Nitrogen-containing spirocyclic compounds, pharmaceutical compositions and uses thereof

Abstract

The present application relates to a nitrogen-containing spirocyclic compound, a pharmaceutical composition, and uses thereof. The nitrogen-containing spirocyclic compound has the structural formula (I). The compound of the present invention has inhibitory activity against TRPV3 and can be used as a TRPV3 antagonist or inhibitor. JPEG2025537242000218.jpg36133

Description

[Technical Field]

[0001] The present invention relates to the pharmaceutical field, and more particularly to a nitrogen-containing spirocyclic compound, a pharmaceutical composition containing the stereoisomer or deuterated form of the compound, and uses of the compound and pharmaceutical composition. [Background technology]

[0002] Transient receptor potential (TRP) proteins are a class of ion channel proteins present in the plasma membrane or membranes of intracellular organelles. They include seven subfamilies: TRPC, TRPV, TRPM, TRPML, TRPP, TRPA, and TRPN. Furthermore, the mammalian transient receptor potential vanilloid receptor subfamily (TRPV) includes TRPV1-6. ​​Recent studies have shown that TRPV3 is primarily expressed in human skin keratinocytes and plays an important role in mediating skin sensation, influencing epidermal keratinocyte proliferation and differentiation and hair growth, participating in inflammatory responses, and maintaining skin homeostasis and normal function. This ion channel is regulated by many factors, such as temperature, osmotic pressure, pH, mechanical force, 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), and TRPV3 inhibitors hold potential therapeutic promise for treating pruritic skin disorders, inflammatory disorders, hair growth disorders, and painful skin disorders. TRPV3 is primarily expressed in skin keratinocytes, but also in tissues such as the tongue, dorsal root ganglion, trigeminal ganglion, spinal cord, and brain. It primarily detects thermal stimuli (32–39°C). The thermal sensitivity of TRPV3 is regulated by calcium in the extracellular fluid, and repeated exposure to heat stimulates the channel current, which continues to increase. It is possible that free nerve endings beneath the skin detect and transmit thermal stimuli through signaling molecules similar to those present in thermosensitive neurons. Therefore, TRPV3 holds potential therapeutic promise for treating painful disorders.

[0003] TRPV3 is activated by monoterpenoid compounds (camphor, borneol, peppermint, etc.) and induces the release of intracellular divalent calcium ions (Ca 2+ Research has shown that TRPV3 inhibitors work by increasing the levels of TRPV3. These aromatic compounds have anti-inflammatory, analgesic, and anti-itching effects and are widely used in pharmaceuticals, cosmetics, and other fields. However, most of these early TRPV3 inhibitors were natural products, lacked specificity, and required high effective doses, potentially causing severe side effects. Research and development of these inhibitors was largely halted due to mediocre molecular structure activity. Existing TRPV3 inhibitors have limited structural types, slowing their development. The development of novel molecules with novel structures and clinical value is needed. Summary of the Invention

[0004] The present application relates to a nitrogen-containing spirocyclic compound of formula (I): JPEG2025537242000002.jpg48168Provided are its stereoisomers, tautomers, solvates, hydrates, epoxides, active metabolites, isotopically labeled compounds, and pharmaceutically acceptable salts.

[0005] wherein ring A is selected from the group consisting of monocyclic or polycyclic ring systems containing 3-12 ring atoms; R 1 are each independently H, halogen, hydroxy, mercapto, nitro, cyano, oxo, 0-2 R f C1-C6 alkyl substituted with 0-2 R f C1-C6 haloalkyl substituted with 0-2 R f C1-C6 alkyloxy substituted with 0-2 R f C1-C6 haloalkyloxy 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 cycloalkyloxy substituted with 0-2 R f C3-C6 halocycloalkyloxy substituted with 0-2 R f aryl substituted with 0-2 R f Aralkyl substituted with 0-2 R f Alkaryl substituted with 0-2 R f heteroaryl substituted with -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 form a 3- to 10-membered ring structure together with the ring A atoms to which they are attached,

[0006] R 2 are each independently H, halogen, hydroxy, mercapto, nitro, cyano, oxo, 0-2 R f C1-C6 alkyl substituted with 0-2 R f C1-C6 haloalkyl substituted with 0-2 R f C1-C6 alkyloxy substituted with 0-2 R f C1-C6 haloalkyloxy 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 cycloalkyloxy substituted with 0-2 R f C3-C6 halocycloalkyloxy substituted with 0-2 R f aryl substituted with 0-2 R f Aralkyl substituted with 0-2 R f Alkaryl substituted with 0-2 R fheteroaryl substituted with -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 form a 3- to 10-membered ring structure together with the ring atoms to which they are attached,

[0007] L1 is a bond or the following structural formula Selected from JPEG2025537242000003.jpg31153,

[0008] X 1 is independently selected at each occurrence from the group consisting of C, O, or N; X 2 is independently selected at each occurrence from the group consisting of C, O, B, or N; X A , X B , X C are each independently CR x or N,

[0009] Rx are each independently H, halogen, hydroxy, mercapto, nitro, cyano, 0-2 R f C1-C6 alkyl substituted with 0-2 R f C1-C6 haloalkyl substituted with 0-2 R f C1-C6 alkyloxy substituted with 0-2 R f C1-C6 haloalkyloxy 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 cycloalkyloxy substituted with 0-2 R f C3-C6 halocycloalkyloxy substituted with 0-2 R f aryl substituted with 0-2 R f Aralkyl substituted with 0-2 R f Alkaryl substituted with 0-2 R f heteroaryl substituted with -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 Rx together with the ring atoms to which they are attached form a 3- to 10-membered ring structure;

[0010] R 0 are each independently selected from H, halogen, or the structural formula of Formula II; JPEG2025537242000004.jpg31170

[0011] wherein each L2 independently represents a bond, -O-, -S-, -N(R 20 )-, -C(O)-, -C(R 20 R 21 )-, -S(O)-, and -S(O2)-;

[0012] each ring C is independently selected from the group consisting of a monocyclic or polycyclic ring system containing 3-12 ring atoms;

[0013] R3 is independently H, halogen, hydroxy, mercapto, nitro, cyano, oxo, or 0-2 R f C1-C6 alkyl substituted with 0-2 R fC1-C6 haloalkyl substituted with 0-2 R f C1-C6 alkyloxy substituted with 0-2 R f C1-C6 haloalkyloxy 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 cycloalkyloxy substituted with 0-2 R f C3-C6 halocycloalkyloxy substituted with 0-2 R f aryl substituted with 0-2 R f Aralkyl substituted with 0-2 R f Alkaryl substituted with 0-2 R f heteroaryl substituted with -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 R3 together with the ring C atom to which they are attached form a 3- to 10-membered ring structure;

[0014] R 11 are each independently 0-2 R f C1-C6 alkylidene substituted with

[0015] R 12 each independently represents H and 0 to 2 R f C1-C6 alkyl substituted with 0-2 R f C1-C6 haloalkyl substituted with 0-2 R f C3-C6 cycloalkyl substituted with and 0-2 R fC-C halocycloalkyl substituted with

[0016] R a and R b each independently represents H and 0 to 2 R f C1-C6 alkyl substituted with 0-2 R f aryl substituted with 0-2 R f aralkyl substituted with -C(O)R c and -C(O)OR d Selected from

[0017] R c are each independently H, halogen, or 0-2 R f C1-C6 alkyl substituted with 0-2 R f aryl substituted with and 0-2 R f aralkyl substituted with

[0018] R d each independently represents H and 0 to 2 R f C1-C6 alkyl substituted with 0-2 R f aryl substituted with and 0-2 R f aralkyl substituted with

[0019] R 20 and R 21 are each independently selected from the group consisting of H, hydroxy, C1-C6 alkyl, aryl, and aralkyl;

[0020] R f are each independently selected from the group consisting of halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 alkyloxy, C1-C6 haloalkyl, C1-C6 haloalkyloxy, C3-C6 cycloalkyl, and C3-C6 halocycloalkyl;

[0021] 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.

[0022] The present application also relates to pharmaceutical compositions comprising a compound of the present application, or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically labeled compound, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0023] The present application also relates to the use of the compounds of the present application, or stereoisomers, tautomers, solvates, hydrates, active metabolites, isotopically labeled compounds, or pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions of the present application, in the manufacture of a medicament for inhibiting the activity of TRPV3.

[0024] The present application also relates to the use of the compounds of the present application, or stereoisomers, tautomers, solvates, hydrates, active metabolites, isotopically labeled compounds, or pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions of the present application, in the manufacture of a medicament for the treatment of a condition mediated by TRPV3 in a subject.

[0025] The present invention further provides a use of the TRPV3 inhibitor for preparing a reagent for inhibiting the TRPV3 ion channel, preferably a use of the TRPV3 inhibitor for preparing a medicine for suppressing skin itching, pain, hair loss, and inflammation caused by TRPV3 overexpression.

[0026] The present application relates to a method of treating a condition mediated by TRPV3, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present application, or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically labeled form, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application.

[0027] The compounds of the present invention can inhibit TRPV3 activity and can be used as TRPV3 antagonists or inhibitors, which greatly promotes the research on the characteristics and properties of TRPV3 ion channels. At the same time, they can also be used to prepare medicines 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 scientific and clinical research. DETAILED DESCRIPTION OF THE INVENTION

[0028] The present invention will be described in more detail below through embodiments, through which the features and advantages of the present invention will be more clearly defined.

[0029] The word "exemplary" is used herein to mean "serving as an example, embodiment, or illustration." Any embodiment described herein as "exemplary" should not be construed as superior or advantageous over other embodiments.

[0030] Furthermore, the technical features in different embodiments of the present application described below can be combined with each other if they are not inconsistent.

[0031] definition The terms "antagonist" and "inhibitor" are used interchangeably and refer to agents that reduce or inhibit biological activity, such as inhibiting the activity of an ion channel such as TRPV3.

[0032] For example, in the present invention, an "effective amount" of a TRPV3 antagonist refers to the amount of the antagonist in a formulation that, when used as part of a desired dosing regimen, produces a desirable clinical or functional result. Effective amounts of TRPV3 antagonists for use in the methods of the present invention include TRPV3 antagonists that are effective in reducing one or more in vitro or in vivo functions of TRPV3 channels, but this theory is not intended to limit the present invention. Exemplary functions include, but are not limited to, intracellular calcium levels, membrane polarization (e.g., antagonists can promote cellular 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 in vitro or in vivo functional activity of TRPV3 activity. When a particular functional activity can only be readily observed in an in vitro assay, the ability of a compound to inhibit TRPV3 function in this in vitro assay serves as a reasonable proxy for the compound's activity. The term "preventing," when used in reference to a condition such as local recurrence (e.g., pain), a disease such as cancer, a complex syndrome such as heart failure, or any other medical condition, is art-recognized and includes administration of a composition that reduces the frequency, delay, onset, or symptomatic manifestation of the condition in a subject relative to subjects not receiving the composition. Thus, cancer prevention includes, for example, a reduction in the number of detectable cancerous growths in a patient population receiving a prophylactic treatment relative to an untreated control population, and / or a delay in the appearance of detectable cancerous growths in a treated population relative to an untreated control population, e.g., a statistically and / or clinically significant amount. Infection prevention includes, for example, a reduction in the number of infection diagnoses in a treated population relative to an untreated control population and / or a delay in the onset of symptoms of infection in a treated population relative to an untreated control population. Pain prevention includes, for example, a reduction in, or alternatively a delay in, the magnitude of pain experienced by subjects in a treated population relative to an untreated control population.

[0033] The present invention provides compounds in prodrug form. The term "prodrug" is intended to encompass compounds that are converted under physiological conditions to the therapeutically active agents of the present invention. A common method for making prodrugs involves hydrolysis under physiological conditions to reveal selected portions of the desired molecule. In other embodiments, the prodrug is converted by enzymatic activity in the host animal. Prodrugs can also be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0034] The term "oxidative metabolite" is intended to encompass compounds obtained by metabolism of a parent compound under normal physiological conditions. Specifically, an oxidative metabolite is formed when the parent compound is oxidized during metabolism. For example, a thioether group can be oxidized to yield the corresponding sulfoxide or sulfone.

[0035] As used herein, the term "solvate" refers to a compound formed by solvation (eg, a compound formed by the combination of solvent molecules and solute molecules or ions).

[0036] As used herein, the term "hydrate" refers to a compound formed by the combination of water with the parent compound.

[0037] The term "treating" includes prophylactic and / or therapeutic treatment. The term "prophylactic or therapeutic" treatment is art-recognized and includes administration of one or more compositions of the invention to a host. When administered prior to clinical manifestation of an unwanted condition (e.g., a disease or other unwanted condition in a host animal), the treatment is prophylactic (i.e., protects the host from developing the unwanted condition), whereas when administered after manifestation of an unwanted condition, the treatment is therapeutic (i.e., intended to reduce, alleviate, or stabilize an existing unwanted condition or its side effects).

[0038] 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, e.g., the amino acid sequence of a human TRPV3 protein, or an equivalent polypeptide or functional, biologically active fragment thereof. In one embodiment, the terms refer to a polypeptide that comprises, consists of, or consists essentially of a TRPV3 amino acid sequence, e.g., as set forth in any of the patent applications referenced herein. TRPV3 proteins can also include orthologs, e.g., mouse, rat, horse, or Drosophila TRPV3.

[0039] TRPV3 includes polypeptides that retain TRPV3 function, including (i) all or a portion of the TRPV3 amino acid sequence, (ii) TRPV3 amino acid sequences with 1 to about 2, 3, 5, 7, 10, 15, 20, 30, 50, 75, or more conservative amino acid substitutions, (iii) amino acid sequences that are at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the TRPV3 amino acid sequence, and (iv) functional fragments thereof. Polypeptides of the present invention also include homologs of human TRPV3 polypeptides, such as orthologs and paralogs. TRPV3 polypeptides and amino acid sequences include, for example, the sequences set forth in any of the patent applications referenced herein.

[0040] The term "TRPV3" also refers to nucleic acids encoding polypeptides of the invention, e.g., nucleic acids containing a sequence consisting of or essentially consisting of a TRPV3 polynucleotide sequence. Nucleic acids of the invention include (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 nucleic acid encoding a polypeptide functionally equivalent to a polypeptide of the invention, (v) a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% homologous or identical to a TRPV3 polypeptide sequence, or (vi) a nucleic acid that has the activity of a polypeptide of the invention and is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% homologous to a TRPV3 polypeptide sequence. The present invention may include all or a portion of the following: (i) nucleic acids encoding polypeptides with at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% homology or identity; (ii) nucleotide sequences that differ from the 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; (iii) nucleic acids evolutionarily related to TRPV3 nucleotide sequences; and (ix) complements of all of the above and other nucleic acids and nucleotide sequences resulting from the degeneracy of the genetic code. Nucleic acids of the present invention also include homologs of TRPV3 nucleic acid sequences, such as orthologs and paralogs, and codon-optimized variants for expression in a particular organism (e.g., a host cell). TRPV3 nucleic acid sequences include, for example, those set forth in any of the patent applications referenced herein. Unless explicitly stated, those skilled in the art can readily assess whether TRPV3 refers to a nucleic acid or a protein.

[0041] As used herein, the term "aliphatic group" means a straight-chain, branched-chain, or cyclic aliphatic hydrocarbon group, and includes saturated and unsaturated aliphatic groups such as alkyl, alkenyl, and alkynyl groups.

[0042] The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups similar in length and optionally substituted to the alkyls described above, but which contain one double or triple bond respectively.

[0043] As used herein, the terms "alkoxyl" or "alkoxy" refer to an alkyl group having an oxygen radical attached thereto, as defined below. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, t-butoxy, and the like. An "ether" is two hydrocarbons covalently linked by an oxygen atom. Thus, the alkyl substituent that renders the alkyl an ether is an alkoxyl or alkoxyl-like group, such as: -O-alkyl, -O-alkenyl, -O-alkynyl, -O-CH2)t-R8, where R8 is selected from the group consisting of hydro, halogen, lower alkyl, lower alkyloxy, amino, or -NHSO2NH2, and t is an integer from 0 to 6.

[0044] The term "alkyl" refers to saturated aliphatic radicals, including straight-chain alkyl groups and branched-chain alkyl groups. In preferred embodiments, a straight-chain or branched-chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C6). 30 Straight chain, C3-C 30 branched), more preferably 20 or less, most preferably 10 or less.

[0045] The term "cycloalkyl" includes saturated and locally 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 is optionally further substituted. Preferred cycloalkyls have 3-12 carbon atoms, more preferably 5, 6, 7, or 8 carbon atoms in their ring structure. Preferred cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclylheptyl, 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]pentyl.

[0046] Furthermore, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and patent claims is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter of which refers to alkyl moieties having substituents replacing a hydrogen atom of one or more carbon atoms of the hydrocarbon backbone. Such substituents include, for example, halogen atoms, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that substituted portions of the hydrocarbon chain can themselves be substituted, if appropriate. For example, substituents of substituted alkyls include substituted or unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphates and phosphinates), sulfonyl (including sulfates, sulfonamides, sulfamoyl, and sulfonates), silyl groups, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.

[0047] Similar substitutions can be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.

[0048] Unless a different number of carbon atoms is specified, "lower alkyl," as used herein, means an alkyl group, as defined above, having from 1 to 10 carbon atoms in its backbone, more preferably from 1 to 6 carbon atoms. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In preferred embodiments, substituents designated herein as alkyl are lower alkyls.

[0049] The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In preferred embodiments, the "alkylthio" moiety is represented by a member selected from the group consisting of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH)t-R8, where t and R8 are as defined above. Representative alkylthio groups include methylthio, ethylthio, and the like.

[0050] The term "aralkyl" refers to an alkyl group substituted with an aryl group (eg, an aromatic or heteroaromatic group).

[0051] As used herein, the term "aryl" includes 5-, 6-, and 7-membered monocyclic aromatic groups, which may contain zero to four heteroatoms, such as benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. These aryl groups containing heteroatoms in the ring structure are also referred to as "aryl heterocycles" or "heteroaromatics." The aromatic ring can be substituted at one or more ring positions with the above-mentioned substituents, such as halogen atoms, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, -CF, -CN, and the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbon atoms share two adjacent rings (the rings are called "fused rings"), where at least one ring is aromatic and the other ring(s) of the ring may be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocyclyl.

[0052] As used herein, the term "carbocycle" refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.

[0053] The term "electron-withdrawing group" refers to a chemical group that attracts electron density from an atom or group of atoms attached to the electron-withdrawing group. The attraction of electron density can be due to an inductive effect or a mesomeric (or resonance) effect. Examples of electron-withdrawing groups attached to aromatic rings include perfluoroalkyl groups such as trifluoromethyl, halogens, carbonyl-containing groups such as azido and acyl, cyano- and imine-containing groups, etc.

[0054] As used herein, the term "heteroatom" means an atom of any element other than a carbon or hydrogen atom. Preferred heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur, and selenium.

[0055] The terms "heterocyclyl" or "heterocyclic group" refer to 3- to 10-membered ring structures, and more preferably 3- to 7-membered ring structures containing 1-4 heteroatoms. Heterocycles can also be polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthine, phenoxanthine, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazinine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocycle can be substituted at one or more positions with substituents such as those described above, for example, halogen atoms, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, -CF, -CN, and the like.

[0056] As used herein, the term "nitro" means -NO2, the term "halogen atom" designates -F, -Cl, -Br, or -I, the term "sulfhydryl" means -SH, the term "hydroxyl" means -OH, and the term "sulfonyl" means -SO2-.

[0057] The terms "polycyclic," "polycyclic group," and "polycyclic system" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocyclyl) in which two or more carbon atoms share two adjacent rings, e.g., the rings are "fused rings" or "spirocycles." Rings joined through non-adjacent atoms are referred to as "bridged" rings, e.g., C5-C 12 and 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]pentyl. Each ring of the polycycle can be substituted with a substituent as described above, such as a halogen atom, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, —CF, —CN, and the like.

[0058] As used herein, the term "protecting group" refers to temporary substituents that protect a potentially reactive functional group from undesired 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. Protecting groups are reviewed in chemistry (Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991).

[0059] As used herein, the term "substituted" is intended to include all permissible substituents for organic compounds. Broadly, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, aralkyl, or heteroaralkyl, any of which may themselves be further substituted), as well as halogen atoms, carbonyl (e.g., ester, carboxyl, or formyl), thiocarbonyl (e.g., thioester, thiocarboxylate, or thioformate), ketone, aldehyde, amino, acylamino, amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxide, sulfate, sulfonate, sulfamoyl, sulfamido, and phosphoryl. Specific substituents include, for example, those described herein above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms such as nitrogen atoms may have hydrogen atom 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 by the permissible substituents of organic compounds.

[0060] "Substituted" or "substituted with" is understood to include the implicit proviso that the substitution is in accordance with the substituted atom and the allowed valence of the substituent, and that the substitution results in a stable compound that does not change spontaneously by, for example, rearrangement, cyclization, elimination, etc. f "Substituted with" means that the corresponding group has 0, 1 or 2 Rf.

[0061] The definition of each expression used herein, when it occurs more than one time in any structure, is intended to be independent of its definitions elsewhere in the same structure.

[0062] 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 utilized by organic chemists of ordinary skill in the art appears in the first volume of each issue of the Journal of Organic Chemistry. This list is usually presented in a table entitled "Standard List of Abbreviations." The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art, are hereby incorporated by reference.

[0063] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all compounds within the scope of the present invention, including cis and trans isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemates, and other mixtures thereof. 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.

[0064] Methods for producing substantially isomerically pure compounds are well known in the art. For example, if a specific enantiomer of a compound of the invention is desired, it can be synthesized by asymmetric synthesis or derivatization with a chiral auxiliary, the resulting diastereomeric mixture separated, and the auxiliary cleaved to provide the desired pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, one can form a diastereomeric salt with an appropriate optically active acid or base, then resolve the formed diastereomers using fractional recrystallization or chromatographic methods well known in the art, and then recover the pure enantiomer. Alternatively, enantiomerically pure synthetic intermediates can be used in combination with reactions that leave the stereochemistry of the asymmetric center unchanged or completely invert it to produce enantiomerically enriched mixtures and enantiomerically pure compounds. Techniques for inverting or leaving a specific stereocenter unchanged and for resolving stereoisomeric mixtures are well known in the art, and selecting the appropriate method for a particular situation is within the ability of one of ordinary skill in the art. See generally Vogel's Encyclopedia of Practical Organic Chemistry, edited by Furniss et al., 5th edition, Longman Scientific and Technical Ltd., Essex, 1991, pp. 809-816; Heller, Acc. Chem. Res., vol. 23, p. 128 (1990).

