Compounds and compositions for use in treating skin disorders

This application claims the benefit of and priority to U.S. Provisional Application Ser. No. 62/967,500, filed Jan. 29, 2020, the contents of which is hereby incorporated by reference in its entirety for all purposes.

The Transient receptor potential vanilloid 3 (TRPV3) is a non-selective cation channel, displaying relatively high permeability to calcium. In addition to calcium ions, TRPV3 channels are permeable to other cations, for example sodium. Thus, TRPV3 channels modulate membrane potential by modulating the flux of cations such as calcium and sodium ions. Although non-selective cation channels such as TRPV3 modulate, among other things, calcium ion flux, they are mechanistically distinct from voltage-gated calcium channels. Generally, voltage-gated calcium channels respond to membrane depolarization and open to permit an influx of calcium from the extracellular medium that results in an increase in intracellular calcium levels or concentrations. In contrast, TRP channels which are non-selective cation channels are generally signal transduction gated, long lasting, and produce more prolonged changes in ion concentration. These mechanistic differences are accompanied by structural differences among voltage-gated and TRP channels. Thus, although many diverse channels act to regulate ion flux and membrane potential in various cell types and in response to numerous stimuli, it is important to recognize the significant structural, functional, and mechanistic differences among different classes of ion channels.

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

In one aspect, the present disclosure provides a compound having the general formula (XXXII):

or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof or physiologically functional derivative thereof,

wherein each of A, E and G, independently of the other, is selected from a monocyclic or polycyclic ring system containing three to twelve atoms; each R 1 is independently cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, ether, aryl, —N(R a )(R b ), —C(O)R C , —CO 2 R c , or two R 1 groups together form a ring system, e.g.,

e.g.,

each of R 2 and R 3 is independently of the other selected from cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl, 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 ; each R a and R b is independently H, hydroxyl, —OR c , C 1 -C 6 alkyl, —C(O)R c , or —C(O)OR c ; R c is H, C 1 -C 6 alkyl, aryl, —OR a , or —N(R a )(R a )>

n is 0, 1, or 2; p is 0, 1, or 2; and q is 0, 1, or 2.

In some embodiments, the present disclosure provides a compound having the general formula (XXXIII)

or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof or physiologically functional derivative thereof,

wherein G is an aryl or a heteroaryl; R 1 is independently cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl, hydroxyalkyl, C 1 -C 6 alkoxy, 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 , or two R 1 groups together form a ring system, e.g.,

e.g.,

each of R 2 and R 3 is independently of the other selected from cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl, 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 ; each R a and R b is independently H, hydroxyl, —OR 4 , C 1 -C 6 alkyl, —C(O)R c , or —C(O)OR 1 ; R c is H, C 1 -C 6 alkyl, aryl, —OR a , or —N(R a )(R a ;

n is 0, 1, or 2; p is 0, 1, or 2; and q is 0, 1, or 2.

In some embodiments, the present disclosure provides a compound having the general formula (XXXXIII)

or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof or physiologically functional derivative thereof,

wherein each one of X A , X B , X C , X D , and X E is selected from N or CH, X F is C, R 1 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, C 1 -C 3 haloalkyl, cyano, ether, —N(R a )(R b ), —C(O)R c , each R a and R b is independently H, C 1 -C 6 alkyl, R 2 and R 6 independently from the other is selected from cyano, nitro, hydroxy, 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 ); R c is H, C 1 -C 6 alkyl, aryl, —OR a , or —N(R a )(R a ); R 3 and R 7 independently from the other is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 6 cycloalkyl; n is 0, 1, or 2; u is 0, 1, or 2; and v is 0, 1, or 2.

In some embodiments, the present disclosure provides methods of using the compounds disclosed herein (e.g., any compounds of formulae I-XXXXIII) in the prevention or treatment of various skin defects/disease/disorders as detailed herein. In some embodiments, the compounds and compositions of the present disclosure are suitable for systemic and/or topical administration.

In order to better understand the subject matter that is disclosed herein and to exemplify 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:

FIG. 1 is a graph showing mRNA levels of Involucrin.

FIGS. 2 A and 2 B are bar graphs showing scratching time and scratching bouts, respectfully. FIGS. 2 A and 2 B , from left to right, G1 naïve, G2 vehicle 1, G3 KM-0001-P1 0.1 mg/kg (mpk), G4 KM-0001-P1 0.01mpk, G5 vehicle 2, G6 HC-030031 4 mg/mouse.

FIG. 3 is a graph showing plasma concentration (ng/ml) of KM-001-P1 after PO administration.

FIG. 4 is a graph showing bioavailability studies of KM-001.

FIGS. 5 A and 5 B are SDS-PAGE images showing effect of various concentrations of KM001 on involucrin and filaggrin, respectively.

FIG. 6 is a bar graph showing the effect of KM-001 on total horizontal counts.

FIGS. 7 A- 7 J are images showing the effect of KM-001 on skin structure and keratin 10 expression.

FIGS. 8 A and 8 B are bar graphs showing mean KM-023 plasma concentration-time profiles in rats in linear and semi-logarithmic scales, respectively.

FIG. 9 A to 9 F are images showing the effect of KM-001 in DS-Nh mouse model.

FIGS. 10 A and 10 B are graphs showing the effect of KM-0023 in SLIGRL-NH 2 itching mouse model.

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

In the following text, when referring to at least one compound it is to be understood as also referring to the compositions, methods, and uses disclosed herein. Thus, whenever providing a feature with reference to the at least one compound, it is to be understood as defining the same feature with respect to the compositions, methods, and uses, mutatis mutandis.

Accordingly, in some embodiments, the present disclosure provides compounds of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

A is bond, aryl, or heteroaryl; E is aryl, heteroaryl, C 3 -C 8 cycloalkyl, or C 3 -C 8 cycloalkenyl; G is aryl, heteroaryl, C 3 -C 8 cycloalkyl, or C 3 -C 8 heterocycloalkyl; L is bond, —(CR a R b ) m —, —O—, —C(O)—, —C(O)N(R a )—, or —CH(OR c )—; P is

In some embodiments, G is phenyl.

In some embodiments, G is aryl or heteroaryl.

In some embodiments, G is 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, indolinyl, 1,2,3,-oxadiazoyl, 1,2,4,-oxadiazoyl, 1,2,5,-oxadiazoyl, 1,3,4,-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 one of

wherein the wavy line indicates a bond to either W or R 1 .

In some embodiments, G is absent, such that a compound of Formula (I′) is provided

In some embodiments, R1 is C 1 -C 3 haloalkyl and n is 1. In some embodiments, W is —C(O)—.

In some embodiments, the compound of Formula (I′) is

In some embodiments, R 2 is alkyl or alkoxy.

In some embodiments, R 2 is —CH 2 OH.

In some embodiments, R 1 is substituted alkoxy (e.g., —OCH 2 CH 2 OH, —OCH 2 CO 2 Et,

In some embodiments, R 1 is cyano, halo, C 1 -C 3 haloalkyl, or C 1 -C 6 alkyl.

In some embodiments, R 1 is halo or C 1 -C 3 haloalkyl.

In some embodiments, R 3 is cyano, halo, C 1 -C 3 haloalkyl, or C 1 -C 6 alkyl.

In some embodiments, R 3 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl.

In some embodiments, n is 1 and R 1 is halo or C 1 -C 3 haloalkyl.

In some embodiments, q is 1 or 2, and R 3 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl.

In some embodiments, n is 1 and q is 1.

In some embodiments, E is aryl or heteroaryl.

In some embodiments, E is phenyl and L is bond or —O—.

In some embodiments, E is aryl, L is bond or —O—, and R 2 is —CH 2 OH.

In some embodiments, A is phenyl, R 2 is —CH 2 OH, L is bond or —O—, and q is 1 or 2.

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

In some embodiments, X and Y are absent.

In some embodiments, X and Z are absent.

In some embodiments, Y and Z are absent.

In some embodiments, X, Y, and Z are absent.

In some embodiments, m is 1, 2, or 3.

In some embodiments, n is 0 or 1.

In some embodiments, q is 1.

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

In some embodiments, E is aryl, and L is —(CH 2 ) m —, —O—, or —C(O)—.

In some embodiments, A is phenyl, and L is —O—.

In some embodiments, A and E are phenyl.

In some embodiments, the present disclosure provides compounds of Formula (II):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides compounds of Formula (III):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides compounds of Formula (IV):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides compounds of Formula (V):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides compounds of Formula (VI):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides compounds of Formula (VII):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides compounds of Formula (VIII):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides compounds of Formula (IX):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides compounds of Formula (X):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides compounds of Formula (XI):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides compounds of Formula (XII):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides compounds of Formula (XIII):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides compounds of Formula (XIV):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides compounds of Formula (XV):

or a pharmaceutically acceptable salt thereof.

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.

In some embodiments, W is —C(O)— or —O—, —NH—, —CH 2 —, —O—CH 2 —, —N—CH 2 —, and —NH—C(O)—. In some embodiments, W is —C(O)— or —O—.

In some embodiments, P is

In some embodiments, X 1 , X 2 , Y and Z are each H.

In some embodiments, P is

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

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

In some embodiments, E is phenyl.

In some embodiments, R 2 is —CH 2 OH, cyano, nitro, hydroxy, —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 ). In some embodiments, R 2 is —CH 2 OH.

In some embodiments, R 1 is halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, or C 1 -C 3 haloalkyl. In some embodiments, R 1 is chloro, fluoro, methyl, —OMe, or —CF 3 .

In some embodiments, R 3 is chloro, fluoro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyl.

In some embodiments, n is 1 and R 1 is halo or C 1 -C 3 haloalkyl.

In some embodiments, q is 1 or 2, and R 3 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl.

In some embodiments, n is 1 and q is 1.

In some embodiments, E is phenyl and L is bond or —O—.

In some embodiments, E is aryl, L is bond or —O—, and R 2 is —CH 2 OH.

In some embodiments, A is phenyl, R 2 is —CH 2 OH, L is bond or —O—, and q is 1 or 2.

In some embodiments, the compound comprises at least 70% chirally pure enantiomer.

In some embodiments, the compound comprises at least 80% chirally pure enantiomer.

In some embodiments, the compound comprises at least 90% chirally pure enantiomer.

In some embodiments, the compound comprises at least 95% chirally pure enantiomer.

In some embodiments, the compound comprises at least 98% chirally pure enantiomer.

In some embodiments, the compound comprises at least 99% chirally pure enantiomer.

In some embodiments, the present disclosure provides a compound of Formula (XVI):

or a pharmaceutically acceptable salt thereof, wherein:

A is bond, aryl, or heteroaryl; E is aryl, heteroaryl, C 3 -C 8 cycloalkyl, or C 3 -C 8 cycloalkenyl; G is aryl, heteroaryl, C 3 -C 8 cycloalkyl, or C 3 -C 8 heterocycloalkyl; L is a bond, —(CR a R b ) m —, —O—, —C(O)—, —CH(OR c )—, or —C(O)N(R a )—; W is —O—, —NR—, or —CR a R b —; X 1 and X 2 together are oxo, or each of X 1 and X 2 is H; Y is H or OH; Z is H, C 1 -C 6 alkyl (e.g., hydroxyalkyl), or C 1 -C 6 alkoxy; each R 1 is independently cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 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 , or two R groups together form a ring system, e.g.,

e.g.,

each R 2 and R 3 is independently cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl (e.g., —CH(OH)CH 2 OH), C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, aryl, —N(R a )(R b ), —C(O)Re, —CO 2 R c , —C(O)N(R a )(R b ), —SO 2 N(R a )(R b ), or —SOR c ;

each R a and R b is independently H, hydroxyl, —OR c , —N(R c )(R c ), C 1 -C 6 alkyl, —C(O)R c , or —C(O)OR c ;

R c is H, C 1 -C 6 alkyl, or aryl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, or 2;

p is 0, 1, or 2; and

q is 0, 1, or 2.

In some embodiments, R 1 is substituted alkoxy (e.g., —OCH 2 CH 2 OH, —OCH 2 CO 2 Et,

In some embodiments, A is aryl.

In some embodiments, L is —(CH 2 ) m —, —O—, or —CH(OR c )—.

In some embodiments, E is aryl or heteroaryl.

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

In some embodiments, X and Y are absent.

In some embodiments, X and Z are absent.

In some embodiments, Y and Z are absent.

In some embodiments, X, Y, and Z are absent.

In some embodiments, R 1 is cyano, halo, C 1 -C 3 haloalkyl, or C 1 -C 6 alkyl.

In some embodiments, R 2 is alkyl or alkoxy.

In some embodiments, m is 1, 2, or 3.

In some embodiments, n is 0 or 1.

In some embodiments, q is 1.

In some embodiments, n is 0 or 1, and R 1 is cyano, halo, C 1 -C 3 haloalkyl, or C 1 -C 6 alkyl.

In some embodiments, q is 1, and R 3 is cyano, halo, C 1 -C 3 haloalkyl, or C 1 -C 6 alkyl.

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

In some embodiments, E is aryl, and L is —(CH 2 ) m —, —O—, or —C(O)—.

In some embodiments, A is phenyl, and L is —O—.

In some embodiments, A and E are phenyl.

In some embodiments, the present disclosure provides a compound of Formula (XVII):

or a pharmaceutically acceptable salt thereof, wherein:

A is bond, aryl, or heteroaryl; E is aryl, heteroaryl, C 3 -C 8 cycloalkyl, or C 3 -C 8 cycloalkenyl; L is a bond, —(CR a R b ) m —, —O—, —C(O)—, or —C(O)N(R a )_; X 1 and X 2 together are oxo, or each of X 1 and X 2 is H; Y is H or OH; Z is H, C 1 -C 6 alkyl (e.g., hydroxyalkyl), or C 1 -C 6 alkoxy; each R 1 is independently cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 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 , or two R 1 groups together form a ring system, e.g.,

e.g.,

each R 2 and R 3 is independently cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl (e.g., —CH(OH)CH 2 OH), C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 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 ;

each R a and R b is independently H, hydroxyl, —OR c , —N(R c )(R c ), C 1 -C 6 alkyl, —C(O)R 1 , or —C(O)OR 1 ;

R c is H, C 1 -C 6 alkyl, or aryl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, or 2;

p is 0, 1, or 2; and

q is 0, 1, or 2.

In some embodiments, the present disclosure provides a compound of Formula (XVII):

or a pharmaceutically acceptable salt thereof, wherein:

A is bond, aryl, or heteroaryl; E is aryl, heteroaryl, C 3 -C 8 cycloalkyl, or C 3 -C 8 cycloalkenyl; L is a bond, —(CR a R b ) m —, —O—, —C(O)—, or —C(O)N(R a ); X 1 and X 2 together are oxo, or each of X 1 and X 2 is H; Y is H or OH; Z is H or C 1 -C 6 alkyl; each R 1 is independently cyano, halo, C 1 -C 3 haloalkyl, C 1 -C 6 alkyl, or or two R groups together form a ring system, e.g.,

e.g.,

each R 2 and R 3 is independently cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl, alkoxy, C 3 -C 8 cycloalkyl, 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 ;

each R a and R b is independently H, hydroxyl, —OR c , —N(R c )(R c ), C 1 -C 6 alkyl, —C(O)R c , or —C(O)OR c ;

R c is H, C 1 -C 6 alkyl, or aryl;

m is 1, 2, 3, 4, 5, or 6;

n is 0, 1, or 2;

p is 0, 1, or 2; and

q is 0, 1, or 2.

In some embodiments, the present disclosure provides a compound of Formula (XVIII)

or a pharmaceutically acceptable salt thereof, wherein:

A is bond, aryl, or heteroaryl; L is a bond, —(CR a R b ) m —, —O—, —C(O)—, or —C(O)N(R a )—; each R 2 and R 3 is independently cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl, alkoxy, C 3 -C 8 cycloalkyl, 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 . each R 4 , R 5 , and R 6 is independently cyano, halo, C 1 -C 3 haloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, or —C(O)N(R a )(R b ); each R a and R b is independently H, hydroxyl, —OR c , —N(R c )(R c ), C 1 -C 6 alkyl, —C(O)R c , or —C(O)OR c , R c is H, C 1 -C 6 alkyl, or aryl; m is 1, 2, 3, 4, 5, or 6; p is 0, 1, or 2; and q is 0, 1, or 2.

In some embodiments, the present disclosure provides a compound of Formula (XIX)

or a pharmaceutically acceptable salt thereof, wherein:

L is bond, —(CR a R b ) m —, —O—, —C(O)—, or —C(O)N(R a )—; each R 2 and R 3 is independently cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl, alkoxy, C 3 -C 8 cycloalkyl, 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 ; each R 4 , R 5 , and R 6 is independently cyano, halo, C 1 -C 3 haloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, or —C(O)N(R a )(R b ); each R a and R b is independently H, hydroxyl, —OR c , —N(R c )(Re), C 1 -C 6 alkyl, —C(O)R c , or —C(O)OR c ; R c is H, C 1 -C 6 alkyl, or aryl; m is 1, 2, 3, 4, 5, or 6; and q is 0, 1, or 2.

In some embodiments, the present disclosure provides a compound of Formula (XX)

or a pharmaceutically acceptable salt thereof, wherein:

L is bond, —(CR a R b ) m —, —O—, —C(O)—, or —C(O)N(R a )—; each R 2 and R 3 is independently cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl, alkoxy, C 3 -C 8 cycloalkyl, 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 ; each R 4 and R 6 is independently cyano, halo, C 1 -C 3 haloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, or —C(O)N(R a )(R b ); each R a and R b is independently H, hydroxyl, —OR c , —N(R c )(R c ), C 1 -C 6 alkyl, —C(O)R c , or —C(O)OR 1 ; R c is H, C 1 -C 6 alkyl, or aryl; and m is 1, 2, 3, 4, 5, or 6.

In some embodiments, the compound comprises at least 70% chirally pure enantiomer.

In some embodiments, the compound comprises at least 80% chirally pure enantiomer.

In some embodiments, the compound comprises at least 90% chirally pure enantiomer.

In some embodiments, the compound comprises at least 95% chirally pure enantiomer.

In some embodiments, the compound comprises at least 98% chirally pure enantiomer.

In some embodiments, the compound comprises at least 99% chirally pure enantiomer.

In some embodiments, the present disclosure provides a compound of Formula (XXI)

or a pharmaceutically acceptable salt thereof, wherein:

R 3 is cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl, alkoxy, 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 ; each R 4 and R 6 is independently cyano, halo, C 1 -C 3 haloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, or —C(O)N(R a )(R b ); each R a and R b is independently H, C 1 -C 6 alkyl, —OR c , —N(R c )(R c ), —C(O)R c , or —C(O)OR c ; R c is H, C 1 -C 6 alkyl, or aryl; and m is 1, 2, 3, 4, 5, or 6.

In some embodiments, L is a bond, —(CH 2 ) m —, —O—, —C(O)—, —C(O)N(R a )—, or —CH(OR c )—.

In some embodiments, L is —(CH 2 ) m —, —O—, or —CH(OR c )—.

In some embodiments, the compound comprises at least 70% chirally pure enantiomer.

In some embodiments, the compound comprises at least 80% chirally pure enantiomer.

In some embodiments, the compound comprises at least 90% chirally pure enantiomer.

In some embodiments, the compound comprises at least 95% chirally pure enantiomer.

In some embodiments, the compound comprises at least 98% chirally pure enantiomer.

In some embodiments, the compound comprises at least 99% chirally pure enantiomer.

In some embodiments, the present disclosure provides a compound of Formula (XXII):

or a pharmaceutically acceptable salt thereof, wherein:

X is —N— or —CH—; Y 1 and Y 2 together are oxo, or each of Y 1 and Y 2 is H; X 1 and X 2 together are oxo, or each of X 1 and X 2 is H; L is bond, —(CR a R b ) m —, —O—, —C(O)—, —C(O)N(R a )—, or —CH(OR c )—; E is aryl, heteroaryl, C 3 -C 8 cycloalkyl, or C 3 -C 8 cycloalkenyl; G is aryl, heteroaryl, C 3 -C 8 cycloalkyl, or C 3 -C 8 heterocycloalkyl; each R 1 is independently cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, —N(R a )(R b ), —C(O)R c , —CO 2 R 1 , —C(O)N(R a )(R b ), —SO 2 N(R a )(R b ), or —SOR c , or two R groups together form a ring system, e.g.,

e.g.,

each R 2 and R 3 is independently cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl (e.g., —CH(OH)CH 2 OH), C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 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 ; n is 0, 1, or 2;

q is 0, 1, or 2;

z is 0 or 1;

each R a and R b is independently H, hydroxyl, —OR c , —N(R c )(R c ), C 1 -C 6 alkyl, —C(O)R c , or —C(O)OR c ; and

R c is H, C 1 -C 6 alkyl, or aryl. The compound of claim 1 , wherein X is —CH—.

In some embodiments, Y 1 and Y 2 together are oxo.

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

The compound of claim 96 , wherein L is bond or —O—.

In some embodiments, E is phenyl.

In some embodiments, G is aryl or heteroaryl.

In some embodiments, G is pyridine.

In some embodiments, R 2 is —CH 2 OH.

In some embodiments, R 1 is halo or C 1 -C 3 haloalkyl.

In some embodiments, R 3 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl.

In some embodiments, n is 1 and R 1 is halo or C 1 -C 3 haloalkyl.

In some embodiments, q is 1 or 2, and R 3 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl.

In some embodiments, z is 1, and Y 1 and Y 2 together are oxo.

In some embodiments, X is —CH— and L is bond or —O—.

In some embodiments, n is 1 and q is 1.

In some embodiments, E is phenyl and L is bond or —O—.

In some embodiments, E is aryl, L is bond or —O—, and R 2 is —CH 2 OH.

In some embodiments, X is —CH—, R 2 is —CH 2 OH, L is bond or —O—, and q is 1 or 2.

In some embodiments, the present disclosure provides a compound of Formula (XXIII):

or a pharmaceutically acceptable salt thereof, wherein:

X is —N— or —CH—; L is bond, —(CR a R b ) m —, —O—, —C(O)—, —C(O)N(R a )_, or —CH(OR c )—; E is aryl, heteroaryl, C 3 -C 8 cycloalkyl, or C 3 -C 8 cycloalkenyl; each R 1 is independently cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 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 , or two R 1 groups together form a ring system, e.g.,

e.g.,

each R 2 and R 3 is independently cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl (e.g., —CH(OH)CH 2 OH), C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 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 ;

n is 0, 1, or 2;

q is 0, 1, or 2;

each R a and R b is independently H, hydroxyl, —OR c , —N(R c )(R c ), C 1 -C 6 alkyl, —C(O)R c , or —C(O)OR c ; and

R c is H, C 1 -C 6 alkyl, or aryl.

In some embodiments, the present disclosure provides a compound of Formula (XXIV):

or a pharmaceutically acceptable salt thereof, wherein:

L is bond, —(CR a R b ) m —, —O—, —C(O)—, —C(O)N(R a )—, or —CH(OR c )—; each R 2 and R 3 is independently cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl (e.g., —CH(OH)CH 2 OH), C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 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 ; each R 4 , R 5 , and R 6 is independently cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, halo, C 1 -C 3 haloalkyl, or —C(O)N(R a )(R b ); q is 0, 1, or 2; each R a and R b is independently H, hydroxyl, —OR c , —N(R)(R′), C 1 -C 6 alkyl, —C(O)R c , or —C(O)OR; and R c is H, C 1 -C 6 alkyl, or aryl.

In some embodiments, the present disclosure provides a compound of Formula (XXV):

or a pharmaceutically acceptable salt thereof, wherein:

each R 3 is independently halo, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 6 alkoxy; each R 4 and R 5 is independently cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, halo, C 1 -C 3 haloalkyl, or —C(O)N(R a )(R b ); q is 0, 1, or 2; each R a and R b is independently H, hydroxyl, —OR c , —N(R c )(R c ), C 1 -C 6 alkyl, —C(O)R c , or —C(O)OR 4 ; and R c is H, C 1 -C 6 alkyl, or aryl.

In some embodiments, the present disclosure provides a compound of Formula (XXVI):

or a pharmaceutically acceptable salt thereof, wherein:

R 3 is halo, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 6 alkoxy; R 5 is cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, halo, C 1 -C 3 haloalkyl, or —C(O)N(R a )(R b ) each R a and R b is independently H, hydroxyl, —OR c , —N(R c )(R′), C 1 -C 6 alkyl, —C(O)R c , or —C(O)OR 1 ; and R c is H, C 1 -C 6 alkyl, or aryl.

In some embodiments, the present disclosure provides a compound of Formula (XXVII)

or a pharmaceutically acceptable salt thereof, wherein

R 3 is-Cl, —F, ethyl, n-propyl, or iso-propyl; R 4 is —Me or —Cl; and y is 1 or 2.

In accordance with some aspects, the present disclosure the provides a compound having the structure of general formula (XXXII):

or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof or physiologically functional derivative thereof,

wherein each of A, E and G, independently of the other, is selected from a ring system containing three to twelve atoms; R 1 is 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, ether, aryl, —N(R a )(R b ), —C(O)R c , —CO 2 R 1 , —C(O)N(R a )(R b ), —SO 2 N(R a )(R b ), or —SOR c , or two R groups together form a ring system, e.g.,

e.g.,

each of R 2 and R 3 is independently of the other selected from cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl (e.g., —CH(OH) CH 2 OH), 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 ; each R a and R b is independently H, hydroxyl, —OR c , C 1 -C 6 alkyl, —C(O)R c , or —C(O)OR c ; R c is H, C 1 -C 6 alkyl, aryl, —OR 1 , or —N(R a )(R a );

n is 0, 1, or 2; p is 0, 1, or 2; and q is 0, 1, or 2.

In accordance with some embodiments, in the compounds of the invention, each one of A, E and G, is selected to be a ring system having three to twelve atoms. A ring system as used herein encompasses a monocyclic ring system, or a polycyclic ring system (e.g., a bicyclic ring system). As noted herein, a ring system (for example, a monocyclic ring system or a bicyclic ring system, which can include fused ring systems) may include only carbon atoms or both carbon atoms and heteroatoms. Hence, a ring system having three to twelve atoms encompasses one or more rings having between three to twelve atoms as a total number of atoms. As appreciated, the atoms may include only carbon atoms or alternatively, may include at least one heteroatom, including, inter alia, N, O or S. In accordance with some embodiments, each one of A, E and G is selected to be an aromatic ring system (either monocyclic or bicyclic aromatic ring system).

In accordance with some embodiments, each of A, E and G is independently of the other selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl.

In accordance with some embodiments, each of A, E and G is independently of the other selected from aryl or heteroaryl.

In accordance with some other embodiments, each one of A, E and G is independently of the other selected from cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl.

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

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

In some other embodiments, each of A, E and G in compounds of the invention, such as those, being compounds of the 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, benzofurna, indole, benzothiophene, benzoimidazole, indazole, benzoxazole, benzoisoxazole, benzothiazole, isobenzfuran, isoidole or purine.

The number of atoms in a ring system may be in accordance with some embodiments between 3 to 8 atoms. Hence, a ring system having three to eight atoms encompasses one or more rings having between three to eight atoms as a total number of atoms. As appreciated, the atoms may include only carbon atoms or alternatively, may include at least one heteroatom, including, inter alia, N, O or S.

In some embodiments, each of A, E and G is independently of the other is selected in compounds of the invention from aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkenyl or C 3 -C 8 heterocycloalkenyl.

In some embodiments, each of A, E and G is independently of the other is selected in compounds of the invention from C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, C 3 -C 8 cycloalkenyl or C 3 -C 8 heterocycloalkenyl.

In some embodiments, each of A, E and G is independently of the other is selected from C 3 -C 8 cycloalkyl or C 3 -C 8 heterocycloalkyl.

In some embodiments, each of A, E and G is independently of the other is selected from C 3 -C 8 cycloalkenyl or C 3 -C 8 heterocycloalkenyl.

In some other embodiments, each of A, E and G is independently of the other is selected from aryl, C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkenyl.

In some other embodiments, each of A, E and G is independently of the other is selected from heteroaryl, C 3 -C 8 heterocycloalkyl or C 3 -C 8 heterocycloalkenyl.

In some embodiments, each one of A, E and G in the compounds of the invention, such as compounds of formula (XXXII) is independently of the other selected from a heteroaryl comprising five atoms or a heteroaryl comprising six atoms.

In some embodiments, each one of A, E and G in the compounds of the invention, such as compounds of formula (XXXII) is independently of the other selected from an aryl comprising five atoms or a aryl comprising six atoms.

In some embodiments, each of A, E and G is independently of the other is a heteroaryl comprising five atoms or six atoms.

In some embodiments, each of A, E and G is independently of the other is a heteroaryl comprising five atoms or six atoms, including carbon atoms and heteroatoms, among which at least one, at least two, at least three heteroatoms or at least four heteroatoms.

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

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

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

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

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

In some embodiments, each of A, E and G is 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.

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

In some other embodiments, E is phenyl.

In some embodiments, A is selected from an aryl or an heteroaryl, each comprising five atoms or six atoms among which at least one, at least two, at least three heteroatoms or at least four heteroatoms.

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

In some other embodiments, A is phenyl.

In some embodiments, G is an aryl or, an heteroaryl, each comprising five atoms or six atoms among which at least one, at least two, at least three heteroatoms or at least four heteroatoms.

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

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.

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

In some embodiments G is selected from the group consisting of:

In some other embodiments, G is pyridine.

In some other embodiments, G is N

In some other embodiments, G is pyrazine.

In some other embodiments, G is

In some embodiments, G is phenyl.

In some embodiments, in the compounds of the invention, for example, 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.

In some other embodiments, in the compounds of the invention, for example, compounds of formula (XXXII), E is phenyl, A is phenyl, and G is pyridine.

In some further embodiments, in the compounds of the invention, for example, compounds of formula (XXXII), E is phenyl, A is phenyl, and G is pyrazine.

In some embodiments, R 1 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, C 1 -C 3 haloalkyl, cyano, ether, —N(R a )(R b ), —C(O)R c , each R a and R b is independently H, C 1 -C 6 alkyl and R c is H or C 1 -C 6 alkyl.

In some other embodiments, R 1 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, C 1 -C 3 haloalkyl, ether, —N(R a )(R b ), each R a and R b is independently H, C 1 -C 6 alkyl.

In some further embodiments, R 1 is at least one of fluorine, chlorine, methyl, methoxy, hydroxy, methyl amine, diethyl ether, or CF 3 .

In some embodiments, R 1 is fluorine.

In some other embodiments, R 1 is methyl.

In some further embodiments, R 1 is methoxy.

In some embodiments, n is 0.

In some embodiments, n is 1 or 2.

In some embodiments, n is 1 or 2 and R 1 is selected from fluorine, chlorine, methyl, methoxy, hydroxy, methyl amine or CF 3 .

In some embodiments, n is 2 and R 1 is at least one of fluorine, chlorine, methyl, methoxy, hydroxy, methyl amine or CF 3 .

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

In some embodiments, n is 1 and R 1 is fluorine.

In some embodiments, R 2 is selected from —CH 2 OH, cyano, nitro, hydroxy, 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 )

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

In some embodiments, R 2 is hydroxyalkyl.

In some embodiments, R 2 is —CH 2 OH (Hydroxymethyl).

In some embodiments, p is 0.

In some embodiments, p is 1 or 2.

In some embodiments, p is 1 or 2 and R 2 is —CH 2 OH (Hydroxymethyl).

In some embodiments, p is 1 or 2 and R 2 is at least one of —CH 2 OH and fluorine.

In some embodiments, R 3 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyl.

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

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

In some embodiments, R 3 is cyclopropyl.

In some embodiments, R 3 is methoxy or ethoxy.

In some embodiments, R 3 is cyclopropyl and fluorine.

In some embodiments, q is 1 or 2.

In some embodiments, q is 1 or 2 and R 3 is at least one of halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 9 cycloalkyl.

In some embodiments, each one of A and E is independently selected from phenyl or a heteroaryl comprising six atoms. In some other embodiments, each one of A and E is phenyl.

Hence, in accordance with some aspects, which may be considered as embodiments, the present disclosure the provides a compound having the structure of general formula (XXXIII):

or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof or physiologically functional derivative thereof, wherein G, R 1 , R 2 , R 3 , n, p and q are as defined for compounds of formula (XXXII).

In some embodiments, a compound having the structure of general formula (XXII) or (XXXIII) is provided by a compound having the structure of general formulae (XXXIIIa), (XXXIIIb), (XXXIIIc) or (XXXIIId).

or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof or physiologically functional derivative thereof, wherein G, R 1 , R 2 , R 3 n, p, and q are as defined herein above for compound of formula (XXXIII), each one of R 6 and R 7 is independently of the other selected from cyano, nitro, hydroxy, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 6 alkyl (e.g., —CH(OH) CH 2 OH), 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 4 ; each R a and R b is independently H, hydroxyl, —OR c , C 1 -C 6 alkyl, —C(O)Re, or —C(O)OR c ; R c is H, C 1 -C 6 alkyl, aryl, —OR a , or —N(R a )(R a ); u is 0, 1, or 2; and v is 0, 1, or 2.

In some embodiments, in compounds of the invention, such as those denoted by general formula (XXXII), the compound is a compound provided by general formula (XXXIII), (XXXIIIa), (XXXIIIb), (XXXIIIc) or (XXXIIId).

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

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

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

In some other embodiments, G is selected from pyridine, pyrazine, pyrimidine, pyridazine.

In some embodiments G is selected from the group consisting of:

In some other embodiments, G is pyridine or pyrazine.

In some other embodiments, G is pyridine.

In some other embodiments, G is

In some other embodiments, G is pyrazine.

In some other embodiments, G is

In some embodiments, G is phenyl.

In some embodiments, R 1 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, C 1 -C 3 haloalkyl, cyano, ether, —N(R a )(R b ), —C(O)R c , each R a and R b is independently H, C 1 -C 6 alkyl and R 4 is H or C 1 -C 6 alkyl.

In some other embodiments, R 1 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, C 1 -C 3 haloalkyl, ether, —N(R a )(R b ), each R a and R b is independently H, C 1 -C 6 alkyl.

In some further embodiments, R 1 is at least one of fluorine, chlorine, methyl, methoxy, hydroxy, methyl amine, diethyl ether, or CF 3 .

In some embodiments, R 1 is fluorine.

In some other embodiments, R 1 is methyl.

In some further embodiments, R 1 is methoxy.

In some embodiments, n is 0.

In some embodiments, n is 1 or 2.

In some embodiments, n is 1 or 2 and R 1 is selected from fluorine, chlorine, methyl, methoxy, hydroxy, methyl amine or CF 3 .

In some embodiments, n is 2 and R 1 is at least one of fluorine, chlorine, methyl, methoxy, hydroxy, methyl amine or CF 3 .

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

In some embodiments, n is 1 and R 1 is fluorine.

In some embodiments, G is selected from pyridine, pyrazine, pyrimidine, pyridazine, n is 1 and R 1 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, C 1 -C 3 haloalkyl, —N(R a )(R b ), each R a and R b is independently H, C 1 -C 6 alkyl.

In some embodiments, G is

n is 1 and R 1 is at least one of fluorine, chlorine, methyl or methoxy.

In some embodiments, G is

n is 1 and R 1 is fluorine or chlorine.

In some embodiments, G is

n is 1 and R 1 is at least one of fluorine, hydroxy, methyl or methoxy.

In some embodiments, G is

n is 1 and R 1 is methyl or methoxy.

In some embodiments, G is

n is 2 and R 1 is selected from methyl and hydroxy.

In some embodiments, R 2 is at least one of —CH 2 OH, cyano, nitro, hydroxy, 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 ).

In some embodiments, R 2 is selected from —CH 2 OH, cyano, nitro, hydroxy, hydroxyalkyl, —NH 2 , halo, aryl, —N(R a )(R b ), —C(O)OH, —CH 2 R 4 , —CO 2 R c , or —C(O)N(R a )(R b )

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

In some embodiments, R 2 is hydroxyalkyl.

In some embodiments, R 2 is —CH 2 OH (Hydroxymethyl).

In some embodiments, p is 0.

In some embodiments, p is 1 or 2.

In some embodiments, p is 1 or 2 and R 2 is —CH 2 OH (Hydroxymethyl).

In some embodiments, p is 1 or 2 and R 2 is at least one of —CH 2 OH and fluorine.

In some embodiments, G is selected from pyridine, pyrazine, pyrimidine, pyridazine, n is 1, R 1 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, C 1 -C 3 haloalkyl, —N(R a )(R b ), each R a and R b is independently H, C 1 -C 6 alkyl, p is 1, R 2 is selected from —CH 2 OH, cyano, nitro, hydroxy, 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 ).

In some embodiments, G is pyridine or pyrazine, n is 1, R 1 is at least one of fluorine, chlorine, methyl or methoxy, p is 1 and R 2 is —CH 2 OH.

In some embodiments, G is pyridine or pyrazine, n is 2, R 1 is at least one of fluorine, chlorine, hydroxy, methyl or methoxy, p is 1 and R 2 is —CH 2 OH.

In some embodiments, R 3 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyl.

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

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

In some embodiments, R 3 is cyclopropyl.

In some embodiments, R 3 is methoxy or ethoxy.

In some embodiments, R 3 is cyclopropyl and fluorine.

In some embodiments, q is 1 or 2.

In some embodiments, q is 1 or 2 and R 3 is at least one of halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyl.

In some embodiments, q is 1 or 2 and R 3 is at least In some embodiments, R 3 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyl.

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

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

In some embodiments, R 3 is cyclopropyl.

In some embodiments, R 3 is methoxy or ethoxy.

In some embodiments, R 3 is cyclopropyl and fluorine.

In some embodiments, q is 1 or 2.

In some embodiments, q is 1 or 2 and R 3 is at least one of halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyl.

In some embodiments, u is 1 or 2, R 7 is fluorine and R 3 is at least one of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyl.

In some embodiments, G is selected from pyridine, pyrazine, pyrimidine, pyridazine, n is 1 or 2, R 1 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, C 1 -C 3 haloalkyl, —N(R a )(R b ), each R a and R b is independently H, C 1 -C 6 alkyl, p is 1 or 2, R 2 is selected from —CH 2 OH, cyano, nitro, hydroxy, 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 ), q is 1 or 2, R 3 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyl.

In some embodiments, G is pyridine or pyrazine, n is 1, R 1 is at least one of fluorine, chlorine, methyl, hydroxy, or methoxy, p is 1, R 2 is —CH 2 OH, q is 1 or 2, R 3 is at least one of fluorine, cyclopropyl, methyl, ethyl or propyl.

In some embodiments, G is pyridine or pyrazine, n is 1, R 1 is at least one of fluorine, chlorine, methyl or methoxy, p is 1, R 2 is —CH 2 OH, q is 2, R 3 is selected from fluorine, cyclopropyl, methyl, ethyl or propyl.

In some embodiments, in compounds of the invention, G is selected from pyridine, pyrazine, pyrimidine, pyridazine, n is 1 or 2, R 1 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, C 1 -C 3 haloalkyl, —N(R a )(R b ), each R a and R b is independently H, C 1 -C 6 alkyl, p is 1 or 2, R 2 is selected from —CH 2 OH, cyano, nitro, hydroxy, hydroxyalkyl, —NH 2 , halo, aryl, —N(R a )(R b ), —C(O)OH, —CH 2 R c , —CO 2 R 1 , or —C(O)N(R a )(R b ), v is 0, u is 0, q is 1 or 2, R 3 is at least one of halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 6 cycloalkyl.

In some embodiments, in compounds of the invention, G is selected from pyridine, pyrazine, pyrimidine, pyridazine, n is 1 or 2, R 1 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, C 1 -C 3 haloalkyl, —N(R a )(R b ), each R a and R b is independently H, C 1 -C 6 alkyl, p is 1 or 2, R 2 is selected from —CH 2 OH, cyano, nitro, hydroxy, 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 ), v is 0, u is 1 or 2, R 3 is at least one of halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 6 cycloalkyl and R 7 is halo.

In some embodiments, G is pyridine or pyrazine, n is 1 or 2, R 1 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, C 1 -C 3 haloalkyl, —N(R a )(R b ), each R a and R b is independently H, C 1 -C 6 alkyl, p is 1 or 2, R 2 is selected from —CH 2 OH, cyano, nitro, hydroxy, 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 ), p is 1, R 2 is —CH 2 OH, v is 0, u is 0, q is 1, R 3 is selected from cyclopropyl, methyl, ethyl or propyl.

In some embodiments, G is pyridine or pyrazine, n is 1 or 2, R 1 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, C 1 -C 3 haloalkyl, —N(R a )(R b ), each R a and R b is independently H, C 1 -C 6 alkyl, p is 1 or 2, R 2 is selected from —CH 2 OH, cyano, nitro, hydroxy, hydroxyalkyl, —NH 2 , halo, aryl, —N(R a )(R b ), —C(O)OH, —CH 2 R c , —CO 2 R 1 , or —C(O)N(R a )(R b ), p is 1, R 2 is —CH 2 OH, v is 0, u is 1 or 2, R 7 is fluorine, R 3 is selected from cyclopropyl, methyl, ethyl or propyl.

In some embodiments, G is pyridine or pyrazine, n is 1, R 1 is halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, p is 1, R 2 is —CH 2 OH, v is 0, u is 0, q is 1, R 3 is selected from cyclopropyl, methyl, ethyl or propyl.

In some embodiments, G is pyridine or pyrazine, n is 1, R 1 is halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, p is 1, R 2 is —CH 2 OH, v is 0, u is 1, R 7 is halo and R 3 is selected from cyclopropyl, methyl, ethyl or propyl.

In some embodiments, G is pyridine or pyrazine, n is 1, R 1 is fluorine, chlorine, methyl or methoxy, p is 1, R 2 is —CH 2 OH, v is 0, u is 0, q is 1, R 3 is selected from cyclopropyl, methyl, ethyl or propyl.

In some embodiments, G is pyridine or pyrazine, n is 1, R 1 is fluorine, chlorine, methyl or methoxy, p is 1, R 2 is —CH 2 OH, v is 0, u is 1, q is 1, R 7 is fluorine and R 3 is selected from cyclopropyl, methyl, ethyl or propyl.

In accordance with some embodiments, the compound of formula (XXXII), (XXXIII) or any variation thereof has the structure of general formulae (XXVIV), (XXXIV) or (XXVV)

or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof or physiologically functional derivative thereof, wherein G, R 1 R 3 , R 7 , R 8 , n and u, v are as defined herein above.

In accordance with some aspects, the present disclosure provides a compound having general formula (XXXXIII)

or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof or physiologically functional derivative thereof,

wherein each of X A , X B , X C , X D , and X E is selected from N or CH, and XF is C, R 1 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, C 1 -C 3 haloalkyl, —N(R a )(R b ), each R a and R b is independently H, C 1 -C 6 alkyl; R 2 and R 6 independently from the other is selected from—CH 2 OH, cyano, nitro, hydroxy, 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 ); R 3 and R 7 independently from the other is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 6 cycloalkyl; n is 0, 1, or 2; u is 0, 1, or 2; and v is 0, 1, or 2.

In some embodiments, R 1 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, C 1 -C 3 haloalkyl, cyano, ether, —N(R a )(R b ), —C(O)R c , each R a and R b is independently H, C 1 -C 6 alkyl and R c is H or C 1 -C 6 alkyl.

In some other embodiments, R 1 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, C 1 -C 3 haloalkyl, ether, —N(R a )(R b ), each R a and R b is independently H, C 1 -C 6 alkyl.

In some further embodiments, R 1 is at least one of fluorine, chlorine, methyl, methoxy, hydroxy, methyl amine, diethyl ether, or CF 3 .

In some embodiments, R 1 is fluorine.

In some other embodiments, R 1 is methyl.

In some further embodiments, R 1 is methoxy.

In some embodiments, n is 0.

In some embodiments, n is 1 or 2.

In some embodiments, n is 1 or 2 and R 1 is selected from fluorine, chlorine, methyl, methoxy, hydroxy, methyl amine or CF 3 .

In some embodiments, n is 2 and R 1 is at least one of fluorine, chlorine, methyl, methoxy, hydroxy, methyl amine or CF 3 .

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

In some embodiments, n is 1 and R 1 is fluorine.

In some embodiments, R 2 is selected from —CH 2 OH, cyano, nitro, hydroxy, hydroxyalkyl, —NH 2 , halo, aryl, —N(R a )(R b ), —C(O)OH, —CH 2 R c , —CO 2 R 1 , or —C(O)N(R a )(R b )

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

In some embodiments, R 2 is hydroxyalkyl.

In some embodiments, R 2 is —CH 2 OH (Hydroxymethyl).

In some embodiments, p is 0.

In some embodiments, p is 1 or 2.

In some embodiments, p is 1 or 2 and R 2 is —CH 2 OH (Hydroxymethyl).

In some embodiments, p is 1 or 2 and R 2 is at least one of —CH 2 OH and fluorine.

In some embodiments, p is 1, v is 1, R 2 is hydroxyalkyl and R 6 is halo.

In some embodiments, p is 1, v is 1, R 2 is —CH 2 OH and R 6 is fluorine.

In some embodiments, R 3 is selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyl.

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

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

In some embodiments, R 3 is cyclopropyl.

In some embodiments, R 3 is methoxy or ethoxy.

In some embodiments, R 3 is cyclopropyl and fluorine.

In some embodiments, q is 1 or 2.

In some embodiments, q is 1 or 2 and R 3 is at least one of halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyl.

In some embodiments, q is 1, u is 1, R 3 is at least one of halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyl and R 7 is halo.

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

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

In some embodiments, the compound o formula (XXXXIII) has a general formula (XXXV) or (XXXVI)

or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof or physiologically functional derivative thereof,

In some embodiments a compound having the structure of general formula (XXVVI) or (XXXV):

or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof or physiologically functional derivative thereof,

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.

In some embodiments, n is 1, and v is 0.

In some embodiments, R 3 is halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 6 cycloalkyl.

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

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

In some embodiments, R 3 is cyclopropyl.

In some embodiments, R 3 is methoxy, ethoxy.

In some embodiments, R 3 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyl.

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

In accordance with some embodiments, the compound having the structure of general formulae selected from (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), or (XXXXII):

In some embodiments, R 7 is halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 6 cycloalkyl and u is 0, 1 or 2.

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

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

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

In some embodiments, the compound having the structure of general formulae selected from (XXXVIIa), (XXXVIIIa), (XXXIXa), (XXXXa), (XXXXIa), or (XXXXIIa):

or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof or physiologically functional derivative thereof, wherein R 1 is as described above. In accordance with some embodiments, the compounds of this invention include mixtures of enantiomers (possibly as a racemic mixture) 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 being represented by the formulas above as racemic mixtures.

Methods of preparing substantially isomerically pure compounds are known in the art. If, for instance, a particular enantiomer of a compound of the present disclosure is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts may be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. Alternatively, enantiomerically enriched mixtures and pure enantiomeric compounds can be prepared by using synthetic intermediates that are enantiomerically pure in combination with reactions that either leave the stereochemistry at a chiral center unchanged or result in its complete inversion. Techniques for inverting or leaving unchanged a particular stereocenter, and those for resolving mixtures of stereoisomers are well known in the art, and it is well within the ability of one of skill in the art to choose an appropriate method for a particular situation. See, 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).

Unless otherwise indicated, when referring to a compound having a chiral atom, it should be clear to refer to a racemic mixture of the compound. As appreciated, chirality may be indicated by a chemical structure of a compound or by a structure name of the compound.

A racemic mixture also denoted as racemate as used denotes that for a chiral compound, there are equal amounts of left- and right-handed enantiomers. In other words, the compound includes a mixture of 50% left-hand enantiomer and 50% right-hand enantiomer.

The term “stereoisomer” as used herein is meant to encompass an isomer that possess identical constitution as a corresponding stereoisomer, but which differs in the arrangement of its atoms in space from the corresponding stereoisomer.

Certain of the compounds described herein may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers or as two or more diastereomers. Accordingly, the compounds of this invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Furthermore, the compounds of this invention include mixtures of diastereomers, as well as purified stereoisomers or diastereomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds of the invention, as defined above, as well as any wholly or partially mixtures thereof. The present invention also covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.

In some embodiments, a compound of the invention comprises at least 60% chirally pure enantiomer

In some embodiments, a compound of the invention comprises at least 70% chirally pure enantiomer.

