Compounds and compositions for use in treating skin disorders

Abstract

As used herein, a compound of formula (XXXII) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or physiologically functional derivative thereof, wherein R 1 , R 2 , R 3 wherein G, A, E, n, p, and q are defined herein, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or physiologically functional derivative thereof. Also provided herein are compositions comprising compounds of formula (XXXII) and methods of using compounds of formula (XXXII), for example, in the treatment or prevention of skin disorders. TIFF2023512664001169.tif41165

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 62 / 967,500, filed January 29, 2020, the entire contents of which are incorporated herein by reference for all purposes. [Background technology]

[0002] Transient receptor potential vanilloid 3 (TRPV3) is a nonselective cation channel that is relatively permeable to calcium. TRPV3 channels are permeable to other cations (e.g., sodium) in addition to calcium ions. Therefore, TRPV3 channels regulate membrane potential by regulating the flux of cations (e.g., calcium ions and sodium ions). Nonselective cation channels, such as TRPV3, specifically regulate calcium ion flux but are mechanistically distinct from voltage-gated calcium channels. Generally, voltage-gated calcium channels respond to membrane depolarization by opening to allow calcium influx from the extracellular medium, thereby increasing intracellular calcium levels or concentrations. In contrast, TRP channels, which are nonselective cation channels, are generally signal-gated, have a longer duration, and change ion concentrations for a longer period of time. These mechanistic differences are due to structural differences between voltage-gated and TRP channels. Thus, although many different channels act to regulate ion flux and membrane potential in different cell types and in response to many stimuli, it is important to recognize the significant structural, functional, and mechanistic differences between different classes of ion channels. Summary of the Invention [Means for solving the problem]

[0003] The present disclosure relates to compounds (e.g., any compound of Formulas I-XXXXIII) and compositions and methods of use thereof for treating or preventing various diseases, conditions, and / or disorders (e.g., various skin disorders). In some embodiments, the compounds disclosed herein are useful for treating or preventing various diseases, conditions, and / or disorders modulated by TRPV3 (e.g., various skin disorders). In some embodiments, the compounds disclosed herein inhibit TRPV3 activity.

[0004] In one aspect, the present disclosure provides a compound having the general formula (XXXII): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer, or physiologically functional derivative thereof, wherein each of A, E, and G is independently selected from a monocyclic or polycyclic ring system containing 3 to 12 atoms; Each R 1 are independently cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl, C1-C6 alkoxy, ether, aryl, -N(R a )(R b ), -C(O)R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c and or two R's 1 The groups taken together form a ring system, e.g. [ka] for example, [ka] Forming R 2 and R 3 each independently of the other is cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl, hydroxyalkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, aryl, -N(R a )(R b ), -C(O)R c , -CH2R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c Selected from R a and R b each independently represents H, hydroxyl, -OR c , C1-C6 alkyl, -C(O)R c , or -C(O)OR c and R c H, C1-C6 alkyl, aryl, -OR a , or -N(R a )(R a ) and Provided is a compound, or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer, or physiologically functional derivative thereof, wherein n is 0, 1, or 2, p is 0, 1, or 2, and q is 0, 1, or 2.

[0005] In some embodiments, the present disclosure provides a compound having the general formula (XXXIII): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer, or physiologically functional derivative thereof, wherein G is aryl or heteroaryl; R 1are independently selected from cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl, hydroxyalkyl, C1-C6 alkoxy, aryl, -N(R a )(R b ), -C(O)R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c and or two R's 1 The groups taken together form a ring system, e.g. [ka] for example, [ka] Forming R 2 and R 3 each independently of the other is cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl, hydroxyalkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, aryl, -N(R a )(R b ), -C(O)R c , -CH2R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c Selected from R a and R b each independently represents H, hydroxyl, -OR c , C1-C6 alkyl, -C(O)R c , or -C(O)OR c and R c H, C1-C6 alkyl, aryl, -OR a, or -N(R a )(R a ) and Provided is a compound, or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer, or physiologically functional derivative thereof, wherein n is 0, 1, or 2, p is 0, 1, or 2, and q is 0, 1, or 2.

[0006] In some embodiments, the present disclosure provides a compound having the general formula (XXXXIII): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer, or physiologically functional derivative thereof, In the formula, X A , X B , X C , X D , and X E are each selected from N or CH; X F is C, R 1 halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, C1-C3 haloalkyl, cyano, ether, -N(R a )(R b ), -C(O)R c Selected from R a and R b are each independently H, C1-C6 alkyl, and R 2 and R 6 are each independently selected from cyano, nitro, hydroxy, hydroxyalkyl, -NH, halo, aryl, -N(R a )(R b ), -C(O)OH, -CHR c , -CO2R c , or -C(O)N(R a )(R b ) and R c H, C1-C6 alkyl, aryl, -OR a , or -N(Ra )(R a ) and R 3 and R 7 are independently selected from halo, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; Provided is a compound, or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer, or physiologically functional derivative thereof, wherein n is 0, 1, or 2, u is 0, 1, or 2, and v is 0, 1, or 2.

[0007] In some embodiments, the present disclosure provides methods of using the compounds disclosed herein (e.g., any compound of Formulas I-XXXXIII) in the prevention or treatment of various skin conditions / diseases / disorders detailed herein. In some embodiments, the compounds and compositions of the present disclosure are suitable for systemic and / or topical administration.

[0008] In order to more fully understand the subject matter disclosed herein, and to illustrate how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which: [Brief explanation of the drawings]

[0009] [Figure 1] 1 is a graph showing involucrin mRNA levels. [Figure 2A] 1 is a bar graph showing scratching time. From left to right, G1 naive, G2 vehicle 1, G3 KM-0001-P1 0.1 mg / kg (mpk), G4 KM-0001-P1 0.01 mpk, G5 vehicle 2, and G6 HC-030031 4 mg / mouse. [Figure 2B] 1 is a bar graph showing the number of scratching bouts. From left to right, G1 naive, G2 vehicle 1, G3 KM-0001-P1 0.1 mg / kg (mpk), G4 KM-0001-P1 0.01 mpk, G5 vehicle 2, and G6 HC-030031 4 mg / mouse. [Figure 3] 1 is a graph showing the plasma concentration (ng / ml) of KM-001-P1 after oral administration. [Figure 4] 1 is a graph showing a bioavailability test of KM-001. [Figure 5] A and B are SDS-PAGE images showing the effect of various concentrations of KM001 on involucrin and filaggrin. [Figure 6] 10 is a bar graph showing the effect of KM-001 on total horizontal counts. [Figure 7A] 1 is an image showing the effect of KM-001 on skin structure and keratin 10 expression. [Figure 7B] 1 is an image showing the effect of KM-001 on skin structure and keratin 10 expression. [Figure 7C] 1 is an image showing the effect of KM-001 on skin structure and keratin 10 expression. [Figure 7D] 1 is an image showing the effect of KM-001 on skin structure and keratin 10 expression. [Figure 7E] 1 is an image showing the effect of KM-001 on skin structure and keratin 10 expression. [Figure 7F] 1 is an image showing the effect of KM-001 on skin structure and keratin 10 expression. [Figure 7G] 1 is an image showing the effect of KM-001 on skin structure and keratin 10 expression. [Figure 7H] 1 is an image showing the effect of KM-001 on skin structure and keratin 10 expression. [Figure 7I] 1 is an image showing the effect of KM-001 on skin structure and keratin 10 expression. [Figure 7J] 1 is an image showing the effect of KM-001 on skin structure and keratin 10 expression. [Figure 8A] 1 is a bar graph showing the mean values ​​of KM-023 plasma concentration-time profiles in rats on linear and semi-logarithmic scales, respectively. [Figure 8B]1 is a bar graph showing the mean values ​​of KM-023 plasma concentration-time profiles in rats on linear and semi-logarithmic scales, respectively. [Figure 9A] 1 shows images showing the effect of KM-001 in a DS-Nh mouse model. [Figure 9B] 1 shows images showing the effect of KM-001 in a DS-Nh mouse model. [Figure 9C] 1 shows images showing the effect of KM-001 in a DS-Nh mouse model. [Figure 9D] 1 shows images showing the effect of KM-001 in a DS-Nh mouse model. [Figure 9E] 1 shows images showing the effect of KM-001 in a DS-Nh mouse model. [Figure 9F] 1 shows images showing the effect of KM-001 in a DS-Nh mouse model. [Figure 10] A and B are graphs showing the effects of KM-0023 in the SLIGRL-NH2 itch mouse model. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present disclosure is based on the development of novel compounds (including purified preparations thereof) that can be used in methods for treating or preventing skin diseases. For example, the present disclosure provides a compound or a salt thereof, or a solvate, hydrate, oxidative metabolite, or prodrug of the compound or a salt thereof.

[0011] In the following text, reference to at least one compound is to be understood as a reference to the compositions, methods, and uses disclosed herein. Thus, whenever a feature is given with respect to at least one compound, it is to be understood that the same feature is defined mutatis mutandis with respect to the compositions, methods, and uses.

[0012] Thus, in some embodiments, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: A is a bond, aryl, or heteroaryl; E is aryl, heteroaryl, C3-C8 cycloalkyl, or C3-C8 cycloalkenyl; G is aryl, heteroaryl, C3-C8 cycloalkyl, or C3-C8 heterocycloalkyl; L is a bond, -(CR a R b ) m -, -O-, -C(O)-, -C(O)N(R a )-, or -CH(OR c )- and P, [ka] and W is -O-, -NR c -, -(CR a R b ) m -, -(CR a R b )mO-, -OC(O)-, -NH-C(O)-, -CH2-C(O)-, or -(CY 1 Y 2 ) z - and X 1 and X 2 together are oxo or X 1 and X 2 each of which is H; Y 1 and Y 2 together are oxo or Y 1 and Y 2 each of which is H; Y is H or OH; Z is H, C1-C6 alkyl (e.g., hydroxyalkyl), or C1-C6 alkoxy; Each R 1are independently selected from cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl, C1-C6 alkoxy, aryl, -N(R a )(R b ), -C(O)R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c and or two R's 1 The groups taken together form a ring system, e.g. [ka] for example, [ka] Forming R 2 and R 3 each independently represents cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl (e.g., —CH(OH)CH2OH), C3-C8 cycloalkyl, C1-C6 alkoxy, aryl, —N(R a )(R b ), -C(O)R c , -CH2R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c and R a and R b each independently represents H, hydroxyl, -OR c , C1-C6 alkyl, -C(O)R c , or -C(O)OR c and R cH, C1-C6 alkyl, aryl, -OR a , or -N(R a )(R a ) and m is 1, 2, 3, 4, 5, or 6; z is 1, 2, 3, 4, 5, or 6; n is 0, 1, or 2; p is 0, 1, or 2; The present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2.

[0013] In some embodiments, E is phenyl.

[0014] In some embodiments, G is aryl or heteroaryl.

[0015] In some embodiments, G is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, and 4-biphenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (furanyl), quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, 1,2,3-oxadiazoyl, 1,2,4-oxadiazoyl, 1,2,5-oxadiazoyl, 1, In some embodiments, G is 3,4-oxadiazoyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. In some embodiments, G is pyridine. In some embodiments, G is [ka] (The wavy line indicates W or R 1 (Indicates a bond with either one).

[0016] In some embodiments, G is absent, such that the compound of formula (I') is shown below: [ka]

[0017] In some embodiments, R1 is C1-C3 haloalkyl and n is 1. In some embodiments, W is -C(O)-.

[0018] In some embodiments, the compound of formula (I') [ka] is.

[0019] In some embodiments, R 2 is alkyl or alkoxy.

[0020] In some embodiments, R 2 is -CH2OH.

[0021] In some embodiments, R 1 is a substituted alkoxy (e.g., -OCH2CH2OH, -OCH2CO2Et, [ka] )

[0022] In some embodiments, R 1 is cyano, halo, C1-C3 haloalkyl, or C1-C6 alkyl.

[0023] In some embodiments, R 1 is halo or C1-C3 haloalkyl.

[0024] In some embodiments, R 3 is cyano, halo, C1-C3 haloalkyl, or C1-C6 alkyl.

[0025] In some embodiments, R 3 is C1-C6 alkyl or C3-C8 cycloalkyl.

[0026] In some embodiments, n is 1 and R 1 is halo or C1-C3 haloalkyl.

[0027] In some embodiments, q is 1 or 2 and R 3 is C1-C6 alkyl or C3-C8 cycloalkyl.

[0028] In some embodiments, n is 1 and q is 1.

[0029] In some embodiments, E is aryl or heteroaryl.

[0030] In some embodiments, E is phenyl and L is a bond or -O-.

[0031] In some embodiments, E is aryl, L is a bond or —O—, and R 2 is -CH2OH.

[0032] In some embodiments, A is phenyl and R 2 is —CH2OH, L is a bond or —O—, and q is 1 or 2.

[0033] In some embodiments, one of X, Y, and Z is absent.

[0034] In some embodiments, X and Y are absent.

[0035] In some embodiments, X and Z are absent.

[0036] In some embodiments, Y and Z are absent.

[0037] In some embodiments, X, Y, and Z are absent.

[0038] In some embodiments, m is 1, 2, or 3.

[0039] In some embodiments, n is 0 or 1.

[0040] In some embodiments, q is 1.

[0041] In some embodiments, p is 1 and R 2 is hydroxy.

[0042] In some embodiments, E is aryl and L is —(CH) m -, -O-, or -C(O)-.

[0043] In some embodiments, A is phenyl and L is -O-.

[0044] In some embodiments, A and E are phenyl.

[0045] In some embodiments, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, the present disclosure provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the present disclosure provides a compound of formula (IV): [ka] or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the present disclosure provides a compound of formula (V): [ka] or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the present disclosure provides a compound of formula (VI): [ka] or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the present disclosure provides a compound of formula (VII): [ka] or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, the present disclosure provides a compound of formula (VIII): [ka] or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments, the present disclosure provides a compound of formula (IX): [ka] or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, the present disclosure provides a compound of formula (X): [ka] or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, the present disclosure provides a compound of formula (XI): [ka] or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, the present disclosure provides a compound of formula (XII): [ka] or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the present disclosure provides a compound of formula (XIII): [ka] or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, the present disclosure provides a compound of formula (XIV): [ka] or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the present disclosure provides a compound of formula (XV): [ka] or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, A is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, and 4-biphenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (furanyl), quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, and indolinyl. In some embodiments, A is phenyl.

[0060] In some embodiments, W is -C(O)- or -O-, -NH-, -CH2-, -O-CH2-, -N-CH2-, and -NH-C(O)-. In some embodiments, W is -C(O)- or -O-.

[0061] In some embodiments, P is [ka] In some embodiments, X 1 , X 2 , Y, and Z are each H.

[0062] In some embodiments, P is [ka] In some embodiments, X 1 and X 2 are each H.

[0063] In some embodiments, L is a bond, —O—, —C(O)—, or —CH(OH)—.

[0064] In some embodiments, E is phenyl.

[0065] In some embodiments, R 2 -CH2OH, cyano, nitro, hydroxy, -NH2, halo, aryl, -N(R a )(R b ), -C(O)OH, -CHR c , -CO2R c , or -C(O)N(R a )(R b In some embodiments, R 2 is -CH2OH.

[0066] In some embodiments, R 1 is halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, or C1-C3 haloalkyl. 1 is chloro, fluoro, methyl, -OMe, or -CF3.

[0067] In some embodiments, R 3 is chloro, fluoro, C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl.

[0068] In some embodiments, n is 1 and R 1 is halo or C1-C3 haloalkyl.

[0069] In some embodiments, q is 1 or 2 and R 3 is C1-C6 alkyl or C3-C8 cycloalkyl.

[0070] In some embodiments, n is 1 and q is 1.

[0071] In some embodiments, E is phenyl and L is a bond or -O-.

[0072] In some embodiments, E is aryl, L is a bond or —O—, and R 2 is -CH2OH.

[0073] In some embodiments, A is phenyl and R 2 is —CH2OH, L is a bond or —O—, and q is 1 or 2.

[0074] In some embodiments, the compound comprises an enantiomer of at least 70% chiral purity.

[0075] In some embodiments, the compound comprises an enantiomer of at least 80% chiral purity.

[0076] In some embodiments, the compound comprises an enantiomer of at least 90% chiral purity.

[0077] In some embodiments, the compound comprises an enantiomer of at least 95% chiral purity.

[0078] In some embodiments, the compound comprises an enantiomer of at least 98% chiral purity.

[0079] In some embodiments, the compound comprises an enantiomer with at least 99% chiral purity.

[0080] In some embodiments, the present disclosure provides a compound of formula (XVI): [ka] or a pharmaceutically acceptable salt thereof, wherein: A is a bond, aryl, or heteroaryl; E is aryl, heteroaryl, C3-C8 cycloalkyl, or C3-C8 cycloalkenyl; G is aryl, heteroaryl, C3-C8 cycloalkyl, or C3-C8 heterocycloalkyl; L is a bond, -(CR a R b ) m-, -O-, -C(O)-, -CH(OR c )-, or -C(O)N(R a )- and W is -O-, -NR c - or -CR a R b - and X 1 and X 2 together are oxo or X 1 and X 2 each of which is H; Y is H or OH; Z is H, C1-C6 alkyl (e.g., hydroxyalkyl), or C1-C6 alkoxy; Each R 1 are independently selected from cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl, C1-C6 alkoxy, aryl, -N(R a )(R b ), -C(O)R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c and or two R's 1 The groups taken together form a ring system, e.g. [ka] for example, [ka] Forming R 2 and R 3 each independently represents cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl (e.g., —CH(OH)CH2OH), C1-C6 alkoxy, C3-C8 cycloalkyl, aryl, —N(R a )(Rb ), -C(O)R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c and R a and R b each independently represents H, hydroxyl, -OR c , -N(R c )(R c ), C1-C6 alkyl, -C(O)R c , or -C(O)OR c and R c is H, C1-C6 alkyl, or aryl; m is 1, 2, 3, 4, 5, or 6; n is 0, 1, or 2; p is 0, 1, or 2; The present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2.

[0081] In some embodiments, R 1 is a substituted alkoxy (e.g., -OCH2CH2OH, -OCH2CO2Et, [ka] )

[0082] In some embodiments, A is aryl.

[0083] In some embodiments, L is —(CH) m -, -O-, or -CH(OR c )-.

[0084] In some embodiments, E is aryl or heteroaryl.

[0085] In some embodiments, one of X, Y, and Z is absent.

[0086] In some embodiments, X and Y are absent.

[0087] In some embodiments, X and Z are absent.

[0088] In some embodiments, Y and Z are absent.

[0089] In some embodiments, X, Y, and Z are absent.

[0090] In some embodiments, R 1 is cyano, halo, C1-C3 haloalkyl, or C1-C6 alkyl.

[0091] In some embodiments, R 2 is alkyl or alkoxy.

[0092] In some embodiments, m is 1, 2, or 3.

[0093] In some embodiments, n is 0 or 1.

[0094] In some embodiments, q is 1.

[0095] In some embodiments, n is 0 or 1 and R 1 is cyano, halo, C1-C3 haloalkyl, or C1-C6 alkyl.

[0096] In some embodiments, q is 1 and R 3 is cyano, halo, C1-C3 haloalkyl, or C1-C6 alkyl.

[0097] In some embodiments, p is 1 and R 2 is hydroxy.

[0098] In some embodiments, E is aryl and L is —(CH) m -, -O-, or -C(O)-.

[0099] In some embodiments, A is phenyl and L is -O-.

[0100] In some embodiments, A and E are phenyl.

[0101] In some embodiments, the present disclosure provides a compound of formula (XVII): [ka] or a pharmaceutically acceptable salt thereof, wherein: A is a bond, aryl, or heteroaryl; E is aryl, heteroaryl, C3-C8 cycloalkyl, or C3-C8 cycloalkenyl; L is a bond, -(CR a R b ) m -, -O-, -C(O)-, or -C(O)N(R a )- and X 1 and X 2 together are oxo or X 1 and X 2 each of which is H; Y is H or OH; Z is H, C1-C6 alkyl (e.g., hydroxyalkyl), or C1-C6 alkoxy; Each R 1 are independently selected from cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl, C1-C6 alkoxy, aryl, -N(R a )(R b ), -C(O)R c , -CO2R c , -C(O)N(R a )(Rb ), -SO2N(R a )(R b ), or -SOR c and or two R's 1 The groups taken together form a ring system, e.g. [ka] for example, [ka] Forming R 2 and R 3 each independently represents cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl (e.g., —CH(OH)CH2OH), C1-C6 alkoxy, C3-C8 cycloalkyl, aryl, —N(R a )(R b ), -C(O)R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c and R a and R b each independently represents H, hydroxyl, -OR c , -N(R c )(R c ), C1-C6 alkyl, -C(O)R c , or -C(O)OR c and R c is H, C1-C6 alkyl, or aryl; m is 1, 2, 3, 4, 5, or 6; n is 0, 1, or 2; p is 0, 1, or 2; The present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2.

[0102] In some embodiments, the present disclosure provides a compound of formula (XVII): [ka] or a pharmaceutically acceptable salt thereof, wherein: A is a bond, aryl, or heteroaryl; E is aryl, heteroaryl, C3-C8 cycloalkyl, or C3-C8 cycloalkenyl; L is a bond, -(CR a R b ) m -, -O-, -C(O)-, or -C(O)N(R a )- and X 1 and X 2 together are oxo or X 1 and X 2 each of which is H; Y is H or OH; Z is H or C1-C6 alkyl; Each R 1 are independently cyano, halo, C1-C3 haloalkyl, C1-C6 alkyl, or —C(O)N(R a )(R b ) and or two R's 1 The groups taken together form a ring system, e.g. [ka] for example, [ka] Forming R 2 and R 3 each independently represents cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl, alkoxy, C3-C8 cycloalkyl, aryl, -N(R a)(R b ), -C(O)R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c and R a and R b each independently represents H, hydroxyl, -OR c , -N(R c )(R c ), C1-C6 alkyl, -C(O)R c , or -C(O)OR c and R c is H, C1-C6 alkyl, or aryl; m is 1, 2, 3, 4, 5, or 6; n is 0, 1, or 2; p is 0, 1, or 2; The present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2.

[0103] In some embodiments, the present disclosure provides a compound of formula (XVIII): [ka] or a pharmaceutically acceptable salt thereof, wherein: A is a bond, aryl, or heteroaryl; L is a bond, -(CR a R b ) m -, -O-, -C(O)-, or -C(O)N(R a )- and R 2 and R 3 each independently represents cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl, alkoxy, C3-C8 cycloalkyl, aryl, -N(R a )(Rb ), -C(O)R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c and R 4 , R 5 , and R 6 each independently represents cyano, halo, C1-C3 haloalkyl, C1-C6 alkyl, C1-C6 alkoxyl, or —C(O)N(R a )(R b ) and R a and R b each independently represents H, hydroxyl, -OR c , -N(R c )(R c ), C1-C6 alkyl, -C(O)R c , or -C(O)OR c and R c is H, C1-C6 alkyl, or aryl; m is 1, 2, 3, 4, 5, or 6; p is 0, 1, or 2; The present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2.

[0104] In some embodiments, the present disclosure provides a compound of formula (XIX): [ka] or a pharmaceutically acceptable salt thereof, wherein: L is a bond, -(CR a R b ) m -, -O-, -C(O)-, or -C(O)N(R a )- and R 2 and R 3each independently represents cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl, alkoxy, C3-C8 cycloalkyl, aryl, -N(R a )(R b ), -C(O)R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c and R 4 , R 5 , and R 6 each independently represents cyano, halo, C1-C3 haloalkyl, C1-C6 alkyl, C1-C6 alkoxyl, or —C(O)N(R a )(R b ) and R a and R b each independently represents H, hydroxyl, -OR c , -N(R c )(R c ), C1-C6 alkyl, -C(O)R c , or -C(O)OR c and R c is H, C1-C6 alkyl, or aryl; m is 1, 2, 3, 4, 5, or 6; The present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2.

[0105] In some embodiments, the present disclosure provides a compound of formula (XX): [ka] or a pharmaceutically acceptable salt thereof, wherein: L is a bond, -(CR a R b ) m-, -O-, -C(O)-, or -C(O)N(R a )- and R 2 and R 3 each independently represents cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl, alkoxy, C3-C8 cycloalkyl, aryl, -N(R a )(R b ), -C(O)R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c and R 4 and R 6 each independently represents cyano, halo, C1-C3 haloalkyl, C1-C6 alkyl, C1-C6 alkoxyl, or —C(O)N(R a )(R b ) and R a and R b each independently represents H, hydroxyl, -OR c , -N(R c )(R c ), C1-C6 alkyl, -C(O)R c , or -C(O)OR c and R c is H, C1-C6 alkyl, or aryl; m is 1, 2, 3, 4, 5, or 6, or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the compound comprises an enantiomer of at least 70% chiral purity.

[0107] In some embodiments, the compound comprises an enantiomer of at least 80% chiral purity.

[0108] In some embodiments, the compound comprises an enantiomer of at least 90% chiral purity.

[0109] In some embodiments, the compound comprises an enantiomer of at least 95% chiral purity.

[0110] In some embodiments, the compound comprises an enantiomer of at least 98% chiral purity.

[0111] In some embodiments, the compound comprises an enantiomer with at least 99% chiral purity.

[0112] In some embodiments, the present disclosure provides a compound of formula (XXI): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 3 is cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl, alkoxy, aryl, -N(R a )(R b ), -C(O)R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c and R 4 and R 6 each independently represents cyano, halo, C1-C3 haloalkyl, C1-C6 alkyl, C1-C6 alkoxyl, or —C(O)N(R a )(R b ) and R a and R b each independently represents H, C1-C6 alkyl, -OR c , -N(R c )(R c ), -C(O)Rc , or -C(O)OR c and R c is H, C1-C6 alkyl, or aryl; m is 1, 2, 3, 4, 5, or 6, or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, L is a bond, —(CH) m -, -O-, -C(O)-, -C(O)N(R a )-, or -CH(OR c )-.

[0114] In some embodiments, L is —(CH) m -, -O-, or -CH(OR c )-.

[0115] In some embodiments, the compound comprises an enantiomer of at least 70% chiral purity.

[0116] In some embodiments, the compound comprises an enantiomer of at least 80% chiral purity.

[0117] In some embodiments, the compound comprises an enantiomer of at least 90% chiral purity.

[0118] In some embodiments, the compound comprises an enantiomer of at least 95% chiral purity.

[0119] In some embodiments, the compound comprises an enantiomer of at least 98% chiral purity.

[0120] In some embodiments, the compound comprises an enantiomer with at least 99% chiral purity.

[0121] In some embodiments, the present disclosure provides a compound of formula (XXII): [ka] or a pharmaceutically acceptable salt thereof, wherein: X is -N- or -CH-; Y 1 and Y 2 together are oxo or Y 1 and Y 2 each of which is H; X 1 and X 2 together are oxo or X 1 and X 2 each of which is H; L is a bond, -(CR a R b ) m -, -O-, -C(O)-, -C(O)N(R a )-, or -CH(OR c )- and E is aryl, heteroaryl, C3-C8 cycloalkyl, or C3-C8 cycloalkenyl; G is aryl, heteroaryl, C3-C8 cycloalkyl, or C3-C8 heterocycloalkyl; Each R 1 are independently selected from cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl, C1-C6 alkoxy, aryl, -N(R a )(R b ), -C(O)R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c and or two R's 1 The groups taken together form a ring system, e.g. [ka] for example, [ka] Forming R 2 and R 3 each independently represents cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl (e.g., —CH(OH)CH2OH), C1-C6 alkoxy, C3-C8 cycloalkyl, aryl, —N(R a )(R b ), -C(O)R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c and n is 0, 1, or 2; q is 0, 1, or 2; z is 0 or 1, R a and R b each independently represents H, hydroxyl, -OR c , -N(R c )(R c ), C1-C6 alkyl, -C(O)R c , or -C(O)OR c and R c is H, C1-C6 alkyl, or aryl, or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, Y 1 and Y 2 together they are oxo.

[0123] In some embodiments, X 1 and X 2 are each H.

[0124] 97. The compound of claim 96, wherein L is a bond or -O-.

[0125] In some embodiments, E is phenyl.

[0126] In some embodiments, G is aryl or heteroaryl.

[0127] In some embodiments, G is pyridine.

[0128] In some embodiments, R 2 is -CH2OH.

[0129] In some embodiments, R 1 is halo or C1-C3 haloalkyl.

[0130] In some embodiments, R 3 is C1-C6 alkyl or C3-C8 cycloalkyl.

[0131] In some embodiments, n is 1 and R 1 is halo or C1-C3 haloalkyl.

[0132] In some embodiments, q is 1 or 2 and R 3 is C1-C6 alkyl or C3-C8 cycloalkyl.

[0133] In some embodiments, z is 1 and Y 1 and Y 2 together they are oxo.

[0134] In some embodiments, X is -CH- and L is a bond or -O-.

[0135] In some embodiments, n is 1 and q is 1.

[0136] In some embodiments, E is phenyl and L is a bond or -O-.

[0137] In some embodiments, E is aryl, L is a bond or —O—, and R 2 is -CH2OH.

[0138] In some embodiments, X is -CH- and R 2 is —CH2OH, L is a bond or —O—, and q is 1 or 2.

[0139] In some embodiments, the present disclosure provides a compound of formula (XXIII): [ka] or a pharmaceutically acceptable salt thereof, wherein: X is -N- or -CH-; L is a bond, -(CR a R b ) m -, -O-, -C(O)-, -C(O)N(R a )-, or -CH(OR c )- and E is aryl, heteroaryl, C3-C8 cycloalkyl, or C3-C8 cycloalkenyl; Each R 1 are independently selected from cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl, C1-C6 alkoxy, aryl, -N(R a )(R b ), -C(O)R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c and or two R's 1 The groups taken together form a ring system, e.g. [ka] for example, [ka] Forming R 2 and R 3 each independently represents cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl (e.g., —CH(OH)CH2OH), C1-C6 alkoxy, C3-C8 cycloalkyl, aryl, —N(R a )(R b ), -C(O)R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c and n is 0, 1, or 2; q is 0, 1, or 2; R a and R b each independently represents H, hydroxyl, -OR c , -N(R c )(R c ), C1-C6 alkyl, -C(O)R c , or -C(O)OR c and R c is H, C1-C6 alkyl, or aryl, or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, the present disclosure provides a compound of formula (XXIV): [ka] or a pharmaceutically acceptable salt thereof, wherein: L is a bond, -(CR a R b ) m-, -O-, -C(O)-, -C(O)N(R a )-, or -CH(OR c )- and R 2 and R 3 each independently represents cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl (e.g., —CH(OH)CH2OH), C1-C6 alkoxy, C3-C8 cycloalkyl, aryl, —N(R a )(R b ), -C(O)R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c and R 4 , R 5 , and R 6 each independently represents cyano, C1-C6 alkyl, C1-C6 alkoxyl, halo, C1-C3 haloalkyl, or —C(O)N(R a )(R b ) and q is 0, 1, or 2; R a and R b each independently represents H, hydroxyl, -OR c , -N(R c )(R c ), C1-C6 alkyl, -C(O)R c , or -C(O)OR c and R c is H, C1-C6 alkyl, or aryl, or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments, the present disclosure provides a compound of formula (XXV): [ka] or a pharmaceutically acceptable salt thereof, wherein: Each R3 are independently halo, C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 alkoxy; R 4 and R 5 each independently represents cyano, C1-C6 alkyl, C1-C6 alkoxyl, halo, C1-C3 haloalkyl, or —C(O)N(R a )(R b ) and q is 0, 1, or 2; R a and R b each independently represents H, hydroxyl, -OR c , -N(R c )(R c ), C1-C6 alkyl, -C(O)R c , or -C(O)OR c and R c is H, C1-C6 alkyl, or aryl, or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments, the present disclosure provides a compound of formula (XXVI): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 3 is halo, C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 alkoxy; R 5 is cyano, C1-C6 alkyl, C1-C6 alkoxyl, halo, C1-C3 haloalkyl, or -C(O)N(R a )(R b ) and R a and R b each independently represents H, hydroxyl, -OR c , -N(R c )(R c ), C1-C6 alkyl, -C(O)R c , or -C(O)ORc and R c is H, C1-C6 alkyl, or aryl, or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments, the present disclosure provides a compound of formula (XXVII) [ka] or a pharmaceutically acceptable salt thereof, wherein: R 3 is -Cl, -F, ethyl, n-propyl, or iso-propyl; R 4 is -Me or -Cl, The present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein y is 1 or 2.

[0144] According to some aspects, the present disclosure provides a compound having the structure of general formula (XXXII): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer, or physiologically functional derivative thereof, wherein each of A, E, and G is independently selected from a ring system containing 3 to 12 atoms; R 1 are independently cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl, C1-C6 alkoxy, ether, aryl, -N(R a )(R b ), -C(O)R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c is selected from or two R's1 The groups taken together form a ring system, e.g. [ka] for example, [ka] Forming R 2 and R 3 each independently of the other is cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl (e.g., —CH(OH)CH2OH), C3-C8 cycloalkyl, C1-C6 alkoxy, aryl, —N(R a )(R b ), -C(O)R c , -CH2R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c Selected from R a and R b each independently represents H, hydroxyl, -OR c , C1-C6 alkyl, -C(O)R c , or -C(O)OR c and R c H, C1-C6 alkyl, aryl, -OR a , or -N(R a )(R a ) and Provided is a compound, or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer, or physiologically functional derivative thereof, wherein n is 0, 1, or 2, p is 0, 1, or 2, and q is 0, 1, or 2.

[0145] According to some embodiments, in the compounds of the present invention, each of A, E, and G is selected to be a ring system having 3 to 12 atoms. As used herein, a ring system includes a monocyclic ring system or a polycyclic ring system (e.g., a bicyclic ring system). As referred to herein, a ring system (e.g., a monocyclic ring system or a bicyclic ring system (which may include a fused ring system)) can include only carbon atoms or can include both carbon atoms and heteroatoms. Thus, a ring system having 3 to 12 atoms includes one or more rings having a total number of atoms of 3 to 12. As will be understood, the atoms can include only carbon atoms or, alternatively, can include at least one heteroatom, particularly including N, O, or S. According to some embodiments, each of A, E, and G is selected to be an aromatic ring system (either a monocyclic or bicyclic aromatic ring system).

[0146] According to some embodiments, each of A, E, and G, independently of the other, is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl.

[0147] According to some embodiments, each of A, E, and G, independently of the other, is selected from aryl or heteroaryl.

[0148] According to some other embodiments, each of A, E, and G, independently of the other, is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl.

[0149] In some other embodiments, each of A, E, and G, independently of the other, is cycloalkyl or heterocycloalkyl.

[0150] In some other embodiments, each of A, E, and G, independently of the other, is cycloalkenyl or heterocycloalkenyl.

[0151] In some other embodiments, each of A, E, and G in the compounds of the invention (e.g., compounds of general formula (XXXII)) is independently selected from 1-naphthyl, 2-naphthyl, 4-biphenyl, quinolyl, isoquinolyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, furan, thipohene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, thiazole, benzofuran, indole, benzothiophene, benzimidazole, indazole, benzoxazole, benzisoxazole, benzothiazole, isobenzofuran, isoindole, or purine.

[0152] The number of atoms in the ring system may be, according to some embodiments, 3 to 8 atoms. Thus, a ring system having 3 to 8 atoms encompasses one or more rings having a total number of atoms of 3 to 8. As will be understood, the atoms may include only carbon atoms or, alternatively, may include at least one heteroatom, including, among others, N, O, or S.

[0153] In some embodiments, each of A, E, and G, independently of the other, is selected from aryl, heteroaryl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkenyl, or C3-C8 heterocycloalkenyl in compounds of the invention.

[0154] In some embodiments, each of A, E, and G, independently of the other, is selected from C-C cycloalkyl, C-C heterocycloalkyl, C-C cycloalkenyl, or C-C heterocycloalkenyl in compounds of the invention.

[0155] In some embodiments, each of A, E, and G, independently of the other, is selected from C3-C8 cycloalkyl or C3-C8 heterocycloalkyl.

[0156] In some embodiments, each of A, E, and G, independently of the other, is selected from C3-C8 cycloalkenyl or C3-C8 heterocycloalkenyl.