[0065] The compounds of the present invention may be identical to or correspond to those anticipated, and may have the same general characteristics (e.g., the ability to inhibit TRPV3 activity), including one or more substituents that do not negatively affect the activity of the compound. Generally, the compounds of the present invention can be prepared using readily available starting materials, reagents, and conventional synthetic methods, for example, by the methods shown in the general reaction schemes set forth below, or modifications thereof. These reactions may also utilize variations that are well known per se but are not described herein.

[0066] In this invention, chemical elements are identified according to the Periodic Table of the Elements. Also, in this invention, the term "hydrocarbon" is intended to include all possible compounds having at least one hydrogen atom and one carbon atom. In general, possible hydrocarbons are intended to include substituted or unsubstituted acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.

[0067] The compounds of the present invention may also contain artificial proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain isotopes of, for example, tritium ( 3 H), iodine-125( 125 I) or carbon 14 ( 14 It is intended that isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. 1 H), deuterium ( 2 H) and tritium ( 3 Unless stated together with H, "hydro" or "H" refers to all isotopes of hydrogen, protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H).

[0068] JPEG2025537242000005.jpg15166

[0069] Certain compounds of the present invention can exist in solvated forms, including hydrated forms, as well as unsolvated forms. Generally, solvated forms are equivalent to unsolvated forms and are within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0070] Where substituents are designated as written from left to right in a conventional chemical formula, they equally include the chemically identical substituents that result from writing the structure from right to left, e.g., -CH2O- is also intended to be listed as -OCH2-, -NHS(O)2- is also intended to represent -S(O)2HN-, etc.

[0071] The term "pharmaceutically acceptable salt" includes salts of active compounds formed with relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When a compound of the present invention contains a relatively acidic functional group, the neutral form of the compound is contacted, neat or in a suitable inert solvent, with a sufficient amount of the desired base to obtain a base addition salt. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino acid, magnesium, or similar salts. When a compound of the present invention contains a relatively basic functional group, the neutral form of the compound is contacted, neat or in a suitable inert solvent, with a sufficient amount of the desired acid to obtain an acid addition salt. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphate, dihydrogenphosphate, sulfuric, monohydrogensulfuric, hydroiodic, phosphoric acid, and the like, as well as salts of relatively non-toxic organic acid derivatives such as acetic, trifluoroacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic acid, and the like, as well as salts of amino acids such as alginate and the like, and organic acid salts such as glucuronic acid, galacturonic acid, and the like (see, e.g., Berge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, Vol. 66, pp. 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.

[0072] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to the parent form of the compound for purposes of the present invention.

[0073] The term "sufficiently low pyrogen activity" with respect to a pharmaceutical formulation means a formulation that does not contain an amount of pyrogen that would cause adverse side effects in a subject to which the formulation is administered, such as irritation, fever, inflammation, diarrhea, respiratory distress, endotoxic shock, etc. For example, the term is meant to include formulations that are free or substantially free of endotoxins, such as lipopolysaccharides (LPS).

[0074] TRPV3 function-related diseases, disorders, or conditions In embodiments for the prevention or treatment of a disease, disorder, or condition, the administered agent modulates TRPV3 protein level and / or activity. In some embodiments, the compound inhibits TRPV3 protein expression and / or activity. In other embodiments, the compound selectively inhibits TRPV3 protein expression. In other words, in some embodiments, the compound preferentially inhibits TRPV3 protein activity relative to the activity of one or more other ion channels.

[0075] In particular embodiments of the methods for preventing or treating a disease or disorder provided herein, the disease or disorder is pain or tactile hypersensitivity, e.g., pain or disease- or disorder-related pain, e.g., cancer pain, skin diseases or disorders, e.g., psoriasis, basal cell carcinoma and squamous cell carcinoma, neurodegenerative diseases or disorders, e.g., Alzheimer's disease (AD), Parkinson's disease, Hutchington's disease, amyotrophic lateral sclerosis (ALS), other brain disorders caused by trauma or other injuries, including aging, inflammatory diseases (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 disease, metabolic disorders such as diabetes, etc. Additional diseases and conditions include post-surgical pain, post-herpetic neuralgia, fibromyalgia, and shingles.

[0076] Because of the critical role calcium regulation plays in many cellular processes, including cell activation, gene expression, intracellular trafficking, and apoptotic cell death, calcium dyshomeostasis is implicated in many diseases and disorders involving this cellular activity, including skin diseases and disorders, neurological and neurodegenerative diseases and disorders, fever-related diseases, disorders, or conditions, incontinence, inflammatory diseases and disorders such as inflammatory bowel disease and Crohn's disease, respiratory diseases and disorders such as chronic cough, asthma, and chronic obstructive pulmonary disease (COPD), digestive disorders such as ulcers and acid reflux, metabolic diseases and disorders including obesity and diabetes, liver and kidney diseases and disorders, malignancies including cancer, aging-related disorders, and pain and tactile hypersensitivity.

[0077] Other treatable diseases and disorders include epilepsy, cognition, vomiting, pain (e.g., migraine), asthma, peripheral vascular disease, hypertension, immune and inflammatory diseases, irritable bowel syndrome, cystitis, depression, age-related degenerative diseases, urinary incontinence, premature ejaculation, cystic fibrosis, diabetes, contraception 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).

[0078] The TRPV3 inhibitors described herein can be used to treat any of the diseases or disorders described above or below, including treating pain associated with any of the diseases or disorders described above or below. When used in a treatment method, the inhibitor can be selected and formulated based on the intended route of administration.

[0079] The compounds and compositions provided herein may be used in connection with the prevention or treatment of pain or pain hyperesthesia, which is manifested in a variety of diseases, disorders, or conditions, including, but not limited to, diabetic neuropathy, chest pain, psoriasis, eczema, dermatitis, burns, postherpetic neuralgia (shingles), nociceptive pain, peripheral neuropathic pain and central neuroendogenous pain, chronic pain, cancer pain and tumor pain, spinal cord injury, crush injury and trauma-induced pain, migraine, cerebrovascular and vascular pain, sickle cell disease pain, musculoskeletal pain, including rheumatoid arthritis pain, osteoarthritis and treatment of the signs and symptoms of rheumatoid arthritis, orofacial pain, including dental and cancer-related, low back or pelvic pain, surgical incision-related pain, inflammatory and non-inflammatory pain, visceral pain, psychogenic 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 acute pain as well as chronic pain, which may be the result of injury, age, or disease.

[0080] Other ion channels are involved in the perception or transmission of pain. For example, N-type calcium channels have been implicated in synaptic transmission, which conveys 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 inflammatory and neuropathic pain models. Available evidence suggests that N-type calcium channel blockers are at least as effective as opiates, do not have many of the side effects of typical opiate-like substances (e.g., respiratory depression), and their analgesic effects are not subject to tolerance development.

[0081] Like TRPV3, TRPV1 and TRPV4 are expressed in a pattern consistent with their involvement in pain. TRPV3 is expressed in pain-sensitive neurons, and this expression is upregulated following injury. Furthermore, TRPV3 is highly expressed in the skin. Therefore, pain treatment strategies include (i) antagonists of TRPV3 function, (ii) combinations of selective antagonists of TRPV3 and TRPV1 and / or TRPV4 function, or (iii) administration of pan-TPR inhibitors that suppress TRPV3, TRPV1, and TRPV4 function.

[0082] In addition to TRPV3 family members, other TRP channels have been implicated in pain perception and / or stimulation. For example, certain TRPM channels, including TRPM8, have been implicated in pain perception and / or stimulation. Accordingly, in certain embodiments, the methods of the invention include treating pain by administering (i) a combination of a selective TRPM3 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 TRPV3 and TRPM8 function, or (iv) a pan-inhibitor that antagonizes TRPV3, TRPM8, and one or more of TRPV1 and TRPV4 function.

[0083] Calcium influx across the plasma membrane of skin cells is a critical signaling element involved in cell differentiation in the skin epidermis (Dotto, Crit Rev Oral Biol Med 10:442-457, 1999). Controlling or regulating calcium influx pathways, and thus critical control points of skin cell growth, can treat or prevent skin diseases or disorders characterized by epidermal hyperplasia, a condition in which skin cells proliferate too rapidly and differentiate too poorly. These diseases include psoriasis, basal cell carcinoma, and squamous cell carcinoma. Bovine eczema, an estimated 7 million people in the United States, suffers from mild to severe disease, with secondary infections resulting in increased susceptibility and cardiac effects due to malformations from the invasive area (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 cancer diagnoses in the United States each year. More than one million new cases are reported annually, and incidence rates are also increasing. Despite being a relatively non-aggressive, slow-growing cancer, BCC causes significant local tissue destruction and disfigurement. SCC is more aggressive and therefore leads to even more complications. Furthermore, given that 80% of lesions occur in the head and neck and the remaining 15% occur on the shoulders, back, or chest, BCC and SCC of the skin have a significant impact on the appearance and quality of life of those who develop them.

[0084] Many skin disorders are accompanied by itching (pruritus). Pruritus and pain share many mechanistic similarities. Both are associated with C-fiber activation, both are potentiated by elevated temperature and increased levels of inflammatory mediators, and both are quelled by opiate-like substances. Decreased neuronal excitability, particularly C-fiber excitability, can relieve pruritus associated with dialysis, dermatitis, pregnancy, ivy rash, allergies, dry skin, chemotherapy, and eczema.

[0085] Acne is a skin disorder with a complex etiology. Among other factors, oil secretion from sebaceous glands contributes to acne development. TRPV3 is also expressed in sebaceous glands and has been shown to regulate secretion in other skin cells, suggesting that antagonizing TRPV3 function may reduce the signs and symptoms of acne.

[0086] In a preferred embodiment, a TRPV3 antagonist is administered to prevent, treat, or alleviate the signs and symptoms of acute pain, chronic pain, tactile sensitivity, pruritus sensitivity, or as part of a burn treatment, such as post-surgical pain, cancer pain, or neuropathic pain.

[0087] In a preferred embodiment, a TRPV3 antagonist is administered to prevent, treat, or alleviate the signs and symptoms of a migraine headache.

[0088] In a preferred embodiment, the TRPV3 antagonist is administered to prevent, treat, or alleviate the signs and symptoms of a disorder or condition selected from the group consisting of diabetic neuropathy, inflammation, psoriasis, eczema, dermatitis, post-herpetic neuropathy (shingles), incontinence, bladder incontinence, fever, hot flashes, and cough.

[0089] In a preferred embodiment, a TRPV3 antagonist is administered to prevent, treat, or alleviate the signs and symptoms of osteoarthritis.

[0090] In a preferred embodiment, a TRPV3 antagonist is administered to prevent, treat, or alleviate the signs and symptoms of rheumatoid arthritis.

[0091] In a preferred embodiment, a TRPV3 antagonist is administered to prevent, treat, or alleviate the signs and symptoms of oral mucositis.

[0092] In one preferred embodiment, the TRPV3 antagonist is administered to promote hair loss or inhibit hair growth in a patient.

[0093] Yet another aspect of the invention relates to the use of a TRPV3 antagonist in the preparation of a medicament for preventing, treating, or alleviating in a patient the symptoms of a disease, disorder, or condition, such as those described below, which symptoms involve TRPV3 activation or reduce the severity of the symptoms in a patient by reducing TRPV3 activity.

[0094] The present application relates to a method for treating a condition mediated by TRPV3, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present application, or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically labeled form, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application.

[0095] Pharmaceutical Composition The compounds of the present invention can be administered alone, but are preferably administered as a pharmaceutical formulation (composition). The compounds of the present invention can be formulated into a formulation for administration in a manner convenient for use in human or veterinary medicine. In some embodiments, the compound contained in the pharmaceutical formulation may be active itself or may be a prodrug that can be converted to an active compound, for example, in a physiological setting.

[0096] Regardless of the route of administration selected, the compounds of the invention used in their appropriate hydrated form, and / or pharmaceutical compositions of the invention, are formulated into pharmaceutically acceptable dosage forms as described below, or by other conventional methods known to those skilled in the art.

[0097] Accordingly, another aspect of the present invention provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the compounds described above, formulated with one or more pharmaceutically acceptable carriers (excipients) and / or diluents. As described in detail below, the pharmaceutical compositions of the present invention can be specifically formulated for administration in solid or liquid form, including the following indications: (1) oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, boli, powders, granules, pastes for application to the tongue, teeth, lips, or gums, mouthwash, or gels; (2) parenteral administration, e.g., subcutaneous, intramuscular, or intravenous injection, e.g., as a sterile solution or suspension; (3) topical application, e.g., to the skin as a cream, ointment, or spray; (4) vaginally or rectally, e.g., as a suppository, cream, or foam; or (5) for inhalation. However, in some embodiments, the compounds of the present invention may simply be dissolved or suspended in sterile water. In some embodiments, the pharmaceutical formulations are non-pyrogenic, i.e., do not elevate a patient's body temperature.

[0098] The TRPV3 antagonist can be administered alone or in combination with other therapeutic agents, for example, in combination with one or more of the following therapeutic agents: anti-inflammatory agents, anti-acne agents, anti-wrinkle agents, anti-scar agents, anti-psoriasis agents, anti-proliferative agents, anti-fungal agents, anti-viral agents, antiseptic agents, anti-migraine agents, keratolytic agents, or hair growth inhibitors.

[0099] The TRPV3 antagonist can typically be administered topically, orally, transdermally, rectally, intravaginally, parenterally, intranasally, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intraorbitally, intracardially, intradermally, intraperitoneally, transtracheally, subcutaneously, subcorneally, intraarticularly, subcapsularly, subarachnoidally, intrathecally, intrasternally, or by inhalation.

[0100] In a preferred embodiment, the TRPV3 antagonist is administered locally.

[0101] In a preferred embodiment, the TRPV3 antagonist is administered orally.

[0102] In a preferred embodiment, the TRPV3 antagonist is administered parenterally.

[0103] As used herein, the term "therapeutically effective amount" refers to an amount of a compound, material, or composition, including a compound of the present invention, effective to inhibit TRPV3 function in at least a subpopulation of cells in an animal, thereby masking the biological consequences of that function in the treated cells at a reasonable benefit / loss ratio applicable to any medical treatment, and producing some desirable therapeutic effect.

[0104] As used herein, the terms "systemic administration," "administering systemically," "peripheral administration," and "administering peripherally" refer to administration of a compound, drug, or other material other than direct administration into the central nervous system, such that it enters the patient's system and is subsequently metabolized and otherwise processed, e.g., subcutaneous administration.

[0105] As used herein, the term "pharmaceutically acceptable" is used to mean compounds, materials, compositions, and / or dosage forms that are, within the reasonable bounds of medical evaluation, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0106] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting an antagonist of the present 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 cellulose derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil. (10) glycols such as propylene glycol, (11) polyols such as glycerin, 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) ethyl alcohol, (20) phosphate buffers, and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0107] As set forth above, certain embodiments of the compounds of the present invention may contain a basic functional group, such as amino or alkylamino, and thus may form pharmaceutically acceptable salts with pharmaceutically acceptable acids. In this regard, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of the compounds of the present invention. These salts can be formed in situ during the final isolation and purification of the compounds of the present invention, or can be formed by separately reacting the purified compounds of the present invention, in their free base form, with a suitable organic or inorganic acid and then isolating the resulting salt. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfonate salts and the like (see, e.g., Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19).

[0108] Pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts or quaternary ammonium salts of the compounds, for example, from non-toxic organic or inorganic acids, including those derived from inorganic acids such as hydrochloride, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and those formed 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, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothionic acid, and the like.

[0109] In other cases, the compounds of the present invention may contain one or more acidic functional groups and, therefore, can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these instances, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic base addition salts of the compounds of the present invention. These salts can be formed in situ during the final isolation and purification of the compounds of the present invention, or can be formed separately by reacting the purified compounds, in their free acid form, with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, magnesium, and aluminum, and analogs. Representative organic amines useful for base addition salt formation also include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and analogs (see, e.g., Berge et al., supra).

[0110] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants such as ascorbic acid palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha tocopherol, and the like; and (3) metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0111] 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 and maintained in the mouth without swallowing, as well as those that are swallowed in part or for subsequent use. The formulations may conveniently be presented in unit dosage form and may be formulated by any method well known in the pharmaceutical arts. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will typically be that amount of the compound that produces a therapeutic effect. This amount will typically be from about 1 percent to about 99 percent of one hundred percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0112] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with a carrier, and, optionally, one or more accessory ingredients. Generally, such formulations typically involve uniformly and intimately associating a compound of the present invention with liquid carriers, or finely divided solids, or both, and then, if necessary, formulating the product into product form.

[0113] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (with a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, as an oil-in-water emulsion or a water-in-oil emulsion, as an elixir or syrup, as lozenges (with an inert base such as gelatin and glycerin, or sucrose and acacia), and / or mouthwashes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0114] The present application relates to a nitrogen-containing spirocyclic compound of formula (I) or JPEG2025537242000006.jpg37146Provided are stereoisomers, tautomers, solvates, hydrates, epoxides, active metabolites, isotopically labeled compounds, and pharmaceutically acceptable salts thereof.

[0115] wherein ring A is selected from the group consisting of monocyclic or polycyclic ring systems containing 3-12 ring atoms; R 1 are each independently H, halogen, hydroxy, mercapto, nitro, cyano, oxo, 0-2 R f C1-C6 alkyl substituted with 0-2 R f C1-C6 haloalkyl substituted with 0-2 R f C1-C6 alkyloxy substituted with 0-2 R f C1-C6 haloalkyloxy 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 cycloalkyloxy substituted with 0-2 R f C3-C6 halocycloalkyloxy substituted with 0-2 R f aryl substituted with 0-2 R f Aralkyl substituted with 0-2 R f Alkaryl substituted with 0-2 R f heteroaryl substituted with -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 form a 3- to 10-membered ring structure together with the atoms of ring A to which they are attached,

[0116] R2 are each independently H, halogen, hydroxy, mercapto, nitro, cyano, oxo, 0-2 R f C1-C6 alkyl substituted with 0-2 R f C1-C6 haloalkyl substituted with 0-2 R f C1-C6 alkyloxy substituted with 0-2 R f C1-C6 haloalkyloxy 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 cycloalkyloxy substituted with 0-2 R f C3-C6 halocycloalkyloxy substituted with 0-2 R f aryl substituted with 0-2 R f Aralkyl substituted with 0-2 R f Alkaryl substituted with 0-2 R f heteroaryl substituted with -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 form a 3- to 10-membered ring structure together with the ring atoms to which they are attached,

[0117] L1 is a bond or the following structural formula Selected from JPEG2025537242000007.jpg31156,

[0118] X 1 is independently selected at each occurrence from the group consisting of C, O, or N; X2 is independently selected at each occurrence from the group consisting of C, O, B, or N; X A , X B , X C are each independently CRx or N,

[0119] Rx are each independently H, halogen, hydroxy, mercapto, nitro, cyano, 0-2 R f C1-C6 alkyl substituted with 0-2 R f C1-C6 haloalkyl substituted with 0-2 R f C1-C6 alkyloxy substituted with 0-2 R f C1-C6 haloalkyloxy 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 cycloalkyloxy substituted with 0-2 R f C3-C6 halocycloalkyloxy substituted with 0-2 R f aryl substituted with 0-2 R f Aralkyl substituted with 0-2 R f Alkaryl substituted with 0-2 R f heteroaryl substituted with -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 Rx together with the ring atoms to which they are attached form a 3- to 10-membered ring structure;

[0120] R 0are each independently H, a halogen, or a structural formula of Formula II Selected from JPEG2025537242000008.jpg21120,

[0121] wherein each L2 independently represents a bond, -O-, -S-, -N(R 20 )-, -C(O)-, -C(R 20 R21) is selected from the group consisting of -, -S(O)-, and -S(O2)-;

[0122] each ring C is independently selected from the group consisting of a monocyclic or polycyclic ring system containing 3-12 ring atoms;

[0123] R3 is independently H, halogen, hydroxy, mercapto, nitro, cyano, oxo, or 0-2 R f C1-C6 alkyl substituted with 0-2 R f C1-C6 haloalkyl substituted with 0-2 R f C1-C6 alkyloxy substituted with 0-2 R f C1-C6 haloalkyloxy 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 cycloalkyloxy substituted with 0-2 R f C3-C6 halocycloalkyloxy substituted with 0-2 R f aryl substituted with 0-2 R f Aralkyl substituted with 0-2 R f Alkaryl substituted with 0-2 R f heteroaryl substituted with -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 R3 together with the ring C atom to which they are attached form a 3- to 10-membered ring structure;

[0124] R 11 are each independently 0-2 R f C1-C6 alkylidene substituted with

[0125] R 12 each independently represents H and 0 to 2 R f C1-C6 alkyl substituted with 0-2 R f C1-C6 haloalkyl substituted with 0-2 R f C3-C6 cycloalkyl substituted with and 0-2 R f C-C halocycloalkyl substituted with

[0126] R a and R b each independently represents H and 0 to 2 R f C1-C6 alkyl substituted with 0-2 R f aryl substituted with 0-2 R f aralkyl substituted with -C(O)R c and -C(O)OR d Selected from

[0127] R c are each independently H, halogen, or 0-2 R f C1-C6 alkyl substituted with 0-2 R f aryl substituted with and 0-2 R f aralkyl substituted with

[0128] R d each independently represents H and 0 to 2 R f C1-C6 alkyl substituted with 0-2 R f aryl substituted with and 0-2 Rf aralkyl substituted with

[0129] R 20 and R 21 are each independently selected from the group consisting of H, hydroxy, C1-C6 alkyl, aryl, and aralkyl;

[0130] R f are each independently selected from the group consisting of halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 alkyloxy, C1-C6 haloalkyl, C1-C6 haloalkyloxy, C3-C6 cycloalkyl, and C3-C6 halocycloalkyl;

[0131] 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.

[0132] In one embodiment, ring A is selected from the group consisting of 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.

[0133] In one embodiment, ring A has the following structural formula: Selected from JPEG2025537242000009.jpg80150.

[0134] In one embodiment, R 1 are each independently H, halogen, cyano, hydroxy, C-C alkyl, C-C haloalkyl, C-C alkyloxy, -N(R a )(R b ) and -R 11OR12, wherein R a and R b are each independently selected from the group consisting of H and C1-C6 alkyl; R 11 are each independently selected from the group consisting of C1-C6 alkylidene; R 12 are each independently selected from the group consisting of H and C1-C6 alkyl.

[0135] In one embodiment, R 1 are each independently selected from the group consisting of H, Cl, F, —CF3, —CN, —CH3, —OH, —OCH3, and —CH2OCH3.