In some embodiments, the compound of the invention comprises at least 80% chirally pure enantiomer.

In some embodiments, the compound of the invention comprises at least 90% chirally pure enantiomer.

In some embodiments, the compound of the invention comprises at least 95% chirally pure enantiomer.

In some embodiments, the compound of the invention comprises at least 98% chirally pure enantiomer.

In some embodiments, the compound of the invention comprises at least 99% chirally pure enantiomer.

The terms “enantiomerically pure”, “enantiomeric purity”, “chiral purity” and “chirally pure” are used alternatively to reflect the fact that one enantiomer is found in the composition in greater proportion in relation to its mirror image. The proportion between two enantiomers is expressed by the absolute proportion of one of the enantiomers, which is at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, and at least 99% or more.

The enantiomeric purity can be determined by types of tests known in the art. Typically, the chiral purity of enantiomers according to the present disclosure is determined by analytical chiral HPLC.

In some embodiments, compounds of the invention, such as compounds provided by formulae (I)—(XXXXIII) comprises at least 70% chirally pure enantiomer, at times at least 80% chirally pure enantiomer, at times at least 90% chirally pure enantiomer, at times at least 95% chirally pure enantiomer, at times at least 98% chirally pure enantiomer, at times at least 99% chirally pure enantiomer.

In accordance with some aspects, which may be considered as embodiments of the invention, the present disclosure provides a compound having the general formula selected from:

wherein the substitutions are as defined in the parent formula (without ′).

In some embodiments, specific examples of compounds or pharmaceutically acceptable salts or hydrates or any stereoisomer thereof of the compounds of Formula I-XXXXIII include, without limitation compounds of Table 2 denoted as 2-29, 2-30, 2-51, 2-53, 2-56, 2-57, 2-67, 2-72 or 2-77. Specifically, compounds of the invention are provided by formulae (XXXII), (XXXIII), (XXVIV), (XXXIV), (XXVV), (XXXV), (XXXVI), (XXVVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), (XXXXII) or (XXXIII) as detailed in Table 2 and Table 4.

In accordance with some aspects, the invention provides a compound selected from the following list:

[3-(2′-Cyclopropyl-3-hydroxymethyl-biphenyl-4-yl)-pyrrolidin-1-yl]-(5-fluoro-pyridin-2-yl)-methanone (denoted herein: KM-001-E1 or compound A)

(5-Fluoro-pyridin-2-yl)-[3-(3-hydroxymethyl-2′-isopropyl-biphenyl-4-yl)-pyrrolidin-1-yl]-methanone (denoted herein: KM-002-E1 or compound B)

[3-(2′-Cyclopropyl-3-hydroxymethyl-biphenyl-4-yl)-pyrrolidin-1-yl]-(5-hydroxy-6-methyl-pyridin-2-yl)-methanone (denoted herein: KM-023-E1 or compound C)

[3-(2′-Cyclopropyl-3-hydroxymethyl-biphenyl-4-yl)-pyrrolidin-1-yl]-(6-methoxy-pyrazin-2-yl)-methanone (denoted herein: KM-031-E1 or compound D)

[3-(2′-Cyclopropyl-3-hydroxymethyl-biphenyl-4-yl)-pyrrolidin-1-yl]-(6-methyl-pyrazin-2-yl)-methanone (denoted herein: KM-032-E1 or compound E)

[3-(2′-Cyclopropyl-3-hydroxymethyl-biphenyl-4-yl)-pyrrolidin-1-yl]-(6-methoxymethyl-pyridin-2-yl)-methanone (denoted herein: KM-036-E1 or compound F)

[3-(2′-Cyclopropyl-3-hydroxymethyl-biphenyl-4-yl)-pyrrolidin-1-yl]-(6-methylamino-pyrazin-2-yl)-methanone (denoted herein: KM-054-E1 or compound G)

[3-(3-Hydroxymethyl-2′-isopropyl-biphenyl-4-yl)-pyrrolidin-1-yl]-(6-methylamino-pyrazin-2-yl)-methanone (denoted herein: KM-069 or compound H)

[3-(2′-Cyclopropyl-3-hydroxymethyl-biphenyl-4-yl)-pyrrolidin-1-yl]-(6-methoxymethyl-pyrazin-2-yl)-methanone (denoted herein: KM-070 or compound I)

[3-(2-Hydroxymethyl-4-indan-4-yl-phenyl)-pyrrolidin-1-yl]-(6-methoxy-pyrazin-2-yl)-methanone (denoted herein: KM-071 or compound J)

In accordance with some embodiments, the compounds of the invention do not include at least one compound of Table 2 denoted as 2-68 or 2-70.

In accordance with some embodiments, the compounds of the invention do not include at least one compound of Table 2 denoted as 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.

For compounds of the disclosure in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound; the two R groups can represent different moieties selected from the Markush group defined for R.

It is further appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

As used herein, “acyl” refers to the group (C 1 -C 6 alkyl)-C(O)—.

As used herein, “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, and can have a number of carbon atoms optionally designated (i.e., C 1 -C 6 means one to six 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, homologs and isomers of, for example, n-pentyl, n-hexyl, and the like. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more substituents which independently are: 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 (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t N(R a ) 2 (where t is 1 or 2), or PO 3 (R a ) 2 , where each R a is independently hydrogen or alkyl.

As used herein, “alkenyl” can be a straight or branched hydrocarbon chain, containing at least one double bond, and having from two to six carbon atoms (i.e. C 2 -C 6 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, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents which independently are: 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 (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t N(R a ) 2 (where t is 1 or 2), or PO 3 (R a ) 2 , where each R a is independently hydrogen or alkyl.

As used herein, “alkoxy” can be a straight chain or branched alkoxy group having from one to six carbon atoms (i.e., C 1 -C 6 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, and the like. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted by one or more substituents which independently are: 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 (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t N(R a ) 2 (where t is 1 or 2), or PO 3 (R a ) 2 , where each R a is independently hydrogen or alkyl.

As used herein, “alkynyl” can be a straight or branched hydrocarbon chain, containing at least one triple bond, having from two to six carbon atoms (i.e. C 2 -C 6 alkynyl). Examples of alkynyl groups, include, but are not limited to, groups such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents which independently are: 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 (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t N(R a ) 2 (where t is 1 or 2), or PO 3 (R a ) 2 , where each R a is independently hydrogen or alkyl.

As used herein, “amide” or “amido” refers to a chemical moiety with the formula —C(O)NR a — or —NR a C(O)— wherein R a is H or C 1 -C 6 alkyl.

As used herein, “amino” or “amine” refers to a —NH 2 radical group.

As used herein, “alkylamino” refers to a group of formula —NH(alkyl), wherein the alkyl group each has 1 to 6 carbons.

As used herein, the term “dialkylamino” refers to a group of formula —N(alkyl) 2 , wherein the two alkyl groups each independently has, 1 to 6 carbons.

As used herein, “aryl” refers to a polyunsaturated, aromatic, hydrocarbon moiety which can be a single ring or multiple rings (e.g., 1 to 2 rings) which are fused together or linked covalently, having from six to twelve carbon atoms (i.e. C 6 -C 12 aryl). Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, and 4-biphenyl. Unless stated otherwise specifically in the specification, an aryl 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, 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(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 (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t N(R a ) 2 (where t is 1 or 2), or PO 3 (R a ) 2 , wherein each R a is independently hydrogen or alkyl.

As used herein, “arylalkyl” refers to an (aryl)alkyl—radical wherein aryl and alkyl moieties are as disclosed herein.

As used herein, “aryloxy” refers to —O-(aryl), wherein the heteroaryl moiety is as defined herein.

As used herein, “arylalkoxy” refers to —O-(arylalkyl), wherein the heteroaryl moiety is as defined herein.

As used herein, “carboxyl” refers to a —(C═O)OH radical.

As used herein, “cyano” refers to a —CN radical.

As used herein, “cycloalkyl” refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 12 ring atoms (i.e. C 3 -C 10 cycloalkyl). Examples of cycloalkyl groups include, but are not limited to, groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkyl group is optionally substituted by one or more substituents which independently are: 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)R a (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t N(R a ) 2 (where t is 1 or 2), or PO 3 (R a ) 2 , where each R a is independently hydrogen or alkyl.

As used herein, “cycloalkenyl” refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and is partially unsaturated, e.g., wherein the monocyclic or polycyclic radical contains one or more double bonds. Cycloalkenyl groups include groups having from 3 to 12 ring atoms (i.e. C 3 -C 12 cycloalkenyl). Examples of cycloalkenyl groups include, but are not limited to, groups such as cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkenyl group is optionally substituted by one or more substituents which independently are: 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)R a (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t N(R a ) 2 (where t is 1 or 2), or PO 3 (R a ) 2 , where each R a is independently hydrogen or alkyl.

As used herein, “C 3 -C 7 cycloalkyloxy” refers to —O—(C 3 -C 7 cycloalkyl), wherein the C 3 -C 7 cycloalkyl moiety is as defined herein.

As used herein, “halo” or “halogen,” independently 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.

As used herein, “haloalkyl” and “haloalkoxy” can include alkyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted by one or more substituents which independently are: 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 (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t N(R a ) 2 (where t is 1 or 2), or PO 3 (R a ) 2 , where each R a is independently hydrogen or alkyl.

As used herein, “heteroalkyl” can include an optionally substituted alkyl, which has one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. A numerical range may be given, e.g. C 1 -C 6 heteroalkyl which refers to the number of carbons in the chain, which in this example includes 1 to 6 carbon atoms. For example, a —CH 2 OCH 2 CH 3 radical is referred to as a “C 3 ” heteroalkyl. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl chain. Unless stated otherwise specifically in the specification, a heteroalkyl group is optionally substituted by one or more substituents which independently are: 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)R a (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t N(R a ) 2 (where t is 1 or 2), or PO 3 (R a ) 2 , where each R a is independently hydrogen or alkyl.

As used herein, “heteroaryl” refers to a 3- to 12-membered aromatic radical (e.g., C 3 -C 12 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic or bicyclic ring system. Bivalent radicals derived from univalent heteroaryl radicals whose names end in “-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding “-idene” to the name of the corresponding univalent 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. The polycyclic heteroaryl group may be fused or non-fused. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryl groups include without limitation, 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, indolinyl, and the like. Unless stated otherwise specifically 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 (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t N(R a ) 2 (where t is 1 or 2), or PO 3 (R a ) 2 , wherein each R a is independently hydrogen or alkyl.

As used herein, “heteraryloxy” refers to —O-(heteroaryl), wherein the heteroaryl moiety is as defined herein.

As used herein, “heterocycloalkyl” can be a stable 3- to 12-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocycloalkyl groups include, but are not limited to, groups such as 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 specifically in the specification, a heterocycloalkyl moiety is optionally substituted by one or more substituents which independently are: 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 (where t is 1 or 2), —S(O) t OR a (where t is 1 or 2), —S(O) t N(R a ) 2 (where t is 1 or 2), or PO 3 (R a ) 2 , wherein each R a is independently hydrogen or alkyl.

As used herein, “hydroxy” or “hydroxyl” refers to —OH.

As used herein, “hydroxyalkyl” refers to an alkyl group having 1 to 6 carbon atoms, which is substituted with a hydroxyl group, e.g., hydroxypropyl.

As used herein, “nitro” refers to —NO 2 .

As used herein, “oxo” refers to ═O.

As used herein, “urea” refers to —NR a —C(O)—NR a 2 or —NR a —C(O)NR a —, wherein R a is H or C 1 -C 6 alkyl.

As used herein, “sulfonylurea” refers to —S(O) 2 —NR a —C(O)—NR a — or

—NR a —C(O)—NR a —SO 2 —, wherein R a is H or C 1 -C 6 alkyl, e.g., an C 1 -C 6 alkyl group as described herein.

As used herein, “sulfonamidyl” refers to —S(O) 2 —NR a — or —NR a —S(O) 2 —, wherein R a is H or C 1 -C 6 alkyl, e.g., an C 1 -C 6 alkyl group as described herein.

In the context of the present disclosure and as described herein, reference to the compounds of any one of the compounds of formulae I-XXXXIII, for example, compounds of formulae (XXXII), (XXXIII), (XXVIV), (XXXIV), (XXVV), (XXXV), (XXXVI), (XXVVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), (XXXXII) or (XXXIII) encompasses solvates, hydrates, pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of the compounds or any variations detailed herein

The term “solvate” refers to an aggregate of a molecule with one or more solvent molecules, such as hydrate, alcoholate (aggregate or adduct with alcohol), and the like.

The term “hydrate” refers to a compound formed by the addition of water. The hydrates may be obtained by any known method in the art by dissolving the compounds in water and recrystallizing them to incorporate water into the crystalline structure.

A “pharmaceutically acceptable prodrug” is a compound that may be converted under physiological conditions to the specified compound or to a pharmaceutically acceptable salt of such compound.

The term “physiologically functional derivative” used herein relates to any physiologically acceptable derivative of a compound as described herein. The physiologically functional derivatives also include prodrugs of the compounds of the invention. Such prodrugs may be metabolized in vivo to a compound of the invention. These pro-drugs may or may not be active themselves and are also an object of the present invention.

The term “pharmaceutically acceptable salt” refers to salts derived from organic and inorganic acids of a compound 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, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, napthalenesulfonate, propionate, succinate, fumarate, maleate, malonate, mandelate, malate, phthalate, and pamoate. The term “pharmaceutically acceptable salt” as used herein also refers to a salt of a compound described herein having an acidic functional group, such as a carboxylic acid functional group, and a base. Exemplary bases include, but are not limited to, hydroxide of alkali metals including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH—(C 1 -C 6 )-alkylamine), 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 such as arginine, lysine, and the like. The term “pharmaceutically acceptable salt” also includes hydrates of a salt of a compound described herein.

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

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

In accordance with some embodiments, the composition is a pharmaceutical composition.

In some embodiments, the composition of the invention may 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 and all solvents, dispersion media, coatings and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated.

In some other embodiments, the pharmaceutical composition may comprise a vehicle, matrix, nano- or micro-particle.

The compounds or the compositions comprising the compounds of the present invention may be useful for a variety of application.

Specifically, the compounds described herein may be useful in affecting multiple physiological/biological process and are selected for treatment, based on various parameters, including, inter alia, on the disorder to be treated or the severity of the disorder or the route of compound administration. For example, prior to treatment, diagnostics of the disorder and the severity may determine these parameters.

Hence, the compounds of the invention may be for use to treat a disease treatable by the compounds.

Specifically, as shown in the examples below, for example in example 1 providing results of patch clamp experiments, compounds of the present disclosure were shown to inhibit flow of ion and specifically of cations such as calcium ions (Ca +2 ) in an cation channel such as Transient Receptor Potential Cation Channel Subfamily V Member 3 (TRPV3). In other words, compounds of the present disclosure were shown to inhibit TRPV3 activity.

TRPV3 is provided in accordance with some embodiments by a protein accession number Q8NET8.

In yet some further aspects, the invention provides a composition comprising an effective amount of any of the compounds of the invention as described above or any vehicle, matrix, nano- or micro-particle comprising the same, specifically, for example the compounds of any one of the compounds of Formulas I-XXXXIII, e.g., any one of the compounds of Formulas (XXXII), (XXXIII), (XXVIV), (XXXIV), (XXVV), (XXXV), (XXXVI), (XXVVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), (XXXXII) or (XXXXIII) as well as the compounds denoted compound A, compound B, compound C, compound D, compound E, compound F, compound G, compound H, compound I or compound J as described herein or any analogs or derivative thereof including any stereoisomer or salt thereof for use in a method of modulating the activity of a cation channel, specifically a Ca +2 channel and more specifically TRPV3.

In some embodiments, the compositions of the invention are for use in inhibiting the activity of a cation channel, specifically a Ca +2 channel and more specifically TRPV3.

Hence, the present disclosure also provides in accordance with some aspects, at least one compound of Formulas I-XXXXIII as an TRPV3 antagonist.

Specifically, the invention provides compounds, specifically, the compounds a defined in Formulae I-XXXXIII, for use as TRPV3 antagonists. Hence, compounds of any of the above structures may be used to inhibit an activity of TRPV3 in vitro or in vivo, and/or can be used in the manufacture of medicaments to inhibit an activity of TRPV3 in vitro or in vivo.

In some embodiments, compounds of any of the above structures being compounds according to the present disclosure may be considered as TRPV3 inhibitors. In some embodiments, a compound of any of the above structures may be used an antagonist of TRPV3.

The terms “antagonist” and “inhibitor” are used interchangeably to refer to an agent that decreases or suppresses a biological activity, such as to repress an activity of an ion channel, such as TRPV3. Hence, compounds of the present invention that may be TRPV3 inhibitors can be used to inhibit an activity of TRPV3, and/or can be used in the manufacture of medicaments to inhibit an activity of TRPV3 in vitro or in vivo.

In yet some further aspects, the invention provides a composition comprising an effective amount of any of the compounds of the invention as described above or any vehicle, matrix, nano- or micro-particle comprising the same, for example the compounds of any one of the compounds of Formulas I-XXXXIII, e.g., any one of the compounds of Formulas (XXXII), (XXXIII), (XXVIV), (XXXIV), (XXVV), (XXXV), (XXXVI), (XXVVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), (XXXXII) or (XXXXIII) as well as the compounds denoted 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 or any analogs or derivative thereof including any stereoisomer or salt thereof for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a TRPV3 mediated disorders in a subject in need thereof.

As used herein the term TRPV3 mediated disorders relates to a disease/disorder/condition involving activation of TRPV3. TRPV3 function has been implicated in multiple physiological processes, including, inter alia, the reception and transduction of skin defects and pain.

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 an increased activation of TRVP3.

In some embodiments, TRPV3 mediated disorder is selected from the following group: acute and/or chronic pain, touch sensitivity, burns, inflammation, diabetic neuropathy, psoriasis, eczema, dermatitis, post-herpetic neuralgia (shingles), migraine, incontinence, fever, hot flashes, osteoarthritis, oral mucositis, cancer pain, bladder cystits, pain associated with Crohn's disease and Irritable Bowel Syndrome (IBS), rheumatoid arthritis, Grierson-Gopalan syndrome (better known as burning feet syndrome), burning mouth syndrome (BMS) and cough.

In accordance with some aspects, the present disclosure provides compounds or pharmaceutical composition comprising an effective amount of any of the compounds of the invention as described above or any vehicle, matrix, nano- or micro-particle comprising the same for use in treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a skin disorder in a subject in need thereof. Specifically, the present disclosure provides a pharmaceutical composition comprising any one of the compounds of Formulas I-XXXXIII, for example, any one of the compounds of Formulas (XXXII), (XXXIII), (XXVIV), (XXXIV), (XXVV), (XXXV), (XXXVI), (XXVVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), (XXXXII) or (XXXXIII) as well as the compounds denoted compound A, compound B, compound C, compound D, compound E, compound F, compound G, compound H, compound I or compound J as described herein or any or any analogs or derivative thereof including any stereoisomer or salt thereof for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a skin disorder in a subject in need thereof.

The compounds of the invention may be administrated in combination with a second active agent.

As described herein, TRPV3 function has been implicated in, among other things, the reception and transduction of skin defects. Specifically, influx of calcium across plasma membrane of skin cells is a critical signaling element involved in cellular differentiation in the skin epidermis (Dotto, 1999 Crit Rev Oral Biol Med 10:442-457). Regulating or modulating the calcium entry pathway, and thus a critical control point for skin cell growth, can treat or prevent skin diseases or disorders that are characterized by epidermal hyperplasia, a condition in which skin cells both proliferate too rapidly and differentiate poorly. Such diseases include psoriasis, and basal and squamous cell carcinomas. Psoriasis, estimated to affect up to 7 million Americans, afflicts sufferers with mild to extreme discomfort, enhanced susceptibility to secondary infections, and psychological impact due to disfigurement of the affected areas (Lebwohl and Ali, 2001 J Am Acad Dermatol 45:487-498). Basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) of the skin represent at least one-third of all cancers diagnosed in the United States each year. More than 1 million new cases are reported annually and incidence is increasing. Despite being relatively non-aggressive, slow-growing cancers, BCCs are capable of significant local tissue destruction and disfigurement. SCCs are more aggressive and thus present even greater complications. Further, given that 80% of lesions are on the head and neck with another 15% on shoulders, back or chest, BCCs and SCCs of the skin can have a significant impact on the appearance and quality of life of the afflicted patient.

As used herein, a skin condition denotes any disease/disorder/condition that affect the skin. As appreciated, the skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Mammalian skin is composed of three primary layers: the epidermis the dermis and the hypodermis. The epidermis is composed of the outermost layers of the skin which forms a protective barrier over the body's surface, responsible for keeping water in the body and preventing pathogens from entering. The epidermis is composed of basal proliferative layer, differentiated suprabasal and spinous layer, Granular terminally differentiated keratinocytes layer and a stratified squamous epithelium. Most of the epidermis (about 95%) is composed of keratinocytes.

A skin disease in accordance with the present disclosure may be characterized by having one of more skin irregularities. Skin irregularity may include at least one symptom of raised bumps, a rash, itchy, scaly (rough skin), peeling skin, ulcers, open sores or lesions, dry, cracked skin, discolored patches of skin, fleshy bumps, warts (or other skin growths), changes in mole color or size, a loss of skin pigment, inflammation or excessive flushing.

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

As shown in the examples below, compounds of the present invention were shown to be effective in normalizing skin structure, skin cells differentiation and barrier function, suggesting that the compounds of the invention can be used as a treatment for skin diseases.

For example, and as shown in Example 12 below, providing results of an engineered CRISPR-Cas9 ABCA12 KO equivalent (3D model), selective inhibition by KM-001 restored skin structure as well as barrier function in a dose dependent manner. In addition, KM-001 normalized Keratin 10 expression in a dose dependent manner.

In addition, as shown in Example 16 below, KM-001 was shown to normalize epidermis differentiation and to reduce inflammation in DS-Nh TRPV3 mutation genetic model.

Further, as shown in Example 17 below, pre-treatment with either dose of oral KM-023 decrease the number of scratches observed 30 minutes post induction.

Hence, the present disclosure encompasses any disease/disorder/condition associated with any part/segment of the skin. The term skin disorders may be interchangeably with the term dermatological disorder.

The skin disease as used herein encompasses an inherent (genetic) skin disease or an acquired skin disease. In some embodiments, the skin disease is a chronic disease. In some embodiments, the skin disorder is one or more of the following: a keratoderma, an ichthyosis, epidermolysis bullosa, pachyonychia congenita, pruritis (itch), dry skin (Xerosis), eczema (including atopic dermatitis) or burns.

In some embodiments, the skin disease relates to improper skin differentiation.

Improper skin differentiation relates to disruption of a differentiation process which tend to affect one or more of the skin epidermal layers; basal, spinous, granular or stratum corneum and may result from various functional mechanisms including Ca +2 dysregulation, keratins deformation, inflammation, collagen deconstruction. The improper skin differentiation may result in one or more of hyperkeratosis, acanthosis, inflammation or dysregulation of barrier function.

In some embodiments, skin disease related to improper skin differentiation include keratoderma, ichthyosis or combination thereof.

It is suggested that normalization of skin differentiation may play a key regulator in treatment of such disease as in turn it can lead to reduction of inflammation and barrier re-construction.

In some embodiments, the skin disorder is a keratoderma.

The term keratoderma and specifically palmoplantar keratoderma also known as keratosis palmaris et plantaris refers a disease/disorder characterized by a thickening of the skin and specifically of palms and soles.

In some embodiments, the keratoderma is at least one of a diffuse keratodermata, a focal keratoderma or a punctate keratoderma.

A diffuse keratoderma often affects the palms and soles, focal keratoderma mainly affects pressure areas, whereas punctate keratoderma typically results in tiny bumps on palms and soles.

In some embodiments, the keratoderma is an inherent (hereditary) keratoderma. A hereditary keratoderma may be caused by a gene abnormality resulting, for example, in an abnormal skin protein (keratin).

In some embodiments, a hereditary palmoplantar keratoderma (PPK) is at least one of diffuse hereditary palmoplantar keratoderma, focal hereditary palmoplantar keratoderma, punctate palmoplantar keratoderma.

In some embodiments, a diffuse hereditary palmoplantar keratoderma is at least one of Mutilating Palmoplantar keratoderma with periorificial keratotic plaques (Olmstead Syndrome), Diffuse palmoplantar keratoderma, Diffuse non-epidermolytic palmoplantar keratoderma, Diffuse epidermolytic palmoplantar keratoderma (diffuse EPPK, Vorner disease, PPK cum degenerations granulose, Progressive Palmoplantar Keratoderma (Greither disease, PPK transgrediens et progrediens), Mal de Meleda (Keratosis extremitatum hereditaria transgrediens et progrediens), PPK Mutilans Vohwinkel (mutilating keratoderma, Vohwinkel syndrome, and palmoplantar keratoderma mutilans), Palmoplantar Keratoderma with sclerodactyly (hardening and thickening of the connective tissues of the fingers and toes) (Huriez syndrome), Palmoplantar Keratoderma with peridontitis (inflammation of the gums) (Papillon-Lefevre Syndrome).

Diffuse palmoplantar keratoderma is a type of palmoplantar keratoderma that is characterized by an even, thick, symmetric hyperkeratosis over the whole of the palm and sole, usually evident at birth or in the first few months of life.

Diffuse non-epidermolytic palmoplantar keratoderma is an autosomal dominantly inherited condition traced to K1 and K16 keratins. Onset of clinical features usually presents within the first two years of life. Even, widespread thickened skin (keratosis) over the palms and soles, a red band at the edges of the keratosis, other keratotic lesions, excessive perspiration, nails may be thickened.

Diffuse epidermolytic palmoplantar keratoderma (diffuse EPPK, Vorner disease, PPK cum degenerations granulose) is the most common type of hereditary PPK. It has an autosomal dominant inheritance traced to KRT9 keratin. Onset of clinical features usually takes place within the first year. Similar to diffuse non-epidermolytic PPK but the skin is fragile and may blister.

Progressive Palmoplantar Keratoderma (Greither disease, PPK transgrediens et progrediens) is transmitted through an autosomal dominant inheritance. Onset of clinical features usually appears between ages 8 and 10. The widespread thickened skin spreads from the palms and the soles to the tops of the hands and feet and up the Achilles tendon (back of the heel). Excessive perspiration and variations in signs and symptoms between affected family members are common. Signs and symptoms tend to be worse during childhood, static after puberty, and improve in middle age.

Diffuse Hereditary PPK with associated features is typically associated with extra palmoplantar skin involvement in several inherited disorders of cornification,

Mal de Meleda (Keratosis extremitatum hereditaria transgrediens et progrediens) is a rare disorder seen in approximately 1 in 100,000 people. It was initially observed in inhabitants of the Adriatic island of Meleda (Miljet). It is transmitted through an autosomal recessive inheritance. Clinical features of the disorder usually appear in early infancy. Palmoplantar keratoderma is often the only manifestation. Widespread thickened skin with a prominent red border, which spreads onto the tops of the hands and feet. The widespread hyperkeratosis may resemble gloves or stockings on the hands and feet. Tight constricting bands around the fingers and toes, which result in spontaneous amputation, have been reported. Individuals may have well defined psoriasis-like plaques or lichenoid patches (small firm lesions set very close together) on the knees and elbows. Excessive sweating. Reddened and thickened skin around the eye socket. Nail changes. A ridged tongue, webbed fingers or toes, hair on the palms or soles, a high arched palate (roof of the mouth), and left-handedness are associated features.

PPK Mutilans Vohwinkel (mutilating keratoderma, Vohwinkel syndrome, and palmoplantar keratoderma mutilans) is a rare disorder that can be transmitted through an autosomal dominant inheritance or an autosomal recessive inheritance. The genetic defect has been traced to the GJB2 gene and connexin 26. Clinical features usually appear in infancy. Presents in infants as a honeycomb-like thickening of the skin on the palms and the soles. Later-forming, constricting, fibrous bands on the fingers and toes lead to progressive strangulation and autoamputation. Starfish-shaped thickened skin may occur on the tops of the fingers and knees. Baldness, deafness, spastic impairment of the muscles, nearsightedness, scaly skin, and nail abnormalities are associated.

Mutilating Palmoplantar keratoderma with periorificial keratotic plaques (Olmstead Syndrome) is a rare disorder transmitted through an autosomal dominant inheritance. Clinical features usually appear within the first year of life. Symmetrical, sharply defined palmoplantar keratoderma surrounded by reddened skin and deformities of the joints that lead to constriction and spontaneous amputation. Horny growths around the eyes and mouth. Nail abnormalities. White thickened patches of skin around the anus and in the mouth. Sparse hair.

Palmoplantar Keratoderma with sclerodactyly (hardening and thickening of the connective tissues of the fingers and toes) (Huriez syndrome) is a rare disorder transmitted through an autosomal dominant inheritance. Clinical symptoms are visible in infancy. Sclerodactyly—scleroderma or hardening and thickening of the connective tissues of the fingers and toes. Widespread thickened skin more marked on the soles than on the palms. Nail abnormalities. Decreased sweating. Associated with squamous cell carcinoma.

Palmoplantar Keratoderma with peridontitis (inflammation of the gums) (Papillon-Lefevre Syndrome) is a rare disease transmitted through an autosomal recessive inheritance. The disorder results from mutations in cathepsin C. It occurs equally among males and females. Clinical features usually appear within the first and fifth years of life. Widespread or focal thickened skin on the palms and the soles. Unless treated, periodontitis results in severe gum disease and loss of teeth by age 5. Patients may exhibit an increased susceptibility to infection. Scaly, red lesions over knees, elbows, and knuckles are occasionally observed. Excessive sweating and body odor.

In some embodiments, the keratoderma is an acquired keratoderma. An acquired keratoderma may be due to a health change or an environment change.

In some embodiments, an acquired keratoderma is a focal keratoderma or a diffuse keratoderma.

In some embodiments, the keratoderma is Olmstead Syndrome.

In some embodiments, the skin disorder is an ichthyosis disease.

Ichthyosis refers to a genetic disease characterized by the presence of excessive amounts of dry surface scales persistently dry, thickened, ‘fish scale’ skin. It is regarded as a disorder of keratinization or cornification, and it is due to abnormal epidermal differentiation or metabolism.

The ichthyosiform dermatoses may be classified according to clinical manifestations, genetic presentation, and histologic findings. Inherited and acquired forms of ichthyosis have been described, and ocular alterations may occur in specific subtypes. There are at least 20 different types of ichthyosis. Some types are inherited at birth and other types are acquired during adulthood.

Inherited types of ichthyosis may be congenital or have delayed onset. Inherited types of ichthyosis may be congenital or have delayed onset. Ichthyosis vulgaris has an autosomal dominant inheritance, meaning an abnormal gene is inherited from a parent. Penetrance is 90%. Onset is delayed until at least three months of age. Recessive X-linked ichthyosis mainly affects males, who have a single X chromosome with the abnormal gene. Females are protected by usually having a normal second X chromosome. Onset may be congenital or delayed by up to 6 months. In autosomal recessive congenital ichthyosis one abnormal gene is inherited from each parent. Congenital ichthyosiform erythroderma (CIE) is a variant of autosomal recessive congenital ichthyosis (ARCI), a rare epidermal disease, characterized by fine, whitish scales on a background of erythematous skin over the whole body. Keratinopathic ichthyoses have recessive and dominant forms and present at birth with a collodion membrane. Harlequin ichthyosis is a rare and severe form of ichthyosis that results in hard, thickened armour-like plates of skin covering the entire body from birth. Harlequin ichthyosis is also called harlequin-type ichthyosis, and harlequin fetus. Lamellar ichthyosis is a rare genetic condition. Infants affected by lamellar ichthyosis are generally born with a shiny, waxy layer of skin (called a collodian membrane) that is typically shed within the first two weeks of life. The skin beneath the collodian membrane is red and scaly. Epidermolytic ichthyosis (EI) is a rare, genetic skin disorder. It becomes apparent at birth, or shortly after birth, with reddening, scaling, and severe blistering of the skin. Hyperkeratosis develops within months and worsens over time. Blister formation decreases but may still occur after skin trauma or during summer months. Skin can be itchy and smelly, and prone to infection. Other features may include reduced sweating; nail abnormalities; and in severe cases, growth failure. Superficial epidermolytic ichthyosis (SEI), formerly know as Ichthyosis bullosa of Siemens (IBS), is a rare keratinization disorder with superficial peeling. Although hyperkeratotic, the skin is unusually fragile and has tendency to shed the outer layers of the epidermis, producing localized denuded areas. Netherton syndrome (ichthyosis linearis circumflexa) is a rare hereditary disorder characterized by scaling skin, hair anomalies, increased susceptibility to atopic eczema (a skin condition that can result in dry, red and flaky skin), elevated IgE levels, and other related symptoms. Netherton syndrome is inherited as an autosomal recessive trait. Pachyonychia congenita (PC) is a rare group of autosomal dominant skin disorders that are caused by a mutation in one of five different keratin genes. Pachyonychia congenita is often associated with thickened toenails, plantar keratoderma, and plantar pain.

There are other types of ichthyosis including but not limited to Chanarin-Dorfman syndrome (neutral lipid storage disease), CHILD syndrome (unilateral hemidysplasia), Conradi-Hunermann syndrome (X-linked dominant chondrodysplasia punctata), Darier disease, epidermal nevi (ichthyosis hystrix, linear epidermal nevus), epidermolytic hyperkeratosis (EHK), erythrokeratodermia variabilis (EKV), Giroux-Barbeau syndrome, Hailey-Hailey disease (benign familial pemphigus), ichthyosis hystrix Curth-Macklin type, keratosis follicularis spinulosa decalvans, KID syndrome (keratitis, ichthyosis, deafness), multiple sulfatase deficiency, peeling skin syndrome, pityriasis rubra pilaris (PRP), Refsum's disease (phytanic acid storage disease), Rud's syndrome, Sjogren-Larsson syndrome, Tay's syndrome (trichothiodystrophy, IBIDS syndrome).

In some embodiments, the skin disorder is Harlequin Ichtyosis.

Ichthyosis can also be due to a new spontaneous mutation.

In some embodiments, the skin disease is itch sensation.

Itch sensation is initiated in the skin by peripheral afferents of primary sensory neurons, with cell bodies located in dorsal root ganglia (DRG) and trigeminal ganglia, then transmitted to the spinal dorsal horn and then further to the brain. Itch used to be regarded as a sub-modality of pain because of their similarities.

TRP channel with major role in itch transmission, TrpA1, is increased in nerve fibers, keratinocytes and tryptase positive mast cells from lesional skin of atopic dermatitis patients. Notably dermal cells in healthy skin have minimal expression of TrpA1. In addition, expression of TrpV3 is also increased in atopic dermatitis lesional skin though its role in itch is not entirely clear. Elevated TrpA 1 expression is also detected in postburn pruritus. Levels of TrpA1 and two other channels TrpV3 and TrpV4 are all higher in post-burn patients with pruritus comparing with post-burn patients without pruritus. Unlike TrpV1 and TrpA1, TrpV3 expression is mainly detected in keratinocytes.

Activation of TrpV3 can trigger release of multiple factors including PGE2, ATP, nitric oxide and NGF, contributing to the inflammation processes in dermatitis. TrpV3 Gly573 mutations are detected in DS-Nh mice (Gly573Ser) and WBN/Kob-Ht rats (Gly573Cys), both spontaneous hairless mutant strains. These animals develop spontaneous dermatitis phenotypes including increased keratinocytes and pruritus. Transgenic mice carrying Gly573Ser mutation mimics dermatitis phenotypes from the two spontaneous mutant rodent strains confirming the causal role of this single amino acid mutation. Recent studies also link this TrpV3 missense mutation to Olmsted Syndrome (OS), a rare congenital disorder featuring palmoplantar, periorificial keratoderma and severe itching. OS patients were identified to carry missense mutation in TrpV3 gene (in most cases Gly573Ser or Gly573Cys).

Dry skin (Xerosis), skin dehydration with constant itch is another chronic itch condition commonly modeled in animals. Repeated skin dehydration with acetone and ether can trigger spontaneous scratching and increase trans-epidermal water loss without infiltration of inflammatory cells mimicking symptoms of Xerosis. In animal model of dry skin, both TrpA1 and TrpV3 are required for induction of spontaneous itch.

In some embodiments, the skin condition is pruritis.

Pruritis or itch is defined as an unpleasant sensation of the skin that provokes the urge to scratch. It is a characteristic feature of many skin diseases and an unusual sign of some systemic diseases. Pruritus may be localized or generalized and can occur as an acute or chronic condition. Itching lasting more than 6 weeks is termed chronic pruritus. Itching can be intractable and incapacitating, as well as a diagnostic and therapeutic challenge. Itch can be produced by mechanical (gentle touch, pressure, vibration, and wool), thermal and electrical stimuli such as transcutaneous or direct nerve stimulation. The sensation is received by free nerve endings in the skin and transmitted via unmyelinated C fibers and myelinated Aδ fibers to the central spinothalamic tracts. 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 chemical substances have also been implicated. Some, such as neuropeptides, act by releasing histamine from mast cells, and itching caused by them responds to antihistamines. Others act independently; therefore, antihistamines are not effective in some forms of pruritus. Opioids have a central pruritic action and also act peripherally by augmenting histamine itch. Patients with tumors and lesions of the central nervous system have been reported to have intractable pruritus. Administration of opioids in epidural anesthesia can also lead to pruritus.

Itching is an important component of some disorders (atopic eczema, dermatitis herpetiformis, lichen simplex chronicus, and nodular prurigo) and these conditions are rarely diagnosed in its absence. Dermatologic Disorders Associated with Chronic Pruritus include but are not limited to the following: autoimmune related: Dermatitis herpetiformis, Dermatomyositis, Pemphigoid, Sjögren's syndrome; genetic related: Darier's disease, Hailey-Hailey disease, Ichthyoses, Sjögren-Larsson syndrome; Infections and Infestations related: Arthropod reactions, Dermatophytosis Folliculitis, Impetigo and other bacterial infections, Insect bites, Pediculosis, Scabies, Viral; Inflammatory related: Asteatosis (dry skin), including aging and senile pruritus, Atopic eczema, Contact dermatitis (irritant, allergic), Drug reactions, “Invisible dermatoses”, Lichen planus, Lichen simplex chronicus, Mastocytosis (urticaria pigmentosa), Miliaria, Psoriasis, Scars, Urticaria; Neoplastic related: Cutaneous T-cell lymphoma or mycosis fungoides (especially Sezary syndrome), Cutaneous B-cell lymphoma, Leukemia cutis; Pregnancy related: Pemphigoid gestationis, Polymorphic eruption of pregnancy, Prurigo gestationis. Select Systemic Causes of Chronic Pruritus may include: Endocrine and Metabolic Diseases, such as Chronic renal failure, Diabetes mellitus (questionable; may be localized to scalp), Hyperthyroidism, Hypothyroidism, Liver disease (with or without cholestasis), Malabsorption, Perimenopausal pruritus; Infectious Diseases such as Helminthosis, HIV infection, Parasitosis; Neoplastic and hematological diseases such as Hodgkin's disease, Iron deficiency, Leukemia, Non-Hodgkin's lymphoma, Multiple myeloma, Plasmacytoma, Polycythemia rubra vera; Visceral Neoplasms sauch as Carcinoid syndrome and Solid tumors of the cervix, prostate, or colon; Pregnancy related disorders such as Pruritus gravidarum (with or without cholestasis); Induced by drugs, such as, Allopurinol, Amiodarone, Angiotensin-converting enzyme inhibitors, Estrogen, Hydrochlorothiazide, Hydroxyethyl cellulose, Opioids, Simvastatin. Other causes of chronic pruritis may result from Neurologic disease (Abscess, Infarcts, Multiple sclerosis, Notalgia Paresthetica, Tumors) or Psychiatric disease (Anxiety disorders, Depression, Obsessive-compulsive disorder).

In some embodiments, the skin condition is Eczema.

Eczema is the name for a group of conditions that cause the skin to become itchy, inflamed, and red in lighter skin tones or brown, purple, gray or ashen in darker skin tones. Eczema is very common. In fact, more than 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, Atopic dermatitis. Atopic dermatitis (AD) is the most common type of eczema, affecting more than 9.6 million children and about 16.5 million adults in the United States. In people with AD the immune system becomes disordered and overactive. This triggers inflammation that damages the skin barrier, leaving it dry and prone to itching and rashes that may appear purple, brown, or grayish hue in darker skin tones and red in lighter skin tones. Research shows that in some cases of atopic dermatitis, there is a mutation of the gene responsible for creating filaggrin.

In some embodiments, the skin condition is a burn.

A burn is a type of injury to skin, or other tissues, caused by heat, cold, electricity, chemicals, friction, or radiation. Burns are classified either by common causes or by degree of severity. Common causes of burns include:

Friction or mechanical burns are caused by an object rubbing off some of the skin. It is both an abrasion (scrape) and a heat burn. Cold burns are caused by exposure to extreme cold temperatures. Thermal burns are caused by exposure to extreme hot temperatures. Radiation burns are caused by either sun radiation or by other sources of radiation, like X-rays or radiation therapy to treat cancer. Chemical burns are caused by strong acids, solvents, or detergents. Electrical burns are caused by the contact with an electrical current.

Burns that affect only the superficial skin layers are known as superficial or first-degree burns. They appear red without blisters and pain typically lasts around three days. When the injury extends into some of the underlying skin layer, it is a partial-thickness or second-degree burn. Blisters are frequently present, and they are often very painful. Healing can require up to eight weeks and scarring may occur. In a full-thickness or third-degree burn, the injury extends to all layers of the skin. Often there is no pain and the burnt area is stiff. Healing typically does not occur on its own. A fourth-degree burn additionally involves injury to deeper tissues, such as muscle, tendons, or bone. The burn is often black and frequently leads to loss of the burned part.

In some embodiments, the skin condition is a scar formation.

Scar formation occurs after an injury and is an area of fibrous tissue that replaces normal skin and is the final condition resulting from a complex repair mechanism of the human body. The various clinical manifestations of scarring are an important topic for physicians in many disciplines. The prevention of excessive scarring is more successful than the treatment afterwards. Pathological scaring is differentiated into two groups: Hypertrophic scars and keloids. Hypertrophic scars generally have cell-rich connective tissue and usually parallel collagen fibers at the surface. There may also be focal nodular areas. In the latter there are numerous alpha-actin-positive myofibroblasts. In keloids, a more cell-poor connective tissue dominates, and the collagen fibers are organized randomly and in larger nodules. The fibers are hypereosinophilic, hyaline, and thicker. In addition—often in the center of the scar—there are cell-poor areas. Alpha-actin-positive myofibroblasts are either absent or found only focally. Between the fibers there are abundant small vessels in both hypertrophic scars as well as in keloid.

The pharmaceutical composition of the invention can be administered and dosed by the methods of the invention, in accordance with good medical practice. Hence, the pharmaceutical compositions or compounds described herein may be adjusted, adapted or configured for administration by a variety of administration routes.

For example, the compositions used in the methods of the invention, described herein below, may be adapted for administration by various 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 appropriate routes. Specific examples include but not limited to, injection (e.g., using a subcutaneous, intramuscular, intravenous, or intradermal injection), intranasal administration and oral administration.

In some embodiments, administration of the compound of the invention is by systemic administration. Hence the compound is adjusted to be suitable for systemic administration. “Systemic administration” and “administered systemically” as used herein mean that the administration of a compound or a composition comprising at least one compound of the invention into the circulatory system so that the entire body is affected.

In accordance with some embodiments, the compounds of the invention or the composition comprising the compounds of the invention are suitable for systemic administration.

In some embodiments, any of the compounds of formulae I-XXXXIII, or a composition comprising any of the compounds of formulae I-XXXXIII, are suitable for systemic administration. In some embodiments, at least the compounds denoted as KM-0023 or a composition the compounds denoted as KM-0023 are suitable for systemic administration.

In some embodiments, the compound is administered enterally.

In some embodiments, the compound is administered orally.

Compositions for oral administration may include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays or tablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders may be desirable.

It should be understood that in addition to the ingredients particularly mentioned above, the compositions may also include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

In some embodiments, the compound is administered parentally.

“Parenteral administration” and “administered parenterally” as used herein includes modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

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

In some embodiments, administration of the compound of the invention is by local administration.

In some embodiments, the compound is administered topically. Hence the compound is adjusted to be suitable for topical administration. “Topical administration” and “administered topically” as used herein mean that the administration of a compound or a composition comprising at least one compound of the is applied to a particular place on or in the body. Typically, topical administration refers to application to body surfaces such as skin or mucous membranes.

The topically administrable compounds may be formulated into a suitable formulation or composition. The carriers may be selected from powders, oils, creams, foams, ointments, lotions, gels, pastes, mousiness, hydrogels or delivery systems such as liposome, niosome, microsponge, microemulsion, microsphere, SLN, aerosol and others.

The compounds of the invention may be effectively dispersed or suspended or solubilized in a liquid medium to form a solution, a suspension or a dispersion that may be applied topically, sprayed onto the skin or delivered by contact via the use of a sponge, a plaster, a pad or any skin dressing. For some applications, controlled release of the compounds of such delivery systems may be essential.

In accordance with some embodiments, the compounds of the invention or the composition comprising the compounds of the invention are suitable for topical administration.

In some embodiments, any of the compounds of formulae I-XXXXIII, or a composition comprising any of the compounds of formulae I-XXXXIII, are suitable for topical administration. In some embodiments, at least the compounds denoted as KM-001, KM-002, KM-031, KM-032, KM-036, KM-054, KM-069 or the composition comprising KM-001, KM-002, KM-031, KM-032, KM-036, KM-054, KM-069 are suitable for topical administration.

In some embodiments, the unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

In accordance with some aspects, the present disclosure provides a method for modulating the activity of a cation channel, for example a Ca +2 channel—e.g. TRPV3. In some embodiments, the methods of the invention comprise inhibiting the activity of a cation channel, for example a Ca +2 channel—e.g. TRPV3 activity in a cell. In more specific embodiments, the method comprising the step of contacting the 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 stereoisomer thereof. In some specific embodiments, the method comprising the step of contacting the cell with an effective amount of at least one compound having the general formula (I)—(XXXXIII), for example, any one of the compounds of Formulas (XXXII), (XXXIII), (XXVIV), (XXXIV), (XXVV), (XXXV), (XXXVI), (XXVVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), (XXXXII) or (XXXXIII) as well as the compounds denoted compound A, compound B, compound C, compound D, compound E, compound F, compound G, compound H, compound I or compound J as described herein or a pharmaceutically acceptable salt or hydrate thereof including any stereoisomer thereof. In some embodiments, the methods of the invention comprise contacting the cell with an effective amount of at least one compound of the invention in at least one of in vitro, in vivo, ex vivo or combinations thereof.

In certain embodiments the compound/s used by the method of the invention may be any compound as defined by the invention. In further embodiments, the method of the invention may involve the use of any of the compositions encompassed by the invention, and specifically, any of the compositions as described herein above.

In yet another aspect, the invention provides a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a TRPV3 mediated disorders in a subject in need thereof. In yet another aspect, the invention provides a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a skin disorder in a subject in need thereof.

In more specific embodiments the methods comprising administering to such subject a therapeutically effective amount of at least one compound/s including any stereoisomer or salt thereof or of any vehicle, matrix, nano- or micro-particle, or a composition comprising the same.

In more specific embodiments, the compound used by the method/s of the invention may have the general formula (I)—(XXXXIII), for example any one of the compounds of Formulas (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.

In some embodiments, the compound used by the method/s of the invention may be denoted compound A, compound B, compound C, compound D, compound E, compound F, compound G, compound H, compound I or compound J as described herein.

In some embodiments, the method/s of the invention comprises topically or systemically administering to a subject a therapeutically effective amount of at least one compound (I)—(XXXXIII), specifically any one of the compounds of Formulas (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.

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

In some other embodiments, the skin disorder is at least one keratoderma.

In some other embodiments, the skin disorder is Olmstead Syndrome.

In some embodiments, the skin disorder is an ichthyosis disease.

In some embodiments, the skin condition is pruritis.

In some specific embodiments, the method/s of the invention comprises topically administering to such subject a therapeutically effective amount of at least one of the compounds denoted herein 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.

In some specific embodiments, the method/s of the invention comprises topically administering to such subject a therapeutically effective amount of the compound denoted herein as compound A.