[0157] In some other embodiments, each of A, E, and G, independently of the other, is selected from aryl, C3-C8 cycloalkyl, or C3-C8 cycloalkenyl.

[0158] In some other embodiments, each of A, E, and G, independently of the other, is selected from heteroaryl, C3-C8 heterocycloalkyl, or C3-C8 heterocycloalkenyl.

[0159] In some embodiments, each of A, E, and G in a compound of the invention (e.g., a compound of Formula (XXXII)) is independently selected from a heteroaryl containing 5 atoms or a heteroaryl containing 6 atoms.

[0160] In some embodiments, each of A, E, and G in a compound of the invention (e.g., a compound of Formula (XXXII)) is independently selected from an aryl containing 5 atoms or an aryl containing 6 atoms.

[0161] In some embodiments, each of A, E, and G, independently of the other, is a heteroaryl containing 5 or 6 atoms.

[0162] In some embodiments, each of A, E, and G, independently of the other, is heteroaryl containing 5 or 6 atoms, including carbon atoms and heteroatoms, of which at least 1, at least 2, at least 3, or at least 4 are heteroatoms.

[0163] In some embodiments, each of A, E, and G, independently of the other, is selected from a 6-membered aryl, a 5-membered aryl, a 6-membered nitrogen-containing heteroaryl, or a 5-membered nitrogen-containing heteroaryl.

[0164] In some embodiments, each of A, E, and G, independently of the other, is selected from a 6-membered aryl or a 6-membered nitrogen-containing heteroaryl.

[0165] In some other embodiments, A is a 6- or 5-membered nitrogen-containing heteroaryl.

[0166] In some other embodiments, E is a 6- or 5-membered nitrogen-containing heteroaryl.

[0167] In some other embodiments, G is a 6- or 5-membered nitrogen-containing heteroaryl.

[0168] In some embodiments, each of A, E, and G, independently of the other, is selected from phenyl, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,3-triazine, 1,2,4-triazine, or 1,3,5-triazine.

[0169] In some embodiments, E is selected from phenyl, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine.

[0170] In some other embodiments, E is phenyl.

[0171] In some embodiments, A is selected from aryl or heteroaryl, each containing 5 atoms or 6 atoms, of which at least 1, at least 2, at least 3, or at least 4 are heteroatoms.

[0172] In some embodiments, A is selected from phenyl, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine.

[0173] In some other embodiments, A is phenyl.

[0174] In some embodiments, G is aryl or heteroaryl, each containing 5 atoms or 6 atoms, of which at least 1, at least 2, at least 3, or at least 4 are heteroatoms.

[0175] In some other embodiments, G is a 6-membered nitrogen-containing heteroaryl.

[0176] In some embodiments, G is selected from phenyl, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,3-triazine, 1,2,4-triazine, or 1,3,5-triazine.

[0177] In some other embodiments, G is selected from phenyl, pyridine, pyrazine, pyrimidine, or pyridazine.

[0178] In some embodiments, G is [ka] is selected from the group consisting of:

[0179] In some other embodiments, G is pyridine.

[0180] In some other embodiments, G is [ka] is.

[0181] In some other embodiments, G is pyrazine.

[0182] In some other embodiments, G is [ka] is.

[0183] In some embodiments, G is phenyl.

[0184] In some embodiments, in compounds of the invention, e.g., compounds of Formula (XXXII), E is phenyl, A is phenyl, and G is selected from phenyl, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,3-triazine, 1,2,4-triazine, or 1,3,5-triazine.

[0185] In some other embodiments, in compounds of the invention, eg, compounds of Formula (XXXII), E is phenyl, A is phenyl, and G is pyridine.

[0186] In some further embodiments, in compounds of the invention, eg, compounds of Formula (XXXII), E is phenyl, A is phenyl, and G is pyrazine.

[0187] In some embodiments, R 1 is halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, C1-C3 haloalkyl, cyano, ether, -N(R a )(R b ), -C(O)R c Selected from R a and R b are each independently H, C1-C6 alkyl, and R c is H or C1-C6 alkyl.

[0188] In some other embodiments, R 1is halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, C1-C3 haloalkyl, ether, -N(R a )(R b ) and R a and R b Each of is independently H, C1-C6 alkyl.

[0189] In some further embodiments, R 1 is at least one of fluorine, chlorine, methyl, methoxy, hydroxy, methylamine, diethyl ether, or CF3.

[0190] In some embodiments, R 1 is fluorine.

[0191] In some other embodiments, R 1 is methyl.

[0192] In some further embodiments, R 1 is methoxy.

[0193] In some embodiments, n is 0.

[0194] In some embodiments, n is 1 or 2.

[0195] In some embodiments, n is 1 or 2 and R 1 is selected from fluorine, chlorine, methyl, methoxy, hydroxy, methylamine, or CF3.

[0196] In some embodiments, n is 2 and R 1 is at least one of fluorine, chlorine, methyl, methoxy, hydroxy, methylamine, or CF3.

[0197] In some embodiments, n is 2 and R 1 is at least one of methyl and hydroxy.

[0198] In some embodiments, n is 1 and R 1 is fluorine.

[0199] In some embodiments, R 2 is -CH2OH, cyano, nitro, hydroxy, hydroxyalkyl, -NH2, halo, aryl, -N(R a )(R b ), -C(O)OH, -CHR c , -CO2R c , or -C(O)N(R a )(R b ) is selected.

[0200] In some embodiments, R 2 is selected from hydroxyalkyl and halo.

[0201] In some embodiments, R 2 is hydroxyalkyl.

[0202] In some embodiments, R 2 is -CH2OH (hydroxymethyl).

[0203] In some embodiments, p is 0.

[0204] In some embodiments, p is 1 or 2.

[0205] In some embodiments, p is 1 or 2 and R 2 is -CH2OH (hydroxymethyl).

[0206] In some embodiments, p is 1 or 2 and R 2 is at least one of —CH2OH and fluorine.

[0207] In some embodiments, R 3is selected from halo, C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl.

[0208] In some embodiments, R 3 is selected from fluorine, cyclopropyl, methyl, ethyl, or propyl.

[0209] In some embodiments, R 3 is selected from methyl, ethyl, or propyl.

[0210] In some embodiments, R 3 is cyclopropyl.

[0211] In some embodiments, R 3 is methoxy or ethoxy.

[0212] In some embodiments, R 3 is cyclopropyl and fluorine.

[0213] In some embodiments, q is 1 or 2.

[0214] In some embodiments, q is 1 or 2 and R 3 is halo, C1-C6 alkyl, It is at least one of C1 to C6 alkoxy, or C3 to C8 cycloalkyl.

[0215] In some embodiments, each of A and E is independently selected from phenyl or heteroaryl containing 6 atoms, hi some other embodiments, each of A and E is phenyl.

[0216] Thus, according to some aspects, which may be considered as embodiments, the present disclosure provides a compound having a structure of general formula (XXXIII): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer, or physiologically functional derivative thereof, wherein G, R 1 , R 2 , R 3 wherein n, p, and q are as defined for compounds of formula (XXXII), or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer, or physiologically functional derivative thereof.

[0217] In some embodiments, the compound having the structure of general formula (XXII) or (XXXIII) is a compound having the structure of general formula (XXXIIIa), (XXXIIIb), (XXXIIIc), or (XXXIIId): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer, or physiologically functional derivative thereof, wherein G, R 1 , R 2 , R 3 , n, p, and q are as defined hereinabove for compounds of formula (XXXIII), and R 6 and R 7 each independently of the other is cyano, nitro, hydroxy, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl (e.g., —CH(OH)CH2OH), C3-C8 cycloalkyl, C1-C6 alkoxy, aryl, —N(R a )(R b ), -C(O)R c , -CH2R c , -CO2R c , -C(O)N(R a )(R b ), -SO2N(R a )(R b ), or -SOR c Selected from R a and R b each independently represents H, hydroxyl, -OR c, C1-C6 alkyl, -C(O)R c , or -C(O)OR c and R c H, C1-C6 alkyl, aryl, -OR a , or -N(R a )(R a ) wherein u is 0, 1, or 2 and v is 0, 1, or 2, or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof, or physiologically functional derivative thereof.

[0218] In some embodiments, in compounds of the present invention (e.g., compounds represented by general formula (XXXII)), the compound is a compound provided by general formula (XXXIII), (XXXIIIa), (XXXIIIb), (XXXIIIc), or (XXXIIId).

[0219] In some other embodiments, G is a 6-membered nitrogen-containing heteroaryl.

[0220] In some embodiments, G is selected from phenyl, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine.

[0221] In some other embodiments, G is selected from phenyl, pyridine, pyrazine, pyrimidine, or pyridazine.

[0222] In some other embodiments, G is selected from pyridine, pyrazine, pyrimidine, and pyridazine.

[0223] In some embodiments, G is [ka] is selected from the group consisting of:

[0224] In some other embodiments, G is pyridine or pyrazine.

[0225] In some other embodiments, G is pyridine.

[0226] In some other embodiments, G is [ka] is.

[0227] In some other embodiments, G is pyrazine.

[0228] In some other embodiments, G is [ka] is.

[0229] In some embodiments, G is phenyl.

[0230] In some embodiments, R 1 is halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, C1-C3 haloalkyl, cyano, ether, -N(R a )(R b ), -C(O)R c wherein R a and R b are each independently H, C1-C6 alkyl, and R c is H or C1-C6 alkyl.

[0231] In some other embodiments, R 1 is halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, C1-C3 haloalkyl, ether, -N(R a )(R b ) and R a and R b Each of is independently H, C1-C6 alkyl.

[0232] In some further embodiments, R 1 is at least one of fluorine, chlorine, methyl, methoxy, hydroxy, methylamine, diethyl ether, or CF3.

[0233] In some embodiments, R 1 is fluorine.

[0234] In some other embodiments, R 1 is methyl.

[0235] In some further embodiments, R 1 is methoxy.

[0236] In some embodiments, n is 0.

[0237] In some embodiments, n is 1 or 2.

[0238] In some embodiments, n is 1 or 2 and R 1 is selected from fluorine, chlorine, methyl, methoxy, hydroxy, methylamine, or CF3.

[0239] In some embodiments, n is 2 and R 1 is at least one of fluorine, chlorine, methyl, methoxy, hydroxy, methylamine, or CF3.

[0240] In some embodiments, n is 2 and R 1 is at least one of methyl and hydroxy.

[0241] In some embodiments, n is 1 and R 1 is fluorine.

[0242] In some embodiments, G is selected from pyridine, pyrazine, pyrimidine, pyridazine, n is 1, and R 1 is halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, C1-C3 haloalkyl, -N(R a )(R b ) and R a and R b Each of is independently H, C1-C6 alkyl.

[0243] In some embodiments, G is [ka] where n is 1 and R 1 is at least one of fluorine, chlorine, methyl, or methoxy.

[0244] In some embodiments, G is [ka] where n is 1 and R 1 is fluorine or chlorine.

[0245] In some embodiments, G is [ka] where n is 1 and R 1 is at least one of fluorine, hydroxy, methyl, or methoxy.

[0246] In some embodiments, G is [ka] where n is 1 and R 1 is methyl or methoxy.

[0247] In some embodiments, G is [ka] where n is 2 and R 1 is selected from methyl and hydroxy. In some embodiments, R 2 is -CH2OH, cyano, nitro, hydroxy, hydroxyalkyl, -NH2, halo, aryl, -N(R a )(R b ), -C(O)OH, -CHR c , -CO2R c , or -C(O)N(R a )(R b ) is at least one of

[0248] In some embodiments, R 2 is -CH2OH, cyano, nitro, hydroxy, hydroxyalkyl, -NH2, halo, aryl, -N(R a )(R b ), -C(O)OH, -CHR c , -CO2R c , or -C(O)N(R a )(R b ) is selected.

[0249] In some embodiments, R 2 is selected from hydroxyalkyl and halo.

[0250] In some embodiments, R 2 is hydroxyalkyl.

[0251] In some embodiments, R 2 is -CH2OH (hydroxymethyl).

[0252] In some embodiments, p is 0.

[0253] In some embodiments, p is 1 or 2.

[0254] In some embodiments, p is 1 or 2 and R 2 is -CH2OH (hydroxymethyl).

[0255] In some embodiments, p is 1 or 2 and R 2 is at least one of —CH2OH and fluorine.

[0256] In some embodiments, G is selected from pyridine, pyrazine, pyrimidine, pyridazine, n is 1, and R 1 is halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, C1-C3 haloalkyl, -N(R a )(R b ) and R a and R b are each independently H, C1-C6 alkyl, p is 1, and R 2 is -CH2OH, cyano, nitro, hydroxy, hydroxyalkyl, -NH2, halo, aryl, -N(R a )(R b ), -C(O)OH, -CHR c , -CO2R c , or -C(O)N(R a )(R b ) is selected.

[0257] In some embodiments, G is pyridine or pyrazine, n is 1, and R 1 is at least one of fluorine, chlorine, methyl, or methoxy, p is 1, and R 2 is -CH2OH.

[0258] In some embodiments, G is pyridine or pyrazine, n is 2, and R 1 is at least one of fluorine, chlorine, hydroxy, methyl, or methoxy, p is 1, and R 2 is -CH2OH.

[0259] In some embodiments, R 3 is selected from halo, C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl.

[0260] In some embodiments, R 3 is selected from fluorine, cyclopropyl, methyl, ethyl, or propyl.

[0261] In some embodiments, R 3 is selected from methyl, ethyl, or propyl.

[0262] In some embodiments, R 3 is cyclopropyl.

[0263] In some embodiments, R 3 is methoxy or ethoxy.

[0264] In some embodiments, R 3 is cyclopropyl and fluorine.

[0265] In some embodiments, q is 1 or 2.

[0266] In some embodiments, q is 1 or 2 and R 3 is halo, C1-C6 alkyl, It is at least one of C1 to C6 alkoxy, or C3 to C8 cycloalkyl.

[0267] In some embodiments, q is 1 or 2 and R 3 In at least some embodiments, R 3 is selected from halo, C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl.

[0268] In some embodiments, R 3is selected from fluorine, cyclopropyl, methyl, ethyl, or propyl.

[0269] In some embodiments, R 3 is selected from methyl, ethyl, or propyl.

[0270] In some embodiments, R 3 is cyclopropyl.

[0271] In some embodiments, R 3 is methoxy or ethoxy.

[0272] In some embodiments, R 3 is cyclopropyl and fluorine.

[0273] In some embodiments, q is 1 or 2.

[0274] In some embodiments, q is 1 or 2 and R 3 is halo, C1-C6 alkyl, It is at least one of C1 to C6 alkoxy, or C3 to C8 cycloalkyl.

[0275] In some embodiments, u is 1 or 2 and R 7 is fluorine, R 3 is at least one of C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl.

[0276] In some embodiments, G is selected from pyridine, pyrazine, pyrimidine, pyridazine; n is 1 or 2; and R 1 is halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, C1-C3 haloalkyl, -N(R a )(R b ) and R a and R bare each independently H, C1-C6 alkyl, p is 1 or 2, and R 2 is -CH2OH, cyano, nitro, hydroxy, hydroxyalkyl, -NH2, halo, aryl, -N(R a )(R b ), -C(O)OH, -CHR c , -CO2R c , or -C(O)N(R a )(R b ), q is 1 or 2, and R 3 is selected from halo, C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl.

[0277] In some embodiments, G is pyridine or pyrazine, n is 1, and R 1 is at least one of fluorine, chlorine, methyl, hydroxy, or methoxy, p is 1, and R 2 is -CHOH, q is 1 or 2, and R 3 is at least one of fluorine, cyclopropyl, methyl, ethyl, or propyl.

[0278] In some embodiments, G is pyridine or pyrazine, n is 1, and R 1 is at least one of fluorine, chlorine, methyl, or methoxy, p is 1, and R 2 is -CHOH, q is 2, and R 3 is selected from fluorine, cyclopropyl, methyl, ethyl, or propyl.

[0279] In some embodiments, in the compounds of the present invention, G is selected from pyridine, pyrazine, pyrimidine, pyridazine, n is 1 or 2, and R 1 is halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, C1-C3 haloalkyl, -N(R a )(R b ) and R a and R bare each independently H, C1-C6 alkyl, p is 1 or 2, and R 2 is -CH2OH, cyano, nitro, hydroxy, hydroxyalkyl, -NH2, halo, aryl, -N(R a )(R b ), -C(O)OH, -CHR c , -CO2R c , or -C(O)N(R a )(R b ), v is 0, u is 0, q is 1 or 2, and R 3 is at least one of halo, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl.

[0280] In some embodiments, in the compounds of the present invention, G is selected from pyridine, pyrazine, pyrimidine, pyridazine, n is 1 or 2, and R 1 is halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, C1-C3 haloalkyl, -N(R a )(R b ) and R a and R b are each independently H, C1-C6 alkyl, p is 1 or 2, and R 2 is -CH2OH, cyano, nitro, hydroxy, hydroxyalkyl, -NH2, halo, aryl, -N(R a )(R b ), -C(O)OH, -CHR c , -CO2R c , or -C(O)N(R a )(R b ), v is 0, u is 1 or 2, and R 3 is at least one of halo, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl, and R 7 is a halo.

[0281] In some embodiments, G is pyridine or pyrazine, n is 1 or 2, and R 1is halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, C1-C3 haloalkyl, -N(R a )(R b ) and R a and R b are each independently H, C1-C6 alkyl, p is 1 or 2, and R 2 is -CH2OH, cyano, nitro, hydroxy, hydroxyalkyl, -NH2, halo, aryl, -N(R a )(R b ), -C(O)OH, -CHR c , -CO2R c , or -C(O)N(R a )(R b ), p is 1, and R 2 is -CHOH, v is 0, u is 0, q is 1, and R 3 is selected from cyclopropyl, methyl, ethyl, or propyl.

[0282] In some embodiments, G is pyridine or pyrazine, n is 1 or 2, and R 1 is halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, C1-C3 haloalkyl, -N( a )(R b ) and R a and R b are each independently H, C1-C6 alkyl, p is 1 or 2, and R 2 is -CH2OH, cyano, nitro, hydroxy, hydroxyalkyl, -NH2, halo, aryl, -N(R a )(R b ), -C(O)OH, -CHR c , -CO2R c , or -C(O)N(R a )(R b ), p is 1, and R 2 is -CHOH, v is 0, u is 1 or 2, and R 7 is fluorine and R 3 is selected from cyclopropyl, methyl, ethyl, or propyl.

[0283] In some embodiments, G is pyridine or pyrazine, n is 1, and R 1 is halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, p is 1, R 2 is -CHOH, v is 0, u is 0, q is 1, and R 3 is selected from cyclopropyl, methyl, ethyl, or propyl.

[0284] In some embodiments, G is pyridine or pyrazine, n is 1, and R 1 is halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, p is 1, R 2 is -CHOH, v is 0, u is 1, and R 7 is the halo and R 3 is selected from cyclopropyl, methyl, ethyl, or propyl.

[0285] In some embodiments, G is pyridine or pyrazine, n is 1, and R 1 is fluorine, chlorine, methyl, or methoxy, p is 1, and R 2 is -CHOH, v is 0, u is 0, q is 1, and R 3 is selected from cyclopropyl, methyl, ethyl, or propyl.

[0286] In some embodiments, G is pyridine or pyrazine, n is 1, and R 1 is fluorine, chlorine, methyl, or methoxy, p is 1, and R 2 is -CHOH, v is 0, u is 1, q is 1, and R 7 is fluorine and R 3 is selected from cyclopropyl, methyl, ethyl, or propyl.

[0287] According to some embodiments, the compound of formula (XXXII), (XXXIII), or any variation thereof, has the structure of general formula (XXVIV), (XXXIV), or (XXVV): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer, or physiologically functional derivative thereof, wherein G, R 1 , R 3 , R 7 , R 8 , n and u, v are as defined herein above.

[0288] According to some aspects, the present disclosure provides a compound having the general formula (XXXXIII): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer, or physiologically functional derivative thereof, In the formula, X A , X B , X C , X D , and X E are each selected from N or CH, and XF is C; R 1 halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, C1-C3 haloalkyl, -N(R a )(R b ) and R a and R b are each independently H, C1-C6 alkyl, R 2 and R 6 are each independently selected from the other: -CHOH, cyano, nitro, hydroxy, hydroxyalkyl, -NH, halo, aryl, -N(R a )(R b ), -C(O)OH, -CHR c , -CO2R c , or -C(O)N(Ra )(R b ) and R 3 and R 7 are independently selected from halo, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; Provided is a compound, or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer, or physiologically functional derivative thereof, wherein n is 0, 1, or 2, u is 0, 1, or 2, and v is 0, 1, or 2.

[0289] In some embodiments, R 1 is halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, C1-C3 haloalkyl, cyano, ether, -N(R a )(R b ), -C(O)R c Selected from R a and R b are each independently H, C1-C6 alkyl, and R c is H or C1-C6 alkyl.

[0290] In some other embodiments, R 1 is halo, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, C1-C3 haloalkyl, ether, -N(R a )(R b ) and R a and R b Each of is independently H, C1-C6 alkyl.

[0291] In some further embodiments, R 1 is at least one of fluorine, chlorine, methyl, methoxy, hydroxy, methylamine, diethyl ether, or CF3.

[0292] In some embodiments, R 1 is fluorine.

[0293] In some other embodiments, R1 is methyl.

[0294] In some further embodiments, R 1 is methoxy.

[0295] In some embodiments, n is 0.

[0296] In some embodiments, n is 1 or 2.

[0297] In some embodiments, n is 1 or 2 and R 1 is selected from fluorine, chlorine, methyl, methoxy, hydroxy, methylamine, or CF3.

[0298] In some embodiments, n is 2 and R 1 is at least one of fluorine, chlorine, methyl, methoxy, hydroxy, methylamine, or CF3.

[0299] In some embodiments, n is 2 and R 1 is at least one of methyl and hydroxy.

[0300] In some embodiments, n is 1 and R 1 is fluorine.

[0301] In some embodiments, R 2 is -CH2OH, cyano, nitro, hydroxy, hydroxyalkyl, -NH2, halo, aryl, -N(R a )(R b ), -C(O)OH, -CHR c , -CO2R c , or -C(O)N(R a )(R b ) is selected.

[0302] In some embodiments, R 2 is selected from hydroxyalkyl and halo.

[0303] In some embodiments, R 2 is hydroxyalkyl.

[0304] In some embodiments, R 2 is -CH2OH (hydroxymethyl).

[0305] In some embodiments, p is 0.

[0306] In some embodiments, p is 1 or 2.

[0307] In some embodiments, p is 1 or 2 and R 2 is -CH2OH (hydroxymethyl).

[0308] In some embodiments, p is 1 or 2 and R 2 is at least one of —CH2OH and fluorine.

[0309] In some embodiments, p is 1, v is 1, and R 2 is hydroxyalkyl, and R 6 is a halo.

[0310] In some embodiments, p is 1, v is 1, and R 2 is -CHOH, and R 6 is fluorine.

[0311] In some embodiments, R 3 is selected from halo, C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl.

[0312] In some embodiments, R 3 is selected from fluorine, cyclopropyl, methyl, ethyl, or propyl.

[0313] In some embodiments, R3 is selected from methyl, ethyl, or propyl.

[0314] In some embodiments, R 3 is cyclopropyl.

[0315] In some embodiments, R 3 is methoxy or ethoxy.

[0316] In some embodiments, R 3 is cyclopropyl and fluorine.

[0317] In some embodiments, q is 1 or 2.

[0318] In some embodiments, q is 1 or 2 and R 3 is halo, C1-C6 alkyl, It is at least one of C1 to C6 alkoxy, or C3 to C8 cycloalkyl.

[0319] In some embodiments, q is 1, u is 1, and R 3 is at least one of halo, C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl, and R 7 is a halo.

[0320] In some embodiments, q is 1, u is 1, and R 3 is at least one of cyclopropyl, methyl, ethyl, or propyl, and R 7 is fluorine.

[0321] In some embodiments, a) X A is N and X B , X C , X D , X E is CH and X F is C; b) X B is N and X A , XC , X D , X E is CH and X F is C;c)X C is N and X A , X B , X D , X E is CH and X F is C; or d) X A , X D is N and X B , X C , X E is CH and X F is C.

[0322] In some embodiments, the compound of formula (XXXXIII) has the general formula (XXXV) or (XXXVI): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer, or physiologically functional derivative thereof.

[0323] In some embodiments, a compound having the structure of general formula (XXVVI) or (XXXV): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer, or physiologically functional derivative thereof.

[0324] In some embodiments, a) X A is N and X B and X C are both CH; b) X B is N and X A and X C are both CH; or c) X C is N and X A and X B are both CH.

[0325] In some embodiments, n is 1 and v is 0.

[0326] In some embodiments, R 3 is halo, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl.

[0327] In some embodiments, R 3 is fluorine, cyclopropyl, methyl, ethyl, or propyl.

[0328] In some embodiments, R 3 is methyl, ethyl, or propyl.

[0329] In some embodiments, R 3 is cyclopropyl.

[0330] In some embodiments, R 3 is methoxy, ethoxy.

[0331] In some embodiments, R 3 is C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl.

[0332] In some other embodiments, R 3 is cyclopropyl and R 1 is F.

[0333] According to some embodiments, the compound has a structure of a general formula selected from (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), or (XXXXII). [ka]

[0334] In some embodiments, R 7is halo, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl; and u is 0, 1, or 2.

[0335] In some embodiments, R 7 is fluorine, cyclopropyl, methyl, ethyl, or propyl.

[0336] In some embodiments, u is 1 and R 7 is fluorine, cyclopropyl, methyl, ethyl, or propyl.

[0337] In some embodiments, u is 1 and R 7 is fluorine.

[0338] In some embodiments, a compound having a structure of a general formula selected from (XXXVIIa), (XXXVIIIa), (XXXIXa), (XXXXa), (XXXXIa), or (XXXXIIa): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer, or physiologically functional derivative thereof, wherein R 1 is as described above. According to some embodiments, the compounds of the present invention include mixtures of enantiomers (possibly as racemic mixtures), as well as purified enantiomers or enantiomerically enriched mixtures. The present invention also encompasses the individual enantiomer(s) (i.e., R or S) of the compounds represented by the above formula, as racemic mixtures.

[0339] Methods for preparing substantially isomerically pure compounds are known in the art. For example, if a specific enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, and the resulting diastereomeric mixture can be separated and the auxiliary cleaved to obtain the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, a diastereomeric salt can be formed with an appropriate optically active acid or base, and then the diastereomers thus formed can be resolved by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomer. Alternatively, enantiomerically enriched mixtures and pure enantiomer compounds can be prepared by using enantiomerically pure synthetic intermediates in combination with reactions that do not change or completely invert the stereochemistry at the chiral center. 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 well within the ability of one skilled in the art. Generally, Furniss et al. (eds.), Vogel's Encyclopedia of Practical Organic Chemistry 5 th Ed., Longman Scientific and Technical Ltd., Essex, 1991, pp. 809-816; and Heller, Acc. Chem. Res. 23:128 (1990).

[0340] Unless otherwise indicated, it should be clear that when referring to a compound having a chiral atom, a reference is made to a racemic mixture of the compound. As will be understood, chirality may be indicated by the chemical structure of the compound or the structural name of the compound.

[0341] A racemic mixture, also called a racemate, is used to describe equal amounts of levorotatory and dextrorotatory enantiomers in a chiral compound, i.e., the compound contains a mixture of 50% levorotatory and 50% dextrorotatory enantiomers.

[0342] As used herein, the term "stereoisomer" is intended to encompass isomers that have identical structure as a corresponding stereoisomer, but that differ from the corresponding stereoisomer in the arrangement of the atoms in space.

[0343] Some of the compounds described herein may contain one or more chiral atoms or may otherwise be capable of existing as two enantiomers or two or more diastereomers. Thus, the compounds of the present invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Furthermore, the compounds of the present invention include mixtures of diastereomers as well as purified stereoisomers or diastereomerically enriched mixtures. Also included within the scope of the present invention are the individual isomers of the compounds of the present invention as defined above, and their complete or partial mixtures. The present invention also encompasses the individual isomers of the compounds represented by the above formulas as mixtures with their isomers in which one or more chiral centers are inverted.

[0344] In some embodiments, the compounds of the invention comprise an enantiomer of at least 60% chiral purity.

[0345] In some embodiments, the compounds of the invention comprise an enantiomer of at least 70% chiral purity.

[0346] In some embodiments, the compounds of the invention comprise an enantiomer of at least 80% chiral purity.

[0347] In some embodiments, the compounds of the invention comprise an enantiomer of at least 90% chiral purity.

[0348] In some embodiments, the compounds of the invention comprise an enantiomer of at least 95% chiral purity.

[0349] In some embodiments, the compounds of the invention comprise an enantiomer of at least 98% chiral purity.

[0350] In some embodiments, the compounds of the invention comprise an enantiomer of at least 99% chiral purity.

[0351] The terms "enantiomerically pure," "enantiomeric purity," "chiral purity," and "chirally pure" are used interchangeably to reflect the fact that a given enantiomer is found in a composition in greater proportion than its mirror image. The ratio between two enantiomers is expressed in terms of the absolute proportion of one enantiomer, which may be at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, and at least 99%, or more.

[0352] Enantiomeric purity can be determined by tests of the type known in the art. Typically, chiral purity of enantiomers according to the present disclosure is determined by analytical chiral HPLC.

[0353] In some embodiments, the compounds of the invention, e.g., compounds represented by Formulae (I)-(XXXXIII), comprise an enantiomer of at least 70% chiral purity, optionally an enantiomer of at least 80% chiral purity, optionally an enantiomer of at least 90% chiral purity, optionally an enantiomer of at least 95% chiral purity, optionally an enantiomer of at least 98% chiral purity, optionally an enantiomer of at least 99% chiral purity.

[0354] According to some aspects, which can be considered embodiments of the present invention, the present disclosure provides compounds having a general formula selected from the following: [ka] [ka] [ka] where the substitutions are as defined in the parent formula (without the ').

[0355] In some embodiments, specific examples of compounds of Formulas I-XXXXIII, or pharmaceutically acceptable salts or hydrates thereof, or any stereoisomer thereof, include, but are not limited to, the compounds in Table 2 designated as 2-29, 2-30, 2-51, 2-53, 2-56, 2-57, 2-67, 2-72, or 2-77. Specifically, the compounds of the present invention are provided by formula (XXXII), (XXXIII), (XXVIV), (XXXIV), (XXVV), (XXXV), (XXXVI), (XXVVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), (XXXXII), or (XXXIII), as detailed in Tables 2 and 4.

[0356] According to some aspects, the present invention provides a compound selected from the list below. [ka] [ka] [ka]

[0357] According to some embodiments, the compounds of the present invention do not include at least one compound designated 2-68 or 2-70 in Table 2.

[0358] According to some embodiments, the compounds of the present invention do not include at least one compound designated 2-41, 2-45, 2-61, 2-63, 2-71, 2-75, 2-78, 2-80, 2-81, 2-82, 2-95, 2-104, 2-110, or 2-111 in Table 2.

[0359] In compounds of the present disclosure in which a variable occurs more than once, each variable may be a different moiety selected from the Markush group defining the variable. For example, if a structure is described having two R groups co-occurring on the same compound, the two R groups may correspond to different moieties selected from the Markush group defined for R.

[0360] It will be further understood that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0361] As used herein, "acyl" refers to the group (C1-C6 alkyl)-C(O)-.

[0362] As used herein, "alkyl," by itself or as part of another substituent, means, unless otherwise stated, straight or branched chain, optionally having a specified number of carbon atoms (i.e., C1-C6 means 1 to 6 carbons). Examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, and homologs and isomers of, e.g., n-pentyl, n-hexyl, and the like. Unless stated otherwise in the specification, alkyl groups are optionally and independently selected from the following: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, -OR ... a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t N(R a )2 (t is 1 or 2), or PO3(R a )2(each R a are independently hydrogen or alkyl).

[0363] As used herein, "alkenyl" can be a straight or branched hydrocarbon chain containing at least one double bond and having 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). Examples of alkenyl groups include, but are not limited to, groups such as ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, and penta-1,4-dienyl. Unless otherwise stated in the specification, alkenyl groups are optional and can independently be one of the following: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, -OR ... a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t N(R a )2 (t is 1 or 2), or PO3(R a )2(each R a are independently hydrogen or alkyl).

[0364] As used herein, "alkoxy" can be a straight-chain or branched alkoxy group having 1 to 6 carbon atoms (i.e., C1-C6 alkoxy). Examples of alkoxy groups include, but are not limited to, groups such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy, pentyloxy, or hexyloxy. Unless otherwise stated in the specification, alkoxy groups are optional and can independently be one of the following: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t N(R a )2 (t is 1 or 2), or PO3(R a )2(each R a are independently hydrogen or alkyl).

[0365] As used herein, "alkynyl" can be a straight or branched hydrocarbon chain containing at least one triple bond and having 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). Examples of alkynyl groups include, but are not limited to, groups such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl. Unless stated otherwise in the specification, alkynyl groups are optionally and independently selected from the following: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, -OR, -O- ... a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t N(R a )2 (t is 1 or 2), or PO3(R a )2(each R a are independently hydrogen or alkyl).

[0366] As used herein, an "amide" or "amido" refers to a group of the formula -C(O)NR a -or-NRa C(O)-(wherein, R a refers to a chemical moiety having a carbon atom (which is H or C1-C6 alkyl).

[0367] As used herein, "amino" or "amine" refers to the -NH2 radical group.

[0368] As used herein, "alkylamino" refers to a group of the formula --NH(alkyl), where the alkyl groups each have 1 to 6 carbons.

[0369] As used herein, the term "dialkylamino" refers to a group of formula -N(alkyl)2, where the two alkyl groups each independently have from 1 to 6 carbons.

[0370] As used herein, "aryl" refers to a polyunsaturated, aromatic hydrocarbon moiety, which may be a single ring or multiple rings (e.g., 1-2 rings) fused or covalently linked together, and has 6 to 12 carbon atoms (i.e., C6-C8). 12 aryl). Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, and 4-biphenyl. Unless otherwise stated in the specification, aryl moieties are optionally and independently selected from the following: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(Ra )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t N(R a )2 (t is 1 or 2), or PO3(R a )2(each R a are independently hydrogen or alkyl).

[0371] As used herein, "arylalkyl" refers to an (aryl)alkyl radical in which the aryl and alkyl portions are as disclosed herein.

[0372] As used herein, "aryloxy" refers to --O-(aryl), where the heteroaryl moiety is as defined herein.

[0373] As used herein, "arylalkoxy" refers to --O-(arylalkyl), where the heteroaryl moiety is as defined herein.

[0374] As used herein, "carboxyl" refers to the --(C.dbd.O)OH radical.

[0375] As used herein, "cyano" refers to the -CN radical.

[0376] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic radical containing only carbon and hydrogen, and may be saturated or partially unsaturated. Cycloalkyl groups include groups having 3 to 12 ring atoms (i.e., C3 to C6 10Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like. Unless stated otherwise in the specification, cycloalkyl groups are optionally and independently selected from the following: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t N(R a )2 (t is 1 or 2), or PO3(R a )2(each R a are independently hydrogen or alkyl).

[0377] As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic radical containing only carbon and hydrogen and that is partially unsaturated (e.g., the monocyclic or polycyclic radical contains one or more double bonds). Cycloalkenyl groups include groups having 3 to 12 ring atoms (i.e., C3 to C6 12 Examples of cycloalkenyl groups include, but are not limited to, groups such as cyclopentenyl, cyclohexenyl, and cycloheptenyl. Unless stated otherwise in the specification, cycloalkenyl groups are optionally and independently selected from the following: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, -OR, -OR, -OR- ... a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t N(R a )2 (t is 1 or 2), or PO3(R a )2(each R a are independently hydrogen or alkyl).

[0378] As used herein, "C3-C7 cycloalkyloxy" refers to -O-(C3-C7 cycloalkyl), where the C3-C7 cycloalkyl moiety is as defined herein.

[0379] As used herein, the terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. The term "halide," by itself or as part of another substituent, refers to a fluoride, chloride, bromide, or iodide atom.

