3 mL of tetrabutylammonium fluoride was added dropwise at 0°C, and the mixture was stirred overnight at room temperature. LCMS confirmed the formation of the product. The reaction solution was quenched by adding dropwise to 30 mL of saturated sodium bicarbonate solution, then extracted three times with ethyl acetate. The organic layer was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain the crude product (103 mg, yield = 86%).

[0316] LC-MS: (M+H) + ; m / z = 388.11;

[0317] Step B: 5-(2-cyclopropylphenyl)-3-(trifluoromethyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol

[0318] 103 mg (0.27 mmol, 1.0 eq) of 5-(2-cyclopropylphenyl)-3-hydroxy-3-(trifluoromethyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-5'-one was dissolved in 5 mL of anhydrous tetrahydrofuran. 99.0 mg (2.66 mmol, 10.0 eq) of lithium aluminum hydride was slowly added at 0°C, and the mixture was stirred at 70°C for 3 h. LCMS confirmed the formation of the product. The reaction solution was filtered through celite and washed with tetrahydrofuran. The product was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to obtain the crude product (100 mg, yield = 100%).

[0319] LC-MS: (M+H) + ; m / z = 373.97;

[0320] Step C: (5-(2-cyclopropylphenyl)-3-hydroxy-3-(trifluoromethyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone

[0321] 57.0 mg (0.40 mmol, 1.5 eq) of 5-fluoropyridine-2-carboxylic acid, 0.08 mL of N,N-diisopropylethylamine, and 153 mg (0.40 mmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 10 mL of tetrahydrofuran and stirred at room temperature for 0.5 h. 100 mg (0.27 mmol, 1.0 eq) of 5-(2-cyclopropylphenyl)-3-(trifluoromethyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was added and stirred at room temperature for 3 h. The product was confirmed to be generated by LCMS, and 5 mL of brine was added thereto, followed by extraction with ethyl acetate three times, drying over anhydrous sodium sulfate, and evaporation to dryness under reduced pressure. The product was prepared and purified (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 a white solid (7.00 mg, yield = 5%).

[0322] LC-MS: (M+H) + ; m / z = 497.29;

[0323] 1 H NMR (400MHz, CDCl3) δ8.40-8.38(m,1H),8.10-8.02(m,1H),7.64-7.62(m,1H),7.57-7.52(m,2H),7.39-7.29(m,2H),7.23-7. 20(m,2H),7.00-6.95(m,1H),4.24-3.89(m,4H),2.65-2.35(m,5H),1.80-1.78(m,1H),0.88-0.80(m,2H),0.75-0.71(m,2H).

[0324] 19 F NMR (376MHz, CDCl3) δ-79.51,-122.46.

[0325] Example 8: (5-Fluoropyridin-2-yl)(1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolan-3,3'-pyrrolidino]-1'-yl)methanone

[0326] Step A: tert-Butyl 3-(2-bromophenyl)-3-hydroxypyrrolidine-1-carboxylate

[0327] 3.00 g (10.6 mmol, 1.0 eq) of o-iodobromobenzene was dissolved in 20 mL of anhydrous tetrahydrofuran, followed by the addition of 0.50 g (12.7 mmol, 1.2 eq) of lithium chloride. After nitrogen was replaced, the reaction mixture was cooled to -78°C. 6.4 mL (12.7 mmol, 1.2 eq) of isopropylmagnesium chloride (2 M) was slowly added dropwise, maintaining the temperature at -78°C. After the addition was complete, the reaction mixture was allowed to react at -78°C for 1 hour. Subsequently, a solution of 2.00 g (10.6 mmol, 1.0 eq) of 1-tert-butoxycarbonyl-3-pyrrolidone (10 mL) in anhydrous tetrahydrofuran was slowly added to the reaction mixture. The reaction mixture was allowed to return to room temperature and the reaction continued for 18 hours. After the reaction was confirmed to be complete by LC-MS, the reaction mixture was quenched with 10 mL of saturated ammonium chloride solution and extracted three times with 50 mL of ethyl acetate. The organic phase was washed with sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (EA / PE = 0-1:6) to give tert-butyl 3-(2-bromophenyl)-3-hydroxypyrrolidine-1-carboxylate (1.00 g, yield = 28%).

[0328] LC-MS:(M+H-Boc) + ;m / z=242,244;

[0329] Step B: tert-Butyl 1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolane-3,3'-pyrrolidine]-1'-carboxylate

[0330] 66.0 mg (0.2 mmol, 1.0 eq) of tert-butyl 3-(2-bromophenyl)-3-hydroxypyrrolidine-1-carboxylate was dissolved in 5 mL of 1,4-dioxane. 108.9 mg (0.5 mmol, 2.5 eq) of neopentyl glycol diboronate, 14.1 mg (0.02 mmol, 0.1 eq) of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, and 37.9 mg (0.4 mmol, 2.0 eq) of potassium acetate were added to the reaction system. After nitrogen was replaced, the temperature was raised to 80°C and the reaction was allowed to proceed for 3 hours. LC-MS results confirmed the reaction was complete, and the system was cooled to room temperature and directly used for the next step.

[0331] LC-MS: (M+Na) + ; m / z = 312;

[0332] Step C: 1H-spiro[benzo[c][1,2]oxaborolan-3,3'-pyrrolidino]-1-ol hydrochloride

[0333] After the reaction mixture of tert-butyl 1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolan-3,3'-pyrrolidino]-1'-carboxylate returned to room temperature, 1 mL (12 mmol, 60.0 eq) of a 4M dioxane hydrochloride solution was added. The mixture then reacted under nitrogen for 1 hour at room temperature. LC-MS confirmed the reaction was complete, and the solvent was evaporated to dryness under reduced pressure to yield 1H-spiro[benzo[c][1,2]oxaborolan-3,3'-pyrrolidino]-1-ol hydrochloride (21.2 mg, 58% yield over two steps).

[0334] LC-MS: (M+H) + ; m / z = 190;

[0335] Step D: (5-Fluoropyridin-2-yl)(1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolan-3,3'-pyrrolidino]-1'-yl)methanone

[0336] 15.8 mg (0.10 mmol, 1.0 eq) of 5-fluoro-2-pyridinecarboxylic acid was dissolved in 1 mL of N,N-dimethylformamide. After nitrogen displacement, 46.9 mg (0.10 mmol, 1.1 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and 29.0 mg (0.20 mmol, 2.0 eq) of N,N-diisopropylethylamine were added sequentially. After stirring at room temperature for 1 minute, 21.2 mg (0.10 mmol, 1.0 eq) of 1H-spiro[benzo[c][1,2]oxaborolan-3,3'-pyrrolidino]-1-ol was added and stirring continued for 30 minutes. LC-MS results confirmed the reaction was complete. The mixture was diluted with 10 mL of saturated sodium chloride solution and 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 sequentially by column chromatography (MeOH / DCM = 0-1:30) and preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) to give (5-fluoropyridin-2-yl)(1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolan-3,3'-pyrrolidine]-1'-yl)methanone (15.9 mg, yield = 45%) as a white solid.

[0337] LC-MS: (M+H) + ; m / z = 429;

[0338] 1H NMR (400MHz, CDCl3) δ8.40(dd,J=56.3,2.9Hz,1H),8.07(ddd,J=10.9,8.7,4.6Hz,1H),7.74(t,J=7.3Hz,1H),7.56 -7.46(m,2H),7.45-7.34(m,2H),5.32(d,J=43.4Hz,1H),4.35-3.96(m,4H),2.50-2.39(m,1H),2.15-2.07(m,1H).

[0339] Example 9: (6-(2-cyclopropylphenyl)-1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolan-3,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone

[0340] Step A: 3-Bromo-2'-cyclopropyl-[1,1'-biphenyl]-4-amine

[0341] 1.50 g (5.00 mmol, 1.0 eq) of 2-bromo-4-iodoaniline was dissolved in 12.5 mL of 1,4-dioxane. 0.80 g (5.00 mmol, 1.0 eq) of 2-cyclopropylphenylboronic acid, 0.30 g (0.30 mmol, 0.05 eq) of tetrakis(triphenylphosphine)palladium, 1.40 g (10.1 mmol, 2.0 eq) of potassium carbonate, and 2.5 mL of water were added to the reaction system. After nitrogen was replaced, the temperature was raised to 80°C and the reaction was allowed to proceed for 2 hours. LC-MS results confirmed the completion of the reaction. The system was cooled to room temperature and diluted with 20 mL of saturated sodium chloride solution. The mixture was then extracted three times with 30 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 (EA / PE = 0-1:10) to give 3-bromo-2'-cyclopropyl-[1,1'-biphenyl]-4-amine (791 mg, yield = 55%).

[0342] LC-MS: (M+H) + ;m / z=288;290;

[0343] Step B: 3'-Bromo-2-cyclopropyl-4'-iodo-1,1'-biphenyl

[0344] 733 mg (2.50 mmol, 1.0 eq) of 3-bromo-2'-cyclopropyl-[1,1'-biphenyl]-4-amine was dissolved in 4 mL of anhydrous tetrahydrofuran and stirred with 8 mL of concentrated hydrochloric acid. The mixture was cooled to 0°C and then slowly added dropwise with 263 mg (3.80 mmol, 1.5 eq) of sodium nitrite in 0.9 mL of water, maintaining the temperature between 0 and 5°C. After the addition was complete, the reaction was continued at 0°C for 30 minutes. Subsequently, 1.69 g (10.2 mmol, 4.0 eq) of potassium iodide was slowly added to the reaction system, and the reaction was continued at 0°C for 30 minutes. After LC-MS confirmed the reaction was complete, the reaction was quenched with 10 mL of 10% aqueous sodium sulfite solution and extracted three times with 50 mL of ethyl acetate. The organic phase was washed sequentially with saturated sodium carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (PE) to give 3'-bromo-2-cyclopropyl-4'-iodo-1,1'-biphenyl (641 mg, yield = 63%).

[0345] 1 H NMR (400MHz, CDCl3) δ7.79 (dd, J=7.1, 3.1Hz, 1H), 7.64 (dd, J=7.1, 2.2Hz, 1H), 7.22-7.07 (m, 3H) ,7.01-6.99(m,1H),6.87-6.86(m,1H),1.73-1.71(m,1H),0.80-0.74(m,2H),0.64-0.55(m,2H).

[0346] Step C: tert-Butyl 3-(3-bromo-2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-3-hydroxypyrrolidine-1-carboxylate

[0347] 389 mg (1.00 mmol, 1.0 eq) of 3'-bromo-2-cyclopropyl-4'-iodo-1,1'-biphenyl was dissolved in 6 mL of anhydrous tetrahydrofuran, and 53.7 mg (1.30 mmol, 1.3 eq) of lithium chloride was added. After nitrogen was replaced, the system was cooled to -78°C, and 0.6 mL (1.30 mmol, 1.3 eq) of isopropylmagnesium chloride (2M) was slowly added dropwise to the former, maintaining the system at -78°C during the process. After the addition, the reaction was continued at -78°C for 1 hour. Subsequently, a solution of 253 mg (1.40 mmol, 1.4 eq) of 1-tert-butoxycarbonyl-3-pyrrolidone (4 mL) in anhydrous tetrahydrofuran was slowly added to the reaction system. Finally, the reaction was allowed to return to room temperature naturally and the reaction was continued for 18 hours. After LC-MS confirmed the reaction was complete, the product was quenched with 5 mL of saturated ammonium chloride solution and extracted three times with 50 mL of ethyl acetate. The organic phase was washed with sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (EA / PE = 0 to 1:6) to afford tert-butyl 3-(3-bromo-2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-3-hydroxypyrrolidine-1-carboxylate (107 mg, yield = 24%).

[0348] LC-MS: (M+H-Boc-OH) + ;m / z=340;342;

[0349] Step D: tert-Butyl 6-(2-cyclopropylphenyl)-1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolane-3,3'-pyrrolidine]-1'-carboxylate

[0350] 107 mg (0.20 mmol, 1.0 eq) of tert-butyl 3-(3-bromo-2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-3-hydroxypyrrolidine-1-carboxylate was dissolved in 6 mL of 1,4-dioxane. 132 mg (0.60 mmol, 2.5 eq) of neopentyl glycol diboronate, 17.1 mg (0.02 mmol, 0.1 eq) of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, and 45.7 mg (0.50 mmol, 2 eq) of potassium acetate were added to the reaction system. After nitrogen was replaced, the temperature was raised to 80°C and the reaction was allowed to proceed for 3 hours. LC-MS results confirmed the reaction was complete. The system was then cooled to room temperature and directly used for the next step.