In some embodiments, the method/s of the 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-fluoro-pyridin-2-yl)-methanone having the structure

including any stereoisomer or salt thereof or of any vehicle, matrix, nano- or micro-particle, or a composition comprising the same. In some embodiments, the method/s of the invention comprises 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 having the structure

including any stereoisomer or salt thereof or of any vehicle, matrix, nano- or micro-particle, or a composition comprising the same

In some specific embodiments, the method/s of the invention comprises systemically administering to such subject a therapeutically effective amount of at least one of the compounds denoted herein 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.

In some specific embodiments, the method/s of the invention comprises systemically administering to such subject a therapeutically effective amount of the compound denoted herein as compound C.

In some embodiments, the method/s of the 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 having the structure

including any stereoisomer or salt thereof or of any vehicle, matrix, nano- or micro-particle, or a composition comprising the same. In some embodiments, the methods of the 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 stereoisomer or salt thereof or of any vehicle, matrix, nano- or micro-particle, or a composition comprising the same.

In yet another aspect, the invention provides a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a skin disorder in a subject in need thereof, specifically a keratoderma, more specifically Olmstead Syndrome, the method comprises administering, specifically topical administrating 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 having the structure

including any stereoisomer or salt thereof or of any vehicle, matrix, nano- or micro-particle, or a composition comprising the same.

In yet another aspect, the invention provides a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a skin disorder in a subject in need thereof, specifically ichthyosis, the method comprises administering, specifically topical administrating 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 having the structure

including any stereoisomer or salt thereof or of any vehicle, matrix, nano- or micro-particle, or a composition comprising the same.

In some embodiments, the method/s of the 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

having the structure including any stereoisomer or salt thereof or of any vehicle, matrix, nano- or micro-particle, or a composition comprising the same.

In yet another aspect, the invention provides a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a skin disorder in a subject in need thereof, specifically a keratoderma, more specifically Olmstead Syndrome, the method comprises administering, specifically systemic administrating 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 having the structure

including any stereoisomer or salt thereof or of any vehicle, matrix, nano- or micro-particle, or a composition comprising the same.

In yet another aspect, the invention provides a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a skin disorder in a subject in need thereof, specifically ichthyosis, the method comprises administering, specifically topical administrating 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 having the structure

including any stereoisomer or salt thereof or of any vehicle, matrix, nano- or micro-particle, or a composition comprising the same.

The present invention provides methods for treating skin disorder. The term “treatment or prevention” refers to the complete range of therapeutically positive effects of administrating to a subject including inhibition, reduction of, alleviation of, and relief from, skin disorder symptoms or undesired side effects of such skin disorder related disorders. More specifically, treatment or prevention includes the prevention or postponement of development of the disease, prevention or postponement of development of symptoms and/or a reduction in the severity of such symptoms that will or are expected to develop. These further include ameliorating existing symptoms, preventing—additional symptoms and ameliorating or preventing the underlying metabolic causes of symptoms.

As used herein, “disease”, “disorder”, “condition” and the like, as they relate to a subject's health, are used interchangeably and have meanings ascribed to each and all of such terms.

The present invention relates to the treatment of subjects, or patients, in need thereof. By “patient” or “subject in need” it is meant any organism who may be affected by the above-mentioned conditions, and to whom the treatment methods herein described 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, fish and exotic aquarium fish. It should be appreciated that the treated subject may be also any reptile or zoo animal. More specifically, the methods and compositions of the invention are intended for mammals. By “mammalian subject” is meant any mammal for which the proposed therapy is desired, including human, equine, canine, and feline subjects, most specifically humans. It should be noted that specifically in cases of non-human subjects, the method of the invention may be performed using administration via injection, drinking water, feed, spraying, oral gavage and directly into the digestive tract of subjects in need thereof. It should be further noted that particularly in case of human subject, administering of the compositions of the invention to the patient includes both self-administration and administration to the patient by another person.

The invention provides methods for treating skin disorders, and further relates to disorders associated or related to skin disorders. It is understood that the interchangeably used terms “associated” and “related”, when referring to pathologies herein, mean diseases, disorders, conditions, or any pathologies which at least one of: share causalities, co-exist at a higher than coincidental frequency, or where at least one disease, disorder condition or pathology causes the second disease, disorder, condition or pathology.

The 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, inhibiting, reducing, eliminating, protecting or delaying the onset of a skin disorder in a subject in need thereof.

The term “about” as used herein indicates 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 value referred to, the deviation range including integer values, and, if applicable, non-integer values as well, constituting a continuous range. As used herein the term “about” refers to +10%.

The terms “comprises”, “comprising”, “includes”, “including”, “having” and their conjugates mean “including but not limited to”. This term encompasses the terms “consisting of” and “consisting essentially of”. The phrase “consisting essentially of” means that the composition or method may include additional ingredients and/or steps, but only if the additional ingredients 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 which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply 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.

As used herein the term “method” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

It is appreciated 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, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

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

Disclosed and described, it is to be understood that this invention is not limited to the particular examples, methods steps, and compositions disclosed herein as such methods steps and compositions may vary somewhat. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only and not intended to be limiting since the scope of the present invention will be limited only by the appended claims and equivalents thereof.

It must 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.

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

At various places in the present specification, substituents of compounds of the disclosure are disclosed in groups or in ranges. It is specifically intended that the disclosure include each and every individual subcombination of the members of such groups and ranges.

Intermediate 1: 3-chloro-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl) pyridine trifluoroacetate salt

To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1 g, 5.3 mmol) in DMF (10 mL) at 0° C. was added NaH (1.2 g, 31 mmol, 60% dispersion in mineral oil), the resulting mixture was stirred at this temperature for 20 min; before 2,3-dichloro-5-(trifluoromethyl)pyridine (1.38 g, 6.4 mmol) was added, the reaction mixture was stirred at rt. for 1.5 h. The reaction was quenched by ice-water at 0° C., diluted with EA (50 mL), washed with LiCi solution and brine, and dried over Na 2 SO4. Concentrate 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 spec: 367 (M+H)

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. was added TFA (5 mL), the resulting mixture was stirred at rt for 2 h; the mixture was concentrated to leave 3-chloro-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl) pyridine as its TFA salt (1.76 g, quant.), Mass spec: 267 (M+H).

Intermediate 2: 2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine trifluoroacetate salt (XJ-000098-129)

The title compound was prepared following procedures 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 spec: 333 (M+H)

The title compound was prepared following procedures described in Intermediate 2 step 2 to give 2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine trifluoroacetate salt (1.76 g, quant.), Mass spec: 233 (M+H)

Intermediate 3: (S)-3-chloro-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine hydrochloride

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

The title compound was prepared following procedures 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 spec: 333 (M+H)

HCl gas was bubbled through a solution of (S)-tert-butyl 3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidine-1-carboxylate (LHH-000206-094) (5 g, 15 mmol) in Et2O/MeOH (20 mL, 5:1) at 0° C. for 3 h, filtered, the (S)-3-chloro-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine hydrochloride was obtained as white solid (3.8 g, 94%), Mass spec: 233 (M+H)

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

The title compound was prepared following procedures 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 spec: 333 (M+H)

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. removal the solvent in vacuum to left dark liquid which was diluted with EA, the organic layer was washed with NaHCO3 solution, brine, dried over Na2SO4, concentrated to give (R)-3-chloro-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (6 g, quant.), Mass spec: 233 (M+H).

Intermediate 5: 3-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)pyrrolidine

To a solution of 2-bromo-5-hydroxybenzaldehyde (10.0 g, 50.0 mmol) in DMF was added iodomethane (3.7 ml, 60.0 mmol), and K 2 CO 3 (20.7 g, 150.0 mmol) at rt. Then the mixture was stirred at 44° C. for 8 h. the mixture was evaporated to obtain a residue, which was dissolved in EA, 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 spec: 215(M+1)

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 stirred at r.t. as Bi(OTf) 3 (6.5 mg, 1% mmol yield) was added. After 1.5 h, the mixture was completed, 20% NaOH solution (10 ml) was added, extracted with EA, dried (Na2SO 4 ) and evaporated, purified by silica gel to give 2-(2-bromo-5-methoxyphenyl)-1,3-dioxane (400 mg, 73% yield), Mass spec: 273(M+1).

To a solution of 2-(2-bromo-5-methoxyphenyl)-1,3-dioxane (272 mg, 1.0 mmol) in 4 ml CH 3 CN was added ethyl acrylate (86.09 mg, 1.0 mmol), Pd(OAc) 2 (11.2 mg, 0.05 mmol), DIPEA (0.5 ml, 3.0 mmol), tri(p-toly)phosphine (30 mg, 0.1 mmol). the mixture was degassed for 5 min, then reflux at 100° C. for overnight. After cooling to r.t., 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 spec: 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).

To a solution of (E)-ethyl 3-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)acrylate (146 mg, 0.5 mmol), in MeNO 2 (152.5 mg, 2.5 mmol) was added dropwise DBU (76 mg, 0.5 mmol) at 0° C., and the mixture was stirred at r.t. for 3 h. the mixture was diluted with water and extracted with EA (3×5 ml), dried (Na2SO4), evaporated and purified by silica gel to give ethyl 3-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)-4-nitrobutanoate (80 mg, 45%) as white solid, Mass spec: 354(M+1).

NiCl 2 · 6 H 2 O (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 MeOH at r.t. After 5 min, NaBH 4 (1.07 g, 28.3 mmol) was added in five portions. Then the mixture was stirred at rt for 30 min, stirred at 70° C. for overnight. The mixture was cooled to r.t. Then filter-ed, the filtrate was evaporated, purified by silica gel to give 4-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)pyrrolidin-2-one (670 mg, 85.9% yield) as white solid, Mass spec: 278(M+1),

1 H-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).

To a solution of 4-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)pyrrolidin-2-one (670 mg, 2.41 mmol) in 10 ml THF was added LAH (184 mg, 4.82 mmol) at 0° C. and then stirred at r.t. for 5 min, then stirred at 70° C. for overnight. The mixture was quenched with 0.18 ml H 2 O, 0.18 ml 15% NaOH solution, 0.55 ml H 2 O by follow, then stirred at r.t. for 15 min, filtered to get the filtrate, evaporated to give the product 3-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)pyrrolidine as white solid (500 mg, 80% yield), Mass spec: 264(M+1).

Intermediate 6: 3-(4-(2-isopropylphenoxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)pyrr-olidine

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

To a solution of 5-(2-isopropylphenoxy)-2-nitrobenzaldehyde (15.0 g, 52.6 mmol) in MeOH (100 ml) was added NaBH 4 (4.0 g, 105.25 mmol) at 0° C., then stirred at rt for 30 min, cooled to 0° C. again, NiCl 2 6H 2 O (2.5 g, 105.2 mmol) was added slowly. Then added another NaBH 4 (4.0 g, 105.25 mmol) slowly at 0° C., stirred at r.t. for 30 min. the mixture was evaporated, added diluted HCl solution to dissolve the inorganic residue, then adjust pH=8 by NH 3 H2O, extracted with EA (3×50 ml), 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 spec: 258(M+1).

A cold solution of Sodium nitrite (1.6 g, 23.0 mmol) in 5 ml water was added dropwise to a stirred cooled suspension of (2-amino-5-(2-isopropylphenoxy)phenyl)methanol (5.0 g, 19.0 mmmol) in water (15 ml) and hydrochloric acid (15 ml), when diazotization was completed, a solution of potassium iodine in water (5 ml) was added. After 1 h at r.t., the mixture was quenched by NaHSO3, extracted with EA (3×20 ml), dried over Na2SO4, evaporated and purified by silica gel to give 2-iodo-5-(2-isopropylphenoxy)phenyl)methanol (2.4 g, 34% yield), Mass spec: 369 (M+1).

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. then stirred at r.t. for overnight. The mixture was diluted with DCM (20 ml), washed with H2O (3×20 ml), the DCM layer was dried, evaporated to give crude 2-(2-iodo-5-(2-isopropylphenoxy)benzyloxy)tetrahydro-2H-pyran (2.4 g, 200% yield), Mass spec: 453 (M+1).

The title compound was prepared following procedures described in Intermediate 5 step3 to give (E)-ethyl 3-(4-(2-isopropylphenoxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)acrylate (1.6 g, 88% yield), Mass spec: 425(M+1).

Step 6: ethyl 3-(4-(2-isopropylphenoxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)-4-nitrobutanoate

The title compound was prepared following procedures described in Intermediate 5 step4 to give ethyl 3-(4-(2-isopropylphenoxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)-4-nitrobutanoate (1.5 g, 83.0% yield), Mass spec: 486(M+1).

The title compound was prepared following procedures described in Intermediate 5 step5 to give 4-(4-(2-isopropylphenoxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)pyrrolidin-2-one

(730 mg, 60.8% yield), Mass spec: 410(M+1).

The title compound was prepared following procedures described in Intermediate 5 step6 to give 3-(4-(2-isopropylphenoxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)pyrrolidine (530 mg, 69.2% yield), Mass spec: 396(M+1).

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

To a solution of 2-bromo-5-fluoropyridine (4.772 g, 27.11 mmol) in toluene (55 mL) was added Pd(cAc) 2 (607.3 mg, 2.711 mmol), BINAP (1.686 g, 2.711 mmol), t-BuoNa (7.81 g, 81.33 mmol) under N2, 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 Na 2 SO 4 . Concentrate 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 spec: 282 (M+H)

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 rt for 1 h; the mixture was concentrated to give (S)-5-fluoro-N-(pyrrolidin-3-yl)pyridin-2-amine (2.5 g, 80%. yield), Mass spec: 189 (M+H)

Intermediate 8: 4-(2-chlorobenzoyl)-2-fluorobenzaldehyde

To a solution of 2-fluoro-4-methylbenzonitrile (5.4 g, 40 mmol) in CCl4 (40 mL) was added NBS (15.7 g, 88 mmol), AIBN (657 mg, 4 mmol), the resulting mixture was stirred at 90° C. for 24 h under N2; the mixture was concentrated to leave 4-(dibromomethyl)-2-fluorobenzonitrile (8.8 g, 80% yield), Mass spec: 292 (M+H)

To a solution of 4-(dibromomethyl)-2-fluorobenzonitrile (8.8 g, 30 mmol) in 90 mL EtOH/H2O was added AgNO3 (10.2 g, 60 mmol), the resulting mixture was refluxed for 3 h; The reaction was diluted with DCM (100 mL), washed with brine, and dried over Na2SO 4 . Concentrate to dryness, the residue was purified by silica gel to give 2-fluoro-4-formylbenzonitrile (2 g, 44.4% yield), Mass spec: 150 (M+H).

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) to rt. for 5 min, The reaction was cooled to −30° C. and 1-bromo-3-chlorobenzene (958 mg, 5 mmol) dropwise to −20° C. for 30 min and warmed at rt. for 1 h, after that, the above solution was added into 2-fluoro-4-formylbenzonitrile (410 mg, 2.75 mmol) in THF (5 ml) to 0° C., the reaction mixture was stirred at 0° C. for 15 min and NH 4 Cl was added for quenching. The layer was separated, dried over Na 2 SO 4 and concentrate to give 4-((2-chlorophenyl)(hydroxy)methyl)-2-fluorobenzonitrile (750 mg, 40% yield) Mass spec: 244 (M−17)

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 to rt. for 1.5 h. The reaction was concentrated to dryness, the residue was purified by Prep-TLC to give 4-(2-chlorobenzoyl)-2-fluorobenzonitrile (530 mg, 80% yield), Mass spec: NO

To a solution of 4-(2-chlorobenzoyl)-2-fluorobenzonitrile (520 mg, 2 mmol) in DCM (15 mL) was added Et3N (203 mg, 2 mmol) and DIBAL-H in hexane (1.5M) (1.4 g, 3.3 mmol) to −78° C. for 45 min. The reaction was poured into icewater, extrcated, separated, dried over Na2SO4 and concentrate to give 4-((2-chlorophenyl)(hydroxy)methyl)-2-fluorobenzaldehyd (470 mg, 70%) Mass spec: 265(M+H)

The title compound was prepared following procedures described in step 4 to give 4-(2-chlorobenzoyl)-2-fluorobenzaldehyde (580 mg, quant), Mass spec: NO, 1 H-NMR (400 Hz, DMSO) δ=10.220 (s, 1H), 8.098-8.116 (m, 2H), 7.566-7.657 (m, 5H).

Intermediate 9: (2′-ethyl-4-(pyrrolidin-3-yl)biphenyl-3-yl)methanol

To a solution of 4-(2-(1,3-dioxan-2-yl)-4-methoxyphenyl)pyrrolidin-2-one (1 g, 3.6 mmol) (intermediate 5 step 5) in 4 mL MeCN at 0° C. was added 3N HCL (4 mL) slowly, the mixture stirred at rt for 30 min, water was added, extracted with EA, washed by brine, dried over Na 2 SO 4 , removal the solvent to left the crude product which was dissolved in 10 mL DCM, to this solution was stirred at 0° C. was added BBr 3 (0.6 mL, 7.2 mmol) drop-wised, and stirred at rt for 1 h, the mixture was poured into ice water, extracted with EA/THF (v:v=3/1), combined organic phase washed with brine, dried over Na 2 SO 4 , removal the solvent to left the crude product which was purified by silica gel to give 5-hydroxy-2-(pyrrolidin-3-yl)benzaldehyde (400 mg, 54.0% yield), Mass spec: 206 (M+1).

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

phenyl trifluoromethanesulfonate (160 mg, 94.0% yield), Mass spec: 338 (M+1).

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 dioxane/water (v:v 4/1) was added PdCl 2 (dppf) (72 mg, 0.09 mmol) and K 3 PO 4 (566 mg, 2.67 mmol), The mixture was stirred at 90° C. for 2 h under N 2 , the mixture was diluted with water, extracted with EA, the organic phase was washed with water, brine, dried over Na 2 SO 4 , removal the solvent to give crude product which was purified by silica gel to give 2′-ethyl-4-(5-oxopyrrolidin-3-yl)biphenyl-3-carbaldehyde (210 mg, 80.1% yield), Mass spec: 294 (M+1).

To a suspension of LAH (0.6225 g, 16.3 mmol) in 10 mL THF at 0° C. was added another solution of 2′-ethyl-4-(5-oxopyrrolidin-3-yl) biphenyl-3-carbaldehyde (1.6 g, 5.4 mmol) in 10 mL THF drop-wised. the mixture was refluxed for 2 h under N 2 , quenched with water (0.6 mL), NaOH (15%) (0.6 mL), and water (1.8 mL), filtered, the filtrate was concentrated to left 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 spec: 282 (M+1).

Intermediate 10: (2′-cyclopropyl-4-(pyrrolidin-3-yl)biphenyl-3-yl)methanol

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 dioxane was added 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 2 (400 mg, 0.89 mmol), the mixture was stirred at 100° C. for 2 h under N 2 . After reaction finished, diluted with water, extracted with EA, the organic layer was washed by water, brine, dried over Na2SO4, removal the solvent to give crude product (2.8 g, quant.) which can be used directly, Mass spec: 316 (M+H).

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/H 2 O (16 mL/1 mL) was added 1-cyclopropyl-2-iodobenzene

(2 g, 8.4 mmol), K 2 CO 3 (1.98 g, 14 mmol) and Pd(dppf)Cl 2 (200 mg, 0.7 mmol), the mixture was stirred at 100° C. for 5 h under N 2 , diluted with EA, the mixture was washed by water, brine, dried over Na 2 SO 4 , removal the solvent to left 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 spec: 321 (M+H).

The title compound was prepared following procedures described in intermediate 9 step 4 to give (2′-cyclopropyl-4-(pyrrolidin-3-yl)biphenyl-3-yl)methanol (200 mg, 50% yield), Mass spec: 294 (M+H).

The title compound was prepared following procedures described in example 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 spec: 354 (M+H).

To a solution of (S)-2-(1-(2-nitrophenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (2.8 g, 8 mmol) in MeOH/H2O (50 mL/50 mL) was added Fe powder and NH 4 Cl, stirred at 80° C. for 2 h, the mixture was filtered, 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 brown oil, Mass spec: 324 (M+H).

To a solution of (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)aniline (1.2 g, 3.7 mmol) in H2O/H2SO4con. (4 mL/4 mL) at 0° C. was added NaNO2 (384 mg, 5.5 mmol) in H2O (2 mL), and stirred at 80° C. for 2 h, the mixture was cooled down to rt, poured into ice-water, adjust the pH with NaHCO3 solution to 7, extracted with EA, dried over Na2SO4, removal the solvent to left 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 clarity oil. Mass spec: 325 (M+H), t R =2.298 min, 1 H-NMR (400 Hz, DMSO) 5=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)

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

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. was added NaH (44 mg, 0.22 mmol, 60% dispersion in mineral oil), and stirred for 30 min at rt before 2-iodopropane (81 mg, 0.48 mmol) was added, the mixture was stirred for 24 h, the mixture was diluted with EA, washed with LiCl solution, brine, dried over Na2SO4, removal the solvent to left the crude product which was purified by silica gel to give the (S)-2-(1-(2-isopropoxyphenyl) yrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (30 mg, 95% yield) as clarity oil. Mass spec: 367 (M+H), t R =3.402 min, 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).

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

The title compound was prepared following procedures 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 spec: 415 (M+H), t R =3.623 min, 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).

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

The title compound was prepared following procedures 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 spec: 393 (M+H), t R =3.691 min, 1 H-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).

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), it was stirred at 100° C. overnight. Quenched with water, extracted with EA, washed with LiCi solution, brine, dried over Na2SO4, removal the solvent to left crude (R)-2-(3-hydroxypyrrolidin-1-yl)benzonitrile (1.7 g, 111% yield) which was used the next step directly without further purification. Mass spec: 189 (M+H)

To a solution of (R)-2-(3-hydroxypyrrolidin-1-yl)benzonitrile (244 mg, 1.3 mmol) in dry DMF (2 mL) at 0° C. was add NaH (120 mg, 4 mmol, 60% dispersion in mineral oil), and stirred for 30 min at this temperature before 2,3-dichloro-5-(trifluoromethyl)pyridine (216 mg, 1 mmol) in 1 mL DMF was added, the mixture was stirred for 1 h at same temperature, the reaction mixture was poured into ice-water, extracted with EA, and organic layer was washed by LiCl solution, brine, dried over Na2SO4, removal the solvent to left 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 light yellow oil, Mass spec: 368 (M+H)

(R)-2-(3-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (100 mg, 0.27 mmol) was added to H2SO4 (con) at 0° C., the mixture was stirred overnight at rt. the reaction mixture was poured in ice-water, and adjust the ph with NaHCO3 solution to 7, extracted with EA, washed with brine, dried over Na2SO4, removal the solvent to left 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 spec: 386 (M+H), t R =2.665 min, 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)

The title compound was prepared following procedures 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 spec: 189 (M+H).

The title compound was prepared following procedures 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 spec: 368 (M+H).

The title compound was prepared following procedures 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 h to give (S)-2-(3-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (110 mg, 66.7% yield), Mass spec: 386 (M+H), t R =2.736 min, 1 H-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).

The title compound was prepared following procedures 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 spec: 350 (M+H).

The title compound was prepared following procedures described in example 16 (step 3) using (S)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzonitrile at 90° C. for 1.5 h to give (S)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzamide (60 mg, 51.9% yield), Mass spec: 368 (M+H), t R =2.774 min, 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).

The title compound was prepared following procedures 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 spec: 350 (M+H).

The title compound was prepared following procedures described in example 16 (step 3) using (R)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzonitrile at 90° C. for 1.5 h to give (R)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzamide (55 mg, 48% yield), Mass spec: 368 (M+H), t R =2.813 min, 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).

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

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 Rany-Nikel (100 mg wet), the mixture was stirred at 60° C. for 1 h under H2 atmosphere, filtered, removal the solvent, the residue was purified by silica gel to give the product, which was stirred in HCl/EA to obtain (R)-(2-(3-(5-(trifluoromethyl)pyridin-2-yloxy) pyrrolidin-1-yl)phenyl)methanamine HCl salt (20 mg, 53.6%). Mass spec: 338 (M+H), t R =1.758 min, 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).

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

The title compound was prepared following procedures described in example 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 spec: 412 (M+H)

The title compound was prepared following procedures 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 h to give (S)-5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (1.8 g, 82% yield), Mass spec: 430 (M+H).

To a solution of (S)-5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (42.9 mg, 0.1 mmol), Pd2(dba)3 (2.25 mg, 0.1 mmol) and dppf (5.78 mg, 0.1 mmol) in DMF (3 ml) was added Zn(Cn)2 (11.2 mg, 1 mmol), the mixture was stirred at 80° C. for 10 min with microwave, filtered, the filtrate was diluted by water, extracted with EA, washed by LiCl solution, brine, dried over Na2SO4, removal the solvent to left 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 spec: 377 (M+H), t R =2.386 min, 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).

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

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/H2O (1 mL/1 mL) was added K2CO3 (27.6 mg, 0.2 mmol) and PdCl2(dppf) (4 mg, 10% Wt), the mixture was stirred at 80° C. for 10 min with microwave, filtered, the filtrate was diluted by water, extracted with EA, washed by LiCi solution, brine, dried over Na2SO4, removal the solvent to left the crude product which 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 spec: 428 (M+H), t R =2.911 min, 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)

Example 23: (S)-2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (Compound 1-64)

The title compound was prepared following procedures described in example 22 using Dioxane/H2O as solvent to give (S)-2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (30 mg, 20% yield), Mass spec: 462 (M+H), t R =3.147 min, 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).

Example 24: (S)-4′-fluoro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (Compound 1-65)

The title compound was prepared following procedures described in example 22 using Dioxane/H2O as solvent to give (S)-4′-fluoro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (23 mg, 20% yield), Mass spec: 446 (M+H), t R =3.082 min, 1 H-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).

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

The title compound was prepared following procedures described in example 22 using DMF as solvent to give (S)-5-(pyridin-3-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (30 mg, 7% yield), Mass spec: 429 (M+H), t R =1.876 min, 1 H-NMR (400 Hz, DMSO) δ=8.847 (Is, 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).

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

The title compound was prepared following procedures described in example 22 using DMF as 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 spec: 429 (M+H), t R =1.712 min, 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).

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

The title compound was prepared following procedures described in example 22 using DMF as 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 spec: 429 (M+H), t R =1.720 min, 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).

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

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%), the mixture was stirred at rt for 12 h under H2 atmosphere, filtered, removal the solvent to left the crude product which was purified by silica gel, the product was stirred in HC/EA for 30 min, filtered, the solid was washed by Et2O to give (S)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide HCl salt (20 mg, 48% yield), Mass spec: 381 (M+H), t R =1.604 min, 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).

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

The title compound was prepared following procedures described in example 5 using Intermediate 3 and DBU as base to give (S)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbonitrile (20 mg, 50% yield), Mass spec: 410 (M+H), t R =3.528 min, 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).

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

The title compound was prepared following procedures 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 spec: 352 (M+H).

The title compound was prepared following procedures 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 spec: 370 (M+H). t R =2.578 min, 1 H-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).

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

The title compound was prepared following procedures 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 spec: 368 (M+H).

The title compound was prepared following procedures 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 spec: 386 (M+H). t R =2.694 min, 1 H-NMR (400 Hz, DMSO) δ=8.616 (s, 1H), 8.055-8.083 dd, 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).

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

The title compound was prepared following procedures 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 spec: 368 (M+H).

The title compound was prepared following procedures 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 spec: 386 (M+H). t R =2.666 min, 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).

Example 33: (S)-3-fluoro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-29)

The title compound was prepared following procedures 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 spec: 352 (M+H).

The title compound was prepared following procedures 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 spec: 370 (M+H). t R =2.757 min, 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).

Example 34: (R)-3-fluoro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-30)

The title compound was prepared following procedures 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 spec: 352 (M+H).

The title compound was prepared following procedures 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 spec: 370 (M+H). t R =0.742 min 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, 2 h), 7.246-7.327 (m, 2H), 6.823-6.845 (d, 1H), 5.776 (br, 11H), 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).

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

The title compound was prepared following procedures described in example 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 spec: 412 (M+H)

The title compound was prepared following procedures 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 h to give (R)-5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (780 mg, 83% yield), Mass spec: 430 (M+H).

The title compound was prepared following procedures described in example 16 (step 3) using (R)-5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide to give (R)-5-cyano-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (150 mg, 31% yield), Mass spec: 377 (M+H), t R =2.350 min, 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).

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

The title compound was prepared following procedures 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 spec: 428 (M+H), t R =2.909 min, 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)

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

The title compound was prepared following procedures 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 spec: 381 (M+H), t R =1.621 min, 1 H-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, 11H), 2.789-2.824 (m, 1H), 2.528-2.548 (m, 1H).

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), the mixture was heated to reflux for overnight, then quenched with water, extracted by EA, dried over Na2SO4, removal the solvent to left the crude 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 spec: 367 (M+H).

To a solution of (S)-methyl 2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoate (300 mg, 0.81 mmol) in THE was added NaOH solution (2 mL, 30%), the mixture was stirred at 60° C. for overnight, diluted with EA, adjust the pH with HCl (1N) to 3, the organic layer was washed by water, brine, dried over Na2SO4, removal the solvent to left 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 spec: 353 (M+H), t R =2.240 min, 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).

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

To a solution (S)-methyl 2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoate (40 mg, 0.11 mmol) in MeOH/MeNH2 aq. (1 mL/1 mL) was heated to 90° C. in a sealed tube for overnight. H2O (6 mL) was added, filtered, washed by water, 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 spec: 366 (M+H), t R =2.500 min, 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).

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

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)2 (64.28 mL, 0.51 mmol) and one drop DMF, the mixture was stirred at rt for 30 min, removal the solvent to give (S)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoyl chloride (130 mg, quant.) which can be used to next step directly.

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), the mixture was stirred at rt, after finished, diluted with DCM (10 mL), washed by water, brine, dried over Na2SO4, removal the solvent to give the crude product which 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 spec: 380 (M+H), t R =2.087 min, 1 H-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).

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

The title compound was prepared following procedures 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 spec: 442 (M+H), t R =3.080 min, 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, 11H), 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).

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

The title compound was prepared following procedures 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 spec: 394 (M+H), t R =2.896 min, 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).

Example 43: (S)—N,N-dibenzyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-52)

The title compound was prepared following procedures described in example (step 2) to give (S)—N,N-dibenzyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (27 mg, 34% yield), Mass spec: 532(M+H), t R =3.616 min, 1 H-NMR (400 Hz, DMSO) &=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).

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

The title compound was prepared following procedures 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 spec: 409(M+H), t R =3.544 min, 1 H-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).

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

The title compound was prepared following procedures 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 spec: 366(M+H), t R =2.637 min, 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).

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

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 rt, the mixture was heated to 100° C. for overnight, water was added, extracted by EA, washed by water, brine, dried over Na2SO4, removal the solvent to left the crude product which purified by silica gel to give (R)-methyl 2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoate (550 mg, 28%), Mass spec: 367 (M+H).

The title compound was prepared following procedures 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 spec: 353 (M+H), t R =2.180 min, 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

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

The title compound was prepared following procedures 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 spec: 366 (M+H), t R =2.571 min, 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).

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

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)2 (36.6 mg, 0.288 mmol) and one drop DMF, the mixture was stirred at rt, after finished, the solvent was removed to give (R)-2-(3-(5-(trifluoromethyl) pyridin-2-yloxy)pyrrolidin-1-yl)benzoyl chloride (quant.); 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 rt, after finished, quenched by water, extracted with EA, washed by water, brine, dried by Na2SO4, removal the solvent to left the crude product which 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 spec: 409 (M+H), t R =3.504 min, 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).

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

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 BnNH2 (45 mg, 0.41 mmol) in Toluene was added Al(Me)3 (2M in toluene, 0.41 mmol) at 110° C. for overnight, quenched with NH 4 Cl solution, extracted by DCM, washed with water, brine, dried over Na2SO4, removal the solvent to left 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 white solid. Mass spec: 442 (M+H), t 1 =3.090 min, 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).

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

The title compound was prepared following procedures 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 spec: 532(M+H), t R =3.618 min, 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).

Example 51: (R)—N-isopropyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-49)

The title compound was prepared following procedures 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 spec: 394 (M+H), t R =2.909 min, 1 H-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.)

Example 52: (R)—N,N-dimethyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-59)

The title compound was prepared following procedures 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 spec: 380 (M+H), t R =2.799 min, 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, 11H), 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).

Example 53: (R)—N,N-dimethyl-1-(2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl) methanamine hydrochloride (Compound 1-60)

The title compound was prepared following procedures 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 spec: 366(M+H), t R =1.988 min, 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).

The title compound was prepared following procedures described in example 5 to give (R)-2-(1-(2-nitrophenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridin (900 mg, 80% yield), Mass spec: 354 (M+H).

The title compound was prepared following procedures described in example 14 (step 2) to give (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)aniline (800 mg, quant.), Mass spec: 324 (M+H).

The title compound was prepared following procedures described in example 14 (step 2) to give (R)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenol (290 mg, 20% yield) as clarity oil. Mass spec: 325 (M+H), t R =1.380 min, 1 H-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).

Example 55: (R)-2-(1-(2-(benzyloxy)phenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-38)

The title compound was prepared following procedures 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 spec: 415 (M+H), t R =3.566 min, 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).

Example 56: (R)-2-(1-(2-(cyclopentyloxy)phenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-36)

The title compound was prepared following procedures 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 spec: 393 (M+H), t R =3.517 min, 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).

Example 57: (R)-2-(1-(2-isopropoxyphenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-37)

The title compound was prepared following procedures 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 spec: 393 (M+H), t R =3.213 min, 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).

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), Pd2(dba)3 (157 mg, 0.17 mmol), BINAP (107 mg, 0.17 mmol) in Toluene was added t-BuONa (165 mg, 1.72 mmol), the mixture was degassed with N2, then heated to 120° C. under microwave for 30 min, removal the solvent to left the crude product which was purified by silica gel to give 70 mg (22% yield), Mass spec: 385 (M+H), t R =3.719 min, 1 H-NMR (400 Hz, DMSO) 5=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).

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), Pd2(dba)3 (157 mg, 0.17 mmol), BINAP (107 mg, 0.17 mmol) in Toluene was added t-BuONa (165 mg, 1.72 mmol), the mixture was degassed with N2, then heated to 120° C. under microwave for 30 min, removal the solvent to left the crude product which was purified by silica gel to give 56 mg (17% yield), Mass spec: 385 (M+H), t R =3.710 min, 1 H-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).

Example 60: (S)-3-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 43)

The title compound was prepared following procedures described in example 5 to give 340 mg (72% yield), Mass spec: 367 (M+H).

The title compound was prepared following procedures described in example 16 (step 3) at 90° C. for 30 min to give (S)-3-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (70 mg, 20% yield), Mass spec: 386 (M+H), t R =2.867 min, 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).

Example 61: (R)-3-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-42)

The title compound was prepared following procedures described in example to give (R)-3-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (300 mg, 63% yield), Mass spec: 367 (M+H).

The title compound was prepared following procedures described in example 16 (step 3) at 90° C. for 30 min to give (R)-3-chloro-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (90 mg, 28.8% yield), Mass spec: 386 (M+H), t R =2.868 min, 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).

Example 62: (S)-5-(trifluoromethyl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-58)

Step 1: (S)-5-(trifluoromethyl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile

The title compound was prepared following procedures 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 spec: 402 (M+H), t R =3.348 min, 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).

The title compound was prepared following procedures described in example 6 with EtOH to give (S)-5-(trifluoromethyl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (45 mg, 42.9% yield), Mass spec: 420 (M+H), t R =3.646 min, 1 H-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).

Example 65: (S)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-carbonitrile (Compound 1-62)

The title compound was prepared following procedures described in example to give (S)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-carbonitrile (90 mg, 17% yield), Mass spec: 410 (M+H), t R =3.483 min, 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).

Example 66: (S)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-carboxamide (Compound 1-63)

The title compound was prepared following procedures 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 spec: 428 (M+H), t R =3.678 min, 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).

Example 67: (S)-2-(1-(3-nitrobiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-66)

The title compound was prepared following procedures described in example to give (S)-2-(1-(4-bromo-2-nitrophenyl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (3.7 g, 85% yield), Mass spec: 432 (M+H).

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/H2O (5 mL/1 mL) was added Pd(dppf)Cl2 (400 mg, 0.5 mmol) and K2CO3 (2 g, 15 mmol), the mixture was degassed by N2, and stirred at 90° C. for 2 h, diluted with EA, washed with water, brine, dried over Na2SO4, removal the solvent to left the 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 spec: 430 (M+H), t R =3.601 min, 1 H-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).

Example 68: (S)-2-(1-(3-methoxybiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-73)

The title compound was prepared following procedures 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 spec: 400 (M+H).

The title compound was prepared following procedures 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 spec: 401 (M+H).

The title compound was prepared following procedures described in example 15a to give (S)-2-(1-(3-methoxybiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (22 mg, 54% yield), Mass spec: 415 (M+H). t R =2.249 min, 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 (m, 1H), 3.283-3.316 (m, 1H), 2.331-2.352 (m, 1H), 2.150 (m, 1H).

Example 69: (S)-2-(1-(3-isopropoxybiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-77)

The title compound was prepared following procedures 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 spec: 443 (M+H). t R =3.874 min, 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).

Example 70: (S)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-2-carboxamide (Compound 1-72)

Step 1: (S)-2-bromo-6-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (YJ-000233-081)

The title compound was prepared following procedures described in example to give (S)-2-bromo-6-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (350 mg, 57% yield), Mass spec: 412 (M+H).

The title compound was prepared following procedures 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 spec: 430 (M+H).

The title compound was prepared following procedures 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 spec: 428 (M+H), t R =2.906 min, 1 H-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, 1H1).

The title compound was prepared following procedures described Intermediate 4 to give crude (S)-6-chloro-2-(pyrrolidin-3-yloxy)quinoline (1.7 g, 89% yield), Mass spec: 249 (M+H)

The title compound was prepared following procedures described in example 5 to give (S)-6-chloro-2-(1-(2-nitrophenyl)pyrrolidin-3-yloxy)quinoline (1.1 g, 67.5% yield), Mass spec: 370 (M+H), t R =3.495 min, 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).

The title compound was prepared following procedures described in example 14 (step 2) to give (S)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)aniline (420 mg, 54% yield), Mass spec: 340 (M+H), t R =3.081 min, 1 H-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).

The title compound was prepared following procedures described in example 14 (step 3) to give (S)-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)phenol (69 mg, 25% yield), Mass spec: 341 (M+H).

The title compound was prepared following procedures described in example 15a to give (S)-6-chloro-2-(1-(2-isopropoxyphenyl)pyrrolidin-3-yloxy)quinoline (33 mg, 43% yield), Mass spec: 383 (M+H). t R =40.596 min, 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, 11H), 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).

The title compound was prepared following procedures described in example 5 to give (S)-2-(1-(4-bromo-2-nitrophenyl)pyrrolidin-3-yloxy)-6-chloroquinoline (824 mg, 65.6% yield), Mass spec: 448 (M+H).

The title compound was prepared following procedures 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 spec: 446 (M+H), t R =4.551 min, 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).

The title compound was prepared following procedures 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 spec: 416 (M+H), t R =3.658 min, 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).

Example 76: (S)-4-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (Compound 1-67)

The title compound was prepared following procedures described in example 5 to give (S)-5-bromo-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzonitrile (270 mg, 63% yield), Mass spec: 428 (M+H).

The title compound was prepared following procedures 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 spec: 446 (M+H).

The title compound was prepared following procedures 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 spec: 444 (M+H), t R =4.144 min, 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, 11H).

Example 77: (R)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(pyridin-3-yl)benzamide hydrochloride (Compound 1-74)

The title compound was prepared following procedures 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 spec: 378 (M+H).

The title compound was prepared following procedures 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 spec: 396 (M+H).

The title compound was prepared following procedures 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 spec: 395 (M+H), t R =1.525 min, 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).

The title compound was prepared following procedures 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 spec: 394 (M+H), t R =2.741 min, 1 H-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).

Example 79: (R)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(pyridin-4-yl)benzamide hydrochloride (Compound 1-82)

The title compound was prepared following procedures 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 spec: 395 (M+H), t R =1.161 min, 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).

Example 80: (R)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(pyridin-2-yl)benzamide (Compound 1-85)

The title compound was prepared following procedures 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 spec: 395 (M+H), t R =1.540 min, 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).

The title compound was prepared following procedures 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 spec: 344 (M+H).

The title compound was prepared following procedures 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 spec: 362 (M+H).

The title compound was prepared following procedures 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 spec: 360 (M+H), t R =2.491 min, 1 H-NMR (400 Hz, DMSO) 5=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).

The title compound was prepared following procedures 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 spec: 361 (M+H), t R =0.700 min, 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).

Example 83: (R)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(pyridin-3-yl)benzamide hydrochloride (Compound 1-87)

The title compound was prepared following procedures 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 spec: 361 (M+H), t R =2.116 min, 1 H-NMR (400 Hz, DMSO) δ=8.843 (s, 1H), 8.461-8.473 (d, 11H), 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).

The title compound was prepared following procedures 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 spec: 361 (M+H), t R =1.474 min, 1 H-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).

Example 85: (R)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-amine (Compound 1-93)

The title compound was prepared following procedures 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 spec: 400 (M+H). t R =3.387 min, 1 H-NMR (400 Hz, DMSO) δ=8.599-8.606 (m, 1H), 8.056-8.084 (dd, 1H), 7.520-7.541 (M, 2 h), 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, 11H), 5.615 (br, 1H), 4.762 (s, 1H), 3.544-3.583 (m, 1H), 3.266-3.299 (m, 11H), 3.118-3.153 (m, 1H), 3.014-3.069 (m, 1H), 2.422-2.509 (m, 1H), 2.030-2.051 (m, 1H).

Example 86: (R)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-ol (Compound 1-89)

The title compound was prepared following procedures 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 spec: 401 (M+H), t R =3.186 min, 1 H-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).

Example 87: (R)-2-(1-(3-methoxybiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-111)

The title compound was prepared following procedures 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 spec: 415 (M+H), t R =3.631 min, 1H-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).

Example 88: (R)-2-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yloxy)ethanol (Compound 1-117)

Step 1: (R)-ethyl 2-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yloxy)acetate

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 by NaHCO3 solution, LiCl solution, and brine, dried over Na2SO4, removal the solvent to left the residue which 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 spec: 487 (M+H).

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) at 0° C. was added LiBH4 (3 mg, 0.16 mmol), the mixture was stirred at rt for 2 h, cooled to 0° C., extracted with DCM, washed with NH4Cl, dried over Na2SO4, removal the solvent to left the 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 spec: 445 (M+H), t R =3.087 min, 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).

Example 89: (S)-ethyl 2-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yloxy)acetate (Compound 134)

The title compound was prepared following procedures 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 spec: 487 (M+H), t R =3.400 min, 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).

Example 90: (S)-2-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yloxy)ethanol (Compound 135)

The title compound was prepared following procedures 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 spec: 445 (M+H), t R =2.922 min, 1 H-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).

Example 91: (R)-5-(4,5-dihydro-1H-imidazol-2-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 100)

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. under microwave for 10 min, then poured into ice water, which caused the product to precipitates 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 spec: 420 (M+H), t R =0.429 min, 1 H-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).

Example 92: (R)-5-(1H-imidazol-2-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-107)

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)Cl2 (21 mg, 10% wt), the mixture was degassed with N2, then heated to 80° C. for 3 h, EA was added, filtered, the organic layer was washed by water, brine, dried over Na2SO4, removal the solvent to get the crude product which could be used directly. The crude product (48 mg, 0.1 mmol) in Dioxane/H2O (5 mL/1 mL) was added 2-iodo-1-trityl-1H-imidazole (38 mg, 2 mmol) (prepared according to PCT 2008096360), Pd(dppf)Cl2 (5 mg, 10% wt) and K2CO3, the mixture was stirred at 100° C. for 1 h, diluted with EA, washed with water, brine, dried over Na2SO4, removal the solvent to left 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 spec: 418 (M+H), t R =2.622 min, 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).

Example 93: (R)-5-(trifluoromethyl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-84)

To 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 DMF was stirred at 100° C. for 2 h, the mixture was washed with LiCi solution, extracted with EA, dried over Na2SO4, evaporated to give the intermediate product as brown oil, which, dissolved in 12 mL EtOH, was added H2O2 (6 mL, 30%) and NaOH solution (12 mL, 6M), stirred at 60° C. for overnight, the mixture was poured into ice-water, the precipitate was filtered, washed by Et20, and dried to give (R)-5-(trifluoromethyl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (200 mg, 47.6% yield), Mass spec: 420 (M+H), t R =2.855 min, 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).

Example 94: (S)-5-phenoxy-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-124)

The 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), Cs2CO3 (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 for 1 h, diluted with EA, washed with water, brine, dried over Na2SO4, removal the solvent to left the crude (S)-5-phenoxy-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (220 mg) which can be used directly, Mass spec: 426 (M+H).

The title compound was prepared following procedures 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 spec: 444 (M+H), t R =3.098 min, 1 H-NMR (400 Hz, DMSO) δ=8.617 (s, 11H), 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).

Example 95: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanamine hydrochloride (Compound 1-125)

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 MeOH was added CoCl2 (206 mg, 1.6 mmol) and NaBH4 (304 mg, 8 mmol) at 0° C., the mixture was stirred at rt, for 12 h, the reaction mixture was filtered, the filtrate was quenched with NH3·H2O, extracted with DCM, dried over Na2SO4, removal the solvent to left the residue which was purified by silica gel, then Prep-HPLC, freezing dryness with HCl to give (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanamine hydrochloride (9 mg, 3%), Mass spec: 380 (M+H), t R =2.177 min, 1 H-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).

Example 96: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (Compound 1-126)

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) at −78° C. was added DIBAL-H (10 ml, 15M in Tol.), the mixture was stirred at this temperature for 3 h, quenched by ice water, extracted with DCM, dried over Na2SO4, removal the solvent to left the residue which was purified by silica gel to give (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbaldehyde (90 mg, 15%), Mass spec: 379 (M+H).

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 NaBh4 (23 mg, 0.72 mmol) at 0° C., the mixture was stirred at rt for 10 min, quenched by NH4Cl solution, extracted with EA, washed by brine, dried over Na2SO4, removal the solvent to left the 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 spec: 381 (M+H), t R =3.035 min, 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).

Example 97: (R)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-amine (Compound 1-116)

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/H2O (21 ml/7 mL) was added Zn (1.4 g, 21.6 mmol) and FeCL3 (175 mg, 1.08 mmol), the mixture was stirred at rt for 3 h, diluted with DCM, filtered and the filtrate was extracted with DCM, washed LiCl solution, dried over na2SO4, removal the solvent to left the residue which 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 spec: 434 (M+H), t R =3.472 min, 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).

Example 98: (R)-2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-ol (Compound 1-113)

The title compound was prepared following procedures 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% yield), Mass spec: 435 (M+H), t R =3.242 min, 1 H-NMR (400 Hz, CDCl3) δ=8.427-8.433 (q, 1H), 7.775-7.803 (m, 1H), 7.432-7.455 (m, 1H), 7.172-7.131 (m, 3H), 7.035-7.039 (m, 1H), 6.944-6.968 (m, 1H), 6.846-6.868 (d, 1H), 5.574-5.706 (m, 1H), 3.624-3.666 (m, 1H), 3.335-3.426 (m, 2H), 3.210-3.238 (m, 1H), 2.505-2.557 (m, 1H), 2.224-2.244 (m, 1H).

Example 99: (R)-2-(1-(2′-chloro-3-methoxybiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-112)

The title compound was prepared following procedures described in example 15a to give (R)-2-(1-(2′-chloro-3-methoxybiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (43 mg, 40% yield), Mass spec: 449 (M+H). t R =3.676 min, 1 H-NMR (400 Hz, CDCl3) δ=8.464-8.470 (q, 1H), 7.767-7.795 (d, 1H), 7.461-7.485 (d, 1H), 7.289-7.385 (m, 3H), 6.997-7.019 (m, 2H), 6.822-6.842 (d, 1H), 5.693-5.733 (m, 1H), 3.969-4.012 (m, 1H), 3.878 (s, 3H), 3.627-3.688 (m, 1H), 3.446-3.568 (m, 1H), 3.413-3.437 (m, 1H), 2.400-2.420 (m, 1H), 2.260-2.269 (m, 1H).