[0380] As used herein, "haloalkyl" and "haloalkoxy" can include alkyl and alkoxy structures substituted with one or more halo groups or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, where halo is fluorine. Unless otherwise stated in the specification, haloalkyl groups are optionally and independently selected from the following: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, -OR, -OR, -OR- ... a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t Ra (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t N(R a )2 (t is 1 or 2), or PO3(R a )2(each R a are independently hydrogen or alkyl).

[0381] As used herein, "heteroalkyl" can include optionally substituted alkyls having one or more skeletal chain atoms selected from atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Numerical ranges may be provided, such as C1-C6 heteroalkyl, which refers to the number of carbon atoms in the chain, in this example, 1 to 6 carbon atoms. For example, the radical -CH2OCH2CH3 is referred to as a "C3" heteroalkyl. Connection to the remainder of the molecule is through either a heteroatom or a carbon within the heteroalkyl chain. Unless otherwise stated in the specification, heteroalkyl groups are optionally and independently selected from the following: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a)S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t N(R a )2 (t is 1 or 2), or PO3(R a )2(each R a are independently hydrogen or alkyl).

[0382] As used herein, "heteroaryl" refers to a 3- to 12-membered aromatic radical (e.g., C3-C6) that contains one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur and may be a monocyclic or bicyclic ring system. 12"Heteroaryl" refers to a heteroaryl group. Divalent radicals derived from monovalent heteroaryl radicals whose names end in "-yl" by removing a hydrogen atom from the atom with the free valence are named by adding "-idene" to the name of the corresponding monovalent radical (e.g., a pyridyl group with two points of attachment is a pyridylidene). An N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. Polycyclic heteroaryl groups can be fused or unfused. The heteroatom(s) in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (furanyl), quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, etc. Unless stated otherwise in the specification, a heteroaryl moiety is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, ═O, ═S, —OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )S(O)t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t N(R a )2 (t is 1 or 2), or PO3(R a )2, where each R a are independently hydrogen or alkyl.

[0383] As used herein, "heteroaryloxy" refers to --O-(heteroaryl), where the heteroaryl moiety is as defined herein.

[0384] As used herein, "heterocycloalkyl" can be a stable 3- to 12-membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of heterocycloalkyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, and the like. Unless stated otherwise in the specification, a heterocycloalkyl moiety is optionally substituted by one or more substituents, which substituents are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, ═O, ═S, —OR a , -SR a , -OC(O)-R a , -N(Ra )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t N(R a )2 (t is 1 or 2), or PO3(R a )2, where each R a are independently hydrogen or alkyl.

[0385] As used herein, "hydroxy" or "hydroxyl" refers to --OH.

[0386] As used herein, "hydroxyalkyl" refers to an alkyl group having 1 to 6 carbon atoms substituted with a hydroxyl group (eg, hydroxypropyl).

[0387] As used herein, "nitro" refers to --NO.sub.2.

[0388] As used herein, "oxo" refers to =O.

[0389] As used herein, "urea" refers to -NR a -C(O)-NR a 2 or -NR a -C(O)NR a -(In the formula, R a refers to H or C1-C6 alkyl).

[0390] As used herein, "sulfonylurea" refers to -S(O)2-NR a -C(O)-NR a -or-NRa -C(O)-NR a -SO2-(wherein, R a refers to H or C1-C6 alkyl (eg, a C1-C6 alkyl group as described herein).

[0391] As used herein, "sulfonamidyl" refers to -S(O)2-NR a -or-NR a -S(O) 2- (In the formula, R a refers to H or C1-C6 alkyl (eg, a C1-C6 alkyl group as described herein).

[0392] In the context of this disclosure, and as described herein, a reference to a compound of any one of Formulas I-XXXXIII, e.g., a compound of formula (XXXII), (XXXIII), (XXVIV), (XXXIV), (XXVV), (XXXV), (XXXVI), (XXVVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), (XXXXII), or (XXXIII), includes solvates, hydrates, pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of that compound, or any variations detailed herein.

[0393] The term "solvate" refers to an aggregate of a molecule with one or more solvent molecules (eg, hydrates, alcoholates (aggregates or adducts with alcohols)).

[0394] The term "hydrate" refers to a compound formed by adding water. Hydrates can be obtained by dissolving the compound in water and recrystallizing it by any method known in the art to incorporate water into the crystal structure.

[0395] A "pharmaceutically acceptable prodrug" is a compound that can be converted under physiological conditions into a specified compound or a pharmaceutically acceptable salt of such compound.

[0396] As used herein, the term "physiologically functional derivative" refers to any physiologically acceptable derivative of the compounds described herein. Physiologically functional derivatives also include prodrugs of the compounds of the present invention. Such prodrugs can be metabolized in vivo to give the compounds of the present invention. These prodrugs may or may not be active themselves, and are also objects of the present invention.

[0397] The term "pharmaceutically acceptable salts" refers to salts derived from organic and inorganic acids of the compounds described herein. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, naphthalenesulfonate, propionate, succinate, fumarate, maleate, malonate, mandelate, malate, phthalate, and pamoate. As used herein, the term "pharmaceutically acceptable salt" also refers to a salt of a compound described herein having an acidic functional group (e.g., a carboxylic acid functional group) and a base. Exemplary bases include, but are not limited to, hydroxides of alkali metals (including sodium, potassium, and lithium); hydroxides of alkaline earth metals (e.g., calcium and magnesium); hydroxides of other metals (e.g., aluminum and zinc); ammonia; organic amines, such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(C1-C6)-alkylamines), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids (e.g., arginine, lysine, etc.). The term "pharmaceutically acceptable salts" also includes hydrates of the salts of the compounds described herein.

[0398] In a further aspect, the present invention relates to a composition comprising an effective amount of at least one compound having the general formula (I)-(XXXXIII), or a pharmaceutically acceptable salt or hydrate thereof (including any stereoisomer thereof), or any vehicle, matrix, nano- or microparticle comprising same.

[0399] In more specific embodiments, the composition comprises an effective amount of at least one compound having formula (XXXII), (XXXIII), (XXVIV), (XXXIV), (XXVV), (XXXV), (XXXVI), (XXVVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), (XXXXII), or (XXXXIII).

[0400] According to some embodiments, the composition is a pharmaceutical composition.

[0401] In some embodiments, the compositions of the present invention can optionally further comprise at least one of pharmaceutically acceptable carrier(s), excipient(s), additive(s), diluent(s), and adjuvant(s). As used herein, "pharmaceutically acceptable carrier" includes any solvent, dispersion medium, coating, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.

[0402] In some other embodiments, the pharmaceutical composition may include a vehicle, matrix, nano- or microparticles.

[0403] The compounds of the present invention or compositions containing the compounds may be useful in a variety of applications.

[0404] In particular, the compounds described herein are useful for affecting multiple physiological / biological processes and are selected for treatment based on various parameters, including, among other things, the disorder to be treated or the severity of the disorder, or the route of administration of the compound. For example, these parameters may be determined by diagnosis of the disorder and its severity prior to administering treatment.

[0405] Thus, the compounds of the invention may be for use in treating diseases treatable by such compounds.

[0406] Specifically, as shown in the following examples, for example, Example 1 showing the results of a patch clamp experiment, the compounds of the present disclosure inhibit the flow of ions, particularly cations (e.g., calcium ions (Ca)) in cation channels (e.g., transient receptor potential cation channel subfamily V member 3 (TRPV3)). +2 )) flow. In other words, compounds of the present disclosure have been shown to inhibit TRPV3 activity.

[0407] TRPV3 is provided according to some embodiments by protein accession number Q8NET8.

[0408] In still further embodiments, the present invention provides cation channels, specifically Ca +2

[0023] Provided is a composition comprising an effective amount of any of the compounds of the invention described above, or any vehicle, matrix, nano- or microparticle comprising same, for use in a method of modulating the activity of a channel, more particularly TRPV3, specifically, for example, any one of the compounds of Formulas I-XXXXIII, e.g., any one of the compounds of Formula (XXXII), (XXXIII), (XXVIV), (XXXIV), (XXVV), (XXXV), (XXXVI), (XXVVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), (XXXXII), or (XXXXIII), and a compound designated Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound I, or Compound J as described herein, and any analog or derivative thereof (including any stereoisomer or salt thereof).

[0409] In some embodiments, the compositions of the present invention target cation channels, specifically Ca +2 It is used to inhibit the activity of channels, more specifically TRPV3.

[0410] Thus, the present disclosure also provides, according to some embodiments, at least one compound of Formula I-XXXXIII as a TRPV3 antagonist.

[0411] Specifically, the present invention provides compounds for use as TRPV3 antagonists, specifically compounds defined by Formulas I-XXXXIII. Accordingly, compounds of any of the above structures can be used to inhibit the activity of TRPV3 in vitro or in vivo and / or can be used in the manufacture of a medicament for inhibiting the activity of TRPV3 in vitro or in vivo.

[0412] In some embodiments, compounds according to the present disclosure having any of the above structures can be considered TRPV3 inhibitors. In some embodiments, compounds according to the present disclosure having any of the above structures can be used as TRPV3 antagonists.

[0413] The terms "antagonist" and "inhibitor" are used interchangeably to refer to an agent that reduces or suppresses biological activity (e.g., suppresses the activity of an ion channel such as TRPV3). Thus, compounds of the invention that may be TRPV3 inhibitors can be used to inhibit the activity of TRPV3 and / or can be used in the manufacture of a medicament for inhibiting the activity of TRPV3 in vitro or in vivo.

[0414] In still further embodiments, the present invention provides a composition comprising any of the compounds of the present invention described above, or any vehicle, matrix, nano- or microparticle comprising same, e.g., any one of the compounds of Formulas I-XXXXIII, e.g., any one of the compounds of Formula (XXXII), (XXXIII), (XXVIV), (XXXIV), (XXVV), (XXXV), (XXXVI), (XXVVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), (XXXXII), or (XXXXIII), and an effective amount of a compound designated Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound I, or Compound J, and any analog or derivative thereof (including any stereoisomer or salt thereof) described herein, for use in a method for treating, preventing, suppressing, reducing, eliminating, protecting against, or delaying the onset of a TRPV3-mediated disorder in a subject in need thereof.

[0415] As used herein, the term TRPV3-mediated disorder refers to a disease / disorder / condition that involves activation of TRPV3. TRPV3 function has been linked to multiple physiological processes, including, inter alia, skin disorders and pain reception and transmission.

[0416] In some embodiments, the TRPV3-mediated disorder is related to at least one mutation in the gene encoding TRVP3. In some other embodiments, the TRPV3-mediated disorder is related to increased activation of TRVP3.

[0417] In some embodiments, the TRPV3-mediated disorder is selected from the following group: acute and / or chronic pain, tactile hypersensitivity, burns, inflammation, diabetic neuropathy, psoriasis, eczema, dermatitis, post-herpetic neuralgia (shingles), migraine, urinary incontinence, fever, hot flashes, osteoarthritis, oral mucositis, cancer pain, cystitis, pain associated with Crohn's disease and irritable bowel syndrome (IBS), rheumatoid arthritis, Grierson-Gopalan syndrome (better known as burning legs syndrome), burning mouth syndrome (BMS), and cough.

[0418] According to some aspects, the present disclosure provides a compound or pharmaceutical composition comprising an effective amount of any of the compounds of the present invention described above, or any vehicle, matrix, nano- or microparticle comprising same, for use in treating, preventing, suppressing, reducing, eliminating, protecting against, or delaying the onset of a skin disorder in a subject in need thereof. Specifically, the disclosure provides a pharmaceutical composition comprising any one of the compounds of Formulas I-XXXXIII, e.g., any one of the compounds of Formula (XXXII), (XXXIII), (XXVIV), (XXXIV), (XXVV), (XXXV), (XXXVI), (XXVVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), (XXXXII), or (XXXXIII), and a compound designated as Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound I, or Compound J described herein, or any analog or derivative thereof, including any stereoisomer or salt thereof, for use in a method for treating, preventing, suppressing, reducing, eliminating, protecting against, or delaying the onset of a skin disorder in a subject in need thereof.

[0419] The compounds of the invention can be administered in combination with a second active agent.

[0420] As described herein, the function of TRPV3 has been implicated in the reception and transmission of skin abnormalities. Specifically, calcium influx across the plasma membrane of skin cells is a critical signaling element involved in epidermal cell differentiation (Dotto, 1999 Crit Rev Oral Biol Med 10:442-457). Controlling or regulating calcium entry pathways, a critical control point in skin cell growth, can treat or prevent skin diseases or disorders characterized by epidermal hyperplasia (a condition in which skin cells proliferate excessively rapidly and differentiate poorly). Such diseases include psoriasis and basal and squamous cell carcinoma. Psoriasis is estimated to affect up to 7 million Americans, and sufferers experience mild to severe discomfort, increased susceptibility to secondary infections, and psychological effects due to disfigurement of the affected areas (Lebwohl and Ali, 2001 J Am Acad Dermatol 45:487-498). Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin represent at least one-third of all cancers diagnosed in the United States each year. More than one million new cases are reported annually, and incidence rates are on the rise. Despite being a relatively indolent, slow-growing cancer, BCC can be significantly destructive and disfiguring to local tissue. SCC is more aggressive and therefore leads to even greater complications. Furthermore, with 80% of lesions occurring on the head and neck and 15% on the shoulders, back, and chest, BCC and SCC of the skin can significantly impact a patient's appearance and quality of life.

[0421] As used herein, a skin condition refers to any disease / disorder / condition that affects the skin. As understood, skin is a typically soft, flexible outer layer of tissue covering the body of vertebrates, with three main functions: protection, regulation, and sensation. Mammalian skin is composed of three main layers: the epidermis, the dermis, and the subcutaneous tissue. The epidermis is the outermost layer of the skin and forms a protective barrier over the body's surface, responsible for retaining moisture and preventing pathogen invasion. The epidermis is composed of a basal proliferative layer, differentiated suprabasal and spinous layers, a granular, terminally differentiated keratinocyte layer, and stratified squamous epithelium. The majority of the epidermis (approximately 95%) is composed of keratinocytes.

[0422] Skin disorders according to the present disclosure may be characterized by having one or more skin irregularities, which may include at least one of the following symptoms: raised bumps, rashes, itching, scaling (rough skin), peeling skin, ulcers, open sores or lesions, dryness, cracked skin, patches of discolored skin, fleshy bumps, warts (or other skin growths), changes in color or size of moles, loss of skin pigment, inflammation, or excessive redness.

[0423] The compounds of the present invention may have a variety of clinical, cosmetic, in vitro, and in vivo applications related to skin disorders / diseases / disorders or diseases having at least one symptom as detailed herein above.

[0424] As shown in the Examples below, the compounds of the present invention have been shown to be effective in normalizing skin structure, skin cell differentiation, and barrier function, suggesting that the compounds of the present invention can be used to treat skin diseases.

[0425] For example, as shown in Example 12 below, which provides results from an engineered CRISPR-Cas9 ABCA12 KO equivalent (3D model), selective inhibition by KM-001 dose-dependently restored skin structure and barrier function. In addition, KM-001 dose-dependently normalized keratin 10 expression.

[0426] In addition, as shown in Example 16 below, KM-001 was shown to normalize epidermal differentiation and reduce inflammation in the DS-Nh TRPV3 mutant genetic model.

[0427] Furthermore, as shown in Example 17 below, pretreatment with any oral dose of KM-023 reduced the number of scratches observed 30 minutes after induction.

[0428] Thus, the present disclosure encompasses any disease / disorder / condition associated with any part / segment of the skin. The term skin disorder may be used interchangeably with the term dermatological disorder.

[0429] As used herein, skin diseases include congenital (genetic) skin diseases or acquired skin diseases. In some embodiments, the skin disease is a chronic disease. In some embodiments, the skin disorder is one or more of the following: keratoderma, ichthyosis, epidermolysis bullosa, pachyonychia congenita, pruritus (itching), dry skin (xerosis), eczema (including atopic dermatitis), or burns.

[0430] In some embodiments, the skin disorder is related to improper skin differentiation.

[0431] Inappropriate skin differentiation is related to a disruption of the differentiation process that tends to affect one or more of the skin epidermal layers: the basal layer, the spinous layer, the granular layer, or the stratum corneum. +2 It can be attributed to a variety of functional mechanisms, including dysregulation, keratin distortion, inflammation, and collagen disruption. Inappropriate skin differentiation can result in one or more of hyperkeratosis, acanthosis, inflammation, or dysregulation of barrier function.

[0432] In some embodiments, the skin disease associated with improper skin differentiation comprises keratoderma, ichthyosis, or a combination thereof.

[0433] Normalization of skin differentiation may lead to reduced inflammation and barrier reconstitution, suggesting that it may play a role as an important regulator in the treatment of such diseases.

[0434] In some embodiments, the skin disorder is keratoderma.

[0435] The term keratosis, especially palmoplantar keratosis (also known as keratosis palmaris et plantaris), refers to a disease / disorder characterized by thickening of the skin, especially of the palms and soles of the feet.

[0436] In some embodiments, the keratoderma is at least one of diffuse keratoderma, focal keratoderma, or punctate keratoderma.

[0437] Diffuse keratoderma often affects the palms and soles of the hands and feet, focal keratoderma often affects mainly pressure areas, while punctate keratoderma typically produces small bumps on the palms and soles of the hands and feet.

[0438] In some embodiments, the keratoderma is a congenital (hereditary) keratoderma. Hereditary keratodermas can be caused by genetic abnormalities, for example, that result in abnormal skin proteins (keratins).

[0439] In some embodiments, the hereditary palmoplantar keratoderma (PPK) is at least one of diffuse hereditary palmoplantar keratoderma, focal hereditary palmoplantar keratoderma, and punctate palmoplantar keratoderma.

[0440] In some embodiments, the diffuse hereditary palmoplantar keratoderma is selected from the group consisting of segmental palmoplantar keratoderma with perioral keratoderma (Olmsted syndrome), diffuse palmoplantar keratoderma, diffuse non-epidermolytic palmoplantar keratoderma, diffuse epidermolytic palmoplantar keratoderma (diffuse EPPK), Vorner's disease, PPK with granular degeneration (PPK cum degenerations granulose), progressive palmoplantar keratoderma (Greither's disease, PPK transgrediens et progrediens), Keratosis extremitatum hereditaria transgrediens et progrediens, and PPK Mutilans. At least one of the following: Vohwinkel (keratoderma mutilans, Vohwinkel syndrome, and palmoplantar keratoderma mutilans), palmoplantar keratoderma with sclerodactyly (hardening and thickening of the connective tissue of the fingers and toes) (Huriez syndrome), or palmoplantar keratoderma with periodontitis (inflammation of the gums) (Papillon-Lefevre syndrome).

[0441] Diffuse palmoplantar keratoderma is a type of palmoplantar keratoderma characterized by uniform, thick, symmetric hyperkeratosis over the palms and soles, which is usually apparent at birth or within the first few months of life.

[0442] Diffuse non-epidermolytic palmoplantar keratoderma is an autosomal dominant condition caused by K1 and K16 keratins. Clinical features usually appear within the first two years of life. Additional features include widespread thickened skin (keratinized epithelium) over the palms and soles, red bands at the edges of the keratinized epithelium, other keratinized epithelial lesions, excessive sweating, and sometimes thickened nails.

[0443] Diffuse epidermolytic palmoplantar keratoderma (diffuse EPPK, Vorner's disease, PPK with granular degeneration) is the most common type of hereditary PPK. It is inherited in an autosomal dominant manner and is caused by the KRT9 keratin. Clinical features usually appear within the first year of life. It is similar to diffuse non-epidermolytic PPK, but the skin is more fragile and may develop blisters.

[0444] Progressive palmoplantar keratoderma (Greither's disease, PPK transgrediens et progrediens) is transmitted by autosomal dominant inheritance. Clinical features usually appear between the ages of 8 and 10 years. Extensive thickening of the skin extends from the palms and soles of the feet to the dorsum of the hands and feet and down to the Achilles tendon (sole of the heel). Excessive sweating is common, and signs and symptoms vary among affected family members. Signs and symptoms tend to worsen during childhood, plateau after adolescence, and improve in middle age.

[0445] Diffuse hereditary PPK with associated features typically involves the extrapalmoplantar skin in several hereditary keratinization disorders.

[0446] Meleda disease (keratosis extremitatum hereditaria transgrediens et progrediens) is a rare disorder affecting approximately 1 in 100,000 people. It was first observed in residents of the Adriatic island of Meleda (Mljet). Meleda disease is transmitted by autosomal recessive inheritance. Clinical features of the disorder usually manifest in early infancy. Palmoplantar keratoderma is often the only finding. Widespread areas of thickened, red skin with prominent edges are present over the dorsum of the hands and feet. Widespread hyperkeratosis of the hands and feet may resemble gloves or stockings. Constriction rings on the fingers and toes (leading to spontaneous amputation) have been reported. Some individuals have well-defined psoriasiform plaques or lichenoid patches (small, firm lesions close together) on the knees and elbows. Excessive sweating. Redness and thickening of the periorbital skin. Nail changes. Associated features include a prominent tongue, padding of the fingers or toes, hair growth on the palms or soles of the feet, a high-arched palate (roof of the mouth), and left-handedness.

[0447] PPK Mutilans Vohwinkel (keratoderma mutilans, Vohwinkel syndrome, and palmoplantar keratoderma mutilans) is a rare disorder transmitted by autosomal dominant or autosomal recessive inheritance. Genetic defects are caused by the GJB2 gene and connexin 26. Clinical features usually appear in infancy. In infancy, it manifests as honeycomb-like thickening of the skin on the palms and soles of the feet. Later, fibrous constriction rings form on the fingers and toes, leading to progressive strangulation and spontaneous amputation. The skin on the tops of the fingers and knees may thicken in a starfish-like pattern. Patients with this condition are also affected by hair loss, hearing loss, muscle spasm damage, myopia, scaly skin, and nail abnormalities.

[0448] Segmental palmoplantar keratoderma with perioral keratotic plaques (Olmsted syndrome) is a rare disorder transmitted by autosomal dominant inheritance. Clinical features usually appear within the first year of life: symmetric, sharply demarcated palmoplantar keratodermas surrounded by reddish skin and joint deformities leading to strangulation and spontaneous amputation; keratinous growths around the eyes and mouth; nail abnormalities; white, thickened patches on the skin around the anus and inside the mouth; and sparse hair.

[0449] Palmar-plantar keratoderma with sclerodactyly (hardening and thickening of the connective tissue of the fingers and toes) (Huriez syndrome) is a rare disorder transmitted by autosomal dominant inheritance. Clinical symptoms are recognizable in infancy. Sclerodactyly: Scleroderma, or hardening and thickening of the connective tissue of the fingers and toes. Widespread skin thickening is more pronounced on the soles than on the palms. Nail abnormalities. Decreased sweating. Associated with squamous cell carcinoma.

[0450] Palmoplantar keratoderma with periodontitis (inflammation of the gums) (Papillon-Lefevre syndrome) is a rare disease transmitted by autosomal recessive inheritance. The disorder is caused by mutations in cathepsin C and affects males and females equally. Clinical features usually appear between the first and fifth years of life. Extensive or localized palmar-plantar skin thickening is present. Untreated, periodontitis can lead to severe gum disease and tooth loss by age five. Patients may exhibit increased susceptibility to infection. Scaly, red lesions may be observed on the knees, elbows, and knuckles. Excessive sweating and body odor are present.

[0451] In some embodiments, the keratoderma is an acquired keratoderma. Acquired keratoderma can result from a change in health or environment.

[0452] In some embodiments, the acquired keratoderma is focal keratoderma or diffuse keratoderma.

[0453] In some embodiments, the keratoderma is Olmsted syndrome.

[0454] In some embodiments, the skin disease is an ichthyosis disease.

[0455] Ichthyosis refers to a genetic disorder characterized by the persistent presence of excessive amounts of dry, superficial scale, resulting in dry, thickened, "fish-like" skin. It is considered a disorder of keratinization or keratinization and results from abnormalities in epidermal differentiation or metabolism.

[0456] Ichthyosa-like dermatitis can be classified according to clinical manifestations, genetic presentation, and histological findings. Both hereditary and acquired forms of ichthyosis have been described, and certain subtypes may involve ocular changes. There are at least 20 different types of ichthyosis. Some forms are transmitted at birth, while others are acquired during adulthood.

[0457] Genetic ichthyosis can be congenital or have a delayed onset. Genetic ichthyosis can be congenital or have a delayed onset. Ichthyosis vulgaris is inherited in an autosomal dominant manner, meaning that the abnormal gene is transmitted from one parent. Penetrance is 90%. Onset is delayed until at least three months of age. X-linked recessive ichthyosis primarily affects males, who have the abnormal gene on one X chromosome. Females are usually protected by having a normal second X chromosome. Onset can be congenital or can be delayed by up to six months. In autosomal recessive congenital ichthyosis, one abnormal gene is transmitted from each parent. Congenital ichthyosiform erythroderma (CIE) is a variant of the rare epidermal disorder autosomal recessive congenital ichthyosis (ARCI) and is characterized by fine whitish scales on a generalized erythematous underlying skin. Keratinopathy ichthyosis comes in recessive and dominant forms and is present at birth with a collodion membrane. Harlequin ichthyosis is a rare and severe form of ichthyosis in which the entire body is covered with hard, thickened, armor-like skin plates from birth. Harlequin ichthyosis is also called harlequin ichthyosis or harlequin fetus. Lamellar ichthyosis is a rare genetic condition. Infants with lamellar ichthyosis are typically born with a shiny, waxy layer of skin (called a collodion membrane), which typically peels off within the first two weeks of life. The skin beneath the collodion membrane is red and scaly. Epidermolytic ichthyosis (EI) is a rare genetic skin disorder. This disorder is manifested at birth or shortly thereafter by redness, scaling, and severe blistering of the skin. Hyperkeratosis develops within several months and worsens over time. Blistering diminishes but may still occur after skin trauma and in summer. The skin may be itchy and odorous and prone to infection. Other features may include decreased sweating, nail abnormalities, and, in severe cases, impaired growth. Superficial epidermolytic ichthyosis (SEI), formerly known as Siemens-type bullous ichthyosis (IBS), is a rare desquamating keratinization disorder. Despite being hyperkeratotic, the skin is abnormally friable, with a tendency for the outer layer of the epidermis to peel off, creating locally exposed areas.Netherton syndrome (flexural linear ichthyosis) is a rare genetic disorder characterized by scaling skin, hair abnormalities, increased susceptibility to atopic eczema (a skin condition that can result in dry, red, scaly skin), elevated IgE levels, and other associated symptoms. Netherton syndrome is transmitted as an autosomal recessive trait. Pachyonychia congenita (PC) is a group of rare autosomal dominant skin disorders caused by mutations in one of five different keratin genes. Pachyonychia congenita is often associated with thickened toenails, plantar keratoderma, and plantar pain.

[0458] Other forms of ichthyosis exist, including but not limited to Shanarin-Dorfman syndrome (neutral lipid storage disease), CHILD syndrome (unilateral hemidysplasia), These include Conradi-Hünermann syndrome (X-linked dominant chondrodysplasia punctata), Darier's disease, epidermal nevus (ichthyosis crus, linear epidermal nevus), epidermolytic keratosis (EHK), erythrokeratoderma fluctuans (EKV), Giroux-Barbeau syndrome, Hailey-Hailey disease (benign familial pemphigus), Curth-Macklin ichthyosis crus, alopecia spiculata follicular keratosis, KID syndrome (keratitis, ichthyosis, hearing loss), multiple sulfatase deficiency, peeling skin syndrome, pityriasis rubra pilaris (PRP), Refsum's disease (phytanic acid storage disease), Rudo syndrome, Sjögren-Larsson syndrome, and Tay syndrome (trichorrhexis, IBIDS syndrome).

[0459] In some embodiments, the skin disease is harlequin ichthyosis.

[0460] Ichthyosis can also result from de novo spontaneous mutations.

[0461] In some embodiments, the skin condition is an itchy sensation.

[0462] Itch sensation originates in the skin by peripheral afferent fibers of primary sensory neurons (whose cell bodies reside in the dorsal root ganglion (DRG) and trigeminal ganglion) and is transmitted to the dorsal horn of the spinal cord and then to the brain. Because of its similarity to pain, itch was once considered a submodality of pain.

[0463] TrpA1, a TRP channel that plays a key role in itch transmission, is increased in nerve fibers, keratinocytes, and tryptase-positive mast cells from lesional skin of patients with atopic dermatitis. Notably, TrpA1 expression is minimal in dermal cells of healthy skin. In addition, TrpV3 expression is also increased in lesional skin of patients with atopic dermatitis, although its role in itch is not fully understood. Elevated TrpA1 expression is also detected in post-burn pruritus. Levels of TrpA1 and two other channels (TrpV3 and TrpV4) are all higher in post-burn patients with pruritus than in post-burn patients without pruritus. Unlike TrpV1 and TrpA1, TrpV3 expression is detected primarily in keratinocytes.

[0464] Activation of TrpV3 induces the release of multiple factors, including PGE2, ATP, nitric oxide, and NGF, which can contribute to the inflammatory process of dermatitis. The Gly573 mutation in TrpV3 has been detected in spontaneously occurring hairless mutant strains, DS-Nh mice (Gly573Ser) and WBN / Kob-Ht rats (Gly573Cys). These animals develop spontaneous dermatitis phenotypes, including increased keratinocyte counts and pruritus. Transgenic mice carrying the Gly573Ser mutation mimic the dermatitis phenotype of the two spontaneously occurring rodent mutant strains, supporting the causal role of this single amino acid mutation. Recent studies have also linked this TrpV3 missense mutation to Olmsted syndrome (OS), a rare congenital disorder characterized by palmoplantar keratoderma, perioral keratoderma, and severe pruritus. OS patients were identified to have missense mutations (often Gly573Ser or Gly573Cys) in the TrpV3 gene.

[0465] Dry skin (xerosis), a condition characterized by constant itch accompanied by dehydration of the skin, is another chronic itch condition commonly modeled in animals. Repeated skin dehydration with acetone and ether can induce spontaneous scratching behavior without inflammatory cell infiltration, increase transepidermal water loss, and produce symptoms similar to xerosis. In animal models of dry skin, both TrpA1 and TrpV3 are required for the induction of spontaneous itch.

[0466] In some embodiments, the skin condition is pruritus.

[0467] Pruritus, or itch, is defined as an unpleasant skin sensation that elicits the urge to scratch. It is a characteristic feature of many skin disorders and an unusual symptom of some systemic diseases. It can be localized or generalized and can occur as either an acute or chronic condition. Itching that persists for more than six weeks is called chronic itch. Itching can be intractable and disabling, and it can also be difficult to diagnose and treat. Itch can be evoked by mechanical stimuli (gentle touch, pressure, vibration, and wool), thermal stimuli, and electrical stimuli (e.g., transcutaneous or direct nerve stimulation). This sensation is received by free nerve endings in the skin and transmitted via unmyelinated C fibers and myelinated A-delta fibers to the central spinothalamic tract. Microneurography studies have demonstrated that itch and pain are transmitted by separate neural pathways. Histamine is one of the most important mediators of itch, although other chemicals have also been linked to itching. Some substances (e.g., neuropeptides) act by releasing histamine from mast cells, and the resulting itching responds to antihistamines. Other substances act independently, and therefore antihistamines are ineffective for some forms of pruritus. Opioids have central antipruritic effects and also act peripherally by potentiating histamine itch. Patients with tumors and lesions of the central nervous system have been reported to have intractable pruritus. Administration of opioids during epidural anesthesia can also lead to pruritus.

[0468] Itch is an important component of several disorders (atopic eczema, dermatitis herpetiformis, lichen simplex chronicus, and prurigo nodularis), and these conditions are rarely diagnosed without the presence of itch. Dermatological disorders associated with chronic pruritus include, but are not limited to: autoimmune-related: dermatitis herpetiformis, dermatomyositis, pemphigoid, Sjögren's syndrome; genetic-related: Darier's disease, Hailey-Hailey disease, ichthyosis, Sjögren-Larsson syndrome; infectious and parasitic disease-related: arthropod reactions, dermatophytoses, folliculitis, impetigo and other bacterial infections, insect bites, lice, scabies, viral; inflammatory-related: sebaceous Deficiency (dry skin) (including age-related and senile pruritus), atopic eczema, contact dermatitis (irritant, allergic), drug reactions, "invisible skin disease", lichen planus, lichen simplex chronicus, mastocytosis (urticaria pigmentosa), miliaria, psoriasis, scarring, urticaria; neoplasm-related: cutaneous T-cell lymphoma or mycosis fungoides (especially Sézary syndrome), cutaneous B-cell lymphoma, leukemia cutis; pregnancy-related: pemphigoid gestationis, polymorphous eruption of pregnancy, exanthema of pregnancy. Systemic causes of chronic pruritus may include: endocrine and metabolic disorders, e.g., chronic renal failure, diabetes (suspected; may be localized to the scalp), hyperthyroidism, hypothyroidism, liver disease (with or without cholestasis), malabsorption, postmenopausal pruritus; infectious diseases, e.g., helminthiasis, HIV infection, parasitic diseases; neoplastic and hematological disorders, e.g., Hodgkin's disease, iron deficiency, leukemia, non-Hodgkin's lymphoma, multiple myeloma, rheumatoid arthritis ... Chronic itching is caused by neurological disorders (abscess, infarction, multiple sclerosis, dorsal paresthesia, tumors) or psychiatric disorders (anxiety disorders, depression, obsessive-compulsive disorder).

[0469] In some embodiments, the skin condition is eczema.

[0470] Eczema is the name for a group of conditions in which skin becomes itchy, inflamed, and red on lighter skin tones, and brown, purple, gray, or off-white on darker skin tones. Eczema is very common. In fact, over 31 million Americans have some form of eczema. There are seven different types of eczema: atopic dermatitis, contact dermatitis, neurodermatitis, dyshidrotic eczema, nummular eczema, seborrheic dermatitis, stasis dermatitis, and atopic dermatitis. Atopic dermatitis (AD) is the most common type of eczema, affecting over 9.6 million children and approximately 16.5 million adults in the United States. The immune system of people with AD becomes unregulated and overactive. This triggers inflammation, which damages the skin barrier, leaving it dry and prone to itching and rashes. The rash may appear purple, brown, or grayish on darker skin tones and reddish on lighter skin tones. Studies have shown that some cases of atopic dermatitis involve mutations in the gene responsible for making filaggrin.

[0471] In some embodiments, the skin condition is a burn.

[0472] A burn is a type of injury to skin or other tissue caused by heat, cold, electricity, chemicals, friction, or radiation. Burns are classified by general cause or severity. Common causes of burns include:

[0473] Friction and mechanical burns occur when an object scrapes a piece of skin. This can be both an abrasion (scratches) and a burn. Low-temperature burns are caused by exposure to extremely cold temperatures. High-temperature burns are caused by exposure to extremely hot temperatures. Radiation burns are caused by solar radiation or other sources of radiation, such as x-rays or radiotherapy for cancer treatment. Chemical burns are caused by strong acids, solvents, or detergents. Electrical burns are caused by contact with an electric current.

[0474] Burns that affect only the surface layer of the skin are known as superficial or first-degree burns. These burns appear red, do not blister, and pain typically lasts around three days. If the damage extends to some of the lower layers of the skin, it is a partial-thickness or second-degree burn. Blisters are often present and are often very painful. Healing can take up to eight weeks and may result in scarring. In full-thickness or third-degree burns, the damage extends to all layers of the skin. There is often no pain, and the burned area becomes hard. They typically do not heal on their own. Fourth-degree burns also involve damage to deeper tissues such as muscle, tendons, or bone. The burn is often black and often results in loss of the burned area.

[0475] In some embodiments, the skin condition is scarring.

[0476] Scar formation, an area of ​​fibrous tissue replacing normal skin after injury, is the final stage of the body's complex repair mechanisms. The various clinical manifestations of scarring are an important topic for physicians across many disciplines. Preventing excessive scarring is more successful than treating it. Pathological scars are classified into two groups: hypertrophic scars and keloids. Hypertrophic scars generally have cellular connective tissue, usually with parallel collagen fibers on the surface. Localized nodular areas may also be present. In the latter, numerous alpha-actin-positive myofibroblasts are present. In keloids, less cellular connective tissue predominates, with collagen fibers randomly organized into larger nodules. The fibers are hypereosinophilic, hyaline, and thicker. Additionally, scars often have a sparsely cellular area in the center. Alpha-actin-positive myofibroblasts are absent or only localized. Between the fibers, in both hypertrophic scars and keloids, there are abundant small blood vessels.

