N-biaryl sulfonamides as modulators of the hippo pathway

Abstract

Provided are compounds of Formula I: and a pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions comprising them and methods of using such compounds or the pharmaceutically acceptable salts thereof.

Description

N-BIARYL SULFONAMIDES AS MODULATORS OF THE HIPPO PATHWAYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 560,203 filed March 01, 2024, the entire contents of which are incorporated by reference herein.BACKGROUND

[0002] Yes-associated protein (Y AP) and transcriptional co-activator with PDZ-binding motif (TAZ) are transcriptional co-activators of the Hippo pathway network and regulate cell proliferation, migration and apoptosis. Inhibition of the Hippo pathway promotes YAP / TAZ translocation to the nucleus, wherein YAP / TAZ interact with transcriptional enhancer associate domain (TEAD) transcription factors and coactivate the expression of target genes and promote cell proliferation. Hyperactivation of YAP and TAZ and / or mutations in one or more members of the Hippo pathway network have been implicated in numerous cancers. Provided are compounds that modulate the Hippo pathway. The compounds bind to the allosteric palmitate pocket of the TEAD1-4 transcription factors and thereby block the interaction between YAP1 / TAZ and TEAD.SUMMARY

[0003] The present disclosure is directed to compounds having structural Formula I:as well as pharmaceutically acceptable salts, esters, and prodrugs thereof, which are TEAD modulators. Also provided are methods of making compounds of Formula I, pharmaceutical compositions comprising compounds of Formula I, methods of using these compounds to treat cancer, and the use of compounds of Formula I in treating cancer.DETAILED DESCRIPTION

[0004] In one embodiment, the present disclosure provides a compound of structural Formula (I):or a pharmaceutically acceptable salt thereof, wherein;X1 is -N- or -CR5-;X2 is -N- or -CR6-;X3 is -N- or -CR7-;X4 is -N- or -CR8-;X5 is -N- or -CR9-;R1is selected from:(1) aryl, unsubstituted or substituted with 1-3 substituents independently selected from R10,(2) -C1-6alkyl-aryl, unsubstituted or substituted with 1-3 substituents independently selected from R10,(3) 4-6 membered heterocyclyl, having 1-3 heteroatoms independently selected from N, O and S. unsubstituted or substituted with 1-3 substituents independently selected from R10,(4) -C1-6alkyl- 4-6 membered heterocyclyl having 1-3 heteroatoms independently selected from N, O and S, unsubstituted or substituted with 1-3 substituents independently selected from R10,(5) -C1-6alkyl- 4-6 membered heteroaryl ring, having 1-3 heteroatoms independently selected from N, O and S wherein, the heteroaryl ring is unsubstituted or substituted with 1-3 substituents independently selected from R10,(6) -C3-10cycloalkyl, unsubstituted or substituted with 1-3 substituents independently- selected from R10,(7) -C1-6alkyl-C3-6cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R10,(8) 8-10 membered fused bicyclic aryl, unsubstituted or substituted with 1-3 substituents selected from R10,(9) -C1-6alkyl- 8-10 membered fused bicyclic aryl, unsubstituted or substituted with 1- 3 substituents selected from R10,(10) -C1-6alkyl- 8-10 membered fused bicyclic heteroaryl ring system having 1-3 heteroatoms independently selected from N, O and S, wherein the heteroary l ring system is unsubstituted or substituted with 1-3 substituents selected from R10(11) 10-11 membered spiro bicyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O and S, unsubstituted or substituted with 1-3 substituents independently selected from R10,(12) 10-11 membered spiro bicyclic cycloalkyl.(13) 14-15 membered tricyclic cycloalkyl,(14) -C1-6alkyl- 5-10 membered bridged cycloalkyl, unsubstituted or substituted with 1- 3 substituents independently selected from R10, and(15) 5-10 membered bridged heterocyclyl having 1-3 heteroatoms independently- selected from N, O and S;R2is -H, -F, -CF3or -CH3;R3is selected from:(1) -C1-6alkyl,(2) aryl,(3) 4-6 membered heterocyclyl, having 1-3 heteroatoms independently selected from N, O and S;(4) -C1-6alkyl-C3-6Cycloalkyl,(5) -C3-8cycloalkyl, unsubstituted or substituted with C1-6alkyl, and(6) -C1-6haloalkyl;R4is selected from:(1) -C1-6alkyl,(2) aryl,(3) C1-6alkyl- 5-6 membered heterocyclyl, having 1-3 heteroatoms independently selected from N, O and S, unsubstituted or substituted with 1-3 substituents independently selected from C1-6alkyl and =0,(4) -CH2CH2OCH3,(5) -C1-6alkyl- 5-6 membered heteroaryl ring, having 1-3 heteroatoms independently selected from N, O and S, wherein the heteroaryl ring is unsubstituted or substituted with 1-3 substituents selected from C1-6alkyl,(6) - C1-6haloalkyl,(7) 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from N, O and S,(8) -CH(CH2OCH3)2,(9) 5-6 membered heteroaryl ring, having 1-3 heteroatoms independently selected from N. O and S. and(10) -C3-8cycloalkyl;R5is selected from:(1) hydrogen,(2) halo,(3) -C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents, and(4) -O-C1-6alkyl, unsubstituted or substituted with 1-3 halogen substituentsR6is selected from:(1) hydrogen,(2) halo,(3) -C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents, and(4) -O-C1-6alkyl, unsubstituted or substituted with 1-3 halogen substituents;R7is selected from:(1) hydrogen,(2) halo,(3) -C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents, and(4) -O-C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents;R8is selected from:(1) hydrogen,(2) halo,(3) -C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents, and(4) -O-C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents;R9is selected from:(1) hydrogen,(2) halo,(3) -C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents, and(4) -O-C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents.When preset, R10is selected from:(1) halo,(2) C1-6haloalkyl,(3) C1-6alkyl,(4) cyano, and(5) -C(O)O- C1-6alkyl.

[0005] In Embodiment 2 of this disclosure are the compounds of Formula I, or Embodiment1, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is(1) aryl, unsubstituted or substituted with 1-3 substituents independently selected from R10,(2) C1-6alkyl-aryl, unsubstituted or substituted with 1-3 substituents independently selected from R10,(3) 4-6 membered heterocyclyl, having 1-3 heteroatoms independently selected from N, O and S wherein, unsubstituted or substituted with 1 -3 substituents independently selected from R10,(4) C1-6alkyl- 4-6 membered heterocyclyl having 1-3 heteroatoms independently selected from N, O and S, unsubstituted or substituted with 1-3 substituents independently selected from R10,(5) C1-6alkyl- 4-6 membered heteroaryl ring, having 1-3 heteroatoms independently selected from N, O and S wherein, the heteroaryl ring is unsubstituted or substituted with 1-3 substituents independently selected from R10.(6) -C3-10cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R10,(7) - C1-6alkyl-C3-6Cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R10,(8) 8-10 membered fused bicyclic aryl, unsubstituted or substituted with 1-3 substituents selected from R10,(9) C1-6alkyl- 8-10 membered fused bicyclic aryl, unsubstituted or substituted with 1- 3 substituents selected from R10,(10) C1-6alkyl- 8-10 membered fused bicyclic heteroaryl ring system having 1-3 heteroatoms independently selected from N, O and S, wherein the heteroaryl ring system is unsubstituted or substituted with 1-3 substituents selected from R10(11) 10-11 membered spiro bicyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O and S. unsubstituted or substituted with 1-3 substituents independently selected from R10,(12) 10-11 membered spiro bicyclic cycloalkyl,(13) 14-15 membered tricyclic cycloalky l,(14) -C1-6alkyl- 5-10 membered bridged cycloalkyl, unsubstituted or substituted with 1- 3 substituents independently selected from R10, or(15) 5-10 membered bridged heterocyclyl having 1-3 heteroatoms independently selected from N, O and S.

[0006] In Embodiment 3 of this disclosure are the compounds of Formula I, or Embodiments 1-2, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is(1) phenyl, unsubstituted or substituted with 1-2 substituents independently selected from -Cl, -Br and -CF3,(2) -CH2-phenyl, unsubstituted or substituted with 1-2 substituents independently selected from -F, -Cl, -Br, -CF3, methyl, cyano,(3) 6 membered heterocyclyl, having 1 heteroatom selected from N, substituted with 1 substituent selected from -CH2CF3,(4) -CH2- 4-6 membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, unsubstituted or substituted with 1-3 substituents independently selected from -CH2CF3, and methyl,(5) -CH2- 4-6 membered heteroaryl ring, having 1-3 heteroatoms independently selected from N, O and S wherein, the heteroaryl ring is unsubstituted or substituted with 1-3 substituents independently selected from methyl, -CF3. - CH2CF3-CHF2, phenyl, cyclobutyl, cyclopropyl, cyclopentyl, and tetrahydropyranyl,(6) cyclohexyl, unsubstituted or substituted with 1-2 substituents independently selected from -F, methyl, -CF3. phenyl, and cyano,(7) -CH2-C3-6cycloalkyl, unsubstituted or substituted with 1-2 substituents independently selected from methyl, -F, -CF3, and cyano,(8) 9-10 membered fused bicyclic aryl, unsubstituted or substituted with 1 substituent selected from -CF3, -OCH3, phenyl, and naphthyl,(9) -CH2- 10 membered fused bicyclic aryl, unsubstituted or substituted with 2 substituents selected from methyl,(10) -CH2- 9 membered fused bicyclic heteroaryl ring system having 2 nitrogen atoms, wherein the heteroaryl ring system is substituted with 1 substituent independently selected from methyl, and cyclopentyl.(11) 10-11 membered spiro bicyclic heterocyclyl having 1 heteroatom independently selected from N and O, unsubstituted or substituted with 1 substituent selected from -CH2CF3and -C(O)O- C1-6alkyl,(12) 10 membered spiro bicyclic cycloalkyl,(13) 14- membered tricyclic cycloalkyl,(14) -CH2- 5 or 8 membered bridged cycloalkyd, unsubstituted or substituted with 1-2 substituents independently selected from -F and cyano, or(15) 8- membered bridged heterocyclyl having 1 oxygen atom.

[0007] In Embodiment 4 of this disclosure are the compounds of Formula I, or Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is phenyl, unsubstituted or substituted with 1-2 substituents independently selected from -Cl, -Br or -CF3.

[0008] In Embodiment 5 of this disclosure are the compounds of Formula I, or Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -CH2-phenyl, unsubstituted or substituted with 1-2 substituents independently selected from -F, -Cl, -Br, -CF3, methyl, and cyano.

[0009] In Embodiment 6 of this disclosure are the compounds of Formula I, or Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is piperdyl substituted with -CH2CF3.

[0010] In Embodiment 7 of this disclosure are the compounds of Formula I, or Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -CH2- 4 or 6 membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, unsubstituted or substituted with 1-3 substituents independently selected from -CH2CF3, -CH2- cyano, and methyl.

[0011] In Embodiment 8 of this disclosure are the compounds of Formula I, or Embodiments 1-3 or 7, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -CH2- piperdinyl substituted one substituent selected from -CH2-cyano and -CH2CF3; -CH2- tetrahydropyranyl; -CH2-morpholinyl substituted with -CH2CF3; or -CH2-oxetanyl substituted with methyl.

[0012] In Embodiment 9 of this disclosure are the compounds of Formula I, or Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -CH2- 4-6 membered heteroaryl ring, having 1-3 heteroatoms independently selected from N, O and S wherein, the heteroaryl ring is unsubstituted or substituted with 1-3 substituents independently selected from methyl, -CF3, -CH2CF3-CHF2, phenyl, cyclobutyl, cyclopropyl, cyclopentyl, and tetrahy dropy rany 1.

[0013] In Embodiment 10 of this disclosure are the compounds of Formula I, or Embodiments 1 -3 or 9, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -CH2- pyridinyl substituted with -CF3; -CH2-isoxazyl substituted with methyl or cyclopropyl; -CH2-thiazolyl unsubstituted or substituted with 2 methyl substituents; -CH2-pyrazolyl substituted with 1-2 methyl substituents, -CHF2, phenyl, tetrahydropyranyl, -CH2CF3, cyclopentyl, and cyclopropyl; -CH2-oxadiazolyl substituted with methyl; -CH2-furanyl substituted with -CF3; or - CH2-imidazolyl substituted with -CH2CF3.

[0014] In Embodiment 11 of this disclosure are the compounds of Formula I, or Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is cyclohexyl, unsubstituted or substituted with 1-2 substituents independently selected from -F, methyl, -CF3, phenyl, and cyano.

[0015] In Embodiment 12 of this disclosure are the compounds of Formula I, or Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -CH2-C3-6cycloalkyl, unsubstituted or substituted with 1-2 substituents independently selected from methyl, -F, -CF3, or cyano.

[0016] In Embodiment 13 of this disclosure are the compounds of Formula I, or Embodiments 1-3 or 12, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -CH2- cyclopropyl unsubstituted or substituted withl-2 substituents independently selected from methyl, -CF3, cyano, and -F; -CH2-cyclohexyl substituted with 2 substituents selected from -F; or -CH2-cyclobutyl substituted with 2 substituents selected from -F.

[0017] In Embodiment 14 of this disclosure are the compounds of Formula I, or Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is 9-10 membered fused bicyclic aryl, unsubstituted or substituted with 1 substituent selected from -CF3, -OCH3, phenyl, and naphthyl.

[0018] In Embodiment 15 of this disclosure are the compounds of Formula I, or Embodiments 1-3 or 14, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is dihydroindenyl substituted with 1 substituent independently selected from -CF3and naphthyl; or tetrahydronaphthal enyl substituted with 1-2- substituents independently selected from -OCH3and phenyl.

[0019] In Embodiment 16 of this disclosure are the compounds of Formula I, or Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -CH2- 10 membered fused bicyclic aryl, unsubstituted or substituted with 2 methyl substituents.

[0020] In Embodiment 17 of this disclosure are the compounds of Formula I, or Embodiments 1-3 or 16, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -CH2- tetrahydronaphthalenyl, substituted with 2 methyl substituents; or -CH2-naphthyl.

[0021] In Embodiment 18 of this disclosure are the compounds of Formula I, or Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, w herein R1is -CH2- 9membered fused bicyclic heteroaryl ring system having 2 nitrogen atoms, substituted 1 substituent independently selected from cyclopentyl and methyl.

[0022] In Embodiment 19 of this disclosure are the compounds of Formula I, or Embodiments 1-3 or 18, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -CH2- indazolyl substituted with 1 substituent independently selected from cyclopentyl and methyl.

[0023] In Embodiment 20 of this disclosure are the compounds of Formula I, or Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is 10-11 membered spiro bicyclic heterocyclyl having 1 heteroatom independently selected fromN and O, unsubstituted or substituted with 1 substituent selected from -CH2CF3, and -C(O)O-C1-6alkyl.

[0024] In Embodiment 20 of this disclosure are the compounds of Formula I, or Embodiments 1-3 or 20, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is oaxaspiro- undecanyl; or azaspiro-decanyl substituted with 1 substituent selected from -CH2CF3and - C(O)O-C1-6alkyl.

[0025] In Embodiment 21 of this disclosure are the compounds of Formula I, or Embodiments 1-3 or 20-21, or a pharmaceutically acceptable salt of any of the foregoing, w herein R1is

[0026] In Embodiment 22 of this disclosure are the compounds of Formula I, or Embodiments 1 -3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is 10 membered spiro bicyclic cycloalkyl.

[0027] In Embodiment 23 of this disclosure are the compounds of Formula I, or Embodiments 1-3 or 22, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is spiro- decanyl.

[0028] In Embodiment 24 of this disclosure are the compounds of Formula I, or Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, w herein R1is 14 membered tricyclic cycloalkyl.

[0029] In Embodiment 25 of this disclosure are the compounds of Formula 1, or Embodiments 1-3 or 24, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is dihydrospiro-cyclohexane-indenyl.

[0030] In Embodiment 26 of this disclosure are the compounds of Formula 1, or Embodiments 1-3 or 24-25, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is

[0031] In Embodiment 27 of this disclosure are the compounds of Formula I, or Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -CH2- 5 or 8 membered bridged cycloalkyl, unsubstituted or substituted with 1-2 substituents independently selected from -F and cyano.

[0032] In Embodiment 28 of this disclosure are the compounds of Formula I, or Embodiments 1-3 or 27, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -CH2- bicyclo-octane substituted with 2 substituents selected from -F; or -CH2-bicyclo-pentanyl substituted with cyano.

[0033] In Embodiment 29 of this disclosure are the compounds of Formula I, or Embodiments 1-3 or 27-28, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is

[0034] In Embodiment 30 of this disclosure are the compounds of Formula I, or Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is 8 membered bridged heterocyclyl having 1 oxygen atom.

[0035] In Embodiment 31 of this disclosure are the compounds of Formula I, or Embodiments 1-3 or 30, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -CH2- oxabicyclo-octanyl.

[0036] In Embodiment 32 of this disclosure are the compounds of Formula I, or Embodiments 1-3 or 30-31, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is

[0037] In Embodiment 33 of this disclosure are the compounds of Formula I, or Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is -H, -CH3or -F.

[0038] In Embodiment 34 of this disclosure are the compounds of Formula 1, or Embodiment 1, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is(1) -C1-6alkyl,(2) aryl,(3) 4- to 6- membered heterocyclyl, having 1-3 heteroatoms independently selected from N, O and S;(4) - C1-6alkyl-C3-6Cycloalkyl,(5) -C3-8cycloalkyl, unsubstituted or substituted with C1-6alkyl, or(6) - C1-6haloalkyl.

[0039] In Embodiment 35 of this disclosure are the compounds of Formula I, or Embodiments 1 or 34, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is(1) methyl, ethyl, and propyl,(2) phenyl,(3) oxetanyl,(4) -CH2-cyclopropyl,(5) cyclopropyl, unsubstituted or substituted with C1-6alkyl, or(6) -CH2CF3, -CH2CH2CH2F, -CH2F, -CH2CHF2, -CH2CH2CF3

[0040] In Embodiment 36 of this disclosure are the compounds of Formula I, or Embodiments 1 or 34-35, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is methyl, ethyl, or propyl.

[0041] In Embodiment 37 of this disclosure are the compounds of Formula I, or Embodiments 1 or 34-35. or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is phenyl.

[0042] In Embodiment 38 of this disclosure are the compounds of Formula I, or Embodiments 1 or 34-35, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is oxetanyl.

[0043] In Embodiment 39 of this disclosure are the compounds of Formula I, or Embodiments 1 or 34-35, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is -CH2- cyclopropyl.

[0044] In Embodiment 40 of this disclosure are the compounds of Formula I, or Embodiments 1 or 34-35, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is cyclopropyl, unsubstituted or substituted with C1-6alkyl.

[0045] In Embodiment 41 of this disclosure are the compounds of Formula I, or Embodiments 1 or 34-35, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is -CH2CF3, -CH2CH2CH2F, -CH2F, -CH2CHF2, or -CH2CH2CF3.

[0046] In Embodiment 42 of this disclosure are the compounds of Formula I, or Embodiment 1, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is(1) - C1-6alkyl,(2) aryl.(3) C1-6alkyl- 5-6 membered heterocyclyl. having 1-3 heteroatoms independently selected from N, O and S, unsubstituted or substituted with 1-3 substituents independently selected from C1-6alky 1 and =0,(4) -CH2CH2OCH3,(5) - C1-6alkyl- 5-6 membered heteroaryl ring, having 1-3 heteroatoms independently selected from N, O and S, wherein the heteroaryl ring is unsubstituted or substituted with 1-3 substituents selected from C1-6alkyl,(6) -C1-6haloalkyl,(7) 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from N, O and S,(8) -CH(CH2OCH3)2,(9) 5-6 membered heteroaryl ring, having 1-3 heteroatoms independently selected from N. O and S,(10) -C3-8cycloalkyl. or(11) -C1-6alkyl-aryl.

[0047] In Embodiment 43 of this disclosure are the compounds of Formula I, or Embodiments 1 or 42, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is(1) methyl,(2) phenyl,(3) -CH2-oxetanyl substituted with 1 methyl; -CH2-tetrahydropyranyl; and -CH2CH2- pyrrolidinyl substituted with 1 substituent selected from =0,(4) -CH2CH2OCH3,(5) -CH2-pyridinyl; -CH2-oxazolyl; -CH2-pyrimidinyl; -CH2-oxadiazolyl substituted with 1 substituent selected from methyl; -CH2-pyrazolyl substituted with 1 substituent selected from methyl; -CH2-isoxazolyl; -CH2-pyridazinyl,(6) -CH2CHF2,(7) tetrahydro-pyran.(8) -CH(CH2OCH3)2,(9) pyrimidinyl and pyridinyl,(10) cyclobutyl, or(11) -CH2-phenyl.

[0048] In Embodiment 44 of this disclosure are the compounds of Formula I, or Embodiments 1 or 42-43, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is methyl.

[0049] In Embodiment 45 of this disclosure are the compounds of Formula 1, or Embodiments 1 or 42-43, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is phenyl.

[0050] In Embodiment 46 of this disclosure are the compounds of Formula I, or Embodiments 1 or 42-43, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is-CH2- oxetanyl substituted with 1 methyl substituent; -CH2-tetrahydropyranyl; or -CH2CH2-pyrrolidinyl substituted with 1 =0 substituent.

[0051] In Embodiment 47 of this disclosure are the compounds of Formula I, or Embodiments 1 or 42-43, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is - CH2CH2OCH3.

[0052] In Embodiment 48 of this disclosure are the compounds of Formula I, or Embodiments 1 or 42-43, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is -CH2- pyridinyl; -CH2-oxazolyl; -CH2-pyrimidinyl; -CH2-oxadiazolyl substituted with 1 methyl substituent; -CH2-pyrazolyl substituted with 1 methyl substituent, -CH2-isoxazolyl; or -CH2- pyridazinyl.

[0053] In Embodiment 49 of this disclosure are the compounds of Formula I, or Embodiments 1 or 42-43, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is - CH2CHF2.

[0054] In Embodiment 50 of this disclosure are the compounds of Formula I, or Embodiments 1 or 42-43, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is tetrahydro-pyran. In Embodiment 51 of this disclosure are the compounds of Formula I, or Embodiments 1 or 42-43, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is -CH(CH2OCH3)2. In Embodiment 52 of this disclosure are the compounds of Formula I, or Embodiments 1 or 42-43, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is pyrimidinyl or pyridinyl.

[0055] In Embodiment 53 of this disclosure are the compounds of Formula I, or Embodiments 1 or 42-43, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is cyclobutyl.

[0056] In Embodiment 54 of this disclosure are the compounds of Formula I, or Embodiments 1 or 42-43, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is -CH2- phenyl.

[0057] In Embodiment 55 of this disclosure are the compounds of Formula I, or Embodiment 1, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is(1) hydrogen,(2) halogen,(3) -C1-6alkyl, unsubstituted or substituted with 1-3 halogen substituents, or(4) -O-C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents.

[0058] In Embodiment 56 of this disclosure are the compounds of Formula I, or Embodiments 1 or 55, or a pharmaceutically acceptable salt of any of the foregoing, wherein R5is hydrogen.

[0059] In Embodiment 57 of this disclosure are the compounds of Formula I, or Embodiment1, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6is(1) hydrogen,(2) halogen,(3) -C1-6alkyl, unsubstituted or substituted with 1-3 halogen substituents, or(4) -O-C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents.

[0060] In Embodiment 58 of this disclosure are the compounds of Formula I, or Embodiments 1 or 57, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6is hydrogen or -F.

[0061] In Embodiment 59 of this disclosure are the compounds of Formula I, or Embodiment1, or a pharmaceutically acceptable salt of any of the foregoing, wherein R7is(1) hydrogen,(2) halo,(3) -C1-6alkyl, unsubstituted or substituted with 1-3 halogen substituents, or(4) -O-C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents.

[0062] In Embodiment 60 of this disclosure are the compounds of Formula I, or Embodiment1 or 59, or a pharmaceutically acceptable salt of any of the foregoing, w herein R7is hydrogen or methyl.