Example 100: (S)-2-(2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yloxy)ethanol (Compound 1-133)

Step 1: (S)-ethyl 2-(2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yloxy)acetate

The title compound was prepared following procedures described in example 89 to give (S)-ethyl 2-(2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yloxy)acetate (143 mg, 90% yield), Mass spec: 521 (M+H).

Step 2: (S)-2-(2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yloxy)ethanol

The title compound was prepared following procedures described in example 90 to give (S)-2-(2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yloxy)ethanol (130 mg, quant.), Mass spec: 479 (M+H), t R =3.003 min, 1 H-NMR (400 Hz, DMSO) δ=8.622 (s, 1H), 8.060-8.089 (q, 1H), 7.509-7.530 (m, 1H), 7.313-7.414 (m, 3H), 6.910-7.044 (m, 3H), 6.739-6.759 (d, 1H), 5.666 (br, 1H), 4.817-4.843 (t, 11H), 3.916-4.018 (m, 3H), 3.701-3.741 (m, 2H), 3.603-3.620 (m, 1H), 3.518-3.581 (m, 1H), 3.336-3.345 (m, 1H), 2.169-2.353 (m, 1H), 2.145-2.154 (m, 1H).

Example 101: (R)-4-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (Compound 1-86)

The title compound was prepared following procedures described in example 5 to give (R)-5-bromo-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzonitrile (410 mg, 47% yield), Mass spec: 428 (M+H).

The title compound was prepared following procedures described in example 64 (step 2) to give (R)-5-bromo-2-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)benzamide (370 mg, 86% yield), Mass spec: 446 (M+H).

The title compound was prepared following procedures described in example 67 (step 2) to give (R)-4-(3-(6-chloroquinolin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (80 mg, 36% yield), Mass spec: 444 (M+H), t R =3.20 min, 1 H-NMR (400 Hz, DMSO) δ=8.226-8.249 (d, 1H), 8.030-8.036 (d, 1H), 7.796-7.875 (m, 2H), 7.687-7.709 (m, 1H), 7.530-7.611 (m, 4H), 7.343-7.434 (m, 2H), 7.285 (s, 1H), 7.248-7.267 (m, 1H), 7.060-7.248 (d, 1H), 6.855-6.878 (d, 1H), 5.826 (br, 1H), 3.912-3.954 (m, 1H), 3.581-3.599 (m, 1H), 3.401-3.438 (m, 1H), 3.335 (m, 1H), 2.372 (m, 1H), 2.275-2.281 (m, 1H).

Example 102: (S)—N-tert-butyl-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-sulfonamide (Compound 1-96)

The solution of 1-bromo-4-fluorobenzene (2.0 mL, 17.2 mmol) in HSO3Cl (10 mL) was heated to 100° C. for 2.5 h, the reaction was drop-wised to ice water, and filtered, the solid was dried under vacuum to give 5-bromo-2-fluorobenzene-1-sulfonyl chloride (3.5 g, 76%). To a solution of 2-methylpropan-2-amine (1.36 g, 18.5 mmol) in 5 mL THF at 0° C. was added 5-bromo-2-fluorobenzene-1-sulfonyl chloride (1 g, 3.7 mmol), the mixture was stirred at rt for 2 h, diluted with EA, washed by water, brine, dried over Na2SO4, removal the solvent to left the residue which was purified by silica gel to give 5-bromo-N-tert-butyl-2-fluorobenzenesulfonamide (1 g, 87% yield), Mass spec: 310 (M+H).

The title compound was prepared following procedures described in example 67 (step 2) to give N-tert-butyl-4-fluorobiphenyl-3-sulfonamide (250 mg, 80.6% yield), Mass spec: 308 (M+H).

Step 3: (S)—N-tert-butyl-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-sulfonamide

To a solution of (R)-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine hydrochloride (153 mg, 0.5 mmol) and N-tert-butyl-4-fluorobiphenyl-3-sulfonamide (174 mg, 0.75 mmol) in 3 mL Dioxane was added DBU (300 mg, 2 mmol), the mixture was stirred at 130° C. for overnight, cooled down to rt, water was added, extracted with EA, dried over Na2SO4, removal the solvent to left the residue which was purified by silica gel to give (S)—N-tert-butyl-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-sulfonamide (40 mg, 15% yield), Mass spec: 520 (M+H), t R =3.639 min, 1 H-NMR (400 Hz, DMSO) δ=8.623 (s, 1H), 8.809-8.125 (m, 2H), 7.841-7.675 (m, 1H), 7.656-7.675 (m, 2H), 7.471-7.508 (m, 3H), 7.360-7.396 (m, 1H), 7.028-7.046 (m, 2H), 5.697 (br, 1H), 3.797-3.838 (m, 1H), 3.573-3.613 (m, 1H), 3.499-3.527 (m, 1H), 3.301-3.314 (m, 1H), 2.456-2.473 (m, 1H), 2.111-2.144 (m, 1H), 1.158 (s, 9H).

A solution of (S)—N-tert-butyl-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-sulfonamide (35 mg, 0.06 mmol) in 2 mL CF3COOH was heated to 40° C. for 5 h, the mixture was treated with NaHCO3 solution to pH to 7, extracted with DCM, dried over Na2SO4, removal the solvent to left residue which was purified by silica gel to give 1-(biphenyl-4-yl)-3-(quinolin-2-yloxy)pyrrolidin-2-one (15 mg, 50% yield), as white solid, Mass spec: 464 (M+H), t R =3.183 min, 1 H-NMR (400 Hz, DMSO) δ=8.622 (s, 1H), 8.801-8.148 (m, 2H), 7.790-7.816 (m, 1H), 7.650-7.696 (m, 2H), 7.462-7.500 (m, 3H), 7.322-7.382 (m, 4H), 7.019-7.040 (m, 1H), 5.694 (br, 1H), 3.905-3.945 (m, 1H), 3.515-3.605 (m, 2H), 3.386-3.436 (m, 1H), 2.414-2.434 (m, 1H), 2.165-2.175 (m, 1H).

To a solution of biphenyl-4-amine (34 mg, 0.2 mmol) in 2 mL DCM at 0° C. was added AlMe3 (0.5 mL, 2M in Tol), the mixture was stirred at rt for 1 h before 3-(quinolin-2-yloxy)dihydrofuran-2(3H)-one (45.8 mg, 0.2 mmol) was added, the mixture was stirred at rt for overnight, quenched by water, extracted with DCM, the organic layer was washed by water, brine, dried over Na2SO4, removal the solvent to left residue which was purified by silica gel to give N-(biphenyl-4-yl)-4-hydroxy-2-(quinolin-2-yloxy)butanamide (40 mg, 50% yield), Mass spec: 399 (M+H).

To a solution of DIAD (60 mg, 0.3 mmol) and (n-Bu)3P (60 mg, 0.3 mmol) in 2 mL THF was stirred at 0° C. for 30 min, before N-(biphenyl-4-yl)-4-hydroxy-2-(quinolin-2-yloxy)butanamide (40 mg, 0.1 mmol) was added, the mixture was stirred at rt for 2 h, quenched by water, extracted with EA, dried over Na2SO4, removal the solvent to left the residue which was purified by re-crystallized form Et20 and hexane to give N-(biphenyl-4-yl)-4-hydroxy-2-(quinolin-2-yloxy)butanamide (21 mg, 55% yield) as white solid, Mass spec: 381 (M+H), t R =3.197 min, 1 H-NMR (400 Hz, DMSO) δ=8.321-8.344 (d, 1H), 7.684-7.947 (m, 9H), 7.348-7.498 (m, 4H), 7.134-7.155 (m, 1H), 6.063-6.106 (t, 1H), 3.988-4.022 (m, 2H), 2.839-2.891 (m, 1H), 2.183-2.237 (m, 1H).

The title compound was prepared following procedures described in example 104 (step 1) to give N-(2-cyanophenyl)-4-hydroxy-2-(quinolin-2-yloxy)butanamide (160 mg, 70.3% yield), Mass spec: 348 (M+H).

The title compound was prepared following procedures described in example 104 (step 2) to give 2-(2-oxo-3-(quinolin-2-yloxy)pyrrolidin-1-yl)benzonitrile (90 mg, 59% yield), Mass spec: 330 (M+H), t R =2.566 min, 1 H-NMR (400 Hz, CD3OD) δ=8.168-8.172 (d, 1H), 7.769-7.864 (m, 4H), 7.614-7.671 (m, 2H), 7.517-7.558 (m, 1H), 7.409-7.449 (m, 1H), 7.053-7.075 (d, 1H), 6.093-6.135 (t, 1H4), 4.019-4.093 (m, 2H), 3.019-3.023 (m, 1H), 2.359-2.413 (m, 1H).

The title compound was prepared following procedures described in example 64 (step 2) to give 2-(2-oxo-3-(quinolin-2-yloxy)pyrrolidin-1-yl)benzamide (25 mg, 50% yield), Mass spec: 348 (M+H), t R =1.968 min, 1 H-NMR (400 Hz, CD3OD) 5=8.308-8.330 (d, 1H), 7.918-7.941 (m, 1H), 7.710-7.808 (m, 3H), 7.365-7.588 (m, 6H), 7.113-7.135 (d, 1H), 5.931-5.795 (t, 1H), 3.841-3.864 (m, 2H), 2.826-2.857 (m, 1H), 2.144-2.198 (m, 1H).

The title compound was prepared following procedures described in example 104 (step 1) to give 4-hydroxy-N-phenyl-2-(quinolin-2-yloxy)butanamide (130 mg, 91% yield), Mass spec: 323 (M+H).

The title compound was prepared following procedures described in example 104 (step 2) to give 1-phenyl-3-(quinolin-2-yloxy)pyrrolidin-2-one (45 mg, 47% yield), Mass spec: 305 (M+H), t R =2.785 min, 1 H-NMR (400 Hz, DMSO) δ=8.304-8.326 (d, 1H), 7.913-7.933 (m, 1H), 7.686-7.743 (m, 4H), 7.407-7.468 (m, 3H), 7.194-7.210 (m, 1H), 7.111-7.133 (d, 1H), 6.025-6.068 (t, 1H), 3.930-3.956 (m, 2H), 2.802-2.855 (m, 1H), 2.138-2.220 (m, 1H).

The title compound was prepared following procedures described in example 104 (step 1) to give N-(2-chlorophenyl)-4-hydroxy-2-(quinolin-2-yloxy)butanamide (120 mg, 51.8% yield), Mass spec: 357 (M+H).

The title compound was prepared following procedures described in example 104 (step 2) to give 1-(2-chlorophenyl)-3-(quinolin-2-yloxy)pyrrolidin-2-one (20 mg, 21% yield), Mass spec: 339 (M+H), t R =2.747 min, 1 H-NMR (400 Hz, DMSO) δ=8.304-8.326 (d, 1H), 7.913-7.918 (m, 1H), 7.791-7.802 (m, 1H), 7.518-7.522 (m, 1H), 7.441-7.478 (m, 5H), 7.111-7.133 (d, 1H), 6.062-6.066 (t, 1H), 3.768-3.853 (m, 2H), 2.849-2.855 (m, 1H), 2.215-2.229 (m, 1H).

The title compound was prepared following procedures described in example 104 (step 1) to give N-(3-cyanobiphenyl-4-yl)-4-hydroxy-2-(quinolin-2-yloxy)butanamide (400 mg, 38% yield), Mass spec: 424 (M+H).

The title compound was prepared following procedures described in example 104 (step 2) to give 4-(2-oxo-3-(quinolin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbonitrile (300 mg, 75% yield), Mass spec: 406 (M+H), t R =3.005 min, 1 H-NMR (400 Hz, DMSO) 6=8.327-8.349 (d, 1H), 8.252-8.257 (d, 1H), 8.120-8.141 (d, 1H), 7.929-7.950 (d, 1H), 7.714-7.826 (m, 5H), 7.451-7.539 (m, 4H), 7.149-7.171 (d, 11H), 6.104-6.148 (t, 1H), 4.053-4.097 (m, 1H), 3.961-4.001 (m, 1H), 2.907-2.942 (m, 11H), 2.263-2.317 (m, 1H).

Example 113: 2′-chloro-4-(2-oxo-3-(quinolin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (Compound 1-114)

The title compound was prepared following procedures described in example 64 (step 2) to give 2′-chloro-4-(2-oxo-3-(quinolin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (18 mg, 39% yield), Mass spec: 458 (M+H), t R =2.629 min, 1 H-NMR (400 Hz, DMSO) δ=8.316-8.338 (d, 1H), 7.926-7.946 (m, 1H), 7.822-7.861 (m, 2H), 7.655-7.738 (m, 4H), 7.413-7.631 (m, 6H), 7.129-7.151 (d, 1H), 5.959-6.004 (t, 1H), 3.901-3.938 (m, 2H), 2.858-2.890 (m, 1H), 2.177-2.232 (m, 1H).

The compound 4-(2-oxo-3-(quinolin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbonitrile (70 mg, 0.17 mmol) in concentrate HCl was heated to 50° C. for 7 h, water was added, filtered and got the crude as light yellow solid, washed with ether, to give the pure 4-(2-oxo-3-(quinolin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (40 mg, 60%), Mass spec: 424 (M+H), t R =2.685 min, 1 H-NMR (400 Hz, DMSO) δ=8.314-8.336 (d, 1H), 7.924-7.968 (m, 2H), 7.820-7.924 (m, 3H), 7.698-7.750 (m, 3H), 7.498-7.552 (m, 4H), 7.421-7.484 (m, 2H), 7.124-7.146 (d, 1H), 5.951-5.995 (t, 1H), 3.897-3.902 (m, 2H), 2.891-2.896 (m, 1H), 2.197-2.204 (m, 1H).

Example 117: (R)-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanamine hydrochloride (Compound 1-109)

To a solution of (R)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbonitrile (50 mg, 0.12 mmol) (prepared as example 67) in 15 mL MeOH and 1.5 mL DCM was added Pd/C (20 mg), and stirred at rt under H2 atmosphere for 2 d, filtered, removal the solvent to left the residue which was purified by Prep-HPLC to give (R)-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanamine hydrochloride (20 mg, 37% yield), Mass spec: 414 (M+H), t R =2.291 min, 1 H-NMR (400 Hz, DMSO) δ=8.622 (s, 1H), 8.441-8.483 (br, 3H), 8.087-8.115 (m, 1H), 7.830-7.835 (m, 1H), 7.620-7.699 (m, 3H), 7.444-7.483 (m, 2H), 7.318-7.354 (m, 1H), 7.211-7.2322 (m, 1H), 7.057-7.079 (m, 1H), 5.690-5.697 (m, 1H), 4.131-4.220 (m, 2H), 3.670-3.709 (m, 1H), 3.411-3.470 (m, 1H), 3.199-3.295 (m, 2H), 2.164-2.478 (m, 1H, 2.126-2.152 (m, 1H).

Example 118: (R)-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (Compound 1-110)

The title compound was prepared following procedures described in example 96 (step 1) to give (R)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbaldehyde (30 mg, 29% yield), Mass spec: 413 (M+H).

The title compound was prepared following procedures described in example 96 (step 2) to give (R)-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (18 mg, 62% yield), Mass spec: 415 (M+H), t R =3.269 min, 1 H-NMR (400 Hz, DMSO) δ=8.622-8.625 (d, 1H), 8.069-8.098 (q, 1H), 7.591-7.682 (m, 3H), 7.286-7.472 (m, 4H), 7.037-7.059 (d, 1H), 6.939-6.961 (d, 1H), 5.667 (br, 1H), 5.127-5.155 (t, 1H), 4.561-4.588 (m, 2H), 3.721-3.749 (m, 1H), 3.366-3.472 (m, 2H), 3.261-3.263 (m, 1H), 2.379-2.406 (m, 1H), 2.134-2.172 (m, 1H).

Example 119: (S)-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (Compound 1-115)

The title compound was prepared following procedures described in example 96 (step 1) using example 29 to give (S)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbaldehyde (57 mg, 28% yield), Mass spec: 413 (M+H).

The title compound was prepared following procedures described in example 96 (step 2) to give (S)-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (31 mg, 53% yield), Mass spec: 415 (M+H), t R =3.141 min, 1 H-NMR (400 Hz, DMSO) δ=8.622 (s, 11H), 8.067-8.095 (q, 1H), 7.590-7.681 (m, 3H), 7.408-7.471 (m, 3H), 7.266-7.303 (m, 1H), 7.035-7.057 (d, 1H), 6.939-6.951 (d, 1H), 5.660-5.667 (m, 1H), 5.132-5.159 (t, 1H), 4.561-4.589 (m, 2H), 3.720-3.761 (m, 1H), 3.377-3.494 (m, 2H), 3.262-3.229 (m, 1H), 2.510-2.514 (m, 1H), 2.386-2.405 (m, 1H).

Example 120: 1-(4-((S)-3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)ethanol 121)

To a solution of (S)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbaldehyde (70 mg, 0.17 mmol) in 3 mL THF was added MeMgbr (0.15 mL, 3M in THF) at 0° C., the mixture was stirred at rt for overnight, quenched by water, extracted by DCM, dried over Na2SO4, removal the solvent to left the residue which was purified by Prep-HPLC to give 1-(4-((S)-3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)ethanol (40 mg, 54% yield), Mass spec: 429 (M+H), t R =2.837 min, 1 H-NMR (400 Hz, DMSO) δ=8.614 (s, 1H), 8.073-8.091 (d, 1H), 7.768-7.774 (m, 1H), 7.595-7.616 (m, 2H), 7.438-7.459 (m, 3H), 7.308-7.328 (m, 1H), 7.056-7.105 (m, 2H), 5.641 (br, 1H), 5.121-5.137 (m, 2H), 2.594-3.672 (m, 2H), 3.151-3.217 (m, 2H), 2.409-2.436 (m, 1H), 2.096-2.118 (m, 1H), 1.337-1.426 (m, 3H).

Example 121: (S)-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanamine (Compound 1-119)

The title compound was prepared following procedures described in example 95 to give (S)-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanamine (19 mg, 17% yield), Mass spec: 414 (M+H), t R =2.409 min, 1 H-NMR (400 Hz, DMSO) δ=8.622 (s, 1H), 8.290-8.352 (br, 3H), 8.095-8.110 (d, 1H), 7.794 (s, 1H), 7.616-7.686 (m, 3H), 7.448-7.486 (m, 2H), 7.321-7.358 (m, 1H), 7.210-7.231 (d, 1H), 8.050-7.071 (d, 1H), 5.675-5.696 (m, 1H), 4.158-4.214 (m, 2H), 3.655-3.711 (m, 1H), 3.196-3.283 (m, 2H), 2.425-2.474 (m, 1H), 2.130-2.162 (m, 1H).

Example 122: (S)-(2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanamine (Compound 1-118)

The title compound was prepared following procedures described in example 95 to give (S)-(2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanamine (30 mg, 20% yield), Mass spec: 448 (M+H), t R =2.300 min, 1 H-NMR (400 Hz, DMSO) 5=8.609 (s, 1H), 8.346 (br, 3H), 8.077-8.105 (d, 1H), 7.512-7.567 (m, 2H), 7.382-7.425 (m, 3H), 7.192-7.213 (d, 1H), 7.048-7.070 (d, 1H), 5.687 (br, 1H), 4.135-4.164 (m, 1H), 3.444-3.466 (m, 2H), 3.280-3.304 (m, 1H), 2.418 (m, 1H), 2.088-2.207 (m, 1H).

Example 123: (S)—N-((2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methyl)acetamide (Compound 1-127)

To a solution of (S)-(2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanamine (50 mg, 0.11 mmol) (Example 122) in 1 mL DCM was added Ac2O (7 drops), the mixture was stirred rt for 2 h, quenched by water, extracted with DCM, dried over Na2SO4, removal the solvent to left the residue which was purified by Prep-HPLC to give (S)—N-((2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methyl)acetamide (20 mg, 37% yield) Mass spec: 490 (M+H), t R =3.196 min, 1 H-NMR (400 Hz, DMSO) δ=8.621-8.623 (d, 1H), 8.253-8.281 (m, 1H), 8.073-8.101 (m, 1H), 7.526-7.547 (m, 1H), 7.351-7.408 (m, 3H), 7.258-7.257 (m, 2H), 7.031-7.064 (m, 2H), 5.649-5.677 (m, 1H), 4.314-4.346 (m, 2H), 3.711-3.752 (m, 1H), 3.453-3.494 (m, 1H), 3.289-3.318 (m, 1H), 3.207-3.249 (m, 1H), 2.442-2.519 (m, 1H), 2.128-2.392 (m, 1H), 2.186 (s, 3H).

Example 124: (S)-(2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (Compound 1-132)

Step 1: (S)-2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbaldehyde

The title compound was prepared following procedures described in example 96 (step 1) using example 29 to give (S)-2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbaldehyde (60 mg, 11% yield), Mass spec: 447 (M+H).

Step 2: (S)-(2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol

The title compound was prepared following procedures described in example 96 (step 2) to give (S)-(2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (40 mg, 66% yield), Mass spec: 449 (M+H), t R =3.039 min, 1 H-NMR (400 Hz, DMSO) δ=8.625-8.628 (d, 1H), 8.071-8.099 (d, 1H), 7.521-7.524 (d, 1H)m 7.362-7.450 (m, 4H), 7.276-7.279 (m, 1H), 7.039-7.061 (d, 1H), 6.920-6.942 (d, 1H), 5.665 (br, 1H), 5.142 (t, 1H), 4.558 (m, 2H), 3.765-3.804 (m, 1H), 3.471-3.519 (m, 1H), 3.402-3.416 (m, 1H), 3.280-3.295 (m, 1H), 2.391-2.403 (m, 1H), 2.122-2.146 (m, 1H).

Example 125: (S)-(2′-chloro-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanamine hydrochloride (Compound 1-122)

To a solution of (S)-2′-chloro-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbonitrile (328 mg, 0.8 mmol) (prepared as example 29) in 5 mL MeOH was added CoCl2 (206 mg, 1.6 mmol) and NaBH4 (304 mg, 8 mmol) at 0° C., the mixture was stirred at rt for 12 h, the reaction mixture was filtered, the filtrate was quenched with NH3·H2O, extracted with DCM, dried over Na2SO4, removal the solvent to left the residue which was purified by silica gel, then Prep-HPLC, freezing dryness with HCl to give (S)-(2′-chloro-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanamine hydrochloride (12 mg, 3%), Mass spec: 414 (M+H), t R =1.667 min, 1 H-NMR (400 Hz, CDCl3) δ=8.952 (br, 3H), 7.971-8.019 (m, 2H), 7.875-7.894 (m, 1H), 7.787-7.807 (m, 1H), 7.659-7.676 (m, 2H), 7.278-7.297 (m, 1H), 7.217-7.257 (m, 1H), 7.104-7.171 (m, 1H), 6.895-6.922 (m, 1H), 5.822 (br, 1H), 4.980-4.994 (m, 1H), 4.692-4.806 (m, 2H), 4.487-4.493 (m, 1H), 3.574-3.605 (m, 2H), 2.702 (m, 1H), 2.403-2.434 (m, 1H).

Example 126: (R)-3-chloro-2-(1-(3-methoxybiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (Compound 1-120)

The title compound was prepared following procedures described in example 14 (step 2) using (R)-3-chloro-2-(1-(3-nitrobiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (prepared as example 67) to give (R)-4-(3-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-amine (291 mg, 78% yield), Mass spec: 464 (M+H).

The title compound was prepared following procedures described in example 14 (step 3) to give (R)-4-(3-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-ol (48 mg, 16% yield), Mass spec: 435 (M+H).

The title compound was prepared following procedures described in example 68 (step 3) to give (R)-3-chloro-2-(1-(3-methoxybiphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (8.6 mg, 17% yield), Mass spec: 449 (M+H), t R =3.737 min, 1 H-NMR (400 Hz, DMSO) δ=8.580-8.582 (d, 1H), 8.368-8.373 (d, 1H), 7.592-7.610 (d, 2H), 7.366-7.405 (m, 2H), 7.230-7.267 (m, 1H), 7.123-7.160 (m, 2H), 6.754-6.774 (d, 1H), 5.685 (br, 1H), 3.824-3.912 (m, 1H), 3.744 (s, 3H), 3.511-3.550 (m, 1H), 3.395-3.425 (m, 1H), 3.211-3.271 (m, 1H), 2.297-2.367 (m, 1H), 2.131-2.163 (m, 1H).

Example 127: (S)-(2′-methyl-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (Compound 1-128)

Step 1: (S)-2′-methyl-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbonitrile

The title compound was prepared following procedures described in example 67 (step 2) to give (S)-2′-methyl-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbonitrile (433 mg, 70% yield), Mass spec: 424 (M+H).

Step 2: (S)-2′-methyl-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbaldehyde

The title compound was prepared following procedures described in example 96 (step 1) to give (S)-2′-methyl-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbaldehyde (150 mg, 74% yield), Mass spec: 427 (M+H).

Step 3: (S)-(2′-methyl-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol

The title compound was prepared following procedures described in example 96 (step 2) to give (S)-(2′-methyl-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (70 mg, 46% yield), Mass spec: 429 (M+H), t R =3.337 min, 1 H-NMR (400 Hz, DMSO) δ=8.625 (s, 1H), 8.073-8.101 (d, 1H), 7.347 (s, 1H), 7.181-7.260 (m, 3H), 7.119-7.144 (m, 2H), 7.042-7.065 (d, 1H), 6.922-6.943 (d, 1H), 5.659-5.666 (m, 1H), 5.093-5.122 (t, 1H), 4.544-4.570 (m, 2H), 3.709-3.751 (m, 1H), 3.462-3.483 (m, 1H), 3.377-3.379 (m, 1H), 3.247-3.259 (m, 1H), 2.410-2.413 (m, 1H), 2.256 (s, 1H), 2.184-2.190 (m, 1H).

Example 128: (S)-(4-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (Compound 1-131)

The title compound was prepared following procedures described in example 5 using (S)-3-methyl-2-(pyrrolidin-3-yloxy)pyridine (prepared as Intermediate 3) and 5-bromo-2-fluorobenzonitrile to give (S)-5-bromo-2-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (2.3 g, 82% yield), Mass spec: 358 (M+H)

The title compound was prepared following procedures described in example 67 (step 2) to give (S)-4-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbonitrile (750 mg, 75% yield), Mass spec: 356 (M+H).

The title compound was prepared following procedures described in example 96 (step 1) to give (S)-4-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbaldehyde (150 mg, 42% yield), Mass spec: 356 (M+H).

The title compound was prepared following procedures described in example 96 (step 2) to give (S)-(4-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (75 mg, 69% yield), Mass spec: 361 (M+H), t R =2.687 min, 1 H-NMR (400 Hz, DMSO) δ=8.001-8.018 (m, 1H), 7.678-7.683 (m, 1H), 7.536-7.606 (m, 3H), 7.406-7.467 (m, 3H), 7.282-7.300 (m, 1H), 6.882-6.963 (m, 2H), 5.598 (br, 1H), 5.135-5.163 (t, 1H), 4.562-4.593 (m, 2H), 3.701-3.726 (m, 1H), 3.474-3.478 (m, 1H), 3.294-3.321 (m, 2H), 2.505-2.514 (m, 1H), 2.128-2.131 (m, 4H).

Example 129: (S)-(4-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (Compound 1-129)

The title compound was prepared following procedures described in example 5 using (S)-3-chloro-2-(pyrrolidin-3-yloxy)pyridine (prepared as Intermediate 3) and 5-bromo-2-fluorobenzonitrile to give (S)-5-bromo-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (5.4 g, 90% yield), Mass spec: 378 (M+H)

The title compound was prepared following procedures described in example 94 (step 1) to give (S)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-phenoxybenzonitrile (129 mg, 50% yield), Mass spec: 392 (M+H)

The title compound was prepared following procedures described in example 94 (step 2) to give (S)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-phenoxybenzonitrile (11 mg, 8% yield), Mass spec: 410 (M+H), t R =2.642 min, 1 H-NMR (400 Hz, DMSO) δ=8.151 (s, 1H), 7.949 (br, 1H), 7.896-7.919 (m, 1H), 7.329-7.378 (m, 3H), 6.877-7.090 (7H), 5.630-5.653 (m, 1H), 3.800-3.846 (m, 1H), 3.480-3.484 (m, 1H), 3.268-3.331 (m, 2H), 2.319-2.352 (m, 1H), 2.171-2.175 (m, 1H).

Example 184: (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)-N-phenylbenzamide (Compound 1-320)

The title compound was prepared following procedures described in Step 2 of Example 178 to give (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-formyl-N-methoxy-N-methylbenzamide (2.2 g, 56% yield), Mass spec: 390 (M+H).

Step 2: (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-N-methoxy-3-(2-methoxyvinyl)-N-methylbenzamide

The title compound was prepared following procedures described in Step 2 of Example 168 to give (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-N-methoxy-3-(2-methoxyvinyl)-N-methylbenzamide (2.4 g, 85% yield), Mass spec: 418 (M+H).

To a solution of aniline (46 mg, 0.5 mmol) was added n-BuLi (0.24 ml, 2.5 M in hexane) at ice water bath, the mixture was stirred for 30 min at this temperature, before (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-N-methoxy-3-(2-methoxyvinyl)-N-methylbenzamide (104 mg, 0.25 mmol) was added, then return to rt slowly, quenched by NH 4 Cl solution, EA was added, washed by brine, removal the solvent to left the crude (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-methoxyvinyl)-N-phenylbenzamide (50 mg, 44% yield), Mass spec: 418 (M+H).

The title compound was prepared following procedures described in Step 3 of Example 168 to give (S)-(S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-oxoethyl)-N-phenylbenzamide (30 mg, 62% yield), Mass spec: 436 (M+H).

The title compound was prepared following procedures described in Step 4 of Example 168 to give (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)-N-phenylbenzamide (10 mg, 48.9% yield), Mass spec: 438 (M+H), t R =2.479 min, 1 H-NMR (400 Hz, DMSO) δ=9.335 (s, 1H), 8.159-8.172 (m, 1H), 7.905-7.925 (m, 1H), 7.737-7.901 (m, 4H), 7.310-7.350 (m, 2H), 7.036-7.083 (m, 2H), 6.931-6.953 (m, 1H), 5.661-5.686 (br, 1H), 4.675-4.901 (t, 1H), 3.828-3.869 (m, 1H), 3.588-3.701 (m, 3H), 3.309-3.363 (m, 2H), 2.514-2.938 (m, 2H), 2.191-2.496 (m, 2H).

Example 185: (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)-N-methyl-N-phenylbenzamide (Compound 1-337)

Step 1: (S,Z)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-methoxyvinyl)-N-methyl-N-phenylbenzamide

To a solution of (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-methoxyvinyl)-N-phenylbenzamide (100 mg, 0.22 mmol) (example 184 step 3) in 4 mL THF was added NaH (17.6 mg, 0.44 mmol) at 0° C., the mixture was stirred for 20 min at rt, then MeI (62 mg, 0.44 mmol) was added, stirred for another 30 min, quenched by water, extracted with EA, washed by water, brine, dried over Na2SO4, removal the solvent to give crude (S,Z)-4-(3-(3-chioropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-methoxyvinyl)-N-methyl-N-phenylbenzamide (80 mg, 78%) which can be used directly, Mass spec: 464 (M+H).

The title compound was prepared following procedures described in Example 184 (step 4) to give (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-N-methyl-3-(2-oxoethyl)-N-phenylbenzamide (70 mg, 85% yield), Mass spec: 450 (M+H).

Step 2: (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)-N-methyl-N-phenylbenzamide

The title compound was prepared following procedures described in Example 184 (step 5) to give (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)-N-methyl-N-phenylbenzamide (20 mg, 85% yield), Mass spec: 452 (M+H), t R =2.559 min, 1 H-NMR (400 Hz, DMSO) δ=8.123-8.140 (m, 1H), 7.883-7.906 (m, 1H), 7.270-7.308 (m, 2H), 7.123-7.187 (m, 3H), 6.997-7.048 (m, 3H), 6.658-6.679 (d, 1H), 5.581-5.592 (br, 1H), 4.569-4.595 (t, 1H), 3.671-3.712 (m, 1H), 3.414-3.475 (m, 3H), 3.346 (s, 3H), 3.155-3.213 (m, 2H), 2.593-2.652 (m, 2H), 2.277-2.325 (m, 1H), 2.087-2.101 (m, 1H).

Example 186: (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-N-(4-fluorophenyl)-3-(2-hydroxyethyl)benzamide (Compound 1-319)

The title compound was prepared following procedures described in Example 184 to give (S)-4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-N-(4-fluorophenyl)-3-(2-hydroxyethyl)benzamide (15 mg, 48.9% yield), Mass spec: 456 (M+H), t R =2.618 min, 1 H-NMR (400 Hz, DMSO) δ=10.001 (s, 1H), 8.160-8.172 (m, 1H), 7.903-7.926 (m, 1H), 7.728-7.904 (m, 4H), 7.152-7.197 (m, 2H), 7.037-7.069 (m, 1H), 6.929-6.950 (m, 1H), 5.661-5.686 (br, 1H), 4.683-4.709 (t, 1H), 3.829-3.870 (m, 1H), 3.590-3.709 (m, 3H), 3.309-3.347 (m, 2H), 2.864-2.937 (m, 2H), 2.176-2.509 (m, 2H).

Example 189: 2-(5-((3-chlorophenyl)(hydroxy)methyl)-2-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)ethanol (Compound 1-329)

The title compound was prepared following procedures described in example 168 to give 2-(5-((3-chlorophenyl)(hydroxy)methyl)-2-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)ethanol (32 mg, 34% yield), Mass spec: 459(M+H), t R =2.523 min 1 H-NMR (400 Hz, DMSO) δ=8.126-8.130 (m, 1H), 7.883-7.907 (m, 1H), 7.401 (s, 1H), 7.165-7.321 (m, 4H), 6.930-7.093 (m, 3H), 5.864-5.874 (d, 1H), 5.569-5.620 (m, 2H), 4.623-4.650 (t, 1H), 3.576-3.638 (m, 3H), 3.328-3.352 (m, 1H), 3.074-3.157 (m, 2H), 2.765-2.801 (m, 2H), 2.339-2.449 (m, 1H), 2.065-2.081 (m, 1H).

Example 190: (S)-(3-chlorophenyl)(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl) phenyl)methanone (Compound 1-328)

The title compound was prepared following procedures described in example 169 to give (S)-(3-chlorophenyl)(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)phenyl)methanone (26 mg, 34% yield), Mass spec: 457(M+H), t R =3.025 min 1 H-NMR (400 Hz, DMSO) δ=8.156-8.160 (m, 1H), 7.901-7.924 (m, 1H), 7.488-7.700 (m, 6H), 7.040-7.071 (m, 1H), 6.878-6.900 (d, 1H), 5.069-5.701 (br, 1H), 4.660-4.686 (t, 1H), 3.934-3.974 (m, 3H), 3.554-3.703 (m, 3H), 3.448-3.490 (m, 2H), 2.840-2.971 (m, 2H), 2.325-2.360 (m, 1H), 2.196-2.009 (m, 1H).

Example 191: (S)-(2-chlorophenyl)(3-(hydroxymethyl)-4-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)phenyl) methanone (Compound 1-332)

To a solution of (S)-5-(2-chlorobenzoyl)-2-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)benzaldehyde (100 mg, 0.25 mmol)(prepared as 168 step 1 (WLX-000371-012)) in 2 mL MeOH was added NaBH4 (29 mg, 0.75 mmol) with stirring for 20 min at 0° C., after finished, quenched by water, extracted with EA, washed by brine, dried over Na2SO4, filtered and removal the solvent to give crude product which was purified by Prep-HPLC to give (S)-(2-chlorophenyl)(3-(hydroxymethyl)-4-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)phenyl) methanone (15 mg, 14% yield), Mass spec: 409 (M+H), t R =2.604 min, 1 H-NMR (400 Hz, DMSO) δ=8.179-8.195 (m, 1H), 7.692-7.725 (m, 2H), 7.449-7.583 (m, 3H), 7.369-7.396 (m, 2H), 6.989-7.006 (m, 1H), 6.799-6.821 (d, 1H), 6.722-6.744 (d, 1H), 5.622-5.633 (br, 1H), 5.221-5.249 (t, 1H), 4.470-4.598 (m, 2H), 3.979-4.020 (m, 1H), 3.616-3.709 (m, 3H), 2.197-2.272 (m, 1H), 2.182-2.190 (m, 1H).

Example 192: (2-chlorophenyl)(3-(hydroxymethyl)-4-((S)-3-(pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (Compound 1-338)

The title compound was prepared following procedures described in example 191 at 0° C. for 1 h to give (2-chlorophenyl)(3-(hydroxymethyl)-4-((S)-3-(pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (10 mg, 48% yield), Mass spec: 411 (M+H), t R =1.325 min, 1 H-NMR (400 Hz, DMSO) δ=8.153-8.171 (m, 1H), 7.672-7.716 (m, 2H), 7.351-7.392 (m, 3H), 7.235-7.277 (m, 1H), 7.039-7.076 (m, 11H), 6.821-6.925 (m, 1H), 6.723-6.821 (m, 2H), 5.850-5.927 (m, 2H), 5.507-5.537 (m, 1H), 5.041-5.067 (m, 1H), 4.437-4.464 (m, 1H), 3.558-3.599 (m, 1H), 3.304-3.321 (m, 1H), 3.089-3.198 (m, 2H), 2.293-2.343 (m, 1H), 2.010-2.044 (m, 1H).

Example 193: (2-chlorophenyl)(4-((S)-3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)methanol (Compound 1-264)

To a solution of (S)-5-(2-chlorobenzoyl)-2-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)benzaldehyde (170 mg, 0.4 mmol)(prepared as 168 step 1 (XXL-000382-079)) in 4 mL MeOH was added NaBH4 (46 mg, 1.2 mmol) with stirring for 20 min at 0° C., after finished, quenched by water, extracted with EA, washed by brine, dried over Na2SO4, filtered and removal the solvent to give crude product which was purified by Prep-HPLC to give (2-chlorophenyl)(4-((S)-3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)methanol (53 mg, 31% yield), Mass spec: 429 (M+H), t R =2.477 min, 1 H-NMR (400 Hz, DMSO) δ=7.977-7.987 (m, 1H), 7.654-7.713 (m, 1H), 7.352-7.390 (m, 3H), 7.238-7.276 (m, 1H), 7.004-7.085 (m, 2H), 6.810-6.836 (d, 1H), 5.882-5.927 (m, 2H), 5.579 (br, 1H1), 5.074-5.099 (t, 1H), 4.445-4.470 (m, 2H), 3.578-3.619 (m, 1H1), 3.337-3.369 (m, 1H), 3.221-3.248 (m, 1H), 3.115-3.138 (m, 1H), 2.330-2.380 (m, 1H), 2.057-2.089 (m, 1H).

Example 194: (S)-(2-chlorophenyl)(4-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)methanone (Compound 1-265)

To a solution of (S)-5-(2-chlorobenzoyl)-2-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)benzaldehyde (170 mg, 0.4 mmol)(prepared as 168 step 1 (XXL-000382-079)) in 4 mL THE was added LiAlH(t-BuO)3 (203 mg, 0.8 mmol) with stirring for 2 h at 30° C., after finished, quenched by water, extracted with EA, washed by brine, dried over Na2SO4, filtered and removal the solvent to give crude product which was purified by Prep-HPLC to give (2-chlorophenyl)(4-((S)-3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)methanol (41 mg, 24% yield), Mass spec: 427 (M+H), t R =2.742 min, 1 H-NMR (400 Hz, DMSO) δ=8.001-8.011 (m, 1H), 7.665-7.711 (m, 2H), 7.449-7.585 (m, 3H), 7.387-7.403 (m, 2H), 7.044-7.051 (m, 1H), 6.736-6.758 (d, 1H), 5.706 (br, 1H), 5.243 (t, 1H), 4.475-4.602 (m, 2H), 4.016-4.052 (m, 1H), 3.631-3.742 (m, 3H), 2.312-2.331 (m, 1H), 2.234-2.236 (m, 1H).

Example 195: (2-chlorophenyl)(4-((S)-3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)methanol (Compound 1-321 & 322)

The title compound was prepared following procedures described in example 193 and separated by SFC to give peak1 and peak2, Mass spec: 429 (M+H), t R =2.450 min (peak1) and t R =2.188 min (peak2), 1 H-NMR (400 Hz, DMSO)

Peak 1: δ=7.977-7.987 (m, 1H), 7.652-7.714 (m, 2H), 7.352-7.393 (m, 3H), 7.257-7.277 (m, 1H), 7.013-7.074 (m, 2H), 6.814-6.835 (d, 1H), 5.858-5.931 (m, 2H), 5.599 (br, 1H), 5.060 (t, 1H), 4.456-4.460 (m, 2H), 3.577-3.618 (m, 1H), 3.345-3.377 (m, 1H), 3.224-3.251 (m, 1H), 3.117-3.130 (m, 1H), 2.346-2.350 (m, 1H), 2.079-2.082 (m, 1H).

Peak 2: δ=7.974-7.990 (m, 1H), 7.680-7.708 (m, 2H), 7.354-7.392 (m, 3H), 7.256-7.272 (m, 1H), 7.025-7.068 (m, 2H), 6.818-6.839 (d, 1H), 5.857-5.936 (m, 2H), 5.606 (br, 1H), 5.057 (t, 1H), 4.442-4.468 (m, 2H), 3.590-3.592 (m, 1H), 3.341-3.360 (m, 1H), 3.222-3.244 (m, 1H), 3.108-3.131 (m, 1H), 2.331-2.381 (m, 1H), 2.057-2.097 (m, 1H).

Example 196: (2-chlorophenyl)(4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)methanol (Compound 1-262)

The title compound was prepared following procedures described in example 193 to give (2-chlorophenyl)(4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)methanol (56.7 mg, 28% yield), Mass spec: 445 (M+H), t R =2.627 min, 1 H-NMR (400 Hz, DMSO) δ=8.125-8.142 (m, 1H), 7.882-7.905 (m, 1H), 7.694-7.712 (m, 1H), 7.350-7.396 (m, 3H), 7.251-7.275 (m, 1H), 7.009-7.068 (m, 2H), 6.816-6.840 (d, 1H), 5.890-5.933 (m, 2H), 5.570-5.584 (br, 1H), 5.081-5.111 (t, 1H), 4.443-4.472 (m, 2H), 3.574-3.615 (m, 1H), 3.336-3.372 (m, 1H), 3.197-3.224 (m, 1H), 3.116-3.129 (m, 1H), 2.321-2.372 (m, 1H), 2.037-2.070 (m, 1H).

Example 197: (S)-(2-chlorophenyl)(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)methanone (Compound 1-263)

The title compound was prepared following procedures described in example 194 to give (S)-(2-chlorophenyl)(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)methanone (37 mg, 20.9% yield), Mass spec: 443 (M+H), t R =2.864 min, H-NMR (400 Hz, DMSO) δ=8.152-8.164 (m, 1H), 7.894-7.913 (m, 1H), 7.717 (s, 1H), 7.466-7.584 (m, 3H), 7.371-7.388 (m, 2H), 7.035-7.065 (m, 1H), 6.743-6.764 (d, 1H), 5.690 (br, 1H), 5.230-5.256 (t, 1H), 4.473-4.601 (m, 2H), 4.014-4.054 (m, 1H), 3.610-3.716 (m, 3H), 2.304-2.326 (m, 1H), 2.210-2.214 (m, 1H).

Example 198: (4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(2-ethylphenyl)methanol (Compound 1-260)

The title compound was prepared following procedures described in example 193 to give (4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(2-ethylphenyl)methanol (20 mg, 30% yield), Mass spec: 439 (M+H), t R =2.606 min, 1 H-NMR (400 Hz, DMSO) δ=7.975-7.987 (m, 1H), 7.655-7.702 (m, 1H), 7.462-7.475 (m, 1H), 7.337-7.343 (m, 1H), 7.136-7.185 (m, 3H), 7.002-7.035 (m, 2H), 6.812-6.832 (m, 1H), 5.818-5.828 (m, 1H), 5.594 (br, 2H), 5.046-5.059 (t, 1H), 4.440-4.465 (m, 2H), 3.567-3.608 (m, 1H), 3.212-3.238 (m, 1H), 3.106-3.119 (m, 1H), 2.618-2.654 (m, 1H), 2.507-2.553 (m, 2H), 2.334-2.368 (m, 1H), 2.070-2.087 (m, 1H), 1.056-1.094 (t, 3H).

Example 199: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(2-ethylphenyl)methanone (Compound 1-251)

The title compound was prepared following procedures described in example 194 to give (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(2-ethylphenyl)methanone (30 mg, 36% yield), Mass spec: 437 (M+H), t R =2.923 min, 1 H-NMR (400 Hz, DMSO) δ=8.001-8.013 (m, 1H), 7.670-7.733 (m, 2H), 7.264-7.448 (m, 4H), 7.164-7.183 (m, 1H), 7.028-7.069 (m, 1H), 6.733-6.755 (m, 1H), 5.701 (br, 1H), 5.223-5.250 (t, 1H), 4.465-4.592 (m, 2H), 3.995-4.035 (m, 1H), 3.604-3.717 (m, 3H), 2.506-2.550 (m, 2H), 2.298-2.331 (m, 1H), 2.223-2.230 (m, 1H), 1.035-1.073 (t, 3H).

Example 200: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(o-tolyl)methanone & (4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(o-tolyl)methanol (Compound 1-246 & 247)

The title compoundS were prepared in one pot by reducing the (S)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-methylbenzoyl)benzaldehyde (84 mg, 0.2 mmol)(prepared as example 168 step 1) with NaBH4 (46 mg, 1.2 mmol) in MeOH at rt for 1 h.

Compound 246: (18 mg, 21% yield), Mass spec: 423 (M+H), t R =2.969 min, 1 H-NMR (400 Hz, DMSO) δ=8.153-8.170 (m, 1H), 7.902-7.925 (m, 1H), 7.707-7.712 (m, 1H), 7.197-7.442 (m, 5H), 7.039-7.070 (m, 1H), 6.751-6.772 (d, 1H), 5.684 (br, 1H), 5.246 (t, 1H), 4.457-4.586 (m, 2H), 3.995-4.036 (m, 1H), 3.603-3.698 (m, 3H), 2.294-2.335 (m, 1H), 2.158-2.208 (m, 4H).

Compound 247: (20 mg, 23% yield), Mass spec: 425 (M+H), t R =2.614 min, 1 H-NMR (400 Hz, DMSO) δ=8.125-8.142 (m, 1H), 7.884-7.907 (m, 1H), 7.502-7.521 (m, 1H), 7.332-7.347 (s, 1H), 7.010-7.213 (m, 5H), 6.819-6.840 (d, 1H), 5.742-5.752 (m, 1H), 5.561-5.608 (m, 1H), 5.078-5.103 (t, 1H), 4.439-4.492 (m, 2H), 3.566-3.507 (m, 1H), 3.334-3.373 (m, 1H), 3.191-3.218 (m, 1H), 3.104-3.132 (m, 1H), 2.326-2.376 (m, 1H), 2.187 (s, 3H), 2.028-2.082 (m, 1H).

Example 201: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(2-ethylphenyl)methanone & (4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(2-ethylphenyl)methanol (Compound 1-256 & 257)

The title compound XXL-000328-069A & XXL-000328-069B was prepared following procedures described in example 200.

Compound 256: (31 mg, 20% yield), Mass spec: 437 (M+H), t R =3.096 min, 1 H-NMR (400 Hz, DMSO) δ=8.150-8.162 (t, 1H), 7.894-7.914 (t, 1H), 7.732-7.736 (d, 1H), 7.159-7.445 (m, 5H), 7.032-7.063 (m, 1H), 6.735-6.757 (d, 1H), 5.678 (br, 1H), 5.283-5.310 (t, 1H), 4.458-4.588 (m, 2H), 3.990-4.031 (m, 1H), 3.577-3.694 (m, 3H), 2.489-2.546 (m, 2H), 2.288-2.322 (m, 1H), 2.171-2.205 (m, 4H), 1.031-1.068 (t, 3H).