[0136] In one embodiment, R 2 are each independently H, cyano, hydroxy, mercapto, oxo, C-C alkyl, C-C haloalkyl, 0-2 R f C3-C6 cycloalkyl, C1-C6 alkyloxy, C1-C6 haloalkyloxy, -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 are each independently selected from the group consisting of C1-C6 alkylidene; R 12 are each independently selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C cycloalkyl, and C-C halocycloalkyl; R a and R b are each independently selected from the group consisting of H and C1-C6 alkyl; R d are each independently selected from the group consisting of H and C1-C6 alkyl; R f are each independently selected from the group consisting of halogen, hydroxy, amino, and C1-C6 alkyl.

[0137] In one embodiment, R 2are each independently protium, deuterium, tritium, -SH, -OH, -OCF3, -CH3, -NH2, -CN, -CONH2, -CH2OH, -CH(O), -CHF2, -COOH, -COOCH3, oxo and JPEG2025537242000010.jpg1874.

[0138] In one embodiment, each L2 is independently selected from the group consisting of a bond, -O-, -S-, -N-, -C(O)-, -CH2-, -CF2-, -C(OH)-, -S(O)-, and -S(O2)-.

[0139] In one embodiment, ring C is selected from the group consisting of a C3-C6 cycloalkane ring, a benzene ring, a benzo-C3-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.

[0140] In one embodiment, ring C has the following structural formula: Selected from JPEG2025537242000011.jpg44155.

[0141] In one embodiment, each R is independently H, cyano, hydroxy, halogen, C-C alkyl, C-C haloalkyl, C-C alkyloxy, C-C haloalkyloxy, C-C 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 R3 together with the ring C atom to which they are attached form a 3- to 10-membered ring structure; where R11 are each independently selected from the group consisting of C1-C6 alkylidene; R 12 are each independently selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C cycloalkyl, and C-C halocycloalkyl; R a and R b are each independently selected from the group consisting of H and C1-C6 alkyl; R c are each independently selected from the group consisting of H, halogen, and C1-C6 alkyl; R d are each independently selected from the group consisting of H and C1-C6 alkyl.

[0142] In one embodiment, each R3 is independently selected from the group consisting of H, cyclopropyl, isopropyl, t-butyl, F, Cl, CN, ethyl, methyl, trifluoromethoxy, methylcarbonyl, methoxymethyl, and -C(CH3)2OH.

[0143] In one embodiment, the compound of formula I JPEG2025537242000012.jpg72150 has the following structural formula JPEG2025537242000013.jpg161155.

[0144] where R 2 , X A , X B , X C and p are defined as in Formula I.

[0145] In one embodiment, the compound of formula I Selected from JPEG2025537242000014.jpg149150.

[0146] where R 2are each independently selected from the group consisting of protium, deuterium, tritium, halogen, oxo, -SH, -OH, -CH3, -CN, -CONH2, -COOH, -COH, -COOCH3, -CF3, -OCH3, -CH2OH, -OCF3, -CHF2, and -NH2.

[0147] In these structural formulas, one or two ring moieties of each spiro ring structure may optionally contain p R 2 R 2 The group definitions may be as described above. In one embodiment, at least one R 2 is -OH.

[0148] In one embodiment, the compound of formula I It is one of the images selected from JPEG2025537242000015.jpg101156.

[0149] where R 2 are each independently selected from the group consisting of protium, deuterium, tritium, a halogen, -CH3, and -CF3.

[0150] In one embodiment, the compound of formula I Selected from JPEG2025537242000016.jpg136156.

[0151] where R 2 are each independently selected from the group consisting of oxo, -SH, -CN, -CONH2, -COOH, -COH, -COOCH3, -OCH3, -CH2OH, -CHF2, -OCF3, and -NH2.

[0152] In one embodiment, the compound of formula I Selected from JPEG2025537242000017.jpg94156.

[0153] JPEG2025537242000018.jpg30156

[0154] JPEG2025537242000019.jpg31160

[0155] JPEG2025537242000020.jpg31135

[0156] JPEG2025537242000021.jpg28122

[0157] In one embodiment, the compound is JPEG2025537242000022.jpg223168JPEG2025537242000023.jpg226170JPEG2025537242000024.jpg175170.

[0158] The present application relates to pharmaceutical compositions comprising a compound of the present application, or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically labeled compound, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0159] The present application also relates to the use of the compounds of the present application, or stereoisomers, tautomers, solvates, hydrates, active metabolites, isotopically labeled compounds, or pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions of the present application, in the manufacture of a medicament for inhibiting the activity of TRPV3.

[0160] The present application also relates to the use of the compounds of the present application, or stereoisomers, tautomers, solvates, hydrates, active metabolites, isotopically labeled compounds, or pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions of the present application, in the manufacture of a medicament for the treatment of a condition mediated by TRPV3 in a subject.

[0161] In one embodiment, the condition is selected from the group consisting of pain, itch, skin disorders, inflammation, abnormal hair growth, incontinence, fever, hot flashes, cystitis, irritable bowel syndrome, and / or coughing.

[0162] In one embodiment, the pain is cancer pain and skin pain.

[0163] In one embodiment, the compound is used in the manufacture of a medicament for inhibiting proliferation and thereby preventing, treating, or alleviating the symptoms of cancer.

[0164] In one embodiment, the cancer is liposarcoma.

[0165] In one embodiment, the abnormal hair growth is hair loss.

[0166] In one embodiment, the skin disorder is selected from the group consisting of cutaneous keratosis, ichthyosis, and pruritus.

[0167] In one embodiment, the cutaneous keratosis is Olmsted syndrome.

[0168] In one embodiment, the ichthyosis is harlequin ichthyosis.

[0169] General synthetic scheme The compounds of the present invention can be prepared using the methods illustrated in the general synthetic schemes and experimental procedures detailed below. These general synthetic 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.

[0170] Representative procedures for preparing compounds of the present invention are summarized in Scheme 1, Scheme 2, Scheme 3, Scheme 4, and Scheme 5. The starting p-halogenated phenylacetonitriles and ethyl bromoacetate compounds are commercially available or can be prepared using methods known in the art, and the representative procedures provide intermediates. Scheme 1 reveals the detailed synthesis of 1-(3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1-one. The synthesis of (3,4-halogenophenyl)-3-cyanopentanedioate 2 can be achieved by reacting p-halogenated phenylacetonitrile with ethyl bromoacetate in a solvent such as tetrahydrofuran. The cyano and ester groups of 2 undergo cyclization under a reducing agent to generate 3. The ester is hydrolyzed under alkaline conditions to give carboxylic acid 4, which then self-cyclizes under acidic conditions to generate 5. 5 reacts with the required boronic acid under Suzuki conditions to couple to intermediate 6. 6 is reduced under reducing agent conditions to generate intermediate 7, which then reacts with a carboxylic acid under condensing agent conditions to generate 8, which is then separated into 8a, 8b, 8c, and 8d by supercritical fluid separation.

[0171] Scheme 1: JPEG2025537242000025.jpg67154

[0172] Scheme 2 shows the synthesis of the required compound, with the final step being a Suzuki reaction to generate 8. The synthesis of intermediate 5 is as described in Scheme 1. Intermediate 5a is generated from intermediate 5 under reducing agent conditions, 5a is reacted with a carboxylic acid to generate 5b, and 5b is coupled with the required boronic acid under Suzuki conditions to generate 8, which is then separated into 8a, 8b, 8c, and 8d by supercritical separation.

[0173] Scheme 2 JPEG2025537242000026.jpg46159

[0174] Scheme 3 shows the synthesis of the required compound belonging to semichiral synthesis, and the synthesis of intermediate 6 is as described in Scheme 1. The intermediate undergoes catalytic reduction in the presence of a chiral ligand to give chiral alcohol 6a, which is then reduced to amide to give 6b, which is condensed with the required carboxylic acid to give 8, which is further separated into 8a and 8b by supercritical separation.

[0175] Scheme 3 JPEG2025537242000027.jpg50159

[0176] Scheme 4 shows the synthesis of the required compound, which also belongs to semichiral synthesis. The synthesis of intermediate 5 is as described in Scheme 1. Intermediate 5 undergoes catalytic reduction using a chiral ligand to give 5a, which is then coupled with the required boronic acid under Suzuki conditions to give 5b, which is reduced under reducing agent conditions to give 5c, which is then condensed with the required carboxylic acid to give 8, which is then separated into 8a and 8b by supercritical separation.

[0177] Scheme 4 JPEG2025537242000028.jpg49155

[0178] Scheme 5 illustrates the synthesis of the desired compound, which also belongs to the semichiral synthesis, and the synthesis of intermediate 5 is described in Scheme 1. Intermediate 5 undergoes catalytic reduction using a chiral ligand to give 5a, which is further reduced with a lactam to give intermediate 5b. 5b is condensed with the desired carboxylic acid to give 5c, which is then reacted with the desired boronic acid under Suzuki conditions to couple to give 8, which is then separated into 8a and 8b by supercritical separation.

[0179] Scheme 5 JPEG2025537242000029.jpg54159

[0180] Preparation of intermediates Preparation Example 1: 5-Bromospiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione (Compound I1) JPEG2025537242000030.jpg30167

[0181] Step A: Diethyl 3-(4-bromophenyl)-3-cyanopentanedioate JPEG2025537242000031.jpg45136

[0182] 20.0 g (102 mmol, 1.0 eq) of 2-(4-bromophenyl)acetonitrile was dissolved in 100 mL of tetrahydrofuran and purged with nitrogen gas three times. The temperature was lowered to -60 °C using dry ice. 224 mL (224 mmol, 2.2 eq) of lithium bis(trimethylsilyl)amine (lithium hexamethyldisilazide) was added dropwise at -60 °C and stirred at room temperature for 3 h. 34.1 g (204 mmol, 2.0 eq) of ethyl bromoacetate was then added dropwise at a temperature below -60 °C and stirred overnight at room temperature. After confirming complete reaction of the starting material by LCMS, the mixture was quenched by adding 200 mL of water. The mixture was then extracted three times with ethyl acetate. The organic layer was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was subjected to column chromatography (PE / EA = 0 to 10:1) to obtain the product (37.4 g, yield = 99%).

[0183] 1 H NMR (400 MHz, CDCl3) δ 7.54 (dd, J = 8.7, 2.7 Hz, 2H), 7.39 (dd, J =8.7, 2.7 Hz, 2H), 4.12-4.10 (m, 4H), 3.25 (d, J = 16.3 Hz, 2H), 3.08 (d, J = 16.3 Hz, 2H), 1.19 (t, J = 7.1 Hz, 6H).

[0184] Step B: Ethyl 2-(3-(4-bromophenyl)-5-oxopyrrolidin-3-yl)acetate JPEG2025537242000032.jpg49140

[0185] 5.00 g (13.8 mmol, 1.0 eq) of diethyl 3-(4-bromophenyl)-3-cyanopentanedioate was dissolved in 50 mL of methanol, 3.70 g (28.5 mmol, 2.1 eq) of anhydrous cobalt chloride was added, and 5.39 g (142 mmol, 10.5 eq) of sodium borohydride was slowly added at 0 °C and stirred at room temperature for 1 h. After confirming the formation of the product by LCMS, the mixture was diluted with 50 mL of hydrochloric acid solution (2 mol / L). The mixture was then extracted three times with dichloromethane, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was subjected to column chromatography (DCM / MeOH = 0-15:1) to obtain the product (3.29 g, yield = 59%).

[0186] LC-MS: (M+H) + m / z = 326.05, 327.17; Step C: 2-(3-(4-bromophenyl)-5-oxopyrrolidin-3-yl)acetic acid JPEG2025537242000033.jpg41128

[0187] 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, and 12.5 mL of aqueous sodium hydroxide (1.0 mol / L) was slowly added at 0 °C. The mixture was stirred at 40 °C for 1 h. After confirming the formation of the product by LCMS, the reaction mixture was acidified with hydrochloric acid (1.0 mol / L) and then extracted three times with dichloromethane. The organic layer was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude product (0.75 g, yield = 82%).

[0188] LC-MS: (M-H) - m / z = 297.66, 298.25;

[0189] Step D: 5-Bromospiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione JPEG2025537242000034.jpg45131

[0190] 7.5 g of polyphosphoric acid was heated to 150 °C, and then 0.75 g (2.52 mmol, 1.0 eq) of 2-(3-(4-bromophenyl)-5-oxopyrrolidin-3-yl)acetic acid was added. The mixture was then stirred at 150 °C for 1 h. After confirming the formation of the product by LCMS, the mixture was slowly poured into ice water while still hot and stirred while adding the mixture. 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 under reduced pressure. The residue was subjected to column chromatography (DCM / MeOH = 0 to 20:1) to give the product (0.65 g, yield = 92%).

[0191] LC-MS: (M+H) + ; m / z = 280.03, 282.04.

[0192] Preparation Example 2: 5-(2-cyclopropylphenyl)spiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione (Compound I2) JPEG2025537242000035.jpg37137

[0193] 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(diphenylphosphine)ferrocene]dichloride palladium and 1.25 g (5.89 mmol, 3.0 eq) of tripotassium phosphate were added, purged with nitrogen gas three times, and stirred at 100 °C for 1 h. After confirming the formation of the product by LCMS, 50 mL of water was added, followed by extraction with ethyl acetate three times. The organic layer was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was subjected to column chromatography (PE / EA=0-10:1) to give the product (620 mg, yield=99%).

[0194] LC-MS: (M+H) + ; m / z = 318.20.

[0195] Preparation Example 3 5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol (Compound I3) JPEG2025537242000036.jpg35125

[0196] 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. After LCMS confirmed complete conversion of the starting material and the formation of the product, the reaction mixture was filtered through diatomaceous earth and washed with tetrahydrofuran. The mixture was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude product (420 mg, yield = 67%).

[0197] LC-MS: (M+H) + ; m / z = 306.26; Preparation Example 4: 5-(2-Isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol (Compound I4) JPEG2025537242000037.jpg27137

[0198] Step A: 5-(2-Isopropylphenyl)spiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione JPEG2025537242000038.jpg57143

[0199] 2.60 g (9.28 mmol, 1.0 eq) 5-bromospiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione, 1.83 g (11.1 mmol, 1.2 eq) (2-isopropylphenyl)boronic acid, 7.88 g (37.1 mmol, 4.0 eq) potassium phosphate, 0.07 g (0.093 mmol, 0.01 eq) [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, and 40 mL (1,4-dioxane:water = 4:1) mixed solvent were added to a 100 mL reaction flask, purged with nitrogen gas three times, and reacted at 100 °C for 4 h. TLC plates (DCM:MeOH = 20:1) confirmed complete reaction of the starting materials. The reaction mixture was added to 50 mL of water and extracted three times with ethyl acetate (50 mL). The organic layers were combined, dried, concentrated, and loaded. The residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to give 2.56 g of a yellow oily product (yield=83%).

[0200] LC-MS: (M+H) + m / z = 320.16; 1H NMR (400 MHz, DMSO-d6) δ 8.08 (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 = 4 Hz, 3H), 1.14 (d, J = 8 Hz, 3H).

[0201] Step B: 5-(2-Isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol JPEG2025537242000039.jpg471421.50 g (4.69 mmol, 1.0 eq) 5-(2-isopropylphenyl)spiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione and 20 mL tetrahydrofuran were added to a 100 mL reaction flask and cooled to 0 °C under a nitrogen atmosphere. 2.67 g (70.4 mmol, 15.0 eq) lithium aluminum hydride was slowly added and stirred at 0 °C for 10 minutes. The reaction mixture was then refluxed for 2 hours. TLC (DCM:MeOH = 20:1) confirmed complete reaction of the starting material. The reaction mixture was quenched by adding 2 mL of water, filtered through diatomaceous earth, and the filter cake was washed with tetrahydrofuran (200 mL) until the product was completely dissolved. The filtrate was concentrated to dryness to give 1.20 g of crude product as a yellow oil.

[0202] LC-MS: (M+H) + ; m / z = 308.14.

[0203] Preparation Example 5: (5-Bromo-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone (compound I5) JPEG2025537242000040.jpg23140

[0204] Step A: 5-Bromo-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol JPEG2025537242000041.jpg34102

[0205] In a 50 mL Schreck 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 a nitrogen atmosphere, 1.1 mL (10.7 mmol, 10.0 eq) of a borane solution in dimethyl sulfide was slowly added via syringe. After the addition, the mixture was heated to 70 °C and reacted for 18 h. LCMS confirmed the formation of the desired product. The reaction mixture was cooled to -10 °C and quenched by slowly adding 2 mL of water. 20 mL of tetrahydrofuran was added to the reaction mixture. The mixture was filtered through diatomaceous earth, and the filter cake was washed with tetrahydrofuran (20 mL x 3) until the product was completely dissolved. The filtrate was concentrated to dryness to obtain 350 mg of crude product as a yellow oil. This reaction was then carried on to the next step.

[0206] LC-MS: (M+H) + m / z = 268.01; Step B: (5-Bromo-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000042.jpg36122

[0207] A 50 mL reaction flask was charged with 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'-tetramethylurea hexafluorophosphate, 665 mg (5.15 mmol, 6.0 eq) of N,N-diisopropylethylamine, and 10 mL of tetrahydrofuran. The reaction mixture was stirred at room temperature for 10 minutes under a nitrogen atmosphere. A solution of 230 mg (0.86 mmol, 1.0 eq) of 5-bromo-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol in 6 mL of tetrahydrofuran was then added to the reaction mixture and stirred at room temperature for 2 hours. After confirming the formation of the desired product by LCMS, the reaction mixture was quenched with 15 mL of water and then extracted three times with ethyl acetate (25 mL). The organic phases were combined, dried and concentrated, and 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%).

[0208] LC-MS: (M+H) + ; m / z = 391.01.

[0209] Example 1: (6-(2-cyclopropylphenyl)-4-hydroxy-3,4-dihydro-2H-spiro[naphthalene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000043.jpg46125

[0210] Step A: 2-(4-bromophenyl)-4-(1,3-dioxolan-2-yl)butanitrile JPEG2025537242000044.jpg37129

[0211] Under a nitrogen atmosphere, 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 mixture was warmed to room temperature and stirred for 3 h. The temperature was then lowered to -78 °C. 2-(2-bromoethyl)-1,3-dioxane (22.0 g, 122 mmol, 1.2 eq) was then slowly added dropwise. After the addition was complete, the mixture was warmed to room temperature and stirred overnight. After TLC confirmed the complete reaction of the starting materials, 200 mL of ice water was slowly added dropwise to quench the reaction, 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 under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA=10 / 1) to obtain the desired product (13.0 g, yield=43%).

[0212] 1 H NMR (400 MHz, CDCl3) δ 7.52-7.48 (m, 2H), 7.23-7.19 (m, 2H), 4.89 (t, J = 4.0 Hz, 1H), 3.99-3.80 (m, 5H), 2.07-1.93 (m, 2H), 1.85-1.78 (m, 2H). JPEG2025537242000045.jpg60117

[0213] Step B: Ethyl 3-(4-bromophenyl)-3-cyano-5-(1,3-dioxolan-2-yl)valerate

[0214] 2-(4-Bromophenyl)-4-(1,3-dioxolan-2-yl)butanitrile (4.0 g, 13.5 mmol, 1.0 eq) was dissolved in 40 mL of tetrahydrofuran. Sodium hydride (1.62 g, 40.5 mmol, 60% in oil, 3 eq) was then added in portions in an ice bath. After the addition was complete, the mixture was heated to 70 °C and stirred for 2 h. Ethyl bromoacetate (2.70 g, 16.2 mmol, 1.2 eq) was then slowly added dropwise. After the addition was complete, the mixture was heated to 70 °C and stirred overnight. TLC confirmed the formation of a new product and some remaining starting material. After cooling, the reaction was quenched by slowly adding 100 mL of ice water dropwise, followed by extraction three times with ethyl acetate (100 mL x 3). The organic layer was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was subjected to silica gel column chromatography (PE / EA=10:1 to 5:1) to obtain the target product (1.6 g, yield=31%).

[0215] 1 H NMR (400 MHz, CDCl3) δ 7.54-7.49 (m, 2H), 7.33-7.30 (m, 2H), 4.82 (t, J = 4.0 Hz, 1H), 4.03 (q, J = 6.8 Hz, 2H), 3.92-3.78 (m, 4H), 3.03-2.88 (m, 2H), 2.24-2.16 (m, 1H), 2.06-1.99 (m, 1H), 1.48-1.39 (m, 1H), 1.36-1.24 (m, 1H), 1.12 (t, J = 7.2 Hz, 3H).

[0216] Step C: Ethyl 3-cyano-3-(2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-5-(1,3-dioxan-2-yl)valerate JPEG2025537242000046.jpg62153

[0217] 1.60 g of ethyl (4.18 mmol, 1.0 eq) 3-(4-bromophenyl)-3-cyano-5-(1,3-dioxolan-2-yl)valerate 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(diphenylphosphine)ferrocene]dichloride palladium and 2.66 g (12.5 mmol, 3.0 eq) of tripotassium phosphate were added, and the mixture was purged with nitrogen gas three times and stirred at 100 °C for 2 h. After cooling, 50 mL of water was added. The mixture was 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 under reduced pressure. The residue was subjected to column chromatography (PE / EA=0 to 5:1) to give the product (1.10 g, yield=63%).

[0218] 1 H NMR (400 MHz, CDCl3) δ 7.50-7.44 (m, 4H), 7.30-7.26 (m, 1H), 7.23-7.19 (m, 2H), 6.94 (d, J = 7.8 Hz, 1H), 4.87 (t, J = 4.4 Hz, 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).

[0219] Step D: 4-(2-(1,3-dioxan-2-yl)ethyl)-4-(2'-cyclopropyl-[1,1'-biphenyl]-4-yl)pyrrolidin-2-one JPEG2025537242000047.jpg59129

[0220] 1.10 g (2.62 mmol, 1.0 eq) ethyl 3-cyano-3-(2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-5-(1,3-dioxan-2-yl)valerate was dissolved in 25 mL of methanol, 714 mg (5.50 mmol, 2.1 eq) of anhydrous cobalt chloride was added, and 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 h. After confirming the formation of the product by LCMS, the reaction was quenched with 50 mL of ice water, extracted three times with dichloromethane, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was subjected to column chromatography (DCM / MeOH = 0-15:1) to give the product (0.80 g, yield = 81%).

[0221] LC-MS: (M+H) + ; m / z = 378.26; 1 H NMR (400 MHz, CDCl3) δ 7.43-7.41 (m, 2H), 7.29-7.24 (m, 1H), 7.22-7.17 (m, 4H), 6.93 (d, J = 8.0 Hz, 1H), 6.02 (s, 1H), 4.76 (t, J = 4.4 Hz, 1H), 3.93-3.78 (m, 4H), 3.74-3.61 (m, 2H), 2.84-2.58 (m, 2H), 2.01-1.93 (m, 2H), 1.90-1.83 (m, 1H), 1.55-1.49 (m, 2H), 0.89-0.80 (m, 2H), 0.71-0.64 (m, 2H).