[0063] In Embodiment 61 of this disclosure are the compounds of Formula 1, or Embodiment1, or a pharmaceutically acceptable salt of any of the foregoing, wherein R8is(1) hydrogen,(2) halo,(3) -C1-6alkyl, unsubstituted or substituted with 1-3 halogen substituents, or(4) -O-C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents.

[0064] In Embodiment 62 of this disclosure are the compounds of Formula I, or Embodiment 1 or 61, or a pharmaceutically acceptable salt of any of the foregoing, wherein R8is hydrogen.

[0065] In Embodiment 63 of this disclosure are the compounds of Formula I, or Embodiment1, or a pharmaceutically acceptable salt of any of the foregoing, wherein R9is(1) hydrogen,(2) halo,(3) -C1-6alkyl, unsubstituted or substituted with 1-3 halogen substituents, or(4) -O-C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents.

[0066] In Embodiment 64 of this disclosure are the compounds of Formula I, or Embodiment 1 or 63, or a pharmaceutically acceptable salt of any of the foregoing, wherein R9is hydrogen, - F, -CF2, or -OCH3.

[0067] In Embodiment 65 of this disclosure are the compounds of Formula I, or Embodiment1, or a pharmaceutically acceptable salt of any of the foregoing, wherein X1is -CR5-; X2is -CR6-; X3is -CR7-; X4is -N-; and X5is -CR9-.

[0068] In Embodiment 66 of this disclosure are the compounds of Formula I, or Embodiment 1, or a pharmaceutically acceptable salt of any of the foregoing, wherein X1is -CR5-; X2is -CR6-; X3is -N-; X4is -N-; and X5is -CR9-.

[0069] In Embodiment 67 of this disclosure are the compounds of Formula I, or Embodiment1, or a pharmaceutically acceptable salt of any of the foregoing, wherein X1is: -CR5-; X2is: -N-; X3is: -CR7-; X4is: -N-; and X5is: -CR9-.

[0070] In Embodiment 68 of this disclosure are the compounds of Formula I, or Embodiment 1, or a pharmaceutically acceptable salt of any of the foregoing, wherein X1is -CR5-; X2is -N-; X3is -N-; X4is -N-; and X5is -CR9-.

[0071] In Embodiment 69 of this disclosure are the compounds of Formula I, or Embodiment 1, or a pharmaceutically acceptable salt of any of the foregoing, wherein X1is: -CR5-; X2is: - CR6-; X3is: -N-; X4is: -CR8-; and X5is: -CR9-.

[0072] In Embodiment 70 of this disclosure are the compounds of Formula I, or Embodiment 1, or a pharmaceutically acceptable salt of any of the foregoing, wherein X1is: -N-; X2is: -CR6-; X3is: -N-; X4is: -N-; and X5is: -CR9-.

[0073] In Embodiment 71 of this disclosure are the compounds of Formula I, or Embodiment 1, or a pharmaceutically acceptable salt of any of the foregoing, wherein X1is: -CR5-; X2is: - CR6-; X3is: -N-; X4is: -N-; and X5is: -N-.

[0074] In Embodiment 72 of the invention, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is: N-(6-(2-Fluoro-5-((3-fluorobenzyl)oxy)phenyl)-3-methoxypyridazin-4-yl)methanesulfonamide,2,2,2-Trifluoro-N-(5-(2-fluoro-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-2- methoxy pyri din-3 -yl)ethane- 1 -sulfonamide.N-(6-(5-((3-Chlorobenzyl)oxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(5-((3-Chloro-4-fluorobenzyl)oxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(5-((3,5-Dichlorobenzyl)oxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(2-Fluoro-5-((4-fluoro-3-methylbenzyl)oxy)phenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(5-((4,4-Difluorocyclohexyl)oxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(5-((4,4-Dimethylcyclohexyl)oxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(2-Fluoro-5-((6-(trifluoromethyl)pyridin-2-yl)methoxy)phenyl)-3- methoxypyridazin-4-yl)methanesulfonamide,N-(6-(5-(Cyclopropylmethoxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide.N-(6-(5-((2,2-Dimethylcyclopropyl)methoxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(5-((2,2-Difluorocyclopropyl)methoxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(5-((5-Cyclopropylisoxazol-3-yl)methoxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(2-Fluoro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(5-((4.5-Dimethylthiazol-2-yl)methoxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(2-Fluoro-5-(thiazol-2-ylmethoxy)phenyl)-3-methoxypyridazin-4- yl)methanesulfonamideN-(6-(5-((5-Cyclopropyl-1-methyl-1H-pyrazol-3-yl)methoxy)-2-fluorophenyl)-3- methoxypyridazin-4-yl)methanesulfonamide,N-(6-(5-((1,4-Dimethyl-1H-pyrazol-3-yl)methoxy)-2-fluorophenyl)-3- methoxypyridazin-4-yl)methanesulfonamide,N-(6-(2-Fluoro-5-((3-methyl-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-3- methoxypyridazin-4-yl)methanesulfonamide,N-(6-(2-Fluoro-5-((3-methylbenzyl)oxy)phenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(3-((3-Oxaspiro[5.5]undecan-9-yl)oxy)phenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(2-Fluoro-3-((3-(trifluoromethyl)benzyl)oxy)phenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(3-Methoxy-6-(6-((3-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)pyridazin-4- yl)methanesulfonamide,N-(6-(6-((3-Fluorobenzyl)oxy)pyridin-2-yl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(3-Methoxy-6-(6-((3-methylbenzyl)oxy)pyridin-2-yl)pyridazin-4- yl)methanesulfonamide,N-(6-(6-((3-Chlorobenzyl)oxy)pyridin-2-yl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(6-((4,4-Difluorocyclohexyl)methoxy)pyridin-2-yl)-3-methoxypyridazin-4- yl)methanesulfonamide.N-(6-(6-((8,8-Difluorobicyclo[3.2.1]octan-3-yl)methoxy)pyridin-2-yl)-3- methoxypyridazin-4-yl)methanesulfonamide,N-(3-Methoxy-6-(6-((4-(trifluoromethyl)cyclohexyl)oxy)pyridin-2-yl)pyridazin-4- yl)methanesulfonamide,N-(6-(6-((4,4-Difluorocyclohexyl)oxy)pyridin-2-yl)-3-rnethoxypyridazin-4- yl)methanesulfonamide,N-(6-(6-((4,4-Dimethylcyclohexyl)oxy)pyridin-2-yl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(3-Methoxy-6-(6-((5-(trifluorornethyl)furan-2-yl)methoxy)pyridin-2-yl)pyridazin-4- yl)methanesulfonamide,N-(3-Methoxy-6-(6-((1-(trifluoromethyl)cyclopropyl)methoxy)pyridin-2-yl)pyridazin-4- yl)methanesulfonamide,N-(6-(6-((3-Cy anobicyclo[1.1.1]pentan-1-yl)methoxy)pyridin-2-yl)-3 - methoxypyridazin-4-yl)methanesulfonamide,N-(6-(6-((3,3-Difluorocyclobutyl)methoxy)pyridin-2-yl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(6-((1-(Difluoromethyl)-1H-pyrazol-3-yl)methoxy)pyridin-2-yl)-3- methoxypyridazin-4-yl)methanesulfonamide,N-(3-Methoxy-6-(6-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)pyridin-2- yl)pyridazin-4-yl)methanesulfonamide,N-(3-Methoxy-6-(6-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridin-2-yl)pyridazin- 4-yl)methanesulfonamide,N-(6-(6-((3-Fluorobenzyl)oxy)pyridin-2-yl)-3-methoxypyridazin-4- yl)ethanesulfonamide,N-(6-(3-((3-Fluorobenzyl)oxy)phenyl)-3-methoxypyridazin-4-yl)ethanesulfonamide,N-(3,5-Difluoro-6'-methoxy-6-((3-(trifluoromethyl)benzyl)oxy)-[2,3'-bipyridin]-5'- yl)methanesulfonamide,N-(3-Fluoro-6'-methoxy-6-((3-(trifluoromethyl)benzyl)oxy)-[2,3'-bipyridin]-5'- yl)methanesulfonamide,N-(5-(2-Fluoro-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-2-methoxypyridin-3- yl)methanesulfonamide,N-(3,6'-Dimethoxy-6-((4-(trifluoromethyl)benzyl)oxy)-[2,3'-bipyridin]-5'- yl)methanesulfonamide,N-(3-Fluoro-6'-methoxy-6-((6-(trifluoromethyl)pyridin-2-yl)methoxy)-[2.3'-bipyndin]-5'-yl)methanesulfonamide,2.2.2-Trifluoro-N-(5-(2-fluoro-3-((3-(trifluoromethyl)benzyl)oxy)phenyl)-2- methoxypyridin-3-yl)ethane-1-sulfonamide,N-(5-(2,6-Difluoro-3-((3-(trifluoromethyl)benzyl)oxy)phenyl)-2-methoxypyridin-3-yl)-2,2,2-trifluoroethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-((2-(2,2,2-trifluoroethyl)-2- azaspiro[4.5]decan-8-yl)oxy)-[2.3'-bipyridin]-5'-yl)ethane-1-sulfonamide,N-(6-((1-Cyclopentyl-1H-indazol-3-yl)methoxy)-3-fluoro-6'-methoxy-[2,3'-bipyridin]- 5'-yl)-2,2,2-trifluoroethane-1-sulfonamide,N-(3-Fluoro-6'-(pyridin-4-ylmethoxy)-6-((1-(2,2,2-trifluoroethyl)piperidin-4- yl)methoxy)-[2,3'-bipyridin]-5'-yl)methanesulfonamide,N-(3-Fluoro-6'-(pyridin-4-ylmethoxy)-6-((1-(2.2.2-trifluoroethyl)piperidin-4-yl)oxy)-[2,3'-bipyridin]-5'-yl)methanesulfonamide,N-(3-Fluoro-6'-(pyridin-2-ylmethoxy)-6-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-[2,3'-bipyridin]-5'-yl)methanesulfonamide,N-(3-Fluoro-6'-(pyridin-4-ylmethoxy)-6-((1-(2,2,2-trifluoroethyl)piperidin-3- yl)methoxy)-[2,3'-bipyridin]-5'-yl)methanesulfonamide,N-(3-Fluoro-6'-(pyridin-2-ylmethoxy)-6-((1-(2,2,2-trifluoroethyl)piperidin-3- yl)methoxy)-[2,3'-bipyridin]-5'-yl)methanesulfonamide,N-(5-Methoxy-2-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-4- yl)methanesulfonamide,N-(2-Methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,3-Fluoro-N-(3-methoxy-6-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridazin-4- yl)propane- 1 -sulfonamide,N-(3-Methoxy-6-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridazin-4- yl)ethanesulfonamide,N-(3-Methoxy-6-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridazin-4-yl)propane-1- sulfonamide,N-(3-Methoxy-6-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridazin-4- yl)cyclopropanesulfonamide,1-Cyclopropyl-N-(6-(3-fluoro-6-((3-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-3- methoxypyridazin-4-yl)methanesulfonamide,2.2.2-Trifluoro-N-[5-[3-fluoro-6-(4-methyl-4-phenyl -cyclohexoxy )-2-pyridyl]-2- methoxy-3-pyridyl]ethanesulfonamide,1-Fluoro-N-(3-fluoro-6'-methoxy-6-((3-(trifluoromethyl)benzyl)oxy)-[2,3'-bipyridin]-5'- yl)methanesulfonamide,N-(6-(3,4-Dichlorophenoxy)-6'-methoxy-[2,3'-bipyridin]-5'-yl)methanesulfonamide, tert- Butyl 8-[[5-fluoro-6-[6-methoxy-5-(2,2,2-trifluoroethylsulfonylamino)-3-pyridyl]-2- pyridyl]oxy]-2-azaspiro[4.5]decane-2-carboxylate,2.2.2-Trifluoro-N-[5-(3fluoro-6-spiro[cyclohexane-4,1'-indane]-1-yloxy-2-pyridyl)-2- methoxy-3-pyridyl]ethanesulfonamide, diastereomer 1.2.2.2-Trifluoro-N-[5-(3-fluoro-6-spiro[cyclohexane-4,1'-indane]-1-yloxy-2-pyridyl)-2- methoxy-3-pyridyl]ethanesulfonamide, diastereomer 2,2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-((6-(trifluoromethyl)pyridin-2-yl)methoxy)- [2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide.2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-((3-(trifluoromethyl)benzyl)oxy)-[2,3'- bipyridin]-5'-yl)ethane-1-sulfonamide,N-(6'-Methoxy-6-((3-(trifluoromethyl)benzyl)oxy)-[2,3'-bipyridin]-5'- yl)methanesulfonamide,N-(6'-Methoxy-5-methyl-6-((3-(trifluoromethyl)benzyl)oxy)-[2,3,-bipyridin]-5,- yl)methanesulfonamide,1-Fluoro-N-(5-(2-fluoro-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-2-methoxypyridin-3- yl)methanesulfonamide,1-Fluoro-N-(2-methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-Methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)ethanesulfonamide,N-(2-Methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)propane-1- sulfonamide,N-(2-Methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)cyclopropanesulfonamide,N-(2-Methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)benzenesulfonamide,N-(2-Methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)propane-2- sulfonamide.N-(2-Methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)oxetane-3- sulfonamide,2.2-Difluoro-N-(2-methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)ethane-1-sulfonamide,3,3,3-Trifluoro-N-(2-methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)propane-1-sulfonamide,3-Fluoro-N-(2-methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)propane-1-sulfonamide.N-(2-Methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)-1- methylcyclopropane-1-sulfonamide,2-Fluoro-N-(2-methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-[5-[3-fluoro-6-[[l-(2,2.2-trifluoroethyl)-4-piperidyl]methoxy]-2- pyridyl]-2-(4-pyridylmethoxy)-3-pyridyl]ethanesulfonamide,2.2.2-Trifluoro-N-[5-[3-fluoro-6-[[3-(trifluoromethyl)phenyl]methoxy]-2 pyridyl]-2-(oxazol-5-ylmethoxy)-3-pyridyl]ethanesulfonamide,2.2.2-Trifluoro-N-[5-[3-fluoro-6-[[1-(2,2.2-trifluoroethyl)-4-piperidyl]oxy]-2-pyridyl]-2-(2-pyridylmethoxy)-3-pyridyl]ethanesulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-(pyridin-4-ylmethoxy)-6-((4-(2,2,2- trifluoroethyl)cyclohexyl)oxy)-[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-(pyridin-3-ylmethoxy)-6-((3-(trifluoromethyl)benzyl)oxy)-[2,3,-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-(pyridin-4-ylmethoxy)-6-((3-(trifluoromethyl)benzyl)oxy)-[2.3'-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-(pyrimidin-5-yloxy)-6-((3-(trifluoromethyl)benzyl)oxy)-[2, 3'-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-(pyridin-2-ylmethoxy)-6-((1-(2,2,2- trifluoroethyl)piperidin-4-yl)oxy)-[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-(pyrimidin-5-ylmethoxy)-6-((3-(trifluoromethyl)benzyl)oxy)-[2,3,-bipyridin]-5,-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-(pyrimidin-2-ylmethoxy)-6-((3-(trifluoromethyl)benzyl)oxy)-[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-(pyrimidin-4-ylmethoxy)-6-((3-(trifluoromethyl)benzyl)oxy)-[2.3'-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(2-methoxy-6-methyl-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)ethane-1-sulfonamide,N-(5-(2-Fluoro-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-2-(pyridin-4- ylmethoxy)pyridin-3-yl)methanesulfonamide.2.2.2-Trifluoro-N-(5-(2-fluoro-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-2-(pyridin-4- ylmethoxy)pyridin-3-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-(spiro[4.5]decan-8-yloxy)-[2,3'-bipyridin]-5'- yl)ethane-1-sulfonamide ,N-(6-((1,5-Diphenyl-1H-pyrazol-4-yl)methoxy)-3-fluoro-6'-methoxy-[2.3'-bipyridin]-5'- yl)-2, 2, 2-trifluoroethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-((5-phenyl-1-(tetrahydro-2H-pyran-4-yl)-1H- pyrazol-4-yl)methoxy)-[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide,N-(6-((1-Cyclobutyl-3-phenyl-1H-pyrazol-4-yl)methoxy)-3-fluoro-6'-methoxy-[2.3'- bipyridin]-5'-yl)-2,2,2-trifluoroethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-((6-(trifluoromethyl)-2,3-dihydro-1H-inden-1- yl)oxy)-[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-((7-methoxy-1,2,3,4-tetrahydronaphthalen-2- yl)oxy)-[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-((4-(naphthalen-2-yl)-2,3-dihydro-1H-inden-2-yl)oxy)-[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide,N-(6-((4,4-Dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)methoxy)-3-fluoro-6'-methoxy- [2,3'-bipyridin]-5'-yl)-2,2,2-trifluoroethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-((7-phenyl-1,2,3,4-tetrahydronaphthalen-2- yl)oxy)-[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide.2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-((1-methyl-1H-indazol-3-yl)methoxy)-[2.3'- bipyridin] -5 '-y l)ethane- 1 -sulfonamide,N-(3-(Difluoromethyl)-6'-methoxy-6-((3-(trifluoromethyl)benzyl)oxy)-[2,3'-bipyridin]-5'-yl)methanesulfonamide,N-(3-Methoxy-6-(5-((3-(trifluoromethyl)benzyl)oxy)pyridin-3-yl)pyridazin-4- yl)methanesulfonamide,N-(6-(3-((3-Fluorobenzyl)oxy)phenyl)-3-methoxypyridazin-4-yl)methanesulfonamide,N-(6-(2-Fluoro-3-((3-fluorobenzyl)oxy)phenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(5-(2-Fluoro-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)phenyl)-2-(pyridin-3- ylmethoxy)pyridin-3-yl)ethanesulfonamid,N-(3-Methoxy-6-(4-((3-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)pyridazin-4- yl)methanesulfonamide,N-(2-Phenoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-(Pyrimidin-5-yloxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-(Pyridin-3-yloxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide.N-(2-((5-Methyl-1,2,4-oxadiazol-3-yl)methoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)methanesulfonamide,N-(2-((1-Methyl-1H-pyrazol-4-yl)methoxy)-5-(3-((3- (trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)methanesulfonamide.N-(2-(2-Methoxyethoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-(2-(2-Oxopyrrolidin-1-yl)ethoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)methanesulfonamide,N-(2-(Pyridin-2-ylmethoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-(Pyridin-3-ylmethoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-(Pyridin-4-ylmethoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-(Oxazol-5-ylmethoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-((Tetrahydro-2H-pyran-4-yl)oxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)methanesulfonamide,N-(2-(Benzyloxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-Cyclobutoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-(Isoxazol-3-ylmethoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-(Pyrimidin-5-ylmethoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-((Tetrahydro-2H-pyran-4-yl)methoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)methanesulfonamide,N-(2-(2,2-Difluoroethoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-((1,3-Dimethoxypropan-2-yl)oxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)methanesulfonamide,N-(2-(Pyridazin-4-ylmethoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-((3-Methyloxetan-3-yl)methoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)methanesulfonamide,N-(6-(3-((4,4-Dimethylcyclohexyl)oxy)phenyl)-3-methoxypyridazin-4- yl)methanesulfonamide ,N-(6-{3-[(1-Cyclopentyl-5-phenyl-1H-pyrazol-4-yl)methoxy]phenyl}-3- methoxypyridazin-4-yl)methanesulfonamide,N-(6-((1-Cyanocyclopropyl)methoxy)-3-fluoro-6'-methoxy-[2,3'-bipyridin]-5'-yl)-2,2,2- trifluoroethane-1-sulfonamide,2,2,2-Trifluoro-N-(3-fluoro-6'-methoxy-6-(3-(trifluoromethyl)phenoxy)-[2,3'-bipyridin]- 5'-yl)ethane-1-sulfonamide,N-{6-[(3-Bromophenyl)methoxy]-3-fluoro-6'-methoxy[2.3'-bipyridin]-5'-yl}-2.2.2- trifluoroethane-1-sulfonamide,2.2.2-Trifluoro-N-{3-fluoro-6'-methoxy-6-[(oxan-4-yl)methoxy][2,3'-bipyridin]-5'- yl} ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6,-methoxy-6-{[4-(2,2,2-trifluoroethyl)morpholin-2- yl]methoxy}[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-{[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4- yl]methoxy} [2, 3'-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-{3-fluoro-6'-methoxy-6-[(oxan-3-yl)methoxy][2,3'-bipyridin]-5,- yl} ethane- 1 -sulfonami de,N-{6-[(3-Cyanophenyl)methoxy]-3-fluoro-6'-methoxy[2,3'-bipyridin]-5'-yl}-2,2,2- trifluoroethane-1 -sulfonamide,2.2.2-Trifluoro-N-{3-fluoro-6'-methoxy-6-[(naphthalen-1-yl)methoxy] [2.3'-bipyridin]-5'- yl} ethane- 1 -sulfonamide,2.2.2-Trifluoro-N-{3-fluoro-6'-methoxy-6-[(oxan-2-yl)methoxy][2,3'-bipyridin]-5'- yl} ethane-1 -sulfonamide,N-(6-{[1-(Cyanomethyl)piperidin-3-yl]methoxy}-3-fluoro-6'-methoxy[2,3'-bipyridin]-5'- yl)-2.2.2-trifluoroethane-1-sulfonamide.2.2.2-Trifluoro-N-{3-fluoro-6,-methoxy-6-[(3-methyloxetan-3-yl)methoxy][2,3'- bipyridin]-5'-yl} ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-{[(3-endo)-8-oxabicyclo[3.2.1]octan-3- yl]oxy}[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide,N-[6-(3,4-Dichlorophenoxy)-3-fluoro-6'-methoxy[2,3'-bipyridin]-5'-yl]-2,2,2- trifluoroethane-1-sulfonamide,N-{6-[3-Bromo-5-(trifluoromethyl)phenoxy]-3-fluoro-6'-methoxy[2,3'-bipyridin]-5'-yl}-2,2,2-trifluoroethane-1-sulfonamide.2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-{[1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3- yl]methoxy}[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide,N-(6-(((1r,4r)-4-Cyanocyclohexyl)oxy)-3-fluoro-6'-methoxy-[2,3'-bipyridin]-5'-yl)-2,2,2- trifluoroethane-1-sulfonamide, orN-(6-((4,4-Dimethylcyclohexyl)oxy)-6'-methoxy-[2,3'-bipyridin]-5'- yl)methanesulfonamide.

[0075] In Embodiment 73 of the invention, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is:

[0076] In one embodiment the present disclosure provides pharmaceutical compositions comprising a compound of the invention, for example, a compound of Formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

[0077] In one embodiment, the present disclosure provides a method for treating cancer in a patient, comprising administering to the patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I. In a further embodiment, the cancer is associated with increased YAP1 and / or TAZ expression.

[0078] In one embodiment, the present disclosure provides a method for inhibiting the progress of cancer in a patient, comprising administering to the patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I.

[0079] In one embodiment, the present disclosure provides a method of treating a disease or disorder in which Hippo pathway inhibition is beneficial, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I. In a further embodiment, the disease or disorder is a cellular proliferative disorder. In a further embodiment, the cellular proliferative disorder is cancer.

[0080] In one embodiment, the present disclosure provides for the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of Formula I, for treating cancer in a patient.

[0081] In one embodiment, the present disclosure provides for the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of Formula I, for the preparation of a medicament useful for the prevention of a cell proliferative disorder.

[0082] In the description that follows conventional structural representation is employed and includes conventional stereochemical notation for certain asymmetric carbon centers.

[0083] Thus, structural representation of compounds of Formula I includes conventional stereochemical notation for some asymmetric carbon centers shown in the example compounds. Accordingly, in such instances, solid black “wedge” bonds represent bonds projecting from the plane of the reproduction medium, “hashed wedge” bonds representing descending bonds into the plane of the reproduction medium, and a “wavey” line appended to a carbon bearing a double bond indicates both possible cis and trans orientations are included. As is conventional, plain solid lines represent all spatial configurations for the depicted bonding. Accordingly, where no specific stereochemical notation is supplied the representation contemplates all stereochemical and spatial orientations of the structural features.