[0351] LC-MS: (M+Na) + ; m / z = 428;

[0352] Step E: 6-(2-Cyclopropylphenyl)-1H-spiro[benzo[c][1,2]oxaborolan-3,3'-pyrrolidino]-1-ol

[0353] After the reaction mixture of tert-butyl 6-(2-cyclopropylphenyl)-1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolane-3,3'-pyrrolidino]-1'-carboxylate returned to room temperature, 3 mL (12 mmol, 60.0 eq) of a 4M dioxane hydrochloride solution was added. The mixture then reacted under nitrogen for 2 hours at room temperature. LC-MS confirmed the reaction was complete, and the solvent was evaporated to dryness under reduced pressure to yield 6-(2-cyclopropylphenyl)-1H-spiro[benzo[c][1,2]oxaborolane-3,3'-pyrrolidino]-1-ol (62.2 mg, 88% yield over two steps).

[0354] LC-MS: (M+H) + ; m / z = 306;

[0355] Step F: (6-(2-Cyclopropylphenyl)-1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolan-3,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone

[0356] 28.8 mg (0.20 mmol, 1.0 eq) of 5-fluoro-2-pyridinecarboxylic acid was dissolved in 1 mL of N,N-dimethylformamide. After nitrogen displacement, 85.3 mg (0.20 mmol, 1.1 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and 52.7 mg (0.40 mmol, 2.0 eq) of N,N-diisopropylethylamine were added sequentially. After stirring at room temperature for 1 minute, 62.2 mg (0.20 mmol, 1.0 eq) of 6-(2-cyclopropylphenyl)-1H-spiro[benzo[c][1,2]oxaborolane-3,3'-pyrrolidino]-1-ol was added and stirring continued for 30 minutes. LC-MS results confirmed the reaction was complete. The mixture was diluted with 10 mL of saturated sodium chloride solution and 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 sequentially by column chromatography (MeOH / DCM = 0-1:50) and preparative chromatography (mobile phase A: 0.1% trifluoroacetic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) to give (6-(2-cyclopropylphenyl)-1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolan-3,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone (11.9 mg, yield = 14%) as a white solid.

[0357] LC-MS: (M+H) + ; m / z = 429;

[0358] 1 H NMR (400MHz, CDCl3) δ8.54-8.27(m,1H),8.07(dd,J=9.4,4.6Hz,1H),7.79(d,J=7.4 Hz,1H),7.64(dd,J=7.9,1.6Hz,1H),7.55-7.47(m,1H),7.42(dd,J=14.9,7.8Hz,1H ),7.29(s,1H),7.23-7.19(m,2H),6.98-6.92(m,1H),4.40-4.01(m,4H),2.59-2.44 (m,1H),2.27-2.13(m,1H),2.02-2.00(m,1H),0.88-0.83(m,2H),0.72-0.71(m,2H).

[0359] Example 10: (5-chloropyridin-2-yl)(6-(2-cyclopropylphenyl)-1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolan-3,3'-pyrrolidino]-1'-yl)methanone

[0360] The experimental procedure was carried out by referring to step F in Example 9, except that 5-fluoro-2-pyridinecarboxylic acid was replaced with 5-chloro-2-pyridinecarboxylic acid to obtain compound Example 10.

[0361] LC-MS: (M+H) + ; m / z = 445.09.

[0362] Example 11: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl-3,5',5'-d3)(5-fluoropyridin-2-yl)methanone

[0363] Step A: 5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3,5',5'-d3-ol

[0364] 100 mg (0.31 mmol, 1.0 eq) of 5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3-ol was dissolved in 5 mL of anhydrous tetrahydrofuran. 120 mg (3.70 mmol, 12.0 eq) of lithium aluminum hydride (d) was slowly added at 0°C and stirred at 70°C for 3 h. LCMS confirmed the formation of the product. The reaction solution was filtered through celite and washed with tetrahydrofuran. The product was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give the crude product (100 mg, yield = 104%).

[0365] LC-MS: (M+H) + ; m / z = 309.19;

[0366] Step B: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl-3,5',5'-d3)(5-fluoropyridin-2-yl)methanone

[0367] 77.0 mg (0.48 mmol, 1.5 eq) of 5-chloropyridine-2-carboxylic acid, 0.16 mL of N,N-diisopropylethylamine, and 187 mg (0.48 mmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 10 mL of tetrahydrofuran and stirred at room temperature for 0.5 h. 100 mg (0.32 mmol, 1.0 eq) of 5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3,5',5'-d3-3-ol was added and stirred at room temperature for 3 h. The product was confirmed to be generated by LCMS, and 5 mL of brine was added thereto, followed by extraction with ethyl acetate three times, drying over anhydrous sodium sulfate, and evaporation to dryness under reduced pressure. Preparative purification (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) afforded a white solid (14.0 mg, yield = 10%).

[0368] LC-MS: (M+H) + ; m / z = 432.19;

[0369] 1 H NMR (400MHz, CDCl3) δ8.47-8.30(m,1H),8.05-8.01(m,1H),7.54-7.42(m,3H),7.32-7.25(m,2H),7.21-7.14(m,2H) ,6.93-6.85(m,1H),4.14-3.77(m,2H),2.66-2.00(m,5H),1.92-1.81(m,1H),0.87-0.82(m,2H),0.74-0.70(m,2H).

[0370] 19 F NMR (376MHz, CDCl3) δ-123.19 (d, J=24.8Hz).

[0371] Example 12: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl-3-d)(5-fluoropyridin-2-yl)methanone

[0372] Step A: 5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-5'-one-3-d

[0373] 150 mg (0.47 mmol, 1.0 eq) of 5-bromospiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione was dissolved in 5 mL of anhydrous tetrahydrofuran. 110 mg (0.57 mmol, 1.2 eq.) of sodium deuterated borohydride was slowly added at 0°C and stirred at room temperature for 2 h. LCMS confirmed the formation of the product. The reaction mixture was quenched with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain the crude product (148 mg, yield = 97%).

[0374] LC-MS: (M+H) + ; m / z = 321.10;

[0375] Step B: 5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3-d-3-ol

[0376] 148 mg (0.46 mmol, 1.0 eq) of 5-bromospiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione was dissolved in 5 mL of anhydrous tetrahydrofuran. 263 mg (6.92 mmol, 15.0 eq) of lithium aluminum hydride was slowly added at 0°C, and the mixture was stirred at 70°C for 3 h. LCMS confirmed the formation of the product. The reaction solution was filtered through celite and washed with tetrahydrofuran. The mixture was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to obtain the crude product (142 mg, yield = 100%).

[0377] LC-MS: (M+H) + ; m / z = 307.11;

[0378] Step C: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl-3-d)(5-fluoropyridin-2-yl)methanone

[0379] 103 mg (0.73 mmol, 1.5 eq) of 5-fluoropyridine-2-carboxylic acid, 0.24 mL of N,N-diisopropylethylamine, and 279 mg (0.73 mmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 5 mL of tetrahydrofuran and stirred at room temperature for 0.5 h. 142 mg (0.43 mmol, 1.0 eq) of 5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was added and stirred at room temperature for 1.5 h. The product was confirmed to be generated by LCMS, and 10 mL of brine was added thereto, followed by extraction with ethyl acetate three times, drying over anhydrous sodium sulfate, and evaporation to dryness under reduced pressure. Preparative purification (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) afforded a white solid (12.0 mg, yield = 5.7%).

[0380] LC-MS: (M+H) + ; m / z = 430.06;

[0381] 1 H NMR (400MHz, CDCl3) δ8.43(d,J=38.7Hz,1H),8.06-8.03(m,1H),7.56-7.43(m,3H),7.32-7.26(m,2H),7.24-7.19(m,2H),6.92(dd,J =7.9,4.2Hz,1H),4.24-3.71(m,4H),2.67-2.53(m,1H),2.31-2.01(m,4H),1.92-1.82(m,1H),0.89-0.82(m,2H),0.74-0.70(m,2H).

[0382] 19 F NMR (376MHz, CDCl3) δ-122.82 (d, J=10.5Hz).

[0383] Example 13: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-hydroxy-6-methylpyridin-2-yl)methanone

[0384] Step A: Synthesis of 5-hydroxy-6-methylpyridinic acid

[0385] 0.97 g (5.16 mmol, 1.0 eq) of 6-bromo-2-methylpyridin-3-ol was dissolved in 30 mL of N,N-dimethylformamide. 2.37 g (51.6 mmol, 10.0 eq) of formic acid, 1.57 g (15.5 mmol, 3.0 eq) of triethylamine, 23.2 mg (0.10 mmol, 0.02 eq) of palladium acetate, and 0.03 g (0.15 mmol, 0.03 eq) of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) were added under an ice-water bath. Carbon monoxide was replaced three times, and the mixture was stirred at 80°C overnight. After extraction, the product was mostly in the aqueous phase. Preparative purification was performed (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30% to 70% B over 55 minutes; flow rate: 70 mL / min), and lyophilization afforded the product (0.78 g, yield = 99%).

[0386] LC-MS:(MH) - ; m / z = 151.87;

[0387] Step B: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-hydroxy-6-methylpyridin-2-yl)methanone

[0388] 150 mg (0.98 mmol, 3.0 eq) of 5-hydroxy-6-methylpyridinic acid, 0.16 mL of N,N-diisopropylethylamine, and 126 mg (0.98 mmol, 3.0 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 10 mL of tetrahydrofuran and stirred at room temperature for 0.5 h. 100 mg (0.33 mmol, 1.0 eq) of 5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was added and stirred at room temperature for 3 h. The product was confirmed to be generated by LCMS. 5 mL of brine was added, and the product was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The product was purified (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 a white solid (5.0 mg, yield = 3.4%).

[0389] LC-MS: (M+H) + ; m / z = 441.21;

[0390] 1H NMR (400MHz, CDCl3) δ7.67(dd,J=11.2,8.3Hz,1H),7.52(d,J=6.2Hz,1H),7.46(dd,J=7.9,1.7Hz,1H),7.35-7.30(m,2H),7.25-7.21(m,2H),7.11(dd,J =14.0,8.3Hz,1H),6.96-6.93(m,1H),5.40-5.36(m,2H),4.17-3.80(m,4H), 2.59-2.01(m,8H),1.93-1.87(m,1H),0.90-0.85(m,2H),0.76-0.72(m,2H).

[0391] Example 14: (5-chloropyridin-2-yl)(5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)methanone

[0392] 77 mg (0.49 mmol, 1.5 eq) of 5-fluoropyridine-2-carboxylic acid, 0.16 mL of N,N-diisopropylethylamine, and 187 mg (0.49 mmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 10 mL of tetrahydrofuran and stirred at room temperature for 0.5 h. 100 mg (0.33 mmol, 1.0 eq) of 5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was added and stirred at room temperature for 3 h. LCMS confirmed that the raw material was completely converted and the product was generated. 20 mL of brine was added thereto, followed by extraction three times with ethyl acetate, drying over anhydrous sodium sulfate, and evaporation to dryness under reduced pressure. Preparative purification (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) was performed and lyophilized to obtain a white solid (32.0 mg, yield = 22%).

[0393] LC-MS: (M+H) + ; m / z = 445.08;

[0394] 1H NMR (400MHz, CDCl3) δ8.61-8.50(m,1H),7.99-7.95(m,1H),7.84-7.78(m, 1H),7.55-7.51(m,1H),7.47-7.44(m,1H),7.34-7.29(m,2H),7.26-7.19(m ,2H),6.94(dd,J=7.7,4.1Hz,1H),5.41-5.35(m,1H),4.26-3.80(m,4H),2 .30-2.20(m,5H),1.93-1.85(m,1H),0.89-0.84(m,2H),0.76-0.72(m,2H).

[0395] Example 15: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone

[0396] 291 mg (2.06 mmol, 1.5 eq) of 5-fluoropyridine-2-carboxylic acid, 0.68 mL of N,N-diisopropylethylamine, and 784 mg (2.06 mmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 65 mL of tetrahydrofuran and stirred at room temperature for 0.5 h. 420 mg (1.37 mmol, 1.0 eq) of 5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was added and stirred at room temperature for 1.5 h. The product was confirmed to be generated by LCMS, and 50 mL of brine was added thereto, followed by extraction with ethyl acetate three times, drying over anhydrous sodium sulfate, and evaporation to dryness under reduced pressure. The product was prepared and purified (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 7 mL / min) and lyophilized to obtain a white solid (83.0 mg, yield = 15%).