[0222] Step E: 3-(3-(2-(2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-5-oxopyrrolidin-3-yl)propanal JPEG2025537242000048.jpg52119

[0223] 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. Then, 10.64 mL of HCl / 1,4-dioxane solution (4.24 mmol, 20 eq, 4 M) was added under ice bath conditions. The mixture was stirred overnight, and complete conversion was confirmed by LCMS. Under ice bath conditions, an aqueous solution of sodium bicarbonate was added to adjust the pH to approximately 7-8. The mixture 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 by distillation under reduced pressure to obtain the crude product (0.50 g, yield = 71%), which was used directly in the next reaction without further purification.

[0224] LC-MS: (M+H) + ; m / z = 334.11; 1 H NMR (400 MHz, CDCl3) δ 9.63 (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).

[0225] Step F: 3-(3-(2-(2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-5-oxopyrrolidin-3-yl)propionic acid JPEG2025537242000049.jpg55135

[0226] 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 t-butanol (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. NaClO (80% mixture with NaCl, 237 mg, 2.1 mmol, 1.4 eq) and NaHPO (180 mg, 1.50 mmol, 1.0 eq) were added. A mixture of (eq) was dissolved in a minimum volume of water and then added to the reaction mixture. The reaction mixture was monitored by TLC until complete consumption of the aldehyde was observed. The reaction mixture was acidified to pH = 3 with NaHSO4 (aq). After extraction with ethyl acetate three times, the organic layer was washed with 50 mL of saturated brine solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (DCM / MeOH = 0-15:1) to obtain the product (300 mg, yield = 57%).

[0227] LC-MS: (M+H) + m / z = 350.21; Step G: 6-(2-Cyclopropylphenyl)-2,3-dihydro-4H-spiro[naphthalene-1,3'-pyrrolidine]-4,5'-dione JPEG2025537242000050.jpg44141

[0228] 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)propionic acid was added with stirring. The mixture was then stirred at 150 °C for 1 h. After confirming the formation of the product by LCMS, the mixture was slowly poured into ice water while still hot and stirred while adding the mixture. 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 under reduced pressure to give the crude product (120 mg, yield = 42%), which was used directly in the next reaction.

[0229] LC-MS: (M+H) + m / z = 332.16; Step H: 6-(2-Cyclopropylphenyl)-3,4-dihydro-2H-spiro[naphthalen-1,3'-pyrrolidin]-4-ol JPEG2025537242000051.jpg45113

[0230] 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. After confirming the formation of the product by LCMS, the reaction mixture was filtered through diatomaceous earth and washed with tetrahydrofuran. The mixture was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude product (50 mg, yield = 43%), which was used directly in the next reaction.

[0231] LC-MS: (M+H) + m / z = 320.22; Step I: (6-(2-cyclopropylphenyl)-4-hydroxy-3,4-dihydro-2H-spiro[naphthalene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000052.jpg45118

[0232] 33.0 mg (0.234 mmol, 1.5 eq) 5-fluoropyridine-2-carboxylic acid, 60.5 mg (0.468 mmol, 3.0 eq) N,N-diisopropylethylamine, and 89.0 mg (0.234 mmol, 1.5 eq) 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea 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) 6-(2-cyclopropylphenyl)-3,4-dihydro-2H-spiro[naphthalene-1,3'-pyrrolidin]-4-ol was added and stirred at room temperature for 1.5 h. After confirming the formation of the product by LCMS, 50 mL of brine was added. It was then extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, evaporated under reduced pressure, 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 (4.15 mg, yield = 6%).

[0233] LC-MS: (M+Na) + ; m / z = 465.11;

[0234] 1 H NMR (400 MHz, CDCl3) δ 8.45-8.35 (m, 1H), 8.02 (dd, J = 8.8, 4.4 Hz, 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).

[0235] Example 2: (5-chloropyridin-2-yl)(6-(2-cyclopropylphenyl)-4-hydroxy-3,4-dihydro-2H-spiro[naphthalen-1,3'-pyrrolidin]-1'-yl)methanone JPEG2025537242000053.jpg49137

[0236] The experimental procedure was the same as that of Step I of Example 1, except that the reagent 5-fluoropyridine-2-carboxylic acid was replaced with 5-chloropyridine-2-carboxylic acid to obtain Example 2 by synthesis.

[0237] LC-MS: (M+Na) + ; m / z = 481.07; 1 H NMR (400 MHz, CDCl3) δ 8.48-8.39 (m, 1H), 8.05 (dd, J = 8.8, 4.4 Hz, 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).

[0238] Example 3: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000054.jpg54141

[0239] Step A: 5-Bromo-1H-indene JPEG2025537242000055.jpg2381

[0240] 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 toluol, and 180 mg (0.94 mmol, 0.1 eq) of p-toluenesulfonic acid monohydrate was added to the reaction mixture. The mixture was stirred at 65 °C under a nitrogen atmosphere for 3 h. After cooling to room temperature, 30 mL of water and 80 mL of ethyl acetate were added, and the organic phase was separated. The aqueous phase was extracted twice with ethyl acetate (2 × 60 mL), and the organic phases were combined. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was subjected to column chromatography (petroleum ether) to give an oil (1.50 g, yield = 82%).

[0241] 1 H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 4.0 Hz, 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).

[0242] Step B: t-Butyl 5-bromo-spiro[indene-1,4'-piperidine]-1'-carboxylate JPEG2025537242000056.jpg2796

[0243] 1.50 g (7.69 mmol, 1.0 eq) of 5-bromo-1H-indene was dissolved in 20 mL of tetrahydrofuran and cooled to 0 °C. Under a nitrogen atmosphere, 19.4 mL (19.2 mmol, 2.5 eq) of lithium bis(trimethylsilyl)amine was added dropwise to the reaction mixture. After the addition, the reaction mixture was stirred at 0 °C for 1 h. Then, a solution of 2.23 g (9.23 mmol, 1.2 eq) of t-butyl bis(2-chloroethyl)carbamate in 20 mL of tetrahydrofuran was added dropwise to the reaction mixture. After the addition, the mixture was allowed to warm to room temperature and react for 16 h. LC-MS analysis confirmed the complete reaction of the starting materials. 40 mL of water and 90 mL of ethyl acetate were added, and the organic phase was separated. The aqueous phase was extracted twice with ethyl acetate (2 x 80 mL), and the organic phases were combined. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether:ethyl acetate=100:1 to 20:1) to obtain an oily product (2.40 g, yield=86%).

[0244] LC-MS: (M-Boc) + m / z = 264.12; Step C: t-Butyl 5-bromo-3-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate JPEG2025537242000057.jpg33103

[0245] 100 mg (0.28 mmol, 1.0 eq) of 5-bromo-t-butyl[indene-1,4'-piperidine]-1'-carboxylate was dissolved in 5 mL of anhydrous tetrahydrofuran. Then, 1.1 mL (0.56 mmol, 2.0 eq) of 9-holobicyclo[3.3.1]nonane was added to the reaction mixture, and the mixture was incubated in a sealed tube at 70 °C for 17 h. The reaction mixture was cooled to room temperature, and 0.55 mL of 1 M aqueous sodium hydroxide solution was added, followed by 0.1 mL (30% mw) aqueous hydrogen peroxide solution. The mixture was stirred for 1 h. 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 give a pale yellow oil (80.0 mg, yield = 80%).

[0246] LC-MS: (M-Boc) + ; m / z = 282.00;

[0247] Step D: 5-Bromo-2,3-dihydrospiro[indene-1,4'-piperidin]-3-ol JPEG2025537242000058.jpg35101

[0248] 80.0 mg (0.21 mmol, 1.0 eq) of t-butyl 5-bromo-3-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate was dissolved in 6 mL of dichloromethane, and then 1 mL (4.31 mmol, 30 eq) of chloride hydride in dioxane was added to the reaction mixture. The reaction was carried out under a nitrogen atmosphere at 40 °C for 1 h. LC-MS confirmed the formation of the desired product. The reaction mixture was concentrated to dryness to give a pale yellow oil (58.0 mg, yield = 98%).

[0249] LC-MS: (M+H) + m / z = 283.95;

[0250] Step E: (5-Bromo-3-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000059.jpg39115

[0251] 48.0 mg (0.34 mmol, 1.2 eq) of 5-fluoropyricarboxylic acid was dissolved in 6 mL of tetrahydrofuran, followed by addition of 129 mg (0.34 mmol, 1.0 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and 0.28 mL (1.70 mmol, 6.0 eq) of N,N-diisopropylethylamine. The mixture was stirred for 10 min under a nitrogen atmosphere. A solution of 80.0 mg (0.28 mmol, 1.0 eq) of 5-bromo-2,3-dihydrospiro[indene-1,4'-piperidin]-3-ol in 3 mL of tetrahydrofuran was added dropwise to the reaction mixture. The mixture was then stirred at room temperature for 2 h. LC-MS analysis confirmed the formation of the desired product. The reaction mixture was cooled to room temperature, quenched with water, and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated to dryness, and then subjected to column chromatography (dichloromethane / methano = 80 / 1 to 30 / 1) to give a pale yellow solid (50.0 mg, yield = 44%).

[0252] LC-MS: (M+H) + m / z = 406.89;

[0253] Step F: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000060.jpg47121

[0254] 50.0 mg (0.12 mmol, 1.0 eq) (5-bromo-3-hydroxy-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)(5-fluoropyridin-2-yl)methanone was dissolved in 6 mL dioxane and 2 mL water. 23.9 mg (0.15 mmol, 1.2 eq) (2-cyclopropylphenyl)boronic acid and 78.2 mg (0.15 mmol, 3.0 eq) potassium phosphate were added to the reaction mixture. 18.0 mg (0.02 mmol, 0.1 eq) [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride was added under a nitrogen atmosphere and the reaction was allowed to proceed at 100 °C for 3 h. LC-MS analysis confirmed the formation of the desired product. The reaction mixture 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 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 the product as a white solid (10.2 mg, yield = 18%).

[0255] LC-MS: (M+H) + ; m / z = 443.42; 1 H NMR (400 MHz, CDCl3) δ 8.48-8.46 (m, 1H), 7.78 (dd, J = 8.6, 4.5 Hz, 1H), 7.56-7.51 (m, 2H), 7.45 (d, J = 7.9 Hz, 1H), 7.31-7.27 (m, 2H), 7.26-7.19 (m, 2H), 6.94 (d, J = 7.8 Hz, 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). 19 F NMR (376 MHz, CDCl3) δ -123.84 (d, J = 3.9 Hz).

[0256] Example 4: (5-Fluoropyridin-2-yl)(3-hydroxy-5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)methanone JPEG2025537242000061.jpg56126

[0257] The experimental procedure was the same as in Step F of Example 3, except that (2-cyclopropylphenyl)boronic acid was replaced with 2-isopropylphenylboronic acid to obtain the compound of Example 4 by synthesis.

[0258] LC-MS: (M+H) + ; m / z = 445.17.

[0259] 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) JPEG2025537242000062.jpg33140

[0260] Step A: 5-(2-cyclopropylphenyl)-3-hydroxy-3-methyl-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-2'-one JPEG2025537242000063.jpg47116

[0261] 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 purged with nitrogen gas three times. At 0 °C, 4 mL (12.0 mmol, 5.0 eq, 3 M) of methylmagnesium chloride was added dropwise and stirred at room temperature for 2 h. After confirming complete conversion of the starting material and the formation of the product by LCMS, 30 mL of saturated ammonium chloride solution was added to quench the reaction. 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 under reduced pressure. The residue was subjected to column chromatography (DCM / MeOH = 0-20:1) to obtain the product (0.60 g, yield = 75%).

[0262] LC-MS: (M+H) + m / z = 334.21; Step B: 5-(2-cyclopropylphenyl)-3-methyl-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol JPEG2025537242000064.jpg4294

[0263] 550 mg (1.65 mmol, 1.0 eq) of 5-(2-cyclopropylphenyl)-3-hydroxy-3-methyl-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-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 the mixture was stirred at 70 °C for 2 h. After confirming complete conversion of the starting materials and the formation of the product by LCMS, the reaction mixture was filtered through diatomaceous earth and washed with tetrahydrofuran. The mixture was dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a reaction mixture containing the product.

[0264] LC-MS: (M+H) + m / z=320.23;

[0265] Step C: (5-(2-cyclopropylphenyl)-3-hydroxy-3-methyl-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000065.jpg36139

[0266] 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'-tetramethylurea hexafluorophosphate were dissolved in 50 mL of tetrahydrofuran and stirred at room temperature for 0.5 h. The reaction mixture containing 5-(2-cyclopropylphenyl)-3-methyl-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was added and stirred at room temperature for 2 h. After confirming the formation of the product by LCMS, 50 mL of brine was added, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, evaporated under reduced pressure, 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 product P1 (118 mg, yield = 14%) and white solid product P2 (135 mg, yield = 16%).

[0267] Example 5 (P1) LC-MS: (M+H) + ; m / z=443.18; 1 H NMR (400 MHz, CDCl3) δ 8.50-8.40 (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).

[0268] Example 6 (P2) LC-MS: (M-OH+H) + m / z=425.18; 1 H NMR (400 MHz, CDCl3) δ 8.49-8.38 (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).

[0269] Example 7: (5-(2-cyclopropylphenyl)-3-hydroxy-3-trifluoromethyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000066.jpg46117

[0270] Step A: 5-(2-cyclopropylphenyl)-3-hydroxy-3-trifluoromethyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-5'-one JPEG2025537242000067.jpg46104

[0271] 100 mg (0.31 mmol, 1.0 eq) 5-(2-cyclopropylphenyl)-3-hydroxy-3-trifluoromethyl-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-5'-one and 270 mg (1.86 mmol, 6.0 eq) (trifluoromethyl)trimethylsilane were dissolved in 5 mL of anhydrous tetrahydrofuran and purged with nitrogen three times. 0.3 mL of tetramethylammonium fluoride was added dropwise at 0 °C and the mixture was stirred overnight at room temperature. After confirming the formation of the product by LCMS, the reaction mixture was quenched by adding 30 mL of saturated sodium bicarbonate solution dropwise. The mixture was 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 under reduced pressure to give the crude product (103 mg, yield = 86%).

[0272] LC-MS: (M+H) + ; m / z = 388.11;

[0273] Step B: 5-(2-cyclopropylphenyl)-3-trifluoromethyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol JPEG2025537242000068.jpg42114

[0274] 103 mg (0.27 mmol, 1.0 eq) of 5-(2-cyclopropylphenyl)-3-hydroxy-3-trifluoromethyl-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-5'-one was dissolved in 5 mL of anhydrous tetrahydrofuran, and 99.0 mg (2.66 mmol, 10.0 eq) of lithium aluminum hydride was slowly added at 0 °C. The mixture was stirred at 70 °C for 3 h. After confirming the formation of the product by LCMS, the reaction mixture was filtered through diatomaceous earth and washed with tetrahydrofuran. The mixture was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude product (100 mg, yield = 100%).

[0275] LC-MS: (M+H) + m / z = 373.97; Step C: (5-(2-cyclopropylphenyl)-3-hydroxy-3-trifluoromethyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000069.jpg45128

[0276] 57.0 mg (0.40 mmol, 1.5 eq) 5-fluoropyridine-2-carboxylic acid, 0.08 mL N,N-diisopropylethylamine, and 153 mg (0.40 mmol, 1.5 eq) 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate were dissolved in 10 mL tetrahydrofuran and stirred at room temperature for 0.5 h. 100 mg (0.27 mmol, 1.0 eq) 5-(2-cyclopropylphenyl)-3-trifluoromethyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was added and stirred at room temperature for 3 h. After confirming the formation of the product by LCMS, 5 mL of brine was added to the mixture, followed by extraction with ethyl acetate three times, drying over anhydrous sodium sulfate, evaporation under reduced pressure, preparation and purification (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min), and lyophilization to obtain a white solid (7.00 mg, yield = 5%).

[0277] LC-MS: (M+H) + m / z = 497.29; 1 H NMR (400 MHz, CDCl3) δ 8.40-8.38 (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). 19 F NMR (376 MHz, CDCl3) δ -79.51, -122.46.

[0278] Example 8: (5-Fluoropyridin-2-yl)(1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolane-3,3'-pyrrolidin]-1'-yl)methanone JPEG2025537242000070.jpg42100

[0279] Step A: t-Butyl 3-(2-bromophenyl)-3-hydroxypyrrolidine-1-carboxylate JPEG2025537242000071.jpg2795

[0280] 3.00 g (10.6 mmol, 1.0 eq) of o-bromoiodobenzene 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. The atmosphere was purged with nitrogen gas, and the system was cooled to -78 °C. 6.4 mL (12.7 mmol, 1.2 eq) of isopropylmagnesium chloride (2M) was slowly added dropwise to the solution. The system was maintained at -78 °C during the addition. The reaction was then continued at -78 °C for 1 hour. A solution of 2.00 g (10.6 mmol, 1.0 eq) of 1-t-butoxycarbonyl-3-pyrrolidone in 10 mL of anhydrous tetrahydrofuran was then slowly added to the reaction system. The system was then allowed to warm to room temperature and continued for 18 hours. After completion of the reaction was confirmed by LC-MS, the system was quenched with 10 mL of saturated ammonium chloride solution. The mixture was extracted three times with 50 mL of ethyl acetate, and the organic phase was washed with sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was subjected to column chromatography (EA / PE = 0 to 1:6) to give t-butyl 3-(2-bromophenyl)-3-hydroxypyrrolidine-1-carboxylate (1.00 g, yield = 28%).

[0281] LC-MS: (M+H-Boc) + m / z = 242, 244; Step B: t-Butyl 1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolane-3,3'-pyrrolidine]-1'-carboxylate JPEG2025537242000072.jpg37108

[0282] 66.0 mg (0.2 mmol, 1.0 eq) of t-butyl 3-(2-bromophenyl)-3-hydroxypyrrolidine-1-carboxylate was dissolved in 5 mL of 1,4-dioxane. Then, 108.9 mg (0.5 mmol, 2.5 eq) of bis(neopentylglycolato)diboron, 14.1 mg (0.02 mmol, 0.1 eq) of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, and 37.9 mg (0.4 mmol, 2.0 eq) of potassium acetate were added to the reaction mixture. After purging with nitrogen gas, the mixture was heated to 80 °C and reacted for 3 hours. After confirming the completion of the reaction by LC-MS, the mixture was cooled to room temperature and used directly in the next reaction.

[0283] LC-MS: (M+Na) + m / z = 312; Step C: 1H-Spiro[benzo[c][1,2]oxaborolan-3,3'-pyrrolidin]-1-ol hydrochloride JPEG2025537242000073.jpg3682

[0284] After cooling the reaction mixture containing t-butyl 1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolane-3,3'-pyrrolidine]-1'-carboxylate to room temperature, 1 mL (12 mmol, 60.0 eq) of a 4 M solution of hydrochloric acid in dioxane was added and the mixture was allowed to react for 1 hour under a nitrogen atmosphere. After confirming the completion of the reaction by LC-MS, the solvent was evaporated under reduced pressure to give 1H-spiro[benzo[c][1,2]oxaborolane-3,3'-pyrrolidine]-1-ol hydrochloride (21.2 mg, 58% overall yield for both steps).

[0285] LC-MS: (M+H) + m / z = 190;

[0286] Step D: (5-Fluoropyridin-2-yl)(1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolan-3,3'-pyrrolidin]-1'-yl)methanone JPEG2025537242000074.jpg48109

[0287] 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 purging with nitrogen, 46.9 mg (0.10 mmol, 1.1 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and 29.0 mg (0.20 mmol, 2.0 eq) of N,N-diisopropylethylamine were added. After stirring at room temperature for 1 minute, 21.2 mg (0.10 mmol, 1.0 eq) of 1H-spiro[benzo[c][1,2]oxaborolane-3,3'-pyrrolidin]-1-ol was added, followed by stirring for 30 minutes. After confirming completion of the reaction by LC-MS, 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 under reduced pressure. The residue was purified 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]oxaborolane-3,3'-pyrrolidin]-1'-yl)methanone (15.9 mg, yield = 45%) as a white solid.

[0288] LC-MS: (M+H) + m / z = 429; 1H NMR (400 MHz, CDCl3) δ 8.40 (dd, J = 56.3, 2.9 Hz, 1H), 8.07 (ddd, J = 10.9, 8.7, 4.6 Hz, 1H), 7.74 (t, J = 7.3 Hz, 1H), 7.56-7.46 (m, 2H), 7.45-7.34 (m, 2H), 5.32 (d, J = 43.4 Hz, 1H), 4.35-3.96 (m, 4H), 2.50-2.39 (m, 1H), 2.15-2.07 (m, 1H).

[0289] Example 9: (6-(2-cyclopropylphenyl)-1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolane-3,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000075.jpg45119

[0290] Step A: 3-Bromo-2'-cyclopropyl-[1,1'-biphenyl]-4-amine JPEG2025537242000076.jpg4296

[0291] 1.50 g (5.00 mmol, 1.0 eq) of 2-bromo-4-iodoaniline was dissolved in 12.5 mL of 1,4-dioxane, followed by the addition of 0.80 g (5.00 mmol, 1.0 eq) of 2-cyclopropylphenylboronic acid, 0.30 g (0.30 mmol, 0.05 eq) of tetra(triphenylphosphine)palladium, 1.40 g (10.1 mmol, 2.0 eq) of potassium carbonate, and 2.5 mL of water. The reaction mixture was purged with nitrogen and heated to 80 °C for 2 h. After confirming completion of the reaction by LC-MS, the mixture was allowed to return to room temperature. The mixture was then diluted with 20 mL of saturated sodium chloride solution and extracted three times with 30 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography (EA / PE=0 to 1:10) to obtain 3-bromo-2′-cyclopropyl-[1,1′-biphenyl]-4-amine (791 mg, yield=55%).

[0292] LC-MS: (M+H) + ; m / z = 288; 290; Step B: 3'-Bromo-2-cyclopropyl-4'-iodo-1,1'-biphenyl JPEG2025537242000077.jpg3590

[0293] 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 8 mL of concentrated hydrochloric acid was added with stirring. The mixture was cooled to 0 °C, and 263 mg (3.80 mmol, 1.5 eq) of sodium nitrite (0.9 mL) in water was slowly added dropwise to the mixture. The mixture was maintained at 0-5 °C during the addition. After the addition, the mixture was incubated at 0 °C for 30 min. 1.69 g (10.2 mmol, 4.0 eq) of potassium iodide was then slowly added to the mixture, and the reaction mixture was incubated at 0 °C for a final 30 min. After confirming the completion of the reaction by LC-MS, the mixture was quenched with 10 mL of 10% aqueous sodium bisulfite solution. The mixture was then extracted three times with 50 mL of ethyl acetate. The organic phase was washed successively with saturated sodium carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was subjected to column chromatography (PE) to obtain 3'-bromo-2-cyclopropyl-4'-iodo-1,1'-biphenyl (641 mg, yield=63%).