Compound 257: (37 mg, 24% yield), Mass spec: 439 (M+H), t R =2.751 min, 1 H-NMR (400 Hz, DMSO) δ=8.126-8.142 (m, 1H), 7.884-7.907 (m, 1H), 7.453-7.481 (m, 1H), 7.333-7.349 (m, 1H), 7.116-7.187 (m, 3H), 7.002-7.043 (m, 2H), 6.819-6.840 (d, 1H), 5.819-5.830 (m, 1H), 5.577-5.588 (m, 1H), 5.035-5.062 (t, 1H), 4.444-4.472 (m, 2H), 3.564-3.605 (m, 1H), 3.189-3.222 (m, 1H), 3.110-3.123 (m, 1H), 2.617-2.640 (m, 1H), 2.512-2.559 (m, 2H), 2.330-2.364 (m, 1H), 2.078-2.084 (m, 1H), 1.056-1.096 (t, 3H).

Example 202: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(p-tolyl)methanone (Compound 1-277)

The title compound was prepared following procedures described in example 194 to give (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(p-tolyl)methanone (60 mg, 61% yield), Mass spec: 423 (M+H), t R =2.954 min, 1 H-NMR (400 Hz, DMSO) δ=8.155-8.172 (m, 1H), 7.897-7.919 (m, 1H), 7.770-7.776 (d, 1H), 7.547-7.585 (m, 3H), 7.324-7.344 (m, 2H), 7.037-7.068 (m, 1H), 6.801-6.823 (d, 1H), 5.689-5.694 (m, 1H), 5.208-5.234 (t, 1H), 4.497-4.623 (m, 2H), 3.980-4.020 (m, 1H), 3.570-3.693 (m, 3H), 2.402 (s, 3H), 2.315-2.348 (m, 1H), 2.205-2.213 (m, 1H).

Example 203: (4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(p-tolyl)methanol (Compound 1-287)

The title compound was prepared following procedures described in example 193 to give (4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(p-tolyl)methanol (40 mg, 50% yield), Mass spec: 421 (M+H), t R =2.587 min, 1 H-NMR (400 Hz, DMSO) δ=8.126-8.142 (m, 1H), 7.885-7.908 (m, 1H), 7.369 (s, 1H), 7.210-7.230 (m, 2H), 7.011-7.095 (m, 4H), 6.830-6.851 (d, 1H), 5.567-5.630 (m, 3H), 5.037 (t, 1H), 4.449-4.462 (m, 2H), 3.573-3.587 (m, 1H), 3.315-3.340 (m, 1H), 3.177-3.204 (m, 1H), 3.096-3.098 (m, 1H), 2.348-2.363 (m, 1H), 2.250 (s, 3H), 2.033-2.067 (m, 1H).

Example 204: (S)-(4-chlorophenyl)(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)methanone (Compound 1-288)

The title compound was prepared following procedures described in example 194 to give (S)-(4-chlorophenyl)(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)methanone (50 mg, 50% yield), Mass spec: 443 (M+H), t R =3.037 min, 1 H-NMR (400 Hz, DMSO) δ=8.158-8.174 (m, 1H), 7.901-7.924 (m, 1H), 7.764-7.769 (d, 1H), 7.551-7.663 (m, 5H), 7.040-7.072 (m, 1H), 6.798-6.820 (d, 1H), 5.695 (br, 1H), 5.225-5.252 (t, 1H), 4.532-4.595 (m, 2H), 4.004-4.045 (m, 1H), 3.603-3.711 (m, 3H), 2.311-2.346 (m, 1H), 2.206-2.221 (m, 1H).

Example 205: (4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(4-(methoxymethyl)phenyl)methanol (Compound 1-290)

The title compound was prepared following procedures described in example 193 to give (4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(4-(methoxymethyl)phenyl)methanol (35 mg, 38% yield), Mass spec: 455 (M+H), t R =2.320 min, 1 H-NMR (400 Hz, DMSO) δ=8.127-8.144 (m, 1H), 7.887-7.910 (m, 1H), 7.216-7.387 (m, 3H), 7.104-7.132 (m, 2H), 7.013-7.045 (m, 2H), 6.835-6.855 (m, 1H), 5.704-5.714 (d, 1H), 5.578-5.619 (m, 2H), 5.041-5.068 (t, 1H), 4.450-4.477 (m, 2H), 4.353 (s, 2H), 3.564-3.590 (m, 1H), 3.328-3.351 (m, 1H), 3.255 (s, 3H), 3.099-3.187 (m, 2H), 2.330-2.366 (m, 1H), 2.064-2.068 (m, 1H).

Example 206: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(4-(methoxymethyl)phenyl)methanone (Compound 1-288)

The title compound was prepared following procedures described in example 194 to (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(4-(methoxymethyl)phenyl)methanone (32 mg, 49% yield), Mass spec: 453 (M+H), t R =2.746 min, 1 H-NMR (400 Hz, DMSO) δ=8.159-8.175 (m, 1H), 7.901-7.925 (m, 1H), 7.778-7.783 (d, 1H), 7.639-7.659 (d, 2H), 7.556-7.584 (m, 1H), 7.452-7.472 (m, 2H), 7.040-7.072 (m, 1H), 6.806-6.872 (d, 1H), 5.693 (br, 1H), 5.215-5.243 (t, 1H), 4.497-4.625 (m, 4H), 3.991-4.031 (m, 1H), 3.585-3.071 (m, 3H), 3.322 (s, 3H), 2.327-2.349 (m, 1H), 2.210-2.223 (m, 1H).

Example 207: (4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(4-fluorophenyl)methanol (Compound 1-278)

The title compound was prepared following procedures described in example 193 to give (4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(4-fluorophenyl)methanol (30 mg, 38% yield), Mass spec: 429 (M+H), t R =2.513 min, H-NMR (400 Hz, DMSO) δ=8.127-8.143 (m, 1H), 7.883-7.907 (m, 1H), 7.352-7.387 (m, 3H), 7.084-7.128 (m, 3H), 7.011-7.043 (m, 1H), 6.841-6.862 (d, 1H), 5.754-5.764 (d, 1H), 5.627-5.637 (m, 1H), 5.582 (br, 1H), 5.035-5.062 (t, 1H), 4.459-4.485 (m, 2H), 3.561-3.615 (m, 1H), 3.341-3.380 (m, 1H), 3.101-3.222 (m, 2H), 2.331-2.382 (m, 1H), 2.039-2.074 (m, 1H).

Example 208: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(4-fluorophenyl)methanone (Compound 1-279)

The title compound was prepared following procedures described in example 194 to (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(4-fluorophenyl)methanone (30 mg, 39% yield), Mass spec: 427 (M+H), t R =2.869 min, 1 H-NMR (400 Hz, DMSO) δ=8.159-8.174 (m, 1H), 7.901-7.920 (m, 1H), 7.722-7.774 (m, 3H), 7.548-7.574 (m, 1H), 7.337-7.381 (m, 2H), 7.040-7.071 (m, 1H), 6.805-6.827 (m, 2H), 5.695 (br, 1H), 5.221-5.248 (t, 1H), 4.502-4.630 (m, 2H), 3.997-4.038 (m, 1H), 3.577-3.707 (m, 3H), 2.315-2.349 (m, 1H), 2.210-2.219 (m, 1H).

Example 209: (2-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-((4-fluorophenyl)(methoxy)methyl) phenyl)methanol (Compound 1-289)

To a solution of (4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(4-fluorophenyl)methanol (42 mg, 0.1 mmol) in 2 mL MeOH was added 1 mL HCl/MeOH (2N), and the mixture was stirred at room temperature for 30 min, removal the solvent to left to crude product which was purified by Prep-HPLC to give (2-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-((4-fluorophenyl)(methoxy)methyl)phenyl)methanol (20 mg, 45% yield), Mass spec: 443 (M+H), t R =2.963 min, 1 H-NMR (400 Hz, DMSO) δ=8.126-8.143 (m, 1H), 7.883-7.906 (m, 1H), 7.335-7.370 (m, 3H), 7.024-7.161 (m, 4H), 6.841-6.861 (d, 1H), 5.573-5.601 (m, 1H), 5.251 (s, 1H), 5.064-5.091 (t, 1H), 4.459-4.489 (t, 2H), 3.596-3.637 (m, 1H), 3.364-3.383 (m, 1H), 3.234-3.245 (m, 4H), 3.124-3.178 (m, 1H), 2.322-2.371 (m, 1H), 2.048-2.081 (m, 1H).

Example 210: (S)-(4-fluorophenyl)(4-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl) phenyl)methanone (Compound 1-293)

The title compound was prepared following procedures described in example 194 to give (S)-(4-fluorophenyl)(4-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)methanone (25 mg, 83% yield), Mass spec: 411 (M+H), t R =2.682 min, 1 H-NMR (400 Hz, DMSO) δ=8.010-8.025 (m, 1H), 7.681-7.769 (m, 4H), 7.548-7.576 (m, 1H), 7.342-7.387 (m, 2H), 7.055-7.062 (m, 1H), 6.800-6.822 (d, 1H), 5.714 (br, 1H), 5.247 (t, 1H), 4.505-4.625 (m, 2H), 4.002-4.044 (m, 1H), 33.599-3.712 (m, 3H), 2.335-2.355 (m, 1H), 2.215-2.246 (m, 1H).

Example 211: (S)-(4-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(p-tolyl)methanone (Compound 1-300)

The title compound was prepared following procedures described in example 194 to give (S)-(4-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(p-tolyl)methanone (20 mg, 50% yield), Mass spec: 407 (M+H), t R =2.766 min, 1 H-NMR (400 Hz, DMSO) δ=8.008-8.020 (m, 1H), 7.666-8.005 (m, 2H), 7.546-7.583 (m, 3H), 7.326-7.346 (m, 2H), 7.032-7.072 (m, 1H), 6.798-6.819 (d, 1H), 5.709 (br, 1H), 5.201-5.228 (t, 1H), 4.499-4.623 (m, 2H), 3.982-4.023 (m, 1H), 3.574-3.691 (m, 3H), 2.358 (s, 3H), 2.245-2.336 (m, 11H), 2.229-2.238 (m, 1H).

Example 212: (4-((S)-3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(o-tolyl)methanol (Compound 1-231)

The title compound was prepared following procedures described in example 193 to give (4-((S)-3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(o-tolyl)methanol (30 mg, 43% yield), Mass spec: 409 (M+H), t R =2.456 min, 1 H-NMR (400 Hz, DMSO) δ=7.972-7.987 (m, 1H), 7.652-7.699 (m, 1H), 7.328-7.339 (m, 1H), 7.193 (m, 1H), 7.003-7.193 (m, 5H), 6.812-6.833 (m, 1H), 5.737-5.746 (d, 1H), 5.575-5.585 (m, 2H), 5.060 (t, 1H), 4.448-4.463 (m, 2H), 3.579-3.607 (m, 1H), 3.337-3.361 (m, 1H), 3.099-3.238 (m, 2H), 2.330-2.363 (m, 1H), 2.179-2.184 (s, 3H), 2.067-2.079 (m, 1H).

Example 213: (S)-(4-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(o-tolyl)methanone (Compound 1-243)

The title compound was prepared following procedures described in example 194 to give (S)-(4-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(o-tolyl)methanone (20 mg, 20% yield), Mass spec: 407 (M+H), t R =2.775 min, H-NMR (400 Hz, DMSO) δ=8.004-8.015 (m, 1H), 7.673-8.707 (m, 2H), 7.200-7.442 (m, 5H), 7.033-7.072 (m, 1H), 6.774-6.766 (m, 1H), 5.702 (br, 1H), 5.222-5.249 (t, 1H), 4.498-4.559 (m, 2H), 3.998-4.038 (m, 1H), 3.605-3.718 (m, 3H), 2.301-2.335 (s, 1H), 2.181-2.227 (m, 4H).

Example 214: (4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(m-tolyl)methanol (Compound 1-281)

The title compound was prepared following procedures described in example 5 using (S)-3-chioro-2-(pyrrolidin-3-yloxy)pyridine hydrochloride (prepared as intermediate 3) and methyl 4-fluoro-3-formylbenzoate to give (S)-methyl 4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-formylbenzoate (2.3 g, 74% yield), Mass spec: 361 (M+H).

The title compound was prepared by reducing the (S)-methyl 4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-formylbenzoate with NaBH4 in MeOH to give (S)-methyl 4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)benzoate (1.5 g, quant.), Mass spec: 362 (M+H).

Step 3: methyl 4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-((tetrahydro-2H-pyran-2-yloxy)methyl)benzoate

To a solution of (S)-methyl 4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)benzoate (1 g, 2.75 mmol) in 20 ml DCM was added DHP (0.3 mL, 3.3 mmol) and PPTS (138 mg, 0.2 mmol), the mixture was stirred at rt overnight, removal the DCM to left the residue which was purified by silica gel to give methyl 4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-((tetrahydro-2H-pyran-2-yloxy)methyl) benzoate (1.2 g, 98% yield), Mass spec: 447 (M+H).

Step 4: (4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)methanol

To a solution of methyl 4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-((tetrahydro-2H-pyran-2-yloxy)methyl)benzoate (1.3 g, 2.9 mmol) in THE was added LAH (220 mg, 5.8 mmol) at 0° C., the mixture was stirred at rt for 2 h, quenched by water, extracted with DCM, washed with water, brine, dried over Na2SO4, removal the solvent to left the crude product (1.1 g, 89% yield) which can be used directly, Mass spec: 419 (M+H).

Step 5: 4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-((tetrahydro-2H-pyran-2-yloxy)methyl) benzaldehyde

The title compound was prepared following procedures described in example 150 (step 1) to give 4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-((tetrahydro-2H-pyran-2-yloxy)methyl)benzaldehyde (150 mg, 50% yield), Mass spec: 417 (M+H).

Step 6: (4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)(m-tolyl)methanol

To a suspension solution of Mg (2 g, 83 mmol) and cat amount 12 in dry tTHF was added 1-bromo-3-methylbenzene (0.1 mL), the mixture was heated to reflux till to red color disappeared, before another 0.9 mL I-bromo-3-methylbenzene was added, stirred for 10 min, then 4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-((tetrahydro-2H-pyran-2-yloxy)methyl) benzaldehyde (280 mg, 0.6 mmol) in THE was added and stirred for another 10 min, quenched by water, diluted with EA, washed with NH 4 Cl solution, brine, dried over Na2SO4, removal the solvent to left the crude product which was purified by silica gel to give (4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)(m-tolyl)methanol (250 mg, 83% yield), Mass spec: 509 (M+H).

Step 7: (4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(m-tolyl)methanol

To a solution of (4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl) (o-tolyl)methanol (70 mg, 0.13 mmol) in EA was added HCl/EA, the mixture was stirred at rt for 30 min, removal the EA, the crude product was purified by Prep-HPLC to give (4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(m-tolyl)methanol (30 mg, 54% yield), Mass spec: 425 (M+H), t R =2.530 min, 1 H-NMR (400 Hz, DMSO) δ=8.126-8.142 (m, 1H), 7.883-7.907 (m, 1H), 7.386 (s, 1H), 7.126-7.167 (m, 4H), 6.999-7.043 (m, 2H), 6.836-6.856 (d, 1H), 5.647-5.657 (m, 1H), 5.566-5.577 (m, 2H), 5.036-5.050 (t, 1H), 4.455-4.468 (m, 2H), 3.566-3.593 (m, 1H), 3.320-3.343 (m, 1H), 3.112-3.215 (m, 2H), 2.348-2.364 (m, 1H), 2.267 (s, 3H), 2.036-2.070 (m, 1H).

Example 215: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(m-tolyl)methanone (Compound 1-282)

Step 1: (4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)(m-tolyl)methanone

The title compound was prepared following procedures described in example 150 (step 1) to give (4-((S)-3-(3-chioropyridin-2-yloxy)pyrrolidin-1-yl)-3-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)(m-tolyl) methadone (60 mg, 98% yield), Mass spec: 507 (M+H).

Step 2: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(m-tolyl)methanone

The title compound was prepared following procedures described in example 214 (step 7) to give (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(m-tolyl)methanone (20 mg, 42% yield), Mass spec: 423 (M+H), t R =2.969 min, 1 H-NMR (400 Hz, DMSO) δ=8.160-8.176 (m, 1H), 7.903-7.926 (m, 1H), 7.779-7.785 (d, 1H), 7.544-7.571 (m, 1H), 7.411-7.464 (m, 4H), 7.041-7.073 (m, 1H), 6.803-6.825 (d, 1H), 5.701 (br, 1H), 5.206-5.233 (t, 1H), 4.531-4.592 (m, 2H), 3.992-4.033 (m, 1H), 3.585-3.703 (m, 3H), 2.331-2.388 (m, 4H), 2.225-2.229 (m, 1H).

Example 216: 2-(2-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-((4-fluorophenyl)(hydroxy)methyl) phenyl)ethanol (Compound 1-296)

Step 1: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-methoxyvinyl)phenyl)(4-fluorophenyl)methanone

The title compound was prepared following procedures described in example 168 (step 2) using (S)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(4-fluorobenzoyl)benzaldehyde (Prepared as example 168 (step 1)) to give (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-methoxyvinyl)phenyl)(4-fluorophenyl)methanone (220 mg, 58% yield), Mass spec: 453 (M+H).

The title compound was prepared following procedures described in example 168 (step 3) to give (S)-2-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(4-fluorobenzoyl)phenyl)acetaldehyde (140 mg, 70% yield), Mass spec: 439 (M+H),

Step 3: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)phenyl)(4-fluorophenyl)methanone

The title compound was prepared following procedures described in example 168 (step 4) to give 2-(2-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-((4-fluorophenyl)(hydroxy)methyl) phenyl)ethanol (30 mg, 59% yield), Mass spec: 443 (M+H), t R =2.307 min, 1 H-NMR (400 Hz, DMSO) δ=8.125-8.141 (m, 1H), 7.883-7.907 (m, 1H), 7.346-7.361 (m, 2H), 7.011-7.153 (m, 5H), 6.926-6.947 (m, 1H), 5.752-5.762 (d, 1H), 5.574-5.609 (m, 2H), 4.608-4.634 (t, 1H), 3.555-3.629 (m, 3H), 3.321-3.345 (m, 1H), 3.079-3.149 (m, 2H), 2.757-2.794 (m, 2H), 2.359-2.497 (m, 1H), 2.079-2.090 (m, 11H).

Example 217: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)phenyl)(4-fluorophenyl)methanone (Compound 1-294)

The title compound was prepared following procedures described in example 169 to give (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)phenyl)(4-fluorophenyl)methanone (70 mg, 50% yield), Mass spec: 441 (M+H), t R =2.887 min, 1 H-NMR (400 Hz, DMSO) δ=8.157-8.174 (m, 1H), 7.903-7.926 (m, 1H), 7.729 (m, 2H), 7.490-7.584 (m, 2H), 7.334-7.379 (m, 2H), 7.041-7.073 (m, 1H), 6.886-6.908 (m, 1H), 5.695 (br, 1H), 4.647-4.673 (t, 1H), 3.920-4.673 (m, 1H), 3.566-3.689 (m, 3H), 3.430-3.471 (m, 2H), 2.835-2.944 (m, 2H), 2.218-2.498 (m, 2H).

Example 218: 2-(2-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(hydroxy(p-tolyl)methyl) phenyl)ethanol (Compound 1-310)

The title compound was prepared following procedures described in example 216 to give 2-(2-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(hydroxy(p-tolyl)methyl)phenyl)ethanol (30 mg, 60% yield), Mass spec: 439 (M+H), t R =2.395 min, 1 H-NMR (400 Hz, DMSO) δ=8.124-8.141 (m, 1H), 7.885-7.907 (m, 1H), 7.207-7.227 (m, 2H), 7.011-7.138 (m, 5H), 6.919-6.940 (m, 1H), 5.544-5.624 (m, 3H), 4.600-4.627 (t, 1H), 3.551-3.625 (m, 3H), 3.309-3.333 (m, 1H), 3.072-3.142 (m, 2H), 2.751-2.789 (m, 2H), 2.342-2.376 (m, 1H), 2.250 (s, 3H), 2.061-2.075 (m, 1H).

Example 219: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)phenyl)(p-tolyl)methanone (Compound 1-295)

The title compound was prepared following procedures described in example 217 to give (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)phenyl)(p-tolyl)methanone (70 mg, 59% yield), Mass spec: 437 (M+H), t R =2.874 min, 1 H-NMR (400 Hz, DMSO) δ=8.158-8.175 (m, 1H), 7.905-7.928 (m, 1H), 7.571-7.592 (m, 3H), 7.489-7.516 (m, 1H), 7.326-7.346 (m, 2H), 7.041-7.073 (m, 1H), 6.885-6.907 (d, 1H), 5.684-5.689 (m, 1H), 4.654-4.681 (t, 1H), 3.921 (m, 1H), 3.637-3.660 (m, 3H), 3.418-3.447 (m, 2H), 2.836-2.937 (m, 2H), 2.315-2.403 (m, 4H), 2.151-2.194 (m, 1H).

Example 220: 2-(5-((4-chlorophenyl)(hydroxy)methyl)-2-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)ethanol (Compound 1-292)

The title compound was prepared following procedures described in example 216 to give 2-(5-((4-chlorophenyl)(hydroxy)methyl)-2-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)ethanol (27 mg, 71% yield), Mass spec: 459 (M+H), t R =2.587 min, 1 H-NMR (400 Hz, DMSO) δ=8.129-8.144 (m, 1H), 7.890-7.912 (m, 1H), 7.330-7.380 (m, 4H), 6.924-7.149 (m, 4H), 5.818-5.827 (m, 1H), 5.583-5.610 (m, 2H), 4.825-4.651 (t, 1H), 3.574-3.627 (m, 3H), 3.323 (m, 1H), 3.069-3.144 (m, 2H), 2.776-2.793 (m, 2H), 2.359-2.375 (m, 11H), 2.065-2.081 (m, 1H).

Example 221: (S)-(4-chlorophenyl)(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)phenyl)methanone (Compound 1-291)

The title compound was prepared following procedures described in example 217 to give (S)-(4-chlorophenyl)(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)phenyl)methanone (38 mg, 63% yield), Mass spec: 457 (M+H), t R =3.066 min, 1 H-NMR (400 Hz, DMSO) δ=8.156-8.171 (m, 1H), 7.900-7.924 (m, 1H), 7.492-7.696 (m, 6H), 7.039-7.071 (m, 1H), 6.878-6.900 (d, 1H), 4.649-4.676 (m, 1H), 3.925-3.965 (m, 1H), 3.641-3.693 (m, 3H), 3.436-3.464 (m, 2H), 2.872-2.944 (m, 2H), 2.340-2.362 (m, 1H), 2.201-2.225 (m, 1H).

Example 222: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)phenyl)(4-fluorophenyl)methanone (Compound 1-315)

The title compound was prepared following procedures described in example 217 to give (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)phenyl)(4-fluorophenyl)methanone (40 mg, 38% yield), Mass spec: 441 (M+H), t R =2.760 min, 1 H-NMR (400 Hz, DMSO) δ=8.005-8.020 (m, 1H), 7.675-7.766 (m, 3H), 7.582-7.588 (m, 1H), 7.490-7.516 (m, 1H), 7.335-7.379 (m, 2H), 7.055 (m, 1H), 6.889-6.911 (d, 1H), 5.706 (br, 1H), 4.660-4.686 (t, 1H), 3.928-3.968 (m, 1H), 3.615-3.676 (m, 3H), 3.416-3.489 (m, 2H), 2.862-2.934 (m, 2H), 2.342-2.376 (m, 1H), 2.210-2.251 (m, 1H).

Example 223: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)phenyl)(4-(methoxymethyl)phenyl)methanone (Compound 1-318)

The title compound was prepared following procedures described in example 217 to give (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)phenyl)(4-(methoxymethyl)phenyl)methanone (11 mg, 27% yield), Mass spec: 467 (M+H), t R =2.751 min, H-NMR (400 Hz, DMSO) δ=8.159-8.171 (m, 1H), 7.906-7.929 (m, 1H), 7.509-7.593 (m, 6H), 7.062-7.074 (m, 1H), 6.886-6.908 (d, 1H), 5.701 (br, 1H), 2.675 (t, 1H), 4.497 (s, 1H), 3.935-3.951 (m, 1H), 3.574-3.697 (m, 3H), 3.321-3.462 (m, 5H), 2.849-2.942 (m, 2H), 2.339-2.367 (m, 1H), 2.220-2.225 (m, 1H).

Example 224: (S)-(4-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)phenyl)(p-tolyl)methanone (Compound 1-309)

The title compound was prepared following procedures described in example 217 to give (S)-(4-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)phenyl)(p-tolyl)methanone (30 mg, 39% yield), Mass spec: 421 (M+H), t R =2.668 min, H-NMR (400 Hz, DMSO) δ=8.003-8.020 (m, 1H), 7.670-7.722 (m, 1H), 7.571-7.591 (m, 3H), 7.486-7.513 (m, 1H), 7.326-7.486 (d, 1H), 7.034-7.074 (m, 1H), 6.889-6.911 (d, 1H), 5.701 (br, 1H), 4.653-4.680 (t, 1H), 3.924-3.928 (m, 1H), 3.612-3.643 (m, 3H), 3.399-3.446 (m, 2H), 2.815-2.959 (m, 2H), 2.403 (s, 3H), 2.245-2.377 (m, 1H), 2.204-2.237 (m, 1H).

Example 225: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)phenyl)(3-fluorophenyl)methanone (Compound 1-311)

The title compound was prepared following procedures described in example 217 to give (S)-(4-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)phenyl)(p-tolyl)methanone (20 mg, 20% yield), Mass spec: 441 (M+H), t R =3.016 min, 1 H-NMR (400 Hz, DMSO) δ=8.159-8.175 (m, 1H), 7.904-7.928 (m, 1H), 7.421-7.607 (m, 6H), 7.042-7.073 (m, 1H), 6.881-6.903 (d, 1H), 5.698 (br, 1H), 4.650-4.677 (t, 1H), 3.933-3.973 (m, 1H), 3.666-3.701 (m, 3H), 3.446-3.489 (m, 2H), 2.857-2.951 (m, 2H), 2.329-2.364 (m, 1H), 2.223-2.229 (m, 1H).

Example 226: 2-(2-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-((3-fluorophenyl)(hydroxy) methyl)phenyl)ethanol (Compound 1-312)

The title compound was prepared following procedures described in example 216 to give 2-(2-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-((3-fluorophenyl)(hydroxy)methyl)phenyl)ethanol (8 mg, 8% yield), Mass spec: 443 (M+H), t R =2.608 min, 1 H-NMR (400 Hz, DMSO) δ=8.124-8.141 (m, 1H), 7.882-7.904 (m, 1H), 7.295-7.350 (m, 1H), 7.151-7.179 (m, 3H), 6.929-7.096 (m, 4H), 5.841-5.851 (d, 1H), 5.569-5.626 (m, 1H), 4.613-4.639 (t, 1H), 3.566-3.638 (m, 3H), 3.326-3.346 (m, 1H), 3.073-3.156 (m, 2H), 2.499-2.799 (m, 2H), 2.339-2.374 (m, 1H), 2.066-2.081 (m, 1H).

Example 227: (S)-(3-chlorophenyl)(3-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-4-(2-hydroxyethyl) phenyl)methanone (Compound 1-314)

The title compound was prepared following procedures described in example 217 to give (S)-(3-chlorophenyl)(3-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-4-(2-hydroxyethyl)phenyl)methanone (18 mg, 45% yield), Mass spec: 457(M+H), t R =3.037 min, 1 H-NMR (400 Hz, DMSO) δ=8.135-8.141 (m, 1H), 7.884-7.907 (m, 1H), 7.703-7.747 (m, 2H), 7.555-7.672 (m, 2H), 7.334-7.375 (m, 2H), 7.200-7.224 (m, 1H), 7.021-7.053 (m, 1H), 5.617-5.644 (m, 1H), 4.719 (br, 1H), 3.693-3.734 (m, 3H), 3.428-3.469 (m, 1H), 3.179-3.275 (m, 2H), 2.889-2.930 (m, 2H), 2.151-2.497 (m, 1H), 2.111-2.144 (m, 1H).

Example 228: (S)-(2-chlorophenyl)(3-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-4-(2-hydroxyethyl)phenyl)methanone (Compound 1-360)

The title compound was prepared following procedures described in example 217 to give (S)-(2-chlorophenyl)(3-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-4-(2-hydroxyethyl)phenyl)methanone (41 mg, 45% yield), Mass spec: 457(M+H), t R =3.048 min, 1 H-NMR (400 Hz, DMSO) δ=8.139-8.141 (m, 1H), 7.617-7.918 (m, 1H), 7.332-7.614 (m, 6H), 7.026-7.097 (m, 2H), 5.613-5.640 (m, 1H), 4.706-4.732 (t, 1H), 3.655-3.717 (m, 3H), 3.430-3.451 (m, 1H), 3.160-3.245 (m, 2H), 2.865-2.909 (m, 2H), 2.404-2.516 (m, 1H), 2.138-2.140 (m, 1H).

Example 229: 2-(4-((2-chlorophenyl)(hydroxy)methyl)-2-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)ethanol (Compound 1-354)

The title compound was prepared following procedures described in example 216 to give 2-(4-((2-chlorophenyl)(hydroxy)methyl)-2-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)ethanol (29 mg, 28% yield), Mass spec: 459(M+H), t R =2.379 min, 1 H-NMR (400 Hz, DMSO) δ=8.136-8.152 (m, 1H), 7.893-7.916 (m, 1H), 7.658-7.682 (m, 1H), 7.235-7.376 (m, 3H), 7.020-7.075 (m, 3H), 6.784-6.807 (m, 1H), 5.929-5.965 (m, 2H), 5.579-5.607 (br, 1H), 4.608-4.634 (t, 1H), 3.567-3.646 (m, 3H), 3.386-3.388 (m, 1H), 3.093-3.159 (m, 2H), 2.735-2.777 (m, 2H), 2.338-2.516 (m, 1H), 2.081-2.101 (m, 11H).

Example 230: (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(2-ethylphenyl)methanone (Compound 1-256)

The title compound was prepared following procedures described in example 194 to give (S)-(4-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(hydroxymethyl)phenyl)(2-ethylphenyl)methanone (29 mg, 28% yield), Mass spec: 437(M+H), t R =2.981 min, 1 H-NMR (400 Hz, DMSO) δ=8.150-8.167 (m, 1H), 7.895-7.918 (m, 1H), 7.736-7.740 (m, 1H), 7.356-7.433 (m, 3H), 7.164-7.185 (m, 2H), 7.034-7.065 (m, 1H), 6.741-6.763 (m, 1H), 5.679-5.690 (br, 1H), 5.213-5.240 (t, 1H), 4.479-4.580 (m, 2H), 3.994-4.035 (m, 1H), 3.601-3.703 (m, 3H), 2.498-2.552 (m, 2H), 2.304-2.328 (m, 1H), 2.200-2.207 (m, 1H), 1.038-1.075 (m, 3H).

The title compound was prepared following procedures described in example 5 using (S)-3-chloro-2-(pyrrolidin-3-yloxy)pyridine hydrochloride (prepared as intermediate 4) and 5-benzoyl-2-fluorobenzonitrile (prepared as intermediate 8 step 4) to give (S)-5-benzoyl-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (135 mg, 33% yield), Mass spec: 404 (M+H).

The title compound was prepared following procedures described in example 64 step 2 to give (S)-5-benzoyl-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)benzamide (47 mg, 55% yield), Mass spec: 422 (M+H), t R =2.305 min, H-NMR (400 Hz, CDCl3) δ=8.050-8.080 (m, 2H), 7.836-7.864 (m, 1H), 7.733-7.755 (m, 2H), 7.468-7.622 (m, 4H), 6.860-7.285 (m, 2H), 6.350 (br, 1H), 5.735-5.741 (br, 1H), 3.962-4.004 (m, 1H), 3.792-3.815 (m, 1H), 3.535-3.573 (m, 2H), 2.372-2.400 (m, 2H).

To a solution of 2-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(hydroxy(phenyl)methyl)benzamide (64 mg, 0.15 mmol) (prepared by reduced example 231 with NaBH4) in dry DCM/THF (5 mL/1 mL) was added Et3SiH (0.2 mL, 1.2 mmol) and BF3·Et2O (00.4 mL, 0.3 mmol), the mixture was stirred at rt for 16 h, quenched by 10% NaOH solution, separated the organic layer, dried over Na2SO4, removal the solvent to left the crude product which was purified by Prep-HPLC to give (S)-5-benzyl-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)benzamide (42 mg, 68%), Mass spec: 408 (M+H), t R =2.914 min, 1 H-NMR (400 Hz, DMSO) δ=8.135-8.152 (m, 1H), 7.878-7.901 (m, 1H), 7.790 (s, 1H), 7.021-7.295 (m, 9H), 6.730-6.751 (d, 1H), 5.618 (br, 1H), 3.785-3.832 (m, 2H), 3.430-3.467 (m, 1H), 3.208-3.299 (m, 2H), 2.275-2.309 (m, 1H), 2.118-2.156 (m, 11H).

Example 233: 2-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(hydroxy(phenyl)methyl)benzamide (Compound 1-137)

The title compound was prepared by reducing the (S)-5-benzoyl-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)benzamide with NaBH4 to give 2-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(hydroxy(phenyl)methyl)benzamide (94 mg, 49% yield), Mass spec: 424 (M+H), t R =2.511 min, 1 H-NMR (400 Hz, DMSO) δ=8.105-8.121 (m, 1H), 7.846-7.869 (m, 1H), 7.724 (s, 11H), 7.143-7.342 (m, 8H), 6.990-7.021 (m, 1H), 6.699-6.720 (d, 1H), 5.684-5.698 (m, 1 h), 5.570-5.591 (m, 2H), 3.749-3.791 (m, 1H), 3.404-3.444 (m, 1H), 3.189-3.280 (m, 2H), 2.247-2.281 (m, 1H), 2.114-2.131 (m, 1H).

Example 234: (S)-5-benzyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-140)

To a solution of 2-fluoro-5-(hydroxy(phenyl)methyl)benzonitrile (684 mg, 3 mmol) (prepared as intermediate 8 step 3) in 10 mL of dry DCM was added Et3SiH (3.84 mL, 24 mmol) and 0.78 mL BF3·Et2O (0.78 mL, 6 mmol), the mixture was stirred at rt for 16 h, quenched by water, separated the organic layer, dried over Na2SO4, removal the solvent to left the crude product which was purified by silica gel to give 5-benzyl-2-fluorobenzonitrile (540 mg, 85%), Mass spec: 212 (M+H).

The title compound was prepared following procedures described in example to give (S)-5-benzyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (70 mg, 13% yield), Mass spec: 424 (M+H).

The title compound was prepared following procedures described in example 64 step 2 to give (S)-5-benzyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (23 mg, 28% yield), Mass spec: 442 (M+H), t R =2.619 min, H-NMR (400 Hz, DMSO) δ=8.608-8.610 (m, 1H), 8.048-8.075 (m, 1H), 7.770 (s, 1H), 7.091-7.295 (m, 8H), 6.987-7.008 (d, 1H), 6.716-6.738 (d, 1H), 5.641-5.647 (m, 1H), 3.831 (s, 2H), 3.761-3.779 (m, 1H), 3.452-3.470 (m, 1H), 3.236-3.293 (m, 2H), 2.289-2.343 (m, 1H), 2.133-2.177 (m, 11H).

Example 235: 5-(hydroxy(phenyl)methyl)-2-((S)-3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-146)

The title compound was prepared following procedures described in example 233 using (S)-5-benzoyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (prepared as example 231) to give 5-(hydroxy(phenyl)methyl)-2-((S)-3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (110 mg, 57% yield), Mass spec: 458 (M+H), t R =2.731 min, 1 H-NMR (400 Hz, DMSO) δ=8.607 (m, 1H), 8.042-8.069 (m, 1H), 7.744 (s, 1H), 7.182-7.368 (m, 8H), 6.981-7.003 (d, 1H), 6.710-6.731 (d, 1H), 5.726-7.736 (m, 1H), 5.644 (s, 2H), 5.595-5.605 (m, 1H), 3.755-3.795 (m, 1H), 3.427-3.491 (m, 1H), 3.234-3.306 (m, 2H), 2.272-2.340 (m, 1H), 2.144-2.177 (m, 1H).

Example 236: (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-methoxyphenoxy)phenyl)methanol (Compound 1-221)

To a solution of (S)-3-chloro-2-(pyrrolidin-3-yloxy)pyridine hydrochloride (4 g, 17 mmol) (prepared as intermediate 3) in 100 mL DMF was added 5-bromo-2-fluorobenzaldehyde (2.3 g, 11.35 mmol) and K2CO3 (2.35 g, 34 mmol), the mixture was stirred at 95° C. overnight, water was added, extracted with DCM, the organic layer was washed by LiCl solution, dried over Na2SO4, removal the solvent to left the crude product which was purified by silica gel to give (S)-5-bromo-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)benzaldehyde (2.0 g, 34% yield), Mass spec: 341 (M+H).

To a solution of (S)-5-bromo-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)benzaldehyde (1 g, 2.62 mmol) in 30 mL MeOH was added NaBH4 (199 g, 5.23 mmol), the mixture was stirred at rt till to finished monitored by TLC, water was added, extracted with EA, the organic layer was washed by water, brine, dried over Na2SO4, removal the solvent to left the crude product which was purified by silica gel to give (S)-(5-bromo-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (910 mg, 91% yield), Mass spec: 383 (M+H).

To a solution of (S)-(5-bromo-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (100 mg, 0.26 mmol) in dioxane/DMF (0.8 mL/0.2 mL) was added 2-methoxyphenol (65 mg, 0.52 mmol), CuI (25 mg, 0.13 mmol), Cs2CO 3 (170 mg, 0.52 mmol) and 2-(dimethylamino)acetic acid hydrochloride (18 mg, 0.13 mmol), the mixture was irradiated by microwave to 160° C. for 1 h, diluted with water, extracted by EA, washed with LiCl solution, brine, dried over Na2SO4, and removal the solvent to left the crude product which was purified by Prep-HPLC to give (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-methoxyphenoxy)phenyl)methanol (30 mg, 27% yield), Mass spec: 427 (M+H), t R =2.694 min, 1 H-NMR (400 Hz, DMSO) δ=8.131-8.147 (m, 1H), 7.895-7.918 (m, 1H), 7.132-7.143 (m, 2H), 6.912-7.049 (m, 5H), 6.652-6.681 (m, 1H), 5.551-5.581 (br, 1H), 5.125-5.153 (t, 1H), 4.461-4.489 (m, 2H), 3.756 (s, 3H), 3.475-3.516 (m, 1H), 3.243-3.301 (m, 1H), 3.029-3.143 (m, 2H), 2.359-2.409 (m, 1H), 2.022-2.057 (m, 1H).

Example 237: (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-ethylphenoxy)phenyl)methanol (Compound 1-222)

The title compound was prepared following procedures described in example 236 step 3 to give (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-ethylphenoxy)phenyl)methanol (42 mg, 38% yield), Mass spec: 425 (M+H), t R =2.694 min, 1 H-NMR (400 Hz, DMSO) δ=8.128-8.144 (m, 1H), 7.893-7.916 (m, 1H), 7.283-7.304 (m, 1H), 7.143-7.181 (m, 1H), 6.956-7.139 (m, 4H), 6.718-6.776 (m, 2H), 5.556-5.586 (br, 1H), 5.161-5.188 (t, 1H), 4.466-4.496 (m, 2H), 3.496-3.537 (m, 1H), 3.262-3.320 (m, 1H), 3.045-3.157 (m, 2H), 2.572-2.629 (q, 2H), 2.374-2.499 (m, 11H), 2.040-2.062 (m, 1H), 1.135-1.173 (t, 3H).

Example 238: (S)-(5-(2-chlorophenoxy)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (Compound 1-223)

The title compound was prepared following procedures described in example 236 step 3 to give (S)-(5-(2-chlorophenoxy)-2-(3-(3-chioropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (32 mg, 28% yield), Mass spec: 431 (M+H), t R =3.126 min, 1 H-NMR (400 Hz, DMSO) δ=8.138-8.151 (m, 1H), 7.903-7.923 (m, 1H), 7.556-7.575 (m, 1H), 7.293-7.331 (m, 1H), 6.942-7.165 (m, 5H), 6.803-6.831 (m, 1H), 5.590 (br, 1H), 5.202-5.207 (t, 1H), 4.448-4.505 (m, 2H), 3.538-3.579 (m, 1H), 3.301-3.341 (m, 1H), 3.071-3.188 (m, 2H), 2.363-2.414 (m, 1H), 2.050-2.082 (m, 1H).

Example 239: (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(o-tolyloxy)phenyl)methanol (Compound 1-173)

The title compound was prepared following procedures described in example 236 step 3 to give (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(o-tolyloxy)phenyl)methanol (1.2 g, 75% yield), Mass spec: 411 (M+H), t R =3.117 min, H-NMR (400 Hz, DMSO) δ=8.110-8.122 (m, 1H), 7.872-7.891 (m, 1H), 7.251-7.268 (m, 1H), 7.119-7.157 (m, 1H), 6.934-7.022 (m, 4H), 6.695-8.772 (m, 2H), 5.551 (br, 1H), 5.098-5.123 (t, 1H), 4.450-4.478 (m, 2H), 3.474-3.516 (m, 1H), 3.242-3.280 (m, 1H), 3.042-3.141 (m, 2H), 2.335-2.386 (m, 1H), 2.178 (s, 3H), 2.009-2.042 (m, 1H).

Example 240: (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(m-tolyloxy)phenyl)methanol (Compound 1-242)

The title compound was prepared following procedures described in example 236 step 3 to give (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(m-tolyloxy)phenyl)methanol (50 mg, 46% yield), Mass spec: 411 (M+H), t R =3.177 min, 1 H-NMR (400 Hz, DMSO) δ=8.135-8.148 (m, 1H), 7.898-7.917 (m, 1H), 7.195-7.234 (m, 1H), 6.969-7.094 (m, 3H), 6.822-6.893 (m, 2H), 6.712-6.815 (m, 2H), 5.588 (br, 1H), 5.138-5.166 (t, 1H), 4.482-4.512 (m, 2H), 3.532-3.559 (m, 1H), 3.317-3.324 (m, 1H), 3.067-3.194 (m, 2H), 2.345-2.414 (m, 1H), 2.266 (s, 3H), 2.061-2.280 (m, 1H).

Example 241: (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(p-tolyloxy)phenyl)methanol (Compound 1-250)

The title compound was prepared following procedures described in example 236 step 3 to give (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(p-tolyloxy)phenyl)methanol (50 mg, 46% yield), Mass spec: 411 (M+H), t R =3.186 min, 1 H-NMR (400 Hz, DMSO) δ=8.134-8.146 (m, 1H), 7.896-7.915 (m, 1H), 7.135-7.156 (m, 2H), 6.960-7.069 (m, 3H), 6.789-6.855 (m, 3H), 5.580 (br, 1H), 5.126-5.153 (t, 1H), 4.472-4.501 (m, 2H), 3.513-3.554 (m, 1H), 3.297-3.327 (m, 1H), 3.050-3.175 (m, 2H), 2.377-2.394 (m, 1H), 2.265 (s, 3H), 2.037-2.071 (m, 1H).

Example 242: (S)-(5-(4-chlorophenoxy)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (Compound 1-249)

The title compound was prepared following procedures described in example 236 step 3 to give (S)-(5-(4-chlorophenoxy)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (40 mg, 35% yield), Mass spec: 431 (M+H), t R =3.315 min, H-NMR (400 Hz, DMSO) δ=8.140-8.157 (m, 1H), 7.904-7.927 (m, 1H), 7.379-7.402 (m, 2H), 6.863-7.115 (m, 6H), 5.589 (br, 1H), 5.172-5.199 (t, 1H), 4.452-4.554 (m, 2H), 3.554-3.594 (m, 1H), 3.316-3.336 (m, 1H), 3.087-3.207 (m, 2H), 2.346-2.415 (m, 1H), 2.037-2.106 (m, J H).

Example 243: (S)-(5-(3-chlorophenoxy)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (Compound 1-248)

The title compound was prepared following procedures described in example 236 step 3 to give (S)-(5-(3-chlorophenoxy)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (40 mg, 35% yield), Mass spec: 431 (M+H), t R =3.316 min, 1 H-NMR (400 Hz, DMSO) δ=8.143-8.159 (m, 1H), 7.906-7.930 (m, 1H), 7.349-7.389 (m, 1H), 6.893-7.137 (m, 7H), 5.601 (br, 1H), 5.205-5.233 (t, 1H), 4.494-4.526 (m, 2H), 3.571-3.612 (m, 1H), 3.344-3.368 (m, 1H), 3.102-3.222 (m, 2H), 2.366-2.417 (m, 1H), 2.062-2.095 (m, 1H).

Example 244: (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-propylphenoxy)phenyl)methanol (Compound 1-266)

The title compound was prepared following procedures described in example 236 step 3 to give (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-propylphenoxy)phenyl)methanol (60 mg, 52% yield), Mass spec: 439 (M+H), t R =3.525 min, 1H-NMR (400 Hz, DMSO) δ=8.135-8.147 (m, 1H), 7.896-7.915 (m, 1H), 7.264-7.283 (m, 1H), 7.139-7.159 (m, 1H), 6.966-7.060 (m, 5H), 6.733-6.771 (m, 1H), 5.582 (br, 1H), 5.112-5.139 (t, 1H), 4.478-4.506 (m, 2H), 3.506-3.547 (m, 1H), 3.291-3.311 (m, 11H), 3.064-3.168 (m, 2H), 2.555-2.592 (q, 2H), 2.507-2.574 (m, 1H), 2.033-2.045 (m, 1H), 1.563-1.619 (m, 2H)2, 0.873-0.910 (t, 3H).

Example 245: (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-fluorophenoxy)phenyl)methanol (Compound 1-270)

The title compound was prepared following procedures described in example 236 step 3 to give (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-fluorophenoxy)phenyl)methanol (58 mg, 54% yield), Mass spec: 415 (M+H), t R =2.922 min, 1 H-NMR (400 Hz, DMSO) δ=8.135-8.151 (m, 1H), 7.899-7.923 (m, 1H), 7.351-7.378 (m, 1H), 6.994-7.151 (m, 6H), 6.814-6.826 (m, 1H), 5.584 (br, 1H), 5.162-5.166 (t, 1H), 4.475-4.506 (m, 2H), 3.546-3.560 (m, 1H), 3.318-3.324 (m, 1H), 3.077-3.152 (m, 2H), 2.379-2.396 (m, 1H), 2.060-2.064 (m, 1H).

Example 246: (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-isopropylphenoxy)phenyl)methanol (Compound 1-271)

The title compound was prepared following procedures described in example 236 step 3 to give (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-isopropylphenoxy)phenyl)methanol (30 mg, 17% yield), Mass spec: 439 (M+H), t R =3.499 min, 1 H-NMR (400 Hz, CD3OD) δ=8.065-8.080 (m, 1H), 7.753-7.776 (m, 1H), 7.338-7.352 (m, 1H), 7.098-7.131 (m, 4H), 6.945-6.951 (m, 1H), 6.799-6.823 (m, 2H), 5.644-5.655 (br, 1H), 4.697 (s, 2H), 3.546-3.560 (m, 1H), 3.337-3.361 (m, 1H), 2.277-3.321 (m, 1H), 3.134-3.166 (m, 1H), 2.462-2.479 (m, 1H), 2.181-2.192 (m, 1H), 1.238-1.306 (m, 6H).

Example 247: (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-phenoxyphenyl)methanol (Compound 1-168)

The title compound was prepared following procedures described in example 236 step 3 to give (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-phenoxyphenyl)methanol (30 mg, 50% yield), Mass spec: 397 (M+H), t R =3.015 min, 1 H-NMR (400 Hz, DMSO) δ=8.142-8.150 (m, 1H), 7.902-7.925 (m, 1H), 7.329-7.369 (m, 2H), 6.949-7.108 (m, 6H), 6.859-6.929 (m, 1H), 5.583 (br, 1H), 5.162-5.177 (t, 1H), 4.485-4.416 (m, 2H), 3.428-3.552 (m, 1H), 3.322-3.343 (m, 1H), 3.061-3.197 (m, 2H), 2.385 (m, 1H), 2.075 (m, 1H).

Example 248: (S)-(2-(3-(5-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-methoxyphenoxy)phenyl)methanol (Compound 1-336)

The title compound was prepared following procedures described in example 236 to give (S)-(2-(3-(5-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-methoxyphenoxy)phenyl)methanol (30 mg, 26% yield), Mass spec: 411 (M+H), t R =2.519 min, 1 H-NMR (400 Hz, DMSO) δ=8.150-8.157 (m, 1H), 7.665-7.716 (m, 1H), 7.128-7.143 (m, 2H), 6.897-6.985 (m, 5H), 6.647-6.677 (m, 1H), 5.441-5.456 (br, 1H), 5.098-5.126 (t, 1H), 4.463 (m, 2H), 3.757 (s, 3H), 3.451-3.492 (m, 1H), 3.240-3.262 (m, 1H), 3.017-3.104 (m, 2H), 2.342-2.358 (m, 1H), 2.007-2.020 (m, 1H).