[0084] As is shown in the examples, and mentioned above, particular asymmetric carbon centers are structurally represented using conventional “Solid Wedge” and “Hash Wedge” bonding representation. For the most part, absolute configuration has not been determined for the example compounds, but has been assigned by analogy to specific example compounds of known stereochemical configurations (determined by X-ray cry stallography) prepared using the same or analogous reaction conditions and starting reagents and isolated under the same chromatographic conditions. Accordingly, specific assignment of the configurations structurally represented herein is meant to identify the specific compounds prepared has having an excess of one particular stereoisomer and is not put forth herein necessarily as being a statement of the absolute determination of the stereochemical structure of said compound unless otherw ise noted in thedata presented.In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry', as (R)- or (5)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.). Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g.. cis or trans.) of an alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0085] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH.

[0086] It will be appreciated that where isomeric mixtures are obtained, the preparation of individual stereoisomers in significant percentages of enantiomeric excess can be carried out, if desired, by separation of the mixture using customary methods, for example by chromatography or crystallization, or by the use of stereochemically uniform starting materials for the synthesis described, or by stereoselective synthesis. Optionally a derivatization can be carried out before a separation of stereoisomers. The separation of a mixture of stereoisomers can be earned out at an intermediate step during the synthesis of a compound of Formula I or it can be done on a final racemic product.

[0087] Where indicated herein, absolute stereochemistry is determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary , with a reagent containing a stereogenic center of known configuration. Unless a particular isomer, salt, solvate (including hydrates) or solvated salt of such racemate, enantiomer, or diastereomer is indicated, the present disclosure includes all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and mixtures thereof.

[0088] Where a wavey line terminates a conventional bond (as opposed to connecting two atoms within a structure) it indicates a point of bonding to a structure, e.g.:indicates a the secondary -butyl moiety is bonded via the methylene group via the bond terminated with the wavey line. Where an alphabetical notation is used to depict a substituent moiety, a dash is employed to indicate the point of bonding to the indicated substrate, e.g.: -CH2- C(O)-CH2Cl indicates the acetyl chloride moiety is bonded via the methylene portion of the moiety.

[0089] Where compounds of Formula I are capable of tautomerization, all individual tautomers as well as mixtures thereof are included in the scope of this disclosure.

[0090] When any variable (e.g., R, R1, n, alkyl, etc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence unless otherwise specified at the point of definition. One of ordinary skill in the art will recognize that choice of combinations of the various substituents defined in a structural representation.i. e. i.e.. i.e.. R1. R2. etc., are to be chosen in conformity with well-known principles of chemical structure connectivity and stability, and combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0091] A "stable" compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject). The compounds of the present disclosure are limited to stable compounds embraced by Formula I.

[0092] Where any variable or moiety is expressed in the form of a range, e.g., (-CH2-)1-4, both of the extrema of the specified range are included (i.e., 1 and 4 in the example) as well as all of the whole number values in between (i.e., 2 and 3 in the example).

[0093] It is understood that reference to “Formula I” also encompasses compounds of Formula IA, unless indicated otherwise.

[0094] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory' only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictatesotherwise. In this application, the use of "or" means "and / or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting.

[0095] As used herein, in some embodiments, ranges and amounts are expressed as "about" a particular value or range. About also includes the exact amount. Hence "about 5 μL" means "about 5 μL" and also "5 μL." Generally, the term "about" includes an amount that is expected to be within experimental error.

[0096] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not. For example, "optionally substituted alkyl" means that the alkyl radical may or may not be substituted and that the description includes both substituted alky l radicals and alkyl radicals having no substitution.

[0097] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation. Alkyl may contain one to fifteen carbon atoms (e.g., C1-15alkyl), unless otherwise stated. In certain embodiments, an alky l comprises one to eight carbon atoms (e.g., C1-8alkyl). In other embodiments, an alkyd comprises one to six carbon atoms (e.g.. C1-6alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-4alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-3alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-2alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., methyl). In other embodiments, the alkyd group is selected from methyl, ethyl, 1 -propyl (n-propyl), 1 -methylethyl (Ao-propyl), 1-butyl (n-butyl), 1 -methylpropyl (sec butyl), 2-methylpropyl (Ao-butyl), 1,1- dimethylethyl (tert-butyl). 1 -pentyl (n-penlyl). In other embodiments, the alkyl group is methyl. The alkyl is attached to the rest of the molecule by a single bond. “Alkydenyl” or “alkylene” refers to a saturated linear or branched aliphatic hydrocarbon group having two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane. The alkylene is a linear or branched group having 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, and more preferably 1 to 6 carbon atoms. Non-limiting examples are methylene, ethylene, propylene, butylene, pentylene, and the like.

[0098] "Halogen" or "halo" as used herein refers to fluoro, chloro, bromo and iodo.

[0099] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent group having 3 to 20 carbon atoms. In some embodiments, cycloalkyl has 3 to 12 carbon atoms. In some classes, cycloalkyd has 3 to 10 carbon atoms. In subclasses of monocyclic cycloalkyd, cycloalkyd has 3 to 8 carbon atoms. Non-limiting examplesof monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, bridged ring, or a fused ring, including fused to a benzene ring. Non-limiting examples of polycyclic cycloalkyl include bicyclo-octanyl, bicyclo-pentanyl, dihydrospiro-cyclohexane-indenyl, indanyl, spiro-decanyl, tetrahydronaphthyl.

[0100] As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein the ring system is aromatic. In an embodiment, aryl is phenyl or naphthyl. In a further embodiment, aryl is phenyl.

[0101] The term “heterocyclyl”, “heterocycle” or “heterocyclic”, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which ring is formed by carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. Atoms forming the heterocyclic ring(s) are referred to as “members” of the heterocyclic ring or ring system. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. The term heterocyclyl, heterocycle or heterocyclic can include heteroaryl moieties when two rings are fused together, as well as spiro ring systems, where one of the rings contains a heteroatom. Examples of heterocyclic elements include, but are not limited to, dihydroisobenzofuranyl, dihydro-pyrrolo[l,2-b]pyrazolyl, imidazolidinyl, indolinyl, isoindolinyl, morpholinyl, (lR,5S)-8-oxabicyclo[3.2.1]octanyl, oxetanyl, piperidinyl, pyrrolidinyl, and tetrahydropyranyl. Non-limiting examples of spiro ring systems include azaspiro [4.5] decanyl, azaspiro[5.5]undecanyl. and oxaspiro[5.5]undecanyl.

[0102] "Heteroaryl" is intended to mean any stable monocyclic or bicyclic ring of up to 7 ring atoms or “members” in each ring, wherein at least one ring is aromatic and wherein one to four of the ring atoms or “members” are heteroatoms independently selected from the group consisting of N, O, and S. In one embodiment, the heteroaryl is a 5- or 6- membered ring containing 1. 2, or 3 heteroatoms independently selected from N, O, and S. The term heteroaryl, can include heteroaryl moieties when two rings are fused together having 8- to 10- members containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. Examples of such heteroaryl groups include, but are not limited to, furanyl, furyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl, triazolyl and the like.

[0103] For use in medicine, the salts of the compounds of Formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds ofFormula I or of their pharmaceutically acceptable salts. “Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Pharmaceutically acceptable salts of the compounds described herein are optionally pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0104] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997), which is hereby incorporated by reference in its entirety ).

[0105] In some embodiments, acid addition salts of basic compounds are prepared by contacting the free base forms w ith a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0106] When the compound of Formula I is acidic, suitable “pharmaceutically acceptable salts” refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium,potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline. N,N'-dibenzylethylenediarnine. diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.

[0107] When the compound of Formula I is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic. pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.

[0108] The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al., '’Pharmaceutical Salts,” J. Pharm. Sci.. 1977:66: 1-19.

[0109] If the compounds of Formula I simultaneously contain acidic and basic groups in the molecule, Formula I also includes zwitterions, in addition to the salt forms described above.Pharmaceutical Compositions

[0110] In certain embodiments, the compound as described herein is administered as the chemical. In other embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)), the disclosure of which is hereby incorporated herein by reference in its entirety.

[0111] Further provided is a pharmaceutical composition comprising an effective amount of at least one compound of Formula I and a pharmaceutically acceptable carrier. The composition may comprise, but is not limited to, one or more fillers, extenders, binders, humectants,disintegrating agents, solution retarding agents, absorption accelerators, absorbants, buffering agents, wetting agents, emulsifiers, suspending agents, lubricants, adsorbents, surfactants, preservatives, as well as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulphate, talc, mannitol, ethyl alcohol, water, sorbitol, stearic acid, magnesium stearate, gums, and the like. The composition may be formulated as a solid, liquid, gel or suspension for oral administration (e g., drench, bolus, tablet, powder, granules, capsule (either solid-filled, semi-solid filled or liquid filled), oral gel, mouth spray, emulsion, suspensions, syrups, elixers); parenteral administration (e.g., subcutaneous, intramuscular, intravenous, epidural injection); topical application (e.g., cream, ointment, controlled-released patch, spray); intravaginal, intrarectal, transdermal, ocular, or nasal administration. In a further embodiment, the pharmaceutical composition of the present disclosure may be formulated for parenteral administration, such as an intravenous formulation.

[0112] The term "composition" as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. This term in relation to pharmaceutical compositions is intended to encompass a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.

[0113] In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active compound, which is a compound of Formula I, is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition made by admixing a compound of Formula I and a pharmaceutically acceptable carrier.

[0114] The formulations of the present disclosure include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature ofthe particular compound being used. For example, disclosed compositions are formulated as a unit dose, and / or are formulated for oral or subcutaneous administration.

[0115] In some instances, exemplary pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, in solid, semisolid, or liquid form, which includes one or more of a disclosed compound, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral applications. In some embodiments, the active ingredient is compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[0116] For preparing solid compositions such as tablets in some instances, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition is readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0117] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following:(1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid;(2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions also comprise buffering agents in some embodiments. Solid compositions of a similar ty pe are also employed as fillers in soft and hard-filled gelatin capsules using suchexcipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0118] In some instances, a tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfaceactive or dispersing agent. Molded tablets are made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, are optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

[0119] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms contain optionally inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzy l benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0120] Suspensions, in addition to the subject composition, optionally contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0121] In some embodiments, formulations for rectal or vaginal administration are presented as a suppository, which are prepared by mixing a subject composition with one or more suitable non irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

[0122] Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component is optionally mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants which are required in some embodiments.

[0123] In some embodiments, the ointments, pastes, creams and gels contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0124] In some embodiments, powders and sprays contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0125] Compositions and compounds disclosed herein are alternatively administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g, fluorocarbon propellant) suspension could be used. Sonic nebulizers are used because they minimize exposing the agent to shear, which result in degradation of the compounds contained in the subject compositions in some embodiments. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

[0126] Pharmaceutical compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which are reconstituted into sterile injectable solutions or dispersions just prior to use, which optionally contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic wi th the blood of the intended recipient or suspending or thickening agents.

[0127] Examples of suitable aqueous and non-aqueous carriers employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. In some embodiments, properfluidity is maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants

[0128] In some embodiments, the dose of the composition comprising at least one compound as described herein differ, depending upon the patient's (e.g., human’s) condition, that is, stage of the disease, general health status, age, and other factors that a person skilled in the medical art will use to determine dose.

[0129] In some instances, pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented) as determined by persons skilled in the medical arts. An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. In some embodiments, the optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0130] In the treatment, prevention, control, amelioration, or reduction of risk of the conditions disclosed herein an appropriate dosage level of the compounds of Formula I will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. A suitable dosage level may be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0. 1 to 50 mg / kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg / kg per day. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 2.0, 3.0, 4.0, 5.0, 7.5, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day or may be administered once or twice per day.

[0131] As the term is used herein, “patients” (alternatively “subjects”) refers to an animal, preferably a mammal, and in one embodiment a human or companion animal. In certain embodiments, the patient is a human in need of treatment. As used herein, the term "administration" and variants thereof (e.g., "administering" a compound) in reference to acompound of Formula I means providing the compound, or a pharmaceutically acceptable salt thereof, to a subject in need of treatment.

[0132] As used herein, "treatment" and "treating" are used interchangeably herein. These terms refers to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is afflicted with the underlying disorder in some embodiments. As used herein, “prevention” and “preventing” are used interchangeably herein and refer to an approach for obtaining prophylactic benefit. Prophylactic benefit includes, in some embodiments, administration of the compounds or compositions to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.Labeled compound

[0133] In the compounds of Formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure relates to all suitable isotopic variations of the compound of Formula I. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates. In some embodiments, examples of isotopes that are incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,15N,180,170,31P,32P,35S,18F, and36C1, respectively. Compounds described herein, and the metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes areparticularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e.,2H, may produce certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compounds, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof is prepared by any suitable method.

[0134] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.The Hippo Signaling Network

[0135] The Hippo signaling network (also known as the Salvador / Warts / Hippo (SWH) pathway) is a master regulator of cell proliferation, death, and differentiation. In some embodiments, the main function of the Hippo signaling pathway is to regulate negatively the transcriptional co activators Yes-associated protein (Y AP) and its paralogue, the transcriptional co-activator with PDZ-binding motif (TAZ; also known as WWTR1). The Hippo kinase cascade phosphorylates and inhibits YAP / TAZ by promoting its cytoplasmic retention and degradation, thereby inhibiting the growth promoting function regulated under the YAP / TAZ control. In an unphosphorylated / de-phosphorylated state, YAP, also known as YAP1 or YAP65, together with TAZ, are transported into the nucleus where they interact with TEAD family of transcription factors to upregulate genes that promote proliferation and migration, and inhibit apoptosis. In some instances, unregulated upregulation of these genes involved in proliferation, migration, and anti-apoptosis leads to development of cancer. In some instances, overexpression of YAP / TAZ is associated with cancer.

[0136] Additional core members of the Hippo signaling pathway comprise the serine / threonine kinases MST1 / 2 (homologues of Hippo / Hpo in Drosophila). Lats1 / 2 (homologues of Warts / Wts), and their adaptor proteins Savl (homologue of Salvador / Sav) and Mob (M0BKL1A and MOBKL1B; homologues of Mats), respectively. In general, MST1 / 2 kinase complexes with the scaffold protein Savl, which in turn phosphorylates and activates Lats1 / 2 kinase. Lats1 / 2 is also activated by the scaffold protein Mob. The activated Lats1 / 2 then phosphorylates and inactivates YAP or its paralog TAZ. The phosphorylation of YAP / TAZ leads to their nuclear export, retention within the cytoplasm, and degradation by the ubiquitin proteasome system.

[0137] In some instances, Lats1 / 2 phosphorylates YAP at the [HXRXXS] consensus motifs. YAP comprises five [HXRXXS] consensus motifs, wherein X denotes any amino acid residue. Insome instances, Lats1 / 2 phosphorylates YAP at one or more of the consensus motifs. In some instances, Lats1 / 2 phosphorylates YAP at all five of the consensus motifs. In some instances, Lats1 / 2 phosphorylate at the S127 amino acid position. The phosphorylation of YAP S127 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of YAP. Mutation of YAP at the S 127 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.

[0138] Additional phosphory lation occurs at the S381 amino acid position in YAP. Phosphorylation of YAP at the S381 position and on the corresponding site in TAZ primes both proteins for further phosphorylation events by CK18 / c in the degradation motif, which then signals for interaction with the -TRCP E3 ubiquitin ligase, leading to polyubiquitination and degradation of YAP.

[0139] In some instances, Lats1 / 2 phosphorylates TAZ at the [HXRXXS] consensus motifs. TAZ comprises four [HXRXXS] consensus motifs, wherein X denotes any amino acid residue. In some instances, Lats1 / 2 phosphorylates TAZ at one or more of the consensus motifs. In some instances, Lats1 / 2 phosphorylates TAZ at all four of the consensus motifs. In some instances, Lats1 / 2 phosphorylate at the S89 amino acid position. The phosphorylation of TAZ S89 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of TAZ. Mutation of TAZ at the S89 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.

[0140] In some embodiments, phosphorylated YAP / TAZ accumulates in the cytoplasm, and undergoes SCFP'TRCP-mediated ubiquitination and subsequent proteasomal degradation. In some instances, the Skp, Cullin, F-box containing complex (SCF complex) is a multi-protein E3 ubiquitin ligase complex that comprises a F-box family member protein (e.g., Cdc4). SkμL a bridging protein, and RBXI which contains a small RING Finger domain which interacts with E2-ubiquitin conjugating enzy me. In some cases, the F-box family comprises more than 40 members, in which exemplary members include F-box / WD repeat-containing protein IA (FBXWIA, βTrCPl, Fbxwl, hsSlimb, plkappaBalpha-E3 receptor subunit) and S-phase kinase- associated proteins 2 (SKP2). In some embodiments, the SCF complex (e.g., SCPβTrCP1) interacts with an E1 ubiquitin-activating enzy me and an E2 ubiquitin-conjugating enzyme to catalyze the transfer of ubiquitin to the YAP / TAZ substrate. Exemplary E1 ubiquitin-activating enzymes include those encoded by the following genes: UBAI, UBA2, UBA3, UBA5. UBA5, UBA7, ATG7, NAEI, and SAEI. Exemplary E2 ubiquitin-conjugating enzymes include those encoded by the following genes: UBE2A, UBE2B, UBE2C, UBE2DI, UBE2D2, UBE2D3, UBE2EI, UBE2E2, UBE2E3, UBE2F, UBE2GI, UBE2G2, UBE2H, UBE21, UBE2JI, UBE2J2, UBE2K, UBE2L3,UBE2L6. UBE2M, UBE2N, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2 UBE2T, UBE2U, UBE2VI, UBE2V2, UBE2ZATG2, BIRC5. and UFCL In some embodiments, the ubiquitinated YAP / TAZ further undergoes the degradation process through the 26S proteasome.

[0141] In some embodiments, the Hippo pathway is regulated upstream by several different families of regulators. In some instances, the Hippo pathway is regulated by the G-protein and its coupled receptors, the Crumbs complex, regulators upstream of the MST kinases, and the adherens junction.YAP / TAZ Interaction with TEAD

[0142] In some embodiments, un-phosphorylated and / or dephosphorylated YAP / TAZ accumulates in the nucleus. Within the nucleus, YAP / TAZ interacts with the TEAD family of transcription factors (e.g., TEADI, TEAD2, TEAD3, or TEAD4) to activate genes involved in antiapoptosis and proliferation, such as for example CTFG, Cyr61, and FGFI.

[0143] In some embodiments, the compounds disclosed herein modulate the interaction between YAP / TAZ and TEAD. In some embodiments, the compounds disclosed herein bind to TEAD, YAP, or TAZ and prevent the interaction between YAP / TAZ and TEAD.

[0144] Also provided is a method for the synthesis of compounds useful as intermediates in the preparation of compounds of Formula I.

[0145] The compounds described herein can be prepared according to the procedures of the following schemes and examples, using appropriate materials and are further exemplified by the following specific examples. Deuterated versions of the compounds of Formula I can be prepared by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the disclosure. The examples further illustrate details for the preparation of the compounds of Formula I. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. Reagents and starting materials for preparing the intermediates and example compounds are commercially available, unless indicated otherwise. All temperatures are degrees Celsius unless otherwise noted. Mass spectra (MS) were measured by electrospray ion-mass spectroscopy (ESI).11H NMR spectra were recorded at 300-500 MHz.SCHEMES AND EXAMPLES

[0146] The abbreviations used herein have the following tabulated meanings. Abbreviations not tabulated below have their meanings as commonly used unless specifically stated otherwise.ABBREVIATIONSThe following abbreviations have been used:ACN acetonitrile aq aqueousBH3·DMS borane dimethyl sulfide complexBINAP Pd G3 Methanesulfonato[2,2'-bis(diphenylphosphino)-1,1'-binaphthyl](2'-amino-1,1'-biphenyl-2-yl)palladium(II)B2pin2 Bis(pinacolato)diboronBrettPhos 2-(Dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'- biphenylBretPhos Pd G4 Methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i- propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) degree CelsiusDAST (diethylamino)sulfur trifluorideDCM dichloromethaneDEAD diethyl azodicarboxylateDIAD diisopropyl azodicarboxylateDMF N,N-dimethyl formamideESI electrospray ionizationEtOAc ethyl acetateEtOH ethanol equiv equivalents g gram h hour(s)HC1 hydrochloric acidHPLC high performance liquid chromatographyHunig’s base N,N-diisopropylethylamineIPA isopropyl alcoholKOAc potassium acetateM molar m-CPBA 3-chloroperbenzoic acid meCgPPh-Pd-G2 [(1,3,5,7-Tetramethyl-6-phenyl-2,4,6-trioxa-6-phosphaadamantane)-2-(2'- amino-1,1'-biphenyl)]palladium(II) chlorideMel methyl iodideMeOH methanol mg milligram Mg(OtBu)2 magnesium di-tert-butoxide min minutes mL milliliter mmol millimoleMs methanesulfonylMS mass spectrometryMTBE methyl tert-butyl etherNaHMDS sodium bis(trimethylsilyl)amideNCS N- chlorosuccinimide nM nanomolar NMP N-methyl -2-pyrroli done N normalNEt3triethylamineNMR nuclear magnetic resonancePCy3tri cyclohexylphosphine Pd(Amphos)Cl2Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) PdCl2(dppf) [1,1 -bis(diphenylphosphine)ferrocene] dichloropalladium(II) PdCl2(dtbpf) [ 1,1'- bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Pd2(dba)s tris(dibenzylideneacetone)dipalladium(0) Pd(PPh3)4tetrakis(triphenylphosphine)palladium(0) pet. ether petroleum ether PhB(OH)2phenylboronic acid PhMe toluenePhOH phenol PMB p-methoxy benzyl PPh3triphenylphosphine prep-TLC preparative TLC PS-PPh3polymer-supported triphenylphosphine p-TSA p-toluenesul Ionic acid monohydrate rt room temperatureSEM-C1 2-(trimethylsilyl)ethoxymethyl chlorideTBME methyl tert-butyl etherTBS tert-butyl dimethylsilylTFA trifluoroacetic acidTHF tetrahydrofuranTLC thin layer chromatography μL microliterXantphos Pd G3 [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'- biphenyl)]palladium(II) methanesulfonateMETHODS OF SYNTHESIS

[0147] The compounds of Formula I can be prepared according to the following general schemes using appropriate materials and are further exemplified by the subsequent specific examples. The illustrative examples below, therefore, are not limited by the compounds listed or by any particular substituents employed for illustrative purposes. Substituent numbering as shown in the schemes does not necessarily correlate to that used in the claims and often, for clarity, a single substituent is show n attached to the compound where multiple substituents are allowed under the definitions in Formula I.

[0148] Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The compounds of Formula I will now be illustrated in the following non-limiting Examples in which, unless otherwise stated. All reactions were stirred (mechanically, stir bar / stir plate, or shaken) and conducted under an ambient (air) atmosphere unless specifically stated otherwise. All temperatures are degrees Celsius (°C) unless otherwise noted. Ambient temperature is 15-25 °C. Most compounds were purified by reverse-phase preparative HPLC, MPLC on silica gel, recry stallization and / or trituration (suspension in a solvent followed by filtration of the solid). The course of the reactions was followed by thin layer chromatography (TLC) and / or LCMS and / or NMR and reaction times are given for illustration only. All end products were analyzed by NMR and LCMS. Intermediates were analyzed by NMR and / or TLC and / or LCMS.GENERAL SYNTHESES

[0149] The compounds of Formula I may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes and synthetic procedures and conditions for the illustrative intermediates and examples. The compounds described herein maybe made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes.