[0294] 1 H NMR (400 MHz, CDCl3) δ 7.79 (dd, J = 7.1, 3.1 Hz, 1H), 7.64 (dd, J = 7.1, 2.2 Hz, 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). Step C: t-Butyl 3-(3-bromo-2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-3-hydroxypyrrolidine-1-carboxylate JPEG2025537242000078.jpg36117

[0295] 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 purging with nitrogen gas, 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 solution. The system was maintained at -78 °C during the addition. After the addition, the reaction was continued at -78 °C for 1 hour. Then, 253 mg (1.40 mmol, 1.4 eq) of 1-t-butoxycarbonyl-3-pyrrolidone in 4 mL of anhydrous tetrahydrofuran was slowly added to the reaction system. The system was then allowed to warm to room temperature and continued for 18 hours. After completion of the reaction was confirmed by LC-MS, the reaction was quenched with 5 mL of saturated ammonium chloride solution. The mixture was extracted three times with 50 mL of ethyl acetate, and the organic phase was washed with sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (EA / PE = 0 to 1:6) to give t-butyl 3-(3-bromo-2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-3-hydroxypyrrolidine-1-carboxylate (107 mg, yield = 24%).

[0296] LC-MS: (M+H-Boc-OH) + ; m / z = 340; 342;

[0297] Step D: t-Butyl 6-(2-cyclopropylphenyl)-1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolane-3,3'-pyrrolidine]-1'-carboxylate JPEG2025537242000079.jpg42108

[0298] 107 mg (0.20 mmol, 1.0 eq) of t-butyl 3-(3-bromo-2'-cyclopropyl-[1,1'-biphenyl]-4-yl)-3-hydroxypyrrolidine-1-carboxylate was dissolved in 6 mL of 1,4-dioxane, followed by 132 mg (0.60 mmol, 2.5 eq) of bis(neopentylglycolato)diboron, 17.1 mg (0.02 mmol, 0.1 eq) of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, and 45.7 mg (0.50 mmol, 2 eq) of potassium acetate. The reaction mixture was purged with nitrogen gas and heated to 80 °C for 3 hours. After confirming completion of the reaction by LC-MS, the mixture was cooled to room temperature and used directly in the next reaction.

[0299] LC-MS: (M+Na) + m / z = 428; Step E: 6-(2-cyclopropylphenyl)-1H-spiro[benzo[c][1,2]oxaborolane-3,3'-pyrrolidin]-1-ol JPEG2025537242000080.jpg4199

[0300] After cooling the reaction mixture containing t-butyl 6-(2-cyclopropylphenyl)-1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolane-3,3'-pyrrolidine]-1'-carboxylate to room temperature, 3 mL (12 mmol, 60.0 eq) of a 4 M solution of hydrochloric acid in dioxane was added. The mixture was then reacted at room temperature for 2 hours under a nitrogen atmosphere. After confirming the completion of the reaction by LC-MS, the solvent was evaporated under reduced pressure to give 6-(2-cyclopropylphenyl)-1H-spiro[benzo[c][1,2]oxaborolane-3,3'-pyrrolidine]-1-ol (62.2 mg, 88% overall yield for both steps).

[0301] LC-MS: (M+H) + m / z = 306;

[0302] Step F: (6-(2-cyclopropylphenyl)-1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolane-3,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000081.jpg46118

[0303] 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 purging with nitrogen, 85.3 mg (0.20 mmol, 1.1 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and 52.7 mg (0.40 mmol, 2.0 eq) of N,N-diisopropylethylamine were added. The mixture was stirred at room temperature for 1 minute, followed by the addition of 62.2 mg (0.20 mmol, 1.0 eq) of 6-(2-cyclopropylphenyl)-1H-spiro[benzo[c][1,2]oxaborolane-3,3'-pyrrolidin]-1-ol. The mixture was then stirred for 30 minutes. After confirming the completion of the reaction by LC-MS, 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 under reduced pressure. The residue was purified 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]oxaborolane-3,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone (11.9 mg, yield = 14%) as a white solid.

[0304] LC-MS: (M+H) + m / z = 429;

[0305] 1H NMR (400 MHz, CDCl3) δ 8.54-8.27 (m, 1H), 8.07 (dd, J = 9.4, 4.6 Hz, 1H), 7.79 (d, J = 7.4 Hz, 1H), 7.64 (dd, J = 7.9, 1.6 Hz, 1H), 7.55-7.47 (m, 1H), 7.42 (dd, J = 14.9, 7.8 Hz, 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).

[0306] Example 10: (5-chloropyridin-2-yl)(6-(2-cyclopropylphenyl)-1-hydroxy-1H-spiro[benzo[c][1,2]oxaborolane-3,3'-pyrrolidin]-1'-yl)methanone JPEG2025537242000082.jpg46133

[0307] The experimental procedure was the same as in Step F of Example 9, except that 5-fluoro-2-pyridinecarboxylic acid was replaced with 5-chloro-2-pyridinecarboxylic acid to obtain the compound of Example 10 by synthesis.

[0308] LC-MS: (M+H) + ; m / z = 445.09.

[0309] Example 11: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl-3,5',5'-d3)(5-fluoropyridin-2-yl)methanone JPEG2025537242000083.jpg44135

[0310] Step A: 5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3,5',5'-d3-3-ol JPEG2025537242000084.jpg54119

[0311] 100 mg (0.31 mmol, 1.0 eq) of 5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was dissolved in 5 mL of anhydrous tetrahydrofuran. 120 mg (3.70 mmol, 12.0 eq) of lithium aluminum deuteride was slowly added at 0 °C and the mixture was stirred at 70 °C for 3 h. After confirming the formation of the product by LCMS, the reaction mixture was filtered through diatomaceous earth and washed with tetrahydrofuran. The mixture was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude product (100 mg, yield = 104%).

[0312] LC-MS: (M+H) + m / z = 309.19; Step B: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl-3,5',5'-d3)(5-fluoropyridin-2-yl)methanone JPEG2025537242000085.jpg45132

[0313] 77.0 mg (0.48 mmol, 1.5 eq) 5-chloropyridine-2-carboxylic acid, 0.16 mL N,N-diisopropylethylamine, and 187 mg (0.48 mmol, 1.5 eq) 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate were dissolved in 10 mL tetrahydrofuran and stirred at room temperature for 0.5 h. 100 mg (0.32 mmol, 1.0 eq) 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. After confirming the formation of the product by LCMS, 5 mL of brine was added to the mixture, followed by extraction with ethyl acetate three times, drying over anhydrous sodium sulfate, evaporation under reduced pressure, and 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 a white solid (14.0 mg, yield = 10%).

[0314] LC-MS: (M+H) + m / z = 432.19; 1 H NMR (400 MHz, CDCl3) δ 8.47-8.30 (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).

[0315] 19 F NMR (376 MHz, CDCl3) δ -123.19 (d, J = 24.8 Hz).

[0316] Example 12: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl-3-d)(5-fluoropyridin-2-yl)methanone JPEG2025537242000086.jpg44121

[0317] Step A: 5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-5'-one-3-d JPEG2025537242000087.jpg47122

[0318] 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, and 110 mg (0.57 mmol, 1.2 eq.) of sodium borohydride was slowly added at 0 °C. The mixture was stirred at room temperature for 2 h. After confirming the formation of the product by LCMS, the reaction mixture was quenched with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude product (148 mg, yield = 97%).

[0319] LC-MS: (M+H) + m / z = 321.10; Step B: 5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-d-3-ol JPEG2025537242000088.jpg45103

[0320] 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, and 263 mg (6.92 mmol, 15.0 eq) of lithium aluminum hydride was slowly added at 0 °C. The mixture was stirred at 70 °C for 3 h. After confirming the formation of the product by LCMS, the reaction mixture was filtered through diatomaceous earth and washed with tetrahydrofuran. The mixture was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude product (142 mg, yield = 100%).

[0321] LC-MS: (M+H) + m / z = 307.11; Step C: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl-3-d)(5-fluoropyridin-2-yl)methanone JPEG2025537242000089.jpg45123

[0322] 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'-tetramethylurea 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. After confirming the formation of the product by LCMS, 10 mL of brine was added. It was then extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, evaporated under reduced pressure, 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 (12.0 mg, yield = 5.7%).

[0323] LC-MS: (M+H) +; m / z = 430.06; 1 H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 38.7 Hz, 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, 4.2 Hz, 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).

[0324] 19 F NMR (376 MHz, CDCl3) δ -122.82 (d, J = 10.5 Hz).

[0325] Example 13: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-hydroxy-6-methylpyridin-2-yl)methanone JPEG2025537242000090.jpg42133

[0326] Step A: Synthesis of 5-hydroxy-6-methylpyridine acid JPEG2025537242000091.jpg2494

[0327] 0.97 g (5.16 mmol, 1.0 eq) of 6-bromo-2-picolin-3-ol was dissolved in 30 mL of N,N-dimethylformamide, and 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-bisdiphenylphosphine-9,9-dimethyloxaanthracene were added under ice-water bath conditions. The mixture was purged with carbon monoxide three times and stirred overnight at 80 °C. After extraction, the majority of the product was in the aqueous phase. 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 the product (0.78 g, yield = 99%).

[0328] LC-MS: (M-H) - m / z = 151.87; Step B: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-hydroxy-6-methylpyridin-2-yl)methanone JPEG2025537242000092.jpg42132

[0329] 150 mg (0.98 mmol, 3.0 eq) of 5-hydroxy-6-methylpyridine 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'-tetramethylurea 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. After confirming the formation of the product by LCMS, 5 mL of brine was added to the mixture, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, evaporated under reduced pressure, 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 (5.0 mg, yield = 3.4%).

[0330] LC-MS: (M+H) + m / z = 441.21; 1 H NMR (400 MHz, CDCl3) δ 7.67 (dd, J = 11.2, 8.3 Hz, 1H), 7.52 (d, J = 6.2 Hz, 1H), 7.46 (dd, J = 7.9, 1.7 Hz, 1H), 7.35-7.30 (m, 2H), 7.25-7.21 (m, 2H), 7.11 (dd, J = 14.0, 8.3 Hz, 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).

[0331] Example 14: (5-chloropyridin-2-yl)(5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)methanone JPEG2025537242000093.jpg4413577 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'-tetramethylurea 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. After complete conversion of the starting material and the formation of the product were confirmed by LCMS, 20 mL of brine was added. The residue was then extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, evaporated under reduced pressure, 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 (32.0 mg, yield = 22%).

[0332] LC-MS: (M+H) + ; m / z = 445.08; 1 H NMR (400 MHz, CDCl3) δ 8.61-8.50 (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, 4.1 Hz, 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).

[0333] Example 15: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000094.jpg45123

[0334] 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'-tetramethylurea 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. After confirming the formation of the product by LCMS, 50 mL of brine was added. The residue was then extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, evaporated under reduced pressure, 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 give a white solid (83.0 mg, yield = 15%).

[0335] LC-MS: (M+H) + m / z = 429.20; 1 H NMR (400 MHz, CDCl3) δ 8.49-8.38 (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, 4.2 Hz, 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).

[0336] Example 16: (5-Fluoropyridin-2-yl)(3-hydroxy-5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)methanone JPEG2025537242000095.jpg47133

[0337] 23.0 mg (0.16 mmol, 1.0 eq) 5-fluoropyridine-2-carboxylic acid, 74.2 mg (0.41 mmol, 1.2 eq) 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 63.0 mg (0.48 mmol, 3.0 eq) N,N-diisopropylethylamine, and 3 mL tetrahydrofuran were added to a 25 mL reaction flask. The reaction mixture was stirred at room temperature for 10 min under a nitrogen atmosphere. 50.0 mg (0.16 mmol, 1.0 eq) 5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was then weighed and dissolved in 3 mL tetrahydrofuran. The mixture was slowly added to the reaction mixture and stirred at room temperature for 1 h. TLC (DCM:MeOH = 20:1) plates confirmed complete reaction of the starting materials. The reaction mixture was concentrated to dryness, 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 the pure product as a white solid (11.2 mg, yield = 16%).

[0338] LC-MS: (M+H) + m / z = 431.15; 1H NMR (400 MHz, CDCl3) δ 8.47-8.37 (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 = 6.8 Hz, 6H).

[0339] 19 F NMR (376 MHz, CDCl3) δ -123.29.

[0340] Example 17: (2-chlorothiazol-4-yl)(5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)methanone JPEG2025537242000096.jpg47123

[0341] The experimental procedure was the same as in Example 15, except that 5-fluoropyridine-2-carboxylic acid was replaced with 2-chlorothiazole-4-carboxylic acid, and the compound in Example 17 was prepared and purified by synthesis.

[0342] LC-MS: (M+H) + ; m / z = 451.08; 1H NMR (400 MHz, CDCl3) δ 8.08-8.04 (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 = 6.1 Hz, 2H), 6.92 (d, J = 7.9 Hz, 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).

[0343] Example 18: (2-chlorothiazol-4-yl)(3-hydroxy-5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)methanone JPEG2025537242000097.jpg46131

[0344] 26.7 mg (0.16 mmol, 1.0 eq) 2-chlorothiazole-4-carboxylic acid, 74.2 mg (0.41 mmol, 1.2 eq) 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 63.0 mg (0.48 mmol, 3.0 eq) N,N-diisopropylethylamine, and 3 mL tetrahydrofuran were added to a 25 mL reaction flask. The reaction mixture was stirred at room temperature for 10 min under a nitrogen atmosphere. 50.0 mg (0.16 mmol, 1.0 eq) 5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was then dissolved in 3 mL tetrahydrofuran and slowly added to the reaction mixture. The mixture was stirred at room temperature for 1 h. TLC (DCM / MeOH = 20 / 1) plates confirmed complete reaction of the starting materials. The reaction mixture was concentrated to dryness, 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 the pure product as a white solid (5.11 mg, yield = 7%).

[0345] LC-MS: (M-OH) + ; m / z = 435.07;

[0346] 1 H NMR (400 MHz, CDCl3) δ 8.08-8.04 (m, 1H), 7.45-7.28 (m, 4H), 7.26-7.11 (m, 3H), 5.36-5.33 (m, 1H), 4.37-3.73 (m, 4H), 3.12-3.00 (m, 1H), 2.65-1.99 (m, 5H), 1.18 (d, J = 6.8 Hz, 6H).

[0347] Example 19: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(6-cyclopropylpyridin-2-yl)methanone JPEG2025537242000098.jpg40160

[0348] 117.4 mg (0.72 mmol, 1.5 eq) 6-cyclopropylpicolinic acid, 0.24 mL N,N-diisopropylethylamine, and 279 mg (0.72 mmol, 1.5 eq) 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate were dissolved in 5 mL tetrahydrofuran and stirred at room temperature for 0.5 h. 150.0 mg (0.48 mmol, 1.0 eq) 5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was added and stirred at room temperature for 3 h. After confirming the formation of the product by LC-MS, 5 mL of brine was added to the mixture, followed by extraction with ethyl acetate three times, drying over anhydrous sodium sulfate, evaporation under reduced pressure, preparation and purification (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min), and lyophilization to obtain a white solid (53.0 mg, yield = 24%).

[0349] LC-MS: (M+H)+ m / z = 451.19; 1 H NMR (400 MHz, CDCl3) δ 7.72-7.59 (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, 4.0 Hz, 1H), 5.39-5.27 (m, 1H), 4.21-3.77 (m, 4H), 2.68-2.51 (m, 1H), 2.41-2.14 (m, 2H), 2.11-2.00 (m, 2H), 1.91-1.83 (m, 2H), 1.08-0.99 (m, 2H), 0.96-0.92 (m, 2H), 0.89-0.82 (m, 2H), 0.77-0.69 (m, 2H).

[0350] Example 20: (6-Cyclopropylpyridin-2-yl)(3-hydroxy-5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)methanone JPEG2025537242000099.jpg43147

[0351] 26.6 mg (0.16 mmol, 1.0 eq) 6-cyclopropylpicolinic acid, 74.2 mg (0.41 mmol, 1.2 eq) 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 63.0 mg (0.48 mmol, 3.0 eq) N,N-diisopropylethylamine, and 3 mL tetrahydrofuran were added to a 25 mL reaction flask. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 10 minutes. 50.0 mg (0.16 mmol, 1.0 eq) 5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was then dissolved in 3 mL tetrahydrofuran and slowly added to the reaction mixture. The mixture was stirred at room temperature for 1 hour. TLC (DCM / MeOH = 20 / 1) plates confirmed complete reaction of the starting materials. The reaction mixture was concentrated to dryness 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 the pure product as a yellow oil (7.93 mg, yield = 10%).

[0352] LC-MS: (M+H) + m / z = 453.16; 1 H NMR (400 MHz, CDCl3) δ 7.84-7.52 (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 = 6.6 Hz, 6H), 1.07-0.94 (m, 4H).

[0353] The compounds of Examples 15, 16, 17, 18, 19 and 20 were each prepared by separating stereoisomers using supercritical fluid chromatography (SFC) to obtain the examples in Table 1.

[0354] Analysis conditions: Equipment: Waters 150 preparative SFC (SFC-26) Column: ChiralCel OD, 250 x 30 mm ID, 10 μm

[0355] Pressure: 100 bar Column temperature: 38℃ Wavelength: 220nm Mobile phase A: CO2; Mobile phase B: Methanol; Gradient: 30% B, 9.5 min; Flow rate: 150 mL / min

[0356] Table 1: Examples 21-44 JPEG2025537242000100.jpg213160JPEG2025537242000101.jpg255157JPEG2025537242000102.jpg255158JPEG20255372420 00103.jpg240161JPEG2025537242000104.jpg224160JPEG2025537242000105.jpg224160JPEG2025537242000106.jpg169160

[0357] Table 1: Examples 21 to 44 Example 45: ((3R)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000107.jpg44137

[0358] Table 1: Examples 21-44 Step A: (3R)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-5'-one JPEG2025537242000108.jpg4399

[0359] Table 1: Examples 21-44. 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-methylpyrrolidone[1,2-c]-1,3,2-oxaborolane, and 4.37 mg (0.096 mmol, 0.6 eq) of borane dimethyl sulfide were added, and the mixture was stirred at room temperature for 3 h. After confirming the formation of the product by LCMS, the reaction mixture was quenched with methanol and evaporated under reduced pressure to give the crude product (46.0 mg, yield = 91%).

[0360] LC-MS: (M+H) + m / z = 320.16; Step B: (3R)-5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol JPEG2025537242000109.jpg38113

[0361] 46.0 mg (0.14 mmol, 1.0 eq) (3R)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-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. After confirming the formation of the product by LCMS, the reaction mixture was filtered through diatomaceous earth and washed with tetrahydrofuran. The mixture was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude product (39.0 mg, yield = 88%).

[0362] LC-MS: (M+H) + m / z = 306.17; Step C: ((3R)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000110.jpg49124

[0363] 27.0 mg (0.19 mmol, 1.5 eq) 5-fluoropyridine-2-carboxylic acid, 0.06 mL N,N-diisopropylethylamine, and 73.0 mg (0.19 mmol, 1.5 eq) 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate were dissolved in 5 mL tetrahydrofuran and stirred at room temperature for 0.5 h. 39.0 mg (0.13 mmol, 1.0 eq) (3R)-5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was added and stirred at room temperature for 1.5 h. After confirming the formation of the product by LCMS, 5 mL of brine was added to the mixture, followed by extraction with ethyl acetate three times, drying over anhydrous sodium sulfate, evaporation under reduced pressure, and 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 a white solid (8.00 mg, yield = 13%, dr = 86:14).

[0364] LC-MS: (M+H) + m / z = 429.20; 1 H NMR (400 MHz, CDCl3) δ 8.44 (dd, J = 38.5, 3.2 Hz, 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, 4.2 Hz, 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).

[0365] 19 F NMR (376 MHz, CDCl3) δ -126.50 (d, J = 20.5 Hz).

[0366] Example 46: ((3S)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000111.jpg46135

[0367] Step A: (3S)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-5'-one JPEG2025537242000112.jpg38117

[0368] 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-methylpyrrolidone[1,2-c]-1,3,2-oxaborolane, and 4.37 mg (0.096 mmol, 0.6 eq) of borane dimethyl sulfide were added, and the mixture was stirred at room temperature for 3 h. After confirming the formation of the product by LCMS, the reaction mixture was quenched with methanol and evaporated under reduced pressure to give the crude product (48.0 mg, yield = 95%).

[0369] LC-MS: (M+H) + m / z = 320.14; Step B: (3S)-5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol JPEG2025537242000113.jpg39117

[0370] 48.0 mg (0.15 mmol, 1.0 eq) (3S)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-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. After confirming the formation of the product by LCMS, the reaction mixture was filtered through diatomaceous earth and washed with tetrahydrofuran. The mixture was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude product (43.0 mg, yield = 93%).

[0371] LC-MS: (M+H) + m / z = 306.16; Step C: ((3S)-5-(2-Cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000114.jpg43126

[0372] 30.0 mg (0.21 mmol, 1.5 eq) 5-fluoropyridine-2-carboxylic acid, 0.07 mL N,N-diisopropylethylamine, and 80.0 mg (0.21 mmol, 1.5 eq) 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate were dissolved in 5 mL tetrahydrofuran and stirred at room temperature for 0.5 h. 43.0 mg (0.14 mmol, 1.0 eq) (3S)-5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was added and stirred at room temperature for 1.5 h. After confirming the formation of the product by LCMS, 5 mL of brine was added. It was then extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, evaporated under reduced pressure, 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 (2.20 mg, yield = 4.0%, dr = 75:15).

[0373] LC-MS: (M+H) + m / z = 429.20; 1 H NMR (400 MHz, CDCl3) δ 8.44 (dd, J = 38.5, 3.2 Hz, 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, 4.2 Hz, 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).

[0374] 19 F NMR (376 MHz, CDCl3) δ -126.82 (d, J = 22.5 Hz).