[0477] The pharmaceutical compositions of the present invention can be administered and administered by the methods of the present invention in accordance with good medical practice. Accordingly, the pharmaceutical compositions or compounds described herein can be adjusted, adapted, or configured for administration by a variety of routes of administration.

[0478] For example, the compositions used in the methods of the invention (described herein below) can be adapted for administration by a variety of modes of administration known in the art, including, for example, systemic, parenteral, intraperitoneal, transdermal, oral (including buccal or sublingual), rectal, topical (including buccal or sublingual), vaginal, intranasal, and any other suitable route. Specific examples include, but are not limited to, injection (e.g., using subcutaneous, intramuscular, intravenous, or intradermal injections), intranasal administration, and oral administration.

[0479] In some embodiments, the compounds of the present invention are administered systemically. Thus, the compounds are formulated to be suitable for systemic administration. As used herein, "systemic administration" and "systemically administered" refer to the administration of a compound or composition comprising at least one compound of the present invention into the circulatory system to affect the entire body.

[0480] According to some embodiments, the compounds of the invention or compositions comprising the compounds of the invention are suitable for systemic administration.

[0481] In some embodiments, any of the compounds of Formulas I-XXXXIII, or any composition comprising any of the compounds of Formulas I-XXXXIII, is suitable for systemic administration. In some embodiments, at least the compound designated KM-0023, or a composition comprising the compound designated KM-0023, is suitable for systemic administration.

[0482] In some embodiments, the compound is administered enterally.

[0483] In some embodiments, the compound is administered orally.

[0484] Compositions for oral administration may include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, lozenges (including liquid-filled), chewable tablets, multi- and nanoparticles, gels, solid solutions, liposomes, films, wafers, sprays, or tablets. Thickeners, flavorings, diluents, emulsifiers, dispersing aids, or binders may be desirable.

[0485] It will be understood that in addition to the ingredients particularly mentioned above, the compositions may include other agents conventionally used in the art having regard to the type of formulation in question (e.g., those suitable for oral administration may include flavoring agents).

[0486] In some embodiments, the compound is administered parenterally.

[0487] As used herein, "parenteral administration" and "administered parenterally" include modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0488] In some embodiments, the formulation is suitable for intravenous injection. In some embodiments, the formulation is suitable for intravenous infusion.

[0489] In some embodiments, administration of the compounds of the present invention is by topical administration.

[0490] In some embodiments, the compound is administered locally. Therefore, the compound is prepared to be suitable for topical administration. As used herein, "topical administration" and "topically administered" refer to the administration of a compound or a composition comprising at least one compound, which is applied to a specific location on the body surface or within the body. Typically, topical administration refers to application to a body surface such as skin or mucous membrane.

[0491] The topically administrable compounds can be formulated into suitable preparations or compositions. The carrier can be selected from powders, oils, creams, foams, ointments, lotions, gels, pastes, mousinesses, hydrogels, or delivery systems (e.g., liposomes, niosomes, microsponges, microemulsions, microspheres, SLNs, aerosols, etc.).

[0492] The compounds of the present invention can be effectively dispersed, suspended, or dissolved in a liquid medium to form a solution, suspension, or dispersion that can be applied topically, sprayed onto the skin, or delivered by contact through the use of a sponge, patch, pad, or any skin dressing. In some applications, controlled release of the compound in such a delivery system can be essential.

[0493] According to some embodiments, the compounds of the present invention or compositions comprising the compounds of the present invention are suitable for topical administration.

[0494] In some embodiments, any of the compounds of Formulas I-XXXIII or compositions comprising any of the compounds of Formulas I-XXXIII are suitable for topical administration. In some embodiments, compounds designated as KM-001, KM-002, KM-031, KM-032, KM-036, KM-054, KM-069 or compositions comprising KM-001, KM-002, KM-031, KM-032, KM-036, KM-054, KM-069 are suitable for topical administration.

[0495] In some embodiments, the unit dosage formulation is one containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

[0496] According to some embodiments, the present disclosure provides a method for detecting cation channels (e.g., Ca +2In some embodiments, the methods of the present invention provide methods for modulating the activity of intracellular cation channels (e.g., Ca). +2 In a more specific embodiment, the method comprises contacting a cell with an effective amount of at least one compound having the general formula (I)-(XXXXIII), or a pharmaceutically acceptable salt or hydrate thereof (including any stereoisomers thereof). In some specific embodiments, the method comprises contacting a cell with an effective amount of at least one compound having the general formula (I)-(XXXXIII), e.g., any one of the compounds of formula (XXXII), (XXXIII), (XXVIV), (XXXIV), (XXVV), (XXXV), (XXXVI), (XXVVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), (XXXXII), or (XXXXIII), as well as a compound designated as Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound I, or Compound J described herein, or a pharmaceutically acceptable salt or hydrate thereof (including any stereoisomer thereof). In some embodiments, the method comprises contacting a cell with an effective amount of at least one compound of the invention in vitro, in vivo, ex vivo, or at least one combination thereof.

[0497] In certain embodiments, the compound(s) used in the methods of the invention can be any compound as defined herein. In further embodiments, the methods of the invention can involve the use of any composition encompassed by the invention, particularly any of the compositions described herein above.

[0498] In yet another aspect, the present invention provides methods for treating, preventing, suppressing, reducing, eliminating, protecting against, or delaying the onset of a TRPV3-mediated disorder in a subject in need thereof. In yet another aspect, the present invention provides methods for treating, preventing, suppressing, reducing, eliminating, protecting against, or delaying the onset of a skin disorder in a subject in need thereof.

[0499] In more specific embodiments, the invention comprises administering to such a subject a therapeutically effective amount of at least one compound(s) (including any stereoisomers or salts thereof), or any vehicle, matrix, nano- or microparticle, or composition comprising same.

[0500] In more specific embodiments, the compound used in the method(s) of the present invention has the general formula (I)-(XXXXIII), e.g., any one of the compounds of formula (XXXII), (XXXIII), (XXVIV), (XXXIV), (XXVV), (XXXV), (XXXVI), (XXVVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), (XXXXII), or (XXXXIII), or a pharmaceutically acceptable salt or hydrate thereof (including any stereoisomers thereof).

[0501] In some embodiments, the compound used in the method(s) of the invention may be designated as Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound I, or Compound J as described herein.

[0502] In some embodiments, the method(s) of the present invention comprise locally or systemically administering to a subject a therapeutically effective amount of at least one compound (I)-(XXXXIII), specifically any one of the compounds of formula (XXXII), (XXXIII), (XXVIV), (XXXIV), (XXVV), (XXXV), (XXXVI), (XXVVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), (XXXXII), or (XXXXIII), or a pharmaceutically acceptable salt or hydrate thereof (including any stereoisomer thereof).

[0503] In some embodiments, the method(s) are for treating, preventing, inhibiting, reducing, eliminating, protecting against, or delaying the onset of a skin disorder in a subject in need thereof.

[0504] In some other embodiments, the skin disease is at least one keratoderma.

[0505] In some other embodiments, the skin disease is Olmsted syndrome.

[0506] In some embodiments, the skin disease is an ichthyosis disease.

[0507] In some embodiments, the skin condition is pruritus.

[0508] In some specific embodiments, the method(s) of the present invention comprise topically administering to such a subject a therapeutically effective amount of at least one of the compounds designated Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound I, or Compound J as described herein.

[0509] In some specific embodiments, the method(s) of the present invention comprise topically administering to such a subject a therapeutically effective amount of a compound designated herein as Compound A.

[0510] In some embodiments, the method(s) of the present invention comprise: [ka] In some embodiments, the method(s) of the present invention comprise administering to a subject a therapeutically effective amount of the compound 3-(2'-cyclopropyl-3-hydroxymethyl-biphenyl-4-yl)-pyrrolidin-1-yl]-(5-fluoro-pyridin-2-yl)-methanone (including any stereoisomer or salt thereof) having the structure: [ka] The present invention relates to a method for treating rheumatoid arthritis, comprising topically administering to a subject a therapeutically effective amount of the compound 3-(2'-cyclopropyl-3-hydroxymethyl-biphenyl-4-yl)-pyrrolidin-1-yl]-(5-fluoro-pyridin-2-yl)-methanone (including any stereoisomers or salts thereof) having the formula:

[0511] In some specific embodiments, the method(s) of the present invention comprise systemically administering to such a subject a therapeutically effective amount of at least one of the compounds designated Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, Compound H, Compound I, or Compound J as described herein.

[0512] In some specific embodiments, the method(s) of the present invention comprise systemically administering to such a subject a therapeutically effective amount of a compound designated herein as Compound C.

[0513] In some embodiments, the method(s) of the present invention comprise providing a compound having the structure: 3-(2′-cyclopropyl-3-hydroxymethyl-biphenyl-4-yl)-pyrrolidin-1-yl]-(5-hydroxy-6-methyl-pyridin-2-yl)-methanone In some embodiments, the method of the present invention comprises administering to a subject a therapeutically effective amount of the compound 3-(2'-cyclopropyl-3-hydroxymethyl-biphenyl-4-yl)-pyrrolidin-1-yl]-(5-hydroxy-6-methyl-pyridin-2-yl)-methanone (including any stereoisomers or salts thereof), or any vehicle, matrix, nano- or microparticle, or composition comprising same, to the subject. In some embodiments, the method of the present invention comprises systemically administering to a subject a therapeutically effective amount of the compound 3-(2'-cyclopropyl-3-hydroxymethyl-biphenyl-4-yl)-pyrrolidin-1-yl]-(5-hydroxy-6-methyl-pyridin-2-yl)-methanone (including any stereoisomers or salts thereof), or any vehicle, matrix, nano- or microparticle, or composition comprising same.

[0514] In yet another aspect, the present invention provides a method for treating, preventing, suppressing, reducing, eliminating, protecting against, or delaying the onset of a skin disorder, particularly keratoderma, and more particularly Olmsted syndrome, in a subject in need thereof, the method comprising administering to a subject a compound having the structure: 3-(2'-cyclopropyl-3-hydroxymethyl-biphenyl-4-yl)-pyrrolidin-1-yl]-(5-fluoro-pyridin-2-yl)-methanone [ka] (including any stereoisomers or salts thereof), or any vehicle, matrix, nano- or microparticle, or composition comprising same, to a subject, in particular topically administering.

[0515] In yet another aspect, the present invention provides a method for treating, preventing, inhibiting, reducing, eliminating, protecting against, or delaying the onset of a skin disorder, specifically ichthyosis, in a subject in need thereof, the method comprising administering to a subject a compound having the structure: 3-(2'-cyclopropyl-3-hydroxymethyl-biphenyl-4-yl)-pyrrolidin-1-yl]-(5-fluoro-pyridin-2-yl)-methanone [ka] (including any stereoisomers or salts thereof), or any vehicle, matrix, nano- or microparticle, or composition comprising same, to a subject, in particular topically administering.

[0516] In some embodiments, the method(s) of the present invention comprise providing a compound having the structure: 3-(2′-cyclopropyl-3-hydroxymethyl-biphenyl-4-yl)-pyrrolidin-1-yl]-(5-hydroxy-6-methyl-pyridin-2-yl)-methanone [ka] (including any stereoisomers or salts thereof), or any vehicle, matrix, nano- or microparticle, or composition comprising same, to a subject.

[0517] In yet another aspect, the present invention provides a method for treating, preventing, suppressing, reducing, eliminating, protecting against, or delaying the onset of a skin disorder, particularly keratoderma, and more particularly Olmsted syndrome, in a subject in need thereof, the method comprising administering to a subject a compound having the structure: 3-(2'-cyclopropyl-3-hydroxymethyl-biphenyl-4-yl)-pyrrolidin-1-yl]-(5-hydroxy-6-methyl-pyridin-2-yl)-methanone [ka] (including any stereoisomers or salts thereof), or any vehicle, matrix, nano- or microparticle, or composition comprising same, is administered to a subject, particularly systemically.

[0518] In yet another aspect, the present invention provides a method for treating, preventing, inhibiting, reducing, eliminating, protecting against, or delaying the onset of a skin disorder, specifically ichthyosis, in a subject in need thereof, the method comprising administering to a subject a compound having the structure: 3-(2'-cyclopropyl-3-hydroxymethyl-biphenyl-4-yl)-pyrrolidin-1-yl]-(5-hydroxy-6-methyl-pyridin-2-yl)-methanone [ka] (including any stereoisomers or salts thereof), or any vehicle, matrix, nano- or microparticle, or composition comprising same, to a subject, in particular topically administering.

[0519] The present invention provides a method for treating skin disorders. The term "treatment or prevention" refers to the full range of therapeutically positive effects of administration to a subject, including suppression, reduction, alleviation, and mitigation of the symptoms of skin disorders or undesirable side effects of such skin disorder-related disorders. More specifically, treatment or prevention includes preventing or postponing the onset of disease, preventing or postponing the onset of symptoms, and / or reducing the severity of such symptoms that have or are expected to develop in the future. Furthermore, it also includes ameliorating existing symptoms, preventing further symptoms, and improving or preventing the underlying metabolic causes of symptoms.

[0520] As used herein, "diseases," "disorders," "conditions," and the like, relating to the health of a subject, are used interchangeably and have the meanings ascribed to each and every such term.

[0521] The present invention relates to the treatment of subjects or patients in need of treatment. By "patient" or "subject in need" is meant any organism that may be suffering from the above-described conditions and for which the treatment methods described herein are desired, including humans, domestic and non-domestic mammals, such as canine and feline subjects, bovine, simian, equine, and murine subjects, rodents, domestic birds, aquaculture organisms, fish, and exotic aquarium fish. It is understood that the subject to be treated may also be any reptile or zoo animal. More specifically, the methods and compositions of the present invention are directed to mammals. By "mammalian subject" is meant any mammal, including human, equine, canine, and feline subjects, for which the proposed therapy is desired, most specifically humans. It should be noted that, particularly for non-human subjects, the methods of the present invention can be carried out using injection, drinking water, feed, nebulization, oral gavage, and direct administration to the digestive tract of a subject in need thereof. It should also be noted that, particularly for human subjects, administration of the compositions of the present invention to a patient includes both self-administration and administration to the patient by another person.

[0522] The present invention provides methods for treating skin disorders and further relates to disorders associated or related to skin disorders. It should be understood that the terms "associated" and "related," used interchangeably herein when referring to conditions, refer to diseases, disorders, conditions, or any conditions that share a causal relationship, coexist at a frequency greater than chance, or in which at least one disease, disorder, condition, or condition causes or corresponds to at least one of a second disease, disorder, condition, or condition.

[0523] The present invention further provides the use of an effective amount of at least one compound and any combination thereof in the preparation of a composition for treating, preventing, suppressing, reducing, eliminating, protecting against, or delaying the onset of a skin disorder in a subject in need thereof.

[0524] As used herein, the term "about" refers to values ​​that may deviate up to 1%, more specifically 5%, more specifically 10%, more specifically 15%, and in some cases up to 20% higher or lower than the stated value, and the deviation range includes integer values ​​and, where applicable, non-integer values, constituting a continuous range. As used herein, the term "about" refers to ±10%.

[0525] The terms "comprises," "comprising," "includes," "including," "having," and conjugations thereof, mean "including," but are not limited to, the following. This term encompasses the terms "consisting of" and "consisting essentially of." The phrase "consisting essentially of" means that a composition or method may include additional components and / or steps, but only if the additional components and / or steps do not materially alter the basic and novel characteristics of the claimed composition or method. Throughout this specification and the examples and claims that follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" should be understood to mean the inclusion of a stated integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps.

[0526] As used herein, the term "method" refers to manners, means, techniques, and procedures for accomplishing a given task, including, but not limited to, manners, means, techniques, and procedures that are known or readily developed from known manners, means, techniques, and procedures to practitioners of chemistry, pharmacology, biology, biochemistry, and medicine.

[0527] It should be understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately, or in any suitable subcombination, or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments should not be considered essential features of those embodiments, unless the embodiment is inoperable without those elements.

[0528] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed below find experimental support in the following examples.

[0529] Although disclosed and described, it is to be understood that the invention is not limited to the specific examples, method steps, and compositions disclosed herein, since such method steps and compositions may vary to some extent. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims and their equivalents.

[0530] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.

[0531] The following examples are representative of techniques employed by the inventors in carrying out aspects of the present invention. It should be understood that while these techniques are exemplary of preferred embodiments for carrying out the invention, those skilled in the art will recognize in light of this disclosure that numerous modifications can be made without departing from the spirit and intended scope of the invention.

[0532] At various places in the present specification, substituents of compounds of the present disclosure are disclosed in groups or in ranges, and the present disclosure is specifically intended to include every individual subcombination of the members of such groups and ranges. [Example]

[0533] Non-limiting Examples Example 1: In vitro testing

[0534] Example 1A: High-Throughput Screening Assay

[0535] This assay measures intracellular Ca after channel activation in cells inducibly expressing TRPV3 channels. 2+ Concentration ([Ca 2+ ] i ) is dependent on detecting an increase in Ca 2+ The rise in fluorescence 2+ Quantification is performed using an indicator dye, which is loaded into cells and then [Ca 2+ ] i When the TRPV3 channel is activated, Ca 2+ This [Ca 2+ ] i Compounds that inhibit the increase in are considered hits for further study.

[0536] A commercially available HEK293 / TREx line (Invitrogen) was stably transfected with the TRPV3 construct and screened by immunostaining to find clones with TRPV3 expression after stimulation with 1 μg / ml tetracycline. Clonal TRPV3-expressing cells were maintained in the manufacturer's recommended growth medium supplemented with 100 μg / ml hygromycin to promote retention of the TRPV3 construct. After growing to near confluence, cells were seeded at a density of approximately 25,000 cells / well in 384-well plates in the presence of 1 μg / ml tetracycline and grown for 20–30 hours. A near-confluent monolayer was obtained. The cells were then treated with Ca 2+To load the dye, Fura-2 / AM or Fluo4 / AM was added to the wells to a final concentration of 2 μM or 1 μM, respectively, and incubated at room temperature for 80 or 60 minutes, respectively. The supernatant was then removed from the cells by rapid inversion of the plate, and 40 μl of Ringer's solution (140 mM NaCl, 4.5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 10 mM glucose, pH 7.4) was then added to each well. After approximately 1 hour of recovery from loading, the cells were assayed using a Hamamatsu FDSS6000 system. This system allows alternating illumination at 340 nM and 380 nM for Fura-2 experiments and 485 nM for Fluo4 experiments. Frames were acquired at a rate of 0.2 Hz. The plate was continuously vortexed throughout the assay, with wells being pipetted after each reagent addition. In the screening assay, 13 μl of diluted stock (50 μM) of each compound to be tested was added to each well for 2 minutes after collection of a short (4-frame) baseline. 13 μl 750 μM 2-APB (2-aminoethyldiphenylborinate) was added to each well to achieve a final concentration of 10 μM of each compound and 150 μM 2-APB. Data were collected for approximately 3 minutes after addition of 2-APB. Fluorescence intensity (for Fluo4) and F340 / F380 ratio (for Fura-2) were measured as [Ca 2+ ] i The negative control consisted of HEK293 / TREx TRPV3 cells exposed to 2-APB but not to the test compound. Positive control cells were typically HEK293 / TREx ("parent") cells exposed to 2-APB but not to the test compound, although in some cases normal HEK / 293 TREx TRPV3 cells exposed to neither 2-APB nor the test compound were also used. These controls defined the screening window, and test compounds that inhibited the fluorescence response by at least 40% were defined as "hits."

[0537] Example 1B: Patch clamp experiments

[0538] Whole-cell patch clamp experiments can detect currents mediated by TRPV3 channels in the cell lines described above. A glass electrode is placed on a single cell, followed by membrane rupture, allowing for voltage control of the cell membrane and measurement of the current across it using an amplifier attached to the electrode. A perfusion system allows for control of the extracellular solution, including the addition of current blockers and activators. Current can be activated by heating the solution above 28°C or by adding 20 μM 2-APB to the solution.

[0539] TRPV3 cells were induced for 20–48 h, removed from the growth plate, and replated at low density (to allow for better physical isolation of single cells) on glass coverslips for measurement. In some cases, cells were grown overnight on glass coverslips at low density. Patch-clamp recordings were performed in whole-cell mode at a holding potential of −40 mV. Voltage ramps of 400 ms duration from −120 mV to +100 mV were applied every 5 s. Evoked currents were quantified at −80 mV and +80 mV. The internal solution consisted of 140 mM cesium aspartate, 10 mM EGTA, 2.27 mM MgCl2, 1.91 mM CaCl2, and 10 mM HEPES, adjusted to pH 7.2 with KOH, and free Ca. 2+ The concentration was calculated to be 50 nM. The external solution was Ringer's solution as described above. Addition of 2-APB or heating the extracellular solution as described above induced TRPV3 currents only in TRPV3-expressing cells, but not in parental HEK293 TREx cells. This current exhibited a small inward component, a reversal near +10 mV, and strong outward rectification, termed phase I. Re-addition of 2-APB or continued or repeated application of heat as a stimulus altered the current profile, resulting in a linear phase II current up to +10 mV. Removal of the stimulus largely eliminated the current, and addition of an inhibitor could subsequently inhibit this current. Compounds of interest were tested against TRPV3 at concentrations up to 30 μM, and the resulting data were used to determine IC values ​​for inhibiting phase 1 and phase 2 TRPV3-mediated currents. 50 was estimated.

[0540] To determine whether a compound is selective for TRPV3 inhibition over other ion channel types, human ERG (hERG), NaV1.2, TRPV1 (hTRPV1) and rat TRPV6 (rTRPV6) channels can be stably transfected and expressed or induced to express in mammalian cell lines. Methods for measuring currents from these channels are well established and have been described in numerous publications (see Weerapura et al., 2002, J Physiology 540:15-27; Rush et al., 2005, J Physiology 564:808-815; Caterina et al., 1997, Nature 389:816-824; Hoenderhop et al., 2001, J Physiology 537:747-761; Clapham et al., 2003, Pharmacol Rev 55:591-596). Compounds of interest can be tested against these channels at concentrations up to 30 μM, and the resulting data can be used to determine IC s for inhibiting the activity of these other ion channels. 50 can be estimated.

[0541] Table 1 shows data obtained in this assay for certain compounds of the present disclosure. P1 refers to the phase 1 current of human (h)TRPV3, and P2 refers to the phase 2 current of human (h)TRPV3. As shown in Table 1, A is the IC 50 B refers to an inhibitor of hTRPV3 with an IC of 0 nM to 10 nM. 50 IC refers to an inhibitor of hTRPV3 with an IC of 10nM to 100nM. 50 refers to an hTRPV3 inhibitor with an IC of 100nM to 1000nM. 50 indicates an inhibitor of hTRPV3 greater than 1000 nM. ND indicates not measured data. [Table 1-1] [Table 1-2] Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17

[0542] Tables 3 and 4 show additional data obtained for certain compounds of the present disclosure. In Tables 3 and 4, Phase 1 refers to the phase 1 current of human (h)TRPV3 or rat (r)TRPV3, and Phase 2 refers to the phase 2 current of human (h)TRPV3 or rat (r)TRPV3. hTRPV3 and rTRPV3 assays were performed as described herein. hERG refers to inhibition of the human ERG (hERG) channel. NaV1.5 refers to the pore-forming α subunit of the voltage-dependent cardiac Na(+) channel, a multi-membrane protein involved in the initiation and conduction of action potentials. hTRPV3 HAMA IC 50 The IC of TRPV3 cells stably expressed in TRex-293 cells 50 Ringer's solubility refers to the solubility of a compound in Ringer's solution. 1 / 2 refers to the hepatic microsomal half-life in either rat or human liver microsomes. 50 is the IC of the test compound against recombinant hTRPV3 cells 50 Refers to...

[0543] hERG Assay: Briefly, cells from a stable CHO cell line expressing the human hERG channel were seeded onto glass coverslips and used for patch clamp assays on the same day. After seal formation and habituation to the whole-cell configuration, voltage steps were applied as follows: from a holding potential of -90 mV, a 2-second long step to +40 mV was applied, followed by a 1.5-second step to -50 mV. These steps were applied once every 5 seconds. hERG currents were measured at the peak of the outward tail current at -50 mV. The pipette solution was potassium aspartate-based, and the external solution was normal Ringer's solution.

[0544] All currents were recorded in whole-cell configuration using an Axopatch 200B controlled by pClamp 10 software (Molecular Devices). Once currents stabilized, compounds were locally perfused onto each cell. Two to three concentrations of test compound were applied to each cell. At the end of compound testing, 10 μM verapamil was applied to completely block hERG currents and assess leak currents.

[0545] Data were analyzed by calculating the degree of current block after compound addition relative to the unblocked current amplitude. Unblocked current was estimated from interpolation of the current amplitude between before compound addition and after compound washout. The resulting percent block at each concentration was used to generate a concentration-response plot and calculated using the Hill equation: percent block = minimum block + (maximum block - minimum block) / (1 + 10^(Hill slope * (logIC)). 50 The minimum block was 0% and the maximum block was 100% (determined by the no block and positive control block conditions, respectively), and the Hill slope and IC 50 is determined by a curve fitting routine.

[0546] hNaV1.5 Assay: Human Na v 1.5 was stably expressed in HEK-293 cells. On the morning of the assay, cells were trypsinized and seeded onto glass coverslips. Compounds were prepared in Ringer's solution at 320 nM, 1, 3.2, 10, or 32 mM by direct dilution from a 10 mM DMSO stock. Compounds were prepared immediately prior to the assay.

[0547] A voltage step protocol on the Nanion Pathchliner v1.5 was activated. Cesium fluoride internal solution was used. Normal Ringer's solution served as the external solution. Data were analyzed by calculating the degree of current block after compound addition relative to the unblocked current amplitude. Unblocked current was estimated from interpolation of the current amplitude between before compound addition and after compound washout. The resulting percent block at each concentration was used to generate concentration-response plots and calculated using the Hill equation: percent block = minimum block + (maximum block - minimum block) / (1 + 10^(Hill slope * (logIC 50 The minimum block was 0% and the maximum block was 100% (determined by the no block and positive control block conditions, respectively), and the Hill slope and IC 50 is determined by a curve fitting routine.

[0548] hTRPV3 HAMA IC 50 Assay: TRex-293 cells stably expressing TRPV3 were seeded in black-sided clear-bottom 384-well plates, induced with tetracycline, and assayed 24–30 hours later on a Hamamatsu FDSS6000. Cells were loaded with the fluorescent calcium indicators Fluo-4AM (1.25 μM) or Fura-2AM (2.5 μM). Calcium ion flux was stimulated by adding 2-APB to a final concentration of 200 μM. Test compounds were typically tested in triplicate at concentrations ranging from 27 nM to 20 μM. Z' was calculated for each plate, and any plates with a Z' value below 0.4 were discarded. IC50 values ​​were calculated using a CBIS from ChemInnovation (San Diego).

[0549] Water Solubility Assay. Briefly, solubility in normal Ringer's solution was measured by dissolving a standard volume range of the indicated compound stock (e.g., 10 μM in DMSO) in normal Ringer's solution at room temperature. After vortexing and incubating for a sufficient time (e.g., 40 min at room temperature), the solution was filtered, quenched with acetonitrile, and analyzed by liquid chromatography. The solubility limit was determined by comparison to a standard curve.

[0550] Metabolic Stability Assay: Metabolic stability was determined by adding compounds dissolved in DMSO to human or rat liver microsomes. Briefly, assays were performed at a starting concentration of 1 μM test article. Reactions were initiated at 37°C by adding NADPH-regenerating components, at which point aliquots were immediately quenched with ice-cold acetonitrile / MeOH / HO solution. The reaction mixtures were incubated on a shaker at 37°C, and additional aliquots were taken at 7, 15, 30, and 60 minutes. After quenching and centrifugation, samples were analyzed by HPLC / MS / MS.

[0551] FLIPR assay: HEK293 cells stably expressing TRPV3 were seeded in culture medium in a 96-well, black-walled, transparent-bottom, 384-well plate and maintained overnight at 37°C and 5% CO2. Cells were treated with HBSS and 20 mM HEPES adjusted to pH 7.4 in the presence of a fluorescent calcium indicator (e.g., Fluo-4AM (5 uM)). The plate was incubated at 37°C and 5% CO2 for approximately 1 hour and cooled to room temperature. Test compounds were added at optimized parameters, and appropriate agonists (e.g., 2-APB (EC 80 Calcium ion flux was stimulated by adding 5- to 6-fold higher concentrations of ATP. Relative fluorescence units (RFU) were measured for each response at the signal maximum-minimum values ​​approximately 90 seconds after addition. [Table 3-1] Table 3-2 Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 3-10 Table 3-11 Table 3-12 Table 3-13 Table 3-14 Table 3-15 Table 3-16 Table 3-17 Table 3-18 Table 3-19 Table 3-20 Table 3-21 Table 3-22 Table 3-23 Table 3-24 Table 3-25 Table 3-26 Table 3-27 Table 3-28 Table 3-29 Table 3-30 Table 3-31 Table 3-32 Table 3-33 Table 3-34 Table 3-35 Table 3-36 Table 3-37 Table 3-38 Table 3-39 Table 3-40 Table 3-41 Table 3-42 Table 3-43 Table 3-44 Table 3-45 Table 4-1 Table 4-2 Table 4-3 Table 4-4 Table 4-5 Table 4-6 Table 4-7 Table 4-8 Table 4-9 Table 4-10 Table 4-11 Table 4-12 [Table 4-13] [Table 4-14] [Table 4-15] [Table 4-16] [Table 4-17] [Table 4-18] [Table 4-19] [Table 4-20] [Table 4-21] [Table 4-22] [Table 4-23] [Table 4-24]

[0552] Example 1C: Additional Screening Assays

[0553] Although exemplary TRPV3 inhibitors provided herein were identified using the assays described in Examples 1A and 1B, other cell-based assays may be used to identify and / or characterize TRPV3 inhibitors. One such assay is described in U.S. Patent Application No. 11,078,188, filed March 11, 2005, the entire contents of which are incorporated herein by reference. TRPV3 protein can be expressed in the prokaryotic cell system described in Application No. 11,078,188, and this system can be used to screen for compounds that modulate the activity of TRPV3 protein. Alternatively, ion channels other than TRPV3 can be expressed in a prokaryotic cell system, and the system can be used to evaluate the activity profile of identified TRPV3 inhibitors with respect to other ion channels.

[0554] Any assays performed to identify and / or characterize compounds that inhibit TRPV3 activity can be performed in a high-throughput manner or on a small scale to examine individual compounds or small numbers of compounds. In addition, any of these assays can be performed (i) as a primary assay to identify compounds that inhibit TRPV3 function, (ii) as a secondary assay to evaluate the specificity of compounds with respect to activity against other ion channels, or (iii) as an assay used in a medicinal chemistry program to optimize the subject compounds.

[0555] Example 1D: Semi-automated patch clamp recording

[0556] Materials and Methods:

[0557] Compounds were tested at room temperature using the whole-cell patch clamp technique with a HEKA EPC 10 usb patch clamp amplifier (HEKA Elektronik, Germany). The output signal from the amplifier was digitized and recorded using PatchMaster (v2x90.5 HEKA Elektronik, Germany). For quality control, the minimum seal resistance was 100 MΩ, and the outward current was stabilized at +80 mV with a rectifying current of at least 1 nA, and the inward current was stabilized at -80 mV with a rectifying current of at least 300 pA.

[0558] NPC-1 chip

[0559] NPC-1 chips (Nanion, Germany) were used to capture single cells. For both wild-type and transfected cells, chips in the 2-3 MOhm and 3-5 MOhm categories were used. The chips were disposable; a new chip was required for each recording. Five microliters of internal solution was applied to the inner hole of the chip, which was then fixed to the top of the internal electrode. The upper unit of the patch-lamp device was assembled on the chip, and 15 μl of external buffer solution was added between the chip hole and the external electrode. Recordings of the current between the electrode and the chip hole were used to confirm proper placement and handling of the chip.

[0560] Preparation of cells for patch clamp:

[0561] Basal nHEK cells at passages 2 or 3, at 70–90% confluence, were used for patch clamping or transfection. For patch clamping, cells were suspended in TrypLE enzyme for 5 min at 37°C and then collected using KBM-Gold medium. Cells were then centrifuged at 110 g for 5 min at room temperature. The supernatant was then removed, and the cells were resuspended in KBM-Gold medium and maintained at room temperature until patch clamping. After initializing the patch clamp system and capturing cells on the chip, the medium was washed with the free cells and replaced with external buffer. For TRPV3-mu transfected cells, cells were maintained in KBM-Gold medium containing 3 μM of the test antagonist.

[0562] Transfection of nHEK cells.

[0563] nHEK cells were transfected according to SOP KP-Lab-001. For patch clamp, cells were seeded in 12-well plates according to SOP section 2.8.2 “Cell preparation for patch clamp” and harvested 24 hours after transfection.

[0564] Whole-cell recording:

[0565] For wild-type nHEK cells, the "intermediate protocol" in the semi-automated Port-a-Patch device software was selected based on the parameters of initial sealing, as measured by resistance, and its ability to maintain sealing throughout the assay.

[0566] The procedure began with the "Startup procedure" protocol (which verifies tip contact and adjusts offset), and then, after the system was ready, 5 μl of cells suspended in extracellular buffer was added and the intermediate protocol was automatically initiated.

[0567] Once the cells were captured by vacuum, the "v-membrane" value was increased to 100%, and then 15 μl of sealing solution was added. The procedure continued automatically through all steps until the final step, "maintain the whole-cell," in which the sealing solution was washed out using three 20 μl washes with external buffer, and the C-fast and C-slow values ​​were adjusted twice using the "Auto E" button.

[0568] The sensitivity of the reading was adjusted by changing the gain from 2.0 to 0.5.

[0569] To start recording, a "Ramp" protocol was initiated and currents were recorded for several minutes until the signals remained stable for both inward and outward currents.

[0570] A similar procedure was used for TRPV3-mu transfected nHEK cells, but antagonists were added at the sealing step according to the "Fragile protocol." If low sealing was observed for all cells, additional sealing or whole-cell maintenance steps were added until sealing reached a minimum of 100 MO.

[0571] Voltage command protocol and compound addition:

[0572] The Nanion system automatically maintained the cells at a holding potential of -40 mV. A voltage ramp was then performed from 80 mV to +80 mV for 160 ms. Finally, the voltage was returned to the holding potential (-40 mV). This voltage command protocol was repeated with a 400 ms period (Figure 1). This command protocol was performed continuously throughout the test, with vehicle controls perfused first. For wild-type cells, this protocol was followed by the addition of 100 μM HC-081790 and test compounds dissolved in the HC solution.

[0573] For TRPV3-mu transfected cells, 1500 nM test compound was added and currents were measured. Antagonists were washed out stepwise by diluting the solution 50% with antagonist-free external buffer for each wash.

[0574] Compound application:

[0575] For TRPV3-wild-type nHEK, once both the inward and outward currents stabilized, 100 μM of the agonist HC-081790 was added in 20 μl of wash 3, and the current was measured for several minutes until the current stabilized. Then, the reading was paused for labeling and buffer exchange. At this step, increasing concentrations of test compound dissolved in the presence of 100 μM HC-081790 were manually added (10 μl of one pulse in a final volume of 20 μl). The solution was then gently mixed, and current recording resumed. Only after the current stabilized was the next concentration of test compound added, and this procedure was continued until a complete response was observed.

[0576] For TRPV3-mu nHEK, test antagonists were added at an initial concentration of 1500 uM (one pulse of 10 μl in a final volume of 20 ul) and then slowly removed from the test environment with external buffer in 15 washing steps.

[0577] Data analysis

[0578] Data analysis was performed using PatchMaster (v2x90.5 HEKA Elektronik, Germany), Excel (Microsoft Excel for Microsoft 365 MSO16.0.12827.20236 64bit), IC50 toolkit (http: / / www.ic50.tk / ), and GraphPad Prism 8.4.2.