[0397] LC-MS: (M+H) + ; m / z = 429.20;

[0398] 1H NMR (400MHz, CDCl3) δ8.49-8.38(m,1H),8.09-8.04(m,1H),7.56-7.44(m,3H),7.34-7.30(m,2H),7.24-7.21(m,2H),6.95(dd,J=7 .8,4.2Hz,1H),5.41-5.30(m,1H),4.17-3.83(m,4H),2.29-2.03(m,5H),1.94-1.85(m,1H),0.90-0.84(m,2H),0.76-0.72(m,2H).

[0399] Example 16: (5-fluoropyridin-2-yl)(3-hydroxy-5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)methanone

[0400] 23.0 mg (0.16 mmol, 1.0 eq) of 5-fluoropyridine-2-carboxylic acid, 74.2 mg (0.41 mmol, 1.2 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 63.0 mg (0.48 mmol, 3.0 eq) of N,N-diisopropylethylamine, and 3 mL of tetrahydrofuran were added to a 25 mL reaction flask. Under nitrogen, the reaction solution was stirred at room temperature for 10 minutes. Then, 50.0 mg (0.16 mmol, 1.0 eq) of 5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol was weighed and dissolved in 3 mL of tetrahydrofuran. The solution was slowly added to the reaction solution and stirred at room temperature for 1 hour. TLC (DCM:MeOH = 20:1) confirmed complete reaction of the starting materials. The reaction solution was concentrated to dryness and 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 pure product as a white solid (11.2 mg, yield = 16%).

[0401] LC-MS: (M+H) + ; m / z = 431.15;

[0402] 1H NMR (400MHz, CDCl3) δ8.47-8.37(m,1H),8.07-8.03(m,1H),7.55-7.47(m ,1H),7.40-7.33(m,3H),7.0-7.26(m,2H),7.21-7.13(m,2H),5.37-5.29 (m,1H),4.25-3.79(m,4H),3.11-3.00(m,1H),2.69-2.37(m,2H),2.28-2 .18(m,1H),2.16-2.00(m,1H),1.89-1.83(m,1H),1.19(d,J=6.8Hz,6H).

[0403] 19 F NMR (376MHz,CDCl3)δ-123.29.

[0404] Example 17: (2-Chlorothiazol-4-yl)(5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)methanone

[0405] The experimental procedure was carried out with reference to Example 15, except that 5-fluoropyridine-2-carboxylic acid was replaced with 2-chlorothiazole-4-carboxylic acid, and the compound Example 17 was obtained through synthesis, preparation and purification.

[0406] LC-MS: (M+H) + ; m / z = 451.08;

[0407] 1 H NMR (400MHz, CDCl3) δ8.08-8.04(m,1H),7.54-7.48(m,1H),7.46-7.41(m,1H),7.32-7.26(m,2H),7.25-7.21(d,J=6.1Hz,2H),6.92(d,J=7 .9Hz,1H),5.37(s,1H),4.33-3.75(m,4H),2.66-2.04(m,4H),2.03-1.98(m,1H),1.90-1.86(m,1H),0.88-0.84(m,2H),0.75-0.71(m,2H).

[0408] Example 18: (2-chlorothiazol-4-yl)(3-hydroxy-5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)methanone

[0409] 26.7 mg (0.16 mmol, 1.0 eq) of 2-chlorothiazole-4-carboxylic acid, 74.2 mg (0.41 mmol, 1.2 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 63.0 mg (0.48 mmol, 3.0 eq) of N,N-diisopropylethylamine, and 3 mL of tetrahydrofuran were added to a 25 mL reaction flask. Under nitrogen, the reaction solution was stirred at room temperature for 10 minutes. Then, 50.0 mg (0.16 mmol, 1.0 eq) of 5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol was weighed and dissolved in 3 mL of tetrahydrofuran. The solution was slowly added to the reaction solution and stirred at room temperature for 1 hour. TLC (DCM / MeOH = 20 / 1) confirmed complete reaction of the starting materials. The reaction solution was concentrated to dryness and 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 pure product as a white solid (5.11 mg, yield = 7%).

[0410] LC-MS: (M-OH) + ; m / z = 435.07;

[0411] 1 H NMR (400MHz, CDCl3) δ8.08-8.04(m,1H),7.45-7.28(m,4H),7.26-7.11(m,3H),5.36-5.3 3(m,1H),4.37-3.73(m,4H),3.12-3.00(m,1H),2.65-1.99(m,5H),1.18(d,J=6.8Hz,6H).

[0412] Example 19: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(6-cyclopropylpyridin-2-yl)methanone

[0413] 117.4 mg (0.72 mmol, 1.5 eq) of 6-cyclopropylpicolinic acid, 0.24 mL of N,N-diisopropylethylamine, and 279 mg (0.72 mmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 5 mL of tetrahydrofuran and stirred at room temperature for 0.5 h. 150.0 mg (0.48 mmol, 1.0 eq) of 5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was added and stirred at room temperature for 3 h. The product was confirmed to be generated by LC-MS, and 5 mL of brine was added thereto, followed by extraction with ethyl acetate three times, drying over anhydrous sodium sulfate, and evaporation to dryness under reduced pressure. The product was prepared and purified (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 a white solid (53.0 mg, yield = 24%).

[0414] LC-MS: (M+H) + ; m / z = 451.19;

[0415] 1 H NMR (400MHz, CDCl3) δ7.72-7.59(m,2H),7.52-7.48(m,1H),7.46-7.40(m,1H),7.34 -7.27(m,1H),7.25-7.15(m,4H),6.92(dd,J=7.8,4.0Hz,1H),5.39-5.27(m,1H),4.2 1-3.77(m,4H),2.68-2.51(m,1H),2.41-2.14(m,2H),2.11-2.00(m,2H),1.91-1.83 (m,2H),1.08-0.99(m,2H),0.96-0.92(m,2H),0.89-0.82(m,2H),0.77-0.69(m,2H).

[0416] Example 20: (6-cyclopropylpyridin-2-yl)(3-hydroxy-5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)methanone

[0417] 26.6 mg (0.16 mmol, 1.0 eq) of 6-cyclopropylpicolinic acid, 74.2 mg (0.41 mmol, 1.2 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 63.0 mg (0.48 mmol, 3.0 eq) of N,N-diisopropylethylamine, and 3 mL of tetrahydrofuran were added to a 25 mL reaction flask. Under nitrogen, the reaction solution was stirred at room temperature for 10 minutes. Then, 50.0 mg (0.16 mmol, 1.0 eq) of 5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol was weighed and dissolved in 3 mL of tetrahydrofuran and slowly added to the reaction solution. The mixture was stirred at room temperature for 1 hour. TLC (DCM / MeOH = 20 / 1) confirmed complete reaction of the starting materials. The reaction solution was concentrated to dryness and 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) to obtain the pure product as a yellow oil (7.93 mg, yield = 10%).

[0418] LC-MS: (M+H) + ; m / z = 453.16;

[0419] 1 H NMR (400MHz, CDCl3) δ7.84-7.52(m,3H),7.41-7.28(m,4H),7.24-7.13(m,3H),5.42-5.27(m,1H), 4.17-3.80(m,4H),3.07-2.97(m,1H),2.49-2.06(m,6H),1.20(d,J=6.6Hz,6H),1.07-0.94(m,4H).

[0420] The examples in Table 1 were prepared by subjecting compound examples 15, 16, 17, 18, 19 and 20 to separation of stereoisomers by supercritical fluid chromatography (SFC).

[0421] Analytical conditions:

[0422] Instrument:WATERS 150 preparative SFC (SFC-26)

[0423] Column: ChiralCel OD, 250×30mm ID, 10μm

[0424] Pressure: 100 bar

[0425] Column temperature: 38°C

[0426] Wavelength: 220nm

[0427] Mobile phase A: CO2; Mobile phase B: methanol; Gradient: 30% B, 9.5 minutes; Flow rate: 150 mL / min

[0428] Table 1: Examples 21 to 44

[0429] Example 45: ((3R)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone

[0430] Step A: (3R)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-5'-one

[0431] 50.0 mg (0.16 mmol, 1.0 eq) of 5-bromospiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione was dissolved in 5 mL of anhydrous tetrahydrofuran. 4.37 mg (0.016 mmol, 0.1 eq) of (S)-3,3-diphenyl-1-methylpyrrolidinone[1,2-c]-1,3,2-oxaborolane and 4.37 mg (0.096 mmol, 0.6 eq) of borane dimethyl sulfide were added and stirred at room temperature for 3 h. LCMS confirmed the formation of the product. The reaction solution was quenched with methanol and evaporated to dryness under reduced pressure to obtain the crude product (46.0 mg, yield = 91%).

[0432] LC-MS: (M+H) + ; m / z = 320.16;

[0433] Step B: (3R)-5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol

[0434] 46.0 mg (0.14 mmol, 1.0 eq) of (3R)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-5'-one was dissolved in 5 mL of anhydrous tetrahydrofuran. 55.0 mg (1.40 mmol, 10.0 eq) of lithium aluminum hydride was slowly added at 0°C, and the mixture was stirred at 70°C for 2 h. LCMS confirmed the formation of the product. The reaction solution was filtered through celite and washed with tetrahydrofuran. The mixture was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to obtain the crude product (39.0 mg, yield = 88%).

[0435] LC-MS: (M+H) +; m / z = 306.17;

[0436] Step C: ((3R)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone

[0437] 27.0 mg (0.19 mmol, 1.5 eq) of 5-fluoropyridine-2-carboxylic acid, 0.06 mL of N,N-diisopropylethylamine, and 73.0 mg (0.19 mmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 5 mL of tetrahydrofuran and stirred at room temperature for 0.5 h. 39.0 mg (0.13 mmol, 1.0 eq) of (3R)-5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was added and stirred at room temperature for 1.5 h. The product was confirmed to be generated by LCMS, and 5 mL of brine was added thereto, followed by extraction three times with ethyl acetate, drying over anhydrous sodium sulfate, and evaporation under reduced pressure. The product was prepared and purified (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) to give a white solid (8.00 mg, yield = 13%, dr = 86:14).

[0438] LC-MS: (M+H) + ; m / z = 429.20;

[0439] 1 H NMR (400MHz, CDCl3) δ8.44(dd,J=38.5,3.2Hz,1H),8.09-8.04(m,1H),7.56-7.44(m,3H),7.34-7.19(m,4H),6.94(dd,J=7.9, 4.2Hz,1H),5.42-5.30(m,1H),4.27-3.80(m,4H),2.70-2.03(m,5H),1.94-1.85(m,1H),0.89-0.84(m,2H),0.76-0.72(m,2H).

[0440] 19 F NMR (376MHz, CDCl3) δ-126.50 (d, J=20.5Hz).

[0441] Example 46: ((3S)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone

[0442] Step A: (3S)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-5'-one

[0443] 50.0 mg (0.164 mmol, 1.0 eq) of 5-bromospiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione was dissolved in 5 mL of anhydrous tetrahydrofuran. 4.37 mg (0.016 mmol, 0.1 eq) of (R)-3,3-diphenyl-1-methylpyrrolidinone[1,2-c]-1,3,2-oxaborolane and 4.37 mg (0.096 mmol, 0.6 eq) of borane dimethyl sulfide were added and stirred at room temperature for 3 h. LCMS confirmed the formation of the product. The reaction solution was quenched with methanol and evaporated to dryness under reduced pressure to obtain the crude product (48.0 mg, 95% yield).

[0444] LC-MS: (M+H) + ; m / z = 320.14;

[0445] Step B: (3S)-5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol

[0446] 48.0 mg (0.15 mmol, 1.0 eq) of (3S)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-5'-one was dissolved in 5 mL of anhydrous tetrahydrofuran. 57.0 mg (1.5 mmol, 10.0 eq) of lithium aluminum hydride was slowly added at 0°C, and the mixture was stirred at 70°C for 2 h. LCMS confirmed the formation of the product. The reaction solution was filtered through celite and washed with tetrahydrofuran. The mixture was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to obtain the crude product (43.0 mg, yield = 93%).

[0447] LC-MS: (M+H) + ; m / z = 306.16;

[0448] Step C: ((3S)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone

[0449] 30.0 mg (0.21 mmol, 1.5 eq) of 5-fluoropyridine-2-carboxylic acid, 0.07 mL of N,N-diisopropylethylamine, and 80.0 mg (0.21 mmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 5 mL of tetrahydrofuran and stirred at room temperature for 0.5 h. 43.0 mg (0.14 mmol, 1.0 eq) of (3S)-5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was added and stirred at room temperature for 1.5 h. The product was confirmed to be generated by LCMS, and 5 mL of brine was added thereto, followed by extraction three times with ethyl acetate, drying over anhydrous sodium sulfate, and evaporation under reduced pressure. The product was purified by preparative method (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) to give a white solid (2.20 mg, yield = 4.0%, dr = 75:15).