[0150] While the compounds of Formula I have been described in conjunction with the specific examples set forth below, many alternatives, modifications, and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications, and variations are intended to fall within the spirit and scope of the present disclosure.INTERMEDIATES

[0151] Intermediate A-l: N-(2-Bromo-5 -methoxy pyridin-4-yl)methanesulfonamideMethanesulfonyl chloride (0.040 mL, 0.49 mmol) was added to an ice-cold solution of 2-bromo- 5-methoxy-pyridin-4-amine (50 mg, 0.25 mmol) in pyridine (1 mL). The mixture was stirred at rt for 3 h, concentrated under reduced pressure, and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 20-100% EtOAc in hexanes) to afford N-(2-bromo-5-methoxypyridin-4-yl)methanesul fonamide. MS (ESI) m / z calc’d for : 281, 283; found: 281, 283.Table lnt-01: The following intermediates were prepared using a similar procedure asIntermediate A-l.

[0152] Intermediate A-5: N-( 6-Chloro-3-methoxypyridazin-4-yl)-JV-(4- methoxybenzyl)methanesulfonamide

[0153] Step 1 : A stirred solution of 3,4,6-trichloropyridazine (251 g, 1.37 mol) in IPA (1.7 L) was added (4-methoxyphenyl)methanamine (563 g, 4. 11 mol ), and reaction was stirred at 62 °C for 12 h. The reaction mixture was quenched with H2O (1.5 L), extracted with EtOAc (1.20 L), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by column chromatography (silica, 0-100% EtOAc in pet. ether) to afford 3,6-dichloro- N-( 4-methoxybenzyl)pyridazin-4-amine. MS (ESI) m / z calc’d for C12H11C12N3O [M+H]+: 284: found: 284.1H NMR (400 MHz, CDCl3) δ 7.25 (d, J= 8.60 Hz, 2H), 6.97 - 6.90 (m, 2H), 6.54 (s, 1H), 5.46 (s, 1H), 4.35 (d, J= 5.28 Hz, 2H), 3.83 (s, 3H).

[0154] Step 2 : Sodium methoxide solution (30 wt%, 201 g, 1.12 mol) was added to a solution of 3,6-dichloro-N-( 4-methoxybenzyl)pyridazin-4-amine (288 g. 1.02 mol) in THF (4 L), and the reaction was stirred at 70 °C for 12 h. The reaction mixture was cooled to rt, quenched with H2O (400 mL) and extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by column chromatography (silica, 10-50% EtOAc in DCM) to afford 6-chloro-3-methoxy-JV-(4-methoxybenzyl)pyridazin-4-amine. MS (ESI) m / z calc’d for C13H14CIN3O2 [M+H]+: 280; found: 280.1H NMR (500 MHz, CDCl3) δ 7.23 (d, J= 8.6 Hz, 2H), 6.94 - 6.89 (m, 2H), 6.73 - 6.69 (m, 1H), 6.54 (s, 1H), 4.44 (d, J= 5.3 Hz, 2H), 4.09 (s, 3H), 3.81 (s, 3H).

[0155] Step 3: 6-Chloro-3 -methoxy -N -(4-methoxybenzyl)pyridazin-4-amine (176 g, 629 mmol ) in THF (700 mL) was cooled to 0 °C. NaHMDS in THF (1 M, 629 mL ) was added dropwise, and the mixture was stirred for 30 min. Methanesulfonyl chloride (108 g, 944 mmol) was added dropwise and stirred for 2 h. The reaction mixture was diluted with sat’d NH4CI and extracted with EtOAc (3x). The combined organic extracts were washed with sat’d NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 5% MeOH / DCM) to give N-(6-chloro-3-methoxypyridazin-4-yl)-N-( 4-methoxybenzyl)methanesulfonamide. MS (ESI) m / z C14H16CIN3O4S [M+H]+calc'd 358, found 358.1H NMR (400 MHz, CDCl3) δ 7.18 (s, 1H), 7.14 - 7.08 (m, 2H), 6.82 - 6.77 (m, 2H), 4.80 (s, 2H), 4.26 (s, 3H), 3.77 (s, 3H), 3.03 (s, 3H).Table Int-02: The following intermediates were prepared using a similar procedure asIntermediate A-5.

[0156] Intermediate A-6: N-(3-Metho\y-6-(tributylstannyl)pyridazin-4-yl)-N-(4- methoxybenzyl)methanesulfonamideA solution of A-(6-chloro-3 -methoxy pyridazin-4-yl)-JV-(4-methoxybenzyl)methanesul fonamide (50.0 g, 140 mmol) in dioxane (500 mL) was placed under an N2atmosphere via sequential vacuum / nitrogen cycles (3x). To the mixture were added Pd2(dba)3(6.40 g, 6.99 mmol), PCy3(4.70 g, 16.77 mmol), and 1,1,1,2,2,2-hexabutyldistannane (121.6 g, 209.6 mmol), and the mixture was placed under an N2 atmosphere via sequential vacuum / nitrogen cycles (3x). The mixture was heated to 100 °C for 18 h, cooled to rt, concentrated under reduced pressure, and purified by column chromatography (silica, 33% EtOAc in pet. ether) to afford N-( 3-methoxy-6- (tributylstannyl)pyridazin-4-yl)-N-(4-methoxybenzyl)methanesulfonamide. MS (ESI) m / z calc’d for C26H44N3O4SSn [M+H]+: 614; found: 614.1H NMR (400 MHz, CDCl3) δ 7.11 (d, J= 8.8 Hz, 2H), 7.05 (s, 1H), 6.76 (d, J= 8.8 Hz, 2H), 4.74 (s, 2H), 4.24 (s, 3H). 3.74 (s, 3H), 3.03 (s. 3H), 1.49 - 1.45 (m, 6H), 1.29 - 1.22 (m, 6H), 1.10 - 1.06 (m, 6H), 0.85 (t, J= 7.2 Hz, 9H).

[0157] Intermediate A-7: (5-(Methylsulfonamido)-6-(pyridin-4-ylmethoxy)pyridin-3- yl)boronic acidA solution of A-[5-iodo-2-(4-pyridylmethoxy)-3-pyridyl]methanesulfonamide (150 mg, 0.37 mmol), B2pin2(140 mg, 0.55 mmol), KOAc (100 mg, 1.02 mmol), and Pd(dppf)Cl2(20 mg, 0.024 mmol) in 1,4-dioxane (5 mL) was heated to 90 °C overnight, cooled to rt, concentrated under reduced pressure, and diluted with EtOAc. The mixture was filtered, concentrated under reduced pressure, and purified by preparative HPLC (reverse phase) to afford (5- (methylsulfonamido)-6-(pyridin-4-ylmethoxy)pyridin-3-yl)boronic acid. MS (ESI) m / z calc’d for C12H15BN3O5S [M+H]+: 324; found: 324.

[0158] Intermediate A-9: 3-Nitro-2-(pyridin-4-ylmethoxy)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridineA solution of 5-iodo-3-nitro-2-(4-pyridylmethoxy)pyridine (650 mg, 1.82 mmol), B2pin2(693 mg, 2.73 mmol), KOAc (536 mg, 5.46 mmol), and Pd(dppf)Cl2(133 mg, 0.18 mmol) in 1,4- di oxane (40 mL) was heated to 90 °C for 16 h, cooled to rt, filtered over Celite, concentrated under reduced pressure, and diluted with EtOAc. The mixture was washed with water (2x) and brine, dried over MgSO4, concentrated under reduced pressure, and purified by prep-TLC (silica) to afford 3-nitro-2-(pyridin-4-ylmethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine. MS (ESI) m / z calc'd for C11H11BN3O5 [M-C6H10+H]+: 276; found: 276.Table Int-03; The following intermediates were prepared using a similar procedure as Intermediate A-9.

[0159] Intermediate A-12: N-(3,6-Dichloropyridazin-4-yl)-N-( 4- methoxybenzyl)methanesulfonamideTo a stirred solution of 3,4,6-trichloropyridazine (2.68 g, 14.6 mmol) and JV-(4- methoxybenzyl)methanesulfonamide (3.0 g. 14 mmol) in DMF (35 mL) at 25 °C was added CS2CO3(4.77 g, 14.6 mmol). The reaction mixture was left to stir overnight, poured into 60 mL of water, and extracted with TBME (3x). The combined organic layers were washed with brine, dried over MgSO4, concentrated under reduced pressure, and purified by column chromatography (silica, 5% EtOAc in DCM) to afford N-( 3,6-dichloropyridazin-4-yl)-N-( 4- methoxybenzyl)methanesulfonamide. MS (ESI) m / z calc’d for C13H13Cl2N3NaO3S [M+Na]+: 384; found: 384.

[0160] Intermediate A-27: N-( 6-Chloro-3-methoxypyridazin-4-yl)-3-lluoropropane- 1 - sulfonamideA mixture of N-( 6-chloro-3-methoxypyridazin-4-yl )-3-fluoro-N-( 4-methoxybenzyl)propane- 1 - sulfonamide (105 mg, 0.26 mmol) and anisole (0.11 mL, 1.0 mmol) in TFA (1 mL) was left to stir at rt for 2.5 h and concentrated under reduced pressure. The residue was treated with PhMe and concentrated under reduced pressure (3x) to afford N-( 6-chloro-3-methoxypyridazin-4-yl)-3-fluoropropane-1-sulfonamide. MS (ESI) m / z calc’d for C8H12CIFN3O3S [M+H]+: 284; found: 284.

[0161] Intermediate A-39: 5-Iodo-3-nitro-2-(pyridin-4-ylmethoxy)pyridineTo a stirred solution of 4-pyridinemethanol (1151 mg, 10.55 mmol) in DMF (15 mL) was added NaH (60%, 316 mg, 7.91 mmol) at 0 °C under N2. The mixture was warmed to rt and left to stir for 30 min. The mixture was treated with 2-chloro-5-iodo-3-nitropyridine (1.5 g, 5.3 mmol), left to stir for 2 h, diluted with EtOAc. and washed with water (2x) and brine. The mixture was dried over MgSO4. concentrated under reduced pressure, and purified by column chromatography (silica, 10-40% EtOAc in isohexane) to afford 5-iodo-3-nitro-2-(4-pyridylmethoxy)pyridine. MS (ESI) m / z calc’d for C11H9IN3O3 [M+H]+: 358; found: 358.Table Int-04: The following intermediates were prepared using a similar procedure asIntermediate A-39.

[0162] Intermediate A-40: 1 -Fluoro-N-( 4-methoxybenzyl)methanesulfonamideA solution of fluoromethanesulfonyl chloride (0.20 mL, 2.4 mmol) and triethylamine (0.67 rnL, 4.8 mmol) in DCM (10 mL) at 0 °C was treated with a solution of 4-methoxy benzylamine (0.63 rnL, 4.8 mmol) in 5 mL of DCM by dropwise addition over 20 min. The reaction mixture was allowed to warm to rt overnight. The reaction mixture was poured into 20 mL of 10% KHSO4(aq) solution and extracted with DCM (3 x 15 rnL). The combined organic layers were washed with 10 rnL of brine, dried over MgSO4. concentrated under reduced pressure, and purified by column chromatography (silica, 10-35% EtOAc in hexanes) to afford 1-fluoro-N-(4- methoxybenzyl)methanesulfonamide. MS (ESI) m / z calc’d for C9H11FNO3S [M-1]-: 232; found: 232.

[0163] Intermediate A-43: N-( 5-Bromo-2-methoxypyridin-3-yl)-2,2,2-trifluoro-N-( 4- methoxy benzyl (ethane- 1 -sulfonamideA solution of N-( 5-bromo-2-methoxypyridin-3-yl)-2, 2, 2-trifluoroethane- 1 -sulfonamide (755 mg, 1.6 mmol), 4-methoxybenzyl alcohol (0.30 mL, 2.4 mmol), and PPh3(1.21 g, 4.61 mmol) in THF (11 mL) was treated with DIAD (0.87 mL, 4.4 mmol) and stirred at rt overnight. The reaction mixture was treated with additional 4-methoxybenzyl alcohol (0.14 mL, 1.1 mmol), PPh3(0.29 g. 1.1 mmol), and DIAD (0.22 mL, 1.1 mmol), and stirred for a 5 h. The mixture was concentrated under reduced pressure and purified by column chromatography (silica. 10-20% EtOAc in hexanes) to afford N-( 5-bromo-2-methoxypyridin-3-yl)-2,2,2-trifluoro-N-( 4- methoxybenzyl)ethane-1-sulfonamide. MS (ESI) m,'z calc’d for C16H17BrF3N2O4S [M+H]+: 469, 471; found: 469, 471.

[0164] Intermediate A-48: JV-(5-Iodo-2-(pyridin-4-ylmethoxy)pyridin-3- yl)methanesulfonamide

[0165] Step 1: A mixture of 5-iodo-3-nitro-2-(4-pyridylmethoxy)pyridine (900 mg, 2.52 mmol). Fe (704 mg, 12.6 mmol), and NH4CI (1348 mg. 25.2 mmol) in EtOH (15 mL) and water (15 mL) was heated to 80 °C for 2 h under N2. The mixture was cooled to rt, filtered over Celite, and concentrated under reduced pressure. The residue was taken up in EtOAc (80 mL) and washed with water (2x) and brine. The mixture was dried over MgSO4and concentrated under reduced pressure to afford 5 -iodo-2-(4-pyridylmethoxy)pyridin-3 -amine. MS (ESI) m / z calc’d for C11H11IN3O [M+H]+: 328; found: 328.

[0166] Step 2 : To a solution of 5-iodo-2-(4-pyridylmethoxy)pyridin-3-amine (300 mg, 0.92 mmol) in pyridine (5 mL) was added MsCl (200 mg, 1.75 mmol). The mixture was stirred at rt for 2 h. diluted with EtOAc, and washed with water and brine. The mixture was dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography (silica.25% EtOAc in pet. ether) to afford A-[5-iodo-2-(4-pyridylmethoxy)-3- pyridyl]methanesulfonamide. MS (ESI) m / z calc’d for C12H13IN3O3S [M+H]+: 406; found: 406.Table Int-05; The following intermediates were prepared using a similar procedure asIntermediate A-48.

[0167] Intermediate A-50: N-( 5-Bromo-2-chloropyridin-3-yl)ethanesulfonamide

[0168] Step 1 : To a stirred solution of 5-bromo-2-chloropyridin-3-amine (4.0 g, 19 mmol) in DCM (50 mL) were added NEt3(13.4 rnL, 96 mmol) and ethanesulfonyl chloride (5.48 mL, 57.8 mmol) at 0 °C. The reaction mixture w as stirred at 25 °C for 2 h and concentrated under reduced pressure to afford crude N-(5-bromo-2-chloropyridin-3-yl)-N-( ethylsulfonyl)ethanesulfonamide. which was used in the next step without further purification. MS (ESI) m'z calc’d for C9H13BrClN2O4S2 [M+H]+: 391, 393; found: 391, 393.

[0169] Step 2 : To a stirred solution of N-( 5-bromo-2-chloropyridin-3-yl)-A- (ethylsulfonyl)ethanesulfonamide (7.5 g, 19 mmol) in MeOH (50 mL) and 1,4-dioxane (50 mL) was added K2CO3(13.2 g. 96 mmol) at 25 °C. The mixture was heated to 60 °C for 5 h, cooled to rt, and concentrated under reduced pressure. The residue was poured into water (150 mL). The mixture was acidified with 2 N aqueous HC1 until pH 5 and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to afford N-( 5-bromo-2-chloropyridin-3- yl)ethanesulfonamide, which was used in the next step without further purification. MS (ESI) m / z calc’d for C7H9BrClN2O2S [M+H]+: 299, 301; found: 299, 301.

[0170] Intermediate C-4: (l,5-Diphenyl-1H -pyrazol-4-yl)methanolTo a stirred solution of l,5-diphenylpyrazole-4-carboxylic acid (92.6 mg, 0.35 mmol) in THF (0.9 mL) was added BH3·DMS (0. 12 mL, 1 .3 mmol) portionwise at 0 °C. The mixture was warmed to rt, left to stir for 2 h, and concentrated under reduced pressure. To the residue was added water and extracted with EtOAc (3x). The combined organic lay ers were dried over Na2SO4, and concentrated under reduced pressure to afford (l,5-diphenylpyrazol-4-yl)methanol. MS (ESI) m / z calc’d for C16H15N2O [M+H]- 251; found: 251.Table Int-06: The following intermediates were prepared using a similar procedure asIntermediate C-4.

[0171] Intermediate C-6: (5-Phenyl-1-(tetrahydro-2H -pyran-4-yl)-1H-pyrazol-4-yl)methanol

[0172] Step 1 : A solution of methyl 3-oxo-3-phenyl-propanoate (0.64 mL, 4.21 mmol) in N,N- dimethylformamide dimethyl acetal (2.8 mL, 21 mmol) was heated to 100 °C in a sealed tube for 12 h. The mixture was cooled to rt, concentrated under reduced pressure, and purified by column chromatography (silica, 5-10% MeOH in DCM) to afford methyl (E)-2-benzoyl-3- (dimethylamino)prop-2-enoate.

[0173] Step 2 : To a stirred solution of tetrahydropyran-4-ylhydrazine hydrochloride (88.3 mg, 0.58 mmol) and methyl (E)-2-benzoyl-3-(dimethylamino)prop-2-enoate (90 mg, 0.39 mmol) in EtOH (1.3 mL) was added NEt3(63 mg, 0.62 mmol). The reaction was heated to 80 °C for 4 h, cooled to rt, concentrated under reduced pressure, and purified by column chromatography (silica, 5% MeOH in DCM) to afford methyl 5-phenyl-1-tetrahydropyran-4-yl-pyrazole-4- carboxylate. MS (ESI) m / z calc’d for C16H19N2O3 [M+H]+: 287; found: 287.

[0174] Step 3: To a stirred solution of methyl 5-phenyl-1-tetrahydropyran-4-yl-pyrazole-4- carboxylate (99.1 mg, 0.35 mmol) in THF (1.2 mL) was added LiAlH4(1.0 M in THF, 1.04 mL, 1.04 mmol) at -10 °C. The reaction was warmed to rt over 1 h. The mixture was diluted with Et2O. cooled to 0 °C. and treated with water, 15% NaOH (aq), and water. The mixture was warmed to rt, left to stir for 15 min, treated with MgSO4, and left to stir for 15 min. The mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (silica, 20-60% EtOAc in hexanes) to afford (5-phenyl- 1 -(tetrahydro-2H -pyran-4-yl)- 1H - pyrazol-4-yl)methanol. MS (ESI) m / z calc’d for C15H19N2O2 [M+H]+: 259; found: 259.Table Int-07: The following intermediates were prepared using a similar procedure asIntermediate C-6.

[0175] Intermediate C-7: 4-(Naphthalen-2-yl)-2,3-dihydro-177-inden-2-olA solution of 4-bromoindan-2-ol (50 mg, 0.23 mmol), 2-naphthylboronic acid (80.7 mg, 0.47 mmol), and K2CO3 (65 mg, 0.47 mmol) in 1,4-dioxane (1 mL) and water (0.25 mL) was sparged with N2. Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (16.6 mg, 0.020 mmol) w as added under a stream of N2. The vial was sealed and heated to 90 °C for 3 h. The mixture was cooled to rt and partitioned between EtOAc and water. The EtOAc layer was washed with brine, dried over MgSO4, concentrated under reduced pressure, and purified by column chromatography (silica, 10-80% EtOAc in hexanes) to afford 4-(naphthalen-2-yl)-2.3- dihydro-17 / -inden-2-ol. MS (ESI) m / z calc’d for C19H15 [M+H-H20]+: 243; found: 243.

[0176] Intermediate C-8: 7-Phenyl-1,2,3,4-tetrahydronaphthalen-2-olA solution of 7-bromotetralin-2-ol (34.5 mg, 0.15 mmol), PhB(OH)2(37 mg, 0.3 mmol), and CsF (46 mg, 0.3 mmol) in 1,4-dioxane (1 mL) and water (0.25 mL) was sparged with N2. Bis(di-tert- butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5.4 mg, 0.01 mmol) was added under a stream of N2. The vial was sealed and heated to 80 °C for 2 h. The mixture was cooled to rt and partitioned between EtOAc and water. The EtOAc layer was washed with brine, dried over MgSO4. concentrated under reduced pressure, and purified by column chromatography (silica, 10-100% EtOAc in hexanes) to afford 7-phenyl-1,2,3,4-tetrahydronaphthalen-2-ol. MS (ESI) m / z calc'd for C16H15 [M+H-H20]+: 207; found: 207.

[0177] Intermediate C-9: ( 1 -Cyclopentyl- 1 H-indazol-3-yl)methanol

[0178] Step 1: To a stirred solution of ethyl 1H-indazole-3 -carboxylate (200 mg. 1.05 mmol) and cyclopentyl methanesulfonate (207 mg, 1.26 mmol) in DMF (3.5 mL) was added CS2CO3(343 mg, 1.05 mmol). The reaction was stirred at ambient temperature overnight, treated with water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford ethyl 1-cyclopentylindazole-3 -carboxylate.

[0179] Step 2 : To a stirred solution of ethyl 1-cyclopenly lindazole-3-carboxylate (149 mg. 0.58 mmol) in THF (1.9 mL) was added LiAlH4 (1.0 M in THF, 1.15 mL, 1.15 mmol) at -10 °C. The reaction was warmed to rt over 1 h. The mixture was diluted with Et2O, cooled to 0 °C, and treated with water, 15% NaOH (aq), and water. The mixture was warmed to rt, left to stir for 15 min, treated with MgSO4, and left to stir for 15 min. The mixture was filtered and concentrated under reduced pressure to afford (5-phenyl-1-(tetrahydro-2 / / -pyran-4-yl)-l / 7-pyrazol-4- yl)methanol. MS (ESI) m / z calc’d for C13H17N2O [M+H]+: 217; found: 217.

[0180] Intermediate C-10: (1 -Methyl- 1H -indazol-3-yl)methanolTo a stirred solution of methyl 1-methylindazole-3-carboxylate (112 mg, 0.59 mmol) in THF (1 mL) was added LiAlHr (1.0 M in THF, 1.17 mL, 1.17 mmol) at -10 °C. The reaction waswarmed to rt over 1 h. The mixture was diluted with Et2O, cooled to 0 °C, and treated with water, 15% NaOH (aq), and water. The mixture was warmed to rt, left to stir for 15 min, treated with MgSO4, and left to stir for 15 min. The mixture was filtered and concentrated under reduced pressure to afford ( 1 -methyl- 1 H -iiidazol-3-yl)methanol. MS (ESI) m / z calc’d for C9H11N2O [M+H]1: 163; found: 163.

[0181] Intermediate AB-1: 3,6-Difluoro-6'-methoxy-[2,3'-bipyridin]-5'-amineA mixture of 2-bromo-3.6-difluoro-pyridine (2.2 g, 11 mmol), Pd(dppf)Cl2(830 mg, 1.13 mmol), and CsF (3.45 g, 22.7 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was heated to 90 °C for 12 h under N2. The reaction mixture was cooled to rt and diluted with EtOAc (100 mL). The organic layer was washed with water (2x) and brine, dried over MgSOi. concentrated under reduced pressure, and purified by column chromatography (silica, 30% EtOAc in pet. ether) to afford 3,6-difluoro-6'-methoxy-[2.3'-bipyridin]-5'-amine. MS (ESI) m / z calc’d for C11H10F2N3O [M+H]+: 238; found: 238.Table Int-08: The following intermediates were prepared using a similar procedure asIntermediate AB-1.

[0182] Intermediate AB-2: N-( 6-(2-Fluoro-5-hydroxyphenyl)-3-methoxypyridazin-4-yl)-N-( 4- methoxybenzyl)methanesulfonamideTo a stirred solution of N-( 6-chloro-3-methoxypyridazin-4-yl)-N-( 4- methoxybenzyl)methanesulfonamide (104 g, 291 mmol), (2-fluoro-5-hydroxyphenyl)boronic acid (68.0 g, 436 mmol) in dioxane (600 mL) and water (100 mL) were added Pd(dppf)Cl2(21 .3g, 29.1 mmol) and Na2CO3(61.6 g, 581 mmol). The mixture was purged with N2for 5 min then heated at 80 °C for 12 h. After cooling to rt, the reaction mixture was quenched with water, extracted with EtOAc (3x), dried over Na2SO4and concentrated under reduced pressure. The residue was purified by column chromatography (silica. 0-100% EtOAc in pet. ether) to afford N-( 6-(2-fluoro-5-hydroxyphenyl)-3-methoxypyndazin-4-yl)-N-(4- methoxybenzyl)methanesulfonamide. MS (ESI) m / z calc’d for C20H20FN3O5S [M+H]+: 434; found: 434.1H NMR (400 MHz, CDCl3) δ 7.71 - 7.65 (m, 2H), 7.26 (s, 1H), 7.16 (d, J= 8.68 Hz, 2H), 7.03 - 6.96 (m, 1H), 6.89 (m, 1H), 6.80 (d, J= 8.68 Hz, 2H), 4.83 (s, 2H), 4.30 (s, 3H), 3.76 (s, 3H), 3.06 (s, 3H).