[0579] Within each cell recording, a percentage of the control value was calculated for the concentration-current response of each test compound based on the peak current and the complete response in the presence of agonist. The percentage of the current remaining after compound addition (I試験 ) to 100% block level (I ブロック ) and subtract it from the 0% block current (I 非ブロック ) to get the residual current ratio.

[0580] Residual current rate = (I test - I block) / (I non-block - I block)

[0581] result:

[0582] As shown in Table 5 below, A is the IC 50 B refers to an inhibitor of hTRPV3 with an IC of 0 nM to 10 nM. 50 IC refers to an inhibitor of hTRPV3 with an IC of 10nM to 100nM. 50 refers to an hTRPV3 inhibitor with an IC of 100nM to 1000nM. 50 indicates an inhibitor of hTRPV3 greater than 1000 nM. ND indicates not measured data. [Table 5-1] [Table 5-2] [Table 5-3]

[0583] Example 2: Synthesis of compounds of the present disclosure

[0584] General Procedure A:

[0585] Abbreviations used: Chromatography = silica gel chromatography; EA = ethyl acetate; DMF = N,N-dimethylformamide; Dess-Martin periodinane = 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-one; DCM = dichloromethane; THF = tetrahydrofuran; LAH = lithium aluminum hydride; DME = 1,2-dimethoxyethane; TEA = triethylamine; EIPEA = ethyldiisopropylamine; DEAD = diethyl azodicarboxylate; DIAD = diisopropyl azodicarboxylate; HATU = 2-(7-aza-1H)-one -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; EDCI = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; HOBt = 1-hydroxybenzotriazole; DIBAL-H = diisobutylaluminum hydride; Bn = benzyl; DMSO = dimethyl sulfoxide; RT = room temperature; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; NCS = N-chlorosuccinimide; LiHMDS = lithium bis(trimethylsilyl)amide; DMAP = 4-dimethylaminopyridine; n-BuLi = n-butyllithium.

[0586] General steps:

[0587] All reagents were purchased from commercial suppliers (Sigma-Aldrich, Alfa, Across, etc.) and used without further purification unless otherwise stated: THF was continuously refluxed and freshly distilled from sodium and benzophenone under nitrogen, and DCM was continuously refluxed and freshly distilled from HCa under nitrogen. The reaction was monitored by TLC on silica gel 60 HSGF254 leached plates (0.15-0.2 mm SiO2) and visualized using UV light and / or staining with a solution of DNP (12 g 2,4-dinitrophenylhydrazine, 60 mL concentrated H2SO4, 80 mL H2O, 200 mL EtOH) followed by heating, or by LCMS (Chromolith SpeedROD, RP-18e, 50 × 4.6 mm, mobile phase: Solvent A: CH3CN / H2O / HCOOH = 10 / 90 / 0.05, Solvent B: CH3CN / H2O / HCOOH = 90 / 10 / 0.05, 0.8 min (10% B, 2.7 min gradient (10-95% B), then 0.8 min (95% B), flow rate: 3 mL / min, temperature: 40 °C), and HPLC (Chromolith SpeedROD RP-18e, 50 × 4.6 mm, mobile phase: Solvent A: CHCN / HO / HCOOH = 10 / 90 / 0.05, Solvent B: CHCN / HO / HCOOH = 90 / 10 / 0.05, monitored at 0.8 min (10% B), 2.7 min gradient (10 to 95% B), then 0.8 min (95% B, flow rate: 3 mL / min, temperature: 40 °C). 1 H spectra were recorded on a Bruker Avance II 400 MHz, and chemical shifts (δ) are reported in ppm relative to tetramethylsilane (δ = 0.000 ppm), and the spectra were calibrated to the residual solvent signal of chloroform (δ = 7.26 for 1H). Data in 1H NMR spectra are reported as follows: chemical shift (multiplicity, hydrogen number). Abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), quant (quintet), m (multiplet), br (broad line).

[0588] Supporting information S2

[0589] HPLC purification was performed on a SHIMADZU LC-8A (column: YMC Pack ODS-A (150 × 30 mm, 10 μm)) or LC-6AD (column: Shim-Pack PREP-ODS-H (250 × 20 mm, 10 μm)) equipped with a UV detector and controlled by LC solution Chemstation software. HO (0.1% HCOOH) and MeOH (MeCN) were used as the mobile phase at the indicated flow rates. Separation of the racemic compounds was also performed using SFC (column type: OD-H 3 × 25 cm column, mobile phase: H / E / M = 80 / 15 / 5 (v / v / v), flow rate: 20 mL / min).

[0590] Section A: Synthesis of intermediates

[0591] Intermediate 1: 3-chloro-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine trifluoroacetate [ka]

[0592] Step 1: tert-butyl 3-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidine-1-carboxylate [ka]

[0593] To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1 g, 5.3 mmol) in DMF (10 mL) at 0 °C, NaH (1.2 g, 31 mmol, 60% dispersion in mineral oil) was added, and the resulting mixture was stirred at this temperature for 20 min. Then, 2,3-dichloro-5-(trifluoromethyl)pyridine (1.38 g, 6.4 mmol) was added, and the reaction mixture was stirred at room temperature for 1.5 h. The reaction was quenched with ice water at 0 °C, diluted with EA (50 mL), washed with LiCl solution and brine, and dried over Na SO . Concentrated to dryness, the residue was purified by silica gel to give tert-butyl 3-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidine-1-carboxylate (1.7 g, 86.7% yield). Mass spectrum: 367 (M+H).

[0594] Step 2: 3-chloro-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine trifluoroacetate [ka]

[0595] To a solution of tert-butyl 3-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidine-1-carboxylate (1.7 g, 4.6 mmol) in DCM (10 mL) at 0 °C, TFA (5 mL) was added, and the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated to give 3-chloro-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (1.76 g, quantitative) as its TFA salt. Mass spectrum: 267 (M+H).

[0596] Intermediate 2: 2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine trifluoroacetate (XJ-000098-129) [ka]

[0597] Step 1: tert-butyl 3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidine-1-carboxylate (XJ-000098-128) [ka]

[0598] The title compound was prepared according to the procedure described in Step 1 of Intermediate 1 to give tert-butyl 3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidine-1-carboxylate (1.7 g, 92.8% yield). Mass spectrum: 333 (M+H).

[0599] Step 2: 2-(Pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine trifluoroacetate [ka]

[0600] The title compound was prepared according to the procedure described in Step 2 of Intermediate 2 to give 2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine trifluoroacetate (1.76 g, quantitative). Mass spectrum: 233 (M+H).

[0601] Intermediate 3: (S)-3-chloro-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine hydrochloride [ka]

[0602] Step 1: (S)-tert-butyl 3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidine-1-carboxylate (LHH-000206-094) [ka]

[0603] The title compound was prepared according to the procedure described in Step 1 of Intermediate 1 to give (S)-tert-butyl 3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidine-1-carboxylate (34 g, 97% yield). Mass spectrum: 333 (M+H).

[0604] Step 2: (S)-3-Chloro-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine hydrochloride [ka]

[0605] To a solution of (S)-tert-butyl 3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidine-1-carboxylate (LHH-000206-094) (5 g, 15 mmol) in EtO / MeOH (20 mL, 5:1) at 0 °C, HCl gas was bubbled for 3 h and filtered to give (S)-3-chloro-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine hydrochloride (3.8 g, 94%) as a white solid. Mass spectrum: 233 (M+H).

[0606] Intermediate 4: (S)-3-chloro-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine hydrochloride [ka]

[0607] Step 1: (R)-tert-butyl 3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidine-1-carboxylate [ka]

[0608] The title compound was prepared according to the procedure described in Step 1 of Intermediate 1 to give crude (R)-tert-butyl 3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidine-1-carboxylate (8.6 g, 126% yield). Mass spectrum: 333 (M+H).

[0609] Step 2: (R)-3-chloro-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine [ka]

[0610] To a solution of (R)-tert-butyl 3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidine-1-carboxylate (8.6 g, 25.9 mmol) in DCM (60 mL) was added TFA (30 mL) at 0 °C, and the mixture was stirred at this temperature for 2 h. The solvent was removed in vacuo to give a dark liquid, which was diluted with EA, and the organic layer was washed with NaHCO3 solution, brine, dried over Na2SO4, and concentrated to give (R)-3-chloro-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (6 g, quantitative). Mass spectrum: 233 (M+H)

[0611] Intermediate 5: 3-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)pyrrolidine [ka]

[0612] Step 1: 2-Bromo-5-methoxybenzaldehyde [ka]

[0613] To a solution of 2-bromo-5-hydroxybenzaldehyde (10.0 g, 50.0 mmol) in DMF, iodomethane (3.7 ml, 60.0 mmol) and K2CO3 (20.7 g, 150.0 mmol) were added at room temperature. The mixture was then stirred at 44 °C for 8 hours. The mixture was evaporated to give a residue, which was dissolved in EA and washed with 5% LiCl solution (3 × 100 ml). The organic layer was dried, evaporated, and purified by silica gel to give 2-bromo-5-methoxybenzaldehyde (9.0 g, 85% yield). Mass spectrum: 215 (M+1).

[0614] Step 2: 2-(2-bromo-5-methoxyphenyl)-1,3-dioxane [ka]

[0615] To a homogeneous mixture of 2-bromo-5-methoxybenzaldehyde (428 mg, 2.0 mmol), propane-1,3-diol (270 mg, 3.6 mmol), and triethyl orthoformate (296 mg, 2.0 mmol) was added Bi(OTf) (6.5 mg, 1% yield) while stirring at room temperature. After 1.5 h, the mixture was complete, and 20% NaOH solution (10 mL) was added. The mixture was extracted with EA, dried (NaSO), evaporated, and purified by silica gel to give 2-(2-bromo-5-methoxyphenyl)-1,3-dioxane (400 mg, 73% yield). Mass spectrum: 273 (M+1).

[0616] Step 3: (E)-Ethyl 3-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)acrylate [ka]

[0617] To a solution of 2-(2-bromo-5-methoxyphenyl)-1,3-dioxane (272 mg, 1.0 mmol) in 4 mL of CHCN was added ethyl acrylate (86.09 mg, 1.0 mmol), Pd(OAc) (11.2 mg, 0.05 mmol), DIPEA (0.5 mL, 3.0 mmol), and tri(p-tri)phosphine (30 mg, 0.1 mmol). The mixture was degassed for 5 minutes and then refluxed at 100 °C overnight. After cooling to room temperature, the mixture was evaporated and purified by silica gel to give (E)-ethyl 3-(2-(1,3-dioxan-2-yl)-4-methoxyphen-yl)acrylate (60 mg, 20.5% yield). Mass spectrum: 293 (M+1). 1 H-NMR(400 Hz, DMSO) δ= 8.173-8.134 (d, 1H), 7.817-7.796 (d, 1H), 7.097-7.069 (d, 1H),6.976-6.948 (d, 1H), 6.418-6.378 (d, 1H),5.705(s, 1H), 4.208-4.155 (m, 4H), 3.999-3.938(m, 2H), 3.799 (s, 3H), 2.084-2.007 (m, 1H), 1.509-1.476(m, 1H), 1.288-1.252 (m,1H)

[0618] Step 4: Ethyl 3-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)-4-nitrobutanoate [ka]

[0619] To a solution of (E)-ethyl 3-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)acrylate (146 mg, 0.5 mmol) in MeNO (152.5 mg, 2.5 mmol) was added DBU (76 mg, 0.5 mmol) dropwise at 0 °C, and the mixture was stirred at room temperature for 3 h. The mixture was diluted with water, extracted with EA (3 × 5 ml), dried (NaSO), evaporated, and purified by silica gel to give ethyl 3-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)-4-nitrobutanoate (80 mg, 45%) as a white solid. Mass spectrum: 354 (M+1).

[0620] Step 5: 4-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)pyrrolidin-2-one [ka]

[0621] NiCl 2. 6H2O (730 mg, 5.66 mmol) was added to a solution of ethyl 3-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)-4-nitrobutanoate (1.0 g, 2.83 mmol) in 10 ml of MeOH at room temperature. After 5 minutes, NaBH4 (1.07 g, 28.3 mmol) was added in five portions. The mixture was then stirred at room temperature for 30 minutes and at 70 °C overnight. The mixture was cooled to room temperature. It was then filtered, and the filtrate was evaporated and purified by silica gel to give 4-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)pyrrolidin-2-one (670 mg, 85.9% yield) as a white solid. Mass spectrum: 278 (M+1),

[0622] 1H-NMR (400 Hz,DMSO) δ= 7.645 (s, 1H), 7.342-7.291 (d, 1H), 6.986-6.980 (d, 1H), 6.900-6.893 (d,1H), 6.878-6.871 (d, 1H), 5.637(s, 1H), 4.140-4.084 (m, 2H), 3.971-3.897 (m, 3H),3.701 (s, 3H), 3.507-3.463 (m, 1H), 3.118-3.077 (m, 1H), 2.483-2.382 (m, 1H), 2.237-2.174(m,1H), 2.017-2.002(m, 1H),1.434-1.402 (m, 1H).

[0623] Step 6: 3-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)pyrrolidine [ka]

[0624] To a solution of 4-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)pyrrolidin-2-one (670 mg, 2.41 mmol) in 10 ml of THF was added LAH (184 mg, 4.82 mmol) at 0 °C, followed by stirring at room temperature for 5 minutes and then at 70 °C overnight. The mixture was quenched with 0.18 ml of HO, 0.18 ml of 15% NaOH solution, followed by 0.55 ml of HO, then stirred at room temperature for 15 minutes, filtered to obtain a filtrate that was evaporated to give the product 3-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)pyrrolidine (500 mg, 80% yield) as a white solid. Mass spectrum: 264 (M+1).

[0625] Intermediate 6: 3-(4-(2-isopropylphenoxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)pyrrolidine [ka]

[0626] Step 1: 5-(2-isopropylphenoxy)-2-nitrobenzaldehyde [ka]

[0627] To a solution of 5-fluoro-2-nitrobenzaldehyde (20.0 g, 118.0 mmol) in 100 mL of DMF, K2CO3 (32.7 g, 237 mmol) and 2-isopropylphenol (19.25 g, 141.6 mmol) were added and stirred at 120 °C for 1 h. When the reaction was nearly complete, the mixture was evaporated to give a residue, which was dissolved in EA, washed with LiCl solution (3 × 100 mL), dried (Na2SO4), concentrated, and purified by silica gel to give 5-(2-isopropylphenoxy)-2-nitrobenzaldehyde (30 g, 91% yield) as a yellow oil. Mass spectrum: 286 (M+1).

[0628] Step 2: (2-amino-5-(2-isopropylphenoxy)phenyl)methanol [ka]

[0629] To a solution of 5-(2-isopropylphenoxy)-2-nitrobenzaldehyde (15.0 g, 52.6 mmol) in MeOH (100 ml) was added NaBH (4.0 g, 105.25 mmol) at 0 °C, followed by stirring at room temperature for 30 min, cooling to 0 °C again, and slowly adding NiCl 6H O (2.5 g, 105.2 mmol). Then, additional NaBH (4.0 g, 105.25 mmol) was slowly added at 0 °C, followed by stirring at room temperature for 30 min. The mixture was evaporated, diluted HCl solution was added to dissolve the inorganic residue, and then the pH was adjusted to 8 with NH H O, extracted with EA (3 × 50 ml), and the EA layer was washed with brine (2 × 100 ml), dried, filtered, and evaporated to give (2-amino-5-(2-isopropylphenoxy)phenyl)methanol (6.0 g, 44% yield). Mass spectrum: 258(M+1).

[0630] Step 3: (2-iodo-5-(2-isopropylphenoxy)phenyl)methanol [ka]

[0631] A cold solution of sodium nitrite (1.6 g, 23.0 mmol) in 5 mL of water was added dropwise to a stirred, cooled suspension of (2-amino-5-(2-isopropylphenoxy)phenyl)methanol (5.0 g, 19.0 mmol) in water (15 mL) and hydrochloric acid (15 mL). Upon completion of diazotization, a solution of potassium iodide in water (5 mL) was added. After 1 h at room temperature, the mixture was quenched with NaHSO, extracted with EA (3 × 20 mL), dried over NaSO, evaporated, and purified on silica gel to give 2-iodo-5-(2-isopropylphenoxy)phenyl)methanol (2.4 g, 34% yield). Mass spectrum: 369 (M+1).

[0632] Step 4: 2-(2-iodo-5-(2-isopropylphenoxy)benzyloxy)tetrahydro-2H-pyran [ka]

[0633] To a solution of 2-iodo-5-(2-isopropylphenoxy)phenyl)methanol (1.0 g, 2.7 mmol) in DCM (8 mL) was added DHP (75 mg, 8.96 mmol) and PPTS (1.0 g, 4.05 mmol) at 0 °C, followed by stirring at room temperature overnight. The mixture was diluted with DCM (20 mL) and washed with HO (3 × 20 mL). The DCM layer was dried and evaporated to give crude 2-(2-iodo-5-(2-isopropylphenoxy)benzyloxy)tetrahydro-2H-pyran (2.4 g, 200% yield). Mass spectrum: 453 (M+1).

[0634] Step 5: (E)-Ethyl 3-(4-(2-isopropylphenoxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)acrylate [ka]

[0635] The title compound was prepared according to the procedure described in Step 3 of Intermediate 5 to give (E)-ethyl 3-(4-(2-isopropylphenoxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)acrylate (1.6 g, 88% yield). Mass spectrum: 425 (M+1).

[0636] Step 6: Ethyl 3-(4-(2-isopropylphenoxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)-4-nitrobutanoate [ka]

[0637] The title compound was prepared according to the procedure described in Step 4 of Intermediate 5 to give ethyl 3-(4-(2-isopropylphenoxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)-4-nitrobutanoate (1.5 g, 83.0% yield). Mass spectrum: 486 (M+1).

[0638] Step 7: 4-(4-(2-isopropylphenoxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)pyrrolidin-2-one [ka]

[0639] The title compound was prepared according to the procedure described in Step 5 of Intermediate 5 to give 4-(4-(2-isopropylphenoxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)pyrrolidin-2-one (730 mg, 60.8% yield). Mass spectrum: 410 (M+1).

[0640] Step 8: 3-(4-(2-isopropylphenoxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)pyrrolidine [ka]

[0641] The title compound was prepared according to the procedure described in Step 6 of Intermediate 5 to give 3-(4-(2-isopropylphenoxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)pyrrolidine (530 mg, 69.2% yield). Mass spectrum: 396 (M+1).

[0642] Intermediate 7: (S)-5-fluoro-N-(pyrrolidin-3-yl)pyridin-2-amine [ka]

[0643] Step 1: (S)-tert-butyl 3-(5-fluoropyridin-2-ylamino)pyrrolidine-1-carboxylate [ka]

[0644] To a solution of 2-bromo-5-fluoropyridine (4.772 g, 27.11 mmol) in toluene (55 mL) was added Pd(cAc) (607.3 mg, 2.711 mmol), BINAP (1.686 g, 2.711 mmol), and t-BuoNa (7.81 g, 81.33 mmol) under N, and the reaction mixture was stirred at 80 °C for 4 h. The reaction was diluted with EA (50 mL), washed with brine, and dried over NaSO. Concentrated to dryness, the residue was purified by silica gel to give tert-butyl (S)-tert-butyl 3-(5-fluoropyridin-2-ylamino)pyrrolidine-1-carboxylate (600 mg, 15% yield). Mass spectrum: 282 (M+H).

[0645] Step 2: (S)-5-Fluoro-N-(pyrrolidin-3-yl)pyridin-2-amine [ka]

[0646] To a solution of 5-fluoro-N-(pyrrolidin-3-yl)pyridin-2-amine (600 mg, 2.135 mmol) in EA (10 mL) was added EA / HCl (10 mL), the resulting mixture was stirred at room temperature for 1 hour, and the mixture was concentrated to give (S)-5-fluoro-N-(pyrrolidin-3-yl)pyridin-2-amine (2.5 g, 80% yield). Mass spectrum: 189 (M+H).

[0647] Intermediate 8: 4-(2-chlorobenzoyl)-2-fluorobenzaldehyde [ka]

[0648] Step 1: 4-(Dibromomethyl)-2-fluorobenzonitrile [ka]

[0649] To a solution of 2-fluoro-4-methylbenzonitrile (5.4 g, 40 mmol) in CCl (40 mL) was added NBS (15.7 g, 88 mmol), AIBN (657 mg, 4 mmol), and the resulting mixture was stirred at 90 °C under N for 24 h. The mixture was concentrated to give 4-(dibromomethyl)-2-fluorobenzonitrile (8.8 g, 80% yield). Mass spectrum: 292 (M+H).

[0650] Step 2: 2-Fluoro-4-formylbenzonitrile [ka]

[0651] To a solution of 4-(dibromomethyl)-2-fluorobenzonitrile (8.8 g, 30 mmol) in 90 mL of EtOH / HO was added AgNO (10.2 g, 60 mmol), and the resulting mixture was refluxed for 3 h. The reaction was diluted with DCM (100 mL), washed with brine, and dried over NaSO. Concentrated to dryness, the residue was purified by silica gel to give 2-fluoro-4-formylbenzonitrile (2 g, 44.4% yield). Mass spectrum: 150 (M+H).

[0652] Step 3: 4-((2-chlorophenyl)(hydroxy)methyl)-2-fluorobenzonitrile [ka]

[0653] To a solution of Mg (300 mg, 12.5 mmol), LiCl (265 mg, 6.25 mmol) in THF (20 mL) was added DIBAL-H (0.05 mL) and allowed to warm to room temperature for 5 minutes. The reaction was cooled to -30 °C, and 1-bromo-3-chlorobenzene (958 mg, 5 mmol) was added dropwise over 30 minutes to -20 °C and warmed to room temperature for 1 hour. The above solution was then added to 2-fluoro-4-formylbenzonitrile (410 mg, 2.75 mmol) in THF (5 mL) and allowed to warm to 0 °C. The reaction mixture was stirred at 0 °C for 15 minutes, and NH4Cl was added to quench. The layers were separated, dried over Na2SO4, and concentrated to give 4-((2-chlorophenyl)(hydroxy)methyl)-2-fluorobenzonitrile (750 mg, 40% yield). Mass spectrum: 244 (M-17).

[0654] Step 4: 4-(2-chlorobenzoyl)-2-fluorobenzonitrile [ka]

[0655] To a solution of 4-((2-chlorophenyl)(hydroxy)methyl)-2-fluorobenzonitrile (740 mg, 2.75 mmol) in DCM (15 mL) was added Dess-Martin (1.4 g, 3.3 mmol) with stirring at room temperature for 1.5 h. The reaction was concentrated to dryness, and the residue was purified by preparative TLC to give 4-(2-chlorobenzoyl)-2-fluorobenzonitrile (530 mg, 80% yield) (mass spectrum not available).

[0656] Step 5: 4-((2-chlorophenyl)(hydroxy)methyl)-2-fluorobenzaldehyde [ka]

[0657] To a solution of 4-(2-chlorobenzoyl)-2-fluorobenzonitrile (520 mg, 2 mmol) in DCM (15 mL) was added EtN (203 mg, 2 mmol) and DIBAL-H (1.4 g, 3.3 mmol) in hexane (1.5 M) at −78° C. over 45 min. The reaction was poured into ice water, extracted, separated, dried over NaSO, and concentrated to give 4-((2-chlorophenyl)(hydroxy)methyl)-2-fluorobenzaldehyde (470 mg, 70%). Mass spectrum: 265 (M+H).

[0658] Step 6: 4-(2-chlorobenzoyl)-2-fluorobenzaldehyde [ka]

[0659] The title compound was prepared according to the procedure described in Step 4 to give 4-(2-chlorobenzoyl)-2-fluorobenzaldehyde (580 mg, quantitative). Mass spectrum: None. 1 H-NMR (400 Hz, DMSO) δ= 10.220 (s, 1H), 8.098-8.116 (m, 2H), 7.566-7.657(m, 5H).

[0660] Intermediate 9: (2'-ethyl-4-(pyrrolidin-3-yl)biphenyl-3-yl)methanol [ka]

[0661] Step 1: 5-Hydroxy-2-(5-oxopyrrolidin-3-yl)benzaldehyde [ka]

[0662] To a solution of 4-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)pyrrolidin-2-one (1 g, 3.6 mmol) (Step 5 of Intermediate 5) in 4 mL of MeCN at 0 °C, 3 N HCl (4 mL) was slowly added, the mixture was stirred at room temperature for 30 min, water was added, extracted with EA, washed with brine, dried over Na2SO4, and the solvent was removed to give the crude product, which was dissolved in 10 mL of DCM. The solution was stirred at 0 °C, BBr3 (0.6 mL, 7.2 mmol) was added dropwise, and stirred at room temperature for 1 h. The mixture was poured into ice water and extracted with EA / THF (v:v=3 / 1). The combined organic phases were washed with brine, dried over Na2SO4, and the solvent was removed to give the crude product, which was purified by silica gel to give 5-hydroxy-2-(pyrrolidin-3-yl)benzaldehyde (400 mg, yield 54.0%). Mass spectrum: 206 (M+1).

[0663] Step 2: 3-Formyl-4-(5-oxopyrrolidin-3-yl)phenyl trifluoromethanesulfonate [ka]

[0664] To a solution of 5-hydroxy-2-(5-oxopyrrolidin-3-yl)benzaldehyde (100 mg, 0.49 mmol) in 2 mL of DCM was added PhNTf2 (208 mg, 0.58 mmol) and DIPEA (0.24 mL, 1.5 mmol). The mixture was stirred at room temperature for 2 h, water was added, extracted with DCM, the organic phase was washed with water, brine, dried over Na2SO4, and the solvent was removed to give the crude product, which was purified by silica gel to give 3-formyl-4-(5-

[0665] (Oxopyrrolidin-3-yl)phenyl trifluoromethanesulfonate (160 mg, yield 94.0%) was obtained. Mass spectrum: 338 (M+1).

[0666] Step 3: 2'-Ethyl-4-(5-oxopyrrolidin-3-yl)biphenyl-3-carbaldehyde [ka]

[0667] To a solution of 3-formyl-4-(pyrrolidin-3-yl)phenyl trifluoromethanesulfonate (300 mg, 0.89 mmol), 2-ethylphenylboronic acid (160 mg, 1.07 mmol) in 10 mL of dioxane / water (v:v 4 / 1) was added PdCl(dppf) (72 mg, 0.09 mmol), and KPO (566 mg, 2.67 mmol). The mixture was stirred under N at 90 °C for 2 h. The mixture was diluted with water and extracted with EA. The organic phase was washed with water, brine, dried over NaSO, and the solvent was removed to give the crude product, which was purified by silica gel chromatography to give 2'-ethyl-4-(5-oxopyrrolidin-3-yl)biphenyl-3-carbaldehyde (210 mg, 80.1% yield). Mass spectrum: 294 (M+1).

[0668] Step 4: (2'-ethyl-4-(pyrrolidin-3-yl)biphenyl-3-yl)methanol [ka]

[0669] To a suspension of LAH (0.6225 g, 16.3 mmol) in 10 mL of THF at 0 °C, a separate solution of 2'-ethyl-4-(5-oxopyrrolidin-3-yl)biphenyl-3-carbaldehyde (1.6 g, 5.4 mmol) in 10 mL of THF was added dropwise. The mixture was refluxed under N for 2 h, quenched with water (0.6 mL), NaOH (15%) (0.6 mL), and water (1.8 mL), filtered, and the filtrate was concentrated to give the crude product, which was purified by silica gel to give the product (2'-ethyl-4-(pyrrolidin-3-yl)biphenyl-3-yl)methanol (800 mg, 48.1% yield). Mass spectrum: 282 (M+1).

[0670] Intermediate 10: (2'-cyclopropyl-4-(pyrrolidin-3-yl)biphenyl-3-yl)methanol [ka]

[0671] Step 1: 2-(5-oxopyrrolidin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde [ka]

[0672] To a solution of 3-formyl-4-(5-oxopyrrolidin-3-yl)phenyl trifluoromethanesulfonate (3 g, 8.9 mmol) (Intermediate 9 (Step 2)) in 8 mL of dioxane, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.3 g, 13.3 mmol), AcOK (1.7 g, 17.8 mmol), and Pd(dppf)Cl (400 mg, 0.89 mmol) were added, and the mixture was stirred at 100 °C under N for 2 h. After completion of the reaction, the mixture was diluted with water and extracted with EA. The organic layer was washed with water, brine, dried over NaSO, and the solvent was removed to give the crude product (2.8 g, quantitative) (directly usable). Mass spectrum: 316 (M+H).

[0673] Step 2: 2'-cyclopropyl-4-(5-oxopyrrolidin-3-yl)biphenyl-3-carbaldehyde [ka]

[0674] To a solution of 2-(5-oxopyrrolidin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.2 g, 7 mmol) in dioxane / HO (16 mL / 1 mL) was added 1-cyclopropyl-2-iodobenzene (2 g, 8.4 mmol), KCO (1.98 g, 14 mmol), and Pd(dppf)Cl (200 mg, 0.7 mmol). The mixture was stirred at 100 °C under N for 5 h, diluted with EA, and the mixture was washed with water, brine, dried over NaSO, and the solvent was removed to give the crude product, which was purified by silica gel to give the product 2'-cyclopropyl-4-(5-oxopyrrolidin-3-yl)biphenyl-3-carbaldehyde (500 mg, 23.9% yield). Mass spectrum: 321 (M+H).

[0675] Step 3: (2'-cyclopropyl-4-(pyrrolidin-3-yl)biphenyl-3-yl)methanol [ka]

[0676] The title compound was prepared according to the procedure described in Step 4 of Intermediate 9 to give (2'-cyclopropyl-4-(pyrrolidin-3-yl)biphenyl-3-yl)methanol (200 mg, 50% yield). Mass spectrum: 294 (M+H).

[0677] Section B: Synthesis of Examples

[0678] Example 4: 2-(1-o-tolylpyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-1) [ka]

[0679] The title compound was prepared according to the procedure described in Example 1 using Intermediate 2 and 1-bromo-2-methylbenzene to give 2-(1-o-tolylpyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (60 mg, 17.8% yield). Mass spectrum: 323 (M+H), t R =3.098 minutes, 1 H-NMR (400 Hz, CDCl3) δ= 8.454 (s, 1H), 7.773-7.801(q, 1H), 7.141-7.176 (m, 2H), 6.829-6.957 (m, 3H), 5.658-5.688 (m, 1H), 3.706-3.747(m, 1H), 3.475-3.534 (m, 1H), 3.304-3.336 (m, 1H), 3.201-3.254 (m, 1H), 3.416-3.465(m, 1H), 2.359 (s, 3H), 2.189-2.227 (m, 1H).

[0680] Example 5: 2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (Compound 1-2) [ka]

[0681] To a solution of 2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (1.2 g, 5.2 mmol) in DMF (15 mL) was added 2-fluorobenzonitrile (814 mg, 6.7 mmol), K2CO3 (2.2 g, 15.6 mmol) at room temperature, and the mixture was stirred at 100 °C overnight, diluted with EA, washed with water and brine, dried over Na2SO4, the solvent was removed, and purified by silica gel to give 2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (400 mg, 23% yield) as a liquid. Mass spectrum: 334 (M+H), t R =1.724 minutes, 1H-NMR (400 Hz, CDCl3) δ= 6.469 (s, 1H), 7.790-7.817(m, 1H), 7.475-7.498 (m, 1H), 7.354-7.398 (m, 1H), 6.816-6.838 (d, 1H), 6.678-6.843(m, 2H), 5.776-5.787 (m, 1H), 4.105-4.146 (m, 1H), 3.882-3.947 (m, 1H), 3.743-3.793(m, 2H), 2.330-2.383 (m, 2H).

[0682] Example 6: 2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-3) [ka]

[0683] To a solution of 2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (Example 5) (100 mg, 0.3 mmol) in NaOH solution (6 mmol / mL, 0.3 mL) and MeOH (5 mL) was added HO (30%, 3 mL), the mixture was heated to 50° C. for 2 h, quenched by adding HCl solution (1N) to pH=3, extracted with EA, and the solvent was removed to give the crude product, which was purified by silica gel to give 2-(3-(5-trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (30 mg, 28% yield) as a white solid. Mass spectrum: 352 (M+H), t R =1.350 minutes, 1H-NMR (400 Hz, CDCl3) δ= 8.444 (s, 1H), 7.783-7.877(m, 3H), 7.398-7.440 (m, 1H), 7.031-7.085 (m, 2H), 6.802-6.823 (d, 1H), 5.817 (br,1H), 5.683-5.716 (m, 1H), 3.661-3.702 (m, 1H), 3.532-3.591 (m, 1H), 3.394-3.423(d, 1H), 3.237-3.294 (m, 1H), 2.435-2.489 (m, 1H), 2.225-2.260 (m, 1H)

[0684] Example 7: (S)-2-(1-o-tolylpyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-7) [ka]

[0685] The title compound was prepared according to the procedure described in Example 1 using t-BuOK to give (S)-2-(1-o-tolylpyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (40 mg, 31% yield). Mass spectrum: 323 (M+H), t R =3.228 minutes, 1 H-NMR (400 Hz, CDCl3) δ= 8.450 (s, 1H), 7.771-7.80(m, 1H), 7.146-7.17 (m, 2H), 6.829-6.956 (m, 3H), 5.663-5.679 (m, 1H), 3.705-3.746(m, 1H), 3.493-3.515 (m, 1H), 3.302-3.335 (m, 1H), 3.219-3.342 (m, 1H), 2.414-2.464(m, 1H), 2.358 (s, 3H), 2.2 (m, 1H).

[0686] Example 8: (R)-2-(1-o-tolylpyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-8) [ka]

[0687] The title compound was prepared according to the procedure described in Example 1 using t-BuOK to give (R)-2-(1-o-tolylpyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (30 mg, 5% yield). Mass spectrum: 323 (M+H), t R =3.241 minutes, 1 H-NMR (400 Hz, CDCl3) δ= 8.450 (s, 1H), 7.771-7.80(m, 1H), 7.146-7.17 (m, 2H), 6.829-6.956 (m, 3H), 5.656-5.687 (m, 1H), 3.705-3.746(m, 1H), 3.493-3.515 (m, 1H), 3.302-3.335 (m, 1H), 3.219-3.342 (m, 1H), 2.414-2.464(m, 1H), 2.358 (s, 3H), 2.187-2.227 (m, 1H).

[0688] Example 9: (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (Compound 1-9) [ka]

[0689] The title compound was prepared according to the procedure described in Example 5 using (R)-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine and 2-fluorobenzonitrile to give (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (1.9 g, 29% yield). Mass spectrum: 334 (M+H), t R =2.909 minutes, 1H-NMR (400 Hz, CDCl3) δ= 8.47 (s, 1H), 7.798-7.826(m, 1H), 7.482-7.505(m, 1H), 7.362-7.406 (m, 1H), 6.825-6.846 (d, 1H), 6.686-6.752(m, 2H), 5.78-5.795 (m, 1H), 4.113-4.154 (m, 1H), 3.890-3.913 (m, 1H), 3.759-3.801(m, 2H), 2.338-2.391 (m, 2H).

[0690] Example 10: (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-10) [ka]

[0691] The title compound was prepared according to the procedure described in Example 6 using (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile to give (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (515 mg, 39.5% yield). Mass Spectrum: 352 (M+H), t R =2.324 minutes, 1 H-NMR (400 Hz, CDCl3) δ= 8.456 (s, 1H), 7.792-7.884(m, 3H), 7.406-7.448 (m, 1H), 7.039-7.093 (m, 2H), 6.810-6.832 (d, 1H), 5.826 (br,1H), 5.691-5.720 (m, 1H), 3.669-3.709 (m, 1H), 3.539-3.581 (m, 1H), 3.404-3.432(d, 1H), 3.258-3.302 (m, 1H), 2.444-2.480 (m, 1H), 2.249-2.267 (m, 1H).