[0375] Example 47: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(6-(methoxymethyl)pyridin-2-yl)methanone JPEG2025537242000115.jpg42143

[0376] Step A: Methyl 6-(methoxymethyl)picolinate JPEG2025537242000116.jpg20111

[0377] 1.00 g (5.98 mmol, 1.0 eq) of methyl 6-(methylol)picolinate was dissolved in 30 mL of anhydrous tetrahydrofuran and purged with nitrogen gas 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 methyl iodide was then added dropwise at 0 °C and stirred overnight at room temperature. After confirming complete reaction of the starting material by LCMS, 50 mL of water was added to quench the reaction. The mixture was then extracted three times with dichloromethane. The organic layer was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was subjected to column chromatography (DCM / MeOH = 0 to 20:1) to obtain the product (222 mg, yield = 20%).

[0378] LC-MS: (M+H) + ; m / z = 182.04; Step B: 6-(Methoxymethyl)picolinic acid JPEG2025537242000117.jpg2297

[0379] 220 mg (1.21 mmol, 1.0 eq) of methyl 6-(methoxymethyl)picolinate was dissolved in 3 mL of tetrahydrofuran, and then 3 mL of aqueous sodium hydroxide (0.5 mol / L) was added and stirred at room temperature for 3 h. After confirming the formation of the product by LCMS, the reaction mixture was acidified with hydrochloric acid (1.0 mol / L) and evaporated under reduced pressure to give the crude product (0.15 g, yield = 74%).

[0380] LC-MS: (M-H) + m / z = 168.05;

[0381] Step C: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(6-(methoxymethyl)pyridin-2-yl)methanone JPEG2025537242000118.jpg45144

[0382] 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'-tetramethylurea 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. After confirming the formation of the product by LCMS, 5 mL of brine was added, followed by extraction with ethyl acetate three times, drying over anhydrous sodium sulfate, evaporation under reduced pressure, and 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 a white solid (11.0 mg, yield = 15%).

[0383] LC-MS: (M+H) + m / z = 455.16; 1 H NMR (400 MHz, CDCl3) δ 7.86-7.76 (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).

[0384] Example 48: (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(6-(methylamino)pyrazin-2-yl)methanone JPEG2025537242000119.jpg45156

[0385] 24.5 mg (0.16 mmol, 1.0 eq) 6-(methylamino)pyrazine-2-carboxylic acid, 74.2 mg (0.41 mmol, 1.2 eq) 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 63.0 mg (0.48 mmol, 3.0 eq) N,N-diisopropylethylamine, and 3 mL tetrahydrofuran were added to a 25 mL reaction flask. The reaction mixture was stirred at room temperature for 10 min under a nitrogen atmosphere. 50.0 mg (0.16 mmol, 1.0 eq) 5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was then weighed and dissolved in 3 mL tetrahydrofuran. The mixture was slowly added to the reaction mixture and stirred at room temperature for 1 h. TLC (DCM:MeOH = 20:1) plates confirmed complete reaction of the starting materials. The reaction mixture was concentrated to dryness, 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 the pure product as a white solid (8.42 mg, yield = 12%).

[0386] LC-MS: (M+H) + ; m / z = 441.14; 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 18.5 Hz, 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, 4.1 Hz, 1H), 5.40-5.28 (m, 1H), 4.21-4.13 (m, 2H), 3.97-3.78 (m, 3H), 3.04-2.94 (m, 3H), 2.66-1.97 (m, 5H), 1.91-1.82 (m, 1H), 0.88-0.82 (m, 2H), 0.74-0.69 (m, 2H).

[0387] The examples in Table 2 were prepared using the method described above in Example 48, except that intermediate I3 and the required different carboxylic acid were prepared by a condensation reaction. Table 2: Examples 49-56 JPEG2025537242000120.jpg255163JPEG2025537242000121.jpg252165JPEG2025537242000122.jpg159168

[0388] Example 57: (3-hydroxy-5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(pyrazolo[1,5-a]pyrimidin-5-yl)methanone JPEG2025537242000123.jpg45127

[0389] 26.6 mg (0.16 mmol, 1.0 eq) pyrazolo[1,5-a]pyrimidine-5-carboxylic acid, 74.2 mg (0.41 mmol, 1.2 eq) 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 63.0 mg (0.48 mmol, 3.0 eq) N,N-diisopropylethylamine, and 3 mL tetrahydrofuran were added to a 25 mL reaction flask. The reaction mixture was stirred at room temperature for 10 min under a nitrogen atmosphere. 50.0 mg (0.16 mmol, 1.0 eq) 5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was then weighed and dissolved in 3 mL tetrahydrofuran. The mixture was slowly added to the reaction mixture and stirred at room temperature for 1 h. TLC (DCM / MeOH = 20:1) plates confirmed complete reaction of the starting materials. The reaction mixture was concentrated to dryness 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 the pure product as a white solid (8.54 mg, yield = 11%).

[0390] LC-MS: (M+H) + ; m / z = 453.37; 1 H NMR (400 MHz, CDCl3) δ 8.79-8.74 (m, 1H), 8.22-8.17 (m, 1H), 7.53-7.48 (m, 1H), 7.41-7.26 (m, 5H), 7.23-7.13 (m, 2H), 6.81-6.73 (m, 1H), 5.41-5.30 (m, 1H), 4.41-3.81 (m, 4H), 3.09-2.99 (m, 1H), 2.70-2.39 (m, 2H), 2.30-2.00 (m, 3H), 1.17 (d, J = 6.8 Hz, 6H).

[0391] The examples in Table 3 were prepared using the method described above in Example 57, except that intermediate I4 and the different carboxylic acids required were prepared by a condensation reaction. Table 3: Examples 58-77 JPEG2025537242000124.jpg216160JPEG2025537242000125.jpg224160JPEG2025537242000126.jpg231163 JPEG2025537242000127.jpg255158JPEG2025537242000128.jpg248162JPEG2025537242000129.jpg235160

[0392] 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'-pyrrolidin]-1'-yl)methanone JPEG2025537242000130.jpg49137

[0393] Step A: 5-Imidazo[1,2-a]pyridin-6-yl)spiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione JPEG2025537242000131.jpg45148

[0394] A 20 mL Schreck tube containing 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(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, and 8 mL of a 4:1 (1,4-dioxane / water) mixed solvent was placed in a flask, purged with nitrogen three times, and incubated at 100 °C for 3 hours. LCMS confirmed the formation of the desired product. The reaction mixture was quenched by adding 10 mL of water. Then, it was 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 obtain 105 mg of a brown oily product (yield = 93%).

[0395] LC-MS: (M+H) + m / z = 318.09; Step B: 5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol JPEG2025537242000132.jpg37139

[0396] In a 50 mL Schreck tube, 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 was dissolved in 5 mL of tetrahydrofuran. Under a nitrogen atmosphere, 144 mg (3.78 mmol, 10.0 eq) of tetrahydrolithium aluminum was slowly added. After the addition, the system was heated to 70 °C and reacted for 3 hours. LCMS confirmed the formation of the desired product. The reaction solution was cooled to -10 °C and quenched by slowly adding 3 mL of water dropwise. Then, 20 mL of tetrahydrofuran was added to the reaction system, and the mixture was filtered through diatomaceous earth. The filter cake was washed with tetrahydrofuran (20 mL x 3). The filtrate was concentrated to dryness to obtain 158 mg of crude product as a yellow oil. This reaction was then carried on to the next step.

[0397] LC-MS: (M+H) + m / z = 310.12; 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'-pyrrolidin]-1'-yl)methanone JPEG2025537242000133.jpg47154

[0398] 65.7 mg (0.47 mmol, 1.2 eq) 5-fluoropyridine-2-carboxylic acid, 177 mg (0.47 mmol, 1.2 eq) 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 301 mg (2.33 mmol, 6.0 eq) N,N-diisopropylethylamine, and 6 mL tetrahydrofuran were added to a 25 mL reaction flask and stirred at room temperature for 10 min under a nitrogen atmosphere. Then, 120 mg (0.39 mmol, 1.0 eq) 5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol in 4 mL tetrahydrofuran was added to the reaction mixture and stirred at room temperature for 2 h. LCMS confirmed the formation of the desired product. The reaction mixture was concentrated to dryness and purified (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 give the pure product as a white solid (25.2 mg, yield = 15%).

[0399] LC-MS: (M+H) + m / z=433.15; 1 H NMR (400 MHz, CDCl3) δ 8.46-8.31 (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).

[0400] 19 F NMR (376 MHz, CDCl3) δ -122.93 (d, J = 75.2 Hz).

[0401] Example 79: (5-fluoropyridin-2-yl)(3-hydroxy-5-imidazo[1,2-a]pyridin-6-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)methanone JPEG2025537242000134.jpg48142

[0402] 100 mg (0.26 mmol, 1.0 eq) (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) 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) potassium phosphate, 18.7 mg (0.03 mmol, 0.1 eq) [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, and 6 mL (1,4-dioxane / water = 4:1) mixed solvent were added to a 20 mL Schreck tube, purged with nitrogen gas three times, and reacted at 100 °C for 3 hours. LCMS confirmed the formation of the desired product. The reaction was quenched by adding 10 mL of water. It was then extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried, and concentrated. The crude product was purified (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 give the pure product as a white solid.

[0403] LC-MS: (M+H) + ; m / z = 433.15.

[0404] 1H NMR (400 MHz, CDCl3) δ 8.47-8.29 (m, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.05 (dd, J = 8.4, 4.2 Hz, 1H), 7.68-7.47 (m, 6H), 7.42-7.32 (m, 2H), 5.40-5.31 (m, 1H), 4.25-3.75 (m, 4H), 2.70-2.34 (m, 2H), 2.23-2.01 (m, 3H). 19F NMR (376 MHz, CDCl3) δ -123.10 (dd, J = 18.8, 7.5 Hz).

[0405] Example 80: (5-(2-ethylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000135.jpg46151

[0406] Step A: 5-(2-ethylphenyl)spiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione JPEG2025537242000136.jpg44150

[0407] 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, followed by the addition of 53.5 mg (0.4 mmol, 1.0 eq) of 2-ethylphenylboronic acid, 20.6 mg (0.02 mmol, 0.05 eq) of tetra(triphenylphosphine)palladium, 98.7 mg (0.7 mmol, 2.0 eq) of potassium carbonate, and 0.4 mL of water. The reaction mixture was purged with nitrogen gas and heated to 100 °C for 2 hours. After confirming completion of the reaction by LC-MS, the mixture was allowed to return to room temperature. The mixture was then diluted with 5 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 under reduced pressure. 5-(2-Ethylphenyl)spiro[indene-1,3'-pyrrolidine]-3,5'(2H)-dione (109 mg, yield=100%) was obtained.

[0408] LC-MS: (M+H) + m / z = 306; Step B: 5-(2-ethylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol JPEG2025537242000137.jpg36124

[0409] 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. The mixture was purged with nitrogen gas and cooled to 0 °C. 40.6 mg (1.1 mmol, 3.0 eq) of lithium aluminum hydride was then slowly added to the former. After the addition, the mixture was heated to 75 °C and reacted for 3 hours. After confirming the completion of the reaction by LC-MS, the mixture was cooled to 0 °C and quenched with 10 μL of water and 10 μL of 15% aqueous sodium hydroxide solution. The mixture was then dried over anhydrous magnesium sulfate, suction filtered, and the filtrate was concentrated by distillation under reduced pressure to give 5-(2-ethylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-3-ol (105 mg, yield = 100%).

[0410] LC-MS: (M+H) + m / z = 294; Step C: (5-(2-ethylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000138.jpg47148

[0411] 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 purging with nitrogen, 149.3 mg (0.4 mmol, 1.1 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and 92.2 mg (0.7 mmol, 2.0 eq) of N,N-diisopropylethylamine were added, followed by 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 then added. The mixture was then stirred for 30 minutes. After confirming completion of the reaction by LC-MS, 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 under reduced pressure. The residue was purified 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'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone (76.9 mg, yield = 52%) as a white solid.

[0412] LC-MS: (M+H) + ; m / z = 417.14; 1H NMR (400 MHz, CDCl3) δ 8.51-8.33 (m, 1H), 8.05 (dd, J = 8.5, 4.4 Hz, 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 = 8.0 Hz, 3H).

[0413] The examples in Table 4 were prepared using the methods described above in Example 79 or Example 80, but where required different boronic acids or boric acid esters for substitution were prepared by Suzuki reaction or the like. Table 4: Examples 81-102 JPEG2025537242000139.jpg255162JPEG2025537242000140.jpg240164JPEG2025537242000141.jpg255162 JPEG2025537242000142.jpg234165JPEG2025537242000143.jpg224165JPEG2025537242000144.jpg240165

[0414] Example 103: (5-fluoropyridin-2-yl)(3-hydroxy-6-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)methanone JPEG2025537242000145.jpg56133

[0415] Step A: 3-(3-bromophenyl)-3-cyanopentan-3-oate diethyl JPEG2025537242000146.jpg37122

[0416] 5.00 g (25.5 mmol, 1.0 eq) of 2-(3-bromophenyl)acetonitrile was dissolved in 50 mL of anhydrous tetrahydrofuran and purged with nitrogen gas three times. The temperature was lowered to -60 °C using dry ice. 5.00 g (56.1 mmol, 2.2 eq) of lithium bis(trimethylsilyl)amine was added dropwise at -60 °C and stirred at room temperature for 3 h. 8.94 g (53.6 mmol, 2.0 eq) of ethyl bromoacetate was then added dropwise at a temperature below -60 °C and stirred overnight at room temperature. LC-MS confirmed the complete reaction of the starting material, and the reaction was quenched by adding 50 mL of water. The mixture 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 evaporated under reduced pressure to give the crude product (10.6 g, yield = 100%).

[0417] LC-MS: (M+Na+H) + ; m / z = 391.87, 393.91.

[0418] Step B: 2-3-(3-bromophenyl)-5-oxopyrrolidin-3-yl)ethyl acetate JPEG2025537242000147.jpg47131

[0419] 10.0 g (27.2 mmol, 1.0 eq) of 3-(3-bromophenyl)-3-cyanopentan-4-yl ester was dissolved in 50 mL of methanol, 7.05 g (54.31 mmol, 2.0 eq) of anhydrous cobalt chloride was added, and 8.22 g (217.3 mmol, 8.0 eq) of sodium borohydride was slowly added at 0 °C and stirred at room temperature for 1 h. After confirming the formation of the product by LC-MS, the mixture was diluted with 50 mL of hydrochloric acid solution (3 mol / L). The mixture was then extracted three times with dichloromethane, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude product (7.66 g, yield = 86%).

[0420] LC-MS: (M+H) + ; m / z = 326.08, 327.95.

[0421] Step C: 2-3-(3-bromophenyl)-5-oxopyrrolidin-3-yl)ethanoic acid JPEG2025537242000148.jpg4197

[0422] 1.00 g (3.07 mmol, 1.0 eq) of 2-(3-bromophenyl)-5-oxopyrrolidin-3-yl)ethyl acetate was dissolved in 20 mL of methanol, and 4.9 mL of aqueous sodium hydroxide (5 mmol / mL) was slowly added at 0 °C. The mixture was stirred at 40 °C for 1 h. After confirming the formation of the product by LC-MS, the reaction mixture was diluted with hydrochloric acid (3.0 mol / L) to acidify it. The mixture was extracted three times with dichloromethane, and the organic layer was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude product (0.86 g, yield = 94%).

[0423] LC-MS: (M-H) + ; m / z = 297.98, 299.76.

[0424] Step D: 6-Bromopyrrole[indene-1,3'-pyrrolidine]-3,5'-2H-dione JPEG2025537242000149.jpg4795

[0425] 4.00 g of polyphosphoric acid was heated to 150 °C, and 0.86 g (2.88 mmol, 1.0 eq) of 2-3-(3-bromophenyl)-5-oxopyrrolidin-3-yl)acetic acid was added. The mixture was then stirred at 150 °C for 1 h. After confirming the formation of the product by LC-MS, the mixture was slowly poured into ice water while still hot and stirred while adding the mixture. 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 under reduced pressure. The residue was subjected to column chromatography (DCM / MeOH = 0-20:1) to obtain the product (0.39 g, yield = 48%).

[0426] LC-MS: (M+H) +; m / z = 279.91, 281.91.

[0427] Step E: 6-(2-Isopropylphenyl)spiro[indene-1,3'-pyrrolidine]-3,5'-2H-dione JPEG2025537242000150.jpg45112

[0428] 150 mg (0.53 mmol, 1.0 eq) of 6-bromopyrrole[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(diphenylphosphine)ferrocene]dichloride palladium and 0.34 g (1.6 mmol, 3.0 eq) of tripotassium phosphate were added, and the mixture was purged with nitrogen gas three times and stirred at 100 °C for 1 h. After confirming the formation of the product by LC-MS, 5 mL of water was added. The mixture was then extracted three times with ethyl acetate. The organic layer was washed with 5 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude product (162 mg, yield = 93%).

[0429] LC-MS: (M+H) + ; m / z=320.10.

[0430] Step F: 6-(2-Isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol JPEG2025537242000151.jpg48144162 mg (0.50 mmol, 1.0 eq) of 5-bromopyrrole[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. After confirming the formation of the product by LC-MS, the reaction mixture was filtered through diatomaceous earth and washed with tetrahydrofuran. The mixture was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude product (110 mg, yield = 71%).

[0431] LC-MS: (M+H) + ; m / z = 308.20.

[0432] Step G: (6-(2-Isopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000152.jpg53152

[0433] 76.0 mg (0.54 mmol, 1.5 eq) 5-fluoropyridine-2-carboxylic acid, 0.17 mL N,N-diisopropylethylamine, and 204 mg (2.06 mmol, 1.5 eq) 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate were dissolved in 5 mL tetrahydrofuran and stirred at room temperature for 0.5 h. 110 mg (0.36 mmol, 1.0 eq) 6-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was added and stirred overnight at room temperature. After confirming the formation of the product by LC-MS, 10 mL of brine was added. It was then extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, evaporated under reduced pressure, 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%).

[0434] LC-MS: (M+H) + m / z = 431.13; 1 H NMR (400 MHz, CDCl3) δ 8.44-8.36 (m, 1H), 8.04-7.98 (m, 1H), 7.51-7.44 (m, 2H), 7.40-7.33 (m, 3H), 7.23-7.13 (m, 3H), 5.42-5.31 (m, 1H), 4.16-3.74 (m, 4H), 3.04-2.95 (m, 1H), 2.70-2.33 (m, 2H), 2.28-2.17 (m, 1H), 2.15-2.10 (m, 1H), 2.08-2.01 (m, 1H), 1.17-1.12 (d, J = 6.8 Hz, 6H). Example 104: (5-fluoropyridin-2-yl)(3-hydroxy-5-(2-isopropylphenoxy)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)methanone JPEG2025537242000153.jpg46145

[0435] 100.0 mg (0.256 mmol, 1.0 eq) (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, followed by 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. The atmosphere was purged with nitrogen gas, and the temperature was raised to 100 °C and the reaction was continued for 18 hours. After confirming the completion of the reaction by LC-MS, the system was allowed to cool to room temperature. The mixture was then diluted with 5 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 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 (5-fluoropyridin-2-yl)(3-hydroxy-5-(2-isopropylphenoxy)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)methanone (2.0 mg, yield = 2%) as a yellow solid.

[0436] LC-MS: (M+H) + m / z = 447.17; 1H NMR (400 MHz, CDCl3) δ 8.45-8.40 (m, 1H), 8.03 (s, 1H), 7.56-7.45 (m, 1H), 7.38-7.33 (m, 1H), 7.23-7.08 (m, 3H), 7.00-6.80 (m, 3H), 5.37-5.18 (m, 1H), 4.17-3.97 (m, 2H), 3.92-3.69 (m, 2H), 3.31-3.20 (m, 1H), 2.62-2.45 (m, 1H), 2.38-2.21 (m, 1H), 2.18-2.09 (m, 1H), 2.08-1.95 (m, 2H), 1.22 (d, J = 7.0 Hz, 6H).

[0437] The examples in Table 5 were prepared using the method described above in Example 15 by reacting the general-purpose intermediate I1 with the required different phenols, sulfur phenols, aromatic amines, or aromatic Grignard reagents, followed by reduction and condensation. Table 5: Examples 105-116 JPEG2025537242000154.jpg231166JPEG2025537242000155.jpg234165JPEG2025537242000156.jpg143167

[0438] The examples in Table 6 were prepared using the method described in Example 14 above, with different substitutions of raw materials and reagents in the reactions. Table 6: Examples 116-133 JPEG2025537242000157.jpg239165JPEG2025537242000158.jpg237165JPEG2025537242000159.jpg242164JPEG2025537242000160.jpg172165

[0439] Example 134: 1'-((5-fluoropyridin-2-yl)methyl)-5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol JPEG2025537242000161.jpg45121

[0440] A 25 mL reaction flask was charged with 50.0 mg (0.16 mmol, 1.0 eq) of 5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol, 24.5 mg (0.19 mmol, 1.2 eq) of 5-fluoropyridine aldehyde, and 5 mL of methanol. The flask 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 submitted to purification. (Mobile phase A: 0.1% formic acid; Mobile phase B: acetonitrile; Gradient: 30%-70% B, 55 minutes; Flow rate: 70 mL / min) to afford the pure product (12.3 mg, 18% yield) as a white solid.

[0441] LC-MS: (M+H) + ; m / z = 417.16; 1 H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 2.8 Hz, 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). 19 F NMR (376 MHz, CDCl3) δ -129.86.

[0442] Example 135: 1'-((5-chloropyridin-2-yl)sulfonyl)-5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol 4.6 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 flask and stirred at room temperature under a nitrogen atmosphere for 1 hour. TLC (DCM / MeOH = 20:1) plates confirmed complete reaction of the starting materials. The reaction mixture was concentrated to dryness, 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 the pure product as a white solid (7.19 mg, yield = 9%).

[0443] LC-MS: (M+H) + ; m / z=483.05; 1 H NMR (400 MHz, CDCl3) δ 8.71-8.70 (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 = 6.6 Hz, 6H).

[0444] The examples in Table 7 were prepared using the method described above in Example 135, with different substitutions of raw materials in the reaction. Table 7: Examples 136-146 JPEG2025537242000163.jpg215166JPEG2025537242000164.jpg255163JPEG2025537242000165.jpg123165

[0445] Example 147: (5-fluoropyridin-2-yl)(3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)methanone JPEG2025537242000166.jpg45117

[0446] Example 147 was prepared by synthesis by following the experimental procedure of Example 15, but replacing the starting material p-bromophenylacetonitrile with benzeneacetonitrile.

[0447] LC-MS: (M+H) + m / z = 313.07

[0448] Example 148: (5-fluoropyridin-2-yl)(5-bromo-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)methanone JPEG2025537242000167.jpg49118 Compound I5 of Intermediate Preparation Example 5 is Example 148.

[0449] LC-MS: (M+H) + ; m / z = 391.01.