[0450] LC-MS: (M+H) + ; m / z = 429.20;

[0451] 1 H NMR (400MHz, CDCl3) δ8.44(dd,J=38.5,3.2Hz,1H),8.09-8.04(m,1H),7.56-7.44(m,3H),7.34-7.19(m,4H),6.94(dd,J=7.9, 4.2Hz,1H),5.42-5.30(m,1H),4.27-3.80(m,4H),2.70-2.03(m,5H),1.94-1.85(m,1H),0.89-0.84(m,2H),0.76-0.72(m,2H).

[0452] 19 F NMR (376MHz, CDCl3) δ-126.82 (d, J=22.5Hz).

[0453] Example 47: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(6-(methoxymethyl)pyridin-2-yl)methanone

[0454] Step A: Methyl 6-(methoxymethyl)picolinate

[0455] 1.00 g (5.98 mmol, 1.0 eq) of methyl 6-(hydroxymethyl)picolinate was dissolved in 30 mL of anhydrous tetrahydrofuran and the atmosphere was replaced with nitrogen three times. 0.36 g (8.97 mmol, 1.5 eq) of sodium hydride was added at 0°C and stirred at room temperature for 0.5 h. 1.70 g (12.0 mmol, 2.0 eq) of iodomethane was then added dropwise at 0°C and stirred overnight at room temperature. LCMS confirmed the complete reaction of the starting material. The product was quenched with 50 mL of water and extracted three times with dichloromethane. The organic layer was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 0-20:1) to afford the product (222 mg, yield = 20%).

[0456] LC-MS: (M+H) + ; m / z = 182.04;

[0457] Step B: 6-(Methoxymethyl)picolinic acid

[0458] Dissolve 220 mg (1.21 mmol, 1.0 eq) of methyl 6-(methoxymethyl)picolinate in 3 mL of tetrahydrofuran, then add 3 mL of 0.5 mol / L sodium hydroxide solution and stir at room temperature for 3 hours. LCMS confirms the formation of the product. The reaction mixture is diluted with 1.0 mol / L hydrochloric acid solution until acidic and evaporated to dryness under reduced pressure to obtain the crude product (0.15 g, yield = 74%).

[0459] LC-MS:(MH) + ; m / z = 168.05;

[0460] Step C: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(6-(methoxymethyl)pyridin-2-yl)methanone

[0461] 41.0 mg (0.24 mmol, 1.5 eq) of 6-(methoxymethyl)pyridine-2-carboxylic acid, 0.08 mL of N,N-diisopropylethylamine, and 93 mg (0.24 mmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 10 mL of tetrahydrofuran and stirred at room temperature for 0.5 h. 50.0 mg (0.16 mmol, 1.0 eq) of 5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was added and stirred at room temperature for 3 h. The product was confirmed to be generated by LCMS, and 5 mL of brine was added thereto, followed by extraction with ethyl acetate three times, drying over anhydrous sodium sulfate, and evaporation to dryness under reduced pressure. Preparative purification (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) afforded a white solid (11.0 mg, yield = 15%).

[0462] LC-MS: (M+H) + ; m / z = 455.16;

[0463] 1 H NMR (400MHz, CDCl3) δ7.86-7.76(m,2H),7.53-7.41(m,3H),7.32-7.26(m,2H ),7.22-7.17(m,2H),6.93-6.90(m,1H),5.38-5.27(m,1H),4.63-4.55(m,2H) ,4.08-3.78(m,4H),3.50-3.45(m,3H),2.68-2.35(m,2H),2.26-2.17(m,1H) ,2.14-2.00(m,2H),1.91-1.82(m,1H),0.89-0.82(m,2H),0.74-0.69(m,2H).

[0464] Example 48: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(6-(methylamino)pyrazin-2-yl)methanone

[0465] A 25 mL reaction flask was charged with 24.5 mg (0.16 mmol, 1.0 eq) of 6-(methylamino)pyrazine-2-carboxylic acid, 74.2 mg (0.41 mmol, 1.2 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 63.0 mg (0.48 mmol, 3.0 eq) of N,N-diisopropylethylamine, and 3 mL of tetrahydrofuran. Under nitrogen, the reaction solution was stirred at room temperature for 10 minutes. Subsequently, 50.0 mg (0.16 mmol, 1.0 eq) of 5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol was weighed and dissolved in 3 mL of tetrahydrofuran and slowly added to the reaction solution. The mixture was stirred at room temperature for 1 hour. TLC (DCM:MeOH = 20:1) confirmed complete reaction of the starting materials. The reaction solution was concentrated to dryness and 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 pure product as a white solid (8.42 mg, yield = 12%).

[0466] LC-MS: (M+H) + ; m / z = 441.14;

[0467] 1 H NMR(400MHz, CDCl3)δ8.29(d,J=18.5Hz,1H),8.03-7.96(m,1H),7.53-7.49(m,1H),7 .47-7.42(m,1H),7.32-7.27(m,1H),7.26-7.23(m,1H),7.22-7.19(m,2H),6.92(dd,J =8.0,4.1Hz,1H),5.40-5.28(m,1H),4.21-4.13(m,2H),3.97-3.78(m,3H),3.04-2.9 4(m,3H),2.66-1.97(m,5H),1.91-1.82(m,1H),0.88-0.82(m,2H),0.74-0.69(m,2H).

[0468] The examples in Table 2 were prepared by the method described above for Example 48, wherein intermediate I3 and the desired different carboxylic acids were prepared by condensation reaction.

[0469] Table 2: Examples 49 to 56

[0470] Example 57: (3-Hydroxy-5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(pyrazolo[1,5-a]pyrimidin-5-yl)methanone

[0471] 26.6 mg (0.16 mmol, 1.0 eq) of pyrazolo[1,5-a]pyrimidine-5-carboxylic acid, 74.2 mg (0.41 mmol, 1.2 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 63.0 mg (0.48 mmol, 3.0 eq) of N,N-diisopropylethylamine, and 3 mL of tetrahydrofuran were added to a 25 mL reaction flask. Under nitrogen, the reaction solution was stirred at room temperature for 10 minutes. Then, 50.0 mg (0.16 mmol, 1.0 eq) of 5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol was weighed and dissolved in 3 mL of tetrahydrofuran. The solution was slowly added to the reaction solution and stirred at room temperature for 1 hour. TLC (DCM / MeOH = 20:1) confirmed complete reaction of the starting materials. The reaction solution was concentrated to dryness and 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) to obtain the pure product as a white solid (8.54 mg, yield = 11%).

[0472] LC-MS: (M+H) + ; m / z = 453.37;

[0473] 1 H NMR (400MHz, CDCl3) δ8.79-8.74(m,1H),8.22-8.17(m,1H),7.53-7.48(m,1H),7.41-7.26(m,5H),7.23-7.13(m,2H),6.81-6.7 3(m,1H),5.41-5.30(m,1H),4.41-3.81(m,4H),3.09-2.99(m,1H),2.70-2.39(m,2H),2.30-2.00(m,3H),1.17(d,J=6.8Hz,6H).

[0474] The examples in Table 3 were prepared by the method described above for Example 57, wherein intermediate I4 and the desired different carboxylic acids were prepared by condensation reaction.

[0475] Table 3: Examples 58-77

[0476] Example 78: (5-Fluoropyridin-2-yl)(3-hydroxy-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl)methanone

[0477] Step A: 5-(Imidazolo[1,2-a]pyridin-6-yl)spiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione

[0478] To a 20 mL Shrek tube was added 100 mg (0.36 mmol, 1.0 eq) of 5-bromospiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione, 105 mg (0.43 mmol, 1.2 eq) of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine, 227 mg (1.07 mmol, 3.0 eq) of potassium phosphate, 26.1 mg (0.04 mmol, 0.1 eq) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, and 8 mL of a mixed solvent (1,4-dioxane / water = 4:1). The atmosphere was purged with nitrogen three times and the reaction was carried out at 100°C for 3 hours. LCMS confirmed the formation of the desired product. The reaction solution was quenched by adding 10 mL of water, and then extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried, and concentrated. The crude product was purified by column chromatography (PE / EA = 50:1 to 1 / 1) to give 105 mg of brown oily product (yield = 93%).

[0479] LC-MS: (M+H) + ; m / z = 318.09;

[0480] Step B: 5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol

[0481] In a 50 mL Shrek tube, dissolve 120 mg (0.38 mmol, 1.0 eq) of 5-(imidazo[1,2-a]pyridin-6-yl)spiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione in 5 mL of tetrahydrofuran. Under nitrogen, slowly add 144 mg (3.78 mmol, 10.0 eq) of lithium aluminum tetrahydride. After addition, heat the system to 70°C and allow to react for 3 hours. LCMS confirms the formation of the desired product. Cool the reaction mixture to -10°C and slowly add 3 mL of water to quench the reaction. Add 20 mL of tetrahydrofuran to the reaction mixture, filter through celite, and wash the filter cake with 3 mL of tetrahydrofuran (20 mL). Concentrate the filtrate to dryness to yield 158 mg of the crude product as a yellow oil. Proceed directly to the next step.

[0482] LC-MS: (M+H) + ; m / z = 310.12;

[0483] Step C: (5-Fluoropyridin-2-yl)(3-hydroxy-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)methanone

[0484] 65.7 mg (0.47 mmol, 1.2 eq) of 5-fluoropyridine-2-carboxylic acid, 177 mg (0.47 mmol, 1.2 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 301 mg (2.33 mmol, 6.0 eq) of N,N-diisopropylethylamine, and 6 mL of tetrahydrofuran were added to a 25 mL reaction flask. Under nitrogen, the reaction solution was stirred at room temperature for 10 minutes. A solution of 120 mg (0.39 mmol, 1.0 eq) of 5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol dissolved in 4 mL of tetrahydrofuran was then added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. LCMS confirmed the formation of the desired product. The reaction solution was concentrated to dryness and sent for preparative purification (mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) to obtain the pure product as a white solid (25.2 mg, yield = 15%).

[0485] LC-MS: (M+H) + ; m / z = 433.15;

[0486] 1H NMR (400MHz, CDCl3) δ8.46-8.31(m,1H),8.02-7.91(m,1H),7.54-7.44(m,1H),7.22-6.83(m,5H) ,5.28-5.18(m,2H),4.11-3.56(m,6H),2.60-2.19(m,2H),2.13-1.94(m,5H),1.32-1.14(m,3H).

[0487] 19 F NMR (376MHz, CDCl3) δ-122.93 (d, J=75.2Hz).

[0488] Example 79: (5-Fluoropyridin-2-yl)(3-hydroxy-5-(imidazo[1,2-a]pyridin-6-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)methanone

[0489] To a 20 mL Shrek tube was added 100 mg (0.26 mmol, 1.0 eq) of (5-bromo-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin-1'-yl)(5-fluoropyridin-2-yl)methanone, 74.9 mg (0.31 mmol, 1.2 eq) of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine, 163 mg (0.77 mmol, 3.0 eq) of potassium phosphate, 18.7 mg (0.03 mmol, 0.1 eq) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, and 6 mL of a mixed solvent (1,4-dioxane / water = 4:1). The atmosphere was purged with nitrogen three times and the reaction was carried out at 100°C for 3 hours. LCMS confirmed the formation of the desired product. The reaction solution was quenched by adding 10 mL of water, and then extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried, and concentrated. The crude product was sent for preparative purification (mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to obtain the pure product as a white solid.

[0490] LC-MS: (M+H) + ; m / z = 433.15.

[0491] 1H NMR (400MHz, CDCl3) δ8.47-8.29(m,1H),8.30(d,J=8.8Hz,1H),8.05(dd,J=8.4,4.2Hz,1H),7.68-7.47 (m,6H),7.42-7.32(m,2H),5.40-5.31(m,1H),4.25-3.75(m,4H),2.70-2.34(m,2H),2.23-2.01(m,3H).

[0492] 19F NMR (376MHz, CDCl3) δ-123.10 (dd, J=18.8, 7.5Hz).

[0493] Example 80: (5-(2-ethylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone

[0494] Step A: 5-(2-ethylphenyl)spiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione

[0495] 100.0 mg (0.4 mmol, 1.0 eq) of 5-bromospiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione was dissolved in 2 mL of 1,4-dioxane. 53.5 mg (0.4 mmol, 1.0 eq) of 2-ethylphenylboronic acid, 20.6 mg (0.02 mmol, 0.05 eq) of tetrakis(triphenylphosphine)palladium, 98.7 mg (0.7 mmol, 2.0 eq) of potassium carbonate, and 0.4 mL of water were added to the reaction system. After nitrogen was replaced, the temperature was raised to 100°C and the reaction was allowed to react for 2 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. 5-(2-ethylphenyl)spiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione (109 mg, yield = 100%) was obtained.