[0692] Example 11: (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (Compound 1-11) [ka]

[0693] The title compound was prepared according to the procedure described in Example 5 using (R)-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine hydrochloride and 2-fluorobenzonitrile to give (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (1.3 g, 60% yield). Mass spectrum: 334 (M+H), t R =2.907 minutes, 1 H-NMR (400 Hz, CDCl3) δ= 8.47 (s, 1H), 7.798-7.826(m, 1H), 7.482-7.505(m, 1H), 7.362-7.406 (m, 1H), 6.825-6.846 (d, 1H), 6.686-6.752(m, 2H), 5.773-5.5.806 (m, 1H), 4.113-4.178 (m, 1H), 3.890-3.954 (m, 1H), 3.750-3.800(m, 2H), 2.349-2.411 (m, 2H).

[0694] Example 12: (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-12) [ka]

[0695] The title compound was prepared according to the procedure described in Example 6 using (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile to give (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (510 mg, 39.3% yield). Mass Spectrum: 352 (M+H), t R =2.335 minutes, 1 H-NMR (400 Hz, CDCl3) δ= 8.455(s, 1H), 7.797-7.822(m, 3H), 7.409-7.447 (m, 1H), 7.043-7.095 (m, 1H), 6.813-6.835(m, 1H), 5.881 (br,1H), 5.708 (br, 1H), 3.674-3.713 (m, 1H), 3.544-3.600 (m, 1H), 3.405-3.431 (m, 1H),3.251-3.403 (m, 1H), 2.462-2.499 (m, 1H), 2.253-2.399 (m, 1H).

[0696] Example 13: (S)-(2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanamine HCl salt (Compound 1-13) [ka]

[0697] To a solution of (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Example 12) (130 mg, 0.54 mmol) in dry THF at 0° C. was added LAH (30 mg, 0.8 mmol), the mixture was heated to 50° C. for 3 h, quenched with NHCl solution, diluted with EA, the organic layer was washed with brine, dried over NaSO, and the solvent was removed to give the crude product, which was purified by stirring in HCl / EA for 30 min, filtered, and washed with ether (10 ml×2) to give (S)-(2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanamine HCl salt (30 mg, 15% yield) as a white solid. Mass spectrum: 338 (M+H), t R =1.793 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.6 (br, 4H), 8.078-8.107 (dd, 1H), 7.509-7.526(d, 1H), 7.312-7.350 (m, 1H), 7.207-7.228 (m, 1H), 7.071-7.110 (m, 2H), 5.653-5.681(m, 1H), 4.092-4.120 (m, 2H), 3.650-3.690 (m, 1H), 3.393-3.415 (m, 1H), 3.215-3.292(m, 2H), 2.432-2.483 (m, 1H), 2.112-2.145 (m, 1H).

[0698] Example 14: (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenol (Compound 1-14) [ka]

[0699] Step 1: (S)-2-(1-(2-nitrophenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine [ka]

[0700] The title compound was prepared according to the procedure described in Example 5 using (S)-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine hydrochloride (Intermediate 3) and 1-fluoro-2-nitrobenzene to give (S)-2-(1-(2-nitrophenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (2.8 g, 80% yield). Mass spectrum: 354 (M+H).

[0701] Step 2: (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)aniline [ka]

[0702] To a solution of (S)-2-(1-(2-nitrophenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (2.8 g, 8 mmol) in MeOH / HO (50 mL / 50 mL) was added Fe powder and NH4Cl, and the mixture was stirred at 80 °C for 2 h. The mixture was filtered, and the filtrate was concentrated and purified by silica gel to give (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)aniline (1.2 g, 46% yield) as a brown oil. Mass spectrum: 324 (M+H).

[0703] Step 3: (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenol [ka]

[0704] To a solution of (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)aniline (1.2 g, 3.7 mmol) in HO / concentrated HSO (4 mL / 4 mL) at 0 °C was added NaNO (384 mg, 5.5 mmol) in HO (2 mL) and stirred at 80 °C for 2 h. The mixture was cooled to room temperature, poured into ice water, adjusted to pH 7 with NaHCO solution, extracted with EA, dried over NaSO, and the solvent was removed to give the crude product, which was purified by silica gel to give (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenol (290 mg, 20% yield) as a clear oil. Mass spectrum: 325 (M+H), t R =2.298 minutes, 1 H-NMR (400 Hz, DMSO) δ= 9.073 (s, 1H), 8.615 (s,1H), 8.055-8.083 (dd, 1H), 7.012-7.034 (d, 1H), 6.613-6.735 (m, 4H), 5.588-5.617(m, 1H), 3.731-3.774 (m, 1H), 3.402-3.501 (m, 2H), 3.158-3.212 (m, 1H), 2.309-2.359(m, 1H), 2.055-2.089 (m, 1H)

[0705] Example 15a: (S)-2-(1-(2-isopropoxyphenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-15) [ka]

[0706] To a solution of (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenol (64 mg, 0.2 mmol) (Example 14) in dry DMF (2 mL) at 0° C., NaH (44 mg, 0.22 mmol, 60% dispersion in mineral oil) was added and stirred at room temperature for 30 minutes, then 2-iodopropane (81 mg, 0.48 mmol) was added and the mixture was stirred for 24 hours, the mixture was diluted with EA, washed with LiCl solution, brine, dried over Na2SO4, and the solvent was removed to give the crude product, which was purified by silica gel to give (S)-2-(1-(2-isopropoxyphenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (30 mg, 95% yield) as a clear oil. Mass spectrum: 367 (M+H), t R =3.402 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.616(s, 1H), 8.055-8.083(dd,1H), 7.011-7.034 (d, 1H), 6.698-6.890 (m, 4H), 6.599-6.527 (m, 1H), 4.500-4.545(m, 1H), 3.682-3.724 (m, 1H), 3.455-3.509 (m, 2H), 3.192-3.247 (m, 1H), 2.307-2.356(m, 1H), 2.083-2.118 (m, 1H), 1.191-1.236 (m, 6H).

[0707] Example 15b: (S)-2-(1-(2-(benzyloxy)phenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-26) [ka]

[0708] The title compound was prepared according to the procedure described in Example 15a using (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenol to give (S)-2-(1-(2-(benzyloxy)phenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (25 mg, 30% yield). Mass spectrum: 415 (M+H), t R =3.623 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.583 (s, 1H), 8.048-8.076(dd, 1H), 7.387-7.425 (m, 2H), 7.283-7.344 (m, 3H), 6.982-7.017 (m, 2H), 6.738-6.875(m, 3H), 5.600 (br, 1H), 5.050 (s, 2H), 3.673-3.716 (m, 1H), 3.466-3.529 (m, 2H),3.213-3.255 (m,1H), 2.307-2.341 (m, 1H), 2.103 (m, 1H).

[0709] Example 15c: (S)-2-(1-(2-(cyclopentyloxy)phenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-25) [ka]

[0710] The title compound was prepared according to the procedure described in Example 15a using (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenol to give (S)-2-(1-(2-(cyclopentyloxy)phenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (41.5 mg, 52.6% yield). Mass spectrum: 393 (M+H), t R =3.691 minutes, 1H-NMR (400 Hz, DMSO) δ= 8.607 (s, 1H), 8.061-8.090(dd, 1H), 7.013-7.034 (d, 1H), 6.688-6.851 (m, 4H), 5.608 (br, 1H), 4.750-4.778(m, 1H), 3.535-3.627 (m, 2H), 3.400-3.430 (m, 1H), 3.159-3.214 (m, 1H), 2.314-2.363(m, 1H), 2.092-2.123 (m, 1H), 2.168-2.184 (m, 2H), 1.497-1.631 (m, 6H).

[0711] Example 16: (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-17) [ka]

[0712] Step 1: (R)-2-(3-hydroxypyrrolidin-1-yl)benzonitrile [ka]

[0713] To a solution of (S)-pyrrolidin-3-ol hydrochloride (1 g, 8.1 mmol) and 2-fluorobenzonitrile (1.27 g, 10.5 mmol) in DMF (20 mL) was added K2CO3 (3.35 g, 24.3 mmol) and stirred at 100 °C overnight. Quenched with water, extracted with EA, washed with LiCl solution, brine, dried over Na2SO4, and the solvent was removed to give crude (R)-2-(3-hydroxypyrrolidin-1-yl)benzonitrile (1.7 g, 111% yield), which was used directly in the next step without further purification. Mass spectrum: 189 (M+H).

[0714] Step 2: (R)-2-(3-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile [ka]

[0715] To a solution of (R)-2-(3-hydroxypyrrolidin-1-yl)benzonitrile (244 mg, 1.3 mmol) in dry DMF (2 mL) at 0 °C, NaH (120 mg, 4 mmol, 60% dispersion in mineral oil) was added and stirred at this temperature for 30 min. Then, 2,3-dichloro-5-(trifluoromethyl)pyridine (216 mg, 1 mmol) in 1 mL of DMF was added, and the mixture was stirred at the same temperature for 1 h. The reaction mixture was poured into ice water and extracted with EA. The organic layer was washed with LiCl solution, brine, dried over Na2SO4, and the solvent was removed to give a brown oil, which was purified by silica gel to give (R)-2-(3-(3-(chloro-5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (220 mg, 59.9% yield) as a pale yellow oil. Mass spectrum: 368 (M+H).

[0716] Step 3: (R)-2-(3-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0717] (R)-2-(3-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (100 mg, 0.27 mmol) was dissolved in H2SO4 (濃縮)at 0°C, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, the pH adjusted to 7 with NaHCO3 solution, extracted with EA, washed with brine, dried over Na2SO4, and the solvent removed to give the crude product, which was purified by silica gel to give (R)-2-(3-(3-(chloro-5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (45 mg, 45% yield). Mass spectrum: 386 (M+H), t R =2.665 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.606 (s, 1H), 8.407-8.412(d, 1H), 7.817 (br, 2H), 7.249-7.324 (m, 3H), 6.740-6.835 (m, 2H), 5.735 (br, 1H),3.859-3.90 (m, 1H), 3.308-3.401 (m, 3H), 2.346 (m, 1H), 2.236-2.344 (m, 1H)

[0718] Example 17: (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-16) [ka]

[0719] Step 1: (S)-2-(3-hydroxypyrrolidin-1-yl)benzonitrile [ka]

[0720] The title compound was prepared according to the procedure described in Example 16 (Step 1) using (S)-pyrrolidin-3-ol hydrochloride to give (S)-2-(3-hydroxypyrrolidin-1-yl)benzonitrile (750 mg, 82% yield). Mass spectrum: 189 (M+H).

[0721] Step 2: (S)-2-(3-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile [ka]

[0722] The title compound was prepared according to the procedure described in Example 16 (Step 2) using (S)-2-(3-hydroxypyrrolidin-1-yl)benzonitrile to give (S)-2-(3-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (160 mg, 53% yield). Mass spectrum: 368 (M+H).

[0723] Step 3: (S)-2-(3-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0724] The title compound was prepared according to the procedure described in Example 16 (Step 3) using (S)-2-(3-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile at 90° C. for 1.5 hours to give (S)-2-(3-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (110 mg, 66.7% yield). Mass spectrum: 386 (M+H), t R =2.736 minutes, 1H-NMR (400 Hz, DMSO) δ= 8.602 (s, 1H), 8.401 (s,1H), 7.772 (s, 1H), 7.241-7.272 (m, 3H), 6.698-6.902 (m, 2H), 5.732 (s, 1H), 3.848-3.889(m, 1H), 3.508-3.526(m, 1H), 3.289-3.351 (m, 2H), 2.511 (m, 1H), 2.236-2.335 (m,1H).

[0725] Example 18: (S)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-19) [ka]

[0726] Step 1: (S)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzonitrile [ka]

[0727] The title compound was prepared according to the procedure described in Example 16 (Step 2) using (S)-2-(3-hydroxypyrrolidin-1-yl)benzonitrile and 2,6-dichloroquinoline to give (S)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzonitrile (210 mg, 60% yield). Mass spectrum: 350 (M+H).

[0728] Step 2: (S)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0729] The title compound was prepared according to the procedure described in Example 16 (Step 3) using (S)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzonitrile at 90° C. for 1.5 hours to give (S)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzamide (60 mg, 51.9% yield). Mass spectrum: 368 (M+H), t R =2.774 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.217-8.239 (d, 1H), 8.022(s, 1H), 7.670-7.805 (m, 3H), 7.219-7.281 (m, 3H), 7.048-7.071 (d, 2H), 5.796 (br,1H), 3.851-3.893 (m, 1H), 3.515-3.533 (m, 1H), 3.318-3.359 (m, 2H), 2.336-2.370(m, 1H), 2.237-2.246 (m, 1H).

[0730] Example 19: (R)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-18) [ka]

[0731] Step 1: (R)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzonitrile [ka]

[0732] The title compound was prepared according to the procedure described in Example 16 (Step 2) using (R)-2-(3-hydroxypyrrolidin-1-yl)benzonitrile and 2,6-dichloroquinoline to give (R)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzonitrile (250 mg, 71% yield). Mass spectrum: 350 (M+H).

[0733] Step 2: (R)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0734] The title compound was prepared according to the procedure described in Example 16 (Step 3) using (R)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzonitrile at 90° C. for 1.5 hours to give (R)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzamide (55 mg, 48% yield). Mass spectrum: 368 (M+H), t R =2.813 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.230 (s, 1H), 8.034 (s,1H), 7.784-7.837 (m, 2H), 7.697 (m, 1H), 7.270-7.360 (m, 3H), 7.061-7.080 (d, 2H),6.748-6.860 (m, 2H), 5.804 (br, 1H), 3.886-3.899(m, 1H), 3.390 (m, 3H), 2.380 (m,1H), 2.252 (m, 1H).

[0735] Example 20: (R)-(2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanamine (Compound 1-20) [ka]

[0736] To a solution of (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Example 10) (33 mg, 0.1 mmol) in EtOH (2 mL) was added Raney nickel (100 mg wet), the mixture was stirred under H atmosphere at 60° C. for 1 h, filtered, the solvent was removed, and the residue was purified by silica gel to give the product, which was stirred in HCl / EA to give (R)-(2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanamine HCl salt (20 mg, 53.6%). Mass spectrum: 338 (M+H), t R =1.758 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.61 (s, 1H), 8.406 (br,3H), 8.084-8.150 (m, 1H), 7.452-7.471 (d, 1H), 7.307-7.345 (t, 1H), 7.181-7.201(d, 1H), 7.057-70.94 (m, 2H), 5.648-5.676 (m, 1H), 4.064-4.125 (m, 1H), 3.602-3.642(m, 2H), 3.343-3.401 (m, 1H), 3.343-3.401 (m, 1H), 3.144-3.237 (m, 2H), 2.421-2.472(m, 1H), 2.091-2.141 (m, 1H).

[0737] Example 21: (R)-(2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanamine (Compound 1-23) [ka]

[0738] Step 1: (S)-5-Bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile [ka]

[0739] The title compound was prepared according to the procedure described in Example 5 using (S)-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine hydrochloride (Intermediate 3) and 5-bromo-2-fluorobenzonitrile to give (S)-5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (3.3 g, 81% yield). Mass spectrum: 412 (M+H).

[0740] Step 2: (S)-5-Bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0741] The title compound was prepared according to the procedure described in Example 16 (Step 3) using (S)-5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile at 90° C. for 1 hour to give (S)-5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (1.8 g, 82% yield). Mass spectrum: 430 (M+H).

[0742] Step 3: (S)-5-cyano-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0743] To a solution of (S)-5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (42.9 mg, 0.1 mmol), Pd(dba) (2.25 mg, 0.1 mmol), and dppf (5.78 mg, 0.1 mmol) in DMF (3 mL) was added Zn(Cn) (11.2 mg, 1 mmol), and the mixture was stirred in a microwave at 80 °C for 10 min, filtered, and the filtrate was diluted with water, extracted with EA, washed with LiCl solution, brine, dried over NaSO, and the solvent was removed to give the crude product, which was purified by silica gel to give (S)-5-cyano-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (9 mg, 23% yield). Mass spectrum: 377 (M+H), t R =2.386 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.623 (s, 1H), 8.064-8.093(m, 1H), 7.950 (s, 1H), 7.486-7.605 (m, 3H), 7.007-7.029 (d, 1H), 6.807-6.829 (d,1H), 5.707 (br, 1H), 3.876-3.918 (m, 1H), 3.587-3.612 (m, 1H), 3.477-3.497 (m, 1H),3.314 (m, 1H), 2.252-2.308 (m, 2H).

[0744] Example 22: (S)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (Compound 1-32) [ka]

[0745] To a solution of (S)-5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (42.9 mg, 0.1 mmol) (Example 22 (Step 2)) and phenylboronic acid (134 mg, 0.11 mmol) in MeCN / HO (1 mL / 1 mL) was added KCO (27.6 mg, 0.2 mmol) and PdCl(dppf) (4 mg, 10 wt%), the mixture was stirred in a microwave at 80 °C for 10 min, filtered, and the filtrate was diluted with water, extracted with EA, washed with LiCl solution, brine, dried over NaSO, and the solvent was removed to give the crude product. This was purified by silica gel to give (S)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (20 mg, 46% yield). Mass spectrum: 428 (M+H), t R =2.911 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.631 (s, 1H), 8.059-8.087(dd, 1H), 7.881 (s, 1H), 7.532-7.612 (m, 4H), 7.026-7.527 (m, 4H), 7.004-7.026 (d,1H), 6.846-6.859 (d, 1H), 5.683 (m, 1H), 3.599-3.901 (m, 1H), 3.555-3.599(m, 1H),3.262-3.325 (m, 2H), 2.198-2.357 (m, 2H)

[0746] Example 23: (S)-2'-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (Compound 1-64) [ka]

[0747] The title compound was prepared according to the procedure described in Example 22 using dioxane / HO as the solvent to give (S)-2'-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (30 mg, 20% yield). Mass spectrum: 462 (M+H), t R =3.147 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.633 (s, 1H), 8.064-8.092(dd, 1H), 7.813 (s, 1H), 7.522-7.542 (d, 1H), 7.313-7.408 (m, 1H), 7.016-7.037 (d,1H), 6.832-6.853 (d, 1H), 5.704 (m, 1H), 3.874-3.915 (m, 1H), 3.570-3.587 (m, 1H)3.410-3.446(m, 1H), 3.415-3.360 (m, 1H)2.243-2.349 (m, 2H).

[0748] Example 24: (S)-4'-Fluoro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (Compound 1-65) [ka]

[0749] The title compound was prepared according to the procedure described in Example 22 using dioxane / HO as the solvent to give (S)-4'-fluoro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (23 mg, 20% yield). Mass spectrum: 446 (M+H), t R =3.082 minutes, 1H-NMR (400 Hz, DMSO) δ= 8.630 (s, 1H), 8.059-8.087(m, 1H), 7.868 (s, 1H), 7.506-7.649 (m, 4H), 7.350 (s, 1H), 7.220-7.264 (m, 2H),7.003-7.025 (d, 1H), 6.834-6.856 (d, 1H), 5.692 (br, 1H), 3.858-3.898 (m, 1H), 3.532-3.574(m, 1H), 3.391-3.428 (m, 1H), 3.316-3.327 (m, 1H), 2.194-2.353 (m, 2H).

[0750] Example 25: (S)-5-(pyridin-3-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-80) [ka]

[0751] The title compound was prepared according to the procedure described in Example 22 using DMF as the solvent to give (S)-5-(pyridin-3-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (30 mg, 7% yield). Mass spectrum: 429 (M+H), t R =1.876 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.847 (1s, 1H, 8.632 (s,1H), 8.462-8.476 (m, 1H), 7.885-8.087 (m, 3H), 7.578-7.650 (m,2H), 7.374-7.433 (m,2H), 7.008-7.027 (d, 1H), 6.865-6.887 (d, 1H), 5.698 (Br, 1H), 3.873-3.914 (m, 1H),3.338-3.615 (m, 3H), 2.199-2.355 (m, 2H).

[0752] Example 26: (S)-5-(pyridin-4-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-83) [ka]

[0753] The title compound was prepared according to the procedure described in Example 22 using DMF as the solvent to give (S)-5-(pyridin-4-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (35 mg, 8.1% yield). Mass spectrum: 429 (M+H), t R =1.712 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.631 (s, 1H), 8.530-8.545(d, 1H), 8.057-8.086 (m, 1H), 7.905 (s, 1H), 7.638-7.745 (m, 4H), 7.398 (s, 1H),7.002-7.024 (d, 1H), 6.857-6.879 (d, 1H), 5.704 (br, 1H), 3.884-3.926 (m, 1H), 3.567-3.615(m, 2H), 3.415-3.417 (m, 1H), 2.245-3.343 (m, 2H).

[0754] Example 27: (S)-5-(pyridin-2-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl) (Compound 1-81) [ka]

[0755] The title compound was prepared according to the procedure described in Example 22 using DMF as the solvent to give (S)-5-(pyridin-2-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (36 mg, 8.2% yield). Mass spectrum: 429 (M+H), tR =1.720 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.595 (s, 1H), 8.538-8.549(d, 1H), 8.028-8.048 (m, 1H), 7.932-7.974 (m, 2H), 7.741-7.850 (m, 3H), 7.314 (br,1H), 7.174-7.202 (m, 1H), 6.976-6.997 (d, 1H), 6.798-6.821 (d, 1H), 5.677 (br, 1H),3.855-3.895 (m, 1H), 3.539-3.604 (m, 2H), 3.274 (m, 1H), 2.186-2.292 (m, 2H).

[0756] Example 28: (S)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (Compound 1-35) [ka]

[0757] To a solution of (S)-5-cyano-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (37.6 mg, 0.1 mmol) (Example 21) in MeOH / AcOH (2 ml / 1 ml) was added Pd / C (10%), and the mixture was stirred under H atmosphere at room temperature for 12 hours, filtered, and the solvent removed to give the crude product. This was purified by silica gel, and the product was stirred in HCl / EA for 30 minutes, filtered, and the solid was washed with EtO to give (S)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide HCl salt (20 mg, 48% yield). Mass spectrum: 381 (M+H), t R =1.604 minutes, 1H-NMR (400 Hz, CD3OD) δ= 8.539 (s, 1H), 7.992-8.041(m, 2H), 7.699-7.805 (dd, 2H), 7.058-7.079 (d, 1H), 5.921-5.936 (m, 1H), 4.149-4.208(m, 3H), 3.964-4.031 (m, 1H), 3.755-3.862 (m, 2H), 2.535-2.734 (m, 1H), 2.489-2.518(m, 1H).

[0758] Example 29: (S)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbonitrile (Compound 1-56) [ka]

[0759] The title compound was prepared according to the procedure described in Example 5 using Intermediate 3 and DBU as a base to give (S)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbonitrile (20 mg, 50% yield). Mass spectrum: 410 (M+H), t R =3.528 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.644 (s, 1H), 8.077-8.105(dd, 1H), 7.770-7.832 (m, 2H), 7.406-7.445 (m, 2H), 7.228-7.325 (m, 3H), 6.917-7.071(dd, 2H), 5.769 (br, 1H), 4.077-4.117 (m, 1H), 3.606-6.794 (m, 3H), 2.283-2.399(m, 2H).

[0760] Example 30: (R)-5-fluoro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-21) [ka]

[0761] Step 1: (R)-5-Fluoro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile [ka]

[0762] The title compound was prepared according to the procedure described in Example 5 using Intermediate 4 and 2,5-difluorobenzonitrile to give (R)-5-fluoro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (230 mg, 50.7% yield). Mass spectrum: 352 (M+H).

[0763] Step 2: (R)-5-Fluoro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0764] The title compound was prepared according to the procedure described in Example 17 (Step 3) to give (R)-5-fluoro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (30 mg, 11% yield). Mass spectrum: 370 (M+H), t R =2.578 minutes, 1H-NMR (400 Hz, DMSO) δ= 8.616 (s, 1H), 8.059-8.087(dd, 1H), 7.943 (s, 1H), 7.442 (s, 1H), 7.001-7.152 (m, 3H), 6.803-6.837 (m, 1H),5.653 (br, 1H), 3.741-3.782 (m, 1H), 3.432-3.494 (m, 1H), 3.228-3.312 (m, 2H), 2.30-2.335(m, 1H), 2.175-2.192 (m, 1H).

[0765] Example 31: (S)-5-fluoro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-31) [ka]

[0766] Step 1: (S)-5-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile [ka]

[0767] The title compound was prepared according to the procedure described in Example 5 using Intermediate 3 and 5-chloro-2-fluorobenzonitrile to give (S)-5-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (196 mg, 53% yield). Mass spectrum: 368 (M+H).

[0768] Step 2: (S)-5-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0769] The title compound was prepared according to the procedure described in Example 17 (Step 3) to give (S)-5-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (80 mg, 38.4% yield). Mass spectrum: 386 (M+H), t R =2.694 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.616 (s, 1H), 8.055-8.083dd, 1H), 7.877 (s, 1H), 7.403 (s, 1H), 7.195-7.271 (m, 2H), 6.995-7.016 (d, 1H),6.750-6.773 (d, 1H), 5.668 (br, 1H), 3.80-3.817 (m, 1H), 3.390-3.398 (m, 1H), 3.288-3.354(m, 2H), 2.168-2.316 (m, 2H).

[0770] Example 32: (R)-5-fluoro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-44) [ka]

[0771] Step 1: (R)-5-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile [ka]

[0772] The title compound was prepared according to the procedure described in Example 5 using Intermediate 3 and 5-chloro-2-fluorobenzonitrile to give (R)-5-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (200 mg, 54% yield). Mass spectrum: 368 (M+H).

[0773] Step 2: (R)-5-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0774] The title compound was prepared according to the procedure described in Example 17 (Step 3) to give (R)-5-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (80 mg, 38.4% yield). Mass spectrum: 386 (M+H), t R =2.666 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.616 (s, 1H), 8.056-8.084(dd, 1H), 7.880 (s, 1H), 7.403 (s, 1H), 7.201-7.271 (m, 2H), 6.996-7.018 (d, 1H),6.750-6.773 (d, 1H), 5.669 (br, 1H), 3.80-3.829 (m, 1H), 3.468-3.509 (m, 1H), 3.259-3.378(m, 2H), 2.205-2.316 (m, 2H).

[0775] Example 33: (S)-3-Fluoro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-29) [ka]

[0776] Step 1: (S)-3-Fluoro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile [ka]

[0777] The title compound was prepared according to the procedure described in Example 5 using Intermediate 3 and 2,3-difluorobenzonitrile to give (S)-3-fluoro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (413 mg, 73% yield). Mass spectrum: 352 (M+H).

[0778] Step 2: (S)-3-Fluoro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0779] The title compound was prepared according to the procedure described in Example 17 (Step 3) to give (S)-3-fluoro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (189 m, 43% yield). Mass spectrum: 370 (M+H), t R =2.757 minutes, 1 H-NMR (400 Hz, CDCl3) δ= 10.267 (s, 1H), 8.453(s, 1H), 8.113-8.133 (dd, 1H), 7.812-7.839 (m, 1H), 7.225-7.326 (m, 2H), 6.824-6.846(d, 1H), 5.769 (br, 1H), 3.693-3.731 (m, 1H), 3.506-3.546 (m, 1H), 3.349-3.430 (m,2H), 2.520-2.558 (m, 1H), 2.278-2.295 (m, 1H).

[0780] Example 34: (R)-3-Fluoro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-30) [ka]

[0781] Step 1: (R)-3-Fluoro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile [ka]

[0782] The title compound was prepared according to the procedure described in Example 5 using Intermediate 3 and 2,3-difluorobenzonitrile to give (R)-3-fluoro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (327 mg, 77.6% yield). Mass spectrum: 352 (M+H).

[0783] Step 2: (R)-3-Fluoro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0784] The title compound was prepared according to the procedure described in Example 17 (Step 3) to give (R)-3-fluoro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (34 mg, 30.8% yield). Mass spectrum: 370 (M+H), t R =2.742 minutes, 1 H-NMR (400 Hz, CDCl3) δ= 10.269 (br, 1H), 8.455(s, 1H), 8.116-8.133 (d, 1H), 7.812-7.840 (d, 2h), 7.246-7.327 (m, 2H), 6.823-6.845(d, 1H), 5.776 (br, 1H), 3.689-3.731 (m, 1H), 3.508-3.547 (m, 1H), 3.350-3.429 (m,2H), 2.520-2.558 (m, 1H), 2.279-2.296 (m, 1H).

[0785] Example 35: (R)-(2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanamine (Compound 1-34) [ka]

[0786] Step 1: (R)-5-Bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile [ka]

[0787] The title compound was prepared according to the procedure described in Example 5 using (R)-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine hydrochloride (Intermediate 4) and 5-bromo-2-fluorobenzonitrile to give (R)-5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (900 mg, 51% yield). Mass spectrum: 412 (M+H).

[0788] Step 2: (R)-5-Bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0789] The title compound was prepared according to the procedure described in Example 16 (Step 3) using (R)-5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile at 90° C. for 1 hour to give (R)-5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (780 mg, 83% yield). Mass spectrum: 430 (M+H).

[0790] Step 3: (R)-5-cyano-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0791] The title compound was prepared according to the procedure described in Example 16 (Step 3) using (R)-5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide to afford (R)-5-cyano-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (150 mg, 31% yield). Mass spectrum: 377 (M+H), t R =2.350 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.620 (s, 1H), 8.059-8.087 (dd, 1H), 7.943 (s,1H), 7.483-7.603 (m, 3H), 7.003-7.025 (d, 1H), 6.807-6.829 (d, 1H), 5.707 (br, 1H),3.877-3.919 (m, 1H), 3.588-3.613 (m, 1H), 3.478-3.497 (m, 1H), 3.420-3.458 (m, 1H),2.254-2.308 (m, 2H).

[0792] Example 36: (R)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (Compound 1-33) [ka]

[0793] The title compound was prepared according to the procedure described in Example 22 to give (R)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (11 mg, 25% yield). Mass spectrum: 428 (M+H), t R =2.909 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.630 (s, 1H), 8.060-8.089(dd, 1H), 7.891 (s, 1H), 7.532-7.612 (m, 4H), 7.251-7.437 (m, 4H), 7.005-7.027 (d,1H), 6.844-6.865 (d, 1H), 5.693 (m, 1H), 3.860-3.901 (m, 1H), 3.555-3.560 (m, 1H),3.297-3.356 (m, 2H), 2.227-2.342 (m, 2H)

[0794] Example 37: (R)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (Compound 1-45) [ka]

[0795] The title compound was prepared according to the procedure described in Example 28 to give (R)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (25 mg, 44% yield). Mass spectrum: 381 (M+H), t R =1.621 minutes, 1H-NMR (400 Hz, CD3OD) δ= 8.524 (s, 1H), 8.150(s, 1H), 8.009-8.037 (m, 1H), 7.872-7.932 (m, 2H), 7.081-7.103 (d, 1H), 5.954 (br,1H), 4.198-4.240 (m, 3H), 3.968-4.081 (m, 2H), 3.853-3.893 (m, 1H), 2.789-2.824(m, 1H), 2.528-2.548 (m, 1H).

[0796] Example 38: (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoic acid (compound 1-24) [ka]

[0797] Step 1: (S)-Methyl 2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoate [ka]

[0798] To a solution of (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Example 12) (1.5 g / 4.2 mmol) in MeOH (10 mL) was added TMSCl (10 mL), and the mixture was heated to reflux overnight, then quenched with water, extracted with EA, dried over NaSO, and the solvent was removed to give the crude product, which was purified by silica gel to give (S)-methyl 2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoate (350 mg, 22.7% yield). Mass spectrum: 367 (M+H).

[0799] Step 2: (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoic acid [ka]

[0800] To a solution of (S)-methyl 2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoate (300 mg, 0.81 mmol) in THF was added aqueous NaOH (2 mL, 30%), the mixture was stirred at 60° C. overnight, diluted with EA, the pH was adjusted to 3 with HCl (1N), the organic layer was washed with water, brine, dried over Na2SO4, and the solvent was removed to give the crude product, which was purified by silica gel to give (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoic acid (120 mg, 41.5% yield). Mass spectrum: 353 (M+H), t R =2.240 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.606 (s, 1H), 8.053-8.047(m, 1H), 7.265-7.245 (m, 1H), 7.016-7.250 (br, 1H), 6.994-7.016 (d, 1H), 6.798-6.994(br, 1H), 6.673-6.694 (br, 1H), 5.664 (br, 1H), 3.685-3.872 (m, 1H), 3.590-3.676(m, 1H), 3.117-3.237 (m, 2H), 2.290-2.329 (m, 1H), 2.167-2.274 (m, 1H).

[0801] Example 39: (S)—N-methyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-39) [ka]

[0802] A solution of (S)-methyl 2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoate (40 mg, 0.11 mmol) in aqueous MeOH / MeNH (1 mL / 1 mL) was heated to 90 °C overnight in a sealed tube. HO (6 mL) was added, filtered, washed with water, and dried under vacuum to give (S)-N-methyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (20 mg, 49.8% yield). Mass spectrum: 366 (M+H), t R =2.500 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.615 (s, 1H), 8.056-8.200(m, 2H), 7.162-7.2545 (m, 2H), 6.994-7.016 (d, 1H), 6.676-6.764 (m, 2H), 5.653 (br,1H), 3.714-3.755 (m, 1H), 3.427-3.492 (m, 1H), 3.251-3.325 (m, 2H), 2.704-2.751(d, 3H), 2.249-2.317 (m, 1H), 2.151-2.199 (m, 1H).

[0803] Example 40: (S)—N,N-dimethyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-48) [ka]

[0804] Step 1: (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoyl chloride [ka]

[0805] To a solution of (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoic acid (120 mg, 0.34 mmol) in DCM was added (COCl) (64.28 mL, 0.51 mmol) and 1 drop of DMF, the mixture was stirred at room temperature for 30 min, and the solvent was removed to give (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoyl chloride (130 mg, quantitative), which could be used directly in the next step.

[0806] Step 2: (S)—N,N-dimethyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0807] To a solution of (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoyl chloride (50 mg, 0.13 mmol) in DCM (3 mL) was added dimethylamine hydrochloride (21 mg, 0.26 mmol) and TEA (52 mg, 0.52 mmol), and the mixture was stirred at room temperature. Upon completion, it was diluted with DCM (10 mL), washed with water, brine, dried over Na2SO4, and the solvent was removed to give the crude product. This was purified by silica gel to give (S)-N,N-dimethyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (20 mg, 40.5% yield). Mass spectrum: 380 (M+H), t R =2.087 minutes, 1H-NMR (400 Hz, CDCl3) δ= 8.451 (s, 1H), 7.770-7.792(d, 1H), 7.241-7.285 (m, 2H), 7.194-7.213 (d, 1H), 7.100-7.117 (d, 1H), 6.706-6.819(m, 2H), 5.673-5.715 (m, 1H), 3.827-3.855 (m, 0.5H), 3.592-3.647 (m, 2.5H), 3.258-3.354(m, 1H), 3.105-3.134 (d, 3H), 2.875-2.942 (d, 3H), 2.269-2.304 (m, 2H).

[0808] Example 41: (S)—N-benzyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-51) [ka]

[0809] The title compound was prepared according to the procedure described in Example 40 (Step 2) to give (S)—N-benzyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (30 mg, 42% yield). Mass spectrum: 442 (M+H), t R =3.080 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.838-8.869 (t, 1H), 8.593(s, 1H), 8.055-8.083 (dd, 1H), 7.214-7.340 (m, 7H), 6.970-6.992 (d, 1H), 6.701-6.780(d, 2H), 5.594 (br, 1H), 4.376-4.419 (dd, 2H), 3.670-3.715 (m, 1H), 3.408-3.432(m, 1H), 3.200-3.270 (m, 2H), 2.506-2.519 (m, 1H), 2.232-2.254 (m, 1H).

[0810] Example 42: (S)—N-isopropyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-46) [ka]

[0811] The title compound was prepared according to the procedure described in Example 40 (Step 2) to give (S)—N-isopropyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (30 mg, 47.7% yield). Mass spectrum: 394 (M+H), t R =2.896 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.574 (s, 1H), 8.056-8.194(dd, 2H), 7.207-7.246 (m, 1H), 7.115-7.248 (m, 1H), 6.985-7.007 (d, 1H), 6.671-6.759(m, 2H), 5.639 (br, 1H), 3.959-4.012 (m, 1H), 3.769-3.810 (m, 1H), 3.452-3.492 (m,1H), 3.264-3.333 (m, 2H), 2.220-2.323 (m, 1H), 2.205-2.212 (m, 1H), 1.070-1.103(m, 6H).