Example 249: (S)-(5-(2-methoxyphenoxy)-2-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (Compound 1-339)

The title compound was prepared following procedures described in example 236 to give (S)-(5-(2-methoxyphenoxy)-2-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (79 mg, 46% yield), Mass spec: 393 (M+H), t R =2.280 min, H-NMR (400 Hz, DMSO) δ=8.161-8.176 (m, 1H), 7.685-7.729 (m, 1H), 7.128-7.143 (m, 2H), 6.911-6.989 (m, 5H), 6.813-6.834 (m, 1H), 6.649-6.678 (m, 1H), 5.499-5.530 (br, 1H), 5.093-5.121 (t, 1H), 4.457-4.481 (m, 2H), 3.759 (s, 3H), 3.467-3.507 (m, 1H), 3.247-3.268 (m, 1H), 3.020-3.114 (m, 2H), 2.332-2.382 (m, 1H), 2.007-2.027 (m, 1H).

Example 250: (S)-(5-(2-methoxyphenoxy)-2-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (Compound 1-340)

The title compound was prepared following procedures described in example 236 to give (S)-(5-(2-methoxyphenoxy)-2-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (40 mg, 35% yield), Mass spec: 407 (M+H), t R =2.509 min, 1 H-NMR (400 Hz, DMSO) δ=7.985-7.998 (m, 1H), 7.535-7.553 (m, 1H), 7.137-7.146 (m, 2H), 6.873-6.989 (m, 5H), 6.656-6.685 (m, 1H), 5.533-5.552 (br, 1H), 4.476-4.488 (m, 2H), 3.762 (s, 3H), 3.482-3.494 (m, 1H), 3.274-3.293 (m, 2H), 3.051-3.111 (m, 2H), 2.319-2.380 (m, 1H), 2.143 (s, 3H), 2.004-2.031 (m, 1H).

Example 251: (S)-(5-(2-ethylphenoxy)-2-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (Compound 1-268)

The title compound was prepared following procedures described in example 236 to give (S)-(5-(2-ethylphenoxy)-2-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (1.2 g, 64% yield), Mass spec: 405 (M+H), t R =3.077 min, 1 H-NMR (400 Hz, DMSO) δ=7.985-7.995 (m, 1H), 7.529-7.547 (m, 1H), 7.289-7.307 (m, 1H), 7.141-7.165 (m, 1H), 6.781-7.077 (m, 4H), 6.723-6.760 (m, 2H), 5.532-5.548 (br, 1H), 5.131-5.158 (t, 1H), 4.480-4.507 (m, 2H), 3.485-3.526 (m, 1H), 3.290-3.312 (m, 1H), 3.062-3.129 (m, 2H), 2.582-2.638 (q, 2H), 2.344-2.361 (m, 1H), 2.138 (s, 3H), 1.998-2.029 (m, 1H), 1.142-1.180 (t, 3H).

Example 252: (S)-(5-(2-methoxyphenoxy)-2-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (Compound 1-345)

The title compound was prepared following procedures described in example 236 to give (S)-(5-(2-methoxyphenoxy)-2-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (73 mg, 64% yield), Mass spec: 407 (M+H), t R =2.442 min, 1 H-NMR (400 Hz, DMSO) δ=7.970-7.976 (m, 1H), 7.516-7.543 (m, 1H), 7.125-7.141 (m, 2H), 6.896-6.984 (m, 4H), 6.645-6.740 (m, 2H), 5.447-5.478 (br, 1H), 5.095-5.123 (t, 1H), 4.448-4.474 (m, 2H), 3.739 (s, 3H), 3.444-3.485 (m, 11H), 3.212-3.252 (m, 1H), 3.011-3.091 (m, 2H), 2.201-2.361 (m, 1H), 2.003 (s, 3H), 1.983-1.990 (m, 1H).

Example 253: (S)-(2-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-methoxyphenoxy)phenyl)methanol (Compound 1-346)

The title compound was prepared following procedures described in example 236 to give (S)-(2-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-methoxyphenoxy)phenyl)methanol (68 mg, 61% yield), Mass spec: 411 (M+H), t R =2.500 min, H-NMR (400 Hz, DMSO) δ=7.979-7.995 (m, 1H), 7.661-7.693 (m, 1H), 7.130-7.145 (m, 2H), 6.915-7.044 (m, 5H), 6.654-6.683 (m, 1H), 5.575-5.605 (br, 1H), 5.099-5.127 (t, 1H), 4.462-4.486 (m, 2H), 3.759 (s, 3H), 3.485-3.526 (m, 1H), 3.244-3.283 (m, 1H), 3.028-3.165 (m, 2H), 2.367-2.419 (m, 1H), 2.040-2.074 (m, 1H).

Example 254: (S)-(5-(2-ethylphenoxy)-2-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (Compound 1-267)

The title compound was prepared following procedures described in example 236 to give (S)-(5-(2-ethylphenoxy)-2-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (50 mg, 45% yield), Mass spec: 409 (M+H), t R =3.058 min, H-NMR (400 Hz, DMSO) δ=7.979-7.994 (m, 1H), 7.663-7.713 (m, 1H), 7.289-7.307 (m, 1H), 6.954-7.184 (m, 5H), 6.722-6.781 (m, 2H), 5.578-5.609 (m, 1H), 5.145-5.173 (t, 1H), 4.471-4.496 (m, 2H), 3.508-3.550 (m, 1H), 3.264-3.304 (m, 1H), 3.149-3.162 (m, 1H), 3.045-3.087 (m, 1H), 2.578-2.634 (q, 2H), 2.367-2.418 (m, 1H), 2.050-2.083 (m, 1H), 1.140-1.177 (t, 3H).

Example 255: (S)-(5-(2-ethylphenoxy)-2-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (Compound 1-268)

The title compound was prepared following procedures described in example 236 to give (S)-(5-(2-ethylphenoxy)-2-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (40 mg, 36% yield), Mass spec: 405 (M+H), t R =3.108 min, H-NMR (400 Hz, DMSO) δ=7.985-7.997 (m, 1H), 7.528-7.546 (m, 1H), 7.285-7.303 (m, 1H), 7.141-7.183 (m, 1H), 7.036-7.074 (m, 2H), 6.953-6.975 (m, 1H), 6.869-6.889 (m, 1H), 6.722-6.777 (m, 2H), 5.523-5.553 (m, 1H), 5.131-5.158 (t, 1H), 4.477-4.504 (m, 2H), 3.484-3.524 (m, 1H), 3.270-3.210 (m, 1H), 3.052-3.127 (m, 2H), 2.579-2.636 (q, 2H), 2.502-2.510 (m, 1H), 2.137 (s, 3H), 2.007-2.041 (m, 1H), 1.141-1.179 (t, 3H).

Example 256: (S)-(5-(2-fluorophenoxy)-2-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (Compound 1-298)

The title compound was prepared following procedures described in example 236 to give (S)-(5-(2-fluorophenoxy)-2-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (76 mg, 38% yield), Mass spec: 399 (M+H), t R =2.735 min, 1 H-NMR (400 Hz, DMSO) δ=7.979-7.966 (m, 1H), 7.657-7.708 (m, 1H), 7.331-7.383 (m, 1H), 6.966-7.196 (m, 6H), 6.804-6.833 (m, 1H), 5.588-5.619 (m, 1H), 5.156-5.184 (t, 1H), 4.479-4.504 (m, 2H), 3.529-3.570 (m, 1H), 3.283-3.323 (m, 1H), 3.168-3.195 (m, 1H), 3.055-3.109 (m, 1H), 2.369-2.498 (m, 1H1), 2.060-2.094 (m, 1H).

Example 257: (S)-(4-(2-chlorophenoxy)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (Compound 1-224)

To a solution of (S)-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine hydrochloride (2.0 g, 8.6 mmol) (prepared as intermediate 3) in 20 mL MeCN was added 4-bromo-2-fluorobenzaldehyde (2.1 g, 10.3 mmol) and DIPEA (5.7 mL, 34.5 mmol), and the mixture was heated to 90° C. for 2 h, removal the solvent, the residue was diluted with EA, washed by water, brine, dried over Na2SO4, removal the solvent to left the crude product which was purified by silica gel to give (S)-4-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzaldehyde (2.4 g, 67% yield) as yellow solid, Mass spec: 415 (M+H).

The title compound was prepared following procedures described in example 236 step 2 to give (S)-(4-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (1.4 g, quant.), Mass spec: 417 (M+H),

Step 3: (S)-(4-(2-chlorophenoxy)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl) methanol

The title compound was prepared following procedures described in example 236 step 3 to give (S)-(4-(2-chlorophenoxy)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl) methanol (35 mg, 37.7% yield), Mass spec: 465 (M+H), t R =3.294 min, 1 H-NMR (400 Hz, DMSO) δ=8.610 (s, 1H), 8.063-8.092 (m, 1H), 7.568-7.591 (m, 1H), 7.165-7.360 (m, 3H), 7.018-7.053 (m, 2H), 6.463-6.468 (d, 1H), 6.303-6.329 (m, 1H), 5.620-5.630 (m, 1H), 5.078-5.082 (m, 1H), 4.462-4.478 (m, 2H), 3.700-3.741 (m, 1H), 3.386-3.436 (m, 2H), 3.218-3.262 (m, 1H), 2.316-2.365 (m, 1H), 2.095-2.134 (m, 1H).

Example 258: (S)-(4-(2-ethylphenoxy)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (Compound 1-228)

The title compound was prepared following procedures described in example 257 step 3 to give (S)-(4-(2-ethylphenoxy)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (30 mg, 27% yield), Mass spec: 459 (M+H), t R =3.457 min, 1 H-NMR (400 Hz, DMSO) δ=8.607 (s, 1H), 8.067-8.088 (m, 1H), 7.013-7.329 (m, 5H), 6.843-6.863 (m, 1H), 6.417 (s, 1H), 6.247-6.267 (d, 1H), 5.624 (br, 1H), 5.030-5.057 (t, 1H), 4.441-4.470 (m, 2H), 3.675-3.716 (m, 1H), 3.413-3.415 (m, 2H), 3.195-3.216 (m, 1H), 2.546-2.603 (m, 1H), 2.312-2.345 (m, 1H), 2.078-2.113 (m, 1H), 1.118-1.155 (t, 3H).

Example 259: (S)-(4-(o-tolyloxy)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (Compound 1-230)

The title compound was prepared following procedures described in example 257 step 3 to give (S)-(4-(o-tolyloxy)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (60 mg, 55% yield), Mass spec: 445 (M+H), t R =3.399 min, H-NMR (400 Hz, DMSO) δ=8.603 (s, 1H), 8.057-8.086 (m, 1H), 7.009-7.306 (m, 5H), 6.853-6.873 (d, 1H), 6.409-6.415 (d, 1H), 6.226-6.253 (q, 1H), 5.608-5.635 (m, 1H), 5.002-5.029 (t, 11H), 4.441-4.468 (m, 2H), 3.670-3.711 (m, 11H), 3.389-3.411 (m, 2H), 3.202-3.222 (m, 1H), 2.309-2.343 (m, 11H), 2.174 (m, 3H), 2.008-2.114 (m, 1H).

Example 260: (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-4-(o-tolyloxy)phenyl)methanol (Compound 1-241)

The title compound was prepared following procedures described in example 257 to give (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-4-(o-tolyloxy)phenyl)methanol (30 mg, 28% yield), Mass spec: 411 (M+H), t R =3.081 min, H-NMR (400 Hz, DMSO) δ=8.134-8.150 (m, 1H), 7.893-7.917 (m, 11H), 7.022-7.309 (m, 5H), 6.856-6.876 (d, 1H), 6.426-6.432 (d, 1H), 6.245-6.271 (q, 1H), 5.584-5.611 (m, 1H), 5.026-5.053 (t, 1H), 4.442-4.474 (m, 21H), 3.672-3.713 (m, 1H), 3.317-3.408 (m, 2H), 3.196-3.217 (m, 1H), 2.300-2.335 (m, 1H), 2.179 (m, 3H), 2.081-2.098 (m, 1H).

Example 261: (S)-(4-(2-chlorophenoxy)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (Compound 1-232)

The title compound was prepared following procedures described in example 257 to give (S)-(4-(2-chlorophenoxy)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (23 mg, 20% yield), Mass spec: 431 (M+H), t R =3.105 min, 1 H-NMR (400 Hz, DMSO) δ=8.135-8.152 (m, 1H), 7.894-7.918 (m, 1H), 7.566-7.590 (m, 1H), 7.288-7.358 (m, 2H), 7.161-7.204 (m, 1H), 7.023-7.055 (m, 2H), 6.480-6.487 (d, 1H), 6.320-6.346 (q, 1H), 5.593-5.619 (m, 1H), 5.069-5.089 (t, 1H), 4.432-4.518 (m, 2H), 3.696-3.737 (m, 1H), 3.370-3.450 (m, 2H), 3.202-3.254 (m, 1H), 2.278-2.354 (m, 1H), 2.075-2.116 (m, 1H).

Example 262: (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-4-(2-ethylphenoxy)phenyl)methanol (Compound 1-233)

The title compound was prepared following procedures described in example 257 to give (S)-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-4-(2-ethylphenoxy)phenyl)methanol (40 mg, 36% yield), Mass spec: 425 (M+H), t R =3.377 min, 1 H-NMR (400 Hz, DMSO) δ=8.128-8.145 (m, 1H), 7.885-7.908 (m, 1H), 7.015-7.324 (m, 5H), 6.842-6.8608 (m, 1H), 6.427-6.433 (d, 1H), 6.262-6.288 (m, 1H), 5.582-5.608 (m, 1H), 5.008-5.034 (t, 1H), 4.444-4.475 (m, 2H), 3.672-3.713 (m, 1H), 3.316-3.404 (m, 2H), 3.182-3.213 (m, 1H), 2.547-2.603 (q, 2H), 2.297-2.345 (m, 1H), 2.079-2.095 (m, 1H), 1.117-1.155 (t, 3H).

Example 263: (S)-(2′-chloro-3-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-yl)methanol (Compound 1-234)

To a solution of (S)-(4-bromo-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (100 mg, 0.26 mol) (prepared as example 257 step 2) in 2 mL Dioxane/H2O (v:v=5:1) was added o-tolylboronic acid (61 mg, 0.39 mmol), K2CO3 (72 mg, 0.52 mmol) and Pd(dppf)Cl (10 mg, 10% wt), the mixture was heated to 90° C. for 2 h under N2, EA was added, washed by water, brine, dried over Na2SO4, removal the solvent to left the crude product which was purified by Prep-HPLC to give (S)-(2′-chloro-3-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-yl)methanol (13.7 mg, 15% yield), Mass spec: 415 (M+H), t R =3.083 min, 1 H-NMR (400 Hz, DMSO) δ=8.135-8.147 (m, 1H), 7.885-7.904 (m, 1H), 7.363-7.535 (m, 5H), 7.030-7.049 (m, 1H), 6.892-6.948 (m, 2H), 5.609-5.622 (m, 1H), 5.141 (t, 1H), 4.505-4.605 (m, 2H), 3.681-3.695 (m, 1H), 3.420-3.461 (m, 1H), 3.321-3.345 (m, 1H), 2.234-3.266 (m, 1H), 2.331-2.414 (m, 1H), 2.080-2.113 (m, 1H).

Example 264: (S)-(3-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-2′-ethylbiphenyl-4-yl)methanol (Compound 1-229)

The title compound was prepared following procedures described in example 263 to give (S)-(3-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-2′-ethylbiphenyl-4-yl)methanol (30 mg, 28% yield), Mass spec: 409 (M+H), t R =3.206 min, 1 H-NMR (400 Hz, DMSO) δ=8.133-8.148 (m, 1H), 7.886-7.909 (m, 1H), 7.409-7.428 (d, 1H), 7.142-7.322 (m, 4H), 7.016-7.048 (m, 1H), 6.745-6.818 (m, 2H), 5.599-5.612 (m, 1H), 5.117-5.145 (t, 1H), 4.509-4.605 (m, 2H), 3.683-3.724 (m, 1H), 3.413-3.472 (m, 1H), 3.319-3.359 (m, 1H), 3.166-3.250 (m, 1H), 2.508-2.589 (q, 2H), 2.337-2.385 (m, 1H), 2.076-2.116 (m, 1H) 1.037-1.075 (t, 3H).

Example 265: (S)-(3-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-2′-methylbiphenyl-4-yl)methanol (Compound 1-240)

The title compound was prepared following procedures described in example 263 to give (S)-(3-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-2′-methylbiphenyl-4-yl)methanol (32 mg, 29% yield), Mass spec: 395 (M+H), t R =3.193 min, 1 H-NMR (400 Hz, DMSO) δ=8.133-8.149 (m, 1H), 7.886-8.133 (m, 1H), 7.410-7.430 (d, 1H), 7.180-7.287 (m, 4H), 7.016-7.048 (m, 1H), 6.774-6.854 (m, 2H), 5.597-5.626 (m, 1H), 5.113-5.141 (t, 1H), 4.536-4.565 (m, 2H), 3.676-3.717 (m, 1H), 3.414-3.451 (m, 1H), 3.317-3.327 (m, 1H), 3.212-3.254 (m, 1H), 2.342-2.391 (m, 1H), 2.241 (s, 3H), 2.072-2.107 (m, 1H).

Example 266: (S)-(2′-methyl-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-yl)methanol (Compound 1-239)

The title compound was prepared following procedures described in example 263 using (S)-(4-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (example 257 step 2) to give (S)-(2′-methyl-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-yl)methanol (20 mg, 23% yield), Mass spec: 429 (M+H), t R =3.254 min, H-NMR (400 Hz, DMSO) δ=8.602-8.603 (d, 1H), 8.054-8.082 (m, 1H), 7.404-7.424 (d, 1H), 7.180-7.287 (m, 4H), 7.014-7.035 (d, 1H), 6.826-6.848 (m, 1H), 6.753-6.756 (d, 1H), 5.621-5.649 (m, 1H), 5.099-5.128 (t, 1H), 4.539-4.562 (m, 2H), 3.67-3.718 (m, 1H), 3.414-3.456 (m, 1H), 3.322-3.345 (m, 1H), 3.212-3.243 (m, 1H), 2.240-2.401 (m, 1H), 2.118 (s, 3H), 2.084-2.101 (m, 1H).

Example 267: (S)-(2′-ethyl-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-yl)methanol (Compound 1-227)

The title compound was prepared following procedures described in example 263 using (S)-(4-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (example 257 step 2) to give (S)-(2′-ethyl-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-yl)methanol (53 mg, 50% yield), Mass spec: 443 (M+H), t R =3.419 min, H-NMR (400 Hz, DMSO) δ=8.606 (s, 1H), 8.062-8.084 (d, 1H), 7.401-7.421 (d, 1H), 7.142-7.324 (m, 4H), 7.017-7.038 (d, 1H), 6.794-6.812 (d, 1H), 6.718 (s, 1H), 5.636 (br, 1H), 5.123-5.150 (t, 1H), 4.541-4.565 (m, 2H), 3.679-3.720 (m, 1H), 3.412-3.452 (m, 1H), 3.339-3.362 (m, 1H), 3.220-3.252 (m, 1H), 2.530-2.587 (q, 2H), 2.351-2.402 (m, 1H), 2.087-2.121 (m, 1H), 1.039-1.076 (t, 3H).

Example 268: (S)-(2′-chloro-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-yl)methanol (Compound 1-225)

The title compound was prepared following procedures described in example 263 using (S)-(4-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (example 257 step 2) to give (S)-(2′-chloro-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-yl)methanol (53 mg, 50% yield), Mass spec: 449 (M+H), t R =3.299 min, 1 H-NMR (400 Hz, DMSO) δ=8.612 (s, 1H), 8.067-8.088 (d, 1H), 7.538-7.555 (m, 1H), 7.389-7.454 (m, 4H), 7.022-7.044 (d, 1H), 6.929-6.946 (d, 1H), 6.865 (s, 1H), 5.645 (br, 1H), 5.143-5.170 (t, 1H), 4.543-4.568 (m, 2H), 3.690-3.731 (m, 1H), 3.446-3.466 (m, 1H), 3.332-3.354 (m, 1H), 3.236-3.247 (m, 1H), 2.373-2.391 (m, 1H), 2.111-2.132 (m, 1H).

Example 269: (S)-(3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-yl)methanol (Compound 1-180)

The title compound was prepared following procedures described in example 263 using (S)-(4-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (example 257 step 2) to give (S)-(3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-yl)methanol (100 mg, 67% yield), Mass spec: 415 (M+H), t R =3.302. 1 H-NMR (400 Hz, DMSO) δ=8.622 (s, 1H), 8.090-8.074 (m, 1H), 7.655-7.636 (m, 2H), 7.459-7.425 (m, 1H), 7.362-7.324 (m, 1H), 7.167-7.035 (m, 3H), 5.546 (s, 1H), 5.165-5.139 (m, 1H), 4.581-4.493 (m, 2H), 3.761-3.747 (m, 1H), 3.520-3.445 (m, 2H), 3.288-3.267 (m, 1H), 2.427 (m, 1H), 2.147-2.110 (m, 1H).

Example 270: (S)-(2′-ethyl-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (Compound 1-149)

To a solution of (S)-(5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (200 mg, 0.48 mol) (prepared as example 236 step 2) in 6 mL Dioxane/H2O (v:v=5:1) was added 2-ethylphenylboronic acid (84.6 mg, 0.576 mmol), K2CO3 (132.45 mg, 0.96 mmol) and Pd(dppf)Cl (20 mg, 10% wt), the mixture was heated to 100° C. for 1.5 h under N2, EA was added, washed by water, brine, dried over Na2SO4, removal the solvent to left the crude product which was purified by Prep-HPLC to give (S)-(2′-ethyl-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (100 mg, 47% yield), Mass spec: 443 (M+H), t R =3.565 min, 1 H-NMR (400 Hz, DMSO) δ=8.591 (s, 1H), 8.042-8.063 (m, 1H), 7.183-7.299 (m, 4H), 7.008-7.107 (m, 3H), 6.891-6.911 (m, 1H), 5.632-5.637 (m, 1H), 5.092 (br, 1H), 4.531 (m, 2H), 3.685-3.713 (m, 1H), 3.427-3.447 (m, 1H), 3.187-3.238 (m, 1H), 2.481-2.575 (q, 2H), 2.361-2.378 (m, 1H), 2.113-2.118 (m, 1H), 1.005-1.042 (t, 3H).

Example 271: (S)-(2′-fluoro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (Compound 1-150)

The title compound was prepared following procedures described in example 270 to give (S)-(2′-fluoro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (53 mg, 50% yield), Mass spec: 433 (M+H), t R =3.327 min, 1 H-NMR (400 Hz, DMSO) δ=8.598 (s, 1H), 8.042-8.070 (d, 1H), 7.545 (s, 1H), 7.221-7.473 (m, 5H), 7.010-7.032 (d, 1H), 6.910-6.931 (d, 1H), 5.633-5.646 (m, 1H), 5.103-5.131 (t, 1H), 4.521-4.511 (m, 2H), 3.715-3.755 (m, 1H), 3.355-3.481 (m, 3H), 2.338-2.387 (m, 1H), 2.100-2.134 (m, 1H).

Example 272: (S)-(2′-methoxy-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol_(Compound 1-151)

The title compound was prepared following procedures described in example 270 to give (S)-(2′-methoxy-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (130 mg, 65% yield), Mass spec: 445 (M+H), t R =3.338 min, 1 H-NMR (400 Hz, DMSO) δ=8.619 (s, 1H), 8.062-8.091 (d, 1H), 7.494-7.499 (d, 1H), 7.235-7.305 (m, 3H), 6.981-7.081 (m, 3H), 6.891-6.913 (d, 1H), 5.639-5.666 (m, 1H), 5.082-5.110 (t, 1H), 4.535-4.560 (m, 2H), 3.750 (s, 1H), 3.690-3.731 (m, 1H), 3.422-3.460 (m, 1H), 3.173-3.337 (m, 2H), 2.367-2.417 (m, 1H), 2.105-2.136 (m, 1H).

Example 273: (S)-(2′-(trifluoromethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (Compound 1-152)

The title compound was prepared following procedures described in example 270 to give (S)-(2′-(trifluoromethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (80 mg, 46% yield), Mass spec: 483 (M+H), t R =3.466 min, 1 H-NMR (400 Hz, DMSO) δ=8.591-8.595 (t, 1H), 8.041-8.069 (m, 1H), 7.515-7.783 (m, 3H), 7.312-7.354 (m, 2H), 7.014-7.089 (m, 2H), 6.867-6.888 (d, 1H), 5.632-5.659 (m, 1H), 5.096-5.122 (t, 1H), 4.512-4.543 (m, 2H), 3.715-3.755 (m, 1H), 3.440-3.481 (m, 2H), 3.241-3.284 (m, 1H), 2.342-2.473 (m, 1H), 2.100-2.133 (m, 1H).

Example 274: (S)-(2′-(methoxymethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (Compound 1-160)

The title compound was prepared following procedures described in example 270 to give (S)-(2′-(methoxymethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (20 mg, 18% yield), Mass spec: 459 (M+H), t R =3.190 min, 1 H-NMR (400 Hz, DMSO) δ=8.622-8.628 (t, 1H), 8.073-8.100 (m, 1H), 7.160-7.485 (m, 6H), 7.039-7.061 (d, 1H), 6.910-6.931 (d, 1H), 5.667 (m, 1H), 5.110-5.137 (t, 1H), 4.543-4.570 (m, 2H), 4.315 (s, 2H), 3.746-3.761 (m, 1H), 3.399-3.480 (m, 2H), 3.277-3.346 (m, 1H), 3.263 (s, 3H), 2.342-2.473 (m, 1H), 2.100-2.133 (m, 1H).

Example 275: (S)-(2′-(trifluoromethoxy)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (Compound 1-161)

The title compound was prepared following procedures described in example 270 to give (S)-(2′-(trifluoromethoxy)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (80 mg, 66% yield), Mass spec: 499 (M+H), t R =3.472 min, 1 H-NMR (400 Hz, DMSO) δ=8.592 (t, 1H), 8.039-8.067 (m, 1H), 7.413-7.469 (m, 5H), 7.235-7.261 (m, 1H), 7.010-7.031 (d, 1H), 6.882-6.904 (d, 1H), 5.641 (br, 11H), 5.148-5.175 (t, 1H), 4.512-4.545 (m, 2H), 3.731-3.771 (m, 1H), 3.472-3.494 (m, 2H), 3.268-3.279 (m, 1H), 2.342-2.473 (m, 1H), 2.120-2.133 (m, 1H).

Example 276: (S)-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (Compound 1-115)

The title compound was prepared following procedures described in example 270 to give (S)-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (1.2 g, 79% yield), Mass spec: 415 (M+H), t R =2.795 min, 1 H-NMR (400 Hz, DMSO) δ=8.590 (s, 1H), 8.033-8.060 (m, 1H), 7.560-7.656 (m, 3H), 7.235-7.440 (m, 4H), 6.906-7.024 (m, 2H), 5.621-5.647 (m, 1H), 5.109-5.137 (t, 11H), 4.535-4.563 (m, 2H), 3.689-3.730 (m, 1H), 3.420-3.462 (m, 1H), 3.208-3.260 (m, 1H), 2.337-2.387 (m, 1H), 2.088-2.129 (m, 11).

Example 277: (S)-3′-(hydroxymethyl)-4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-carbonitrile (Compound 1-252)

The title compound was prepared following procedures described in example 270 to give (S)-3′-(hydroxymethyl)-4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-carbonitrile (500 mg, 80% yield), Mass spec: 440 (M+H), t R =3.534. 1 H-NMR (400 Hz, DMSO) δ=8.504 (s, 1H), 7.964-7.942 (m, 1H), 7.814-7.756 (m, 5H), 7.577-7.550 (m, 1H), 7.063-7.042 (m, 1H), 6.976-6.953 (m, 1H), 5.745 (s, 1H), 4.796-4.725 (m, 3H), 3.849-3.820 (m, 1H), 3.622-3.331 (m, 3H), 2.466-2.265 (m, 2H).

Example 278: (S)-3′-(hydroxymethyl)-4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-carboxamide (Compound 1-253)

The title compound was prepared following procedures described in example 6 from example 277 to give (S)-3′-(hydroxymethyl)-4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-carbonitrile (30 mg, 28% yield), Mass spec: 458 (M+H), t R =3.832. 1 H-NMR (400 Hz, DMSO)δ=8.509 (s, 1H), 7.970-7.927 (m, 3H), 7.765-7.715 (m, 3H), 7.569-7.548 (m, 1H), 7.085-7.064 (m, 1H), 6.984-6.963 (m, 1H), 5.741-5.721 (m, 1H), 4.941-4.768 (m, 3H), 3.813-3.786 (m, 1H), 3.595-3.303 (m, 3H), 2.496-2.447 (m, 1H), 2.248-2.232 (m, 1H).

Example 279: (S)-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3,4′-diyl)dimethanol (Compound 1-261)

Step 1: (S)-3′-(hydroxymethyl)-4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-yl)biphenyl-4-carbaldehyde

The title compound was prepared following procedures described in example 270 to give (S)-3′-(hydroxymethyl)-4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-carbaldehyde (200 mg, 95% yield), Mass spec: 443 (M+H).

To a solution of (S)-3′-(hydroxymethyl)-4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-carbaldehyde (100 mg, 0.23 mmol) in 2 mL MeOH was added NaBHJ4 (22 mg, 0.58 mmol), the mixture was stirred at rt for 10 min, quenched by NH4Cl solution, diluted with EA, washed by water, brine, dried over Na2SO4, removal the solvent to left the crude product which was purified by Prep-HPLC to give (S)-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3,4′-diyl)dimethanol (40 mg, 40% yield), Mass spec: 445 (M+H), t R =2.710. 1 H-NMR (400 Hz, DMSO) δ=8.501 (s, 1H), 7.932-7.961 (m, 1H), 7.695-7.701 (d, 1H), 7.586-7.607 (m, 2H), 7.397-7.497 (i, 3H), 7.057-7.078 (d, 1H), 6.953-6.975 (d, 1H), 5.701-5.715 (m, 1H), 4.757 (s, 2H), 4.642 (s, 2H), 3.714-3.755 (m, 1H), 3.494-3.514 (m, 1H), 3.375-3.407 (m, 1H), 3.288-3.325 (m, 1H), 2.443-2.477 (m, 1H), 2.201-2.231 (m, 1H).

Example 280: (S)-(4-(3-(5-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (Compound 1-147)

The title compound was prepared following procedures described in example 270 to give (S)-(4-(3-(5-chloropyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (25 mg, 30% yield), Mass spec: 381 (M+H), t R =3.009, 1 H-NMR (400 Hz, DMSO)δ=8.240-8.247 (d, 1H), 7.803-7.833 (m, 1H), 7.589-7.677 (m, 3H), 7.409-7.447 (m, 4H), 6.890-6.948 (m, 2H), 5.540 (br, 1H), 5.159-5.187 (t, 1H), 4.552-4.581 (m, 2H), 3.689-3.716 (m, 1H), 3.417-3.472 (m, 1H), 3.244-3.376 (m, 2H), 2.331-2.365 (m, 3H), 2.091-2.117 (m, 2H).

Example 281: (S)-4′-(3-(5-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3′-(hydroxymethyl)biphenyl-2-carbonitrile (Compound 1-155)

Step 1: (S)-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol

To a solution of (S)-(5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (100 mg, 1.24 mmol) (prepared as example 236 step 2) in 4 mL Dioxane was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (182 mg, 0.71 mmol). K2CO3 (70 mg, 0.79 mmol) and Pd(dppf)Cl (20 mg, 20% Wt.), the mixture was stirred at 110° C. for 5 h, EA was added, washed by water, brine, dried over Na2SO4, removal the solvent to left the crude product (130 mg, 116% yield) which can be used to next step directly without further purification, Mass spec: 465 (M+H).

Step 2: (S)-4′-(3-(5-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3′-(hydroxymethyl)biphenyl-2-carbonitrile

The title compound was prepared following procedures described in example 270 to give (S)-4′-(3-(5-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3′-(hydroxymethyl)biphenyl-2-carbonitrile (20 mg, 19% yield), Mass spec: 440 (M+H), t R =3.059, 1 H-NMR (400 Hz, DMSO)δ=8.629 (s, 1H), 8.070-8.088 (q, 1H), 7.891-7.910 (m, 1H), 7.732-7.773 (m, 1H), 7.395-7.582 (m, 4H), 6.947-7.063 (m, 2H), 5.681-5.687 (m, 1H), 5.188-5.215 (t, 1H), 4.564-4.598 (m, 2H), 3.809-3.850 (m, 1H), 3.442-3.560 (m, 2H), 3.345-3.568 (m, 1H), 2.374-2.394 (m, 1H), 2.157-2.173 (m, 1H).

Example 282: (S)-1-(3′-(hydroxymethyl)-4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-2-yl)ethanone (Compound 1-157)

The title compound was prepared following procedures described in example 270 to give (S)-1-(3′-(hydroxymethyl)-4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-2-yl)ethanone (30 mg, 31% yield), Mass spec: 457 (M+H), t R =3.027, 1 H-NMR (400 Hz, DMSO)δ=8.597 (s, 1H), 8.043-8.071 (q, 1H), 7.299-7.525 (m, 5H), 7.011-7.066 (m, 2H), 6.878-6.900 (m, 1H), 5.643 (br, 1H), 5.132-5.158 (t, 1H), 4.503-4.536 (m, 2H), 3.729 (m, 1H), 3.378-3.484 (m, 2H), 3.254-3.265 (m, 1H), 2.314-2.368 (m, 1H), 2.100-2.140 (m, 1H), 2.036 (s, 3H).

Example 283: 1-(3′-(hydroxymethyl)-4′-((S)-3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-2-yl)ethanol (Compound 1-171)

The title compound was prepared following procedures described in example 279 step 2 to give 1-(3′-(hydroxymethyl)-4′-((S)-3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-2-yl)ethanol (30 mg, 30% yield), Mass spec: 457 (M+H), t R =2.928, 1 H-NMR (400 Hz, DMSO)δ=8.625 (s, 1H), 8.075-8.101 (q, 1H), 7.603-7.622 (d, 1H), 7.234-7.362 (m, 3H), 7.044-7.106 (m, 3H), 6.920-6.941 (m, 1H), 5.665-5.677 (m, 1H), 5.123-5.149 (t, 1H), 4.991-4.999 (d, 1H), 4.817-4.843 (m, 1H), 4.553 (m, 2H), 3.714-3.738 (m, 1H), 3.442-3.478 (m, 2H), 3.248-3.313 (m, 1H), 2.478-2.501 (m, 1H), 2.391-2.410 (m, 1H), 1.205-1.230 (s, 3H).

Example 284: 1-(4-((S)-3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)ethane-1,2-diol (Compound 1-148)

The title compound was prepared following procedures described in example 270 using (S)-5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzaldehyde (example 236 step 1) to give (S)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbaldehyde (900 mg, 90% yield), Mass spec: 413 (M+H).

To a solution of Me3SOI (321 mg, 1.45 mmol) in 3 mL DMSO was added NaH (34.9 mg, 1.45 mmol, 60% content) at 0° C., then allowed to return to rt for 30 min, before a solution of (S)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carbaldehyde (300 mg, 0.727 mmol) in 1 mL DMSO was added. The mixture was stirred at rt for 2 h, EA was added, washed by water, brine, dried over Na2SO4, removal the solvent to left the crude product (240 mg) which can be used to next step directly.

Step 3: 1-(4-((S)-3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)ethane-1,2-diol

To a solution of 2-((3S)-1-(3-(oxiran-2-yl)biphenyl-4-yl)pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (200 mg, crude) in 4 mL DCM/H2O (v:v=1:1) was added TFA (1.5 mL) slowly, the mixture was stirred at rt for overnight, diluted with DCM, adjust the pH with naHCO3 to 7, the organic layer was washed by water, brine, dried over Na2SO4, removal the solvent to left the crude product which was purified by Prep-HPLC to give 1-(4-((S)-3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)ethane-1,2-diol (13 mg, ˜14% yield), Mass spec: 445 (M+H), t R =2.775, 1 H-NMR (400 Hz, DMSO)δ=8.591 (s, 1H), 8.041-8.591 (m, 1H), 7.658-7.687 (m, 1H), 7.560-7.581 (in, 2H), 7.390-7.492 (m, 3H), 7.280-7.297 (m, 1H), 7.011-7.115 (m, 2H), 5.617-5.639 (m, 1H), 5.128-5.182 (m, 1H), 4.971-4.990 (m, 1H), 4.713-4.771 (m, 1H), 3.397-3.686 (m, 4H), 3.134-3.285 (m, 2H), 2.383-2.408 (m, 1H), 2.075-2.095 (m, 1H).

Example 285: (S)-2-hydroxy-1-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)ethanone (Compound 1-178) IDC-1550 C 3

To a solution of 1-(4-((S)-3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)ethane-1,2-diol (130 mg, 0.3 mmol) in 4 mL DCM was added MnO2 (261 mg, 3 mmol), the mixture was stirred at rt for 4 h, filtered to remove the MnO2, the filtrate was concentrated to left the crude product which was purified by Prep-HPLC to give (S)-2-hydroxy-1-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)ethanone (30 mg, 22% yield), Mass spec: 443 (M+H), t R =3.318, 1 H-NMR (400 Hz, DMSO)δ=8.654 (s, 1H), 8.130-8.151 (m, 1H), 7.578-7.613 (m, 2H), 7.392-7.498 (m, 4H), 7.256-7.293 (m, 1H), 7.129-7.151 (m, 11H), 6.796-6.869 (m, 11H), 5.456-5.505 (m, 1H), 5.279-5.287 (m, 0.5H), 5.133-5.142 (m, 0.5H), 4.846-5.002 (m, 1.5H), 4.835-4.863 (m, 0.5H), 3.958-4.000 (m, 1H), 3.728-3.813 (m, 2H), 3.403-3.420 (m, 11H), 2.579-2.652 (m, 1H), 1.985-2.056 (m, 1H).

Example 286: (S)—N-(2-hydroxyethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (Compound 1-153)

To a solution of (S)-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine hydrochloride (1.98 g, 8.37 mmol) and methyl 5-bromo-2-fluorobenzoate (1.5 g, 6.44 mol) in 8 mL DMSO was added DBU at rt, the mixture was heated to 100 for 3 h, diluted with EA, washed by water, brine, dried over Na2SO4, removal the solvent to left the crude product which was purified by silica gel column to give (S)-methyl 5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzoate (800 mg, 28% yield), Mass spec: 445 (M+H).

The title compound was prepared following procedures described in example 270 to give (S)-methyl 4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxylate (240 mg, 69% yield), Mass spec: 443 (M+H).

Step 3: (S)—N-(2-hydroxyethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide

To a solution of (S)-methyl 4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxylate (90 mg, 0.2 mmol) was dissolved in 2-aminoethanol (1 mL), then mixture was stirred at 100° C. for overnight, 0.1 mL MeOH was added, the mixture was purified by Prep-HPLC to give (S)—N-(2-hydroxyethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (40 mg, 42% yield), Mass spec: 472 (M+H), t R =3.048, 1 H-NMR (400 Hz, DMSO)δ=8.614 (s, 1H), 8.395 (m, 1H), 8.057-8.085 (m, 1H), 7.267-7.615 (m, 7H), 6.999-7.021 (d, 1H), 6.835-6.857 (d, 1H), 5.666 (br, 1H), 4.726 (br, 1H), 3.830 (m, 1H), 3.485-3.543 (m, 2H), 2.221-2.313 (m, 2H).

Example 287: (S)-2′-chloro-N-(2-hydroxyethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (Compound 1-156)

The title compound was prepared following procedures described in example 286 to give (S)-2′-chloro-N-(2-hydroxyethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxamide (20 mg, 25% yield), Mass spec: 506 (M+H), t R =2.930, 1 H-NMR (400 Hz, DMSO)δ=8.613-8.635 (d, 1H), 8.345-8.362 (m, 1H), 8.062-8.068 (m, 1H), 7.520-7.538 (m, 1H), 7.256-7.402 (m, 5H), 7.008-7.045 (d, 1H), 6.823-6.858 (d, 1H), 5.671 (br, 1H), 4.676-4.703 (t, 1H), 3.838-3.869 (m, 1H), 3.422-3.521 (m, 4H), 3.238-3.278 (m, 3H), 2.213-2.317 (m, 2H).

Example 288: (S)-3′-(hydroxymethyl)-4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-2-carboxamide (Compound 1-159)

The title compound was prepared following procedures described in example 281 step 1 to give 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (120 mg crude), Mass spec: 248 (M+H).

Step 2: (S)-3′-(hydroxymethyl)-4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-2-carboxamide

The title compound was prepared following procedures described in example 281 step 2 to give (S)-3′-(hydroxymethyl)-4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-2-carboxamide (20 mg, ˜18% yield), Mass spec: 458 (M+H), t R =2.462, 1 H-NMR (400 Hz, DMSO)δ=8.621 (s, 1H), 8.065-8.094 (m, 1H), 7.569 (s, 1H), 7.223-7.470 (m, 7H), 7.041-7.063 (d, 1H), 6.869-6.889 (d, 1H), 5.660 (br, 1H), 5.104 (br, 1H), 4.537 (m, 2H), 3.709-3.751 (m, 1H), 3.433-3.474 (m, 2H), 3.232-3.275 (m, 1H), 2.381-2.400 (m, 1H), 2.138-2.146 (m, 1H).

Example 289: (S)-3′-(hydroxymethyl)-N,N-dimethyl-4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-2-carboxamide (Compound 1-167)

The title compound was prepared following procedures described in example 281 step 2 to give (S)-3′-(hydroxymethyl)-4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-2-carboxamide (6 mg, 5% yield), Mass spec: 486 (M+H), t R =2.758, 1 H-NMR (400 Hz, CDCl3) δ=8.457 (s, 1H), 7.796-7.818 (m, 1H), 7.351-7.450 (s, 6H), 7.076-7.095 (d, 11H), 6.856-6.877 (d, 1H), 5.722 (br, 1H), 4.797-4.874 (m, 2H), 3.287-3.711 (m, 5H), 2.910 (s, 3H), 2.455-2.485 (m, 4H), 2.273 (m, 1H).

Example 290: (S)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxylic acid (Compound 1-165)

To a solution of (S)-methyl 4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxylate (50 mg, 0.113 mmol) (example 285 step 2) in 2 ml MeOH/THF (v:v=1:1) was added 1 mL 30% NaOH solution, the mixture was stirred at 60° C. for 5 h, adjust the pH to 4 with 3N HCl solution, extracted with EA, washed by brine, dried over Na2SO4, removal the solvent to left the crude product which was purified by Prep-HPLC to give (S)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxylic acid (20 mg, 41% yield), Mass spec: 429 (M+H), t R =2.930, 1 H-NMR (400 Hz, DMSO) δ=8.618 (s, 1H), 8.044-8.073 (m, 1H), 7.510-7.637 (m, 4H), 7.225-7.393 (m, 3H), 7.003-7.018 (d, 1H), 6.808-6.829 (d, 1H), 5.667 (br, 1H), 3.893-3.924 (m, 1H), 3.540-3.563 (m, 1H), 3.243-3.289 (m, 2H), 2.279-2.293 (m, 1H), 2.203-2.205 (m, 1H).

Example 291: (S)-2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxylic acid (Compound 1-166)

The title compound was prepared following procedures described in example 290 to give (S)-2′-chloro-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-carboxylic acid (30 mg, 62% yield), Mass spec: 463 (M+H), t R =3.078, 1 H-NMR (400 Hz, DMSO) δ=8.619 (s, 1H), 8.060-8.078 (m, 1H), 7.517-7.535 (m, 2H), 7.324-7.381 (m, 4H), 6.886-7.040 (m, 2H), 5.697 (br, 1H), 3.900-3.930 (m, 1H), 3.548-3.611 (m, 1H), 3.225-3.256 (m, 2H), 2.315-2.329 (m, 1H), 2.226-2.245 (m, 1H).

Example 292: (S)-(5-(pyridin-2-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl) methanol (Compound 1-254)

To a solution of (S)-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (200 mg, 043 mmol) (example 281 step 1), 2-bromopyridine (74 mg, 047 mmol) in 5 mL MeCN and 1 mL H2O was added Pd(Ph3P)4 (46.2 mg, 0.04 mmol) and K2CO3 (178 mmol, 1.29 mmol), the mixture was stirred at 80° C. for 2 h under N2, diluted with EA, the organic layer was washed by water, brine, dried over Na2SO4, removal the solvent to left the crude product which was purified by Prep-HPLC to give (S)-(5-(pyridin-2-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl) methanol (21 mg, 12% yield) as yellow solid, Mass spec: 416 (M+H), t R =3.186. 1 H-NMR (400 Hz, DMSO) δ=8.629-8.583 (m, 2H), 8.123-8.069 (m, 2H), 7.880-7.780 (m, 3H), 7.244-7.217 (m, 1H), 7.058-7.037 (m, 1H), 6.912-6.891 (m, 1H), 5.682-5.663 (m, 1H), 5.199-5.172 (m, 1H), 4.629-4.530 (m, 2H), 3.844-3.803 (m, 1H), 3.581-3.374 (m, 3H), 2.401-2.149 (m, 2H).

Example 293: (S)-(5-(3-methylpyridin-2-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (Compound 1-255)

The title compound was prepared following procedures described in example 292 to give (S)-(5-(3-methylpyridin-2-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (20 mg, 10.8% yield), Mass spec: 430 (M+H), t R =2.211. 1 H-NMR (400 Hz, DMSO) δ=8.628-8.627 (m, 1H), 8.448-8.438 (m, 1H), 8.100-8.072 (m, 1H), 7.676-7.603 (m, 2H), 7.386-7.361 (m, 1H), 7.232-7.202 (m, 1H), 7.063-6.892 (m, 2H), 5.676 (s, 1H), 5.161-5.134 (m, 1H), 4.578-4.546 (m, 2H), 3.802-3.761 (m, 1H), 3.526-3.281 (m, 3H), 2.416-2.358 (m, 4H), 2.167-2.133 (m, 1H).

Example 294: (S)-tert-butyl (3′-(hydroxymethyl)-4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-yl)methylcarbamate (Compound 1-269)

Step 1: (S)-(4′-(aminomethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol

To a solution of (S)-3′-(hydroxymethyl)-4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-carbonitrile (200 mg, 0.45 mmol) (example 277) in 2 mL EtOH was added 100 mg Ni and 0.5 mL TEA, the mixture was stirred at 40° C. for overnight under H2 atmosphere, filtered, the filtrate was concentrated to give (S)-(4′-(aminomethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (crude 170 mg, 85% yield) which can be used to next step directly, Mass spec: 444 (M+H).

Step 2: (S)-tert-butyl (3′-(hydroxymethyl)-4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-yl)methylcarbamate

To a solution of (S)-(4′-(aminomethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (170 mg, 0.38 mmol) in 2 ml DCM at 0° C. was added (Boc)2O (166 mg, 0.76 mmol) and TEA (0.1 mL, 0.76 mmol), the mixture was stirred at rt for 2 h, diluted with DCM, the organic layer was washed by water, brine, dried over Na2SO4, removal the solvent to left the crude product which was purified by prep-HPLC to give (S)-tert-butyl (3′-(hydroxymethyl)-4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-4-yl)methylcarbamate (25 mg, 12% yield), Mass spec: 544 (M+H), t R =3.223, 1 H-NMR (400 Hz, DMSO) δ=8.494-8.500 (q, 1H), 7.937-7.953 (m, 1H), 7.682 (s, 1H), 7.557-7.577 (m, 2H), 7.465-7.487 (m, 1H), 7.314-7.335 (m, 2H), 7.056-7.077 (d, 1H), 6.953-6.975 (d, 1H), 5.702-5.717 (m, 1H), 4.754 (s, 2H), 4.265 (s, 2H), 3.711-3.752 (m, 1H), 3.493-3.552 (m, 1H), 3.373-3.401 (m, 1H), 3.268-3.325 (m, 1H), 2.445-2.495 (m, 1H), 2.214-2.226 (m, 1H), 1.436 (s, 9H).