[0496] LC-MS: (M+H) + ; m / z = 306;

[0497] Step B: 5-(2-ethylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol

[0498] 109.0 mg (0.4 mmol, 1.0 eq) of 5-(2-ethylphenyl)spiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione was dissolved in 3 mL of anhydrous tetrahydrofuran and the atmosphere was replaced with nitrogen. The system was cooled to 0°C, and then 40.6 mg (1.1 mmol, 3.0 eq) of lithium aluminum tetrahydride was slowly added to the solution. After the addition was complete, the temperature was raised to 75°C and the reaction was allowed to proceed for 3 hours. After LC-MS results confirmed the reaction was complete, the system was cooled to 0°C and quenched with 10 μL of water, followed by 10 μL of 15% aqueous sodium hydroxide solution. The solution was then dried over anhydrous magnesium sulfate. The filtrate was filtered and concentrated by vacuum distillation to yield 5-(2-ethylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3-ol (105 mg, yield = 100%).

[0499] LC-MS: (M+H) + ; m / z = 294;

[0500] Step C: (5-(2-ethylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone

[0501] 50.4 mg (0.4 mmol, 1.0 eq) of 5-fluoro-2-pyridinecarboxylic acid was dissolved in 2 mL of N,N-dimethylformamide. After replacing the atmosphere with nitrogen, 149.3 mg (0.4 mmol, 1.1 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and 92.2 mg (0.7 mmol, 2.0 eq) of N,N-diisopropylethylamine were added sequentially. After stirring at room temperature for 1 minute, 105 mg (0.4 mmol, 1.0 eq) of 5-(2-ethylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was added and stirring continued for 30 minutes. LC-MS results confirmed the reaction was complete. The mixture was diluted with 10 mL of saturated sodium chloride solution and 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 sequentially by column chromatography (EA / PE = 0-1:1) and preparative chromatography (mobile phase A: 0.1% trifluoroacetic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) to give (5-(2-ethylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone (76.9 mg, yield = 52%) as a white solid.

[0502] LC-MS: (M+H) + ; m / z = 417.14;

[0503] 1H NMR (400MHz, CDCl3) δ8.51-8.33(m,1H),8.05(dd,J=8.5,4.4Hz,1H),7.55-7.47(m,1H),7.39-7.27(m, 5H),7.23-7.16(m,2H),5.35-5.32(m,1H),4.21-3.81(m,4H),2.68-2.03(m,7H),1.13(t,J=8.0Hz,3H).

[0504] The examples in Table 4 were prepared by the method of Example 79 or Example 80 described above, substituting different boronic acids or boronic esters as required to prepare the same by Suzuki reaction or the like.

[0505] Table 4: Examples 81-102

[0506] Example 103: (5-Fluoropyridin-2-yl)(3-hydroxy-6-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)methanone

[0507] Step A: Diethyl 3-(3-bromophenyl)-3-cyanopentanedioate

[0508] 5.00 g (25.5 mmol, 1.0 eq) of 2-(3-bromophenyl)acetonitrile was dissolved in 50 mL of anhydrous tetrahydrofuran and the atmosphere was replaced with nitrogen three times. The mixture was cooled to -60°C with dry ice. 5.00 g (56.1 mmol, 2.2 eq) of lithium bistrimethylsilylamide was added dropwise at -60°C and stirred at room temperature for 3 h. Then, 8.94 g (53.6 mmol, 2.0 eq) of ethyl bromoacetate was added dropwise below -60°C and stirred at room temperature overnight. LC-MS confirmed the complete reaction of the starting material. The mixture was quenched with 50 mL of water and extracted three times with ethyl acetate. The organic layer was washed with 50 mL of saturated saline solution, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain the crude product (10.6 g, yield = 100%).

[0509] LC-MS: (M+Na+H) + ; m / z=391.87,393.91.

[0510] Step B: Ethyl 2-(3-(3-bromophenyl)-5-oxopyrrolidin-3-yl)acetate

[0511] Dissolve 10.0 g (27.2 mmol, 1.0 eq) of diethyl 3-(3-bromophenyl)-3-cyanopentanedioate in 50 mL of methanol, add 7.05 g (54.31 mmol, 2.0 eq) of anhydrous cobalt chloride, and slowly add 8.22 g (217.3 mmol, 8.0 eq) of sodium borohydride at 0°C. Stir at room temperature for 1 hour. LC-MS confirms the formation of the product, and the mixture is diluted with 50 mL of 3 mol / L hydrochloric acid. Extract three times with dichloromethane, wash the organic layer with 50 mL of saturated brine, dry over anhydrous sodium sulfate, and evaporate to dryness under reduced pressure to obtain the crude product (7.66 g, yield = 86%).

[0512] LC-MS: (M+H) + ; m / z=326.08,327.95.

[0513] Step C: 2-(3-(3-bromophenyl)-5-oxopyrrolidin-3-yl)acetic acid

[0514] 1.00 g (3.07 mmol, 1.0 eq) of ethyl 2-(3(3-bromophenyl)-5-oxopyrrolidin-3-yl)acetate was dissolved in 20 mL of methanol. 4.9 mL of sodium hydroxide solution (5 mmol / mL) was slowly added at 0°C, and the mixture was stirred at 40°C for 1 h. LC-MS confirmed the formation of the product. The reaction solution was diluted with hydrochloric acid solution (3.0 mol / L) until acidic, then extracted three times with dichloromethane. The organic layer was washed with 10 mL of saturated saline solution, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain a crude product (0.86 g, yield = 94%).

[0515] LC-MS:(MH) + ; m / z=297.98,299.76.

[0516] Step D: 6-Bromopyrrolo[indene-1,3'-pyrrolidine]-3,5'-2H-dione

[0517] 4.00 g of polyphosphoric acid was heated to 150°C, followed by the addition of 0.86 g (2.88 mmol, 1.0 eq) of 2-(3-(3-bromophenyl)-5-oxopyrrolidin-3-yl)acetic acid. The mixture was then stirred at 150°C for 1 hour. LC-MS confirmed the formation of the product, and the hot mixture was slowly poured into ice water with stirring. The mixture was then extracted three times with dichloromethane, and the organic layer was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 0-20:1) to afford the product (0.39 g, yield = 48%).

[0518] LC-MS: (M+H) +; m / z=279.91,281.91.

[0519] Step E: 6-(2-Isopropylphenyl)spiro[indene-1,3'-pyrrolidine]-3,5'-2H-dione

[0520] 150 mg (0.53 mmol, 1.0 eq) of 6-bromopyrrolo[indene-1,3'-pyrrolidine]-3,5'-2H-dione and 110 mg (0.64 mmol, 1.2 eq) of (2-cyclopropylphenyl)boronic acid were dissolved in 5 mL of a dioxane / water mixture (V:V = 4:1). 30 mg (0.05 mmol, 0.1 eq) of 1,1-bis(diphenylphosphino)diphenylferric palladium chloride and 0.34 g (1.6 mmol, 3.0 eq) of tripotassium phosphate were then added. The atmosphere was purged with nitrogen three times and stirred at 100°C for 1 hour. 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 brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain the crude product (162 mg, yield = 93%).

[0521] LC-MS: (M+H) + ; m / z = 320.10.

[0522] Step F: 6-(2-Isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol

[0523] 162 mg (0.50 mmol, 1.0 eq) of 5-bromopyrrolo[indene-1,3'-pyrrolidine]-3,5'-2H-dione was dissolved in 20 mL of tetrahydrofuran. 0.29 g (7.51 mmol, 15.0 eq) of lithium aluminum hydride was slowly added at 0°C, and the mixture was stirred at 70°C for 2 h. LC-MS confirmed the formation of the product. The reaction solution was filtered through celite and washed with tetrahydrofuran. The mixture was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to obtain the crude product (110 mg, yield = 71%).

[0524] LC-MS: (M+H) + ; m / z = 308.20.

[0525] Step G: (6-(2-Isopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone

[0526] 76.0 mg (0.54 mmol, 1.5 eq) of 5-fluoropyridine-2-carboxylic acid, 0.17 mL of N,N-diisopropylethylamine, and 204 mg (2.06 mmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were dissolved in 5 mL of tetrahydrofuran and stirred at room temperature for 0.5 h. 110 mg (0.36 mmol, 1.0 eq) of 6-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was added and stirred at room temperature overnight. The product was confirmed to be generated by LC-MS, and 10 mL of brine was added thereto, followed by extraction with ethyl acetate three times, drying over anhydrous sodium sulfate, and evaporation under reduced pressure. The product was prepared and purified (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) to give a white solid (16.0 mg, yield = 10%).

[0527] LC-MS: (M+H) + ; m / z = 431.13;

[0528] 1 H NMR (400MHz, CDCl3) δ8.44-8.36(m,1H),8.04-7.98(m,1H),7.51-7.44(m,2H),7.40-7.33(m,3H),7.23-7.13(m,3H),5.42-5.31(m,1H),4.1 6-3.74(m,4H),3.04-2.95(m,1H),2.70-2.33(m,2H),2.28-2.17(m,1 H),2.15-2.10(m,1H),2.08-2.01(m,1H),1.17-1.12(d,J=6.8Hz,6H).

[0529] Example 104: (5-Fluoropyridin-2-yl)(3-hydroxy-5-(2-isopropylphenoxy)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)methanone

[0530] 100.0 mg (0.256 mmol, 1.0 eq) of (5-bromo-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone was dissolved in 2 mL of 1,4-dioxane, and then 38.3 mg (0.282 mmol, 1.1 eq) of 2-isopropylphenol, 4.9 mg (0.0256 mmol, 0.1 eq) of cuprous iodide, 7.3 mg (0.0512 mmol, 0.2 eq) of trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine, and 163.0 mg (0.768 mmol, 3.0 eq) of potassium phosphate were added to the reaction system. After nitrogen was replaced, the temperature was raised to 100°C and the reaction was carried out for 18 hours. LC-MS confirmed the reaction was complete. 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 preparative chromatography (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 (5-fluoropyridin-2-yl)(3-hydroxy-5-(2-isopropylphenoxy)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)methanone (2.0 mg, yield = 2%) as a yellow solid.

[0531] LC-MS: (M+H) + ; m / z = 447.17;

[0532] 1 H NMR (400MHz, CDCl3) δ8.45-8.40(m,1H),8.03(s,1H),7.56-7.45(m,1H),7.3 8-7.33(m,1H),7.23-7.08(m,3H),7.00-6.80(m,3H),5.37-5.18(m,1H),4.1 7-3.97(m,2H),3.92-3.69(m,2H),3.31-3.20(m,1H),2.62-2.45(m,1H),2.3 8-2.21(m,1H),2.18-2.09(m,1H),2.08-1.95(m,2H),1.22(d,J=7.0Hz,6H).

[0533] The examples in Table 5 were prepared by the method of Example 15 described above, using the general intermediate I1 and the desired different phenols, thiophenols, aromatic amines or aromatic Grignard reagents, followed by reduction and condensation.

[0534] Table 5: Examples 105-116

[0535] The examples in Table 6 were prepared by the method described above for Example 14, by substituting different starting materials and reagents in the reaction.

[0536] Table 6: Examples 116-133

[0537] Example 134: 1'-((5-fluoropyridin-2-yl)methyl)-5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol

[0538] 50.0 mg (0.16 mmol, 1.0 eq) of 5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol, 24.5 mg (0.19 mmol, 1.2 eq) of 5-fluoropyridinaldehyde, and 5 mL of methanol were added to a 25 mL reaction flask. The temperature was cooled to 0°C, and 20.5 mg (0.32 mmol, 2.0 eq) of sodium cyanoborohydride was added to the reaction mixture. The mixture was warmed to room temperature and stirred for 20 minutes. LCMS confirmed complete reaction of the starting materials. The reaction mixture was quenched with 2 mL of water, concentrated to dryness, and sent for preparation. (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 obtain the pure product as a white solid (12.3 mg, yield = 18%).

[0539] LC-MS: (M+H) + ; m / z = 417.16;

[0540] 1 H NMR (400MHz, CDCl3) δ8.40 (d, J = 2.8Hz, 1H), 7.42-7.32 (m, 4H), 7.28-7.26 (m, 2H), 7.23-7.15 (m, 3H), 5.29- 5.21(m,1H),3.88-3.84(m,2H),3.08-2.89(m,2H),2.76-2.68(m,2H),2.37-2.33(m,1H),2.24-2.13(m,2H), 2.09-1.99(m,2H),1.17(d,J=6.8Hz,6H).