[0183] Intermediate AB-3: N-( 6-(5-Bromo-2-fluorophenyl)-3-methoxypyridazin-4-yl)-N-( 4- methoxybenzyl)methanesulfonamideA 1 L three-necked round bottom flask was charged with N-( 6-chloro-3-methoxypyridazin-4-yl)- N-( 4-methoxy benzyl )methanesulfonamide (40.0 g, 112 mmol), (5-bromo-2-fluorophenyl)boronic acid (44 g, 200 mmol). Pd(PPh3)4(12.9 g. 11.2 mmol ). Na2CO3(23.7 g, 224 mmol ), PhMe (200 mL), and EtOH (200 rnL). The reaction mixture was purged with N2 for 5 min and heated at 80 °C for 12 h. The mixture was cooled, H2O (400 mL) was added and the mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0-100% EtOAc in pet. ether) to afford N-(6-(5-bromo-2-lluorophenyl)- 3-methoxypyridazin-4-yl)-N-( 4-methoxybenzyl)methanesulfonamide. MS (ESI) m / z calc’d for C20H19BrFN3O4S [M+H]+: 496, 498; found: 496, 498.1H NMR (400 MHz, CDCl3) δ 8.17 (m, 1H), 7.61 (d, J= 1.48 Hz, 1H), 7.50 (m, 1H), 7.15 (d, J= 8.56 Hz, 2H), 7.03 (m, 1H), 6.78 (d, J = 8.56 Hz, 2H), 4.83 (s, 2H), 4.32 (s, 3H), 3.75 (s, 3H), 3.07 (s, 3H).

[0184] Intermediate AB-4: N -(6-(6-Chloropyridin-2-yl)-3-methoxypyridazin-4-yl)-JV-(4- methoxybenzyl)methanesulfonamideTo a solution of N-( 6-chloro-3-methoxypyridazin-4-yl)-N-( 4- methoxybenzyl)methanesulfonamide (83.0 g, 232 mmol) in dioxane (492 mL) and H2O (164 mL) were added K2CO3(96.18 g, 695.9 mmol), 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (61.11 g, 255.1 mmol), and Pd(dppf)Cl2(16.97 g, 23.20 mmol). The reaction vessel was sealed, evacuated and backfilled with N2then heated to 80 °C for 2 h. The reaction was cooled to ambient temperature, quenched with NH4CI and extracted with EtOAc (3x). The combined organic layers were washed with brine (3x), dried overNa2SO4and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 5% MeOH in DCM) to afford N-(6-(6-chloropyri din-2 -yl)-3-methoxypyridazin-4-yl)-N-(4- methoxybenzyl)methanesulfonamide. MS (ESI) m / z calc’d for C19H19CIN4O4S [M+H]+: 435; found: 435.1H NMR (400 MHz, CDCl3) δ 8.36 (d, J= 8.0 Hz, 1H), 8.03 (t, J= 9.2 Hz, 2H), 7.63 (d, J= 7.2 Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 4.84 (s, 2H), 4.20 (s, 3H), 3.66 (s, 3H), 3.26 (s, 3H).

[0185] Intermediate AB-5: N-( 6-(6-Chloropyridin-2-yl)-3-methoxypyridazin-4- yl)methanesulfonamideA solution of N-(6-(6-chloropyridin-2-yl)-3-methoxypyridazin-4-yl)-,V-(4- methoxybenzyl)methanesulfonamide (35.0 g, 80.5 mmol ) in DCM (105 mL) was cooled to 0 °C. TFA (161.7 g, 1.42 mol) was added and the mixture stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica, EtOAc in DCM then MeOH in DCM) to afford N-( 6-(6-chloropyridin-2- yl)-3-methoxypyridazin-4-yl)methanesulfonamide. MS (ESI) m / z calc’d for C11H11CIN4O3S [M+H]+: 315; found: 315.1H NMR (400 MHz, CDCl3) δ 10.20 (s, 1H). 8.36 - 8.27 (m, 2H), 8.06 (t, J= 7.60 Hz, 1H), 7.66 (d, J= 8.0 Hz, 1H), 4.11 (s, 3H), 3.23 (s, 3H).

[0186] Intermediate AB-7: N-( 6-(3-Hydroxyphenyl)-3-methoxypyridazin-4-yl)-N-( 4- methoxybenzyl)methanesulfonamideA suspension of 3-hydroxybenzeneboronic acid (578 mg. 4. 19 mmol), N-(6-chloro-3-methoxy- pyridazin-4-yl)-N-[(4-methoxyphenyl)methyl]methanesulfonamide (1.00 g, 2.79 mmol), CsF (1.27 g, 8.38 mmol), and Pd(Amphos)C12 (49 mg, 0.07 mmol) in 1,4-dioxane (13 rnL) and water (1.3 mL) was sparged with N2for 3 min. The vessel was sealed and heated to 80 °C for 4 h, cooled to rt, poured into brine, and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO4. concentrated under reduced pressure, and purified by column chromatography (silica, 20-65% EtOAc in hexanes) to afford N-( 6-(3-hy droxyphenyl)-3- methoxypyridazin-4-yl)-N-(4-methoxybenzyl)methanesulfonamide. MS (ESI) m / z calc’d for C20H22N3O5S [M+H]+: 416; found: 416.Table Int-09; The following intermediates were prepared using a similar procedure asIntermediate AB-7.

[0187] Intermediate AB-9: N-( 3-chloro-6-(3-hydroxyphenyl)pyridazin-4-yl)-JV-(4- methoxybenzyl)methan esulfonamideA suspension of 3-hydroxybenzeneboronic acid (69.5 mg, 0.50 mmol), N-( 3,6-dichloropyridazin- 4-yl)- N-[(4-methoxyphenyl)methyl ] methanesulfonamide (166 mg, 0.46 mmol), CS2CO3(224 mg, 0.69 mmol), and PdCl2(dppf) (17 mg, 0.02 mmol) in 1,4-dioxane (1.75 mL) and water (0.25 mL) was sparged with N2 for 3 min. The vessel was sealed and heated to 80 °C for 4 h. The reaction mixture was cooled to rt, poured into 30 mL of brine and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with 10 mL of brine, dried over MgSO4, concentratedunder reduced pressure, and purified by column chromatography (silica, 20-60% EtOAc in hexanes) to afford N-(3-chloro-6-(3-hydroxy phenyl )pyridazin-4-y 1 )-N-( 4- methoxybenzyl)methanesulfonamide. MS (ESI) m / z calc’d for C19H19CIN3O4S [M+H]+: 420; found: 420.

[0188] Intermediate BC-3: 2-Bromo-3-fluoro-6-((1-(2,2,2-trifluoroethyl)piperidin-4- yl)methoxy)pyridineTo a stirred solution of (1-(2,2,2-trifluoroethyl)piperidin-4-yl)methanol (450 mg, 2.28 mmol) in NMP (10 mL) with an inert atmosphere of N2 was added NaH (91.2 mg, 2.28 mmol) at 0 °C. The resulting solution was stirred at rt for 30 min and treated with 2-bromo-3,6-difluoropyridine (300 mg, 1.55 mmol). The reaction mixture was left to stir at rt for 2 h and concentrated under reduced pressure. The residue was diluted with EtOAc, washed with brine, dried over NaiSOi. concentrated under reduced pressure, and purified by column chromatography (silica, 20% EtOAc in pet. ether) to afford 2-bromo-3-fluoro-6-((1-(2.2.2-trifluoroethyl)piperidin-4- yl)methoxy)pyridine. MS (ESI) m 'z calc’d for C13H16BrF4N2O [M+H]+: 371, 373; found: 371, 373.

[0189] Intermediate BC-6: 2-Bromo-1-fluoro-4-((3-(trifluoromethyl)benzyl)oxy)benzeneTo a stirred solution of 3-bromo-4-fluorophenol (1.0 g, 5.2 mmol) in DMF (26 rnL) were added 1 -(bromo methyl)-3 -(trifl uoromethyl)benzene (1.25 g. 5.24 mmol) and K2CO3(1.45 g,10.5 mmol). The reaction mixture was heated to 80 °C for 1 h. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried, concentrated under reduced pressure, and purified by column chromatography (silica. 1-10% EtOAc in hexanes) to afford 2- bromo-1-fluoro-4-((3-(trifluoromethyl)benzyl)oxy)benzene. MS (ESI) m / z calc’d for C14H10BrF4O [M+H]+: 349, 351; found: 349, 351.Table lnt-10: The following intermediates were prepared using a similar procedure as Intermediate BC-6.

[0190] Intermediate BC-11, BC-16: 2-Chloro-3-methyl-6-((3-(trifluoromethyl)benzyl)oxy)pyridine and 6-chloro-3-methyl-2-((3-(trifluoromethyl)benzyl)oxy)pyridineA mixture of CS2CO3(347 mg, 1.06 mmol), 2,6-dichloro-3-methylpyridine (150 mg. 0.93 mmol), [3 -(trifluoromethyl)phenyl] methanol (0.13 mL, 0.93 mmol), and BrettPhos (25 mg, 0.05 mmol) in PhMe (1.8 mL) was sparged with N2 for 3 min. The reaction mixture was treated with BrettPhos Pd G4 (43 mg, 0.05 mmol) under a continuous N2 stream. The vessel was sealed and heated to 90 °C for 16 h. The reaction mixture w as diluted with EtOAc and filtered over Celite.The fdtrate was concentrated under reduced pressure and purified by column chromatography (silica, 5-10% DCM in hexanes) to afford 2-chloro-3-methyl-6-((3- (trifluoromethyl)benzyl)oxy)pyridine and 6-chloro-3-methyl-2-((3- (trifluoromethyl)benzyl)oxy)pyridine. MS (ESI) m / z calc'd for C14H12CIF3NO [M+H]+: 302; found: 302.Table Int-11: The following intermediates were prepared using a similar procedure as Intermediate BC-11.

[0191] Intermediate BC-12: 2-Chloro-3-methyl-6-((4-(trifluoromethyl)benzyl)oxy)pyridineA mixture of CS2CO3(241 mg, 0.74 mmol), 2,6-dichloro-3-methylpyridine (100 mg, 0.62 mmol), and [4-(trifluoromethyl)phenyl]methanol (0.08 mL, 0.62 mmol) in PhMe (1.2 mL) was sparged with N2for 3 min. The reaction mixture was treated with BINAP Pd G3 (30.6 mg, 0.03 mmol) under continuous N2stream. The vessel was sealed and heated to 90 °C for 16 h. The reaction mixture was diluted with EtOAc and filtered over Celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica, 5-25% DCM in hexanes) to afford 2-chloro-3-methyl-6-((4-(trifluoromethyl)benzyl)oxy)pyridine. MS (ESI) m / z calc’d for C14H12CIF3NO [M+H]+: 302; found: 302.

[0192] Intermediate BC-17: 2-Bromo-3-fluoro-6-((3-(trifluoromethyl)benzyl)oxy)pyridineA suspension of NaH (60%, 14.9 mg, 0.37 mmol) in DMF (1 mL) at 0 °C was treated with (3- (trifluoromethyl)phenyl)methanol (0.04 mL, 0.3 mmol). The ice bath was removed, and the mixture was allowed to stir at rt for 30 min. The reaction mixture was cooled back to 0 °C and treated with 2-bromo-3,6-difluoropyridine (0.04 mL, 0.3 mmol). The ice bath was removed, and the reaction was stirred at rt for 3 h. The reaction mixture was poured into water (30 mL) and extracted with TBME (3x). The combined organic layers were washed with brine, dried over MgSO4, concentrated under reduced pressure, and purified by column chromatography (silica, 5- 10% DCM in hexanes) to afford 2-bromo-3-fluoro-6-((3 -(trill uoromethyl)benzyl)oxy)pyri dine. MS (ESI) m / z calc’d for C13H9BrF4NO [M+H]+: 350, 352; found: 350, 352.Table Int-12: The following intermediates were prepared using a similar procedure as Intermediate BC-17.

[0193] Intermediate BC-19: 2-Bromo-1,3-difluoro-4-((3-(trifluoromethyl)benzyl)oxy)benzeneTo a stirred solution of 3-bromo-2,4-difluorophenol (109 mg, 0.52 mmol) and 1 -(bromomethyl)- 3-(trifluoromethyl)benzene (119 mg, 0.50 mmol) in DMF (1 mL) was added CS2CO3(188 mg, 0.58 mmol). The mixture was heated to 80 °C for 4 h, cooled to rt, and poured into water. The mixture was extracted with TBME (3x). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to afford 2-bromo-1,3-difluoro-4- ((3-(trifluoromethyl)benzyl)oxy)benzene. MS (ESI) m / z calc’d for C14H7B1F5O [M-H] 365, 367; found: 365, 367.

[0194] Intermediate BC-20: 2-Chloro-3-(difluoromethyl)-6-((3-(trifluoromethyl)benzyl)oxy)pyridineTo a stirred solution of 2-chloro-6-((3-(trifluoromethyl)benzyl)oxy)nicotinaldehyde (34.5 mg, 0.11 mmol) in DCM (1 mL) at 0 °C was added diethylaminosulfur trifluoride (0.13 mL, 0.99mmol). The ice bath was removed, and the mixture was stirred for 2 h at rt. The reaction mixture was cooled to 0 °C and treated with sat’d NaHCO3(10 mL). The reaction mixture was vigorously stirred for 30 min, treated with an additional sat’d NaHCO3(10 mL), and left to stir for 30 min. The reaction mixture was extracted with DCM (3x). The combined organic layers were washed with brine, dried over MgSO4. concentrated under reduced pressure, and purified by column chromatography (silica, 5-15% DCM in hexanes) to afford 2-chloro-3-(difluoromethyl)-6-((3- (trifluoromethyl)benzyl)oxy)pyridine. MS (ESI) m / z calc’d for C15H10CIF5NO [M+H]+: 338; found: 338.

[0195] Intermediate BC-29: (6-((3-(Trifluoromethyl)benzyl)oxy)pyridin-2-yl)boronic acid,To a solution of 2-bromo-6-((3-(trifluoromethyl)benzyl)oxy)pyridine (300 mg, 0.903 mmol) in dioxane (2 mL) was added PdCl2(dppf) (33.0 mg, 0.045 mmol), KO Ac (266 mg, 2.71 mmol) and B2pin2(413 mg, 1.63 mmol) under N2. The reaction mixture was heated to 80 °C in a microwave reactor for 1 h. The reaction mixture was cooled to rt, filtered, concentrated under reduced pressure to afford crude (6-((3-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)boronic acid, which was used directly without further purification. MS (ESI) m / z calc’d for C13H12BF3NO3 [M+H]+: 298; found: 298.Table Int-13; The following intermediates were prepared using a similar procedure as Intermediate 29.

[0196] Intermediate BC-32: 3-Bromo-5-((3-(trifluoromethyl)benzyl)oxy)pyridine1-(Bromomethyl)-3-(trifluoromethyl)benzene (275 mg, 1.15 mmol) was added to a stirred mixture of 5-bromopyridin-3-ol (200 mg, 1.15 mmol) and Ag2O (1065 mg, 4.60 mmol) in DMF (2 mL) at rt. The mixture was heated to 60 °C for 18 h, cooled to rt, treated with water (5 mL), and extracted with EtOAc (2 xlO mL). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography (silica, 33% EtOAc in pet. ether) to afford 3-bromo-5-((3- (trifluoromethyl)benzyl)oxy)pyridine. MS (ESI) m / z calc’d for C13H10BrF3NO [M+H]+: 332, 334; found: 332, 334.1H NMR (400 MHz, CDCl3) δ 8.32 (dd, J= 4.7, 2.4 Hz, 2H), 7.69 (s, 1H), 7.66 - 7.57 (m. 2H), 7.58 - 7.50 (m. 1H), 7.45 (t, J = 2.2 Hz, 1H), 5. 14 (s, 2H).Table Int-14: The following intermediates were prepared using a similar procedure asIntermediate BC-32.

[0197] Intermediate BC-34: 2-Bromo-4-((2,2-dimethylcyclopropyl)methoxy)-1- fluorobenzene

[0198] Step 1: DIAD (0.305 ml, 1.57 mmol) was added to a stirred mixture of PPh3(494 mg, 1.89 mmol) and 3-bromo-4-fluorophenol (200 mg, 1.047 mmol) and 3-methylbut-2-en-1-ol (135 mg, 1 .57 mmol) in THF (5 ml) at rt. The mixture was stirred at rt for 16 h and purified by prep- TLC (silica, 6% EtOAc in pet. ether) to afford 2-bromo-1-fluoro-4-((3-methylbut-2-en-1- yl)oxy)benzene.

[0199] Step 2: ZnEt2(0.965 mL, 1 M, 0.965 mmol) was added dropwise over 10 min to a stirred mixture of 2-bromo-1-fluoro-4-((3-methylbut-2-en-1-yl)oxy)benzene (100 mg, 0.386mmol) in DCM (4 mL) at -40 °C. The mixture was left to stir at that temperature for 10 min. Diiodomethane (310 mg, 1.16 mmol) was added dropwise over 2 min and the reaction mixture was allowed to warm to rt and stirred for 16 h. The mixture was treated with HC1 (IM, 0.5 mL) and extracted with DCM (2 x 15 mL). The combined organic layers were washed with brine dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography (silica, pet. ether) to afford 2-bromo-4-((2,2-dimethylcyclopropyl)methoxy)-1- fluorobenzene.1H NMR (500 MHz, CDCl3) δ 7.36-7.41 (m, 1H), 6.70 (dd, J = 2.8, 10.5 Hz, 1H), 6.61 (ddd, J= 0.9, 2.8, 8.8 Hz, 1H), 4.03 (dd, J= 6.4, 10.1 Hz, 1H), 3.78 (dd, J= 8.5, 10.1 Hz, 1H), 1.11 (d, J = 2.6 Hz, 6H), 1.02-1.07 (m, 1H), 0.60 (dd, J= 4.7, 8.6 Hz, 1H), 0.25 (t, J= 4.9 Hz, 1H).

[0200] Intermediate BC-35: 4-(3-Bromo-4-fluorophenoxy)-1-(2,2,2-trifluoroethyl)piperidine

[0201] Step 1; To a stirred solution of 3-bromo-4-fluorophenol (0.50 g. 2.6 mmol) in THF (20 mL) were added PPh3(1.03 g. 3.93 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (1.05 g, 5.24 mmol), and DIAD (0.763 mL, 3.93 mmol) at 25 °C under N2. The reaction mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure and purified by column chromatography (silica, 0-20% EtOAc in pet. ether) to afford tert-butyl 4-(3-bromo-4- fluorophenoxy )piperidine- 1 -carboxylate.

[0202] Step 2:_To a stirred solution of tert-butyl 4-(3-bromo-4-fluorophenoxy)piperidine-1- carboxylate (4.28 g, 11.4 mmol) in DCM (36 mL) was added TFA (12 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. The mixture was diluted with a sat’d NaHCO3(80 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 4-(3- bromo-4-fluorophenoxy)piperidine. MS (ESI) m / z calc’d for C11H14BrFNO [M+H]+: 274, 276; found: 274, 276.

[0203] Step 3:_TO a stirred solution of 4-(3-bromo-4-fluorophenoxy)piperidine (3. 14 g, 11.5 mmol) in THF (5 mL) was added NEt3(4.79 mL, 34.4 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 10 min, treated with 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.48 mL,17.2 mmol), and left to stir for 16 h. The mixture was concentrated under reduced pressure and purified by column chromatography (silica, 0-18% EtOAc in pet. ether) to afford 4-(3-bromo-4- fluorophenoxy)-1-(2,2,2-trifluoroethyl)piperidine.1H NMR (400 MHz, CD3OD) δ 7.17 (dd, J = 5.6, 2.9 Hz, 1H), 7.11 (t, J= 8.7 Hz, 1H), 6.97 - 6.89 (m, 1H), 4.35 (tt, J= 7.6. 3.8 Hz, 1H), 3.08 (q, J = 9.9 Hz, 2H), 2.90 (ddd. J= 11.3, 7.2. 3.6 Hz. 2H), 2.62 (ddd, J= 11.6, 8.5, 3.2 Hz, 2H), 2.05 - 1.92 (m, 2H), 1.84 - 1.70 (m, 2H).

[0204] Intermediate ABC-1: 6-((3-Bromobenzyl)oxy)-3-fluoro-6'-methoxy-[2,3'-bipyridin]-5'- amineA vial containing 3-bromobenzyl alcohol (200 mg, 1.07 mmol) and NMP (5 mL) was purged with a N2needle and cooled to 0 °C. To this solution was added NaH (60% dispersion in mineral oil, 42.8 mg, 1.07 mmol), at which point the reaction mixture was warmed to rt and aged for 30 min. 3,6-Difluoro-6'-methoxy-[2,3'-bipyridin]-5'-amine (200 mg, 0.84 mmol) was added, and the resulting mixture was stirred at rt for 2 h, and diluted with EtOAc. The organic layer was washed with brine, separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica, 33% EtOAc in pet. ether) to afford 6-((3-bromobenzyl)oxy)-3-fluoro-6'-methoxy-[2,3'-bipyridin]-5'-amine. MS (ESI) m / z calc’d for C18H16BrFN3O2 [M+H]+: 404, 406; found: 404, 406.EXAMPLES

[0205] Example 1-1: N-( 6-(2-Fluoro-5-((3-fluorobenzyl)oxy)phenyl)-3-methoxypyridazin-4- yl)methanesulfonamide

[0206] Step 1 : To a solution of (3-fluorophenyl)methanol (43.6 mg, 0.346 mmol), N-(6-(2- fluoro-5-hydroxyphenyl)-3-methoxypyridazin-4-yl)- N-(4-methoxybenzyl)methanesulfonamide (100.0 mg, 0.231 mmol) and PPh; (91 mg, 0.346 mmol) in dioxane (2307 μL) was addeddropwise DEAD (63.0 μL. 0.346 mmol). The resulting mixture was stirred at 80 °C overnight. The reaction mixture was cooled to rt and concentrated under reduced pressure. The resulting material was purified by preparative HPLC (reverse phase, C18, ACN / water with 0.1% TFA modifier) to give N-( 6-(2-fluoro-5-((3-fluorobenzyl)oxy)phenyl)-3-methoxypyridazin-4-yl)-N-(4- methoxybenzyl)methanesulfonamide. MS (ESI) m / z calc’d for C27H25F2N3O5S [M+H]1: 542; found: 542.

[0207] Step 2: A mixture of N-(6-(2-fluoro-5-((3-fluorobenzyl)oxy)phenyl)-3- methoxypyridazin-4-yl)-N-(4-methoxybenzyl)methanesulfonamide (68.0 mg, 0.126 mmol) in TFA (3.0 ml) was stirred for 3 h at 80 °C. and monitored by LCMS. The resulting solution was concentrated under reduced pressure, The residue was purified by preparative HPLC (reverse phase, C18, ACN / Water + 0.1% TFA modifier) to give N-( 6-(2-fluoro-5-((3- fluorobenzyl)oxy)phenyl)-3-methoxypyridazin-4-yl)methanesulfonamide. MS (ESI) m z calc’d for C19H17F2N3O4S [M+H]+: 422; found: 422.1H NMR (499 MHz, DMSO-d6) d 7.57 - 7.40 (m, 4H), 7.40 - 7.28 (m, 3H), 7.28 - 7. 14 (m, 2H), 5.20 (s, 2H). 4.04 (s, 3H). 3.09 (s. 3H).