Example 295: (S)-(5-(6-chloro-5-ethylpyrimidin-4-yloxy)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (Compound 1-358)

To a solution of dimethyl 2-ethylmalonate (1 g, 5.3 mmol) in EtOH (15 mL) was added NH 3 /H2O (15 ml) with stirring at rt. for 24 h. The mixture was concentrated, washed by water, dried over Na2SO4, removal the solvent to left the solid crude product, the solid was dried under reduced pressure to give 2-ethylmalonamide (134 mg, 16.5% yield).

To a solution of 2-ethylmalonamide (130 mg, 1 mmol) in 3 mL EtOH was added HCONH2 (68 mg, 1.5 mmol) and EtONa in EtOH (1.3M), the mixture was refluxed for 16, concentrated to dry, water was added, HCl solution was used to adjust pH to 4, the precipitate was filtered and washed by water, dried over under reduced pressure to give 5-ethylpyrimidine-4,6-diol (30 mg, 21.4% yield), Mass spec: 141 (M+H).

A solution of 5-ethylpyrimidine-4,6-diol (449 mg, 3.2 mmol) in POCl3 (12 mL) was heated to 125° C. for 2 h, The mixture was concentrated, the residue was diluted by DCM and washed by NaHCO3 solution, dried over Na2SO4, removal the solvent to give crude 4,6-dichloro-5-ethylpyrimidine (430 mg, 76.6% yield) which can be used to next step directly, Mass spec: 177(M+H).

Step 4: (S)-5-(6-chloro-5-ethylpyrimidin-4-yloxy)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)benzaldehyde

To a solution of (S)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-hydroxybenzaldehyde (63 mg, 0.2 mmol) in 2 mL DMSO was added NaH (15 mg, 0.6 mmol) with stirring at 0° C. for 30 min, before 4,6-dichloro-5-ethylpyrimidine (71 mg, 0.4 mmol) was added, the resulting mixture was stirred at rt. for 15 min, concentrated, diluted with DCM, washed by water, dried over Na2SO4, removal the solvent to give (S)-5-(6-chloro-5-ethylpyrimidin-4-yloxy)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)benzaldehyde (75 mg, 83.3% yield), Mass spec: 459 (M+H).

Step 5: (S)-(5-(6-chloro-5-ethylpyrimidin-4-yloxy)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol

To a solution of (S)-5-(6-chloro-5-ethylpyrimidin-4-yloxy)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)benzaldehyde (69 mg, 0.15 mmol) in 2 mL MeOH was added NaBH4 (18 mg, 0.45 mmol) with stirring at 0° C., the mixture was stirred at rt for 5 min, diluted with DCM, washed by water, dried over Na2SO4, removal the solvent to give(S)-(5-(6-chloro-5-ethylpyrimidin-4-yloxy)-2-(3-(3-chioropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (25 mg, 36.2% yield). Mass spec: 461 (M+H), t R =3.445 min, 1 H-NMR (400 Hz, DMSO) δ=8.427 (s, 1H), 8.162-8.145 (m, 1H), 7.926-7.903 (m, 1H), 7.205 (s, 1H), 7.061-6.993 (m, 3H), 5.629-5.600 (m, 1H), 5.222-5.195 (m, 1H), 4.579-4.474 (m, 2H), 3.641-3.600 (m, 1H), 3.413-3.131 (m, 3H), 2.840-2.784 (m, 2H), 2.423-2.373 (m, 1H), 2.110-2.076 (m, 1H), 1.243-1.206 (m, 3H).

Example 296: (S)-(5-(6-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-ethylpyrimidin-4-yloxy)-2-fluorophenyl)methanol (Compound 1-359)

To a solution of 4-fluorophenol (2.24 g, 20 mmol) in 20 mL DMF was added imidazole (3.4 g, 50 mmol) and TBSCl (3.62 g, 24 mmol) with stirring at rt for 16 h. The mixture was diluted with DCM and washed by LiCi solution, dried over Na2SO4, removal the solvent to left the crude product which was purified by silica gel to give tert-butyl(4-fluorophenoxy)dimethylsilane (4.4 g, 97.8% yield).

To a solution of tert-butyl(4-fluorophenoxy)dimethylsilane (2.04 g, 9 mmol) in 20 mL THF was added t-BuLi (4 mL, 2.5M) with stirring at −78° C. for 30 min under N2, before DMF (731 mg) was added at this temperature. Quenched with NH 4 Cl solution, extracted with EA, dried over Na2SO4, removal the solvent to left the crude product which was purified by silica gel to give 5-(tert-butyldimethylsilyloxy)-2-fluorobenzaldehyde (1.5 g, 65.5% yield).

To a solution of 5-(tert-butyldimethylsilyloxy)-2-fluorobenzaldehyde (508 mg, 2 mmol) in 10 mL THF was added TBAF (2.4 mL, 2.4 mmol) with stirring at rt for 1 h. The reaction mixture was concentrated to left the crude product which was purified by silica gel to give 2-fluoro-5-hydroxybenzaldehyde (147 mg, 52.5%).

To a solution of 2-fluoro-5-hydroxybenzaldehyde (31 mg, 0.22 mmol) and 4,6-dichloro-5-ethylpyrimidine (35 mg, 0.2 mmol) in 2 mL MeCN was added DIPEA (80 mg, 0.6 mmol), the resulting mixture was stirred at 70° C. for 16 h. removal the solvent to left the crude product which was purified by silica gel to give 5-(6-chloro-5-ethylpyrimidin-4-yloxy)-2-fluorobenzaldehyde (30 mg, 48.4% yield), Mass spec: 281 (M+H).

Step 5: (S)-5-(6-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-ethylpyrimidin-4-yloxy)-2-fluorobenzaldehyde

To a solution of (S)-3-chloro-2-(pyrrolidin-3-yloxy)pyridine hydrochloride (95 mg, 0.4 mmol) and 5-(6-chloro-5-ethylpyrimidin-4-yloxy)-2-fluorobenzaldehyde (113 mg, 0.4 mmol) in 5 mL DMF was added K2CO3 (166 mg, 1.2 mmol), the mixture was stirred at 70° C. for 8 h. diluted with DCM, washed by LiCl solution, dried over Na2SO4, removal the solvent to left the crude product which was purified by silica gel to give (S)-5-(6-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-ethylpyrimidin-4-yloxy)-2-fluorobenzaldehyde (70 mg, 39.3% yield), Mass spec: 443 (M+H).

Step 6: (S)-5-(6-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-ethylpyrimidin-4-yloxy)-2-fluorobenzaldehyde

The title compound was prepared following procedures described in Example 295 step 5 to give (S)-5-(6-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-ethylpyrimidin-4-yloxy)-2-fluorobenzaldehyde (33 mg, 47.1% yield), Mass spec: 445 (M+H), t R =3.180 min, 1 H-NMR (400 Hz, DMSO) δ=8.182-8.165 (m, 1H), 8.037 (s, 1H), 7.929-7.905 (m, 1H), 7.185-7.129 (m, 2H), 7.078-6.984 (m, 2H), 5.679-5.670 (m, 1H), 5.355-5.326 (m, 1H), 4.555-4.540 (m, 2H), 4.099-4.057 (m, 1H), 3.875-3.765 (m, 31H), 2.812-2.735 (m, 2H), 2.325-2.237 (m, 2H), 1.192-1.155 (m, 3H).

Example 297: (S)-2-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)thiazole-4-carboxylic acid (Compound 1-184)

To a solution of ethyl 2-aminothiazole-5-carboxylate (3 g, 17.4 mmol) and KBr (7.25 g, 60 mmol) in 40 mL 27% H2SO4 solution was added NaNO2 (16 g, 225 mmol) in 40 mL water drop-wised during 1 h with stirring at 0° C. After finished, the mixture was kept at 0° C. for another 1 h, The resulting mixture was poured into water, extracted with EA, dried over Na2SO4, removal the solvent to left the crude product which was purified by siligel to give ethyl 2-bromothiazole-5-carboxylate (1.4 g, 34.1% yield), Mass spec: 238 (M+H).

To a solution of ethyl 2-bromothiazole-5-carboxylate (1.4 g, 5.93 mmol) and phenylboronic acid (868 mg, 7.12 mmol) in 18 ml Dioxane/H2O (v:v=5:1) was added Pd(pddf)C 12 .DCM (140 mg) and K2CO3 (2.46 g, 17.8 mmol) with stirring to 90° C. for 2 h under N2. The mixture was extracted with EA, dried over Na2SO4, removal the solvent to left the crude product which was purified by silica gel to give ethyl 2-phenylthiazole-5-carboxylate (700 mg, 54% yield), Mass spec: 234 (M+H).

To a solution of ethyl 2-phenylthiazole-5-carboxylate (23 mg, 0.1 mmol) in 0.5 mL con.H2SO4 was added NBS (21 mg, 0.12 mmol) with stirring at it for 3 h. The mixture was poured into ice water, and extracted with EA, dried over Na2SO4, removal the solvent to left the crude product which was purified by silica gel to give ethyl 2-(3-bromophenyl)thiazole-5-carboxylate (28 mg, 93.3% yield), Mass spec: 232 (M+H).

Step 4: (S)-2-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)thiazole-4-carboxylic acid

To a solution of (S)-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine hydrochloride (46 mg, 0.2 mmol) (Intermediate 3), ethyl 2-(3-bromophenyl)thiazole-5-carboxylate (75 mg, 0.24 mmol), t-BuONa (58 mg, 0.6 mmol) and Pd 2 (dba) 3 (5 mg) in 1 mL Dioxane was added x-phos (5 mg), the mixture was heated to 110° C. by microwave for 30 min, diluted with EA, washed by water, brine, removal the solvent to left the crude product which was purified by Pre-HPLC to give ((S)-2-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)thiazole-4-carboxylic acid (10 mg, 11.6% yield). Mass spec: 436 (M+H), t R =3.080. 1 H-NMR (400 Hz, DMSO) δ=8.654 (s, 1H), 8.128-8.075 (m, 2H), 7.316-7.277 (m, 1H), 7.166-7.018 (m, 3H), 6.722-6.702 (m, 1H), 5.774-5.768 (m, 1H), 3.810-3.772 (m, 1H), 3.597-3.481 (m, 3H), 2.423-2.396 (m, 1H), 2.294-2.263 (m, 1H).

Example 298: 2-(3-((S)-3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)cyclohexa-2,4-dienyl)thiazol-4-ol (Compound 1-177)

To a solution of (S)-2-(4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)thiazole-4-carboxylic acid (Example 297)(160 mg, 0.37 mmol), ClCO2′Bu (60 mg, 0.44 mmol) in 3 mL THE was added DIPEA (7 mg, 0.55 mmol) at 0° C., the mixture was stirred at rt. for 2 h, and NaBH4 (14 mg, 0.37 mmol) in MeOH (1 mL) was added dropwise at 0° C., the mixture was stirred at rt for another 2 h. The mixture was quenched by water, extracted with EA, dried over Na2SO4, removal the solvent to left crude product which was purified by Prep-HPLC to give 2-(3-((S)-3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)cyclohexa-2,4-dienyl)thiazol-4-ol (20 mg, 12.8% yield), Mass spec: 422 (M−H), t R =3.035, 1 H-NMR (400 Hz, DMSO) δ=8.653 (s, 1H), 8.101-8.073 (m, 1H), 7.436 (m, 1H), 7.304-7.265 (m, 2H), 7.062-7.025 (m, 2H), 6.708-6.684 (m, 1H), 5.769-5.755 (s, 1H), 4.612 (s, 1H), 3.804-3.601 (m, 3H), 3.372-3.306 (m, 2H), 2.405-2.392 (m, 11H), 2.298-2.291 (m, 1H).

Example 299: (S)-ethyl 2-phenyl-5-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)thiazole-4-carboxylate (Compound 1-206)

To a solution of ethyl 2-aminothiazole-5-carboxylate (3 g, 17.4 mmol) in 35 mL MeCN was added NCS (2.65 g, 19.2 mmol) with stirring at 82° C. for 5 h. The mixture was quenched by water, extracted with EA, dried over Na2SO4, removal the solvent to left the crude product which was purified by silica gel to give ethyl 2-amino-4-chlorothiazole-5-carboxylate (2.8 g, 77.8% yield), Mass spec: 207 (M+H).

To a solution of ethyl 2-amino-4-chlorothiazole-5-carboxylate (1 g, 5 mmol) and CuBr2 (1.34 g, 6 mmol) in 35 mL MeCN was added t-BuONO (875 mg, 8.5 mmol) with stirring at 82° C. for 5 h. The mixture was quenched with water, extracted with EA, washed by brine, dried over Na2SO4, removal the solvent to left the crude product which was purified by silica gel to give ethyl 2-bromo-4-chlorothiazole-5-carboxylate (1 g, 74%), Mass spec: 270 (M+H).

The title compound was prepared following procedures described in step 2 of example 297 to give ethyl 4-chloro-2-phenylthiazole-5-carboxylate (280 mg, 35% yield), Mass spec: 268 (M+H).

Step 4: (S)-ethyl 2-phenyl-5-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)thiazole-4-carboxylate

To a solution of (S)-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine hydrochloride (460 mg, 2 mmol) (intermediate 3) and ethyl 4-chloro-2-phenylthiazole-5-carboxylate (267 mg, 1 mmol) in 3 mL DMF was stirred at 70° C. overnight. The mixture was extracted with EA, washed by LiCl solution, brine, dried over Na2SO4, removal the solvent to left the crude product which was purified by Prep-HPLC to give (S)-ethyl 2-phenyl-5-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)thiazole-4-carboxylate (250 mg, 54% yield), Mass spec: 464 (M+H), t R =3.373. 1 H-NMR (400 Hz, DMSO) δ=8.633 (s, 1H), 8.106-8.078 (m, 1H), 7.787-7.766 (m, 2H), 7.487-7.414 (m, 3H), 7.060-7.038 (m, 1H), 5.740 (s, 1H), 4.284-4.222 (m, 2H), 4.034-3.993 (m, 1H), 3.703-3.672 (m, 1H), 3.550-3.474 (m, 2H), 2.448-2.424 (m, 1H), 2.323-2.307 (m, 1H), 1.307-1.272 (m, 3H).

Example 301: (S)-2-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-isopropylphenoxy)phenyl)ethanol (Compound 1-327)

To a solution of (methoxymethyl)triphenylphosphonium chloride (1.08 g, 3.14 mmol) in 14 ml THF was added LiHMDS (657 mg, 3.93 mmol) slowly at 0° C. during 20 min. the resulting solution was added To a solution of (S)-5-bromo-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)benzaldehyde (1.0 g, 2.6 mmol, prepared as example 236 step1) in 5 ml THE slowly at 0° C. After 5 min, the reaction was completed detected by TLC and LCMS, then the reaction was quenched by the addition of ice-water, the aqueous layer was extracted with EA, the organic layer was dried over Na2SO 4 , removal the solvent to left the crude product which was purified by silica gel to give (S, E)-2-(1-(4-bromo-2-(2-methoxyvinyl)phenyl)pyrrolidin-3-yloxy)-3-chloropyridine as oil (700 mg, 66% yield), Mass spec: 409 (M+1).

To a solution of (S, E)-2-(1-(4-bromo-2-(2-methoxyvinyl)phenyl)pyrrolidin-3-yloxy)-3-chloropyridine (200 mg, 0.49 mmol) in 6 ml acetone was added 4 ml 10% HCl, stirred at 50° C. for 2 h and the reaction was quenched by NaHCO 3 , extracted with DCM, washed with brine, dried over Na 2 SO 4 , removal the solvent to left the crude product which was purified by silica gel to give (S)-2-(5-bromo-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)acetaldehyde (160 mg, 82% yield), Mass spec: 395 (M+1).

To a solution of (S)-2-(5-bromo-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)acetaldehyde (200 mg, 0.50 mmol) in 6 ml MeOH was added NaBH 4 (38 mg, 1.0 mmol) at 50° C. stirred for 10 min and the mixture was quenched by water, extracted with DCM (3×15 ml), was washed with brine, dried over Na 2 SO 4 , removal the solvent to left the crude product which was purified by silica gel to give (S)-2-(5-bromo-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)ethanol (110 mg, 55% yield), Mass spec: 397(M+1).

To a solution of (S)-2-(5-bromo-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)ethanol (110 mg, 0.276 mmol), 2-isopropylphenol (75 mg, 0.553 mmol), CuI (26 mg, 0.138 mmol), Cs2CO 3 (180 mg, 0.533 mmol) and 2-(dimethylamino)acetic acid hydrochloride (19 mg, 0.138 mmol) in 1.0 ml dioxane and 0.2 ml DMF was heated at 160° C. in microwave for 1 h. The mixture was diluted with water, extracted with EA, washed with LiCl solution, washed with brine, dried over Na 2 SO 4 , filtered, removal the solvent to left the crude product which was purified by Prep-HPLC to give (S)-2-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-isopropylphenoxy)phenyl)ethanol (45 mg, 36.3% yield), Mass spec: 453(M+1), t R =3.300 min, 1 H-NMR (400 Hz, DMSO) δ=8.145-7.919 (d, 1H), 7.915-7.895 (m, 1H), 7.371-7.181 (d, 1H), 7.177-7.018 (m, 4H), 6.833-6.766 (m, 2H), 6.675-6.646 (m, 1H), 5.594-5.565 (s, 1H), 4.654-4.628 (m, 1H), 3.639-3.534 (m, 3H), 3.328-3.205 (m, 2H), 3.133-3.033 (m, 2H), 2.800-2.765 (m, 2H), 2.513-2.424 (m, 1H), 2.076-2.056 (s, 1H), 1.198-1.180 (d, 6H).

To a solution of (S)-2-(5-bromo-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)ethanol (300 mg, 0.75 mmol) in 4 ml THE was added n-BuLi (0.9 ml, 2.25 mmol) slowly at −78° C., then stirred at −78° C. for 30 min, before the solution of 1,2-bis(2-ethylphenyl)disulfane (309 mg, 1.13 mmol) in 2 ml THF was added at −78° C. After addition, the mixture was stirred at −40° C. for 3 h, then the reaction was quenched by H2O, extracted with EA, dried over Na2SO4, removal the solvent to left the crude product which was purified by silica gel to give (S)-2-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-ethylphenylthio)phenyl)ethane 150 mg, 44.1% yield), Mass spec: 455 (M+1).

To a solution of (S)-2-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-ethylphenylthio)phenyl)ethanol (150 mg, 0.33 mmol) in MeOH/H 2 O (v:v=2/1) was added oxone (405 mg, 0.66 mmol) and stirred at r.t. for overnight. The mixture was extracted with EA, washed with water, dried over Na2SO 4 , removal the solvent to left the crude product which was purified by Prep-HPLC to give (S)-2-(2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-(2-ethylphenylsulfonyl)phenyl)ethane (20 mg, 12.5% yield), Mass spec: 487 (M+1), t R =1.677 min 1 H-NMR (400 Hz, DMSO) δ=8.497-8.483 (m, 1H), 7.762-7.725 (m, 1H), 7.589-7.592 (m, 2H), 7.461-7.377 (m, 5H), 7.277-7.256 (m, 1H), 5.853-5.836 (m, 1H), 4.249-4.230 (m, 1H), 4.151-4.122 (m, 3H), 3.876 (m, 1H), 3.630-3.620 (m, 2H), 3.475-3.309 (m, 3H), 3.155-3.100 (m, 2H), 2.921-2.865 (m, 1H), 2.251-2.152 (m, 1H), 1.293-1.250 (m, 3H).

Example 318: 3-((4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)phenyl)(hydroxy)methyl)benzonitrile (Compound 1-356)

Step 1: 2-((3S)-1-(4-bromo-2-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)phenyl)pyrrolidin-3-yloxy)-3-chloropyridine

To a solution of (S)-2-(5-bromo-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)ethanol (1.1 g, 2.7 mmol), DHP (907 mg, 10.8 mmol) and PPTS (1.1 g, 4.05 mmol) in 5 ml DCM was stirred at rt for overnight. The reaction was completed detected by TLC, washed by water, NH 4 Cl solution, dried over Na2SO4, and removal the solvent to give the crude 2-((3S)-1-(4-bromo-2-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)phenyl)pyrrolidin-3-yloxy)-3-chloropyridine (670 mg, 51.9% yield) which can be used to next step directly, Mass spec: 481 (M+1).

Step 2: 3-((4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)phenyl)(hydroxy)methyl)benzonitrile

To a solution of 2-((3S)-1-(4-bromo-2-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)phenyl)pyrrolidin-3-yloxy)-3-chloropyridine (100 mg, 0.21 mmol) in 3 ml THF was added n-BuLi (0.1 ml, 0.25 mmol, 2.5M in hexane) at −78° C., and the reaction was stirred at rt for this temperature for 1 h, then 3-formylbenzonitrile (27 mg, 0.21 mmol) in 1 ml THF was added and stirred for 30 min, quenched with NH 4 Cl solution, extracted with EA, dried over Na2SO4, removal the solvent to left the crude product which was purified by prep-TLC to give 3-((4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)phenyl)(hydroxy)methyl)benzonitrile (35 mg, 31.5% yield), Mass spec: 534(M+1).

Step 3: 3-((4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)phenyl)(hydroxy)methyl)benzonitrile

To a solution of 3-((4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)phenyl)(hydroxy)methyl)benzonitrile (20 mg, 0.045 mmol) in 1 ml EA was added 1 ml HCl/EA at 0° C., the mixture was stirred at rt and monitored by TLC. After finished, removal the solvent to left the crude product which was purified by Prep-HPLC to give 3-((4-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-3-(2-hydroxyethyl)phenyl)(hydroxy)methyl)benzonitrile (5.7 mg, 28.5% yield), Mass spec: 450 (M+1), t R =2.393 min 1 H-NMR (400 Hz, DMSO) δ=8.168-8.154 (m, 1H), 7.816-7.734 (m, 2H), 7.681-7.535 (m, 2H), 7.334-7.312 (m, 1H), 7.160-7.084 (m, 2H), 6.995-6.962 (m, 1H), 6.893-6.967 (m, 1H), 6.521-6.500 (m, 1H), 6031 (s, 1H), 5.577 (s, 1H), 4.644-4.607 (m, 1H), 3.646-3.593 (m, 3H), 3.273-3.259 (m, 3H), 3.166-3.088 (m, 2H), 2.370-2.333 (m, 1H), 2.084-2.051 (m, 1H).

Example 319: (S)-2-(4-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)ethanol (Compound 1-193)

To a solution of(S)-2-(5-bromo-2-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)phenyl)ethanol (90 mg, 0.24 mmol, prepared as example 301 step3), phenylboronic acid (43.6 mg, 0.36 mmol), Pd(dppf)Cl 2 (13.5 mg, 15%) and K 2 CO 3 (98.1 mg, 0.72 mmol) in 2 ml dioxane/H2O (v:v=5:1) and degassed for 2 min, then heated to 85° C. for 1 h under N 2 . Diluted with EA, washed by water, brine, dried over Na2SO4, removal the solvent to left crude product which was purified by Prep-HPLC to give(S)-2-(4-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)ethanol (30 mg, 33.7% yield), Mass spec: 375 (M+1). t R =2.861 min 1 H-NMR (400 Hz, DMSO) δ=8.010-7.995 (m, 1H), 7.599-7.530 (m, 3H), 7.450-7.393 (m, 4H), 7.298-7.262 (m, 1H), 7.044-7.024 (m, 1H), 6.905-6.875 (m, 1H), 5.605-5.579 (m, 1H), 4.694-4.667 (m, 1H), 3.728-3.643 (m, 3H), 3.476-3.455 (m, 1H), 3.224-3.171 (m, 2H), 2.910-2.858 (m, 2H), 2.382-2.333 (m, 1H), 2.139 (s, 3H), 2.118-2.093 (m, 1H).

To a solution of (S)-3-chloro-2-(pyrrolidin-3-yloxy)pyridine hydrochloride (4.0 g, 17.1 mmol), 5-bromo-2-fluorobenzonitrile (4.1 g, 20.5 mmol), Cs 2 CO 3 (16.7 g, 51.3 mmol) in 10 ml DMF was stirred at 100° C. for 3 h. then the mixture was diluted 50 ml EA and washed with 10% LiCl solution, the EA layer was dried over Na 2 SO 4 , filtered and removal the solvent to left the crude product which was purified by silica gel to give (S)-5-bromo-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile as brown solid (2.8 g, 37.3%), Mass Spec: 378 (M+1).

To a solution of (S)-5-bromo-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (1.0 g, 2.6 mmol), 2-chlorophenol (665 mg, 5.2 mmol), CuCl (129 mg, 1.3 mmol), Cs 2 CO 3 (1.7 g, 5.2 mmol) and 2,2,6,6-tetramethylheptane-3,5-dione (239 mg, 1.3 mmol) in 3 ml NMP, and degassed with N 2 for 1 min, then heated at 220° C. in microwave for 30 min, the mixture was filtered and the filtrate was evaporated and purified by silica gel to give (S)-5-(2-chlorophenoxy)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile as solid (100 mg, 9.1% yield), Mass Spec: 426 (M+1).

To a solution of (S)-5-(2-chlorophenoxy)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (50 mg, 0.1 mmol) in 4 ml EtOH and 0.6 ml DMSO was added KOH at rt, then stirred at 60° C. for 5 min, then the mixture was cooled to rt and added H2O2 (0.3 ml). After stirring for 30 min at rt, the precipitate was filtered, and the solid was washed with 10 ml EtOH and 5 ml Et 2 O, dried in vacuo to give (S)-5-(2-chlorophenoxy)-2-(3-(3-chioropyridin-2-yloxy)pyrrolidin-1-yl)benzamide as white solid (10.0 mg, 21.2% yield), Mass Spec: 444(M+1), t R =3.035 min 1 H-NMR (400 Hz, DMSO) δ=8.161-8.145 (m, 1H), 7.987 (s, 1H), 7.920-7.897 (m, 1H), 7.575-7.552 (m, 1H), 7.425 (s, 1H), 7.314-7.295 (m, 1H), 7.158-7.139 (m, 1H), 7.065-6.898 (m, 5H), 5.642 (s, 1H), 3.805 (m, 1H), 3.506 (m, 1H), 3.336-3.249 (m, 2H), 2.362-2.308 (m, 1H), 2.179-2.165 (m, 1H).

Compound 1-220

Step 1: (S)-(2-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol

A solution of (S)-(5-bromo-2-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (700 mg, 1.93 mmol) (prepared as example 236 step2), (Pin) 2 B 2 (983.7 mg, 3.87 mmol), Pd(dppf)Cl 2 DCM (157 mg, 0.193 mmol) and K 2 CO 3 (799.0 mg, 5.79 mmol) in 10 ml Dixoane was degassed with N 2 for 2 min, and stirred at 90° C. for 2 h under N 2 . The mixture was diluted with EA, washed by water, brine, dried over Na2SO4, removal the solvent to left the crude product which was purified by silica gel to give (S)-(2-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (200 mg, 25% yield) as oil, Mass spec: 411(M+1).

To a solution of (S)-(2-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (100 mg, 0.24 mmol), 2-bromopyridine (42.6 mg, 0.27 mmol), Pd(PPh 3 ) 4 (28 mg, 0.024 mmol) and K 2 CO 3 (100 mg, 0.72 mmol) in 2 ml MeCN and 0.4 ml H 2 O was degassed for 2 min, and stirred at 80° C. for 2 h, The mixture was diluted with EA, washed by water, brine, dried over Na2SO4, removal the solvent to left the crude product which was purified by Prep-HPLC to give (S)-(2-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)-5-(pyridin-2-yl)phenyl)methanol (40 mg, 39% yield), Mass spec: 362(M+1), t R =0.819 min, 1 H-NMR (400 Hz, DMSO) δ=8.685-8.671 (d, 1H), 8.473-8.455 (m, 1H), 8.350-8.330 (d, 1H), 8.096-7.994 (m, 3H), 7.781-7.764 (m, 1H), 7.615-7.589 (m, 1H), 6.919-6.793 (m, 2H), 5.606 (s, 1H), 4.683-4.590 (m, 2H), 4.010 (m, 1H), 3.695-3.665 (m, 3H), 2.328-2.286 (m, 1H), 2.210-2.180 (m, 4H).

Example 333: (S)-(6-(2-methoxyphenyl)-3-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (Compound 1-186)

To a solution of 2-bromo-5-fluoropyridine (10 g, 56.8 mmol) was dissolved in 120 mL Et 2 O. was added n-BuLi (27.27 ml, 2.5 M in hexane) slowly under N 2 at −78° C. during 20 min, the mixture was stirred at −78° C. for 30 min, before DMF (6.63 ml, 85.2 mmol) was added slowly. the reaction was monitored by TLC, after finished, quenched by water, con HCl (8 ml) was added, stirred at r.t for 30 min, diluted with EA, combined the organic layer, dried over Na 2 SO 4 , removal the solvent which was purified by silica gel to give 6-bromo-3-fluoropicolinaldehyde (3.6 g, 31.3% yield) as light-yellow solid, Mass spec: 204 (M+H).

To a solution of 6-bromo-3-fluoropicolinaldehyde (500 mg, 2.45 mmol) in 8 mL MeCN was added DIPEA (1.26 g, 9.8 mmol) and (S)-3-methyl-2-(pyrrolidin-3-yloxy)pyridine (524 mg, 2.94 mmol) (prepared as intermediate 4) with stirring. The mixture was stirred at 80° C. for 2 h, removal the solvent to left the crude product which was purified by silica gel to give (S)-6-bromo-3-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)picolinaldehyde (400 mg, 60% yield), Mass spec: 362 (M+H).

To a solution of (S)-6-bromo-3-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)picolinaldehyde (450 mg, 1.24 mmol) in 4 mL MeOH was added NaBH 4 (56.5 mg, 1.5 mmol) at 0° C. Then the mixture was stirred at r.t for 30 min, the reaction was quenched by H2O, extracted by DCM, washed with water and brine, dried over Na 2 SO 4 , removal the solvent to left the crude product which was purified to give (S)-(6-bromo-3-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (450 mg, quant.), Mass spec: 364 (M+H).

To a solution of (S)-(6-bromo-3-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (50 mg, 0.13 mmol) in 1.5 ml dioxane/H 2 O (v:v=5:1) was added 2-methoxyphenylboronic acid (25 mg, 0.164 mmol), K 2 CO 3 (56.9 mg, 0.41 mmol) and pd(dppf)Cl 2 (10 mg) with stirring. Then the mixture was stirred at 90° C. under N 2 for 2 h, the reaction was the product was extracted by EA, washed by water and brine. Removal the solvent to left crude product which was purified by Pre-HPLC to give (S)-(6-(2-methoxyphenyl)-3-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (20 mg, 20% yield). Mass spec: 392 (M+H), t R =1.908 min, 1 H-NMR (400 Hz, DMSO) δ=8.010-8.023 (d, 1H), 7.745-7.812 (m, 2H), 7.541-7.559 (d, 1H), 7.293-7.382 (m, 2H), 7.059-7.152 (m, 2H), 6.894-6.952 (d, 1H), 5.644 (s, 1H), 4.706-4.736 (m, 1H), 3.902-3.912 (m, 1H), 3.886 (s, 1H), 3.599-3.618 (m, 11H), 3.367-3.498 (m, 1H), 2.315-2.348 (m, 1H), 2.149-2.181 (m, 1H), 2.154 (s, 3H).

Example 334: (S)-(6-phenoxy-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (Compound 1-139)

The title compound was prepared following procedures described in example 333 to (S)-(6-phenoxy-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (20 mg, 50% yield), Mass spec: 432 (M+H), t R =2.449 min, 1 H-NMR (400 Hz, DMSO) δ=8.632 (s, 1H), 8.071-8.099 (m, 1H), 8.024-8.042 (d, 1H), 7.748-7.769 (d, 1H), 7.423-7.461 (m, 2H), 7.331-7.349 (m, 1H), 7.056-7.235 (d, 11H), 5.715 (m, 1H), 5.164-5.190 (m, 1H), 4.680-4.719 (m, 2H), 3.882-3.606 (m, 1H), 3.546-3.606 (m, 2H), 3.389-3.542 (m, 11H), 3.334-2.385 (m, 1H), 2.230-2.231 (m, 1H).

Example 335: (S)-(3-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)-6-o-tolylpyridin-2-yl)methanol (Compound 1-179)

The title compound was prepared following procedures described in example 333 to give (S)-(3-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)-6-o-tolylpyridin-2-yl)methanol (20 mg, 23% yield), Mass spec: 376 (M+H), t R =2.196 min, 1 H-NMR (400 Hz, DMSO) δ=8.011-8.027 (m, 1H), 7.546-7.564 (d, 1H), 8.024-8.042 (d, 1H), 7.748-7.769 (d, 1H), 7.423-7.461 (m, 2H), 7.331-7.349 (m, 1H), 7.056-7.235 (d, 1H), 5.715 (m, 1H), 5.164-5.190 (m, 1H), 4.680-4.719 (m, 2H), 3.882-3.606 (m, 1H), 3.546-3.606 (m, 2H), 3.389-3.542 (m, 1H), 3.334-2.385 (m, 1H), 2.230-2.231 (m, 1H).

Example 336: (S)-(6-(2-ethylphenyl)-3-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (Compound 1-187)

The title compound was prepared following procedures described in example 333 to give (S)-(6-(2-ethylphenyl)-3-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (30 mg, 29% yield), Mass spec: 390 (M+H), t R =2.436 min, 1 H-NMR (400 Hz, DMSO) δ=8.011-8.022 (d, 1H), 7.540-7.558 (d, 1H), 7.234-7.310 (m, 6H), 6.891-6.922 (m, 1H), 5.641 (s, 1H), 5.065-5.091 (m, 1H), 4.611-4.714 (m, 2H), 3.855-3.895 (m, 1H), 3.565-3.605 (m, 1H), 3.410-3.478 (m, 2H), 2.673-2.728 (m, 2H), 2.509-2.510 (m, 1H), 2.334-2.354 (m, 1H), 2.320 (s, 3H), 1.048-1.086 (m, 3H).

Example 337: (S)-2-(6-(hydroxymethyl)-5-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)benzonitrile (Compound 1-192)

The title compound was prepared following procedures described in example 333 to give (S)-2-(6-(hydroxymethyl)-5-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)benzonitri (30 mg, 30% yield), Mass spec: 387 (M+H), t R =2.821 min, 1 H-NMR (400 Hz, DMSO) δ=8.015-8.024 (m, 1H), 7.895-7.946 (m, 2H), 7.725-7.782 (m, 2H), 7.656-7.710 (m, 1H), 7.509-7.559 (m, 2H), 7.260-7.282 (d, 1H), 5.656-5.666 (m, 1H), 5.031-5.056 (m, 1H), 4.698-4.807 (m, 2H), 3.943-3.984 (m, 1H), 3.659-3.677 (m, 1H), 3.514-3.561 (m, 2H), 2.308-2.342 (m, 1H), 2.178-2.202 (m, 1H), 2.114 (s, 3H).

Example 338: (S)-(6-o-tolyl-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (Compound 1-182)

The title compound was prepared following procedures described in example 333 to give (S)-(6-o-tolyl-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (28 mg, 50% yield), Mass spec: 430 (M+H), t R =2.563 min, 1 H-NMR (400 Hz, DMSO) δ=8.633 (s, 1H), 8.076-8.104 (m, 1H), 7.376-7.396 (m, 2H), 7.322-7.343 (m, 4H), 7.039-7.016 (m, 1H), 5.713 (s, 1H), 5.099-5.125 (m, 1H), 4.613-4.719 (m, 2H), 3.877-3.917 (m, 1H), 3.538-3.598 (m, 2H), 3.417-3.459 (m, 1H), 2.505-2.513 (m, 1H), 2.375 (s, 3H), 2.198-2.216 (m, 11H).

Example 339: (S)-(6-(2-methoxyphenyl)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (Compound 1-183)

The title compound was prepared following procedures described in example 333 to give (S)-(6-(2-methoxyphenyl)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol

(18 mg, 23% yield), Mass spec: 446 (M+H), t R =2.069 min, 1 H-NMR (400 Hz, DMSO) δ=8.632 (s, 1H), 8.071-8.099 (m, 1H), 7.781-7.800 (m, 1H), 7.682-7.704 (m, 1H), 7.325-7.349 (m, 1H), 7.196-7.218 (m, 1H), 7.056-7.098 (m, 1H), 7.056-7.057 (m, 1H), 7.106-7.036 (m, 2H), 5.694-5.720 (m, 1H), 5.126-5.153 (m, 1H), 4.610-4.716 (m, 2H), 3.858-3.899 (m, 1H), 3.825 (s, 3H), 3.521-3.581 (m, 2H), 3.410-3.432 (m, 1H), 2.357-2.371 (m, 1H), 2.191-2.208 (m, 1H).

Example 340: (S)-(6-(2-ethylphenyl)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (Compound 1-196)

The title compound was prepared following procedures described in example 333 to give (S)-(6-(2-ethylphenyl)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (16 mg, 20% yield), Mass spec: 444 (M+H), t R =2.776 min, 1 H-NMR (400 Hz, DMSO) δ=8.622 (s, 1H), 8.066-8.094 (m, 1H), 7.229-7.307 (m, 6H), 7.033-7.055 (d, 1H), 5.697-5.722 (m, 1H), 5.068-5.094 (m, 1H), 4.607-4.713 (m, 2H), 3.871-3.912 (m, 1H), 3.530-3.594 (m, 2H), 3.372-3.445 (m, 1H), 2.668-2.724 (m, 2H), 2.361-2.395 (m, 1H), 2.193-2.218 (m, 1H), 1.044-1.081 (m, 3H).

Example 341: (S)-2-(6-(hydroxymethyl)-5-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)benzonitrile (Compound 1-197)

The title compound was prepared following procedures described in example 333 to give (S)-2-(6-(hydroxymethyl)-5-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)benzonitrile (17 mg, 24% yield), Mass spec: 441 (M+H), t R =3.084 min, 1 H-NMR (400 Hz, DMSO) δ=8.636 (s, 1H), 8.074-8.103 (m, 1H), 7.894-7.944 (m, 2H), 7.748-7.787 (m, 2H), 7.513-7.549 (m, 1H), 7.254-7.276 (d, 1H), 3.633-3.684 (m, 2H), 3.513-3.516 (m, 1H), 2.348-2.397 (m, 1H), 2.204-2.248 (m, 1H).

Example 342: (S)-(6-(2-ethylphenyl)-3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (Compound 1-185)

The title compound was prepared following procedures described in example 333 to give (S)-(6-(2-ethylphenyl)-3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (30 mg, 37% yield), Mass spec: 390 (M+H), t R =2.388 min, 1 H-NMR (400 Hz, DMSO) δ=8.022 (s, 1H), 7.532-7.554 (m, 1H), 7.218-7.309 (m, 6H), 6.727-6.784 (d, 1H), 5.577 (d, 1H), 5.074-5.100 (m, 11H), 4.633-4.677 (m, 2H), 3.841-3.880 (m, 1H), 3.411-3.570 (m, 311), 2.671-2.727 (m, 2H), 2.304-2.337 (m, 1H), 2.135-2.150 (m, 1H), 1.046-1.084 (m, 3H).

Example 343: (S)-(3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)-6-o-tolylpyridin-2-yl)methanol (Compound 1-189)

The title compound was prepared following procedures described in example 333 to give (S)-(3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)-6-o-tolylpyridin-2-yl)methanol (30 mg, 37% yield), Mass spec: 376 (M+H), t R =2.132 min, 1 H-NMR (400 Hz, DMSO) δ=8.022 (s, 1H), 7.530-7.551 (d, 1H), 7.216-7.396 (m, 6H), 6.728-6.749 (d, 1H), 5.577 (d, 1H), 5.088-5.114 (m, 1H), 4.637-4.680 (m, 2H), 3.839-3.866 (m, 1H), 3.373-3.570 (m, 3H), 2.350 (s, 3H), 2.305-2.350 (m, 1H), 2.214 (s, 3H), 2.152-2.214 (m, 1H).

Example 344: (S)-2-(6-(hydroxymethyl)-5-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)benzonitrile (Compound 1-190)

The title compound was prepared following procedures described in example 333 to give (S)-2-(6-(hydroxymethyl)-5-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)benzonitrile (20 mg, 22% yield), Mass spec: 387 (M+H), t R =2.803 min, 1 H-NMR (400 Hz, DMSO) δ=8.009 (s, 1H), 7.892-7.943 (m, 2H), 7.718-7.785 (m, 2H), 7.529-7.556 (m, 2H), 7.238-7.259 (d, 1H), 6.728-6.749 (d, 1H), 5.598 (s, 1H), 5.037-5.062 (m, 1H), 4.725-4.769 (m, 2H), 3.934-3.950 (m, 1H), 3.516-3.640 (m, 3H), 2.331-2.332 (m, 1H), 2.214-2.215 (m, 1H).

Example 345: (S)-(6-(2-methoxyphenyl)-3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (Compound 1-191)

The title compound was prepared following procedures described in example 7 using (S)-(6-bromo-3-(3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol and 2-methoxyphenylboronic acid (20 mg, 23% yield), Mass spec: 392 (M+H), t R =1.884 min, 1 H-NMR (400 Hz, DMSO) δ=8.000 (s, 1H), 7.780-7.800 (m, 1H), 7.675-7.697 (m, 1H), 7.526-7.553 (m, 1H), 7.304-7.325 (m, 1H), 7.176-7.179 (d, 1H), 7.097-7.117 (d, 1H), 7.014-7.052 (m, 1H), 6.725-6.747 (d, 1H), 5.570 (s, 1H), 5.121-5.148 (m, 1H), 4.633-4.675 (m, 2H), 3.824-3.860 (m, 1H), 3.824 (s, 3H), 3.535-3.554 (m, 1H), 3.382-3.441 (m, 2H), 2.318-2.334 (m, 1H), 2.138-2.212 (m, 1H).

Example 346: (S)-(3-(3-(5-chloropyridin-2-yloxy)pyrrolidin-1-yl)-6-o-tolylpyridin-2-yl)methanol (Compound 1-195)

The title compound was prepared following procedures described in example 333 to give (S)-(3-(3-(5-chloropyridin-2-yloxy)pyrrolidin-1-yl)-6-o-tolylpyridin-2-yl)methanol (20 mg, 30% yield), Mass spec: 396 (M+H), t R =2.368 min, 1 H-NMR (400 Hz, DMSO) δ=8.25-8.256 (d, 1H), 7.811-7.840 (m, 2H), 6.916-7.395 (m, 6H), 6.893-6.916 (d, 1H), 5.587 (s, 1H), 5.095-5.120 (m, 1H), 4.636-4.680 (m, 2H), 3.846-3.886 (m, 1H), 3.497-3.578 (m, 2H), 3.415-3.423 (m, 1H), 5.121-5.148 (m, 1H), 4.633-4.675 (m, 2H), 3.824-3.860 (m, 1H), 3.824 (s, 3H), 3.535-3.554 (m, 1H), 2.350 (s, 3H), 2.336-2.350 (m, 1H), 2.144-2.174 (m, 1H).

Example 347: (S)-(3-(3-(5-chloropyridin-2-yloxy)pyrrolidin-1-yl)-6-(2-ethylphenyl)pyridin-2-yl)methanol (Compound 1-201)

The title compound was prepared following procedures described in example 333 to give (S)-(3-(3-(5-chloropyridin-2-yloxy)pyrrolidin-1-yl)-6-(2-ethylphenyl)pyridin-2-yl)methanol (20 mg, 30% yield), Mass spec: 396 (M+H), t R =2.577 min, 1 H-NMR (400 Hz, DMSO) δ=8.242-8.249 (d, 1H), 7.827-7.834 (m, 1H), 7.227-7.295 (m, 6H), 6.889-6.911 (d, 1H), 5.578-5.584 (m, 1H), 5.064-5.089 (m, 1H), 4.614-4.706 (m, 2H), 3.855-3.883 (m, 1H), 3.520-3.597 (m, 2H), 3.389-3.442 (m, 1H), 2.687-2.742 (m, 2H), 2.335-2.504 (m, 1H), 2.164-2.172 (m, 1H), 1.044-1.082 (m, 3H).

Example 348: (S)-(3-(3-(5-chloropyridin-2-yloxy)pyrrolidin-1-yl)-6-(2-methoxyphenyl)pyridin-2-yl)methanol (Compound 1-202)

The title compound was prepared following procedures described in example 333 to give (S)-(3-(3-(5-chloropyridin-2-yloxy)pyrrolidin-1-yl)-6-(2-methoxyphenyl)pyridin-2-yl)methanol (20 mg, 30% yield), Mass spec: 412 (M+H), t R =1.964 min, 1 H-NMR (400 Hz, DMSO) δ=8.244-8.251 (d, 1H), 7.827-7.834 (m, 1H), 7.778-7.831 (m, 2H), 7.676-7.679 (d, 1H), 7.302-7.345 (m, 1H), 7.183-7.203 (m, 1H), 7.096-7.117 (m, 2H), 7.688-7.691 (m, 1H), 5.580 (s, 1H), 5.105-5.130 (m, 1H), 4.601-4.708 (m, 2H), 3.835 (s, 3H), 3.822-3.863 (m, 1H), 3.372-3.560 (m, 3H), 2.318-2.353 (m, 1H), 2.167-2.168 (m, 1H).

Example 349: (S)-(6-(2-ethylphenyl)-3-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (Compound 1-204)

The title compound was prepared following procedures described in example 333 to give (S)-(6-(2-ethylphenyl)-3-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (24 mg, 26% yield), Mass spec: 394 (M+H), t R =2.259 min, 1 H-NMR (400 Hz, DMSO) δ=8.010-8.022 (d, 1H), 7.684-7.728 (m, 1H), 7.235-7.299 (m, 6H), 7.034-7.074 (m, 1H), 5.706 (s, 1H), 5.092-5.118 (m, 1H), 4.609-4.716 (m, 2H), 3.887-3.928 (m, 1H), 3.538-3.595 (m, 2H), 3.410-3.453 (m, 1H), 2.675-2.730 (m, 2H), 2.361-2.395 (m, 3H), 2.185-2.226 (m, 1H), 1.049-1.087 (m, 3H).

Example 350: (S)-(3-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-6-(2-methoxyphenyl)pyridin-2-yl)methanol (Compound 1-213)

The title compound was prepared following procedures described in example 333 to give (S)-(3-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-6-(2-methoxyphenyl)pyridin-2-yl)methanol (65 mg, 60% yield), Mass spec: 396 (M+H), t R =1.772 min, 1 H-NMR (400 Hz, DMSO) δ=8.005-8.018 (m, 1H), 7.728-7.804 (m, 1H), 7.673-7.720 (m, 2H), 7.305-7.347 (m, 1H), 7.201-7.224 (m, 1H), 7.015-7.071 (m, 3H), 5.692-5.696 (m, 1H), 5.125-5.150 (m, 1H), 4.609-4.715 (m, 2H), 3.863-3.904 (m, 1H), 3.824 (s, 3H), 3.514-3.574 (m, 2H), 3.380-3.441 (m, 1H), 2.357-2.391 (m, 1H), 2.176-2.210 (m, 1H).

Example 351: (S)-(3-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-6-o-tolylpyridin-2-yl)methanol (Compound 1-216)

The title compound was prepared following procedures described in example 333 to give (S)-(3-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-6-o-tolylpyridin-2-yl)methanol (29 mg, 31% yield), Mass spec: 380 (M+H), t R =2.803 min, 1 H-NMR (400 Hz, DMSO) δ=8.007-8.019 (d, 1H), 7.673-7.723 (m, 1H), 7.239-7.396 (m, 6H), 7.032-7.072 (m, 1H), 5.704 (s, 1H), 5.103-5.130 (m, 1H), 4.613-4.720 (m, 2H), 3.883-3.923 (m, 1H), 3.532-3.591 (m, 2H), 3.360-3.448 (m, 1H), 2.352-2.394 (m, 1H), 2.352 (s, 3H), 2.201-2.224 (m, 1H).