[0812] Example 43: (S)—N,N-Dibenzyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-52) [ka]

[0813] The title compound was prepared according to the procedure described in Example 40 (Step 2) to give (S)—N,N-dibenzyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (27 mg, 34% yield). Mass spectrum: 532 (M+H), t R =3.616 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.395-8.461 (d, 1H), 7.775-7.797(m, 1H), 7.236-7.396 (m, 10H), 7.115-7.157 (m, 2H), 6.733-6.842 (m, 3H), 5.512-5.601(d, 1H), 4.975-5.176 (dd, 1H), 4.401-4.536 (m, 1.5H), 4.130-4.272 (m, 1.5H), 3.550-3.562(m, 0.5H), 3.338-3.506 (m, 2H), 3.257-3.327 (m, 1.5H), 2.125-2.195 (m, 2H).

[0814] Example 44: (S)-tert-butyl 2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoate (Compound 1-54) [ka]

[0815] The title compound was prepared according to the procedure described in Example 40 (Step 2) to give (S)-tert-butyl 2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoate (32 mg, 49% yield). Mass spectrum: 409 (M+H), t R =3.544 minutes, 1H-NMR (400 Hz, CDCl3) δ= 8.429 (s, 1H), 7.754-7.781(m, 1H), 7.536-7.559 (m, 1H), 7.288-7.348 (m, 1H), 6.737-6.829 (m, 3H), 5.690 (br,1H), 3.896-3.937 (m, 1H), 3.635-3.654(m, 1H), 3.257-3.601 (m, 1H), 3.22-3.250 (m,1H), 2.310-2.343 (m, 2H), 1.586 (s, 9H).

[0816] Example 45: (S)—N,N-dimethyl-1-(2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanamine hydrochloride (Compound 1-61) [ka]

[0817] The title compound was prepared according to the procedure described in Example 13 to give (S)—N,N-dimethyl-1-(2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanamine hydrochloride (21 mg, 33.7% yield). Mass spectrum: 366 (M+H), t R =2.637 minutes, 1 H-NMR (400 Hz, DMSO) δ= 9.980 (br, 1H), 8.611(s, 1H), 8.082-8.110 (m, 1H), 7.432-7.556 (m, 1H),7.290-7.404 (m, 1H), 7.270-7.384(m, 1H), 7.044-7.270 (m, 2H), 5.660 (br, 1H), 4.362-4.374 (d, 2H), 3.626-3.702 (m,1H), 3.327-3.628 (m, 1H), 3.156-3.221 (m, 2H), 2.671-2.739 (dd, 6H), 2.140-2.479(m, 1H), 2.118-2.139 (m, 1H).

[0818] Example 46: (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoic acid (Compound 1-41) [ka]

[0819] Step 1: (R)-Methyl 2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoate [ka]

[0820] To a solution of (R)-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine hydrochloride (Intermediate 4) (1.2 g, 5.2 mmol) and methyl 2-fluorobenzoate (1.2 g, 7.8 mmol) in DMSO (8 mL) was added DBU (1.58 g, 10.4 mmol) at room temperature, the mixture was heated to 100 °C overnight, water was added, extracted with EA, washed with water, brine, dried over Na SO , and the solvent was removed to give the crude product, which was purified by silica gel to give (R)-methyl 2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoate (550 mg, 28%). Mass spectrum: 367 (M+H).

[0821] Step 2: (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoic acid [ka]

[0822] The title compound was prepared according to the procedure described in Example 38 (Step 2) to give (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoic acid (20 mg, 40.6% yield). Mass spectrum: 353 (M+H), t R=2.180 minutes, 1 H-NMR (400 Hz, CDCl3) δ= 8.440 (s, 1H), 8.310-8.334(d, 1H), 7.836-7.864 (d, 1H), 7.620-7.658 (m, 1H), 7.413-7.453 (m, 2H), 6.950-6.971(d, 1H), 5.794-5.821 (m, 1H), 3.656 (m, 1H), 3.519-3.544 (m, 1H), 3.411-3.440 (m, 1H), 3.309-3.331 (m, 1H), 2.579-2.616 (m, 1H), 2.400-2.419 (m, 1H).0

[0823] Example 47: (R)—N-methyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-47) [ka]

[0824] The title compound was prepared according to the procedure described in Example 39 to give (R)-N-methyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (25 mg, 50% yield). Mass spectrum: 366 (M+H), t R =2.571 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.611 (s, 1H), 8.190-8.199(d, 1H), 8.057-8.078 (d, 1H), 7.214-7.252 (m ,1H), 7.142-7.161 (m, 1H), 6.993-7.015(m, 1H), 6.678-6.766 (m, 2H), 5.650 (br, 1H), 3.713-3.753 (m, 1H), 3.250-3.304 (m,3H), 2.705-2.715 (d, 3H), 2.272-2.304 (m,1H), 2.171-2.197 (m, 1H).

[0825] Example 48: (R)-tert-butyl 2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoate (Compound 1-55) [ka]

[0826] To a solution of (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoic acid (Example 46) (45 mg, 0.13 mmol) in DCM (1 mL) was added (COCl) (36.6 mg, 0.288 mmol) and 1 drop of DMF, the mixture was stirred at room temperature, and upon completion, the solvent was removed to give (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoyl chloride (quantitative). To the benzoyl chloride in DCM (1 mL) was added 2-methylpropan-2-ol (13.5 mg, 0.153 mmol) and TEA (3 drops), the mixture was stirred at room temperature, and upon completion, the mixture was quenched with water, extracted with EA, washed with water, brine, dried over NaSO, and the solvent was removed to give the crude product. This was purified by silica gel to give (R)-tert-butyl 2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoate (10 mg, 19% yield). Mass spectrum: 409 (M+H), t R =3.504 minutes, 1 H-NMR (400 Hz, CDCl3) δ= 8.403 (s, 1H), 7.728-7.757(m ,1H), 7.516-7.539 (m, 1H), 7.259-7.305 (m, 1H), 6.720-6.822 (m, 3H), 5.669 (br,1H), 3.878-3.919 (m, 1H), 3.615-3.633 (m, 3H), 3.244-2.249 (m, 1H), 2.204-3.232(d, 1H), 2.307-2.315 (m,2H).

[0827] Example 49: (R)—N-benzyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-50) [ka]

[0828] To a solution of (R)-methyl 2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoate (50 mg, 0.137 mmol) (Example 46, Step 1) and BnNH (45 mg, 0.41 mmol) in toluene was added Al(Me) (2 M in toluene, 0.41 mmol) at 110 °C overnight, quenched with NHCl solution, extracted with DCM, washed with water, brine, dried over NaSO, and the solvent was removed to give the crude product, which was purified by silica gel to give (R)-N-benzyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (40 mg, 66% yield) as a white solid. Mass spectrum: 442 (M+H), t R =3.090 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.594-8.860 (t, 1H), 8.594(s, 1H), 8.054-8.081 (dd, 1H), 7.216-7.342 (m, 7H), 6.969-6.991 (d, 1H), 6.705-6.783(d, 2H), 5.595 (br, 1H), 4.379-4.422 (dd, 2H), 3.433-3.713 (m, 1H), 3.392-3.433(m, 1H), 3.204-3.294 (m, 2H), 2.506-2.514 (m, 1H), 2.114-2.123 (m, 1H).

[0829] Example 50: (R)—N,N-dibenzyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-53) [ka]

[0830] The title compound was prepared according to the procedure described in Example 49 to give (R)—N,N-dibenzyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (35 mg, 48% yield). Mass spectrum: 532 (M+H), t R =3.618 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.562--8.619 (d, 1H),8.072-8.111 (m, 1H), 7.215-7.331 (m, 9H), 7.098-7.157 (m, 3H), 6.981-7.002 (m, 1H),6.684-6.775(m, 2H), 5.466-5.578 (d, 1H), 4.446-4.958 (dd, 1H), 4.147-4.407 (m, 3H), 3.645-3.6866(m, 1H), 3.161-3.267 (m, 2H), 2.107-2.219 (m, 1H), 1.984-1.995 (m, 1H).

[0831] Example 51: (R)—N-isopropyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-49) [ka]

[0832] The title compound was prepared according to the procedure described in Example 49 to give (R)-N-isopropyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (25 mg, 46% yield). Mass spectrum: 394 (M+H), t R =2.909 minutes, 1H-NMR (400 Hz, DMSO) δ= 8.573 (s, 1H), 8.170-8.190(d, 1H), 8.052-8.081 (d, 1H), 7.210-7.248 (m, 1H), 7.118-7.140 (m, 1H), 6.984-7.006(d, 1H), 6.710-6.760 (m, 1H), 6.673-6.691 (t, 1H), 5.639 (br, 1H), 3.960-4.012 (m,1H), 3.768-3.809 (m, 1H), 3.474- 3.492 (m, 1H), 3.295-3.345 (m, 2H), 2.291-2.325(m, 1H), 2.203-2.210 (m, 1H), 1.070-1.103 (m, 6H).

[0833] Example 52: (R)—N,N-dimethyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-59) [ka]

[0834] The title compound was prepared according to the procedure described in Example 49 to give (R)—N,N-dimethyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (110 mg, 71% yield). Mass spectrum: 380 (M+H), t R =2.799 minutes, 1 H-NMR (400 Hz, CDCl3) δ= 8.451 (s, 1H), 7.770-7.792(d, 1H), 7.214-7.285 (m, 2H), 7.100-7.119 (m, 3H), 5.671-5.713 (m, 1H), 3.829-3.856(m, 1H), 3.592-3.662 (m, 2H), 3.466-3.504 (m, 1H), 3.134-3.257 (d, 3H), 2.873-2.942(d, 3H), 2.268-2.304 (m, 2H).

[0835] Example 53: (R)—N,N-dimethyl-1-(2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanamine hydrochloride (Compound 1-60) [ka]

[0836] The title compound was prepared according to the procedure described in Example 13 to give (R)—N,N-dimethyl-1-(2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanamine hydrochloride (25 mg, 52% yield). Mass spectrum: 366 (M+H), t R =1.988 minutes, 1 H-NMR (400 Hz, DMSO) δ= 10.151 (br, 1H), 8.609(s, 1H), 8.081-8.609 (m, 1H), 7.569-7.588 (m, 1H), 7.382-7.420 (m, 1H), 7.268-7.288(m, 1H), 7.048-7.129 (m, 2H), 5.645-5.673 (m, 1H), 4.364-4.376 (m, 1H), 3.635-3.676(m, 1H), 3.330-3.390 (m, 1H), 3.148-3.220 (m, 1H), 2.664-2.728 (dd, 6H), 2.430-2.513(m, 1H), 2.094-2.112 (m, 1H).

[0837] Example 54: (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenol (Compound 1-40) [ka]

[0838] Step 1: (R)-2-(1-(2-nitrophenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine [ka]

[0839] The title compound was prepared according to the procedure described in Example 5 to give (R)-2-(1-(2-nitrophenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (900 mg, 80% yield). Mass spectrum: 354 (M+H).

[0840] Step 2: (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)aniline [ka]

[0841] The title compound was prepared according to the procedure described in Example 14 (Step 2) to give (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)aniline (800 mg, quantitative). Mass spectrum: 324 (M+H).

[0842] Step 3: (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenol [ka]

[0843] The title compound was prepared according to the procedure described in Example 14 (Step 2) to afford (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenol (290 mg, 20% yield) as a clear oil. Mass spectrum: 325 (M+H), t R =1.380 minutes, 1H-NMR (400 Hz, CD3OD) δ= 8.492 (s, 1H), 7.926-7.955(dd, 1H), 6.953-6.975(d, 1H), 6.858-6.877 (m, 1H), 6.744-6.810 (m, 3H), 5.659-5.698(m, 1H), 4.622-4.651 (m, 1H), 3.734-3.777 (m, 1H), 3.401-3.511 (m, 2H), 3.208-3.321(m, 1H), 2.202-2.501 (m, 1H), 2.146-2.184 (m. 1H).

[0844] Example 55: (R)-2-(1-(2-(benzyloxy)phenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (compound 1-38) [ka]

[0845] The title compound was prepared according to the procedure described in Example 15a using (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenol and (bromomethyl)benzene to give (R)-2-(1-(2-(benzyloxy)phenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (8 mg, 76% yield). Mass spectrum: 415 (M+H), t R =3.566 minutes, 1 H-NMR (400 Hz, CD3OD) δ= 8.42 (s, 1H), 7.907-7.943(dd, 1H), 7.331-7.447 (m, 2H), 7.254-7.323 (m, 3H), 7.002-7.026 (m, 1H), 6.837-6.928(m, 4H), 5.617 (br, 1H), 5.067 (s, 2H), 3.615-3.693 (m, 2H), 3.501-3.543 (m, 1H),3.251-3.321 (m,1H), 2.201-2.451 (m, 1H), 2.167-2.188 (m, 1H).

[0846] Example 56: (R)-2-(1-(2-(cyclopentyloxy)phenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-36) [ka]

[0847] The title compound was prepared according to the procedure described in Example 15a using (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenol and iodocyclopentane to give (R)-2-(1-(2-(cyclopentyloxy)phenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (11 mg, 85% yield). Mass spectrum: 393 (M+H), t R =3.517 minutes, 1 H-NMR (400 Hz, CD3OD) δ= 8.488 (s, 1H), 7.928-7.956(dd, 1H), 6.826-6.965 (m, 5H), 5.644 (br, 1H), 4.809-4.837 (m, 1H), 3.568-3.640(m, 3H), 3.216-3.236 (m, 1H), 2.399-2.449 (m, 1H), 2.178-2.231 (m, 1H), 1.779-1.884(m, 5H), 1.616-1.665 (m, 3H).

[0848] Example 57: (R)-2-(1-(2-isopropoxyphenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-37) [ka]

[0849] The title compound was prepared according to the procedure described in Example 15a using (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenol and 2-bromopropane to give (R)-2-(1-(2-isopropoxyphenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (8.5 mg, 78% yield). Mass spectrum: 393 (M+H), t R =3.213 minutes, 1 H-NMR (400 Hz, CD3OD) δ= 8.499 (s, 1H), 7.928-7.956(dd, 1H), 6.808-6.965 (m, 5H), 5.678 (br, 1H), 4.559-4.635 (m, 1H), 3.691-3.734(m, 1H), 3.321-3.580 (m, 2H), 3.250-3.285 (m, 1H), 2.193-2.443 (m, 1H), 2.168-2.190(m, 1H), 1.278-1.293 (m, 6H).

[0850] Example 58: (S)-2-(1-(biphenyl-2-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (compound 1-27) [ka]

[0851] To a solution of (S)-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine hydrochloride (200 mg, 0.86 mmol) (Intermediate 3), 2-bromobiphenyl (0.18 mL, 1.04 mmol), Pd(dba) (157 mg, 0.17 mmol), and BINAP (107 mg, 0.17 mmol) in toluene, t-BuONa (165 mg, 1.72 mmol) was added, and the mixture was degassed with N and then heated to 120 °C in a microwave for 30 min. The solvent was removed to give the crude product, which was purified by silica gel to give 70 mg (22% yield). Mass spectrum: 385 (M+H), t R =3.719 minutes, 1H-NMR (400 Hz, DMSO) δ= 8.497 (s, 1H), 8.020-8.047(dd, 1H), 7.314-7.403 (m, 4H), 7.182-7.246 (m, 2H), 7.083-7.101 (m, 1H), 6.871-6.969(m, 3H), 5.418 (br, 1H), 3.116-3.327 (m, 2H), 2.981-3.011 (m, 1H), 2.877-2.904 (m,1H), 2.183-2.217 (m, 1H), 1.988-2.005 (m, 1H).

[0852] Example 59: (R)-2-(1-(biphenyl-2-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (compound 1-28) [ka]

[0853] To a solution of (R)-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine hydrochloride (200 mg, 0.86 mmol) (Intermediate 3), 2-bromobiphenyl (0.18 mL, 1.04 mmol), Pd(dba) (157 mg, 0.17 mmol), and BINAP (107 mg, 0.17 mmol) in toluene, t-BuONa (165 mg, 1.72 mmol) was added, and the mixture was degassed with N and then heated to 120 °C in a microwave for 30 min. The solvent was removed to give the crude product, which was purified by silica gel to give 56 mg (17% yield). Mass spectrum: 385 (M+H), t R =3.710 minutes, 1H-NMR (400 Hz, DMSO) δ= 8.497 (s, 1H), 8.022-8.049(dd, 1H), 7.315-7.404 (m, 4H), 7.183-7.247 (m, 2H), 7.085-7.103 (m, 1H), 6.892-6.972(m, 3H), 5.420 (br, 1H), 3.118-3.316 (m, 2H), 2.982-3.013 (m, 1H), 2.877-3.004 (m,1H), 2.188-2.222 (m, 1H), 1.991-2.008 (m, 1H).

[0854] Example 60: (S)-3-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 43) [ka]

[0855] Step 1: (S)-3-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile [ka]

[0856] The title compound was prepared according to the procedure described in Example 5 to give 340 mg (72% yield). Mass spectrum: 367 (M+H).

[0857] Step 2: (S)-3-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0858] The title compound was prepared according to the procedure described in Example 16 (Step 3) at 90° C. for 30 minutes to give (S)-3-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (70 mg, 20% yield). Mass spectrum: 386 (M+H), t R =2.867 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.590 (s, 1H), 8.398 (br,1H), 8.064-8.091 (dd, 1H), 7.602 (br, 1H), 7.473-7.522 (m, 2H), 7.174-7.212 (m,1H), 7.046-7.068 (m, 1H), 5.645 (br, 1H), 3.758-3.796 (m, 1H), 3.455-3.503 (m, 1H),3.292-3.353 (m, 2H), 2.375-2.410 (m, 1H), 2.098-2.106 (m, 1H).

[0859] Example 61: (R)-3-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-42) [ka]

[0860] Step 1: (R)-3-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile [ka]

[0861] The title compound was prepared according to the procedure described in Example 5 to give (R)-3-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (300 mg, 63% yield). Mass spectrum: 367 (M+H).

[0862] Step 2: (R)-3-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0863] The title compound was prepared according to the procedure described in Example 16 (Step 3) at 90° C. for 30 minutes to give (R)-3-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (90 mg, 28.8% yield). Mass spectrum: 386 (M+H), t R =2.868 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.601 (s, 1H), 8.406 (br,1H), 8.074-8.103 (dd, 1H), 7.613 (br, 1H), 7.487-7.532 (m, 2H), 7.184-7.223 (m,1H), 7.056-7.077 (m, 1H), 5.656 (br, 1H), 3.769-3.807 (m, 1H), 3.474-3.514 (m, 1H),3.302-3.364 (m, 2H), 2.510-2.513 (m, 1H), 2.402-2.420 (m, 1H).

[0864] Example 62: (S)-5-(trifluoromethyl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-58) [ka]

[0865] Step 1: (S)-5-(trifluoromethyl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile [ka]

[0866] The title compound was prepared according to the procedure described in Example 5 to give (S)-5-(trifluoromethyl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (120 mg, 59.8% yield). Mass spectrum: 402 (M+H), t R =3.348 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.474 (s, 1H), 7.804-7.832(dd, 1H), 7.733 (s, 1H), 7.533-7.562 (d, 1H), 6.825-6.847 (d, 1H), 6.719-6.741 (d,1H), 5.813 (br, 1H), 4.136-4.177 (m, 1H), 3.958-3.989 (m, 1H), 3.851-3.881 (m, 2H),2.361-2.436 (m, 2H).

[0867] Step 2: (S)-5-(trifluoromethyl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0868] The title compound was prepared according to the procedure described in Example 6 using EtOH to give (S)-5-(trifluoromethyl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (45 mg, 42.9% yield). Mass Spectrum: 420 (M+H), t R =3.646 minutes, 1H-NMR (400 Hz, DMSO) δ= 8.627 (s, 1H), 8.062-8.089(m, 1H), 7.949 (m, 1H), 7.504-7.528 (m, 1H), 7.452 (s, 1H), 7.002-7.024 (d, 1H),6.850-6.873 (m, 1H), 5.707 (br, 1H), 3.874-3.914 (m, 1H), 3.584-3.601 (m, 1H), 3.394-3.461(m, 2H), 2.257-2.267 (m, 2H).

[0869] Example 65: (S)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-carbonitrile (Compound 1-62) [ka]

[0870] The title compound was prepared according to the procedure described in Example 5 to give (S)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-carbonitrile (90 mg, 17% yield). Mass spectrum: 410 (M+H), t R =3.483 minutes, 1 H-NMR (400 Hz, CDCl3) δ= 8.478 (s, 1H), 7.795-7.8(d, 1H), 7.544-7.592 (m, 3H), 7.420-7.494 (m, 3H), 6.940-6.960 (d, 1H), 6.825-6.848(m, 2H), 5.809 (br, 1H), 3.988 (m, 1H), 3.823-3.852 (m, 2H), 2.385-2.399 (m, 2H).

[0871] Example 66: (S)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-carboxamide (Compound 1-63) [ka]

[0872] The title compound was prepared according to the procedure described in Example 63 (Step 3) to give (S)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-carboxamide (32 mg, 44% yield). Mass spectrum: 428 (M+H), t R =3.678 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.624 (s, 1H), 8.059-8.087(m, 1H), 7.813 (s, 1H), 7.662-7.683 (m, 2H), 7.447-7.484 (m, 2H), 7.319-7.394 (m, 3H), 6.954-7.026 (m, 3H), 5.697 (br, 1H), 3.874-3.915 (m, 1H), 3.601-3.618 (m, 1H),3.421-3.473 (m, 2H), 2.328-2.350 (m, 1H), 2.222-2.240 (m, 1H).

[0873] Example 67: (S)-2-(1-(3-nitrobiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-66) [ka]

[0874] Step 1: (S)-2-(1-(4-bromo-2-nitrophenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine [ka]

[0875] The title compound was prepared according to the procedure described in Example 5 to give (S)-2-(1-(4-bromo-2-nitrophenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (3.7 g, 85% yield). Mass spectrum: 432 (M+H).

[0876] Step 2: (S)-2-(1-(3-nitrobiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine [ka]

[0877] To a solution of (S)-2-(1-(4-bromo-2-nitrophenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (2.2 g, 5 mmol) and phenylboronic acid (732 mg, 6 mmol) in dioxane / HO (5 mL / 1 mL) was added Pd(dppf)Cl (400 mg, 0.5 mmol) and KCO (2 g, 15 mmol). The mixture was degassed with N and stirred at 90 °C for 2 h, diluted with EA, washed with water, brine, dried over NaSO, and the solvent was removed to give a residue which was purified by silica gel to give (S)-2-(1-(3-nitrobiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (2.3 g, 94% yield). Mass spectrum: 430 (M+H), t R =3.601 minutes, 1H-NMR (400 Hz, DMSO) δ= 8.625 (s, 1H), 8.022-8.091(m, 2H), 7.830-8.016 (d, 1H), , 7.660-7.681 (d, 2H), 7.351-7.369 (m, 2H), 7.314-7.338(m, 1H), 7.188-7.210 (d, 1H), 7.027-7.050 (d, 1H), 5.744 (br, 1H), 3.613-3.815 (m, 1H), 3.595-3.613 (m, 1H), 3.332-3.345 (m, 1H), 3.180-3.322 (m, 1H), 2.293-2.351(m, 2H).

[0878] Example 68: (S)-2-(1-(3-methoxybiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-73) [ka]

[0879] Step 1: (S)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-amine [ka]

[0880] The title compound was prepared according to the procedure described in Example 14 (Step 2) to give (S)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-amine (830 mg, 59.5% yield). Mass spectrum: 400 (M+H).

[0881] Step 2: (S)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-ol [ka]

[0882] The title compound was prepared according to the procedure described in Example 14 (Step 3) to give (S)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-ol (105 mg, 21% yield). Mass spectrum: 401 (M+H).

[0883] Step 3: (S)-2-(1-(3-methoxybiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine [ka]

[0884] The title compound was prepared according to the procedure described in Example 15a to give (S)-2-(1-(3-methoxybiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (22 mg, 54% yield). Mass spectrum: 415 (M+H), t R =2.249 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.628 (s, 1H), 8.059-8.088(dd, 1H), 7.619-7.637 (d, 2H), , 7.393-7.431 (m, 2H), 7.255-7.292 (m, 1H), 7.144-7.178(m, 2H), 7.021-7.043 (d, 1H), 6.767-6.788 (d, 1H), 5.656 (br, 1H), 3.846-3.882 (m,4H), 3.557-3.575 (m, 1H), 3.407-3.437 (,.1H), 3.283-3.316 (m, 1H), 2.331-2.352 (m,1H), 2.150 (m, 1H).

[0885] Example 69: (S)-2-(1-(3-isopropoxybiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-77) [ka]

[0886] The title compound was prepared according to the procedure described in Example 15a using (S)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-ol and 2-iodopropane to give (S)-2-(1-(3-isopropoxybiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (18 mg, 40% yield). Mass spectrum: 443 (M+H), t R =3.874 minutes, 1 H-NMR (400 Hz, CDCl3) δ= 8.468 (s, 1H), 7.771-7.798(m, 1H), 7.559-7.580 (m, 2H), 7.409-7.447 (m, 2H), 7.285-7.332 (m, 1H), 7.113-7.163(m, 2H), 6.823-6.858 (m, 2H), 5.715 (br, 1H), 4.650-4.682 (m, 1H), 3.935-3.977 (m,1H), 3.595-3.652 (m, 2H), 3.425-3.445 (m, 1H), 2.396-2.415 (m, 1H), 2.246-2.272(m, 1H), 1.386-1.414 (m, 6H).

[0887] Example 70: (S)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-2-carboxamide (Compound 1-72) [ka]

[0888] Step 1: (S)-2-Bromo-6-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (YJ-000233-081) [ka]

[0889] The title compound was prepared according to the procedure described in Example 5 to give (S)-2-bromo-6-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (350 mg, 57% yield). Mass spectrum: 412 (M+H).

[0890] Step 2: (S)-2-Bromo-6-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0891] The title compound was prepared according to the procedure described in Example 17 (Step 3) to give (S)-2-bromo-6-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (300 mg, 82% yield). Mass spectrum: 430 (M+H).

[0892] Step 3: (S)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-2-carboxamide [ka]

[0893] The title compound was prepared according to the procedure described in Example 67 (Step 2) to give (S)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-2-carboxamide (45 mg, 35% yield). Mass spectrum: 428 (M+H), t R =2.906 minutes, 1H-NMR (400 Hz, DMSO) δ= 8.610 (s, 1H), 8.062-8.091(m,1H), 7.515 (s, 1H), 7.289-7.358 (m, 5H), 7.171-7.238 (m, 2H), 7.006-7.027 (d, 1H),6.760-6.781 (d, 1H),6.544-6.562 (d, 1H), 5.684 (br, 1H), 3.893-3.935 (m, 1H), 3.471-3.612(m, 3H), 2.290-2.314 (m, 1H), 2.193-2.200 (m, 1H).

[0894] Example 71: (S)-6-chloro-2-(1-(2-nitrophenyl)pyrrolidin-3-yloxy)quinoline (Compound 1-68) [ka]

[0895] Step 1: (S)-6-chloro-2-(pyrrolidin-3-yloxy)quinoline [ka]

[0896] The title compound was prepared according to the procedure described in Intermediate 4 to give crude (S)-6-chloro-2-(pyrrolidin-3-yloxy)quinoline (1.7 g, 89% yield). Mass spectrum: 249 (M+H).

[0897] Step 2: (S)-6-chloro-2-(1-(2-nitrophenyl)pyrrolidin-3-yloxy)quinoline [ka]

[0898] The title compound was prepared according to the procedure described in Example 5 to give (S)-6-chloro-2-(1-(2-nitrophenyl)pyrrolidin-3-yloxy)quinoline (1.1 g, 67.5% yield). Mass spectrum: 370 (M+H), t R =3.495 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.221-8.243 (d, 1H), 8.020-8.027(d, 1H), 7.667-7.798 (m, 3H),7.468-7.511 (m, 1H), 7.065-7.121 (m, 2H), 6.790-6.828(m, 1H), 5.848 (br, 1H), 3.767-3.808 (m, 1H), 3.551-3.582 (m, 1H), 3.258-3.277 (m,1H), 3.132-3.161 (m, 1H), 2.373-2.396 (m, 1H), 2.311-2.327 (m, 1H).

[0899] Example 72: (S)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)aniline (Compound 1-69) [ka]

[0900] The title compound was prepared according to the procedure described in Example 14 (Step 2) to give (S)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)aniline (420 mg, 54% yield). Mass spectrum: 340 (M+H), t R =3.081 minutes, 1H-NMR (400 Hz, DMSO) δ= 8.230-8.243 (d, 1H), 8.023-8.029(d, 1H), 7.657-7.787 (dd, 2H), 7.096-7.119 (d, 1H), 6.896-6.918 (m, 1H), 6.747-6.787(m, 1H), 6.654-6.676 (m, 1H), 6.517-6.558 (m, 1H), 5.710 (br, 1H), 4.687 (br, 2H),3.524-3.566 (m, 1H), 3.195-3.234 (m, 1H), 3.112-3.147 (m, 1H), 3.026-3.143 (m, 1H),2.469-2.486 (m, 1H), 2.041-2.077 (m, 1H).

[0901] Example 73: (S)-6-chloro-2-(1-(2-isopropoxyphenyl)pyrrolidin-3-yloxy)quinoline (Compound 1-76) [ka]

[0902] Step 1: (S)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)phenol [ka]

[0903] The title compound was prepared according to the procedure described in Example 14 (Step 3) to give (S)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)phenol (69 mg, 25% yield). Mass spectrum: 341 (M+H).

[0904] Step 2: (S)-6-chloro-2-(1-(2-isopropoxyphenyl)pyrrolidin-3-yloxy)quinoline [ka]

[0905] The title compound was prepared according to the procedure described in Example 15a to give (S)-6-chloro-2-(1-(2-isopropoxyphenyl)pyrrolidin-3-yloxy)quinoline (33 mg, 43% yield). Mass spectrum: 383 (M+H), t R =4.596 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.223-8.246 (d, 1H), 8.027(d, 1H), 7.669-7.795 (dd, 2H), 7.707-7.092 (d, 1H), 6.863-6.883 (d ,1H), 6.713-6.810(m, 3H), 5.715 (br,1H), 4.515-4.545 (m, 1H), 3.801-3.844 (m, 1H), 3.426-3.530 (m,2H), 3.252-3.264 (m,1H), 2.372-2.391 (m, 1H), 2.148 (m, 1H), 1.177-1.226 (m, 6H).

[0906] Example 74: (S)-6-chloro-2-(1-(3-nitrobiphenyl-4-yl)pyrrolidin-3-yloxy)quinoline (Compound 1-70) [ka]

[0907] Step 1: (S)-2-(1-(4-bromo-2-nitrophenyl)pyrrolidin-3-yloxy)-6-chloroquinoline [ka]

[0908] The title compound was prepared according to the procedure described in Example 5 to give (S)-2-(1-(4-bromo-2-nitrophenyl)pyrrolidin-3-yloxy)-6-chloroquinoline (824 mg, 65.6% yield). Mass spectrum: 448 (M+H).

[0909] Step 2: (S)-6-chloro-2-(1-(3-nitrobiphenyl-4-yl)pyrrolidin-3-yloxy)quinoline [ka]

[0910] The title compound was prepared according to the procedure described in Example 67 (Step 2) to give (S)-6-chloro-2-(1-(3-nitrobiphenyl-4-yl)pyrrolidin-3-yloxy)quinoline (673 mg, 82% yield). Mass spectrum: 446 (M+H), t R =4.551 minutes, 1 H-NMR (400 Hz, CDCl3) δ= 8.037 (s, 1H), 7.911-7.933(d, 1H), 7.770-7.792 (d, 1H), 7.683-7.7.716 (m, 2H), 7.562-7.602 (m, 3H), 7.350-7.471(m, 2H), 7.285-7.346 (m, 1H), 7.059-7.081 (d, 1H), 6.885-6.907 (d, 1H), 5.949 (br,1H), 3.924-3.965 (m, 1H), 3.749-3.772 (m, 1H), 3.452-3.459 (m, 1H), 3.257-3.287(m,1H), 2.431-2.461 (m, 2H).

[0911] Example 75: (S)-4-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-amine (Compound 1-71) [ka]

[0912] The title compound was prepared according to the procedure described in Example 14 (Step 2) to give (S)-4-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-amine (287 mg, 68.9% yield). Mass spectrum: 416 (M+H), t R =3.658 minutes,1 H-NMR (400 Hz, CDCl3) δ= 7.921-7.943 (d, 1H),7.764-7.786 (d, 1H),7.714-7.720 (d, 1H), 7.559-7.586 (m, 3H), 7.401-7.439 (m, 2H),7.297-7.334 (m, 1H), 7.109-7.131 (m, 1H), 6.959-7.026 (m, 3H), 5.841 (br, 1H), 4.021(br, 2H), 3.595-3.622 (m, 1H), 3.402-3.434 (m, 2H), 3.190-3.208 (m, 1H), 2.565-2.616(m,1H), 2.227-2.250 (m, 2H).

[0913] Example 76: (S)-4-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (Compound 1-67) [ka]

[0914] Step 1: (S)-5-Bromo-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzonitrile [ka]

[0915] The title compound was prepared according to the procedure described in Example 5 to give (S)-5-bromo-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzonitrile (270 mg, 63% yield). Mass spectrum: 428 (M+H).

[0916] Step 2: (S)-5-Bromo-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0917] The title compound was prepared according to the procedure described in Example 64 (Step 2) to give (S)-5-bromo-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzamide (300 mg, 106% yield). Mass spectrum: 446 (M+H).

[0918] Step 3: (S)-4-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide [ka]

[0919] The title compound was prepared according to the procedure described in Example 67 (Step 2) to give (S)-4-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (80 mg, 36% yield). Mass spectrum: 444 (M+H), t R =4.144 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.229-8.252 (d, 1H), 8.032-8.037(d, 1H), 7.799-7.873 (m, 2H), 7.683-7.711 (m, 1H), 7.533-7.611 (m, 4H), 7.341-7.435(m, 2H), 7.287 (s, 1H), 7.268 (m ,1H), 7.062-7.064 (d, 1H), 6.858-6.880 (d, 1H),5.825 (br ,1H), 3.912-3.954 (m ,1H), 3.582-3.601 (m ,1H), 3.430-3.453 (m, 2H), 2.372(m, 1H), 2.283 (m, 1H).

[0920] Example 77: (R)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(pyridin-3-yl)benzamide hydrochloride (Compound 1-74) [ka]

[0921] Step 1: (R)-5-Bromo-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile [ka]

[0922] The title compound was prepared according to the procedure described in Example 5 using (R)-3-chloro-2-(pyrrolidin-3-yloxy)pyridine (prepared as Intermediate 4) to give (R)-5-bromo-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (2.3 g, 80% yield). Mass spectrum: 378 (M+H).

[0923] Step 2: (R)-5-Bromo-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0924] The title compound was prepared according to the procedure described in Example 64 (Step 2) to give (R)-5-bromo-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)benzamide (1.5 g, 82% yield). Mass spectrum: 396 (M+H).

[0925] Step 3: (R)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(pyridin-3-yl)benzamide hydrochloride [ka]

[0926] The title compound was prepared according to the procedure described in Example 67 (Step 2) to give (R)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(pyridin-3-yl)benzamide hydrochloride (23.6 mg, 10.5% yield). Mass spectrum: 395 (M+H), t R =1.525 minutes, 1 H-NMR (400 Hz, DMSO) δ= 9.159-9.162 (d, 1H), 8.705-8.799(m, 2H), 8.130-8.146 (m, 1H), 8.003-8.036 (m, 1H), 7.865-7.886 (m, 2H), 7.747-7.862(m, 2H), 7.429 (s, 1H), 7.013-7.044 (m, 1H), 6.892-6.915 (d, 1H), 5.661 (br ,1H),3.901-3.942 (m ,2H), 3.252-3.360 (m,2H), 2.215-2.326 (m, 2H).