[0208] Example 1-2: 2,2,2-Trifluoro-N-(5-(2-fluoro-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-2-methoxypyridin-3-yl)ethane-1-sulfonamide

[0209] Step 1 : To a mixture of 2.2.2-trifluoro-N-(5-(2-fluoro-5-hydroxyphenyl)-2- methoxypyridin-3-yl)-N-(4-methoxybenzyl)ethane-1-sulfonamide (17.9 mg, 0.036 mmol), 3- (trifluoromethyl)benzyl alcohol (0.010 mL, 0.072 mmol), and polymer-supported PPh3(2.26 mmol / g, 33 mg, 0.075 mmol) in THF (0.50 mL) was added DIAD (0.010 mL, 0.072 mmol). The resulting suspension was stirred at rt for 6 h, at which point the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (silica, 10-40% EtOAc in hexanes) to afford 2.2.2-trifluoro-A'-(5-(2-fluoro-5- ((3-(trifluoromethyl)benzyl)oxy)phenyl)-2-methoxypyridin-3-yl)-N-(4-methoxybenzyl)ethane-1- sulfonamide. MS (ESI) m / z calc’d for C30H26F7N2O5S [M+H]+: 659; found: 659.

[0210] Step 2: A mixture of 2.2.2-trifluoro-N-( 5-(2-fluoro-5-((3- (trifluoromethyl)benzyl)oxy)phenyl)-2-methoxypyridin-3-yl)- N-(4-methoxybenzyl)ethane-1- sulfonamide (16 mg, 0.024 mmol), anisole (0.021 mL, 0.19 mmol), and TFA (1 mL) was heated to 90 °C for 1 h, then cooled to rt. The reaction mixture was concentrated under reduced pressure. To the residue was added PhMe. and the reaction mixture was concentrated under reduced pressure (3x). The residue was diluted with water containing a small amount of sat’d NaHCO3The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4. fdtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica. 10-40% EtOAc in hexanes) to afford 2,2,2- trifluoro-N-( 5-(2-fluoro-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-2-methoxypyri din-3- yl)ethane-1-sulfonamide. MS (ESI) m / z calc’d for C22H18F7N2O4S [M+H]+: 539; found: 539.1H NMR (400 MHz, CDCl3) δ 8.16 (dd, J= 2.1, 1.5 Hz, 1H), 7.97 (dd, J= 2.1, 1.5 Hz, 1H), 7.71 (s, 1H), 7.62 (t, J= 8.3 Hz, 2H), 7.53 (t, J = 7.7 Hz, 1H), 7.11 (dd, J= 9.8. 9.0 Hz, 1H), 7.02 (s. 1H), 6.99 (dd. J= 6.2. 3.1 Hz. 1H). 6.96 - 6.91 (m. 1H), 5.12 (s. 2H), 4.07 (s, 3H), 3.87 (q, J= 8.8 Hz, 2H).Table Ex-01: The following compounds were prepared using a similar procedure as the above examples.

[0211] Example 1-22: N-(6-(2-Fluoro-3-((3-(trifluoromethyl)benzyl)oxy)phenyl)-3- methoxypyridazin-4-yl)methanesulfonamide

[0212] Step 1: A mixture of N-( 6-(2-fluoro-3-hydroxyphenyl)-3-methoxypyridazin-4-yl)-N-(4- methoxybenzyl)methanesulfonamide (25 mg, 0.060 mmol) in DMF (0.5 mL) was heated to80 °C. To this mixture was added CS2CO3(19 mg, 0.060 mmol). The reaction mixture was stirred at 80 °C for 4 h, then cooled to rt, at which point the mixture was diluted with water. The aqueous layer was extracted with TBME (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered, then concentrated under reduced pressure to afford N-(6-(2- fluoro-3-((3-(trifluoromethyl)benzyl)oxy)phenyl)-3-methoxypyridazin-4-yl)-N-( 4- melhoxybcnzyl)methanesulfonamide which was used without further purification. MS (ESI) m / z calc’d for C28H26F4N3O5S [M+H]+: 592; found: 592.

[0213] Step 2; A mixture of N-( 6-(2-fluoro-3-((3-(trifluoromethyl)benzyl)oxy)phenyl)-3- methoxypyridazin-4-yl)-N-(4-methoxybenzyl)methanesulfonamide (30 mg, 0.050 mmol), anisole (22 mg, 0.20 mmol), and TFA (1 mL) was stirred at rt for 2.5 h. The reaction mixture was concentrated under reduced pressure. To the residue was added PhMe, and the reaction mixture was concentrated under reduced pressure (3x). The residue was purified by column chromatography (silica, EtOAc in hexanes) to afford N-( 6-(2-fluoro-3-((3- (trifluoromethyl)benzyl)oxy)phenyl)-3-methoxypyridazin-4-yl)methanesulfonamide. MS (ESI) m / z calc’d for C20H18F4N3O4S [M+H]+: 472; found: 472.1H NMR (400 MHz, CDCI3) δ 7.89 (d, J= 2.0 Hz. 1H), 7.74 (s, 1H), 7.67 (d, J= 7.6 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.57 - 7.51 (m, 1H), 7.21 (s, 1H), 7.18 (dd, J = 8.0, 1.2 Hz, 1H), 7.13 - 7.07 (m, 1H), 5.22 (s, 2H), 4.25 (s, 3H), 3.21 (s, 3H).

[0214] Example 2-1: JV-(3-Methoxy-6-(6-((3-(trifluoromethyl)benzyl)oxy)pyridin-2- yl)pyridazin-4-yl)methanesulfonamideTo a solution of (3-(trifluoromethyl)phenyl)methanol (41.1 mg, 0.233 mmol) in DMF (1.5 ml) was added NaH (18.66 mg, 0.466 mmol) at rt and stirred for 15 min. Then to the mixture was added N-(6-(6-chloropyridin-2-yl)-3-methoxypyridazin-4-yl)methanesulfonamide (100 mg, 0.233 mmol) in DMF (1.5 ml) dropwise. The mixture was heated in a microwave oven at 150°C for 45 min. H2O was added to the mixture and extracted with EtOAc (3x). The combined organic fractions were washed with brine, dried Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, C18, ACN / water with 0.1% TFA modifier) to give N-( 3-methoxy-6-(6-((3-(trifluoromethyl)benzyl)oxy)pyridin-2- yl)pyridazin-4-yl)methanesulfonamide. MS (ESI) m / z calc’d for C19H17F3N4O4S [M+H]+: 455; found: 455.1H NMR (499 MHz. DMSO-d6) δ 7.96 (t, J = 7.8 Hz, 1H), 7.86 (s, 3H), 7.84 (s, 1H), 7.70 (d, J= 7.8 Hz, 1H), 7.64 (t, J= 7.7 Hz. 1H), 7.11 (d, J= 8.2 Hz, 2H), 5.63 (s, 2H), 4.07 (s, 3H), 3.12 (s, 3H).

[0215] Example 2-2: N-(6-(6-((3-Fluorobenzyl)oxy)pyridin-2-yl)-3-methoxypyridazin-4- yl)methanesulfonamideTo a solution of (3-fluorophenyl)methanol (1202 mg, 9.53 mmol) in DMF (10 mL) was added NaH (381 mg, 9.53 mmol) portionwise. The reaction mixture was stirred a for 10 min. To this reaction mixture was added N-( 6-(6-chloropyndin-2-yl)-3-methoxypyridazin-4- yl)methanesulfonamide (300 mg, 0.953 mmol). The reaction mixture was stirred at 50 °C for 14 h. The reaction was monitored by LCMS, after stirred at 50 °C for 14 h, the reaction was finished. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a brown mixture. DCM was added to the mixture and solid precipitates from solution. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, C 18, ACN / water with 0. 1 % TFA modifier) to giveN-(6-(6-((3-fluorobenzyl)oxy)pyridin-2-yl)-3-methoxypyridazin-4-yl)methanesulfonamide. MS (ESI) m / z calc'd for C18H18FN4O4S [M+H]+: 405; found: 405.Table Ex-02: The following compounds were prepared using a similar procedure as the above examples.

[0216] Example 3-1: N-( 6-(6-((3-Fluorobenzyl)oxy)pyridin-2-yl)-3-methoxypyridazin-4- yl)ethanesulfonamide

[0217] Step 1 : To a stirred solution of N-(6-(6-((3-fluorobenzyl)oxy)pyridin-2-yl)-3- methoxypyridazin-4-yl)methanesulfonamide (140 mg, 0.346 mmol) in DCM (3 mL) was added NEt3(0.145 ml, 1.039 mmol) and ethanesulfonyl chloride (0.164 ml, 1.731 mmol) at 25 °C. After the addition was finished, the reaction was stirred at 25 °C. The reaction was monitored by LCMS. After stirring at 25 °C for 16 h, the reaction was finished. The solvent was removedunder reduced pressure to give crude N-( 6-(6-((3-fluorobenzyl)oxy)pyridin-2-yl)-3- methoxypyridazin-4-yl)-N-(methylsul fonyl)ethanesul fonamide, which was purified by prep-TLC (silica, 50% EtOAc in pet. ether) to give N-(6-(6-((3-fluorobenzyl)oxy)pyridin-2-yl)-3- methoxypyridazin-4-yl)-N-(methylsulfonyl)ethanesulfonamide. MS (ESI) m / z calc’d for C20H22FN4O6S2 [M+H]1: 497; found: 497.

[0218] Step 2: K2CO3(40. 1 mg, 0.290 mmol) was added to a stirred mixture of N-( 6-(6-((3- fluorobenzyl)oxy)pyridin-2-yl)-3-methoxypyridazin-4-yl)-N-(methylsulfonyl)ethanesulfonamide (48 mg, 0.097 mmol) in MeOH (3 ml) at 25 °C for 1 h. LCMS showed starting material was consumed and a new product was formed. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, ACN / water with 0.1% TFA modifier) to give N-( 6-(6-((3-fluorobenzyl)oxy)pyridin-2-yl)- 3-methoxypyridazin-4-yl)ethanesulfonamide. MS (ESI) m / z calc’d for C19H20FN4O4S [M+H]+: 419; found: 419.1H NMR (500MHz. CDCl3) δ 8.38 (s, 1H), 7.97 (d, J= 7.5 Hz, 1H), 7.79 (t, J = 7.9 Hz. 1H), 7.35 (dt, J = 5.9, 7.9 Hz, 1H), 7.29 - 7.27 (m, 1H). 7.21 (br d. J = 9.5 Hz. 1H), 7.04 - 6.94 (m, 2H), 5.50 (s, 2H), 4.22 (s, 3H), 3.30 (q, J= 7.3 Hz, 2H), 1.44 (t, J = 7.4 Hz, 3H).Table Ex-03: The following compounds were prepared using a similar procedure as the above example.

[0219] Example 4-1: N-(3,5-Difluoro-6'-methoxy-6-((3-(trifluoromethyl)benzyl)oxy)-[2,3'- bipyridin]-5'-yl)methanesulfonamideA suspension of CsF (15 mg, 0.11 mmol), methansulfonamide N-[2-methoxy-5-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl] (15 mg, 0.05 mmol). Pd(dtbpf)Cl2(1 mg, 2 pmol), and 2-bromo-3,5-difluoro-6-[[3-(trifluoromethyl)phenyl]methoxy]pyridine (11 mg, 0.03 mmol) in a mixture of 1,4-dioxane (0.9 mL) and water (0.1 mL) was sparged with N2for 3 min.The vessel was sealed and heated to 80 °C for 4 h. The reaction mixture was cooled and poured into 30 mL of brine and extracted with EtOAc (3 x 20 rnL). The combined organic layers were rinsed with brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. Purification was achieved by column chromatography (silica, 15-50% EtOAc in hexanes) to give N-(3,5-difluoro-6'-methoxy-6-((3-(trifluoromethyl)benzyl)oxy)-(2,3,-bipyridin]-5'- yl)methanesulfonamide. MS (ESI) m / z calc’d for C20H17F5N3O4S [M+H]+: 490; found: 490.1H NMR (400 MHz, CDCl3) δ 8.55 (dd, J= 2.0, 1.3 Hz, 1H), 8.41 (d, J= 2.1 Hz, 1H), 7.78 - 7.75 (m, 1H), 7.74 - 7.67 (m, 1H), 7.58 (d, J= 7.8 Hz, 1H), 7.51 (t, J= 7.7 Hz, 1H), 6.74 (s, 1H), 5.58 (s, 2H), 4.08 (d, J= 0.4 Hz, 3H). 3.02 (s, 3H).Table Ex-04: The following compounds were prepared using a similar procedure as the above example.

[0220] Example 5-1: 2,2,2-Trifluoro-N-[5-[3-fluoro-6-(4-methyl-4-phenyl-cyclohexoxy)-2- pyridyl]-2-methoxy-3-pyridyl]ethanesulfonamide

[0221] Step 1 : To a microwave vial were added 2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-3-amine (16.5 mg, 0.070 mmol), 2-bromo-3-fluoro-6-(4-methyl-4- phenyl-cyclohexoxy)pyridine (20 mg, 0.052 mmol), Pd(Amphos)Cl2(1.9 mg, 3.0 pmol) and CsF (25.9 mg, 0. 170 mmol). The vessel was back filled with N2(5x) and was charged with degassed 9: 1 dioxane / H2O (3.4 mL). The vessel was sealed and heated to 80 °C for 1.5 h. The reaction was cooled to rt and poured into 30 mL of brine. The resulting biphasic solution was extracted with EtOAc (3 x 15 mL). The combined organic layers were rinse with 10 mL of brine, dried over MgSO4, filtered, and concentrated under reduced pressure to yield crude 5-[3-fluoro-6-(4-methyl- 4-phenyl-cyclohexoxy)-2-pyridyl]-2-methoxy-pyridin-3-amine. The residue was carried on crude into the next step. MS (ESI) m / z calc’d for C24H27FN3O2 [M+H]+: 408; found: 408.

[0222] Step 2 : A solution of crude 5-[3-fluoro-6-(4-methyl-4-phenyl-cyclohexoxy)-2-pyridyl]- 2-methoxy-pyridin-3-amine (20 mg. 0.049 mmol) in pyridine (0.80 mL) at rt was treated with 2,2,2-trifluoroethanesulfonyl chloride (0.01 mL, 0.07 mmol) and heated to 50 °C for 3 h. The reaction was cooled and concentrated under reduced pressure. The reaction mixture was poured into 20 mL of water and extracted with EtOAc (3 x 10 mL). The combined organic layers were rinsed with 10 mL of brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10-50% EtOAc in hexanes) to provide 2,2,2-trifluoro-A-[5-[3-fluoro-6-(4-methyl-4-phenyl-cyclohexoxy)-2-pyridyl]-2- methoxy-3-pyridyl]ethanesulfonamide, as a mixture of cis / trans isomers. MS (ESI) m / z calc'd for C26H28F4N3O4S [M+H]+: 554; found: 554.1H NMR (400 MHz, CDCl3) δ 8.67 (dd. J= 2.0, 0.9 Hz. 1H), 8.49 (d. J= 2.0 Hz. 1H), 7.46 - 7.40 (m. 6H), 7.22 - 7.20 (m, 1H), 6.98 (s, 1H), 6.69 (dd, J= 8.8, 2.7 Hz, 1H), 5.10 (d, J= 3.9 Hz, 1H), 4.08 (s, 3H), 1.92 - 1.88 (m, 4H), 1.65 (s, 4H), 1.30 (s, 3H).

[0223] Example 5-2: 1-Fluoro-N-( 3-fluoro-6'-methoxy-6-((3-(trifluoromethyl)benzyl)oxy)-2,3-bipyridin]-5'-yl)methanesulfonamide

[0224] Step 12 A suspension of CsF (27 mg, 0.18 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3-pyridinamine, (21 mg, 0.086 mmol), Pd(dtbpf)Cl2(1.9 mg, 0.003 mmol) and 2-bromo-3-fluoro-6-[[3-(trifluoromethyl)phenyl]methoxy]pyridine (20 mg, 0.057 mmol) in a mixture of 1 ,4-dioxane (0.9 mL) and water (0. 1 mL) was sparged with N2 for 3 min. The vessel was sealed and heated to 80 °C for 4 h. The reaction mixture was cooled, poured into 30 mL of brine and extracted with EtOAc (3 x 20 mL). The combined organic layers were rinsed with 10 mL of brine, dried over MgSO4filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica. 10-30% EtOAc in hexanes) to afford 5- [3-fluoro-6-[[3-(trifluoromethyl)phenyl]methoxy]-2-pyridyl]-2-methoxy-pyridin-3-amine. MS (ESI) m / z calc’d for C19H16F4N3O2 [M+H]+: 394; found: 394.

[0225] Step 2 : A solution of crude 5-[3-fluoro-6-[[3-(trifluoromethyl)phenyl]methoxy]-2- pyridyl]-2-methoxy pyridin-3-amine (25 mg, 0.0631 mmol) in pyridine (0.4 mL) at rt was treated with fluoromethanesulfonyl chloride (0.01 mL, 0.13 mmol) and heated to 50 °C for 2 h. The reaction was cooled and concentrated under reduced pressure. The reaction mixture was poured into 20 mL of water and extracted w ith EtOAc (3 x 10 mL). The combined organic layers w ere rinsed with 10 mL of brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10-40% EtOAc in hexanes) to afford 1-fluoro-N-(3-fluoro-6,-methoxy-6-((3-(trifluoromethyl)benzyl)oxy)-[2.3'-bipyridin]-5'- yl)methanesulfonamide. MS (ESI) m / z calc’d for C20H17F5N3O4S [M+H]+: 490; found: 490.1H NMR (400 MHz, CDCl3) δ 8.66 (dd, J= 2.1, 1.1 Hz, 1H), 8.49 (d, J= 2.1 Hz, 1H), 7.74 (s, 1H), 7.67 (d, J= 7.6 Hz, 1H), 7.57 (d, J= 7.8 Hz, 1H), 7.53 - 7.38 (m. 2H), 6.97 (s, 1H), 6.78 (dd, J = 8.8, 2.7 Hz, 1H). 5.48 (s. 2H), 5.22 (s. 1H), 5.11 (s, 1H), 4.09 (s, 3H).

[0226] Example 5-3: JV-(6-(3,4-Dichlorophenoxy)-6'-methoxy-[2,3'-bipyridin]-5'- yl)methanesulfonamide

[0227] Step 1 : A vial containing 2-bromo-6-(3,4-dichlorophenoxy)pyridine (280.6 mg, 0.88 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-13,2-dioxaborolan-2-yl)pyridin-3-amine (200 mg, 0.80 mmol), Pd(dppf)Cl2(30.8 mg, 0.040 mmol), CsF (364 mg, 2.4 mmol), dioxane (5 mL) and water ( 1 mL) was purged with a N2needle. The reaction mixture was stirred at 90 °C for 8 h, then cooled to rt. The reaction mixture was filtered through a plug of silica gel, and the filtrate was diluted with EtOAc and water. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by prep-TLC to afford 6-(3,4-dichlorophenoxy)-6'-methoxy-[2.3'-bipyridin]-5'-amine. MS (ESI) m / z calc’d for C17H14CI2N3O2 [M+H]+: 362; found: 362.

[0228] Step 2; To 6-(3,4-dichlorophenoxy)-6'-methoxy-[2,3'-bipyridin]-5'-amine (50 mg, 0.14 mmol) was added pyridine (2 mL). The resulting solution w-as cooled to 0 °C, and MsCl (24 mg. 0.21 mmol) was added. The reaction was stirred at 0 °C for 2 h. then warmed to rt. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, ACN / water with 0.05% formic acid modifier) to afford N-( 6-(3,4-dichlorophenoxy)-6'-methoxy-[2,3'-bipyridin]- 5'-yl)methanesulfonamide. MS (ESI) m / z calc'd for C18H16CI2N3O4S [M+H]+: 440; found: 440. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J= 2.1 Hz, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.78 (t, J= 7.9 Hz, 1H), 7.50 (d, J= 8.8 Hz, 1H), 7.43 (d, J = 7.5 Hz, 1H), 7.33 (d, J= 2.6 Hz, 1H), 7.14 (dd, J= 8.8, 2.6 Hz, 1H), 6.90 (d, J= 8.1 Hz, 1H), 6.73 (s. 1H), 4.04 (s, 3H), 2.98 (s, 3H).Table Ex-05: The following compounds were prepared using a similar procedure as the above examples.

[0229] Example 6-1: 2,2,2-Trifluoro-A-[5-[3-fluoro-6-[[l-(2.2,2-trifluoroethyl)-4- piperidyl]methoxy]-2-pyridyl]-2-(4- pyridylmethoxy )-3-pyridyl] ethanesulfonamide

[0230] Step 1 : A mixture of 2-bromo-3-fluoro-6-[[1-(2,2,2-trifluoroethyl)-4- piperidyl]methoxy]pyridine (50 mg, 0.13 mmol), 3-nitro-2-(4-pyridylmethoxy)-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (150 mg, 0.42 mmol), PdCl2(dppf) (9.9 mg, 0.013 mmol) and CsF (61 mg, 0.40 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL) was stirred for 3 h at 90 °C under N2. The mixture was cooled, filtered over Celite, and concentrated under reduced pressure. The residue was taken up in EtOAc (30 mL), and the organics were washed with water (2 x 30 mL) then brine. The organics were collected, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was then purified by prep-TLC to afford 3-fluoro2-[5-nitro-6- (4-pyridylmethoxy)-3-pyridyl]-6-[[1-(2.2.2-trifluoroethyl)-4- piperidyl]methoxy]pyridine. MS (ESI) m / z calc’d for C24H22F4N5O4 [M-H]-: 520; found: 520.

[0231] Step 2 : A mixture of 3-fluoro-2-[5-nitro-6-(4-pyridylmethoxy)-3-pyridyl]-6-[[l-(2,2,2 trifluoroethyl)-4- piperidyl]methoxy]pyridine (48 mg. 0.092 mmol) and Na2S2O4(240 mg, 1.38 mmol) in THF (6 mL) and water (3 mL) was stirred at rt for 2 h. The reaction was taken up in EtOAc (30 mL), and the organics were washed with water (2 x 30 mL) then brine (1 x 30 mL). The organics were collected, dried over MgSO4. filtered, and concentrated under reduced pressure. The crude 5-[3-fluoro-6-[[1-(2,2,2-trifluoroethyl)-4-piperidyl]methoxy]-2-pyridyl]-2- (4-pyridylmethoxy)pyridin-3-amine was carried forward crude. MS (ESI) m / z calc’d for C24H24F4N5O2 [M-H]": 490; found: 490.

[0232] Step 3; To 5-[3-fluoro-6-[[1-(2,2,2-trifluoroethyl)-4-piperidyl]methoxy]-2-pyridyl]-2- (4-pyridylmethoxy)pyridin-3-amine (37 mg, 0.075 mmol) in anhydrous pyridine (2 mL) at 0 °C was added 2,2,2-trifluoroethanesulfonyl chloride (28 mg, 0.15 mmol). The mixture was stirred for 46 h at rt. The reaction was concentrated under reduced pressure. The residue was taken up in EtOAc (30 mL), and the organics were washed with water (2 x 30 mL) then brine (1 x 30 mL). The organics were collected, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was then purified by preparative HPLC (reverse phase. ACN / water with 0.1% TFA modifier) to afford 2.2.2-trifluoro-A-[5-[3-fluoro-6-[[1-(2.2.2-trifluoroethyl)-4- piperidyl]methoxy]-2-pyridyl]-2-(4- pyridylmethoxy )-3-pyridyl] ethanesulfonamide. MS (ESI) m z calc’d for C26H25F7N5O4S [M-H]-: 636; found: 636.1H NMR (400 MHz, CD3OD) δ 8.77 (s, 2H), 8.58 (s, 2H), 8.04 (d, J= 5.5 Hz, 2H), 7.69 - 7.49 (m, 1H), 6.78 (dd, J= 8.8, 2.6 Hz, 1H). 5.84 (s. 2H), 4.40 - 4.31 (m, 2H), 4.31 - 4.24 (m, 2H), 3.67 (q, J= 9.6 Hz, 2H), 3.39 (d, J= 12.1 Hz. 2H), 2.87 (t, J = 11.8 Hz, 2H). 2.01 (d, J = 15.4 Hz. 2H). 1.65 (d. J = 7. 1 Hz. 2H). 1.31 - 1.29 (m, 1H).