[0450] Example 149: 1'-(5-chloropyridin-2-yl)-5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol JPEG2025537242000168.jpg43133

[0451] 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 mixture was purged with nitrogen three times and stirred at 100 °C for 3 h. After confirming the formation of the product by LC-MS, 10 mL of brine was added. The mixture was then extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, evaporated under reduced pressure, 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 (17.0 mg, yield = 12%).

[0452] LC-MS: (M+H) + m / z = 417.15; 1 H NMR (400 MHz, CDCl3) δ 8.13 (dd, J = 5.9, 2.5 Hz, 1H), 7.56-7.50 (m, 1H), 7.47-7.36 (m, 2H), 7.30 (dd, J = 6.4, 2.4 Hz, 1H), 7.27-7.19 (m, 3H), 6.94 (d, J = 7.7 Hz, 1H), 6.43-6.32 (m, 1H), 5.45-5.34 (m, 1H), 3.87-3.54 (m, 4H), 2.63-2.61 (m, 1H), 2.49-2.41 (m, 1H), 2.31-2.29 (m, 1H), 2.25-2.08 (m, 2H), 1.93-1.87 (m, 1H), 0.92-0.80 (m, 2H), 0.79-0.70 (m, 2H). Example 150: 5-(2-cyclopropylphenyl)-1'-(6-fluorobenzo[c]isothiazol-3-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol JPEG2025537242000169.jpg47136

[0453] 20.0 mg (65.0 μmol, 1.0 eq) 5-(2-cyclopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol, 24.5 mg (131 μmol, 2.0 eq) 3-chloro-6-fluorobenzo[c]isothiazole, 25.3 mg (196 μmol, 3.0 eq) N,N-diisopropylethylamine, and 3 mL DMF were added to a 25 mL reaction flask, purged with nitrogen gas three times, heated to 80 °C, and stirred overnight. LC-MS confirmed the complete reaction of the starting materials. After cooling, 20 mL of water was added to the reaction mixture, which was then extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, suction 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%).

[0454] LC-MS: (M+H) + m / z = 457.12; 1 H NMR (400 MHz, CDCl3) δ 7.76 (dd, J = 9.8, 5.1 Hz, 1H), 7.54-7.51 (m, 1H), 7.47-7.44 (m, 1H), 7.31-7.27 (m, 2H), 7.24-7.21 (m, 2H), 7.07 (d, J = 10.7 Hz, 1H), 6.93 (d, J = 7.7 Hz, 1H), 6.67-6.63 (m, 1H), 5.41 (s, 1H), 3.98-3.76 (m, 4H), 2.69-2.58 (m, 2H), 2.47-2.42 (m, 1H), 2.31-2.18 (m, 2H), 1.90-1.83 (m, 1H), 0.87-0.84 (m, 2H), 0.75-0.71 (m, 2H).

[0455] 19 F NMR (376 MHz, CDCl3) δ -112.83.

[0456] Example 151: 1'-(5-chlorobenzo[d]thiazol-2-yl)-5-(2-isopropylphenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol JPEG2025537242000170.jpg44151The experimental procedure was similar to that of Example 149, and the compound of Example 151 was prepared by synthesis.

[0457] LC-MS: (M+H) + m / z = 475.06 Example 152: 5-(2-cyclopropylphenyl)-1'-(7-chloroimidazo[1,2-a]pyridin-3-yl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol JPEG2025537242000171.jpg45144

[0458] Example 152 was prepared by Buchwald-Hartwig coupling using intermediate I3 and 3-bromo-7-chloroimidazo[1,2-α]pyridine.

[0459] LC-MS: (M+H) + m / z = 456.08 The examples in Table 8 were prepared using the method described above in Example 152, but with different substitutions of raw materials in the reaction, via the Buchwald-Hartwig coupling reaction.

[0460] Table 8: Examples 153-158 JPEG2025537242000172.jpg219166JPEG2025537242000173.jpg102168

[0461] Example 159: 2-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-carbonyl)-5-fluoropyridine-1-oxide JPEG2025537242000174.jpg47143

[0462] (5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone was dissolved in dichloromethane, and m-chloroperoxybenzoic acid was added to the mixture under ice-water bath, and the mixture was oxidized to prepare Example 159.

[0463] LC-MS: (M+H) + m / z = 445.13 Example 160: 2-(3-2'-cyclopropyl-3-methylol)-[1,1'-biphenyl]-4-yl)pyrrolidine-1-carbonyl)-5-fluoropyridine-1-oxide JPEG2025537242000175.jpg39158 The experimental procedure referred to Example 159, and Example 160 was prepared by synthesis.

[0464] LC-MS: (M+H) + m / z = 433.15 Example 161: (5-fluoropyridin-2-yl)(1-hydroxy-6-(2-isopropylphenyl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)methanone

[0465] JPEG2025537242000176.jpg73167

[0466] Step A: 1-(t-butyl) 4-ethyl-4-(4-bromobenzyl)piperidine-1,4-dicarboxylate JPEG2025537242000177.jpg38113

[0467] Under a nitrogen atmosphere, a 250 mL three-neck flask was charged with 10.0 g (38.9 mmol, 1.0 eq) of N-Boc-4-piperidinium formate ethyl ester and 60 mL of anhydrous tetrahydrofuran, and 23.3 mL (46.7 mmol, 2 M, 1.2 eq) of lithium diisopropylamide solution was added dropwise at a temperature controlled between -70 and -60 °C. Heat was released during the addition. After the addition, the reaction was maintained at room temperature for 1 hour. Then, a solution of 9.70 g (38.9 mmol, 1.0 eq) of p-bromobenzyl bromide in 25 mL of tetrahydrofuran was added dropwise at a temperature controlled between -70 and -60 °C. The temperature was then allowed to rise naturally. The reaction was continued for 4 hours with stirring. Samples were taken for intermediate analysis by LC-MS. The reaction was considered complete if the residual p-bromobenzyl bromide concentration was 5% or less. The reaction mixture was quenched by dropwise addition of saturated ammonium chloride solution (60 mL) at a temperature controlled between 10 and 25°C. Ethyl acetate (100 mL) was added, the mixture was stirred for 10 minutes, and the mixture was allowed to stand for 5 minutes. The mixture was separated, and the aqueous phase was extracted twice with ethyl acetate (50 mL). The organic phases were combined and dried over anhydrous sodium sulfate. After suction filtration, the organic phase was concentrated under reduced pressure to dryness to obtain the crude product (13.8 g), which was used directly in the next reaction without further purification.

[0468] LC-MS: (M-100+H) + ; m / z = 325.98; 327.98.

[0469] Step B: 4-(4-Bromobenzyl)-1-(t-butoxycarbonyl)piperidine-4-carboxylic acid JPEG2025537242000178.jpg39124

[0470] 5.00 g (11.7 mmol, 1.0 eq) of 1-(t-butyl) 4-ethyl-4-(4-bromobenzyl)piperidine-1,4-dicarboxylate and 30 mL of methanol were added to a 250 mL one-neck flask, and 2.80 g (70.2 mmol, 6.0 eq) of sodium hydroxide in water (30 mL) was added with stirring. The mixture was then heated to 85 °C and refluxed for 24 h. LC-MS confirmed complete conversion of the starting material. The reaction mixture was cooled, concentrated to dryness under reduced pressure, and dichloromethane (150 mL) was added to separate the lower organic layer. The pH of the system was adjusted to 5-6 with 6 M hydrochloric acid, and the phases were separated. The aqueous phase was extracted once with dichloromethane (150 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a pale yellow oil (4.50 g, yield = 96%).

[0471] LC-MS: (M-100+H) + ; m / z = 297.92;299.92.

[0472] Step C: t-Butyl 6-bromo-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylic acid JPEG2025537242000179.jpg32131

[0473] 36.0 g of polyphosphoric acid was added to a 250 mL three-neck flask and heated to 120 °C. 4.50 g (11.34 mmol, 1.0 eq) of 4-(4-bromobenzyl)-1-(t-butoxycarbonyl)piperidine-4-carboxylic acid was dissolved in 20 mL of dichloromethane and added dropwise with stirring. After the addition was complete, the reaction was continued for 3 hours with stirring. The reaction was terminated when no remaining starting materials were detected by LC-MS. The hot reaction mixture was quenched by slowly pouring it into 200 g of ice water (quench temperature: 25-35 °C). The pH of the system was then adjusted to 9-10 with aqueous sodium hydroxide, and 3.70 g (17.0 mmol, 1.5 eq) of di-t-butyl dicarbonate was added and stirred at room temperature for 3 hours. The mixture was extracted twice with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to give a pale yellow solid (4.00 g, yield=93%).

[0474] LC-MS: (M-100+H) + ; m / z = 279.91; 281.90.

[0475] Step D: t-Butyl 6-(2-isopropylphenyl)-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate JPEG2025537242000180.jpg40125

[0476] 1.10 g (2.89 mmol, 1.0 eq) t-butyl 6-bromo-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate and 569 mg (3.47 mmol, 1.2 eq) (2-isopropylphenyl)boronic acid were dissolved in 10 mL of a 4:1 1,4-dioxane / water mixture, followed by the addition of 210 mg (289 μmol, 0.1 eq) of palladium [1,1'-bis(diphenylphosphine)ferrocene]dichloride and 1.84 g (8.67 mmol, 3.0 eq) of tripotassium phosphate. The atmosphere was purged with nitrogen gas three times and the mixture was stirred at 100 °C for 1 hour. After confirming the formation of the product by LC-MS, 50 mL of water was added. The organic layer was then extracted three times with ethyl acetate, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, suction filtered, and evaporated under reduced pressure. The residue was subjected to column chromatography (petroleum ether / ethyl acetate = 0-10:1) to give a pale yellow solid (780 mg, yield = 65%).

[0477] LC-MS: (M-100+H) + ; m / z = 320.12; Step E: t-Butyl 1-hydroxy-6-(2-isopropylphenyl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate JPEG2025537242000181.jpg42109

[0478] 780 mg (1.86 mmol, 1.0 eq.) t-butyl 6-(2-isopropylphenyl)-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate was dissolved in 10 mL of anhydrous methanol, and 106 mg (2.79 mmol, 1.5 eq.) sodium borohydride was slowly added at 0 °C. The mixture was stirred in an ice bath for 1 hour. LC-MS confirmed complete conversion of the starting material and the formation of the product. The reaction was quenched with saturated aqueous sodium carbonate, filtered through diatomaceous earth, and washed with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give 800 mg of a pale yellow oil.

[0479] LC-MS: (M-100+H) + ; m / z = 322.20; Step F: 6-(2-Isopropylphenyl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-ol Hydrochloride JPEG2025537242000182.jpg38118

[0480] 800 mg (1.89 mmol, 1.0 eq) of t-butyl 1-hydroxy-6-(2-isopropylphenyl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate was dissolved in 10 mL of anhydrous dichloromethane, and 2.0 mL of HCl / 1,4-dioxane solution (4 M) was added in an ice bath. The mixture was stirred for 1 hour in an ice bath, and LC-MS confirmed complete conversion of the starting material. Concentration under reduced pressure gave a pale yellow solid (600 mg, yield = 88%).

[0481] LC-MS: (M+H) + ; m / z = 322.17; 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 JPEG2025537242000183.jpg43167

[0482] 29.6 mg (209.6 μmol, 1.5 eq) 5-fluoropyridine-2-carboxylic acid, 90.1 mg (698.5 μmol, 5.0 eq) N,N-diisopropylethylamine, and 79.7 mg (209.6 μmol, 1.5 eq) 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate were dissolved in 5 mL of tetrahydrofuran and stirred at room temperature for 10 min. 50 mg (139.7 μmol, 1.0 eq) of 6-(2-isopropylphenyl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-ol hydrochloride was added and stirred at room temperature for 1.5 h. After confirming complete conversion of the starting material and the formation of the product by LC-MS, 50 mL of saturated aqueous sodium chloride solution was added. The residue was then extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, suction filtered, evaporated under reduced pressure, and purified by HPLC (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 two isomers (Example 161A, 9.05 mg, yield: 15%; Example 161A, 3.11 mg, yield: 5%).

[0483] Example 161A: LC-MS: (M+H) + m / z = 427.23; 11H NMR (400 MHz, CDCl3) δ 8.43 (dd, J = 5.8, 2.8 Hz, 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 = 7.0 Hz, 6H). 19 19F NMR (376 MHz, CDCl3) δ -123.95 (d, J = 2.9 Hz). Example 161B: LC-MS: (M + H) + ; m / z = 427.18; 1 1H NMR (400 MHz, CDCl3) δ 8.43 (dd, J = 5.8, 2.8 Hz, 1H), 7.75 - 7.70 (m, 1H), 7.56 - 7.51 (m, 1H), 7.39 - 7.32 (m, 3H), 7.27 - 7.25 (m, 1H), 7.22 - 7.14 (m, 3H), 4.87 - 4.84 (m, 1H), 4.34 - 4.24 (m, 1H), 3.85 - 3.81 (m, 1H), 3.52 - 3.42 (m, 2H), 3.14 - 2.99 (m, 2H), 2.88 - 2.83 (m, 1H), 2.05 - 1.96 (m, 1H), 1.87 - 1.77 (m, 1H), 1.74 - 1.65 (m, 2H), 1.16 (d, J = 7.0 Hz, 6H). 19 19F NMR (376 MHz, CDCl3) δ -123.96 (d, J = 3.0 Hz).

[0484] Example 162: (S)-5-(2-cyclopropylphenyl)-1'-(5-fluoropyrrolidinecarbonyl)spiro[indene-1,3'-pyrrolidin]-3(2H)-one 20.0 mg (46.7 μmol, 1.0 eq) ((1S,3R)-5-(2-cyclopropylphenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone was dissolved in 1 mL of dichloromethane, followed by the addition of 23.8 mg (56.0 μmol, 1.2 eq) of Deiss-Martin reagent. The reaction mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by LC-MS, the mixture 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 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-fluoropyrrolidinecarbonyl)spiro[indene-1,3'-pyrrolidin]-3(2H)-one (11.7 mg, yield = 58.8%), a white solid.

[0485] LC-MS: (M+H) + m / z = 427.17; 1H NMR (400 MHz, CDCl3) δ 8.42 (dd, J = 44.0, 2.8 Hz, 1H), 8.09 (d, J = 4.1 Hz, 1H), 7.84 (d, J = 9.9 Hz, 1H), 7.78 (d, J = 7.9 Hz, 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, 3.9 Hz, 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).

[0486] Example 163: (5-(2-cyclopropyl-4-phenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone JPEG2025537242000185.jpg5014048.3 mg (0.30 mmol, 1.0 eq) of 5-fluoro-2-pyridinecarboxylic acid was dissolved in 2 mL of N,N-dimethylformamide. After purging with nitrogen gas, 143 mg (0.40 mmol, 1.1 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and 88.5 mg (0.70 mmol, 2.0 eq) of N,N-diisopropylethylamine were added and stirred at room temperature for 1 minute. After that, 111 mg (0.30 mmol, 1.0 eq) of 5-(2-cyclopropyl-4-phenyl)-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-3-ol was added. The mixture was then stirred for 30 minutes. After confirming the completion of the reaction by LC-MS, the reaction 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 under reduced pressure. The residue was purified 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-phenyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-1'-yl)(5-fluoropyridin-2-yl)methanone (86.4 mg, yield = 57%) as a white solid.

[0487] LC-MS: (M+H + ) + m / z = 447.14; 1H NMR (400 MHz, CDCl3) δ 8.46-8.35 (m, 1H), 8.06-8.01 (m, 1H), 7.54-7.46 (m, 2H), 7.42-7.39 (m, 1H), 7.32-7.28 (m, 1H), 7.01-6.86 (m, 3H), 5.37-5.28 (m, 1H), 4.24-3.76 (m, 4H), 2.68-2.46 (m, 1H), 2.41-2.11 (m, 3H), 2.09-2.00 (m, 1H), 1.86-1.77 (m, 1H), 0.85-0.79 (m, 2H), 0.66-0.63 (m, 2H).

[0488] Example 164: 2-(2-(1'-(5-fluoropyridoyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-5-yl)phenyl)-2-methylpropionitrile JPEG2025537242000186.jpg45148

[0489] 100 mg (256 μmol, 1.0 eq) (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, followed by the addition of 130 mg (511 μmol, 2.0 eq) bis(pinacolato)diboron, 18.7 mg (25.6 μmol, 0.1 eq) [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, and 100 mg (1.02 mmol, 4.0 eq) potassium acetate to the reaction system, which was then stirred at 100 °C under a nitrogen atmosphere for 3 hours. After cooling to room temperature, 57.3 mg (256 μmol, 1.0 eq) 2-(2-bromophenyl)-2-methylpropionitrile, 23.6 mg (20.4 μmol, 0.08 eq) tetra(triphenylphosphine)palladium, 70.7 mg (551 mmol, 2.0 eq) potassium carbonate, and 0.4 mL water were added to the reaction mixture and stirred at 100 °C under a nitrogen atmosphere for 2 h. LC-MS analysis confirmed the complete reaction of the starting materials. The mixture was then cooled to room temperature, and 5 mL of water and 10 mL of ethyl acetate were added. The organic phase was separated. The aqueous phase was extracted twice with ethyl acetate (10 mL), and the combined organic phases were combined. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by column chromatography (methano / dichloromethane = 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 a white solid (8.70 mg, yield = 7%).

[0490] LC-MS: (M+Na) + ; m / z=478.18; 1H NMR (400 MHz, CDCl3) δ 8.52-8.35 (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).

[0491] Example 165: 2-(3-(1'-(5-fluoropyridoyl)-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-5-yl)phenyl)-2-methylpropionitrile JPEG2025537242000187.jpg48158

[0492] 180 mg (952 μmol, 1.0 eq) of (3-(2-cyanopropyl-2-yl)phenyl)boronic acid was dissolved in 2 mL of 1,4-dioxane, followed by 372 mg (952 μmol, 1.0 eq) of (5-bromo-3-hydroxy-2,3-dihydrospiro[indene-1,3'-pyrrolidine]-1'-yl)(5-fluoropyridin-2-yl)methanone, 34.8 mg (0.026 mmol, 0.05 eq) of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, 606 mg (2.85 mmol, 3.0 eq) of potassium phosphate, and 0.4 mL of water. The reaction mixture was then purged with nitrogen gas and heated to 100 °C for 3 hours. After confirming completion of the reaction by LC-MS, the mixture was allowed to cool to room temperature. The crude product was then diluted with 5 mL of saturated sodium chloride solution, extracted three times with 10 mL of ethyl acetate, dried over anhydrous sodium sulfate, suction 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 (22.0 mg, yield = 5%).

[0493] LC-MS: (M+H) + ; m / z = 456.23; 1 H NMR (400 MHz, CDCl3) δ 8.41 (dd, J = 47.8, 2.8 Hz, 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, 7.9 Hz, 1H), 5.39-5.32 (m, 1H), 4.08-4.08 (m, 1H), 3.94-3.93 (m, 1H), 3.92-3.76 (m, 2H), 2.70-2.53 (m, 1H), 2.46-2.34 (m, 1H), 2.26-1.99 (m, 3H), 1.78 (s, 6H).

[0494] Inhibitory activity test of the compounds of the present invention In this study, HEK-293 cells transiently expressing TRPV3 were used for experimental detection.

[0495] The operation steps are as follows: The cells were cultured in DMEM medium containing 10% fetal bovine serum at a temperature of 37°C and a carbon dioxide concentration of 5%.

[0496] Day 1: Plate cells in a 6-well plate, 5 x 10 cells per well. 5 were inoculated individually.

[0497] Day 2: Transfection was performed using Lipofectamine 3000 transfection reagent at a ratio of 1 μg:2 μL of plasmid to transfection reagent. The total amount of plasmid used per well was 3 μg. Specifically, two sterile centrifuge tubes were prepared and 100 μL of Opti-MEM was added to each tube. 6 μL of Lipofectamine 3000 was added to one tube and mixed well. 3 μg of plasmid was added to the other tube and mixed well, followed by 6 μL of P3000 and mixing well. The diluted plasmid DNA was then added to the diluted Lipofectamine 3000 and incubated at room temperature for 10–15 minutes. The DNA-liposome complex was then added dropwise to the cells, gently shaken to mix well, and then cultured in an incubator. The liquid was replaced after 4–6 hours.

[0498] Day 3: Digest the cells and plate them at 8 x 10 cells per well in a 24-well plate with a pre-placed cover slide. 3 cells were seeded.

[0499] Day 4: Patch clamp testing was performed.

[0500] The voltage stimulation protocol for recording TRPV3 currents using whole-cell patch clamp was as follows: after forming a whole-cell seal, the cell membrane voltage clamp was set to -80 mV. The membrane potential was first recorded at 0 mV, and then a voltage was applied from -100 mV, followed by a 100 ms depolarization ramp to 100 mV, and finally back to 0 mV. Data collection was repeated every 5 seconds to observe the inhibitory effects of drugs on peak currents. Experimental data were collected using an EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0501] A microelectrode puller was used to pull a glass capillary into a recording electrode. The electrode, filled with intracellular solution, was inserted into the microelectrode holder. Under an inverted microscope, a microelectrode manipulator was used to immerse the electrode in the extracellular solution, and the electrode resistance (Rpip) was recorded. The electrode was then brought into contact with the cell surface, and negative pressure suction was applied to form a high-resistance seal (GΩ). At this point, fast capacitance compensation was performed, and negative pressure was continued to rupture the cell membrane, forming the whole-cell recording mode. Subsequently, slow capacitance compensation was performed, and experimental parameters such as film capacitance (Cm) and series resistance (Rs) were recorded. Leak compensation was not performed.

[0502] Administration began after the TRPV3 currents recorded from all cells stabilized. Each drug concentration was allowed to act for 5 minutes (or until the current stabilized) before detecting the next concentration. Multiple concentrations of each test compound were tested. The coverslips covered with cells were placed in a recording chamber under an inverted microscope. Blank control extracellular solution and working solutions of the test compounds were perfused into the recording chamber in order from low to high concentrations using gravity perfusion, allowing the cells to act on the compounds. Fluid exchange during recording was performed using a peristaltic pump. Currents detected by each cell in compound-free extracellular solution served as its own control. Each concentration was tested twice independently using at least two cells. All electrophysiological tests were performed at room temperature.

[0503] Compounds prepared using the above analytical process were tested, and the results are shown in Table 9. The table details the percent inhibition at 0.3 μM for selected examples, where "A" indicates an inhibition value between 70% and 100%, "B" indicates an inhibition value between 50% and 69.99%, "C" indicates an inhibition value between 25% and 49.99%, "D" indicates an inhibition value less than 25%, and "ND" indicates that the data is unconfirmed.