Example 352: (S)-2-(5-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-6-(hydroxymethyl)pyridin-2-yl)benzonitrile (Compound 1-217)

The title compound was prepared following procedures described in example 333 to give (S)-2-(5-(3-(3-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-6-(hydroxymethyl)pyridin-2-yl)benzonitrile (20 mg, 21% yield), Mass spec: 391 (M+H), t R =2.650 min, 1 H-NMR (400 Hz, DMSO) δ=8.203-8.205 (d, 1H), 7.926-8.010 (m, 2H), 7.673-7.894 (m, 3H), 7.509-7.550 (m, 1H), 7.262-7.283 (d, 1H), 7.036-7.076 (m, 1H), 5.725-5.730 (m, 1H), 5.047-5.072 (m, 1H), 4.699-4.808 (m, 2H), 3.968-4.009 (m, 1H), 3.625-3.654 (m, 2H), 3.519-3.555 (m, 1H), 2.352-2.387 (m, 1H), 2.223-2.247 (m, 2H).

Example 353: (S)-2-(5-(3-(5-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-6-(hydroxymethyl)pyridin-2-yl)benzonitrile (Compound 1-208)

The title compound was prepared following procedures described in example 333 to give (S)-2-(5-(3-(5-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-6-(hydroxymethyl)pyridin-2-yl)benzonitrile (20 mg, 20% yield), Mass spec: 394 (M+H). t R =2.354 min, 1 H-NMR (400 Hz, DMSO) δ=8.175-8.182 (d, 1H), 7.695-7.703 (m, 1H), 7.223-7.308 (m, 6H), 6.880-6.911 (m, 1H), 5.560 (m, 1H), 5.063-5.090 (m, 1H), 4.632-4.675 (m, 2H), 3.854-3.869 (m, 1H), 3.387-3.556 (m, 3H), 2.688-2.706 (m, 2H), 2.330-2.350 (m, 1H), 2.156-2.158 (m, 1H), 1.044-1.082 (m, 3H).

Example 354: (S)-(3-(3-(5-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-6-o-tolylpyridin-2-yl)methanol (Compound 1-207)

The title compound was prepared following procedures described in example 333 to give (S)-(3-(3-(5-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-6-o-tolylpyridin-2-yl)methanol (20 mg, 20% yield), Mass spec: 380 (M+H), t R =2.088 min, 1 H-NMR (400 Hz, DMSO) δ=8.175-8.183 (d, 1H), 7.674-7.725 (m, 1H), 7.220-7.391 (m, 6H), 6.879-6.911 (m, 1H), 5.553-5.560 (m, 1H), 5.080-5.106 (m, 1H), 4.635-4.678 (m, 2H), 3.838-3.879 (m, 1H), 3.419-3.573 (m, 3H), 2.329 (s, 3H), 2.347-2.370 (m, 1H), 2.155-2.157 (m, 1H).

Example 355: (S)-(3-(3-(5-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-6-(2-methoxyphenyl)pyridin-2-yl)methanol (Compound 1-209)

The title compound was prepared following procedures described in example 333 to give (S)-(3-(3-(5-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-6-(2-methoxyphenyl)pyridin-2-yl)methanol (20 mg, 20% yield), Mass spec: 396 (M+H), t R =1.738 min, 1 H-NMR (400 Hz, DMSO) δ=8.182-8.189 (d, 1H), 7.782-7.801 (d, 1H), 7.679-7.707 (m, 2H), 7.327 (m, 1H), 7.182-7.204 (m, 1H), 7.098-7.119 (m, 1H), 7.034 (m, 1H), 6.883-6.914 (m, 1H), 5.557 (br, 1H), 5.123-5.136 (m, 1H), 4.635-4.678 (m, 2H), 3.825-3.868 (m, 1H), 3.868 (s, 3H), 3.341-3.543 (m, 3H), 2.346 (m, 1H), 2.160 (m, 1H).

Example 356: (S)-2-(5-(3-(5-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-6-(hydroxymethyl)pyridin-2-yl)benzonitrile (Compound 1-210)

The title compound was prepared following procedures described in example 333 to give (S)-2-(5-(3-(5-fluoropyridin-2-yloxy)pyrrolidin-1-yl)-6-(hydroxymethyl)pyridin-2-yl)benzonitrile (20 mg, 20% yield), Mass spec: 391(M+H), t R =2.732 min, 1 H-NMR (400 Hz, DMSO) δ=8.184-8.192 (d, 1H), 7.892-7.943 (m, 1H), 7.686-7.782 (m, 3H), 7.509-7.547 (m, 1H), 7.241-7.509 (d, 1H), 6.883-6.915 (m, 1H), 5.582 (m, 1H), 5.046-5.072 (m, 1H), 4.726-4.772 (m, 2H), 3.928-3.968 (m, 1H), 3.376-3.645 (m, 3H), 2.340 (m, 1H), 2.198 (m, 1H).

Example 357: (S)-2-(3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)-6-o-tolylpyridin-2-yl)ethanol (Compound 1-200)

To a solution of (methoxymethyl)triphenylphosphonium chloride (1.28 g, 4.14 mmol) in 8 ml THF was added LDA (4.2 ml, 8.28 mmol) at 0° C. under N 2 , the mixture was stirred at this temperature for 10 min, before It was added to (S)-6-bromo-3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)picolinaldehyde (500 mg, 1.38 mmol) (prepared as example 333 step 2) in 5 mL THE drop wise, the resulting mixture was stirred at 0° C. for 30 min, quenched by water, and diluted with EA, the organic layer was washed by water and brine, dried over Na 2 SO 4 , removal the solvent to left the crude product which was purified by silica gel to give (S)-6-bromo-2-(2-methoxyvinyl)-3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridine (300 mg, 60% yield), Mass spec: 390 (M+1).

To a solution of (S)-6-bromo-2-(2-methoxyvinyl)-3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridine (300 mg, 0.76 mmol) was dissolved in 4 mL actone was added 4 mL 10% HCl solution slowly, Then the reacting mixture was stirred at 60° C. for 3 h, the mixture was adjusted the PH to 9 with NaHCO 3 solution, extracted with EA, the organic layer was washed with water and brine, dried over Na2SO 4 , removal the solvent to left the crude (S)-2-(6-bromo-3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)acetaldehyde (300 mg, quant.) which can be used directly, Mass spec: 376 (M+1).

To a solution of (S)-2-(6-bromo-3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)acetaldehyde (300 mg, 0.79 mmol) in 6 mL MeOH/DCM (v:v=3:1) was added NaBH 4 (45.2 mg, 1.2 mmol) slowly at 0° C., the mixture was stirred at r.t for 20 min. the mixture was quenched by water, and extracted with DCM, washed with water and brine, dried over Na 2 SO 4 , removal the solvent to left the crude (S)-2-(6-bromo-3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)ethanol (300 mg, quant.) which can be used directly, Mass spec: 378 (M+1).

To a solution of (S)-2-(6-bromo-3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)ethanol (100 mg, 0.26 mmol) in 1.5 mL dioxane/H 2 O (v:v=5:1) was added o-tolylboronic acid (53 mg, 0.39 mmol), K 2 CO 3 (109 mg, 0.78 mmol) and pd (dppf)Cl 2 (20 mg), the mixture was stirred at 90° C. under N2 for 2 h. the mixture was diluted with EA, the organic layer was washed by water and brine, dried over Na2SO 4 , removal the solvent to left the crude product which was purified by Pre-HPLC to give (S)-2-(3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)-6-o-tolylpyridin-2-yl)ethanol (20 mg, 20% yield). Mass spec: 390 (M+H), 1 H-NMR (400 Hz, DMSO) δ=7.999 (s, 1H), 7.558-7.532 (m, 1H), 7.372-7.331 (m, 2H), 7.260-7.245 (m, 4H), 6.670-6.740 (m, 1H), 5.552 (s, 1H), 4.724-4.696 (m, 1H), 3.867-3.817 (m, 2H), 3.747-3.706 (m, 1H), 3.482-3.441 (m, 1H), 3.331-3.210 (m, 2H), 3.034-2.973 (m, 2H), 2.395-2.351 (m, 4H), 2.213 (m, 3H), 2.115-2.074 (m, 1H).

Example 359: (S)-2-(6-(2-ethylphenyl)-3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)ethanol (Compound 1-218)

The title compound was prepared following procedures described in example 357 to give (S)-2-(6-(2-ethylphenyl)-3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)ethanol (30 mg, 30% yield), Mass spec: 403 (M+1), t R =2.099 min, 1 H-NMR (400 Hz, DMSO) δ=7.996 (s, 1H), 7.533-7.559 (m, 1H), 7.194-7.356 (m, 6H), 6.740-6.762 (m, 1H), 5.545-5.552 (m, 1H), 4.699-4.727 (m, 1H), 3.811-3.844 (m, 2H), 3.705-3.746 (m, 1H), 3.442-3.480 (m, 1H), 3.228-3.274 (m, 2H), 2.990-3.031 (m, 2H), 2.682-2.738 (m, 2H), 2.682-2.738 (m, 1H), 2.509 (s, 3H), 2.079-2.103 (m, 1H), 1.039-1.076 (m, 3H).

Example 360: (S)-(5-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)-2,2′-bipyridin-6-yl)methanol (Compound 1-244)

To a solution of (S)-6-bromo-3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)picolinaldehyde (100 mg, 0.277 mmol) (prepared as example 333 step 2), 2-(tributylstannyl)pyridine (102 mg, 0.277 mmol), and LiCl (99 mg, 1.662) in 2 mL dixoane were added Pd(PPh 3 ) 4 (32.3 mg, 0.028 mmol), the mixture was degassed for 2 min with N2, stirred at 100° C. overnight under N2, then added Sat. KF solution, stirred for another 1 h, extracted with EA, the organic layer was dried over Na 2 SO 4 , removal the solvent to left the crude product which was purified by Prep-TLC to give the crude (S)-5-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)-2,2′-bipyridine-6-carbaldehyde (60 mg, 60.6% yield) as brown solid, Mass spec: 361 (M+H).

(S)-(5-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)-2,2′-bipyridin-6-yl)methanol

To a solution of S)-5-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)-2,2′-bipyridine-6-carbaldehyde (60 mg, 0.167 mmol) in 2 mL MeOH was added NaBH 4 at 0° C., the mixture was stirred for 5 min, and quenched with water, removal the solvent to left the residue which was purified by Pre-HPLC to give (S)-(5-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)-2,2′-bipyridin-6-yl)methanol (3.1 mg, 5% yield) as yellow solid, Mass spec: 363 (M+H), t R =1.936 min, 1 H-NMR (400 Hz, DMSO) δ=8.538-8.592 (d, 1H), 8.325-8.345 (d, 1H), 8.148-8.170 (d, 1H), 8.004-8.008 (d, 1H), 7.835-7.878 (m, 1H), 7.526-7.553 (m, 1H), 7.241-7.324 (m, 1H), 7.219-7.241 (m, 1H), 6.726-6.746 (m, 2H), 5.579-5.597 (m, 1H), 4.673-4.762 (m, 2H), 3.907-3.948 (m, 1H), 3.501-3.631 (m, 3H), 2.323-2.338 (m, 1H), 2.212 (s, 3H), 2.152-2.170 (m, 1H).

Example 361: (S)-(6-(pyrimidin-2-yl)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (Compound 1-245)

The title compound was prepared following procedures described in example 360 to give (S)-(6-(pyrimidin-2-yl)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (30 mg, 15% yield), Mass spec: 418 (M+H), t R =2.338 min, 1 H-NMR (400 Hz, DMSO) δ=8.872-8.883 (d, 1H), 8.635 (s, 1H), 8.228-8.250 (d, 1H), 8.070-8.098 (m, 1H), 7.396-7.420 (m, 1H), 7.208-7.230 (d, 1H), 7.032-7.054 (d, 1H), 5.744 (s, 1H), 5.548 (m, 1H), 4.717-4.820 (m, 2H), 4.008-4.048 (m, 1H), 3.617-3.735 (m, 3H), 2.500-2.508 (m, 1H), 2.250-2.265 (m, 1H).

Example 362: (S)-(6-phenoxy-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (Compound 1-199)

The title compound was prepared following procedures described in example 236 step 3 using (S)-6-bromo-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)picolinaldehyde (prepared as 333 step 1) and phenol to give (S)-6-phenoxy-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)picolinaldehyde (50 mg, 58% yield), Mass spec: 430 (M+H).

The title compound was prepared following procedures described in example 333 step 2 to give (S)-(6-phenoxy-3(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (25 mg, 50% yield), Mass spec: 432 (M+1), t R =3.242 min, 1H-NMR (400 Hz, DMSO) δ=8.606 (s, 1H), 8.063-8.085 (d, 1H), 7.354-7.445 (m, 3H), 7.027-7.150 (m, 4H), 6.816-6.836 (d, 1H), 5.656 (s, 1H), 4.873-4.900 (m, 1H), 4.463-4.486 (m, 1H), 3.696-3.737 (m, 1H), 3.387-3.449 (m, 2H), 3.236-3.265 (m, 1H), 2.124-2.139 (m, 1H).

Example 363: (S)-(6-(2-methoxyphenoxy)-3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (Compound 1-205)

The title compound was prepared following procedures described in example 362 to give (S)-(6-(2-methoxyphenoxy)-3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (30 mg, 50% yield), Mass spec: 378 (M+1), t R =2.781 min, 1 H-NMR (400 Hz, DMSO) δ=7.974-7.978 (d, 1H), 7.537-7.543 (m, 1H), 7.406-7.515 (d, 1H), 7.131-7.168 (m, 2H), 7.046-7.049 (d, 1H), 6.936-6.952 (m, 1H), 6.713-6.734 (d, 11H), 6.626-6.649 (d, 11H), 5.484-5.512 (m, 1H), 4.726-4.752 (m, JH), 4.408-4.435 (m, 2H), 3.705 (s, 3H), 3.594-3.635 (m, 1H), 3.233-3.239 (m, 1H), 3.153-3.183 (m, 2H), 2.3172.350 (m, 1H), 2.200 (s, 3H), 2.015-2.031 (m, 3H).

Example 364: (S)-(6-(o-tolyloxy)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (Compound 1-226)

The title compound was prepared following procedures described in example 362 to give (S)-(6-(o-tolyloxy)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (30 mg, 30% yield), Mass spec: 446 (M+1), t R =3.252 min, 1 H-NMR (400 Hz, DMSO) δ=8.604 (s, 1H), 8.061-8.089 (d, 1H), 7.418-7.440 (d, 1H), 7.283-7.302 (d, 2H), 7.175-7.194 (m, 1H), 6.939-7.108 (m, 2H), 6.919-6.939 (d, 1H), 6.702-6.724 (d, 1H), 5.637 (s, 1H), 4.827-4.854 (m, 1H), 4.432-4.455 (m, 2H), 3.654-3.695 (m, 1H), 3.319-3.414 (m, 2H), 3.192-3.234 (m, 1H), 2.356-2.406 (m, 1H), 2.140 (s, 3H), 2.086-2.140 (m, 1H).

Example 365: (S)-(6-(2-ethylphenoxy)-3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (Compound 1-214)

The title compound was prepared following procedures described in example 362 to give (S)-(6-(2-ethylphenoxy)-3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (20 mg, 30% yield), Mass spec: 406 (M+1), 1 H-NMR (400 Hz, DMSO) δ=7.979 (s, 1H), 7.543-7.522 (m, 1H), 7.416-7.395 (m, 1H), 7.323-7.305 (m, 1H), 7.216-7.101 (m, 2H), 6.924-6.905 (m, 1H), 3.734-6.687 (m, 2H), 5.512-5.506 (s, 1H), 4.845-4.818 (m, 1H), 4.445-4.430 (m, 2H), 3.654-3.628 (m, 1H), 3.327-3.206 (m, 3H), 2.573-2.504 (m, 2H), 2.333-2.316 (m, 1H), 2.200 (s, 3H), 2.060-2.043 (m, 1H), 1.139-1.119 (m, 3H).

Example 366: (S)-(3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)-6-(o-tolyloxy)pyridin-2-yl)methanol (Compound 1-203)

The title compound was prepared following procedures described in example 362 to give (S)-(3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)-6-(o-tolyloxy)pyridin-2-yl)methanol (30 mg, 42% yield), Mass spec: 392 (M+1), 1 H-NMR (400 Hz, DMSO) δ=7.980-7.976 (m, 1H), 7.544-7.517 (m, 1H), 7.422-7.401 (m, 1H), 7.302-7.283 (m, 1H), 7.213-7.175 (m, 1H), 7.108-7.090, (m, 1H) 6.940-6.921 (m, 1H), 6.735-6.696 (m, 2H), 5.522-5.493 (s, 1H), 4.827-4.799 (m, 1H), 4.454-4.427 (m, 2H), 3.666-3.626 (m, 1H), 3.389-3.321 (m, 1H), 3.273-3.184 (m, 2H), 2.351-2.302 (m, 1H), 2.202-2.123 (m, 6H), 2.063-2.029 (m, 1H).

Example 367: (S)-(6-(2-ethylphenoxy)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (Compound 1-212)

To a solution of (S)-(6-bromo-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (100 mg, 0.24 mmol) ((prepared as 333 step 2) in 1.8 ml dioxane/DMF (v:v==5:1) was added Cs 2 CO 3 (155.82 mg, 0.48 mmol) and 2-ethylphenol (58.2 mg, 0.48 mmol), CuI (22.7 mg, 0.12 mmol) and 2-(dimethylamino)acetic acid hydrochloride (16.7 mg, 0.12 mmol), the mixture was irradiated by microwave at 160° C. for 1 h, water was added, extracted with EA, the organic layer was washed with LiCi solution and brine, dried over Na 2 SO 4 , removal the solvent to left the crude product which was purified by Pre-HPLC to give (S)-(6-(2-ethylphenoxy)-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (30 mg, 20% yield), Mass spec: 460 (M+H), t R =3.543 min, 1 H-NMR (400 Hz, DMSO) δ=8.603 (s, 1H), 8.061-8.088 (m, 1H), 7.416-7.4380 (d, 1H), 7.305-7.324 (d, 1H), 7.182-7.217 (m, 1H), 7.105-7.141 (m, 1H), 7.023-7.044 (d, 1H), 6.909-6.298 (d, 1H), 6.697-6.719 (d, 1H), 5.639 (m, 1H), 4.849-4.874 (m, 1H), 4.446-4.468 (m, 2H), 3.660-3.701 (m, 1H), 3.197-3.349 (m, 3H), 2.536-2.574 (m, 2H), 2.358-2.408 (m, 1H), 2.106-2.123 (m, 1H), 1.101-1.139 (m, 3H).

Example 369: (R)-2-phenyl-5-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)isonicotinamide (Compound 1-99)

A solution of (R)-2-phenyl-5-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)isonicotinonitrile (100 mg, 0.244 mmol) (example 368 step 4) in 2 mL con H 2 SO4 was stirred at r.t for overnight, and the mixture was poured into ice water, adjusted the pH with 30% NaOH solution to 11, extracted with DCM, dried over Na 2 SO 4 , removal the solvent to left the crude product which was purified by silica gel to give (R)-2-phenyl-5-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)isonicotinamide (50 mg, 50% yield), Mass spec: 429 (M+1), t R =2.485 min, 1 H-NMR (400 Hz, DMSO)␣, 8.638 (s, 1H), 8.224 (s, 1H), 7.970-8.095 (m, 4H), 7.629-7.667 (m, 2H), 7.415-7.453 (m, 2H), 7.320-7.338 (m, 1H), 7.020-7.042 (m, 1H), 5.732 (s, 1H), 3.902-3.943 (m, 1H), 3.642-3.664 (m, 1H), 3.329-3.461 (m, 2H), 2.273-2.338 (m, 2H).

Example 370: (R)-6-phenyl-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)picolinamide (Compound 1-98)

To a solution of 5-fluoro-2-phenylpyridine (100 mg, 0.57 mmol) in 5 mL DCM was added m-CPBA (200 mg, 1.15 mmol), the mixture was stirred at r.t overnight. water was added and combined the organic layer, dried over Na 2 SO 4 , removal the solvent to left the crude product which was purified by silica gel to give 5-fluoro-2-phenylpyridine 1-oxide (80 mg, 80% yield), Mass spec: 190 (M+1).

To a solution of 5-fluoro-2-phenylpyridine 1-oxide (80 mg, 0.42 mmol) in 4 mL CHCl 3 was added POC13 (123 mg, 0.82 mmol), Then the mixture was heated to 65° C. overnight, LCMS indicated 80% yield SM, 0.25 ml POCl 3 was added and the mixture was heated to 75° C. for 6 h again, the mixture was cooled to r.t and ice was added, extracted with DCM, organic layer was washed with NaHCO 3 solution, dried over Na 2 SO 4 , removal the solvent to left the crude product which was purified by silica gel to give 2-chloro-3-fluoro-6-phenylpyridine (30 mg, 34% yield), Mass spec: 208 (M+1).

The title compound was prepared following procedures described in example 368 step 3 to give 3-fluoro-6-phenylpicolinonitrile (10 mg, 50% yield), Mass spec: 199 (M+1).

The title compound was prepared following procedures described in example 368 step 4 to give (R)-6-phenyl-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)picolinonitrile (170 mg, 85% yield) as white solid, Mass spec: 411 (M+1), t R =3.335 min, 1 H-NMR (400 Hz, DMSO) δ=8.642-8.648 (m, 1H), 8.101-8.108 (m, 1H), 8.035-8.058 (d, 1H), 7.399-7.480 (m, 4H), 7.048-7.070 (d, 1H), 5.786-5.790 (m, 1H), 4.079-4.120 (m, 1H), 3.779-3.833 (m, 3H), 2.322-2.332 (m, 2H).

The title compound was prepared following procedures described in example 369 to give (R)-6-phenyl-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)picolinamide (55 mg, 80% yield) as white solid, Mass spec: 429 (M+1), t R =2.852 min, 1 H-NMR (400 Hz, DMSO) δ=8.635 (s, 1H), 8.020-8.086 (m, 3H), 7.850-7.923 (m, 2H), 7.412-7.451 (m, 3H), 7.267-7.339 (m, 2H), 7.006-7.028 (d, 1H), 5.713 (s, 1H), 3.893-3.935 (m, 1H), 3.589-3.607 (m, 1H), 3.362-3.449 (m, 2H), 2.258-2.328 (m, 2).

Example 371: (S)-(5-phenyl-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (Compound 1-188)

A mixture of 5-bromo-3-nitropicolinonitrile (500 mg, 2.2 mmol) in DMF was added H 2 SO 4 (0.01 ml) and TBAF (6.6 ml) at −40° C., the mixture was stirred at −40° C. for 30 min, quenched with HCl solution (2M) at −40° C. to pH=3, The mixture was extracted with EA, washed with brine, dried over Na 2 SO4, removal the solvent to left the crude 5-bromo-3-fluoropicolinonitrile (500 mg, quant.) which can be used to next step directly, Mass spec: 201 (M+1)

The title compound was prepared following procedures described in example 368 step 4 to give (S)-5-bromo-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)picolinonitrile (340 mg, 80%), Mass spec: 413 (M+1).

The title compound was prepared following procedures described in example 357 step 4 to give (S)-5-phenyl-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)picolinonitrile (300 mg, 8% yield), Mass spec: 411 (M+1).

The title compound was prepared following procedures described in example 368 step 5 to give (S)-5-phenyl-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)picolinaldehyde (80 mg, 26% yield), Mass spec: 414 (M+1).

The title compound was prepared following procedures described in example 368 step 6 to give (S)-(5-phenyl-3-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol (20 mg, 25% yield), Mass spec: 416 (M+1), t R =3.591 min, 1 H-NMR (400 Hz, DMSO) δ=8.629 (s, 11H), 8.266 (s, 1H), 8.075-8.094 (m, 1H), 7.717-7.735 (m, 2H), 7.395-7.512 (m, 3H), 7.312 (s, 1H), 7.031-7.053 (d, 1H), 5.717 (m, 1H), 5.132-5.158 (m, 1H), 4.639-4.676 (m, 2H), 3.904-3.944 (m, 1H), 3.584-3.651 (m, 2H), 3.408-3.413 (m, 1H), 2.363-2.395 (m, 1H), 2.200-2.218 (m, 1H).

Example 373: (R)-5-phenyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)nicotinamide (Compound 1-92)

To solution of methyl 5-bromo-2-chloronicotinate (3.8 g, 15.2 mmol) and (S)-pyrrolidin-3-ol (22.4 g, 18.2 mmol) in 30 mL MeCN was added TEA (4.2 ml, 30.4 mmol), the mixture was stirred at 60° C. for 1 h, removed MeCN, the residue was diluted with EA, the organic layer was washed with water and brine, dried over Na 2 SO 4 , removal the solvent to left the crude product which was purified by silica gel to give (R)-methyl 5-bromo-2-(3-hydroxypyrrolidin-1-yl)nicotinate (4.1 g, 9% yield), Mass spec: 301 (M+1).

The title compound was prepared following procedures described in example 357 step 4 to give (R)-methyl 2-(3-hydroxypyrrolidin-1-yl)-5-phenylnicotinate (3 g, 50% yield), Mass spec: 299 (M+1).

The title compound was prepared following procedures described in intermediate 1 step 1 to give 5-phenyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)nicotinate (250 mg, 80% yield), Mass spec: 444 (M+1).

The title compound was prepared following procedures described in intermediate 38 step 2 to give (R)-5-phenyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)nicotinic acid (150 mg, 75% yield), Mass aspect: 430 (M+1), t R =2.658 min, 1 H-NMR (400 Hz, DMSO), ␣␣␣=8.567-8.615 (m, 2H), 8.047-8.107 (m, 2H), 7.627-7.649 (m, 2H), 7.426-7.464 (m, 2H), 7.306-7.342 (m, 1H), 7.015-7.038 (d, 1H), 55.67 (m, 1H), 3.949-3.992 (m, 1H), 3.730-3.801 (m, 3H), 2.238-2.301 (m, 2H).

To a solution of (R)-5-phenyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)nicotinic acid (140 mg, 0.33 mmol) in 2 mL DCM was added 0.04 ml (COCl) 2 and one drop DMF, It was stirred at r.t for 3 h, then evaporated to dry; the residue was dissolved in 2 ml THF and NH 3 in THF was added, the mixture was stirred at r.t overnight, removal the solvent to left the crude product which was purified by silica gel to give (R)-5-phenyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)nicotinamide (50 mg, 36% yield), Mass spec: 429 (M+1), t R =2.257 min, 1 H-NMR (400 Hz, DMSO) □□=8.620 (s, 1H), 8.473-8.478 (d, 1H), 8.047-8.075 (m, 2H), 7.830-7.835 (d, 1H), 7.625-7.643 (d, 1H), 7.440-7.474 (m, 3H), 7.310-7.328 (m, 1H), 7.005-7.028 (d, 1H), 5.693 (s, 2H), 3.938-3.969 (m, 1H), 3.612-3.744 (m, 3H), 2.225-2.288 (m, 2H).

The title compound was prepared following procedures described in example 373 to give (R)-2-(3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)-5-phenylnicotinamide (100 mg, 50% yield), Mass spec: 395 (M+1), t R =1.342 min, 1 H-NMR (400 Hz, DMSO)ξξ=8.492-8.498 (d, 1H), 8.162-8.172 (m, 1H), 7.991 (s, 1H), 7.894-7.912 (m, 1H), 7.829-7.835 (m, 1H), 7.637-7.657 (d, 1H), 7.424-7.476 (m, 3H), 7.312-7.330 (m, 1H), 7.040-7.059 (m, 1H), 5.659-5.669 (m, 1H), 3.960-3.991 (m, 1H), 3.657-3.760 (m, 3H), 2.213-2.218 (m, 2H).

Example 375: (S)-tert-butyl 2-(6-(hydroxymethyl)-5-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)benzyl (methyl)carbamate (Compound 1-258)

Step 1: (S)-2-(6-(hydroxymethyl)-5-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)benzaldehyde

The title compound was prepared following procedures described in example 357 step 4 to give (S)-2-(6-(hydroxymethyl)-5-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)benzaldehyde (280 mg, 55% yield), Mass spec: 390 (M+1).

Step 2: (S)-(6-(2-((methylamino)methyl)phenyl)-3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol

To a solution of (S)-2-(6-(hydroxymethyl)-5-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)benzal (250 mg, 0.641 mmol) in 2 mL DMSO was added MeNH 2 (86 mg, 12.8 mmol) at r.t, the mixture was stirred at 40° C. for 2 h, then NaBH (OAc) 3 (204 mg, 0.96 mmol) in 1 mL DMSO was added dropwise at rt, the resulting mixture was stirred overnight at r.t, quenched by 10% citric acid solution, extracted with EA, the aqueous layer was basified by addition of a 10% K 2 CO 3 solution to PH=10, extracted with EA, combined organic layer which was washed with brine, dried over N 2 SO 4 , removal the solvent to left the crude (S)-(6-(2-((methylamino)methyl)phenyl)-3-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)methanol which can be used directly (180 mg, 70% yield), Mass spec: 405 (M+1).

Step 3: (S)-tert-butyl 2-(6-(hydroxymethyl)-5-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)benzyl (methyl)carbamate

The title compound was prepared following procedures described in example 294 step 2 to give 2-(6-(hydroxymethyl)-5-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)pyridin-2-yl)benzyl (methyl)carbamate (15 mg, 8% yield), Mass spec: 505 (M+1), t R =2.626 min, 1 H-NMR (400 Hz, DMSO) δ=8.000-8.004 (m, 1H), 7.533-7.555 (m, 1H), 7.316-7.405 (m, 4H), 7.180-7.241 (m, 2H), 6.723-6.743 (d, 1H), 5.566-5.586 (m, 1H), 5.055-5.082 (m, 1H), 4.576-4.677 (m, 4H), 3.858-3.898 (m, 1H), 3.430-3.580 (m, 3H), 2.656 (s, 3H), 2.502-2.515 (m, 1H), 2.140-2.156 (m, 1H), 1.297-1.400 (m, 9H).

Example 435: (S)-(5-(3,6-dihydro-2H-pyran-4-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (Compound 1-280)

To a solution of dihydro-2H-pyran-4 (3H)-one (1 g, 0.01 mol) in THE was added LDA (Prepared: To a solution of diisopropylamine (1.54 ml, 0.011 mol) in dry THF (10 ml) was added n-BuLi (4.39 ml, 2.5 Min hexane) drop-wised in ice-salt bath during 10 min under N 2 , the mixture was stirred at this temperature for 30 min) drop-wised during 20 min at −78° C., the mixture was stirred for 3 h at this temperature, then a solution of 1,1,1-trifluoro-N-phenyl-N— (trifluoromethylsulfonyl)methanesulfonamide (3.75 g, 0.105 mol) in THF was added drop-wised, the resulting mixture was stirred at −78° C. for 2 h, then allowed to warm to rt and stirred for 18r, removed the solvent to left the residue which was partitioned between EA and water, EA layer was washed with water, 2M NaOH solution and brine, dried over Na 2 SO 4 , removal the solvent to left the crude 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (1.1 g, 70% yield), which can be used directly.

The title compound was prepared following procedures described in example 281 step 1 to give 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100 mg, quant.) which can be used directly.

Step 3: (S)-(5-(3,6-dihydro-2H-pyran-4-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol

To a solution of (S)-(5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (200 mg, 0.5 mmol) in 2 ml dioxane/H 2 O (v:v=5:1) was added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100 mg), K2CO3 (276 mg, 2 mmol) and Pd (PPh 4 ) 3 (5 mg), the mixture was heated to reflux for 2 h under N 2 , diluted with EA, the organic layer was washed by water, brine, dried over Na2SO 4 , removal the solvent to left the crude product which was purified by Prep-HPLC to give (S)-(5-(3,6-dihydro-2H-pyran-4-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (15 mg, 7.5% yield), Mass spec: 421 (M+1), t R =2.895 min, 1 H-NMR (400 Hz, DMSO) δ=8.611 (s, 1H), 8.060-8.088 (m, 1H), 7.461-7.466 (m, 1H), 7.209-7.236 (m, 1H), 7.021-7.043 (m, 1H), 6.828-6.850 (m, 1H), 6.088 (s, 1H), 5.624-5.651 (m, 1H), 4.495-4.518 (m, 2H), 4.203-4.210 (m, 2H), 3.657-3.698 (m, 1H), 3.414-3.437 (m, 1H), 3.200-3.306 (m, 2H), 2.411 (m, 2H), 2.361-2.381 (m, 1H), 2.120-2.340 (m, 1H).

Example 436: (S)-(5-(tetrahydro-2H-pyran-4-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (Compound 1-276)

To a solution of (S)-(5-(3,6-dihydro-2H-pyran-4-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (20 mg, 0.047 mmol) in 2 ml MeOH was added Pd/C (5 mg), the mixture was stirred for 3 h at rt under H 2 , filtered and the filtrate was concentrated, The residue was purified by silica gel to give (S)-(5-(tetrahydro-2H-pyran-4-yl)-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)methanol (5 mg, 25% yield), Mass spec: 423 (M+1), t R =2.622 min, 1 H-NMR (400 Hz, DMSO) δ=8.605 (s, 1H), 8.060-8.088 (m, 1H), 7.269-7.273 (m, 1H), 7.010-7.044 (m, 2H), 6.853-6.873 (m, 1H), 5.614 (m, 1H), 5.033 (m, 1H), 4.481-4.502 (m, 2H), 3.920-3.954 (m, 2H), 3.115-3.588 (m, 6H), 2.680 (m, 1H), 2.088 (m, 1H), 2.086 (m, 1H), 1.624-1.660 (m, 4H).

Example 437: (S)-tert-butyl 4-(3-(hydroxymethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)-5,6-dihydropyridine-1 (2H)-carboxylate (Compound 1-272)

The title compound was prepared following procedures described in example 435 to give (S)-tert-butyl 4-(3-(hydroxymethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)-5,6-dihydropyridine-1 (2H)-carboxylate (10 mg, 12.5% yield), Mass spec: 520 (M+1), t R =3.292 min, 1 H-NMR (400 Hz, DMSO) δ=8.611 (s, 1H), 8.065-8.087 (m, 1H), 7.445-7.450 (m, 1H), 7.196-7.217 (m, 1H), 7.019-7.042 (m, 1H), 6.818-6.840 (m, 1H), 5.998 (s, 2H), 5.634 (s, 1H), 5.069-5.096 (m, 1H), 4.486-4.513 (m, 2H), 3.927 (s, 2H), 3.195-3.655 (m, 6H), 2.442 (s, 2H), 2.340-2.375 (m, 1H), 2.085-2.117 (m, 1H).

Example 438: (S)-tert-butyl 4-(3-(hydroxymethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)piperidine-1-carboxylate (Compound 1-273)

The title compound was prepared following procedures described in example 436 to give (S)-tert-butyl 4-(3-(hydroxymethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)piperidine-1-carboxylate (60 mg, 70% yield), Mass spec: 522 (M+1), t R =3.355 min, 1 H-NMR (400 Hz, DMSO) δ=8.467 (s, 1H), 7.912-7.934 (m, 1H), 7.264 (s, 1H), 6.930-7.080 (m, 3H), 5.644-5.658 (m, 1H), 4.870 (s, 2H), 4.173-4.206 (m, 2H), 3.570-3.598 (m, 1H), 3.134-3.382 (m, 3H), 2.853 (s, 2H), 2.667 (m, 1H), 2.426-2.460 (m, 1H), 2.147-2.165 (m, 1H), 1.779-1.810 (m, 1H), 1.511-1.576 (m, 2H).

Example 439: (S)-tert-butyl 4-(3-(2-hydroxyethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (Compound 1-299)

The title compound was prepared following procedures described in Example 435 step 3 using (S)-2-(5-bromo-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)ethanol to give 4-(3-(2-hydroxyethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (180 mg, 36% yield), Mass spec: 534 (M+1), t R =3.129 min, 1 H-NMR (400 Hz, DMSO) δ=8.612 (s, 1H), 8.065-8.093 (m, 1H), 7.227-7.232 (m, 1H), 6.922-7.159 (m, 3H), 6.010 (m, 1H), 5.617-5.647 (m, 1H), 4.648-4.674 (m, 1H), 3.571 (s, 2H), 3.136-3.627 (m, 8H), 2.789-2.806 (m, 2H), 2.366-2.406 (m, 3H), 2.114-2.366 (m, 1H).

Example 440: (S)-tert-butyl 4-(3-(2-hydroxyethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)piperidine-1-carboxylate (Compound 1-301)

The title compound was prepared following procedures described in Example 436 to give (S)-tert-butyl 4-(3-(2-hydroxyethyl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)phenyl)piperidine-1-carboxylate (112 mg, 74% yield), Mass spec: 536 (M+1), t R =3.161 min, 1 H-NMR (400 Hz, DMSO) δ=8.604 (s, 11H), 8.061-8.089 (m, 1H), 6.930-7.047 (m, 4H), 5.593-5.623 (m, 1H), 3.050-3.154 (m, 2H), 2.759-2.778 (m, 3H), 2.507-2.564 (m, 1H), 2.065-2.078 (m, 1H), 1.684-1.716 (m, 2H), 1.448-1.471 (m, 3H).

Example 442: (S)-6-(1-(3-(hydroxymethyl)biphenyl-4-yl)pyrrolidin-3-yloxy)nicotinonitrile (Compound 1-143)

The title compound was prepared following procedures described in Example 67 step 2 to using (S)-6-(1-(4-bromo-2-formylphenyl)pyrrolidin-3-yloxy)nicotinonitrile (prepared as example 136 step 1) give (S)-6-(1-(3-formylbiphenyl-4-yl)pyrrolidin-3-yloxy)nicotinonitrile (600 mg, 83% yield), Mass spec: 382 (M+1).

The title compound was prepared following procedures described in Example 96 step 2 to give (S)-6-(1-(3-(hydroxymethyl)biphenyl-4-yl)pyrrolidin-3-yloxy)nicotinonitrile (20 mg, 30% yield), Mass spec: 384 (M+1), t R =2.873 min, 1 H-NMR (400 Hz, DMSO) δ=8.722-8.729 (m, 1H), 8.148-8.176 (m, 1H), 7.587-7.676 (m, 3H), 7.407-7.468 (m, 3H), 7.265-7.302 (m, 1H), 6.932-7.046 (m, 2H), 5.642-5.669 (m, 1H), 5.159-5.186 (t, 1H), 4.552-4.579 (m, 2H), 3.703-3.745 (m, 1H), 3.443-3.465 (m, 1H), 3.235-3.354 (m, 2H), 2.397-2.520 (m, 1H), 2.363-2.377 (m, 1H).

Example 443: (S)-6-(1-(3-(hydroxymethyl)biphenyl-4-yl)pyrrolidin-3-yloxy)nicotinamide (Compound 1-144)

The title compound was prepared following procedures described in Example 6 to give (S)-6-(1-(3-formylbiphenyl-4-yl)pyrrolidin-3-yloxy)nicotinamide (300 mg, quant.), Mass spec: 388 (M+1).

The title compound was prepared following procedures described in Example 96 step 2 to give (S)-6-(1-(3-(hydroxymethyl)biphenyl-4-yl)pyrrolidin-3-yloxy)nicotinamide (40 mg, 26% yield), Mass spec: 390(M+1), t R =2.394 min, 1 H-NMR (400 Hz, DMSO) δ=8.674-8.681 (m, 1H), 8.148-8.176 (m, 1H), 7.587-7.676 (m, 3H), 7.407-7.468 (m, 1H), 7.965 (s, 1H), 7.649-7.655 (d, 1H), 7.562-7.584 (m, 2H), 7.378-7.441 (m, 4H), 7.273-7.378 (m, 1H), 6.858-6.926 (q, 2H), 5.613-5.625 (m, 1H), 5.100-5.127 (t, 1H), 4.533-4.562 (m, 2H), 3.685-3.726 (m, 1H), 3.434-3.457 (m, 1H), 3.339-3.342 (m, 1H), 3.232-3.243 (m, 2H), 2.473-2.486 (m, 1H), 2.340-2.345 (m, 1H).

Example 444: (S)-(4-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (Compound 1-141)

The title compound was prepared following procedures described in Example 124 to give (S)-(4-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (25 mg, 30% yield), Mass spec: 361 (M+1), t R =3.077 min, 1 H-NMR (400 Hz, DMSO) δ=7.992-7.999 (q, 1H), 7.671-7.677 (d, 1H), 7.524-7.608 (m, 3H), 7.406-7.456 (m, 3H), 7.281-7.299 (m, 1H), 6.919-6.940 (d, 1H), 6.726-6.747 (d, 1H), 5.531 (br, 1H), 5.129-5.143 (t, 1H), 4.550-4.580 (m, 2H), 3.696-3.710 (m, 1H), 3.443 (m, 1H), 3.295-3.342 (m, 2H), 2.311-2.333 (m, 1H), 2.212 (s, 3H), 2.091 (m, 1H).

Example 445: 1-(2′-chloro-4-((S)-3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)ethanol (Compound 1-172)

The title compound was prepared following procedures described in Example 301 step 1 to give (S)-6-(1-(4-bromo-2-vinylphenyl)pyrrolidin-3-yloxy)-5-chloropyridin-3-ide (1.7 g, 77% yield), Mass spec: 378 (M+1).

The title compound was prepared following procedures described in Example 301 step 2 to give 1-(5-bromo-2-((S)-3-(3-chloropyridin-2-yloxy)pyrrolidin-1-yl)phenyl)ethanol (300 mg, 29% yield), Mass spec: 397 (M+1).

The title compound was prepared following procedures described in Example 67 step 2 to give 1-(2′-chloro-4-((S)-3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)ethanol (17 mg, 32% yield), Mass spec: 409 (M+1), t R =3.125 min, 1H-NMR (400 Hz, DMSO) δ=7.969-7.981 (d, 1H), 7.502-7.547 (m, 3H), 7.322-7.381 (m, 3H), 7.028-7.236 (m, 2H), 6.853-6.883 (m, 1H), 5.566 (br, 1H), 5.052-5.114 (m, 2H), 3.345-3.346 (m, 2H), 3.181-3.322 (m, 2H), 2.471-2.484 (m, 1H), 2.113-2.131 (m, 4H), 1.288-1.371 (dd, 3H).

Example 446: 1-(4-((S)-3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)ethanol (Compound 1-169)

The title compound was prepared following procedures described in Example 445 to give 1-(4-((S)-3-(3-methylpyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)ethanol (27 mg, 55% yield), Mass spec: 375 (M+1), t R =2.898 min, 1 H-NMR (400 Hz, DMSO) δ=8.005 (d, 1H), 7.760-7.780 (d, 1H), 7.543-7.615 (m, 3H), 7.440-7.460 (m, 3H), 7.309 (m, 1H), 7.115-7.129 (m, 1H), 6.886-6.911 (m, 1H), 5.581 (br, 1H), 5.145 (m, 2H), 3.440-3.637 (m, 2H), 3.119-3.264 (m, 2H), 2.365-2.380 (m, 1H), 2.077-2.160 (m, 4H), 1.333-1.419 (dd, 3H).

Example 455: (S)-(4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-2,3′-diyl)dimethanol (Compound 1-174)

The title compound was prepared following procedures described in example 279 to give (S)-(4′-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-2,3′-diyl)dimethanol (8 mg, 10% yield), Mass spec: 445 (M+1), t R =2.845 min, 1 H-NMR (400 Hz, DMSO) δ=8.625 (s, 1H), 8.073-8.100 (m, 1H), 7.548-7.566 (m, 1H), 7.292-7.348 (m, 3H), 7.163-7.193 (m, 2H), 7.041-7.064 (d, 1H), 6.905-6.926 (d, 1H), 5.666 (br, 1H), 5.105-5.132 (t, 2H), 4.536-4.561 (t, 2H), 4.429-4.442 (d, 2H), 3.728-3.756 (m, 1H), 3.446-3.487 (m, 2H), 3.253-3.374 (m, 1H), 2.338-2.406 (m, 1H), 2.141 (m, 1H).

Example 456: (S)-(2′-((dimethylamino)methyl)-4-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (Compound 1-219)

To a solution of (S)-3′-(hydroxymethyl)-4′-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-2-carbaldehyde (150 mg, 0.387 mmol) (prepared as example 279 step 1) in 3 mL DMSO was added Me2NH HCl (62 mg, 0.77 mmol), the mixture was stirred at 40° C. for 30 min to form a cleat solution. To this reaction mixture was added a solution NaB(OAc) 3 H (123 mg, 0.58 mmol) in DMSO drop-wised, and stirred at rt for another 4 h, the mixture was quenched by 10% citric acid solution, the water layer was basified by 10% K 2 CO 3 solution, extracted with EA, dried over Na 2 SO 4 , removal the solvent to left the crude product which was purified by Prep-HPLC to give (S)-(2′-((dimethylamino)methyl)-4-(3-(5-methylpyridin-2-yloxy)pyrrolidin-1-yl)biphenyl-3-yl)methanol (30 mg, 18%), Mass spec: 418 (M+1), t R =1.721 min, 1 H-NMR (400 Hz, CDCl3) δ=11.915 (br, 1H), 7.853-8.037 (m, 2H), 7.421-7.485 (m, 3H), 7.264-7.312 (m, 2 h), 7.132-7.168 (m, 2H), 6.690-6.709 (d, 1H), 5.652 (d, 1H), 4.811-4.920 (m, 2H), 4.302 (s, 2H), 3.944 (br, 1H), 3.651 (br, 11H), 3.506 (m, 2H), 2.589 (m, 7H), 2.218-2.326 (m, 4H).

Example 457: (R)-5-benzoyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-154)

To a solution of (R)-2-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyridine (279 mg, 1.2 mmol)(intermediate 4) in 4 mL DMF was added 5-benzoyl-2-fluorobenzonitrile (226 mg, 1 mmol) (prepared as intermediate 8 step 4) and K 2 CO 3 , the mixture was stirred at 100° C. for 16 h, the mixture was diluted with EA, the organic layer was washed by LiCl solution, brine, dried over Na2SO4, removal the solvent to left th crude product which was purified by silica gel to give (R)-5-benzoyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzonitrile (350 mg, 80% yield), Mass spec: 438 (M+1).

The title compound was prepared following procedures described in example 6 to give (R)-5-benzoyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (120 mg, 78% yield), Mass spec: 456 (M+1), t R =2.697 min, 1 H-NMR (400 Hz, DMSO) δ=8.630-8.633 (d, 1H), 8.069-8.098 (q, 1H), 7.953 (s, 1H), 7.521-7.702 (m, 7H), 7.401 (s, 1H), 6.852-7.017 (d, 1H), 6.829-6.841 (d, 1H), 5.728 (br, 1H), 3.926-3.969 (m, 11H), 3.439-3.662 (m, 3H), 2.273-2.331 (m, 2H).

Example 458: (S)-5-benzoyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (Compound 1-130)

The title compound was prepared following procedures described in example 457 to give (S)-5-benzoyl-2-(3-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-1-yl)benzamide (36 mg, 66% yield), Mass spec: 456 (M+1), t R =2.462 min, 1 H-NMR (400 Hz, DMSO) δ=8.635 (s, 1H), 8.071-8.099 (m, 1H), 7.947 (s, 1H), 7.522-7.697 (m, 7H), 7.399 (s, 1H), 7.019-7.040 (d, 1H), 6.831-6.854 (d, 1H), 5.727-5.734 (m, 1H), 3.927-3.970 (m, 1H), 3.440-3.664 (m, 3H), 2.276-2.336 (m, 2H).

Intermediate 300: ((2S,4S)-1-(4-phenylcyclohexa-1,5-dienyl)-4-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidin-2-yl)methanol (Compound 1-363)

Step 1: (2S,4S)-1-(tert-butoxycarbonyl)-4-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidine-2-carboxylic acid

To a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (4 g, 17.3 mmol) in 50 mL DMSO was added t-BuOK (4.84 g, 43.2 mmol) in 40 mL THF with stirring to rt. for 1.5 h, before 2-chloro-5-(trifluoromethyl)pyridine (3.76 g, 20.8 mmol) was added at rt, and resulting mixture was stirred for overnight. And quenched with water, extracted with EA, dried over Na2SO4, removal the solvent to left the crude product which was purified by silica gel to give (2S,4S)-1-(tert-butoxycarbonyl)-4-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidine-2-carboxylic acid (4.3 g, 66.6% yield), Mass spec: 377 (M+H).

Step 2: (2S, 4S)-tert-butyl 2-(hydroxymethyl)-4-(5-(trifluoromethyl)pyridin-2-yloxy)pyrrolidine-1-carboxylate

The title compound was prepared following procedures described in Examp