[0927] Example 78: (R)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (Compound 1-75) [ka]

[0928] The title compound was prepared according to the procedure described in Example 67 (Step 2) to give (R)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (49.8 mg, 24.9% yield). Mass spectrum: 394 (M+H), t R =2.741 minutes, 1H-NMR (400 Hz, DMSO) δ= 8.126-8.143 (m, 1H), 7.849-7.878(m, 2H), 7.499-7.582 (m, 4H), 7.299-7.407 (m, 2H), 7.223-7.259 (m, 2H), 7.003-7.036(m, 1H), 6.630-6.851 (m, 1H), 5.642 (br, 1H), 3.856-3.898 (m, 1H), 3.509-3.549(m, 1H), 3.381-3.403 (m, 1H), 3.266-3.284 (m, 1H), 2.283-2.318 (m, 1H), 2.171-2.202(m, 1H).

[0929] Example 79: (R)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(pyridin-4-yl)benzamide hydrochloride (Compound 1-82) [ka]

[0930] The title compound was prepared according to the procedure described in Example 67 (Step 2) to give (R)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(pyridin-4-yl)benzamide hydrochloride (90 mg, 45% yield). Mass spectrum: 395 (M+H), t R =1.161 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.671-8.693 (m, 1H), 8.130-8.147(m, 1H), 8.018 (m, 2H), 7.930 (m, 1H), 7.862-7.885 (m, 2H), 7.514-7.821 (m, 1H),7.014-7.045 (m, 1H), 6.878-6.901 (m, 1H), 5.665 (br, 1H), 3.916-3.956 (m, 1H),3.585-3.650 (m, 1H), 3.507-3.528 (m, 2H), 2.283-2.328 (m, 1H), 2.195-2.235 (m,1H).

[0931] Example 80: (R)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(pyridin-2-yl)benzamide (Compound 1-85) [ka]

[0932] The title compound was prepared according to the procedure described in Example 67 (Step 2) to give (R)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(pyridin-2-yl)benzamide (21.5 mg, 53% yield). Mass spectrum: 395 (M+H), t R =1.540 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.571-8.582 (d, 1H), 8.158-8.174(m, 1H), 7.964-8.002 (m, 2H), 7.770-7.913 (m, 4H), 7.351 (m, 1H), 7.204-7.234 (m,1H), 7.036-7.068 (m, 1H), 6.841-6.863 (m, 1H), 5.682 (br, 1H), 3.908-3.948 (m,1H), 3.570-3.610 (m, 2H), 2.291-2.345 (m, 1H), 2.234-2.244 (m, 1H).

[0933] Example 81: (R)-4-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (Compound 1-78) [ka]

[0934] Step 1: (R)-5-Bromo-2-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile [ka]

[0935] The title compound was prepared according to the procedure described in Example 5 using (R)-2-(pyrrolidin-3-yloxy)pyridine (prepared as Intermediate 4) to give (R)-5-bromo-2-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (700 mg, 60% yield). Mass spectrum: 344 (M+H).

[0936] Step 2: (R)-5-Bromo-2-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0937] The title compound was prepared according to the procedure described in Example 64 (Step 2) to give (R)-5-bromo-2-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (450 mg, 55% yield). Mass spectrum: 362 (M+H).

[0938] Step 3: (R)-4-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide [ka]

[0939] The title compound was prepared according to the procedure described in Example 67 (Step 2) to give (R)-4-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (40 mg, 40% yield). Mass spectrum: 360 (M+H), t R =2.491 minutes, 1H-NMR (400 Hz, DMSO) δ= 8.195 (m, 1H), 7.897 (m,1H), 7.527-7.703 (m, 5H), 7.269-7.416 (m, 4H), 6.989 (m, 1H), 6.784-6.860 (dd, 2H),5.606 (br, 1H), 3.837-3.862 (m, 1H), 3.519-3.563 (m, 1H), 3.331-3.365 (m, 2H), 2.286(m, 1H), 2.189 (m, 1H).

[0940] Example 82: (R)-2-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)-5-(pyridin-4-yl)benzamide (Compound 1-79) [ka]

[0941] The title compound was prepared according to the procedure described in Example 67 (Step 2) to give (R)-2-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)-5-(pyridin-4-yl)benzamide (30 mg, 46% yield). Mass spectrum: 361 (M+H), t R =0.700 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.522-8.537 (d, 2H), 8.180-8.193(d, 1H), 7.903 (s, 1H), 7.627-7.671 (m, 5H), 7.386 (s, 1H), 6.775-6.991 (m, 3H),5.609 (br, 1H), 3.863-3.893 (m, 1H), 3.567-3.591 (m, 1H), 3.312-3.381 (m, 2H),2.288 (m, 1H), 2.199 (m, 1H).

[0942] Example 83: (R)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(pyridin-3-yl)benzamide hydrochloride (Compound 1-87) [ka]

[0943] The title compound was prepared according to the procedure described in Example 67 (Step 2) to give (R)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(pyridin-3-yl)benzamide hydrochloride (20 mg, 20.5% yield). Mass spectrum: 361 (M+H), t R =2.116 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.843 (s, 1H), 8.461-8.473(d, 1H), 8.186-8.197 (d, 1H), 7.787-7.992 (m, 2H), 7.579-7.701 (m, 3H), 7.360 (m, 2H), 6.784-6.991 (m, 3H), 5.610 (br, 1H), 3.856 (m, 1H), 3.556-3.566 (m, 1H), 3.420(m, 1H), 3.297-3.337 (m, 1H), 2.209-2.308 (m, 2H).

[0944] Example 84: (R)-5-(pyridin-2-yl)-2-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-88) [ka]

[0945] The title compound was prepared according to the procedure described in Example 67 (Step 2) to give (R)-5-(pyridin-2-yl)-2-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (100 mg, 61% yield). Mass spectrum: 361 (M+H), t R =1.474 minutes, 1H-NMR (400 Hz, DMSO) δ= 8.664-8.676 (m, 1H), 8.179-8.197(m, 1H), 7.957-7.977 (m, 1H), 7.871-7.875 (m, 2H), 7.694-7.697 (d, 1H), 7.479 (s,1H), 7.329-7.376 (m, 4H), 6.969-6.999 (m, 1H), 6.781-6.802 (d, 1H), 5.609 (br, 1H),3.868-3.884 (m, 1H), 3.593-3.610 (m, 1H), 3.435-3.440 (m, 1H), 3.297-3.312 (m,1H), 2.285-2.331 (m, 1H), 2.186-2.198 (m, 1H).

[0946] Example 85: (R)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-amine (Compound 1-93) [ka]

[0947] The title compound was prepared according to the procedure described in Example 14 (Step 2) using (R)-2-(1-(3-nitrobiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (prepared as Example 67) to give (R)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-amine (360 mg, 39% yield). Mass Spectrum: 400 (M+H), t R =3.387 minutes, 1H-NMR (400 Hz, DMSO) δ= 8.599-8.606 (m, 1H), 8.056-8.084(dd, 1H), 7.520-7.541 (M, 2h), 7.382-7.420 (M, 2H), 7.253-7.292 (m, 1H), 7.034-7.057(d, 1H), 6.944-6.984 (m, 2H), 6.825-6.851 (m, 1H), 5.615 (br, 1H), 4.762 (s, 1H),3.544-3.583 (m, 1H), 3.266-3.299 (m, 1H), 3.118-3.153 (m, 1H), 3.014-3.069 (m, 1H),2.422-2.509 (m, 1H), 2.030-2.051 (m, 1H).

[0948] Example 86: (R)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-ol (Compound 1-89) [ka]

[0949] The title compound was prepared according to the procedure described in Example 14 (Step 3) to give (R)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-ol (50 mg, 12% yield). Mass spectrum: 401 (M+H), t R =3.186 minutes, 1H-NMR (400 Hz, DMSO) δ= 9.285 (s, 1H), 8.621-8.623(d, 1H), 8.060-8.088 (m, 1H), 7.381-7.552 (m, 4H), 7.238-7.275 (m, 1H), 7.002-7.042(m, 3H), 6.718-6.738 (d, 1H), 5.629 (br, 1H), 3.807-3.850 (m, 1H), 3.483-3.572 (m,2H), 3.259-3.328 (m, 1H), 2.312-2.365 (m, 1H), 2.078-2.128 (m, 1H).

[0950] Example 87: (R)-2-(1-(3-methoxybiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-111) [ka]

[0951] The title compound was prepared according to the procedure described in Example 68 (Step 3) to give (R)-2-(1-(3-methoxybiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (50 mg, 50% yield). Mass spectrum: 415 (M+H), t R =3.631 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.629 (s, 1H), 8.059-8.087(q, 1H), 7.619-7.639 (d, 2H), 7.393-7.431 (m, 2H), 7.274-7.293 (m, 1H), 7.145-7.184(m, 2H), 7.022-7.044 (d, 1H), 6.767-6.788 (d, 1H), 5.656 (br, 1H), 3.848-3.833 (m,4H), 3.557-3.677 (m, 1H), 3.410-30440 (m, 1H), 3.297-3.318 (m ,1H), 2.505-2.514(m, 1H), 2.331-2.337 (m, 1H).

[0952] Example 88: (R)-2-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yloxy)ethanol (Compound 1-117) [ka]

[0953] Step 1: (R)-Ethyl 2-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yloxy)acetate [ka]

[0954] To a solution of (R)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-ol (60 mg, 0.15 mmol) in DMF was added ethyl 2-bromoacetate (49.5 mg, 0.3 mmol), K2CO3 (50 mg, 0.3 mmol), and KI(). The mixture was stirred at 45 °C for 1 h, diluted with DCM, washed with NaHCO3 solution, LiCl solution, and brine, dried over Na2SO4, and the solvent was removed to give a residue that was purified by silica gel to give (R)-ethyl 2-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yloxy)acetate (70 mg, 90% yield). Mass spectrum: 487 (M+H).

[0955] Step 2: (R)-2-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yloxy)ethanol [ka]

[0956] To a solution of (R)-ethyl 2-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yloxy)acetate (40 mg, 0.08 mmol) in DME (1 mL) was added LiBH (3 mg, 0.16 mmol) at 0 °C, the mixture was stirred at room temperature for 2 h, cooled to 0 °C, extracted with DCM, washed with NH Cl, dried over Na SO and the solvent was removed to give a residue which was purified by silica gel to give (R)-2-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yloxy)ethanol (17 mg, 35%). Mass spectrum: 445 (M+H), t R =3.087 minutes, 1 H-NMR (400 Hz, CDCl3) δ= 8.462-8.467 (q, 1H),7.777-7.806 (d, 1H), 7.556-7.579 (d, 2H), 7.417-7.455 (m, 2H), 7.196-7.342 (m, 3H),6.929-6.949 (d, 1H), 6.856-6.877 (d, 1H), 5.719 (br, 1H),4.221-4.242 () m, 2H),3.816-3.887 (m, 3H), 3.559-3.703 (m, 2H), 3.345-3.358 (m, 1H), 2.428-2.462 (m, 1H),2.264-2.281 (m, 1H).

[0957] Example 89: (S)-Ethyl 2-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yloxy)acetate (Compound 134) [ka]

[0958] The title compound was prepared according to the procedure described in Example 88 (Step 1) to give (S)-ethyl 2-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yloxy)acetate (190 mg, 90% yield). Mass spectrum: 487 (M+H), t R =3.400 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.617-8.620 (d, 1H), 8.061-8.089(m, 1H), 7.603-7.624 (m, 2H), 7.388-7.426 (2H), 7.139-7.288 (m, 3H), 7.022-7.043(d, 1H), 6.784-6.805 (d, 1H), 5.671 (br, 1H), 4.863 (s, 2H), 4.135-4.188 (q, 2H),3.904-3.948 (m, 1H), 3.549-3.637 (m, 2H), 3.343-3.347 (m, 1H), 2.327-2.360 (m, 1H),2.162-2.165 (m, 1H).

[0959] Example 90: (S)-2-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yloxy)ethanol (Compound 135) [ka]

[0960] The title compound was prepared according to the procedure described in Example 88 (Step 2) to give (S)-2-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yloxy)ethanol (90 mg, 75% yield). Mass spectrum: 445 (M+H), t R =2.922 minutes, 1H-NMR (400 Hz, DMSO) δ= 8.618-8.624 (s, 1H), 8.057-8.086(m, 1H), 7.605-7.627 (m, 2H), 7.385-7.424 (m, 2H), 7.247-7.284 (m, 1H), 7.142-7.187(m, 2H), 7.018-7.040 (d, 1H), 6.750-6.771 (d, 1H), 5.672 (br, 1H), 4.840-4.868 (t,1H), 4.043-4.082 (m, 2H), 3.892-3.935 (m, 1H), 3.737-3.767 (m, 2H), 3.593-3.624(m, 1H), 3.469-3.499 (m, 1H), 3.332-3.335 (m, 1H), 2.319-2.325 (m, 1H), 2.116-2.119(m, 1H).

[0961] Example 91: (R)-5-(4,5-dihydro-1H-imidazol-2-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 100) [ka]

[0962] To a solution of (R)-5-cyano-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Example 35) (100 mg, 0.26 mmol) in ethane-1,2-diamine was added sulfur (33 mg, 0.13 mmol). The mixture was heated to 80° C. in a microwave for 10 minutes and then poured into ice water to precipitate the product as a solid. The product was purified by vacuum filtration and dried to give (R)-5-(4,5-dihydro-1H-imidazol-2-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (21 mg, 17% yield). Mass spectrum: 420 (M+H), t R =0.429 minutes, 1H-NMR (400 Hz, DMSO) δ= 8.625 (s, 1H), 8.335 (br,1H), 8.060-8.089 (dd, 1H), 7.865 (s, 1H), 7.146-7.406 (m, 4H), 7.001-7.022 (d, 1H),5.701 (br, 1H), 3.813-3.877 (m, 2H), 3.728 (s, 4H), 3.293-3.387 (m, 2H), 2.250-2.330(m, 1H), 2.234-2.244 (m, 1H).

[0963] Example 92: (R)-5-(1H-imidazol-2-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-107) [ka]

[0964] To a solution of (R)-5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Example 35, Step 2) (214 mg, 0.5 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (254 mg, 1 mmol) in dioxane (2 mL) was added AcOK (147 mg, 1.5 mmol), Pd(dppf)Cl (21 mg, 10 wt%), and the mixture was degassed with N and then heated to 80 °C for 3 h. EA was added, filtered, and the organic layer was washed with water, brine, dried over NaSO, and the solvent was removed to give the crude product (which could be used directly). The crude product (48 mg, 0.1 mmol) in dioxane / HO (5 mL / 1 mL) was added to 2-iodo-1-trityl-1H-imidazole (38 mg, 2 mmol) (prepared according to PCT2008096360), Pd(dppf)Cl (5 mg, 10 wt%), and KCO, and the mixture was stirred at 100 °C for 1 h, diluted with EA, washed with water, brine, dried over NaSO, and the solvent was removed to give the crude product, which was purified by silica gel to give (R)-5-(1H-imidazol-2-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (10 mg, 24% yield). Mass spectrum: 418 (M+H), t R =2.622 minutes, 1 H-NMR (400 Hz, DMSO) δ= 12.565 (s, 1H), 8.624(s, 1H), 8.052-8.080 (dd, 1H), 7.792 (s, 1H), 7.248-7.345 (m, 5H), 7.005-7.026 (m,2H), 5.694 (br, 1H), 3.848-3.888 (m, 1H), 3.492-3.630 (m, 3H), 2.331-2.352 (m, 1H),2.210-2.246 (m, 1H).

[0965] Example 93: (R)-5-(trifluoromethyl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-84) [ka]

[0966] A solution of (R)-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine hydrochloride (250 mg, 1.07 mmol) (Intermediate 4), 2-fluoro-5-(trifluoromethyl)benzonitrile (189 mg, 1.0 mmol), and K2CO3 (414 mg, 3 mmol) in 5 mL of DMF was stirred at 100 °C for 2 h, and the mixture was washed with LiCl solution, extracted with EA, dried over Na2SO4, and evaporated to give the intermediate product as a brown oil. This was dissolved in 12 mL of EtOH, and HO (6 mL, 30%) and NaOH solution (12 mL, 6 M) were added. The mixture was stirred at 60 °C overnight, poured into ice water, and the precipitate was filtered, washed with EtO, and dried to give (R)-5-(trifluoromethyl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (200 mg, 47.6% yield). Mass spectrum: 420 (M+H), t R =2.855 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.613-8.617 (d, 1H), 8.050-8.077(dd, 1H), 7.933 (s, 1H), 7.494-7.521 (m, 1H), 7.437-1.441 (d, 1H), 6.991-7.013 (d,1H), 6.840-6.862 (d, 1H), 5.699 (br, 1H), 3.864-3.906 (m, 1H), 3.550-3.593 (m, 1H),3.400-3.471 (m, 1H), 3.313-3.336 (m, 1H), 2.297-2.329 (m, 1H), 2.224-2.256 (m, 1H).

[0967] Example 94: (S)-5-phenoxy-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-124) [ka]

[0968] Step 1: (S)-5-phenoxy-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile [ka]

[0969] A mixture of (S)-5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (205 mg, 0.5 mmol) (Example 27, Step 2), phenol (94 mg, 1 mmol), CuI (47 mg, 0.25 mmol), CsCO (326 mg, 1 mmol), and 2-(dimethylamino)acetic acid hydrochloride (35 mg, 0.25 mmol) in dioxane / DMF (1.5 mL / 0.5 mL) was stirred at 160 °C under microwave irradiation for 1 h, diluted with EA, washed with water, brine, dried over NaSO, and the solvent removed to give crude (S)-5-phenoxy-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (220 mg) (use directly). Mass spectrum: 426 (M+H).

[0970] Step 2: (S)-5-phenoxy-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide [ka]

[0971] The title compound was prepared according to the procedure described in Example 63 (Step 3) to give (S)-5-phenoxy-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (30 mg, 22% yield). Mass spectrum: 444 (M+H), t R =3.098 minutes, 1H-NMR (400 Hz, DMSO) δ= 8.617 (s, 1H), 8.064-8.093(q, 1H), 7.941 (s, 1H), 7.328-7.374 (m, 3H), 6.861-7.088 (m, 7H), 5.665 (br, 1H),3.762-3.791 (m, 1H), 3.473-3.494 (m, 1H), 3.257-3.338 (m, 2H), 2.330-2.351 (m, 1H),2.188-2.190 (m, 1H).

[0972] Example 95: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanamine hydrochloride (Compound 1-125) [ka]

[0973] To a solution of (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbonitrile (300 mg, 0.8 mmol) in 5 mL of MeOH, CoCl (206 mg, 1.6 mmol) and NaBH (304 mg, 8 mmol) were added at 0 °C. The mixture was stirred at room temperature for 12 h. The reaction mixture was filtered, and the filtrate was quenched with NH.HO, extracted with DCM, dried over NaSO, and the solvent was removed to give a residue. This was purified by silica gel followed by preparative HPLC and lyophilized with HCl to give (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanamine hydrochloride (9 mg, 3%). Mass spectrum: 380 (M+H), t R =2.177 minutes, 1H-NMR (400 Hz, DMSO) δ= 8.479 (br, 3H), 8.153-8.168(q, 1H), 7.851-7.937 (m, 2H), 7.622-7.604 (m, 3H), 7.444-7.483 (m, 2H),7.318-7.335(m, 1H), 7.234-7.255 (d, 1H), 7.043-7.234 (m, 1H), 5.668 (br, 1H), 4.163-4.194 (m,2H), 3.694-3.734 (m, 1H), 3.418-3.477 (m, 1H), 3.239-3.282 (m, 2H), 2.421-2.471(m, 1H), 2.128-2.161 (m, 1H).

[0974] Example 96: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (Compound 1-126) [ka]

[0975] Step 1: (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbaldehyde [ka]

[0976] To a solution of (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbonitrile (600 mg, 1.6 mmol) in DCM / THF (4 mL / 3 mL) was added DIBAL-H (10 mL, 1.5 M in toluene) at −78° C. The mixture was stirred at this temperature for 3 h, quenched with ice water, extracted with DCM, dried over NaSO, and the solvent was removed to give a residue that was purified by silica gel to give (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbaldehyde (90 mg, 15%). Mass spectrum: 379 (M+H).

[0977] Step 2: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol [ka]

[0978] To a solution of (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbaldehyde (90 mg, 0.25 mmol) in MeOH was added NaBh (23 mg, 0.72 mmol) at 0 °C, the mixture was stirred at room temperature for 10 min, quenched with NH Cl solution, extracted with EA, washed with brine, dried over Na SO and the solvent was removed to give a residue which was purified by silica gel to give (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (61 mg, 64%). Mass spectrum: 381 (M+H), t R =3.035 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.157-8.166 (d, 1H), 7.901-7.925(q, 1H), 7.681-7.686 (d, 1H), 7.591-7.610 (m, 2H), 7.408-7.474 (m, 3H), 7.285-7.303(m, 1H), 7.044 (m, 1H), 6.951-7.044 (m, 1H), 5.641 (br, 1H), 5.136-5.164 (m, 1H),4.579 (m, 2H), 3.722-3.749 (m, 1H), 3.470-3.491 (m, 1H), 3.266-3.322 (m, 2H), 2.376-2.379(m, 1H), 2.141-2.149 (m, 1H).

[0979] Example 97: (R)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-amine (Compound 1-116) [ka]

[0980] To a solution of (R)-2-(1-(2'-chloro-3-nitrobiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (500 mg, 1.08 mmol) (prepared as Example 67) in DMF / HO (21 mL / 7 mL) was added Zn (1.4 g, 21.6 mmol) and FeCl (175 mg, 1.08 mmol). The mixture was stirred at room temperature for 3 hours, diluted with DCM, filtered, and the filtrate was extracted with DCM, washed with LiCl solution, dried over NaSO, and the solvent was removed to give a residue. This was purified by silica gel to give (R)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-amine (100 mg, 20% yield). Mass spectrum: 434 (M+H), t R =3.472 minutes, 1 H-NMR (400 Hz, DMSO) δ= 8.620 (s, 1H), 8.071-8.099(q, 1H), 7.495-7.515 (m, 1H), 7.313-7.382 (m, 3H), 7.048-7.070 (m, 1H), 6.938-6.958(m, 1H), 6.745-6.750 (m, 1H), 6.586-6.610 (m, 1H), 5.618 (br, 1H), 4.778 (m, 2H),3.561-3.602 (m, 1H), 3.277-3.317 (m, 1H), 3.060-3.163 (m, 2H), 2.430-2.506 (m, 1H),2.045-2.079 (m, 1H).

[0981] Example 98: (R)-2'-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-ol (Compound 1-113) [ka]

[0982] The title compound was prepared according to the procedure described in Example 14 (Step 3) to give (R)-2'-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-ol (310 mg, 50% y...

Claims

1. A compound of formula (XXXII), 【Chemical Formula 990】 or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, During the ceremony, G is pyridinyl, pyrazinyl, or thiazolyl; A is, 【Chemistry 1008】 and E is phenyl or pyrazinyl; Each R １ are independently selected from cyano, nitro, hydroxy, halo, C １ ~C ３ Haloalkyl, C １ ~C ３ Haloalkoxy, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, -C １ ~C ６ Alkoxy-C １ ~C ６ Alkyl, aryl, -N(R ａ ) (R ｂ ), -C(O)R ｃ , -CO ２ R ｃ , -C(O)N(R ａ ) (R ｂ ), -SO ２ N (R ａ ) (R ｂ ), or -SOR ｃ and or two R's １ the groups taken together form a ring system, R ２ and R ３ each independently selected from cyano, nitro, hydroxy, halo, C １ ~C ３ Haloalkyl, C １ ~C ３ Haloalkoxy, C １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, C ３ ~C ８ Cycloalkyl, C １ ~C ６ Alkoxy, aryl, -N(R ａ ) (R ｂ ), -C(O)R ｃ , -CH ２ R ｃ , -CO ２ R ｃ , -C(O)N(R ａ ) (R ｂ ), -SO ２ N (R ａ ) (R ｂ ), or -SOR ｃ and R ａ and R ｂ each independently represents H, hydroxyl, -OR ｃ , C １ ~C ６ Alkyl, —C(O)R ｃ , or —C(O)OR ｃ and each R ｃ However, independently, H, C １ ~C ６ alkyl or aryl, The compound, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein n is 0, 1, or 2, p is 1, or 2, and q is 0, 1, or 2.

2. A is 【Chemistry 1009】 2. The compound of claim 1, wherein:

3. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein E is phenyl.

4. 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein G is pyridinyl or pyrazinyl.

5. n is 1 or 2, and each R １ But independently, Halo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, hydroxy, C １ ~C ３ Haloalkyl, cyano, -C １ ~C ６ Alkoxy-C １ ~C ６ Alkyl, —N(R ａ ) (R ｂ ), or -C(O)R ｃ and R ａ and R ｂ each independently is H or C １ ~C ６ alkyl, and each R ｃ are independently H or C １ ~C ６ 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein R is alkyl.

6. Each R １ are independently selected from fluorine, chlorine, methyl, methoxy, hydroxy, methylamine, -CH ２ OCH ３ , or -CF ３ 6. The compound of claim 5, wherein:

7. Each R ２ are independently cyano, nitro, hydroxy, C １ ~C ６ Hydroxyalkyl, —NH ２ , halo, aryl, -N(R ａ ) (R ｂ ), -C(O)OH, -CH ２ R ｃ , -CO ２ R ｃ , or —C(O)N(R ａ ) (R ｂ 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein

8. Each R ２ But independently, C １ ~C ６ 8. The compound of claim 7, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein: R is hydroxyalkyl or halo.

9. Each R ２ are independently -CH ２ 9. The compound of claim 7 or 8, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein R is OH or fluorine.

10. q is 1 or 2, and each R ３ But independently, Halo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, or C ３ ~C ８ 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, which is cycloalkyl.

11. Each R ３ 11. The compound of claim 10, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein is independently fluorine, cyclopropyl, methyl, ethyl, or propyl.

12. A compound of formula (XXXIII), 【Chemical 993】 or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein G is pyridinyl, pyrazinyl, or thiazolyl; Each R １ are independently selected from cyano, nitro, hydroxy, halo, C １ ~C ３ Haloalkyl, C １ ~C ３ Haloalkoxy, C １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Alkoxy, -C １ ~C ６ Alkoxy-C １ ~C ６ Alkyl, aryl, -N(R ａ ) (R ｂ ), -C(O)R ｃ , -CO ２ R ｃ , -C(O)N(R ａ ) (R ｂ ), -SO ２ N (R ａ ) (R ｂ ), or -SOR ｃ and or two R's １ the groups taken together form a ring system, R ２ and R ３ each independently selected from cyano, nitro, hydroxy, halo, C １ ~C ３ Haloalkyl, C １ ~C ３ Haloalkoxy, C １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, C ３ ~C ８ Cycloalkyl, C １ ~C ６ Alkoxy, aryl, -N(R ａ ) (R ｂ ), -C(O)R ｃ , -CH ２ R ｃ , -CO ２ R ｃ , -C(O)N(R ａ ) (R ｂ ), -SO ２ N (R ａ ) (R ｂ ), or -SOR ｃ and R ａ and R ｂ each independently represents H, hydroxyl, -OR ｃ , C １ ~C ６ Alkyl, —C(O)R ｃ , or —C(O)OR ｃ and each R ｃ However, independently, H, C １ ~C ６ alkyl or aryl, The compound, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein n is 0, 1, or 2, p is 1, or 2, and q is 0, 1, or 2.

13. G, 【Chemical 1010】 13. The compound of claim 12, wherein:

14. n is 1 or 2, and each R １ But independently, Halo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, hydroxy, C １ ~C ３ Haloalkyl, cyano, -C １ ~C ６ Alkoxy-C １ ~C ６ Alkyl, —N(R ａ ) (R ｂ ), or -C(O)R ｃ and R ａ and R ｂ each independently is H or C １ ~C ６ alkyl, and each R ｃ are independently H or C １ ~C ６ 14. The compound of claim 12 or 13, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein:

15. Each R １ are independently selected from fluorine, chlorine, methyl, methoxy, hydroxy, methylamine, -CH ２ OCH ３ , or -CF ３ 15. The compound of claim 14, wherein:

16. Each R ２ are independently cyano, nitro, hydroxy, C １ ~C ６ Hydroxyalkyl, —NH ２ , halo, aryl, -N(R ａ ) (R ｂ ), -C(O)OH, -CH ２ R ｃ , -CO ２ R ｃ , or —C(O)N(R ａ ) (R ｂ 16. The compound according to any one of claims 12 to 15, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein

17. Each R ２ But independently, C １ ~C ６ 17. The compound of claim 16, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, which is hydroxyalkyl or halo.

18. Each R ２ are independently -CH ２ 17. The compound of claim 16, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein R is OH or fluorine.

19. q is 1 or 2, and each R ３ But independently, Halo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, or C ３ ~C ８ 19. The compound of any one of claims 12 to 18, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, which is cycloalkyl.

20. Each R ３ 20. The compound of claim 19, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein is independently fluorine, cyclopropyl, methyl, ethyl, or propyl.

21. A compound of formula (XXXXIII), 【Chemistry 1011】 or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, During the ceremony, G is pyridinyl, pyrazinyl, or thiazolyl; Each R １ But independently, Halo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, hydroxy, C １ ~C ３ Haloalkyl, cyano, -C １ ~C ６ Alkoxy-C １ ~C ６ Alkyl, —N(R ａ ) (R ｂ ), or -C(O)R ｃ and R ａ and R ｂ each independently is H or C １ ~C ６ is alkyl, R ２ and R ６ each independently selected from cyano, nitro, hydroxy, C １ ~C ６ Hydroxyalkyl, —NH ２ , halo, aryl, -N(R ａ ) (R ｂ ), -C(O)OH, -CH ２ R ｃ , -CO ２ R ｃ , or —C(O)N(R ａ ) (R ｂ ) and Each R ｃ However, independently, H, C １ ~C ６ alkyl or aryl, R ３ and R ７ each independently represents a halo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, or C ３ ~C ６ is cycloalkyl, The compound, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein n is 0, 1, or 2, u is 0, 1, or 2, and v is 0, 1, or 2.

22. Compounds of formula (XXXV) or (XXXVI): 【Chemical Formula 998】 22. The compound of claim 21, wherein:

23. n is 1 or 2, and each R １ But independently, Halo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, hydroxy, C １ ~C ３ haloalkyl, or —N(R ａ ) (R ｂ ) and R ａ and R ｂ each independently is H or C １ ~C ６ alkyl, and each R ｃ are independently H or C １ ~C ６ 23. The compound of claim 21 or 22, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein:

24. n is 1 or 2, and each R １ are independently selected from fluorine, chlorine, methyl, methoxy, hydroxy, methylamine, -CH ２ OCH ３ , or -CF ３ 24. The compound according to any one of claims 21 to 23, wherein:

25. (i) n is 1 or 2, and each R １ are independently fluorine, chlorine, methyl, methoxy, hydroxy, methylamine, or —CF ３ is; (ii) n is 2 and each R １ are independently fluorine, chlorine, methyl, methoxy, hydroxy, methylamine, or —CF ３ is; (iii) n is 2 and each R １ is independently methyl or hydroxy; (iv) n is 1 and R １ is fluorine; or (v) n is 2 and one of R １ is methyl, and the other R １ 25. The compound of any one of claims 21 to 24, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein is hydroxy.

26. R ２ -cyano, nitro, hydroxy, C １ ~C ６ Hydroxyalkyl, —NH ２ , halo, aryl, -N(R ａ ) (R ｂ ), -C(O)OH, -CH ２ R ｃ , -CO ２ R ｃ , or —C(O)N(R ａ ) (R ｂ 26. The compound according to any one of claims 21 to 25, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein

27. R ２ But C １ ~C ６ 27. The compound of any one of claims 21 to 26, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, which is hydroxyalkyl or halo.

28. (i) R ２ Ga-CH ２ (ii) R is OH; ２ is fluorine; (iii) v is 1 and R ２ is C １ ~C ６ hydroxyalkyl, and R ６ is halo; or (iv) v is 1 and R ２ Ga-CH ２ OH and R ６ The compound according to any one of claims 21 to 27, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein is fluorine.

29. R ３ But, Halo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, or C ３ ~C ６ 29. The compound of any one of claims 21 to 28, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, which is cycloalkyl.

30. R ３ 30. The compound of any one of claims 21 to 29, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein is fluorine, cyclopropyl, methyl, ethyl, or propyl.

31. (i) R ３ But, Halo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, or C ３ ~C ８ (ii) u is 1 and R ３ But, Halo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, or C ３ ~C ８ is cycloalkyl, and R ７ is halo; or (iii) u is 1 and R ３ is cyclopropyl, methyl, ethyl, or propyl, and R ７ The compound according to any one of claims 21 to 28, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, wherein is fluorine. 【Request Item 32】 【Chemistry 1012】 【Chemical 1013】 【Chemical 1014】 【Chemical 1015】 or a stereoisomer, racemate, or pharmaceutically acceptable salt thereof.

33. structure: 【Chemical 1002】 (or a stereoisomer, racemate, or pharmaceutically acceptable salt thereof).

34. structure: 【Chemical 1003】 (or a stereoisomer, racemate, or pharmaceutically acceptable salt thereof).

35. A compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, comprising an enantiomer of at least 95% chiral purity.

36. 36. A composition comprising a therapeutically effective amount of at least one compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, for use in a method for treating, preventing, suppressing, reducing, eliminating, protecting against, or delaying the onset of a skin disorder in a subject in need thereof.

37. structure: 【Chemical 1004】 37. The composition of claim 36, comprising a compound having the formula: or a stereoisomer, racemate, or pharmaceutically acceptable salt thereof.

38. structure: 【Chemistry 1005】 37. The composition of claim 36, comprising a compound having the formula: or a stereoisomer, racemate, or pharmaceutically acceptable salt thereof.

39. A composition comprising at least one compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, or a pharmaceutical composition comprising at least one compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt, racemate, or stereoisomer thereof, and a pharmaceutically acceptable carrier, for inhibiting TPRV3 activity in a cell.

40. 40. The composition of claim 39, wherein the subject is a subject suffering from a skin disorder.

41. 40. The composition of any one of claims 36 to 39, wherein the skin disorder comprises at least one keratoderma.

42. 42. The composition of claim 41, wherein the at least one keratoderma is Olmsted syndrome.

43. 42. The composition of claim 41, wherein the at least one keratoderma is Meleda's disease.

44. 42. The composition of claim 41, wherein the at least one keratoderma comprises punctate palmoplantar keratoderma.

45. 42. The composition of claim 41, wherein the at least one keratoderma comprises pachyonychia congenita.

46. The composition of any one of claims 36 to 39, wherein the skin disorder is ichthyosis.

47. 47. The composition of claim 46, wherein the ichthyosis is harlequin ichthyosis.

48. 47. The composition of claim 46, wherein the ichthyosis is X-linked ichthyosis.

49. The composition of any one of claims 36 to 48, wherein the composition is for administration by injection.

50. The composition of any one of claims 36 to 48, wherein the composition is for transdermal administration.

51. The composition of any one of claims 36 to 48, wherein the composition is for topical administration.

52. The composition of any one of claims 36 to 48, wherein the composition is for oral administration.

53. The composition of any one of claims 36 to 48, wherein the composition is for buccal administration.

54. structure: 【Chemical Engineering 1101】 34. The compound of claim 33, wherein:

55. structure: 【Chemical Engineering 1102】 55. The compound of claim 54, having the formula:

56. structure: 【Chemical 1103】 35. The compound of claim 34, wherein:

57. structure: 【Chemical 1104】 57. The compound of claim 56, having the formula:

58. structure: 【Chemical 1105】 38. The composition of claim 37, comprising a compound having the formula:

59. structure: 【Chemical Engineering 1106】 59. The composition of claim 58, comprising a compound having the formula:

60. structure: 【Chemical 1107】 39. The composition of claim 38, comprising a compound having the formula:

61. structure: 【Chemical 1108】 61. The composition of claim 60, comprising a compound having the formula:

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