[0541] 19 F NMR (376MHz,CDCl3)δ-129.86.

[0542] Example 135: 1'-((5-chloropyridin-2-yl)sulfonyl)-5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol

[0543] 34.6 mg (0.16 mmol, 1.0 eq) 5-chloropyridine-2-sulfonyl chloride, 49.5 mg (0.48 mmol, 3.0 eq) triethylamine, 50.0 mg (0.16 mmol, 1.0 eq) 5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol, and 3 mL tetrahydrofuran were added to a 25 mL reaction vial. Under nitrogen, the mixture was stirred at room temperature for 1 hour. TLC (DCM / MeOH = 20:1) confirmed complete reaction. The reaction mixture was concentrated to dryness and sent for preparative purification (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30% to 70% B over 55 minutes; flow rate: 70 mL / min). The product was lyophilized to afford the pure product as a white solid (7.19 mg, yield = 9%).

[0544] LC-MS: (M+H) + ; m / z = 483.05;

[0545] 1 H NMR (400MHz, CDCl3) δ8.71-8.70(m,1H),7.99-7.89(m,2H),7.40-7.31(m,3H),7.26-7.12(m,4H),5.36-5.26(m,1H),3.90-3 .66(m,3H),3.59(m,1H),3.04-2.97(m,1H),2.52-2.30(m,2H),2.17-1.94(m,2H),1.85-1.80(m,1H),1.17(d,J=6.6Hz,6H).

[0546] The examples in Table 7 were prepared by the method described above for Example 135, by substituting different starting materials in the reaction under basic conditions.

[0547] Table 7: Examples 136-146

[0548] Example 147: (5-Fluoropyridin-2-yl)(3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)methanone

[0549] The experimental operation was carried out with reference to Example 15, except that the starting material p-bromophenylacetonitrile was replaced with benzyl cyanide, and Example 147 was prepared by synthesis.

[0550] LC-MS: (M+H) + ; m / z = 313.07

[0551] Example 148: (5-Fluoropyridin-2-yl)(3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)methanone

[0552] Compound I5 in Intermediate Preparation Example 5 is Example 148.

[0553] LC-MS: (M+H) + ; m / z = 391.01.

[0554] Example 149: 1'-(5-chloropyridin-2-yl)-5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-3-ol

[0555] 100 mg (327 μmol, 1.0 eq) of 5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was dissolved in 10 mL of N,N-dimethylformamide, and 94.0 mg (491 μmol, 1.5 eq) of 2-bromo-5-chloropyridine and 213 mg (654 μmol, 2.0 eq) of cesium carbonate were added. The atmosphere was purged with nitrogen three times and stirred at 100°C for 3 h. LC-MS confirmed the formation of the product. 10 mL of brine was added, and the product was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Preparative purification (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30% to 70% B over 55 minutes; flow rate: 70 mL / min) afforded a white solid (17.0 mg, yield = 12%).

[0556] LC-MS: (M+H) + ; m / z = 417.15;

[0557] 1H NMR (400MHz, CDCl3) δ8.13 (dd, J=5.9, 2.5Hz, 1H), 7.56-7.50 (m, 1H), 7.47-7.36 (m, 2H) ,7.30(dd,J=6.4,2.4Hz,1H),7.27-7.19(m,3H),6.94(d,J=7.7Hz,1H),6.43-6.32(m,1 H),5.45-5.34(m,1H),3.87-3.54(m,4H),2.63-2.61(m,1H),2.49-2.41(m,1H),2.31-2 .29(m,1H),2.25-2.08(m,2H),1.93-1.87(m,1H),0.92-0.80(m,2H),0.79-0.70(m,2H).

[0558] Example 150: 5-(2-Cyclopropylphenyl)-1'-(6-fluorobenzo[c]isothiazol-3-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol

[0559] Add 20.0 mg (65.0 μmol, 1.0 eq) of 5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol, 24.5 mg (131 μmol, 2.0 eq) of 3-chloro-6-fluorobenzo[c]isothiazole, 25.3 mg (196 μmol, 3.0 eq) of N,N-diisopropylethylamine, and 3 mL of DMF to a 25 mL reaction flask. The atmosphere was purged with nitrogen three times, and the temperature was raised to 80°C with stirring overnight. LC-MS confirmed complete reaction of the starting materials. After cooling, 20 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative chromatography (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 a white solid (1.36 mg, yield = 4%).

[0560] LC-MS: (M+H) + ; m / z = 457.12;

[0561] 1H NMR(400MHz, CDCl3)δ7.76(dd,J=9.8,5.1Hz,1H),7.54-7.51(m,1H),7.47-7.44(m,1 H),7.31-7.27(m,2H),7.24-7.21(m,2H),7.07(d,J=10.7Hz,1H),6.93(d,J=7.7Hz,1 H),6.67-6.63(m,1H),5.41(s,1H),3.98-3.76(m,4H),2.69-2.58(m,2H),2.47-2.42 (m,1H),2.31-2.18(m,2H),1.90-1.83(m,1H),0.87-0.84(m,2H),0.75-0.71(m,2H).

[0562] 19 F NMR (376MHz,CDCl3)δ-112.83.

[0563] Example 151: 1'-(5-chlorobenzo[d]thiazol-2-yl)-5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol

[0564] The experimental operation was carried out with reference to Example 149, and compound Example 151 was prepared by synthesis.

[0565] LC-MS: (M+H) + ; m / z = 475.06

[0566] Example 152: 5-(2-cyclopropylphenyl)-1'-(7-chloroimidazo[1,2-a]pyridin-3-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol

[0567] Intermediate I3 and 3-bromo-7-chloroimidazo[1,2-A]pyridine were reacted via Buchwald-Hartwig coupling reaction to give Example 152.

[0568] LC-MS: (M+H) + ; m / z = 456.08

[0569] The examples in Table 8 were prepared by the method described above for Example 152 by substituting different starting materials in the reaction and performing a Buchwald-Hartwig coupling reaction.

[0570] Table 8: Examples 153-158

[0571] Example 159: 2-(5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-carbonyl)-5-fluoropyridine-1-oxide

[0572] (5-(2-Cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl)(5-fluoropyridin-2-yl)methanone was dissolved in dichloromethane, and m-chloroperbenzoic acid was added to the mixture under ice-water bath, and Example 159 was prepared by oxidation.

[0573] LC-MS: (M+H) + ; m / z = 445.13

[0574] Example 160: 2-(3-(2'-cyclopropyl-3-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)pyrrolidine-1-carbonyl)-5-fluoropyridine-1-oxide

[0575] The experimental operation was carried out with reference to Example 159, and Example 160 was prepared by synthesis.

[0576] LC-MS: (M+H) + ; m / z = 433.15

[0577] Example 161: (5-Fluoropyridin-2-yl)(1-hydroxy-6-(2-isopropylphenyl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)methanone

[0578] Step A: 1-(tert-Butyl)4-ethyl-4-(4-bromobenzyl)piperidine-1,4-dicarboxylate

[0579] Under nitrogen protection, 10.0 g (38.9 mmol, 1.0 eq) of ethyl N-Boc-4-piperidincarboxylate and 60 mL of anhydrous tetrahydrofuran were added to a 250 mL three-necked flask, and 23.3 mL (46.7 mmol, 2 M, 1.2 eq) of lithium diisopropylamide solution was added dropwise at -70 to -60 ° C. Heat was released during the addition, and the reaction was kept warm for 1 hour after the addition was completed. 9.70 g (38.9 mmol, 1.0 eq) of tetrahydrofuran solution (25 mL) of p-bromobenzyl bromide was added dropwise at -70 to -60 ° C. The temperature was allowed to rise naturally after the addition was completed. The reaction was stirred for 4 hours, and the sample was taken for LC-MS control. The reaction was considered complete if the residual p-bromobenzyl bromide was less than 5%. The reaction solution was temperature controlled at 10-25 ° C and quenched by adding saturated ammonium chloride solution (60 mL), ethyl acetate (100 mL) was added, stirred for 10 minutes, allowed to stand for 5 minutes, and the liquids were separated. The aqueous phase was extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product (13.8 g), which was used directly in the next reaction without purification.

[0580] LC-MS:(M-100+H) + ; m / z = 325.98; 327.98.

[0581] Step B: 4-(4-bromobenzyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid

[0582] 5.00 g (11.7 mmol, 1.0 eq) of 1-(tert-butyl)-4-ethyl-4-(4-bromobenzyl)piperidine-1,4-dicarboxylate and 30 mL of methanol were added to a 250 mL single-necked flask. Aqueous sodium hydroxide (30 mL) containing 2.80 g (70.2 mmol, 6.0 eq) was added with stirring. The mixture was then heated to 85°C and refluxed for 24 hours. LC-MS confirmed complete conversion of the starting material. The reaction mixture was cooled, the methanol was concentrated under reduced pressure, and dichloromethane (150 mL) was added. The lower organic phase was separated and the pH was adjusted to 5-6 with 6 M hydrochloric acid. The phases were separated, and the aqueous phase was extracted once with dichloromethane (150 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a light yellow oil (4.50 g, yield = 96%).

[0583] LC-MS:(M-100+H) + ; m / z = 297.92; 299.92.

[0584] Step C: tert-Butyl 6-bromo-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate

[0585] 36.0 g of polyphosphoric acid was added to a 250 mL three-necked flask and heated to 120°C. 4.50 g (11.34 mmol, 1.0 eq) of 4-(4-bromobenzyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid was dissolved in 20 mL of dichloromethane and added dropwise with stirring. The mixture was stirred for 3 hours after addition. LC-MS analysis indicated no residual starting material, and the reaction was terminated. The hot reaction solution was slowly poured into 200 g of ice water to quench (quenching temperature was 25-35°C). The pH of the system was then adjusted to 9-10 with aqueous sodium hydroxide solution. 3.70 g (17.0 mmol, 1.5 eq) of di-tert-butyl dicarbonate was added and stirred at room temperature for 3 hours. The system was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a light yellow solid (4.00 g, yield = 93%).

[0586] LC-MS:(M-100+H) + ; m / z = 279.91; 281.90.

[0587] Step D: tert-Butyl 6-(2-isopropylphenyl)-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate

[0588] 1.10 g (2.89 mmol, 1.0 eq) of tert-butyl 6-bromo-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate and 569 mg (3.47 mmol, 1.2 eq) of (2-isopropylphenyl)boronic acid were dissolved in 10 mL of a 1,4-dioxane / water mixture (V:V = 4:1). 210 mg (289 μmol, 0.1 eq) of 1,1-bis(diphenylphosphino)diphenylferric palladium chloride and 1.84 g (8.67 mmol, 3.0 eq) of tripotassium phosphate were then added. The atmosphere was purged with nitrogen three times and stirred at 100°C for 1 hour. LC-MS confirmed the formation of the product. 50 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 0-10:1) to give a light yellow solid (780 mg, yield = 65%).

[0589] LC-MS:(M-100+H) + ; m / z = 320.12;

[0590] Step E: tert-Butyl 1-hydroxy-6-(2-isopropylphenyl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate

[0591] Dissolve 780 mg (1.86 mmol, 1.0 eq.) of tert-butyl 6-(2-isopropylphenyl)-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate in 10 mL of anhydrous methanol. Slowly add 106 mg (2.79 mmol, 1.5 eq.) of sodium borohydride at 0°C. Stir in an ice bath for 1 hour, then analyze by LC-MS to confirm complete conversion of the starting material and formation of the product. Quench the reaction mixture with saturated aqueous sodium carbonate solution, filter through celite, and wash with ethyl acetate. The organic phase is separated, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to yield a light yellow oil (800 mg).

[0592] LC-MS:(M-100+H) + ; m / z = 322.20;

[0593] Step F: 6-(2-Isopropylphenyl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-ol hydrochloride

[0594] 800 mg (1.89 mmol, 1.0 eq) of tert-butyl 1-hydroxy-6-(2-isopropylphenyl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate was dissolved in 10 mL of anhydrous dichloromethane. 2.0 mL of HCl / 1,4-dioxane solution (4 M) was added under ice-bath. After stirring under ice-bath for 1 hour, the mixture was analyzed by LC-MS. The conversion of the starting material was complete, and the mixture was concentrated under reduced pressure to give a light yellow solid (600 mg, yield = 88%).