[0233] Example 6-2: 2,2,2-Trifluoro-A-[5-[3-fluoro-6-[[3-(trifluoromethyl)phenyl]methoxy]-2 pyridyl]-2-(oxazol-5-ylmethoxy)-3-pyridyl]ethanesulfonamide

[0234] Step 1: A mixture of 5-[[3-nitro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2 pyridyl] oxymethyl] oxazole (75 mg, 0.22 mmol), 2-bromo-3-fluoro-6-[[3- (trifluoromethyl)phenyl] methoxy] pyridine (50 mg, 0.14 mmol), PdCl2(dppf) (10 mg, 0.014 mmol) and CsF (65 mg, 0.43 mmol) in 1,4-di oxane (4 rnL) and water (0.4 mL) was stirred under N2 at 90 °C for 3 h. The mixture was filtered over Celite and concentrated under reduced pressure. The residue was taken up in EtOAc (30 mL), and the organics were washed with water (2 x 30 mL) and then brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by prep-TLC (25% EtOAc in pet. ether) to afford 5-[[5-[3-fluoro-6-[[3- (trifluoromethy l)phenyl] methoxy] -2-pyridy 1] -3 -nitro-2-py ridy 1] oxymethyl] oxazole. MS (ESI) m / z calc’d for C22H13F4N4O5 [M-H]-: 489; found: 489.

[0235] Step 2: A mixture of 5-[[5-[3-fluoro-6-[[3-(trifluoromethyl)phenyl]methoxy]-2- pyridyl]-3-nitro-2-pyridyl]oxymethyl]oxazole (45 mg, 0.092 mmol) and Na2S2O4(240 mg, 1.38 mmol) in THF (3 mL) and water (1.5 mL) was stirred at rt for 2 h. The reaction was taken up in EtOAc (30 ml). The organics washed with water (2 x 30 mL) then brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude 3-fluoro-6'-(oxazol-5-ylmethoxy)-6- ((3-(trifluoromethyl)benzyl)oxy)-[2,3'-bipyridin]-5'-amine was carried forward crude. MS (ESI)459; found: 459.

[0236] Step 3:_TO a mixture of 5-[3-fluoro-6-[[3-(trifluoromethyl)phenyl]methoxy]-2-pyridyl]- 2-(oxazol-5-ylmethoxy)pyridin-3-amine (28 mg, 0.06 mmol) in pyridine (1 mL) cooled to 0 °C was added 2,2,2-trifluoroethanesulfonyl chloride (22 mg, 0.12 mmol). The mixture was stirred for 48 h at 25 °C. The reaction was taken up in EtOAc (40 mL). The organics were washed with water (2 x 40 mL) then brine (1 x 40 rnL) solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was then purified by preparative HPLC (reverse phase, ACN / water with 0.1% TFA modifier) to afford 2,2,2-trifluoro-A-[5-[3-fluoro-6-[[3- (trifluoromethy l)phenyl] methoxy] -2 pyridyl] -2-(oxazol-5 -y Imethoxy )-3 - pyridyl] ethanesulfonamide. MS (ESI) m / z calc’d for C24H16F7N4O5S [M-H]-: 605; found: 605.1H NMR(400 MHz. CDCl3) δ 8.71 (d, J = 1.1 Hz, 1H). 8.57 (d, J = 2.0 Hz, 1H). 7.95 (s. 1H).7.77 (s, 1H), 7.69 (d, J= 7.6 Hz, 1H), 7.60 (d, J= 7.9 Hz, 1H), 7.56 - 7.45 (m, 2H), 7.27 (s, 1H), 6.83 (dd, J= 8.8, 2.7 Hz, 1H), 5.59 (s, 2H), 5.51 (s, 2H), 3.86 (q, J = 8.8 Hz, 2H).

[0237] Example 6-3: 2,2,2-Trifluoro-A-[5-[3-fluoro-6-[[1-(2.2.2-trifluoroethyl)-4- piperidyl]oxy]-2-pyridyl]-2-(2-pyridylmethoxy)-3-pyridyl]ethanesulfonamide

[0238] Step 1 : A mixture of 2-bromo-3-fluoro-6-[1 -(2,2,2-trifluoroethyl)-4- piperidyl]methoxy]pyridine (50 mg, 0.13 mmol), 3-nitro-2-(2-pyridylmethoxy)-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (57 mg, 0.16 mmol), PdCl2(dppl) (9.5 mg, 0.013 mmol) and CsF (59 mg, 0.40 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL) was stirred for 3 h at 90 °C under N2. The mixture was cooled, filtered over Celite, and concentrated under reduced pressure. The residue was taken up in EtOAc (30 mL), and the organics were washed with water (2 x 30 mL), then brine. The organics were collected, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was then purified by prep-TLC (25% EtOAc in pet. ether) to afford 3-fluoro-5'-nitro-6'-(pyridin-2-ylmethoxy)-6-((l -(2,2,2- trifluoroethyl)piperidin-4-yl)methoxy)-2,3,-bipyridine. MS (ESI) m / z calc’d for C24H22F4N5O4 [M H] 520; found: 520.

[0239] Step 2 : A mixture of 3-Fluoro-5'-nitro-6'-(pyridin-2-ylmethoxy)-6-((1-(2,2,2- trifluoroethyl)piperidin-4-yl)methoxy)-2,3'-bipyridine (43 mg, 0.082 mmol) and Fe (22 mg, 0.41 mmol) in EtOH (4 mL) and water (4 mL) was stirred at 80 °C for 2 h. The mixture was cooled, taken up in EtOAc (30 mL), filtered over Celite, and the organics were washed with water (2 x 30 mL) and brine (1 x 30 mL). The organics were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to afford 3-fluoro-6'-(pyri din-2-ylmethoxy)-6-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-[2.3'-bipyridin]-5'-amine which was carried on to the next step. MS (ESI) m / z calc’d for C24H24F4N5O2 [M-H]-: 490; found: 490.

[0240] Step 3 : To a mixture of 3-fluoro-6'-(py ridin-2-ylmethoxy)-6-((l -(2,2,2- trifluoroethyl)piperidin-4-yl)rnethoxy)-[2,3'-bipyridin]-5'-amine (31 mg, 0.078 mmol) in pyridine (2 mL) was added 2.2.2-trifluoroethanesulfonyl chloride (14 mg, 0.078 mmol) at 0 °C. The mixture was stirred and allowed to warm to rt over 2 h. The mixture was partitioned between water and EtOAc. The organic layer was collected, dried over MgSO4. filtered, and concentrated under reduced pressure. The crude was then purified by preparative HPLC (reverse phase, ACN / water with 0.1% TFA modifier) to afford 2,2,2-trifluoro-A-[5-[3-fluoro-6-[[l-(2,2,2- trifluoroethyl)-4-piperidyl]oxy]-2-pyridyl]-2-(2-pyridylmethoxy)-3-pyridyl]ethanesulfonamide. MS (ESI) m / z calc’d for C26H25F7N5O4S [M-H]-: 636; found: 636. '1H NMR (400 MHz, CD3OD) 5 8.67 - 8.44 (m, 3H), 7.87 (td, J= 7.7, 1.5 Hz, 1H), 7.67 - 7.47 (m, 2H), 7.43 - 7.32 (m, 1H), 6.72 (dd, J= 8.9. 2.6 Hz, 1H), 5.65 (s, 2H), 5.11 (tt, J= 8.3, 3.9 Hz, 1H), 4.78 - 4.76 (m, 2H), 4.25 (q, J= 9.5 Hz, 2H). 3.09 (q, J= 9.9 Hz, 2H). 2.95 (dd. J= 11.2, 5.3 Hz, 2H), 2.74 - 2.58 (m, 2H), 2.11 (d, J= 10.7 Hz, 2H), 1.85 - 1.83 (m, 2H).Table Ex-06: The following compounds were prepared using a similar procedure as the above examples.

[0241] Example 7-1: 2,2,2-Trifluoro-N-( 3-fluoro-6,-methoxy-6-(spiro[4.5]decan-8-yloxy)-[2, 3'-bipyridin]-5'-yl)ethane-1-sulfonamide

[0242] Step 1 : To a stirred suspension of NaH (17.0 mg, 0.71 mmol) in DMF (0.5 ml) was added dropwise a solution of spiro[4.5]decan-8-ol (52.5 mg, 0.34 mmol) in DMF (0.5 ml) at 0 °C under N2. The reaction mixture was stirred for 30 min. A solution of 2-bromo-3,6- difluoropyridine (55.0 mg, 0.28 mmol) in DMF (0.5 mL) was added dropwise. The reaction mixture was allowed to warm to rt and stirred overnight. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 5-40% EtOAc in hexanes) to give 2-bromo-3-fluoro-6-(spiro[4.5]decan-8-yloxy)pyridine. MS (ESI) m / z calc’d for C15HwBrFNO [M+H]+: 328, 330; found: 328, 330.

[0243] Step 2 : A suspension of 2-bromo-3-fluoro-6-(spiro[4.5]decan-8-yloxy)pyridine (11.0 mg, 0.034 mmol), 2.2.2-trifluoro-N-( 2-methoxy-5-(4,4,5,5-tetramethyl-L3.2-dioxaborolan-2- yl)pyridin-3-yl)ethane-1-sulfonamide (15.9 mg, 0.040 mmol), CsF (15.8 mg, 0.10 mmol) and Pd(Amphos)Cl2(1.2 mg, 1.7 μmol) in a mixture of 1,4-dioxane (0.5 mL) and water (0.05 mL) was sparged with N2for 3 min. The vessel was sealed and heated to 80 °C for 1 h. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried andconcentrated under reduced pressure. The crude was punfied by column chromatography (silica. 10-60% EtOAc / hexanes) to give 2,2,2-trifluoro-N-(3-fluoro-6'-methoxy-6-(spiro[4.5]decan-8- yloxy)-[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide. MS (ESI) m / z calc’d for C23H27F4N3O4S [M+H]+: 518; found: 518.1H NMR(400 MHz, CDCl3) δ 8.68 (s. 1H), 8.51 (d, J= 1.8 Hz. 1H), 7.48 - 7.33 (m. 1H), 7.03 (s. 1H), 6.64 (dd, J= 8.8, 2.6 Hz. 1H), 5. 13 - 4.94 (m, 1H), 4.09 (s, 3H), 3.87 (q, J= 8.7 Hz, 2H), 1.96 (s, 2H), 1.64 - 1.59 (m, 3H), 1.57 (s, 3H), 1.51 - 1.44 (m, 2H), 1.42 (s, 2H), 1.26 (d, J= 8.2 Hz, 2H), 1.00 - 0.71 (m, 2H).Table Ex-07: The following compounds were prepared using a similar procedure as the above example.

[0244] Example 8-1: N-(3-(Difluoromethyl)-6'-methoxy-6-((3-(trifluoromethyl)benzyl)oxy)-[2,3'-bipyridin]-5'-yl)methanesulfonamide

[0245] Step 1 : A mixture of CS2CO3(355 mg, 1.09 mmol), 6-bromo-2-chloro-pyridine-3- carbaldehyde (220 mg. 1.0 mmol), and (3-(trilluoromethyl)phenyl)methanol (0.12 mL. 0.91 mmol) in PhMe (1.8 mL) was sparged with N2for 3 min. The reaction mixture was treated with BINAP Pd G3 (45 mg, 0.05 mmol) under continuous N2stream. The vessel was sealed and heated to 90 °C for 16 h. The reaction mixture was filtered over Celite, concentrated under reduced pressure, and purified by column chromatography (silica, 5-20% EtOAc in hexanes) to afford 2-chloro-6-((3-(trifluoromethyl)benzyl)oxy)nicotinaldehyde.

[0246] Step 2 : A solution of 2-chloro-6-((3-(trifluoromethyl)benzyl)oxy)nicotinaldehyde (34.5 mg, 0.11 mmol) in DCM (1.0 mL) at 0 °C was treated with DAST (15.0 pl, 0.11 mmol). The ice bath was removed and reaction mixture was stirred for 2 h at rt. The reaction mixture was cooled to 0 °C and quenched with 10 mL of sat’d NaHCO3and vigorously stirred for 30 min. An additional portion of 10 mL of sat’d NaHCO3was added and the reaction was stirred for another 30 min. The reaction mixture was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine, dried over MgSO4. filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 5-15% DCM in hexanes) to give 2-chloro-3-(difluoromethyl)-6-((3-(trifluoromethyl)benzyl)oxy)pyridine. MS (ESI) m / z calc’d for C14H9CIF5NO [M+H]+: 338; found: 338.

[0247] Step 3 : A suspension of CsF (15.2 mg, 0.10 mmol), N-(2-methoxy-5-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide (16.4 mg, 0.050 mmol), Pd(dppf)Cl2(1.1 mg, 1.5 pmol) and 2-chloro-3-(difluoromethyl)-6-((3- (trifluoromethyl)benzyl)oxy)pyridine (10.1 mg, 0.030 mmol) in a mixture of 1,4-dioxane (2.0 ml) and water (0.22 ml) was sparged with N2 for 3 min. The vessel was sealed and heated to 80 °C for 4 h. The reaction mixture was poured into 30 mL of water and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography(silica. 15-50% EtOAc in hexanes) to give N-( 3-(difluoromethyl)-6'-methoxy-6-((3- (trifluoromethyl)benzyl)oxy)-[2,3,-bipyridin]-5'-yl)methanesulfonamide. MS (ESI) m / z calc’d for C21H19F5N3O4S [M+H]+: 504; found: 504.1H NMR (400 MHz, CDCl3) δ 8.12 (d, J= 2.2 Hz, 1H), 8.04 (d, J= 2.2 Hz, 1H), 8.01 (d, J= 8.7 Hz, 1H), 7.72 (s, 1H), 7.65 (d, 7.5 Hz, 1H),7.57 (d, J= 7.8 Hz, 1H). 7.50 (t. J= 7.7 Hz. 1H), 6.93 (d. J= 8.6 Hz. 1H), 6.77 (d. J= 13.8 Hz, 1H), 6.62 (s, 1H), 5.50 (s, 2H), 4.20 - 4.00 (m, 3H), 3.06 (d, J= 1.2 Hz, 3H).

[0248] Example 9-1: N-( 3-Methoxy-6-(5-((3-(trifluoromethyl)benzyl)oxy)pyridin-3- yl)pyridazin-4-yl)methanesulfonamide

[0249] Step 1: N-( 6-Chloro-3-metho.\y pyridazin-4-yl )-N-( 4- methoxybenzyl)methanesulfonamide (265 mg, 0.741 mmol) was added to a stirred mixture of 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((3-(trifluoromethyl)benzyl)oxy)pyridine (702 mg, 1.852 mmol), CS2CO3(483 mg, 1.481 mmol), PdC12(dtbpf) (48.3 mg, 0.074 mmol) in 1,4- dioxane (2 mL), and water (0.2 mL) at rt and the mixture was heated with stirring at 80 °C for 18 h under N2. The mixture was cooled to rt, water (10 mL) was added and the mixture was extracted with EtOAc (2 x 30 mL). The combined organic fractions were washed with brine, dried over Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 33% EtOAc in pet. ether) to give N-( 3-methoxy-6-(5-((3- (trifluoromethyl)benzyl)oxy)pyridin-3-yl)pyridazin-4-yl)-N-( 4- methoxybenzyl)methanesulfonamide. MS (ESI) calc’d for C27H25F3N4O5S [M+H]+: 575; found: 575.1H NMR (400 MHz, CDCl3) δ 8.73 (d, J= 4.70 Hz, 1H, 8.60 (d, J= 1.56 Hz, 1H), 8.45 (d, J = 3.13 Hz, 1H), 7.94 - 7.89 (m, 1H), 7.72 (s, 1H), 7.65 - 7.56 (m, 1H), 7.57 - 7.40 (m, 2H), 7.16 (d, J= 8.61 Hz, 1H), 7.12 - 7.05 (m, 1H), 6.82 - 6.71 (m, 2H), 5.25 - 5.14 (m, 1H), 4.86 - 4.75 (m. 2H), 4.37 - 4.24 (m, 3H), 3.83 - 3.69 (m, 3H), 3.05 (d, J= 19.95 Hz. 3H), 2.04 (s, 1H).

[0250] Step 2: N-( 3-Methoxy-6-(5-((3-(trifluoromethyl)benzyl)oxy)pyridin-3-yl)pyridazin-4- yl)-N-( 4-methoxybenzyl)methanesulfonamide (175 mg, 0.305 mmol) was added to a stirred mixture of TFA (0.023 mL, 0.31 mmol) and anisole (0.132 mL, 1.22 mmol) and stirred at 50 °C for 40 min by microwave irradiation. LCMS showed starting material remained and new productformed. Volatiles were removed by concentration under reduced pressure. The residue was purified by preparative HPLC (reverse phase, C18, ACN / water with 0.1% TFA modifier) to give N-( 3-methoxy-6-(5-((3-(trifluoromethyl)benzyl)oxy)pyridin-3-yl)pyridazin-4- yl)methanesulfonamide. MS (ESI) calc’d for C19H17F3N4O4S [M+H]C 455; found: 455.1H NMR (400 MHz. CDCl3) δ 8.95 (br s, 1H), 8.70 (br s, 1H), 8.48 (br s. 1H), 7.91 (s, 1H), 7.74 (s, 1H), 7.70 - 7.64 (m, 2H), 7.62 - 7.55 (m, 1H), 5.35 (s, 2H), 4.30 (s, 3H), 3.26 (s, 3H).

[0251] Example 10-1: N-( 6-(3-((3-Fluorobenzyl)oxy)phenyl)-3-methoxypyridazin-4- yl)methanesulfonamide

[0252] Step 1: meCgPPh-Pd-G2 (45.0 mg, 0.075 mmol) was added to a stirred mixture of N- (3-methoxy-6-(tributylstannyl)pyridazin-4-yl)-N-(4-methoxybenzyl)methanesulfonamide (686 mg, 1.12 mmol) and 1-bromo-3-((3-fluorobenzyl)oxy)benzene (210 mg, 0.747 mmol) in 1,4- dioxane (5 mL). The resulting suspension was heated to 80 °C for 16 h, then cooled to rt. The mixture was diluted with EtOAc and washed with water (2x). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on column chromatography (silica, EtOAc in hexanes) to afford N-( 6-(3-((3-fluorobenzyl)oxy )phenyl)-3- methoxypyridazin-4-yl)-N-(4-methoxybenzyl)methanesulfonamide. MS (ESI) m / z calc’d for C27H27FN3O5S [M+H]+: 524; found: 524.1H NMR (500 MHz, CDCl3) δ 7.60 (d. J= 1.8 Hz. 1H), 7.50 (s, 1H), 7.42 - 7.32 (m, 3H), 7.25 - 7.12 (m, 4H), 7.09 - 6.98 (m, 2H), 6.85 - 6.73 (m, 2H), 5.12 (s, 2H), 4.84 (s, 2H), 4.33 (s, 3H), 3.74 (s, 3H), 3.07 (s, 3H).

[0253] Step 2; N-(6-(3-((3-Fluorobenzyl)oxy)phenyl)-3-methoxypyridazin-4-yl)-N-( 4- methoxybenzyl)methanesulfonamide (180 mg, 0.344 mmol) was added to a stirred mixture of TFA (530 μL, 6.88 mmol) and anisole (149 μL. 1.38 mmol), and the reaction mixture was heated to 50 °C for 40 min under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, ACN / water with 0.1% TFA modifier) to afford N-( 6-(3-((3-fluorobenzyl)oxy)phenyl)-3-methoxypyridazin-4- yl)methanesulfonamide. MS (ESI) m / z calc’d for C19H19FN3O4S [M+H]+: 404; found: 404.1HNMR (400 MHz, CDCl3) δ 7.95 (d, J = 1.96 Hz, 1H). 7.86 (br d, J = 2.74 Hz, 1H). 7.33 - 7.40 (m, 1H), 7.23 - 7.27 (m, 1H), 4.28 (s, 3H), 3.24 (s, 3H).Table Ex-08: The following compounds were prepared using a similar procedure as the above example.

[0254] Example 11-1 : N-(2-Phenoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide

[0255] Step 1: A suspension of 2-chloro-5-iodo-3-nitro-pyridine (1.06 g. 3.72 mmol), cesium fluoride (1.18 g, 7.77 mmol), [3-[[3-(trifluoromethyl)phenyl]methoxy]phenyl]boronic acid (1.00 g, 3.38 mmol) and PdC12(dppf)·CH2Cl2complex (110.3 mg, 0. 14 mmol) in a mixture of 1,4- dioxane (16 mL) and water (1.6 mL) was sparged with N2 for 3 min. The vessel was sealed and heated to 100 °C overnight. The reaction mixture was poured into 40 mL of brine and extracted with EtOAc (3 x 20 mL). The combined organic layers were rinsed with 10 mL of brine, dried with MgSO4. filtered, and concentrated under reduced pressure. Purification was achieved by column chromatography (silica, 5-15% EtOAc in hexanes) to afford 2-chloro-3-nitro-5-(3-((3- (trifluoromethyl)benzyl)oxy)phenyl)pyridine. MS (ESI) m / z calc’d for C19H13CIF3N2O3 [M+H]+: 409; found 409.

[0256] Step 2 : To a suspension of 2-chloro-3-nitro-5-(3-((3- (trifluoromethyl)benzyl)oxy)phenyl)pyridine (150 mg, 0.37 mmol) and K2CO3 (154 mg 1.11 mmol) in DMF (5 mL) was added PhOH (70 mg, 0.74 mmol). The mixture was stirred at 80 °C for 16 h. The mixture was diluted with EtOAc, and the organic layer was washed with brine. The separated organic layer was diluted with pet. ether until a ratio of 1 :5 EtOAc:pet. ether was achieved. Dilution induced precipitation of crystals, which were filtered and dried to provide the product 3-nitro-2-phenoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridine.

[0257] Step 3: A mixture of 3-nitro-2-phenoxy-5-(3-((3- (trifluoromethyl)benzyl)oxy)phenyl)pyridine (100 mg, 0.21 mmol), NH4CI (113 mg, 2.10 mmol), and Fe powder (58 mg, 1.05 mmol) in w ater (1 mL) and 10 mL EtOH was stirred for 3 h at 90 °C under N2. The reaction mixture was diluted with EtOAc (50 mL) and filtered over Celite. The organic phase was dried over anhydrous Na2SO4. filtered, and concentrated under reduced pressure to afford 2-phenoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-amine. The resulting product was used in the next step without further purification. MS (ESI) m / z calc’d for C25H20F3N2O2 [M+H]+: 437; found: 437.

[0258] Step 4; To a solution of 2-phenoxy-5-(3-((3- (trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-amine (85 mg. 0.19 mmol) in pyridine (3 mL) at 0 °C under an inert atmosphere of N2was added methanesulfonyl chloride (47.3 μL, 0.61 mmol). The ice bath was removed, and the reaction was stirred for 2 h at rt. The reaction mixture w as concentrated under reduced pressure, diluted with EtOAc, washed with brine, and dried over anhydrous Na2SO4. The residue was purified by column chromatography (silica, 25% EtOAc in pet. ether) to afford the desired product N-(2 -phenoxy-5-(3-((3- (trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)methanesulfonamide. MS (ESI) m / z C26H21F3N2O4S [M+H]+calc’d 515; found 515.1H NMR(400 MHz, CD3OD) δ 8.11 (s, 2H),7.81 - 7.71 (m. 2H). 7.66 - 7.55 (m. 2H), 7.47 - 7.36 (m. 3H), 7.28 - 7.17 (m, 5H), 7.09 - 7.02 (m, 1H), 5.23 (s, 2H), 3.12 (s, 3H); note, one proton is not observed due to exchange.Table Ex-09: The following compounds were prepared using a similar procedure as the above example.