[0504] Table 9: Inhibition rate (%) of hTRPV3 by a single concentration of compounds of the present invention (0.3 μM) JPEG2025537242000188.jpg255138JPEG2025537242000189.jpg210140

[0505] Table 10: Inhibition rate of different hTRPs by compounds (0.3 μM) JPEG2025537242000190.jpg52142Note: The selectivity ratio refers to the ratio of the inhibition rate for the TRPV3 ion channel to the inhibition rate for other ion channels when the test concentration of the compound is the same.

[0506] Liver microsome metabolic stability test 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 water were added to the culture medium. The final concentration of microsomes was 0.5 mg / mL.

[0507] At the start of the reaction, 4 μL of a 100 μM test compound solution or a control compound solution with a final concentration of 1 μM was added, and the reaction was carried out at 37°C.

[0508] Aliquots of 50 μL were taken from the reaction mixture 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. Aliquots of 100 μL of the supernatant were mixed with 100 μL of ultrapure water and used for LC-MS / MS analysis.

[0509] Table 11: Metabolic stability test results for liver microsomes JPEG2025537242000191.jpg48146

[0510] Balance dialysis for plasma protein binding tests 1. The dialysis membrane was soaked (water: 60 minutes, 20% ethanol: 20 minutes, dialysis buffer: 20 minutes). 2. The test compound was diluted to 200 μM in dimethyl sulfoxide (working solution). 3. The plasma was thawed in a 37°C water bath and centrifuged at 3220 g for 10 minutes to remove clots. 4. The supernatant was transferred to a new tube and preheated in a 37°C water bath for 10 minutes. 5. The HTD dialysis device was assembled according to the manufacturer's guidelines. 6. 3 μL of 200 μM test compound was added to 597 μL of plasma and spun at 1000 rpm for 2 minutes. 7. 50 μL of spiked plasma was transferred to a 96-well plate, and 50 μL of dialysis buffer and 200 μL of methanol were added. IS* was used as the TO sample. 8. 120 μL of spiked plasma and 120 μL of dialysis buffer were added in duplicate to the chambers of the HTD dialysis device. 9. The dialysis device was covered with a breathable cover, and the dialyzer and spiked plasma were incubated at 37°C (100 rpm, 5% CO2) for 6 hours. 10. 50 μL of the dialysis buffer and dialyzed sample from the plasma chamber were transferred to another 96-well plate, and 50 μL of blank plasma or dialysis buffer and 200 μL of methanol were added. IS* was designated as the B and P samples. 11. 50 μL of the remaining spiked plasma (as described in step 9) was transferred to a 96-well plate, and 50 μL of dialysis buffer and 200 μL of methanol were added. IS* was designated as the T6 sample. 12. The sample plate was centrifuged at 3220 g for 40 minutes. 13. 100 μL of the supernatant was transferred to an analytical plate containing an appropriate amount of water and subjected to LC-MS / MS analysis. 14. The data were analyzed.

[0511] Table 12: Results of plasma protein binding studies of compounds of the invention JPEG2025537242000192.jpg28146

[0512] Parallel artificial membrane permeability assay (lipid PAMPA) experiments 1. Test compounds were prepared in 10 mM DMSO and diluted 1000-fold with PBS to 10 μM. 2. Lecithin was sonicated in dodecane at 18 mg / mL. 3. 300 μL / well of a 10 μM test compound solution was added to the donor chamber (bottom) in triplicate. 4. 5 μL / well of lecithin / dodecane was added to the receptor chamber (top), and within 10 minutes, 300 μL / well of PBS (pH 7.4) was added to the receptor chamber. 5. 50 μL of 10 μM test compound was transferred to a sample plate containing 200 μL of cold methanol. 6. The receptor chamber was inserted into the donor chamber and incubated at 25°C for 16 hours. 7. After 16 hours of incubation, 50 μL each from the receptor and donor chambers was transferred to a sample plate containing 200 μL of cold methanol and IS*. 8. The sample plate was centrifuged at 3220 g for 40 minutes at 4°C. 9. 100 μL of the supernatant was transferred to an analysis plate containing an appropriate amount of H2O and subjected to LC-MS / MS analysis. 10. The data was analyzed.

[0513] Table 13: Results of permeability test of compounds of the present invention through parallel artificial membranes JPEG2025537242000193.jpg29154

[0514] Caco-2 cell permeability experiment Cell plate preparation: 1. Preheating the transwell plate: Before seeding the cells, 100 μL of medium was added to the upper layer of the transwell plate, and 600 μL of medium was added to the lower layer. These were pre-incubated at 37°C for 1 hour under 5% CO2. 2. Caco-2 cells were treated by adding 100 μL of cell suspension (4 x 105 cells / mL) to each well and cultured in a 37°C, 5% CO2 incubator for 14-21 days. 3. The medium was changed every other day for the first 7 days, and daily thereafter. 4. Transepithelial resistance (TEER) was measured using EVOM3.

[0515] Testing Procedure: 1. HBSS (10 mM HEPES, pH 7.4) buffer was preheated, and the upper and lower layers of the transwell plate were washed twice each and incubated at 37°C for 30 minutes. 2. Working solution: HBSS buffer was diluted to 5 μM with 1 mM DMSO. 3. AB direction: 200 μL of the 5 μM working solution was added to the upper layer, and 600 μL of HBSS buffer was added to the lower layer. 4. BA direction: 600 μL of the 5 μM working solution was added to the lower layer, and 200 μL of HBSS buffer was added to the upper layer, and the mixture was incubated for 2 hours. 5. C0 sample: 100 μL of the working solution was transferred to a sample plate containing 400 μL of methanol (internal standard). 6. After 2 hours of incubation, 100 μL each from the upper and lower layers of the chamber was transferred to a sample plate containing 400 μL of methanol (internal standard). 7. After mixing and centrifugation, the supernatant was mixed with a certain amount of water and used for LC-MS / MS data analysis. 8. After step 6, 200 μL of 100 μM fluorescent yellow solution was added to the upper chamber and 600 μL of HBSS buffer solution was added to the lower chamber. After incubation at 37°C and 5% CO2 for 30 minutes, 50 μL of each solution was transferred to a black plate and the fluorescence value was read. 9. The data was analyzed.

[0516] Table 14: Results of permeability test of compounds of the present invention against Caco-2 cells JPEG2025537242000194.jpg33159

[0517] Pharmacokinetic experiments Male SD rats were divided into groups of three and orally administered the compound of the example (10 mg / kg) or intravenously (2 mg / kg). Animals were fasted overnight from 10 hours before administration until 4 hours after administration. Blood samples were collected from the oral administration group at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, and from the intravenous administration group at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after injection. After isoflurane anesthesia using a small animal anesthesia machine, 0.3 mL of whole blood was collected from the retinal venous plexus and placed in a heparin anticoagulation tube. After 5 minutes of centrifugation at 4°C and 4000 rpm, the plasma was transferred to a centrifuge tube and stored at -80°C until analysis. Plasma samples were extracted using protein precipitation, and the extracts were analyzed by LC-MS / MS.

[0518] Table 15: Pharmacokinetic parameters of different compounds administered orally to rats at 10 mg / kg JPEG2025537242000195.jpg55163

[0519] Table 16: Pharmacokinetic parameters following intravenous administration of 2 mg / kg of the compound to rats JPEG2025537242000196.jpg54163

[0520] From the above results, it can be seen that the injection and oral pharmacokinetic properties of the compounds of the examples of the present invention are superior to those of the existing compound KM-001 (compounds of Examples 2 to 72 of Patent WO2021154966A1, i.e., Example KM-001), and the oral bioavailability of the examples reaches 80.6%. When the pharmacokinetic properties of the compounds of other examples of the present invention were tested according to the same method, the obtained pharmacokinetic performance was also superior to that of KM-001.

[0521] Compound stability assessment The stability of the compound of Example 21 and KM-001-E1 of WO2021154966A1 was compared as an example.

[0522] The compound of Example 21 and KM-001-E1 were accurately weighed, placed in a penicillin bottle, and left to stand for 5 to 10 days under conditions of room temperature and 92.5% humidity (open air), to examine the stability of the compounds.

[0523] Analysis conditions: Equipment:Thermo U3000-ISQEC Column: Xtimate UHPLC C18 1.8μm 4.6*50mm Column temperature: 35℃ Wavelength: 210nm, 254nm

[0524] Mobile phase A: 0.05% formic acid in water; Mobile phase B: 0.05% formic acid in acetonitrile; Gradient: 30% B 0-1.2 min, 95% B 1.2-3.3 min, 30% B 3.3-4.5 min;

[0525] Analysis of decomposition impurities of each compound using LC-MS under 92.5% humidity open conditions: The main impurity in Example 21 was m / z 427.17 with a retention time of 2.55 minutes. The main impurities in KM-001-E1 were m / z=431.14 and m / z=415.16 with retention times of 2.31 minutes and 2.64 minutes, respectively. After standing for 5 days, the peak area ratios reached 2.48% and 2.43%, respectively. Analysis of LC-MS and NMR data suggests that the main impurity produced in Example 21 is a ketone, and the main impurities produced in KM-001-E1 are an aldehyde and a carboxylic acid. The specific structures are as follows: JPEG2025537242000197.jpg42147

[0526] From the above results, it can be seen that the stability of the compounds of the examples of the present invention is superior to that of the existing compound KM-001-E1.

[0527] The above compound 21 of the present invention has a secondary alcohol structure and is more chemically stable than the primary alcohol compounds of WO2021154966A1: as an alcohol, the former is only oxidized to a ketone, while the latter is oxidized to an aldehyde and further to a carboxylic acid, and the amount and level of oxidation impurities are higher than those of the above compound 21 of the present invention.

[0528] Similarly, based on the same structural features, the stability of the compounds of the examples of the present invention having the same secondary alcohol structure is superior to that of the compounds of WO2021154966A1.

[0529] While preferred embodiments of the present invention have been disclosed to illustrate the invention, it should be understood by those skilled in the art that various modifications, additions, and substitutions could be made thereto without departing from the concept and scope of the invention as defined in the appended claims.

Claims

1. a nitrogen-containing spirocyclic compound of formula (I), or a stereoisomer, tautomer, solvate, hydrate, epoxide, active metabolite, isotopically labeled compound, or pharmaceutically acceptable salt thereof; wherein Ring A is selected from the group consisting of monocyclic or polycyclic ring systems containing 3-12 ring atoms; R １ are each independently H, halogen, hydroxy, mercapto, nitro, cyano, oxo, and optionally 1 to 2 R f C substituted with １ -C ６ alkyl, 0-2 R f C substituted with １ -C ６ Haloalkyl, 0-2 R f C substituted with １ -C ６ Alkyloxy, 0-2 R f C substituted with １ -C ６ haloalkyloxy, 0-2 R f C substituted with ３ -C ６ cycloalkyl, 0-2 R f C substituted with ３ -C ６ halocycloalkyl, 0-2 R f C substituted with ３ -C ６ cycloalkyloxy, 0-2 R f C substituted with ３ -C ６ halocycloalkyloxy, 0-2 R f aryl substituted with 0-2 R f aralkyl substituted with 0-2 R f alkaryl substituted with 0-2 R f heteroaryl substituted with -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 -SO ２ N (R ａ ) (R ｂ ) or -SOR ｃ or two R １ form a 3- to 10-membered ring structure together with the ring A atoms to which they are attached, R ２ are each independently H, halogen, hydroxy, mercapto, nitro, cyano, oxo, 0-2 R f C substituted with １ -C ６ alkyl, 0-2 R f C substituted with １ -C ６ Haloalkyl, 0-2 R f C substituted with １ -C ６ Alkyloxy, 0-2 R f C substituted with １ -C ６ haloalkyloxy, 0-2 R f C substituted with ３ -C ６ cycloalkyl, 0-2 R f C substituted with ３ -C ６ halocycloalkyl, 0-2 R f C substituted with ３ -C ６ cycloalkyloxy, 0-2 R f C substituted with ３ -C ６ halocycloalkyloxy, 0-2 R f aryl substituted with 0-2 R f aralkyl substituted with 0-2 R f alkaryl substituted with 0-2 R f heteroaryl substituted with -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 -SO ２ N (R ａ ) (R ｂ ) or -SOR ｃ or two R ２ form a 3- to 10-membered ring structure together with the ring atoms to which they are attached, L １ is a bond or is selected from the following structural formulas: X １ is independently selected at each occurrence from the group consisting of C, O, or N; X ２ is independently selected at each occurrence from the group consisting of C, O, B, or N; X Ａ , X Ｂ , X Ｃ are each independently CRx or N; Each Rx is independently H, halogen, hydroxy, mercapto, nitro, cyano, 0-2 R f C substituted with １ -C ６ alkyl, 0-2 R f C substituted with １ -C ６ Haloalkyl, 0-2 R f C substituted with １ -C ６ Alkyloxy, 0-2 R f C substituted with １ -C ６ haloalkyloxy, 0-2 R f C substituted with ３ -C ６ cycloalkyl, 0-2 R f C substituted with ３ -C ６ halocycloalkyl, 0-2 R f C substituted with ３ -C ６ cycloalkyloxy, 0-2 R f C substituted with ３ -C ６ halocycloalkyloxy, 0-2 R f aryl substituted with 0-2 R f aralkyl substituted with 0-2 R f alkaryl substituted with 0-2 R f heteroaryl substituted with -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 -SO ２ N (R ａ ) (R ｂ ) or -SOR ｃ or two Rx together with the ring atoms to which they are attached form a 3- to 10-membered ring structure; R ０ are each independently selected from the group consisting of H, halogen, or a structural formula of Formula II; Here, L ２ are each independently a bond, —O—, —S—, —N(R ２０ )-, -C(O)-, -C(R ２０ R ２１ -S(O)-, -S(O)-, and -S(O)-; each ring C is independently selected from the group consisting of a monocyclic or polycyclic ring system containing 3-12 ring atoms; R ３ are each independently H, halogen, hydroxy, mercapto, nitro, cyano, oxo, 0-2 R f C substituted with １ -C ６ alkyl, 0-2 R f C substituted with １ -C ６ Haloalkyl, 0-2 R f C substituted with １ -C ６ Alkyloxy, 0-2 R f C substituted with １ -C ６ haloalkyloxy, 0-2 R f C substituted with ３ -C ６ cycloalkyl, 0-2 R f C substituted with ３ -C ６ halocycloalkyl, 0-2 R f C substituted with ３ -C ６ cycloalkyloxy, 0-2 R f C substituted with ３ -C ６ halocycloalkyloxy, 0-2 R f aryl substituted with 0-2 R f aralkyl substituted with 0-2 R f alkaryl substituted with 0-2 R f heteroaryl substituted with -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 -SO ２ N (R ａ ) (R ｂ ) or -SOR ｃ or two R ３ form a 3- to 10-membered ring structure together with the ring C atom to which they are attached, R １１ each independently represents 0 to 2 R f C substituted with １ -C ６ alkylidene; R １２ are each independently H, 0 to 2 R f C substituted with １ -C ６ alkyl, 0-2 R f C substituted with １ -C ６ Haloalkyl, 0-2 R f C substituted with ３ -C ６ Cycloalkyl and 0-2 R f C substituted with ３ -C ６ halocycloalkyl; R ａ and R ｂ are each independently H, 0 to 2 R f C substituted with １ -C ６ alkyl, 0-2 R f aryl substituted with 0-2 R f aralkyl substituted with —C(O)Rc and —C(O)OR ｄ Selected from R ｃ are each independently H, halogen, or 0-2 R f C substituted with １ -C ６ alkyl, 0-2 R f aryl substituted with and 0-2 R f aralkyl substituted with R ｄ are each independently H, 0 to 2 R f C substituted with １ -C ６ alkyl, 0-2 R f aryl substituted with and 0-2 R f aralkyl substituted with R ２０ and R ２１ are each independently H, hydroxy, C １ -C ６ selected from the group consisting of alkyl, aryl and aralkyl; R f are each independently halogen, hydroxy, amino, C １ -C ６ Alkyl, C １ -C ６ Alkyloxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkyloxy, C ３ -C ６ Cycloalkyl and C ３ -C ６ 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. Ring A is a benzene ring, a pyridine ring, a quinoline ring, a piperidine ring, C ３ -C ６ The nitrogen-containing spirocyclic compound according to claim 1, which is selected from the group consisting of a 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. Ring A has the following structural formula: The nitrogen-containing spirocyclic compound according to claim 1, which is selected from the group consisting of:

4. R １ are each independently H, halogen, cyano, hydroxy, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkyloxy, —N(R ａ ) (R ｂ ) and -R １１ OR １２ and R ａ and R ｂ are independently H and C １ -C ６ alkyl, R １１ are each independently C １ -C ６ alkylidene, and R １２ are independently H and C １ -C ６ The nitrogen-containing spirocyclic compound according to claim 1, wherein the nitrogen-containing spirocyclic compound is selected from the group consisting of alkyl.

5. R １ are each independently H, Cl, F, or —CF ３ , -CN, -CH ３ , —OH, —OCH ３ , -CH ２ OCH ３ The nitrogen-containing spirocyclic compound according to claim 4, selected from the group consisting of:

6. R ２ are each independently H, halogen, cyano, hydroxy, mercapto, oxo, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, 0-2 R f C substituted with ３ -C ６ Cycloalkyl, C １ -C ６ Alkyloxy, C １ -C ６ haloalkyloxy, -R １１ OR １２ , -R １１ SR １２ , -CH(O), -C(O)OR ｄ and -C(O)N(R ａ ) (R ｂ ), wherein R １１ are each independently C １ -C ６ alkylidene, and R １２ are each independently H, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl and C ３ -C ６ halocycloalkyl; R ａ and R ｂ are independently H and C １ -C ６ alkyl, R ｄ are independently H and C １ -C ６ alkyl, R f are each independently halogen, hydroxy, amino and C １ -C ６ The nitrogen-containing spirocyclic compound according to claim 1, wherein the nitrogen-containing spirocyclic compound is selected from the group consisting of alkyl.

7. R ２ are each independently protium, deuterium, tritium, a halogen, —SH, —OH, or —OCF ３ , -CH ３ , -OCH ３ , -CF ３ , -NH ２ , -CN, -CONH ２ , -CH ２ OH, -CH(O), -CHF ２ , -COOH, -COOCH ３ , oxo and The nitrogen-containing spirocyclic compound according to claim 6, selected from the group consisting of:

8. L ２ each independently represents a bond, —O—, —S—, —N—, —C(O)—, or —CH ２ -, -CF ２ 2. The nitrogen-containing spirocyclic compound according to claim 1, wherein the nitrogen-containing spirocyclic compound is selected from the group consisting of —, —C(OH)—, —S(O)—, and —S(O2)—.

9. Ring C is C ３ -C ６ Cycloalkane ring, benzene ring, benzo-C ３ -C ６ Cycloalkane ring, C ５ -C １２ 2. The nitrogen-containing spirocyclic compound according to claim 1, which is selected from the group consisting of a bridged carbocycle, 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.

10. Ring C has the following structural formula The nitrogen-containing spirocyclic compound according to claim 9, selected from the group consisting of:

11. R ３ are each independently H, cyano, hydroxy, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkyloxy, C １ -C ６ Haloalkyloxy, C ３ -C ６ cycloalkyl, -R １１ OR １２ , -R １１ SR １２ , -C(O)R ｃ , -C(O)OR ｄ and -C(O)N(R ａ ) (R ｂ ) or two R ３ form a 3- to 10-membered ring structure together with the ring C atom to which they are attached, Here, R １１ are each independently C １ -C ６ alkylidene, and R １２ are each independently H, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl and C ３ -C ６ halocycloalkyl; R ａ and R ｂ are independently H and C １ -C ６ alkyl, R ｃ are each independently H, halogen and C １ -C ６ alkyl, R ｄ are independently H and C １ -C ６ 2. The compound of claim 1, wherein the compound is selected from the group consisting of alkyl.

12. R ３ are each independently H, cyclopropyl, isopropyl, t-butyl, F, Cl, CN, ethyl, methyl, trifluoromethoxy, methylcarbonyl, methoxymethyl, -C(CH ３ ) ２ 12. The nitrogen-containing spirocyclic compound according to claim 11, wherein the nitrogen-containing spirocyclic compound is selected from the group consisting of OH.

13. of Formula I is the following structural formula It is one of the choices, Here, R ２ , X Ａ , X Ｂ , X Ｃ and p are defined as in formula I. The nitrogen-containing spirocyclic compound of claim 1 .

14. of Formula I is the following structural formula It is one of the choices, Here, R ２ are each independently protium, deuterium, tritium, halogen, oxo, —SH, —OH, or —CH ３ , -CN, -CONH ２ , -COOH, -COH, -COOCH ３ , -CF ３ , -OCH ３ , -CH ２ OH, -OCF ３ , -CHF ２ , and —NH ２ The nitrogen-containing spirocyclic compound according to claim 1, which is selected from the group consisting of:

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

16. of Formula I is the following structural formula It is one of the choices, Here, R ２ are each independently protium, deuterium, tritium, a halogen, or —CH ３ and -CF ３ The nitrogen-containing spirocyclic compound according to claim 14, selected from the group consisting of:

17. Wherein, R ２ are independently oxo, —SH, —CN, or —CONH ２ , -COOH, -COH, -COOCH ３ , -OCH ３ , -CH ２ OH, -CHF ２ , -OCF ３ and -NH ２ The nitrogen-containing spirocyclic compound according to claim 1, which is selected from the group consisting of:

18. The nitrogen-containing spirocyclic compound according to claim 1, selected from:

19.

20. A nitrogen-containing spirocyclic compound according to claim 1.

21. The compound is the following compound The nitrogen-containing spirocyclic compound according to claim 1, which is selected from the group consisting of:

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

23. Use of a compound according to any one of claims 1 to 21, or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically labeled compound, or pharmaceutically acceptable salt thereof, and a pharmaceutical composition according to claim 22, in the manufacture of a drug for inhibiting the activity of TRPV3.

24. Use of a compound of any one of claims 1-21, or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically labeled form, or pharmaceutically acceptable salt thereof, and a pharmaceutical composition of claim 22, in the manufacture of a medicament for the treatment of a condition mediated by TRPV3 in a subject.

25. 25. The use of 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 coughing.

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

27. 27. The use of claim 26 in the manufacture of a medicament for inhibiting proliferation and thereby preventing, treating or alleviating the symptoms of cancer.

28. 28. The use of claim 27, wherein the cancer is liposarcoma.

29. 26. The use according to claim 25, wherein the hair growth disorder is hair loss.

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

31. 31. The use according to claim 30, wherein the cutaneous keratosis is Olmsted syndrome.

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

33. A method for treating a condition mediated by TRPV3, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1-21, or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically labeled form, or pharmaceutically acceptable salt thereof, and a pharmaceutical composition according to claim 22.

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