[0595] LC-MS: (M+H) + ; m / z = 322.17;

[0596] Step G: 6-(2-Isopropylphenyl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-ol(5-fluoropyridin-2-yl)(1-hydroxy-6-(2-isopropenylphenyl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)methanone

[0597] Dissolve 29.6 mg (209.6 μmol, 1.5 eq) of 5-fluoropyridine-2-carboxylic acid, 90.1 mg (698.5 μmol, 5.0 eq) of N,N-diisopropylethylamine, and 79.7 mg (209.6 μmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate in 5 mL of tetrahydrofuran and stir at room temperature for 10 minutes. Add 50 mg (139.7 μmol, 1.0 eq) of 6-(2-isopropylphenyl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-ol hydrochloride and stir at room temperature for 1.5 hours. LC-MS confirmed that the raw material was completely converted and the product was generated. 50 mL of saturated sodium chloride aqueous solution was added thereto, followed by extraction three times with ethyl acetate, drying over anhydrous sodium sulfate, filtration and evaporation under reduced pressure. The product was sent for HPLC preparation and purification (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min), and lyophilization to obtain two isomers (Example 161A, 9.05 mg, yield = 15%; Example 161A, 3.11 mg, yield = 5%).

[0598] Example 161A: LC-MS: (M+H) + ; m / z = 427.23;

[0599] 1 H NMR (400MHz, CDCl3) δ8.43 (dd, J=5.8, 2.8Hz, 1H), 7.75-7.70 (m, 1H),7.53-7.48(m,1H),7.39-7.32(m,3H),7.28-7.25(m,1H),7.22-7.14(m,3H),4.87-4.84(m,1H),4.34-4.24(m,1H),3.85-3.81(m,1H) ,3.52-3.42(m,2H),3.14-3.01(m,2H),2.86-2.77(m,1H),2.06-1.95(m,1H),1.87-1.78(m,1H),1.77-1.65(m,2H),1.16(d,J=7.0Hz,6H).

[0600] 19 F NMR (376MHz, CDCl3) δ-123.95 (d, J=2.9Hz).

[0601] Example 161B: LC-MS: (M+H) + ; m / z = 427.18;

[0602] 1H NMR(400MHz, CDCl3)δ8.43(dd,J=5.8,2.8Hz,1H),7.75-7.70(m,1H),7.56-7.51(m,1 H),7.39-7.32(m,3H),7.27-7.25(m,1H),7.22-7.14(m,3H),4.87-4.84(m,1H),4.34 -4.24(m,1H),3.85-3.81(m,1H),3.52-3.42(m,2H),3.14-2.99(m,2H),2.88-2.83(m ,1H),2.05-1.96(m,1H),1.87-1.77(m,1H),1.74-1.65(m,2H),1.16(d,J=7.0Hz,6H).

[0603] 19 F NMR (376MHz, CDCl3) δ-123.96 (d, J=3.0Hz).

[0604] Example 162: (S)-5-(2-cyclopropylphenyl)-1'-(5-fluoropicolinyl)spiro[indene-1,3'-pyrrolidino]-3(2H)-one

[0605] 20.0 mg (46.7 μmol, 1.0 eq) of ((1S,3R)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone was dissolved in 1 mL of dichloromethane. 23.8 mg (56.0 μmol, 1.2 eq.) of Dess-Martin reagent was added to the reaction system, and the mixture was stirred at room temperature for 2 hours. LC-MS results confirmed the reaction was complete. The system was diluted with 5 mL of saturated sodium bicarbonate solution and 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 preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) to give (S)-5-(2-cyclopropylphenyl)-1'-(5-fluoropicolinyl)spiro[indene-1,3'-pyrrolidino]-3(2H)-one (11.7 mg, yield = 58.8%) as a white solid.

[0606] LC-MS: (M+H) + ; m / z = 427.17;

[0607] 1H NMR (400MHz, CDCl3) δ8.42(dd,J=44.0,2.8Hz,1H),8.09(d,J=4.1Hz,1H),7.84(d,J=9.9H z,1H),7.78(d,J=7.9Hz,1H),7.65-7.58(m,1H),7.52-7.51(m,1H),7.30-7.26(m,1H),7. 25-7.17(m,2H),6.97(dd,J=7.7,3.9Hz,1H),4.38-4.10(m,2H),4.09-3.86(m,2H),2.93- 2.69(m,2H),2.45-2.43(m,1H),2.18-2.17(m,1H),1.84-1.76(m,1H),0.87-0.83(m,2H), 0.73-0.70(m,2H).

[0608] Example 163: (5-(2-Cyclopropyl-4-fluorophenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone

[0609] 48.3 mg (0.30 mmol, 1.0 eq) of 5-fluoro-2-pyridinecarboxylic acid was dissolved in 2 mL of N,N-dimethylformamide. After replacing the atmosphere with nitrogen, 143 mg (0.40 mmol, 1.1 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and 88.5 mg (0.70 mmol, 2.0 eq) of N,N-diisopropylethylamine were added sequentially. After stirring at room temperature for 1 minute, 111 mg (0.30 mmol, 1.0 eq) of 5-(2-cyclopropyl-4-fluorophenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was added and stirring continued for 30 minutes. LC-MS results confirmed the reaction was complete. The mixture was diluted with 10 mL of saturated sodium chloride solution and 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 sequentially by column chromatography (methanol / dichloromethane = 0-1:40) and preparative chromatography (mobile phase A: 0.1% trifluoroacetic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) to give (5-(2-cyclopropyl-4-fluorophenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl)(5-fluoropyridin-2-yl)methanone (86.4 mg, yield = 57%) as a white solid.

[0610] LC-MS: (M+H + ) + ; m / z = 447.14;

[0611] 1 H NMR (400MHz, CDCl3) δ8.46-8.35(m,1H),8.06-8.01(m,1H),7.54-7.46(m,2H),7.42-7.39(m,1H),7.32-7.28(m,1H),7.01-6.86(m,3H),5.37-5. 28(m,1H),4.24-3.76(m,4H),2.68-2.46(m,1H),2.41-2.11(m,3H),2.0 9-2.00(m,1H),1.86-1.77(m,1H),0.85-0.79(m,2H),0.66-0.63(m,2H).

[0612] Example 164: 2-(2-(1'-(5-fluoropyridinoyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-5-yl)phenyl)-2-methylpropionitrile

[0613] 100 mg (256 μmol, 1.0 eq) of (5-bromo-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone was dissolved in 2 mL of 1,4-dioxane. 130 mg (511 μmol, 2.0 eq) of pinacol diboronate, 18.7 mg (25.6 μmol, 0.1 eq) of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, and 100 mg (1.02 mmol, 4.0 eq) of potassium acetate were added to the reaction system. The mixture was stirred at 100°C under nitrogen for 3 hours. After the system was cooled to room temperature, 57.3 mg (256 μmol, 1.0 eq) of 2-(2-bromophenyl)-2-methylpropionitrile, 23.6 mg (20.4 μmol, 0.08 eq) of tetrakis(triphenylphosphine)palladium, 70.7 mg (551 mmol, 2.0 eq) of potassium carbonate and 0.4 mL of water were added to the reaction system, and the reaction was stirred at 100 ° C under nitrogen protection for 2 hours. The reaction of the raw materials was confirmed to be complete by LC-MS results. The temperature was cooled to room temperature, 5 mL of water and 10 mL of ethyl acetate were added, and the organic phase was separated. The aqueous phase was extracted twice with ethyl acetate (10 mL). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by column chromatography (methanol / dichloromethane = 0-1:30) and preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 minutes; flow rate: 70 mL / min) to give a white solid (8.70 mg, yield = 7%).

[0614] LC-MS: (M+Na) +; m / z = 478.18;

[0615] 1 H NMR (400MHz, CDCl3) δ8.52-8.35(m,1H),8.11-7.97(m,1H),7.62-7.48(m,2H),7.48-7.37(m,2H),7.36-7.26(m,3H),7.20-7. 11(m,1H),5.43-5.26(m,1H),4.24-4.02(m,2H),4.02-3.81(m,2H),2.69-2.32(m,2H),2.24-2.02(m,3H),1.79-1.59(m,6H).

[0616] Example 165: 2-(3-(1'-(5-fluoropyridinoyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin-5-yl)phenyl)-2-methylpropionitrile

[0617] 180 mg (952 μmol, 1.0 eq) of (3-(2-cyanopropan-2-yl)phenyl)boronic acid was dissolved in 2 mL of 1,4-dioxane, and then 372 mg (952 μmol, 1.0 eq) of (5-bromo-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidino]-1'-yl)(5-fluoropyridin-2-yl)methanone, 34.8 mg (0.026 mmol, 0.05 eq) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 606 mg (2.85 mmol, 3.0 eq) of potassium phosphate and 0.4 mL of water were added to the reaction system. After nitrogen was replaced, the temperature was raised to 100°C and the reaction was carried out for 3 hours. The reaction was confirmed to be complete by LC-MS. The system was cooled to room temperature and diluted with 5 mL of saturated sodium chloride solution. The product was then extracted three times with 10 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30% to 70% B over 55 minutes; flow rate: 70 mL / min) and lyophilized to afford a white solid (22.0 mg, yield = 5%).

[0618] LC-MS: (M+H) + ; m / z = 456.23;

[0619] 1H NMR (400MHz, CDCl3) δ8.41(dd,J=47.8,2.8Hz,1H),8.06-8.04(m,1H),7.68-7.63(m,2H),7.60-7.43(m,5H),7.35(dd,J=10.3,7.9Hz,1H),5.3 9-5.32(m,1H),4.08-4.08(m,1H),3.94-3.93(m,1H),3.92-3.76(m,2H) ,2.70-2.53(m,1H),2.46-2.34(m,1H),2.26-1.99(m,3H),1.78(s,6H).

[0620] Inhibitory activity test of the compounds of the present invention

[0621] In this study, HEK-293 cells transiently expressing TRPV3 were used for experimental detection.

[0622] The steps are as follows:

[0623] The cells were cultured in DMEM medium containing 10% fetal bovine serum at 37°C and a carbon dioxide concentration of 5%.

[0624] Day 1: Seed cells into 6-well plates, 5×10 cells per well. 5 cell.

[0625] 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. To one tube, add 6 μL of Lipofectamine 3000 and mix thoroughly. To the other tube, add 3 μg of plasmid 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 incubate in an incubator. Change the medium after 4-6 hours.

[0626] Day 3: Digest the cells and seed them into 24-well plates with coverslips placed on them, with 8×10 cells per well. 3 cells.

[0627] Day 4: Patch clamp assay was performed.

[0628] The voltage stimulation protocol for whole-cell patch-clamp recording of TRPV3 currents was as follows: after whole-cell seal formation, the cell membrane voltage was clamped at -80 mV. The membrane potential was first recorded at 0 mV. Then, the voltage was 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 drugs on the peak current. Data were acquired using an EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0629] 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.

[0630] 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 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.

[0631] Each compound prepared was tested using the analytical procedure described above, and the results obtained are shown in Table 9. Details of the inhibition (%) at a concentration of 0.3 μM are shown in the table for selected examples, where "A" indicates an inhibition value of 70% to 100%, "B" indicates an inhibition value in the range of 50% to 69.99%, "C" indicates an inhibition value in the range of 25% to 49.99%, "D" indicates an inhibition value less than 25%, and "ND" indicates data not determined.

[0632] Table 9: Inhibition rate (%) of the compounds of the present invention on hTRPV3 at a single concentration (0.3 μM)

[0633] Table 10: Inhibition rate of compounds on different hTRP (0.3 μM) Note: “Selectivity ratio” refers to the ratio of the inhibition rate of the compound on TRPV3 ion channel to the inhibition rate of other ion channels at the same test concentration.

[0634] Liver microparticle metabolic stability test

[0635] 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.

[0636] 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.

[0637] 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.

[0638] Table 11: Liver microsome metabolic stability test results

[0639] Equilibrium dialysis test for plasma protein binding

[0640] 1. Soak the dialysis membrane (water: 60 min, 20% ethanol: 20 min, dialysis buffer: 20 min). 2. Dilute the test compound to 200 μM in dimethyl sulfoxide (working solution). 3. Thaw the plasma in a 37°C water bath and centrifuge the plasma at 3220g for 10 minutes to clear blood clots. 4. Transfer the supernatant to a new tube and preheat in a 37°C water bath for 10 minutes. 5. Assemble the HTD dialysis device according to the manufacturer's guidelines. 6. Add 3 μL of 200 μM test compound to 597 μL of plasma and spin at 1000 rpm for 2 minutes. 7. Transfer 50 μL of spiked plasma to a 96-well plate, then add 50 μL of dialysis buffer and 200 μL of methanol, with IS* as the T0 sample. 8. Add 120 μL of spiked plasma and 120 μL of dialysis buffer to the chamber of the HTD dialysis device in duplicate. 9. Cover the dialysis apparatus with a breathable cap and incubate the dialysis apparatus and the remaining spiked plasma at 37°C (100 rpm, 5% CO2) for 6 hours. 10. Transfer 50 μL of the dialyzed sample from the dialysis buffer and plasma compartments to separate 96-well plates, then add 50 μL of blank plasma or dialysis buffer and 200 μL of methanol, IS* as B and P samples. 11. Transfer 50 μL of the remaining spiked plasma (as described in step 9) to a 96-well plate, then add 50 μL of dialysis buffer and 200 μL of methanol, IS* as the T6 sample. 12. Centrifuge the sample plate at 3220 g for 40 minutes. 13. Transfer 100 μL of the supernatant to an analytical plate containing an appropriate volume of water for LC-MS / MS. 14. Data analysis.

[0641] Table 12: Results of plasma protein binding test of compounds of the present invention

[0642] Parallel artificial membrane permeability assay (lipid PAMPA) experiments

[0643] 1. Prepare the test compound in 10 mM DMSO and dilute 1000-fold with PBS to 10 μM. 2. Sonicate lecithin in dodecane at 18 mg / ml. 3. Add 300 μL / well of the 10 μM test compound solution to the donor chamber (bottom) in triplicate. 4. Add 5 μL / well of lecithin / dodecane to the acceptor chamber (top), followed by 300 μL / well of PBS (pH 7.4) over 10 minutes. 5. Transfer 50 μL of the 10 μM test compound to the sample plate containing 200 μL of cold methanol, IS* = C0. 6. Insert the acceptor chamber into the donor chamber and incubate at 25°C for 16 hours. 7. After the 16-hour incubation, transfer 50 μL from both the acceptor and donor chambers to the sample plate containing 200 μL of cold methanol and IS*. 8. Centrifuge the sample plate at 3220 g at 4°C for 40 minutes. 9. Transfer 100 μL of the supernatant to an assay plate containing an appropriate volume of H 2 O for LC-MS / MS analysis. 10. Data analysis.

[0644] Table 13: Results of the artificial membrane permeability test of the compounds of the present invention

[0645] Caco-2 cell permeability assay

[0646] Cell plate preparation:

[0647] 1. Preheat the Transwell plate: Before plating cells, add 100 μL of culture medium to the top layer and 600 μL of culture medium to the bottom layer of the Transwell plate. Pre-incubate at 37°C, 5% CO2 for 1 hour. 2. For Caco-2 cell culture, add 100 μL of cell suspension (4 x 105 cells / mL) to each well and culture in a 37°C, 5% CO2 incubator for 14-21 days. 3. Change the cell culture medium every other day for 7 days, and daily thereafter. 4. Measure the transepithelial electrical resistance (TEER) using the EVOM3.

[0648] Experimental process:

[0649] 1. Preheat HBSS (10mM HEPES, pH 7.4) buffer and wash the upper and lower layers of the Transwell plate twice, then incubate at 37°C for 30 min. 2. Working Solution: Dilute the test compound to 5μM in 1mM DMSO in HBSS buffer. 3. AB Direction: Add 200μL of 5μM working solution to the upper layer and 600μL of HBSS buffer to the lower layer. 4. BA Direction: Add 600μL of 5μM working solution to the lower layer and 200μL of HBSS buffer to the upper layer, and incubate for 2 hours. 5. C0 Sample: Transfer 100μL of working solution to a sample plate containing 400μL of methanol (internal standard). 6. After 2 hours of incubation, transfer 100μL from each of the upper and lower layers of the chamber to a sample plate containing 400μL of methanol (internal standard). 7. Mix and centrifuge. Mix the supernatant with a certain amount of water. Samples are then used for LC-MS / MS data analysis. 8. After completing step 6, add 200 μL of 100 μM Lucifer Yellow solution to the upper chamber and 600 μL of HBSS buffered saline to the lower chamber. Incubate at 37°C, 5% CO2 for 30 minutes. Remove 50 μL of each sample and place it on a black plate to read the fluorescence value. 9. Data analysis.

[0650] Table 14: Permeability test results of the compounds of the present invention on caco-2 cells

[0651] Pharmacokinetic experiments

[0652] Male SD rats were divided into groups of 3 per group and were administered the example compound (10 mg / kg) orally ...

[0653] Table 15: Pharmacokinetic parameters of different compounds after oral administration to rats at 10 mg / kg

[0654] Table 16: Pharmacokinetic parameters of the compound after intravenous administration of 2 mg / kg in rats

[0655] The above results indicate that the injectable and oral pharmacokinetic properties of the Example compounds of the present invention are superior to those of the existing compound KM-001 (Compound Example 2-72 in Patent WO2021154966A1, i.e., Example KM-001), and the oral bioavailability of the Example compounds reached 80.6%. The remaining Example compounds of the present invention were tested using the same method, and the resulting pharmacokinetic properties were also superior to those of KM-001.

[0656] Compound stability investigation

[0657] Taking compound Example 21 and compound KM-001-E1 in WO2021154966A1 as examples, the stability of the two was compared:

[0658] Compound Example 21 and KM-001-E1 were accurately weighed and placed in vials, respectively, and placed at room temperature and 92.5% humidity (open) for 5-10 days to investigate the stability of the compounds.

[0659] Analytical conditions:

[0660] Instrument: Thermo U3000-ISQEC

[0661] Column: Xtimate UHPLC C18 1.8μm 4.6*50mm

[0662] Column temperature: 35°C

[0663] Wavelength: 210nm, 254nm

[0664] Mobile phase A: 0.05% formic acid in water; Mobile phase B: 0.05% formic acid in acetonitrile; Gradient: 30% B 0-1.2 minutes, 95% B 1.2-3.3 minutes, 30% B 3.3-4.5 minutes;

[0665] By LC-MS analysis of the degradation impurities of each compound under the condition of 92.5% humidity, the main impurity of Example 21 has m / z = 427.17, retention time is 2.55min, and the peak area accounts for only 0.3% after 10 days; the main impurities of KM-001-E1 have m / z = 431.14 and m / z = 415.16, retention times are 2.31min and 2.64min respectively, and the peak area accounts for 2.48% and 2.43% respectively after 5 days. Based on the analysis of LC-MS and NMR data, it can be inferred that the main impurity produced in Example 21 is ketone, while the main impurities produced by KM-001-E1 are aldehydes and carboxylic acids. The specific structure is as follows:

[0666] From the above results, it can be seen that the stability of the example compounds of the present invention is better than that of the existing compound KM-001-E1.

[0667] The above-mentioned compound 21 in this case has a secondary alcohol structure and is more chemically stable than the primary alcohol compound in WO2021154966A1: although both are alcohols, the former can only be oxidized to ketones; the latter can be oxidized to aldehydes and further oxidized to carboxylic acids, and the number and level of oxidative impurities are greater than those of the above-mentioned compound 21 in this case.

[0668] Similarly, based on the same structural characteristics, the stability of the compounds in the embodiments of the present application with the same secondary alcohol structure is better than that of the compounds in WO2021154966A1.

[0669] 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. A nitrogen-containing spiro compound of formula (I) or its stereoisomers, tautomers, solvates, hydrates, oxides, active metabolites, isotope-labeled substances, or pharmaceutically acceptable salts, in, Ring A is selected from a monocyclic or polycyclic ring system containing 3 to 12 ring atoms; R 1 Each independently selected from H, halogen, hydroxy, mercapto, nitro, cyano, oxo, optionally substituted with 1-2 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; L1 is selected from a bond, or the following structural formula: X 1 is independently selected at each occurrence from C, O or N; X 2 is independently selected at each occurrence from C, O, B or N; X A 、X B 、X C Each independently CR x or N; R x Each independently selected from H, halogen, hydroxyl, thiol, nitro, cyano, 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 x 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 Wherein, L2 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; n is 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; m is 1 or 2; r is 1 or 2.

2. The nitrogen-containing spiro compound according to claim 1, wherein Ring A is selected from a benzene ring, a pyridine ring, a quinoline ring, a piperidine ring, a C3-C6 cycloalkyl ring, an isoquinoline ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, a thiazole ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, an isothiazole ring, an indole ring, a benzimidazole ring, a furan ring, an oxazole ring, an oxadiazole ring, a quinoxaline ring and a purine ring.

3. The nitrogen-containing spiro compound according to claim 1, wherein Ring A is selected from the following structural formula:

4. The nitrogen-containing spiro compound according to claim 1, 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.

5. The nitrogen-containing spiro compound according to claim 4, wherein R 1 Each is independently selected from H, Cl, F, -CF3, -CN, -CH3, -OH, -OCH3, -CH2OCH3.

6. The nitrogen-containing spiro compound according to claim 1, wherein R 2 Each independently selected from H, halogen, cyano, hydroxyl, mercapto, oxo, 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 、-CH(O)、-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.

7. The nitrogen-containing spiro compound according to claim 6, wherein R 2 Each independently selected from protium, deuterium, tritium, halogen, -SH, -OH, -OCF3, -CH3, -OCH3, -CF3, -NH2, -CN, -CONH2, -CH2OH, -CH(O), -CHF2, -COOH, -COOCH3, oxo and 8. The nitrogen-containing spiro compound according to claim 1, wherein L2 is each independently selected from a bond, -O-, -S-, -N-, -C(O)-, -CH2-, -CF2-, -C(OH)-, -S(O)- and -S(O2)-.

9. The nitrogen-containing spiro compound according to claim 1, 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.

10. The nitrogen-containing spiro compound according to claim 9, wherein Ring C is selected from the following structural formulas:

11. The compound according to claim 1, 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.

12. The nitrogen-containing spiro compound according to claim 11, wherein R 3 Each is independently selected from H, cyclopropyl, isopropyl, tert-butyl, F, Cl, CN, ethyl, methyl, trifluoromethoxy, methylcarbonyl, methoxymethyl, -C(CH3)2OH.

13. The nitrogen-containing spiro compound according to claim 1, wherein In formula I Select one of the following structural formulas: Among them, R 2 、X A 、X B 、X C And p is defined as in Formula I.

14. The nitrogen-containing spiro compound according to claim 1, wherein In formula I Select one of the following structural formulas: Among them, R 2 Each is independently selected from protium, deuterium, tritium, halogen, oxo, -SH, -OH, -CH3, -CN, -CONH2, -COOH, -COH, -COOCH3, -CF3, -OCH3, -CH2OH, -OCF3, -CHF2, and -NH2.

15. The nitrogen-containing spiro compound according to claim 14, wherein At least one R 2 It is -OH.

16. The nitrogen-containing spiro compound according to claim 14, wherein In formula I Select one of the following structural formulas: Among them, R 2 Each is independently selected from protium, deuterium, tritium, halogen, -CH3 and -CF3.

17. The nitrogen-containing spiro compound according to claim 1, wherein In formula I Selected from the following structural formula: Among them, R 2 independently selected from oxo, -SH, -CN, -CONH2, -COOH, -COH, -COOCH3, -OCH3, -CH2OH, -CHF2, -OCF3 and -NH2.

18. The nitrogen-containing spiro compound according to claim 1, wherein In formula I Selected from the following structural formula:

19. The nitrogen-containing spiro compound according to claim 1, wherein L1 is 20. The nitrogen-containing spiro compound according to claim 1, wherein Ring A is Alternatively, Ring A is Alternatively, Ring A is 21. The nitrogen-containing spiro compound according to claim 1, wherein The compound is selected from the following compounds:

22. A pharmaceutical composition comprising the compound according to any one of claims 1 to 21 or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotope-labeled substance or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

23. Use of the compound according to any one of claims 1 to 21 or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotope-labeled substances or pharmaceutically acceptable salts, and the pharmaceutical composition according to claim 22 in the preparation of a medicament for inhibiting TRPV3 activity.

24. Use of the compound of any one of claims 1 to 21 or its stereoisomers, tautomers, solvates, hydrates, active metabolites, isotopically labeled substances or pharmaceutically acceptable salts, and the pharmaceutical composition of claim 22 in the preparation of a medicament for treating a TRPV3-mediated disorder in a subject.

25. The use according to claim 24, 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.

26. The use according to claim 24, wherein The pain is cancer pain and skin pain.

27. The use according to claim 26, wherein Used for preparing drugs for inhibiting proliferation, thereby preventing, treating or alleviating cancer symptoms.

28. The use according to claim 27, wherein The cancer is liposarcoma.

29. The method according to claim 25, wherein The abnormal hair growth is alopecia.

30. The use according to claim 25, wherein The skin disorder is selected from the group consisting of keratosis pilaris, ichthyosis, and pruritus.

31. The use according to claim 30, wherein Keratosis pilaris is Olmsted syndrome.

32. The use according to claim 31, wherein The ichthyosis is harlequin ichtyosis.

33. 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 21 or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically labeled substance, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 22, to a patient in need thereof.

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