[0259] Example 12-1 : N-(6-(3-((4,4-Dimethylcyclohexyl)oxy)phenyl)-3-methoxypyridazin-4- yl)methanesulfonamide

[0260] Step 1 : To a mixture of N-(3-chloro-6-(3-hydroxyphenyl)pyridazin-4-yl)-N-(4- methoxybenzyl)methanesulfonamide (20 mg, 0.048 mmol), polymer-supported PPh3(2.26 mmol / g, 85 mg, 0.19 mmol) in THF (0.9 mL) was added DIAD (0.037 mL, 0.19 mmol) and 4,4- dimethylcyclohexanol (0.022 mL, 0.19 mmol). The resulting suspension was stirred at rt for 16 h, at which point the reaction mixture w as fdtered. The fdtrate w as concentrated under reduced pressure. The crude residue was purified by column chromatography (silica, 10-35% EtOAc in hexanes) to afford N-( 3-chloro-6-(3-((4.4-dimethylcyclohexyl)oxy)phenyl)pyridazin-4-yl)-N-( 4-methoxybenzyl)methanesulfonamide. MS (ESI) m / z calc’d for C27H33CIN3O4S [M+H]+: 530; found: 530.

[0261] Step 2 : To a mixture of methanol (6 μL, 0.14 mmol) in DMF (0.4 mL) was added sodium hydride (60% dispersion in mineral oil, 2.8 mg, 0.071 mmol). The reaction mixture was aged for 15 min, at which point N-( 3-chloro-6-(3-((4,4- dimethylcyclohexyl)oxy)phenyl)pyridazin-4-yl)- N-(4-methoxybenzyl)methanesulfonamide (19 mg, 0.035 mmol) was added. The reaction mixture was stirred at rt, then diluted with water. The aqueous layer was extracted with TBME (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica, 15-55% EtOAc in hexanes) to afford N-(6-(3 - ((4,4-dimethylcyclohexyl)oxy)phenyl)-3-methox pyridazin-4-yl)- N-(4- methoxybenzyl)methanesulfonamide. MS (ESI) m / z calc’d for C28H36N3O5S [M+H]+: 526; found: 526.

[0262] Step 3; A mixture of N-( 6-(3-((4,4-dimethylcyclohexyl)oxy)phenyl)-3- methoxypyridazin-4-yl )-N-( 4-methoxy benzyl )methanesulfonamide (5.0 mg, 0.010 mmol), anisole (4 μL, 0.038 mmol), and TFA (0.4 mL) was heated to 50 °C for 40 min by microwave irradiation. The reaction mixture was concentrated under reduced pressure. To the residue was added PhMe. and the reaction mixture was concentrated under reduced pressure (3x). The crude residue was purified by column chromatography (silica, 20-50% EtOAc in DCM) to afford N-(6- (3-((4,4-dimethylcyclohexyl)oxy)phenyl)-3-methoxypyridazin-4-yl)methanesulfonamide. MS (ESI) m / z calc’d for C20H28N3O4S [M+H]+: 406; found: 406.1H NMR(400 MHz, CDCl3) δ 7.85 (s, 1H), 7.64 - 7.60 (m, 1H). 7.46 (d, J= 7.8 Hz, 1H). 7.37 (t. J= 7.9 Hz. 1H), 7.17 (s, 1H), 7.00 (dd, J = 8.4, 1.6 Hz, 1H), 4.36 (tt, J = 8.4. 3.9 Hz. 1H), 4.25 (s. 3H), 3.18 (s, 3H), 1.94 - 1.85 (m, 2H), 1.77 - 1.65 (m, 2H), 1.54 - 1.47 (m, 2H), 1.34 - 1.23 (m, 2H), 0.98 (s, 3H), 0.95 (s, 3H).Table Ex- 10: The following compounds were prepared using a similar procedure as the above example.

[0263] Example 13-1: N-( 6-((1-Cyanocyclopropyl)methoxy)-3-fluoro-6'-methoxy-[2,3'- bipyridin] -5 '-yl)-2,2,2-trifluoroethane- 1 -sulfonamide

[0264] Step 1 : A vial containing 1-(hydroxymethyl)cyclopropanecarbonitrile (37 mg, 0.38 mmol) and NMP (5 mL) was purged with a N2needle. To this solution was added sodium hydride (60% dispersion in mineral oil, 16 mg, 0.40 mmol), at which point the reaction mixture was aged for 15 min at rt. 3,6-Difluoro-6'-methoxy-[2,3'-bipyridin]-5'-amine (50 mg. 0.21 mmol) w as added, and the resulting mixture was stirred at rt for 1 h, diluted with EtOAc, and quenched by addition of sat’d NH4CI. The organic layer was separated, and then washed w ith brine. The organic layer w as dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by prep-TLC to afford N-( 6-((1-cy anocyclopropy l)methoxy)-3-fluoro- 6'-methoxy-[2.3,-bipyridin]-5,-yl)-2.2.2-trifluoroethane-1-sulfonamide. MS (ESI) m / z calc’d for C16H16FN4O2 [M+H]+: 315; found: 315.

[0265] Step 2 : To N-( 6-((1-cyanocyclopropyl)methoxy)-3-fluoro-6'-methoxy-[2,3'-bipyridin]- 5'-yl)-2,2,2-trifluoroethane-1-sulfonamide (50 mg, 0.16 mmol) was added pyridine (3 mL) and 2,2,2-trifluoroethanesulfonyl chloride (60 mg. 0.33 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted w ith EtOAc and quenched by addition of water. The organic layer was separated and then washed with brine. The combined organic layers w ere dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative HPLC (reverse phase, ACN / water with 0.05% formic acid modifier) to afford A- (6-((1-cyanocyclopropyl)methoxy)-3-fluoro-6'-methoxy-[2.3'-bipyridin]-5'-yl)-2.2.2- trifluoroethane-1 -sulfonamide. MS (ESI) m / z calc’d for C18H17F4N4O4S [M+H]+: 461; found: 461.11H NMR(400 MHz, CD3OD) δ 8.64 (s, 1H), 8.46 (d, J= 1.9 Hz, 1H), 7.67 - 7.59 (m, 1H), 6.85 (dd, J= 8.8. 2.6 Hz, 1H), 4.43 (s, 2H), 4.24 (q, J= 9.4 Hz, 2H), 4.07 (s, 3H), 1.39 - 1.32 (m, 2H), 1.26 - 1.20 (m, 2H).

[0266] Example 13-2: 2,2,2-Trifluoro-N-( 3-fluoro-6'-methoxy-6-(3-(trifluoromethyl)phenoxy)- [2, 3'-bipyridin]-5'-yl)ethane-1-sulfonamide

[0267] Step 1 : To a mixture of 3-(trifluoromethyl)phenol (70 mg. 0.43 mmol) and 3,6-difluoro- 6'-methoxy-[2,3'-bipyridin]-5'-amine (50 mg, 0.21 mmol) was added NMP (5 mL) and K2CO3 (70 mg, 0.50 mmol). The reaction mixture was heated to 135 °C for 48 h, then cooled to rt. The reaction mixture was diluted with EtOAc, and the organic layer w as washed sequentially with sat’d NH4CI and brine. The organic layer was dried over Na2SO4. filtered, and concentrated under reduced pressure. The crude residue was purified by prep-TLC to afford 3-fluoro-6'- methoxy-6-(3-(trifluoromethyl)phenoxy)-[2,3'-bipyridin]-5'-amine. MS (ESI) m / z calc’d for C18H14F4N3O2 [M+H]+: 380; found: 380.

[0268] Step 2: To 3-fluoro-6'-methoxy-6-(3-(trifluoromethyl)phenoxy)-[2,3'-bipyridin]-5'- amine (40 mg. 0. 11 mmol) was added pyridine (3 mL). The resulting solution was cooled to 0 °C, and 2,2,2-trifluoroethanesulfonyl chloride (50 mg, 0.27 mmol) was added. The reaction mixture w as aged for 20 min at 0 °C, at which point it w as warmed to rt and stirred for 36 h. The reaction mixture was diluted with EtOAc and quenched by addition of brine. The organic layer was separated, dried over Na2SO4. filtered, and concentrated under reduced pressure. The crude residue w as purified by preparative HPLC (reverse phase, ACN / water with 0.05% formic acid modifier) to afford 2,2,2-trifluoro-N-( 3-fluoro-6'-methoxy-6-(3-(trifluoromethyl)phenoxy)-[2,3'- bipyridin]-5'-yl)ethane-1-sulfonamide. MS (ESI) m / z calc’d for C20H15F7N3O4S [M+H]+: 526; found: 526.1H NMR (400 MHz. CDCl3) δ 8.53 (s, 1H). 8.22 (s, 1H), 7.60 - 7.52 (m. 2H), 7.51 - 7.46 (m, 1H), 7.46 - 7.39 (m, 2H), 6.99 (s, 1H), 6.94 (dd, J= 8.7, 2.1 Hz, 1H), 4.05 (s, 3H), 3.75 (q, J = 8.7 Hz, 2H).Table Ex- 11: The following compounds were prepared using a similar procedure as the above examples.- Ill -

[0269] Example 13-17: N-(6-(((1r,4r)-4-Cyanocyclohexyl)oxy)-3-fluoro-6,-methoxy-[2,3'- bipyridin]-5'-yl)-2,2,2-trifluoroethane-1-sulfonamide

[0270] Step 1 : To a mixture of 4-hydroxycyclohexanecarbonitrile (70 mg, 0.56 mmol) and 3,6- difluoro-6'-methoxy-[2,3'-bipyridin]-5'-amine (80 mg, 0.34 mmol) was added NMP and Mg(OtBu)2(300 mg. 1.8 mmol). The reaction mixture was heated to 90 °C overnight, then cooled to rt. The reaction mixture was poured into sat’d NH4CI. The aqueous layer was extracted with EtOAc. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by prep-TLC to afford a mixture of (1s,4s)-4-((5'-amino-3-fluoro-6,-methoxy-[2,3'-bipyridin]-6-yl)oxy)cyclohexane-1-carbonitrile and (lr,4r)-4-((5'-amino-3-fluoro-6'-methoxy-[2,3,-bipyridin]-6-yl)oxy)cyclohexane-1- carbonitrile. MS (ESI) m / z calc’d for C18H20FN4O2 [M+H]+: 343; found: 343.

[0271] Step 2; To (lr,4r)-4-((5'-amino-3-fluoro-6'-methoxy-[2,3'-bipyridin]-6- yl)oxy)cyclohexane-1-carbonitrile (42 mg, 0. 12 mmol) was added pyridine (3 mL). The resulting solution was cooled to 0 °C, and 2,2,2-trifluoroethanesulfonyl chloride (48 mg, 0.26 mmol) wasadded. The reaction was warmed to rt and stirred for 1 h. The reaction mixture was diluted with EtOAc and quenched by addition of brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative HPLC (reverse phase, ACN / water with 0.05% formic acid modifier) to afford N-( 6-(((lr,4r)-4- cyanocyclohexyl)oxy)-3-fluoro-6,-methoxy-[2,3'-bipyridin]-5'-yl)-2,2,2-trifluoroethane-1- sulfonamide. MS (ESI) m / z calc’d for C20H21F4N4O4S [M+H]+: 489, found: 489.1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.55 (s, 1H), 7.43 (t, J= 9.5 Hz, 1H), 7.04 (s, 1H), 6.68 (d, J= 8.8 Hz, 1H), 5.14 (s, 1H), 4.09 (s, 3H), 3.85 (q, J= 8.8 Hz, 2H), 2.78 (s, 1H), 2.13 - 2.01 (m, 2H), 2.03 - 1.92 (m. 4H), 1.93 - 1.80 (m. 2H).

[0272] Example 14-1: N-( 6-((4,4-Dimethylcyclohexyl)oxy)-6'-methoxy-[2,3'-bipyridin]-5'- yl)methanesulfonamide

[0273] Step 1: To 6-fluoro-6,-methoxy-[2,3'-bipyridin]-5'-amine (650 mg, 2.97 mmol) was added pyridine (6 mL). The resulting solution was cooled to 0 °C, and methanesulfonyl chloride(500 mg, 4.36 mmol) was added. The reaction was warmed to rt and stirred for 5 h. The reaction mixture was quenched by addition of water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica, 33% EtOAc in pet. ether) to afford N-( 6-fluoro-6'-methoxy-[2,3'-bipyridin]-5'-yl)methanesulfonamide. MS (ESI) m / z calc’d for C12H13FN3O3S [M+H]+: 298; found: 298.

[0274] Step 2 : A vial containing cyclohexanol (60 mg, 0.47 mmol) and DMF (3 mL) was purged with a N2needle. To this solution was added sodium hydride (60% dispersion in mineral oil, 28 mg, 0.28 mmol), at which point the reaction mixture was aged for 20 min at rt. N-(6- Fluoro-6'-methoxy-[2,3'-bipyridin]-5'-yl)methanesulfonamide (50 mg, 0.17 mmol) was added, and the resulting mixture was stirred at 65 °C for 2 h, then cooled to rt. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, ACN / water with 0.05% formic acid modifier) to afford N-( 6-((4,4-dimethylcyclohexyl)oxy)-6'-methoxy-[2,3'-bipyridin]-5'- yl)methanesulfonamide. MS (ESI) m / z calc’d for C20H28N3O4S [M+H]+: 406; found: 406.1HNMR (400 MHz, CD3OD) δ 8.57 (d, J = 2.2 Hz, 1H). 8.45 (d, J = 2.2 Hz, 1H). 7.70 - 7.64 (m. 1H), 7.36 (d, J = 7.4 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 5. 16 - 5.08 (m, 1H), 4.05 (s, 3H), 3.02 (s, 3H), 2.05 - 1.93 (m, 2H), 1.78 - 1.66 (m, 2H), 1.59 - 1.48 (m, 2H), 1.48 - 1.35 (m, 2H), 1.00 (s, 3H), 0.98 (s, 3H).Reverse Phase prep-HPLC Methods:TFA modifier

[0275] Reverse-phase preparative-HPLC [Waters SunFire OBD C18, 19 mm X 150 mm(5 μm); gradient elution, ACN / H2O / 0. 1% TFA], Electrospray (ESI) mass-triggered fraction collected was employed using positive ion polarity scanning to monitor for the target mass.HPLC Gradient:NH4OH modifier

[0276] Reverse-phase preparative-HPLC [Waters XBridge OBD Cl 8, 19 mm X 150 mm(5 pm); gradient elution, ACN / H2O / 0.1% NH4OH]. Electrospray (ESI) mass-triggered fraction collected was employed using positive ion polarity scanning to monitor for the target mass.HPLC Gradient:YAP / TEAD CELLULAR ACTIVITY ASSAYQuantitation of compound potency on the inhibition of TEAD-Luc activity in TEAD Reporter-MCF7 cell line.

[0277] The TEAD Reporter-MCF7 cell line containing the firefly luciferase gene under the control of TEAD responsive elements stably integrated into the human breast cancer cell line was purchased from BPS Bioscience (Cat# 60618). The cells were cultured with complete culture medium (EMEM 88%. 1% Non-essential amino acids, 1 mM sodium pyruvate, 10% fetal bovine serum, 10 ng / mL insulin and 400 μg / mL G418 sulfate) prior to the assay. For the assay, the cells were harvested, resuspended in the complete culture medium without G418, and seeded into white solid bottom 384-well cell culture microplates in 25 μL with 10,000 cells per well. The plates were incubated at 37 °C in a CO2incubator for 20-24 h, and the compounds were then transferred from Echo LDV plates directly into the 384-well white tissue culture plates with an Echo. The plates were incubated at 37 °C in a CO2incubator for 24 h and equal volume of ONE- Glo™ EX Luciferase reagent (Promega, Cat#E8150) was added. After mixing on a shaker at room temperature for 10 min, the luciferase activity was measured with an Envision. The percentage inhibition and EC50 values of compounds were calculated with Spotfire.Required Materials1. TEAD reporter-MCF-7 Cells (BPS Bioscience, #60618)2. Complete Cell Culture Medium (without selection antibiotics) EMEM 89% (ATCC. #30-2003)FBS 10% (Hyclone, #SH30088.03) 1% Non essential amino acids (Gibco) 1 mM sodium pyruvate (Gibco) Pen / Strep, 1% (Gibco, #15140-122) 10 ng / mL insulin (Sigma, #10516)3. Complete Cell Culture Medium (with selection antibiotics) EMEM 89% (ATCC, #30-2003)Fl% Non essential amino acids (Gibco) 1 mM sodium pyruvate (Gibco) BS 10% (Hyclone, #SH30088.03) 10 ng / mL insulin (Sigma, #10516) 400 pg / mL G418 sulfate (Agilent, #200049-21)4. Miscellaneous tissue culture equipment and reagents.5. White solid 384-well tissue culture plate (Greiner, Cat# 781080)6. One Gio EX luciferase assay system (Promega, #E8150)Table of MCF7 Cellular Assay Data

[0278] The following table tabulates the biological data disclosed for the compounds of Formula I. The biological data was collected using the methodology described above. For each compound, TEAD-Luc EC50values are listed in nanomolar (nM) concentration units.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein;X1is -N- or -CR5-;X2is -N- or -CR6-;X3is -N- or -CR7-;X4is -N- or -CR8-;X5is -N- or -CR9-;R1is selected from:(1) aryl, unsubstituted or substituted with 1-3 substituents independently selected from R10,(2) -C1-6alkyl-aryl, unsubstituted or substituted with 1-3 substituents independently selected from R10,(3) 4-6 membered heterocyclyl, having 1-3 heteroatoms independently selected from N, O and S, unsubstituted or substituted with 1-3 substituents independently selected from R10,(4) -C1-6alkyl- 4-6 membered heterocyclyl having 1-3 heteroatoms independently selected from N, O and S, unsubstituted or substituted with 1-3 substituents independently selected from R10,(5) -C1-6alkyl- 4-6 membered heteroaryl ring, having 1-3 heteroatoms independently selected from N, O and S wherein, the heteroaryl ring is unsubstituted or substituted with 1-3 substituents independently selected from R10,(6) -C3-10cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R10,(7) -C1-6alkyl-C3-6cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R10.(8) 8-10 membered fused bicyclic aryl, unsubstituted or substituted with 1-3 substituents selected from R10,(9) -C1-6alkyl- 8-10 membered fused bicyclic and, unsubstituted or substituted with 1- 3 substituents selected from R10,(10) -C1-6alkyl- 8-10 membered fused bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from N, O and S, unsubstituted or substituted with 1-3 substituents selected from R10(11) 10-11 membered spiro bicyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O and S. unsubstituted or substituted with 1-3 substituents independently selected from R10,(12) 10-11 membered spiro bicyclic cycloalkyl,(13) 14-5 membered tricyclic cycloalkyl,(14) -C1-6alkyl- 5-10 membered bridged cycloalkyl, unsubstituted or substituted with 1- 3 substituents independently selected from R10, and(15) 5-10 membered bridged heterocyclyl having 1-3 heteroatoms independently selected from N, O and S;R2is -H, -F, -CF3or -CH3;R3is selected from:(1) -C1-6alkyl,(2) aryl,(3) 4- to 6- membered heterocyclyl, having 1-3 heteroatoms independently selected from N. O and S;(4) -C1-6alkyl-C3-6cycloalkyl,(5) -C3-8cycloalkyl, unsubstituted or substituted with C1-6alkyl, and(6) -C1-6haloalkyl;R4is selected from:(1) -C1-6alkyl,(2) aryl,(3) C1-6alkyl- 5-6 membered heterocyclyl, having 1-3 heteroatoms independently selected from N, O and S, unsubstituted or substituted with 1-3 substituents independently selected from C1-6alkyl and =O.(4) -CH2CH2OCH3,(5) -C1-6alkyl- 5-6 membered heteroaryl ring, having 1-3 heteroatoms independently selected from N, O and S, wherein the heteroaryl ring is unsubstituted or substituted with 1-3 substituents selected from C1-6alkyl,(6) -C1-6haloalkyl,(7) 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected from N, O and S,(8) -CH(CH2OCH3)2,(9) 5-6 membered heteroaryl ring, having 1-3 heteroatoms independently selected from N. O and S, and(10) -C3-8cycloalkyl;R5is selected from:(1) hydrogen,(2) halo,(3) -C1-6alkyl, unsubstituted or substituted with 1-3 halogen substituents, and(4) -O-C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents;R6is selected from:(1) hydrogen,(2) halo,(3) -C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents, and(4) -O-C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents;R7is selected from:(1) hydrogen,(2) halo,(3) -C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents, and(4) -O-C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents;R8is selected from:(1) hydrogen,(2) halo,(3) -C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents, and(4) -O-C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents;R9is selected from:(1) hydrogen,(2) halo,(3) -C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents, and(4) -O-C1-3alkyl. unsubstituted or substituted with 1-3 halogen substituents.When preset, R10is selected from:(1) halo,(2) C1-6haloalkyl.(3) C1-6alkyl,(4) cyano, and(5) -C(O)O-C1-6alkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is(1) aryl, unsubstituted or substituted with 1-3 substituents independently selected from R10,(2) C1-6alkyl-aryl, unsubstituted or substituted with 1-3 substituents independently selected from R10,(3) 4-6 membered heterocyclyl, having 1-3 heteroatoms independently selected from N, O and S, unsubstituted or substituted with 1-3 substituents independently selected from R10,(4) C1-6alkyl- 4-6 membered heterocyclyl having 1-3 heteroatoms independently selected from N, O and S, unsubstituted or substituted with 1-3 substituents independently selected from R10,(5) C1-6alkyl- 4-6 membered heteroaryl ring, having 1-3 heteroatoms independently selected from N, O and S, wherein the heteroaryl ring is unsubstituted or substituted with 1-3 substituents independently selected from R10.(6) -C3-10cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R10,(7) -C1-6alkyl-C3-6Cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R10,(8) 8-10 membered fused bicyclic aryl, unsubstituted or substituted with 1-3 substituents selected from R10,(9) C1-6alkyl- 8-10 membered fused bicyclic aryl, unsubstituted or substituted with 1- 3 substituents selected from R10,(10) C1-6alkyl- 8-10 membered fused bicyclic heteroaryl ring system having 1-3 heteroatoms independently selected from N, O and S, wherein the heteroaryl ring system is unsubstituted or substituted with 1-3 substituents selected from R10(11) 10-11 membered spiro bicyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O and S, unsubstituted or substituted with 1-3 substituents independently selected from R10,(12) 10-11 membered spiro bicyclic cycloalkyl.(13) 14-15 membered tricyclic cycloalkyl,(14) -C1-6alkyl- 5-10 membered bridged cycloalkyl, unsubstituted or substituted with 1- 3 substituents independently selected from R10, or(15) 5-10 membered bridged heterocyclyl having 1-3 heteroatoms independently- selected from N, O and S.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2is - H, -CH3, or -F.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3is(1) -C1-6alkyl,(2) aryl,(3) 4-6 membered heterocyclyl, having 1-3 heteroatoms independently selected fromN, O and S;(4) -C1-6alkyl-C3-6cycloalkyl,(5) -C3-8Cycloalkyl, unsubstituted or substituted with C1-6alkyl, or(6) -C1-6haloalkyl.

5. The compound of claim 1. or a pharmaceutically acceptable salt thereof, wherein R4is(1) -C1-6alkyl,(2) aryl,(3) C1-6alkyl- 5-6 membered heterocyclyl, having 1-3 heteroatoms independently selected from N, O and S, unsubstituted or substituted with 1-3 substituents independently selected from C1-6alkyl and =0,(4) -CH2CH2OCH3,(5) -C1-6alkyl- 5-6 membered heteroaryl ring, having 1-3 heteroatoms independently- selected from N, O and S, wherein the heteroaryl ring is unsubstituted or substituted with 1-3 substituents selected from C1-6alkyl,(6) -C1-6haloalkyl,(7) 5-6 membered heterocyclyl having 1-3 heteroatoms independently selected fromN, O and S,(8) -CH(CH2OCH3)2,(9) 5-6 membered heteroaryl ring, having 1-3 heteroatoms independently selected from N. O and S. or(10) -C3-8cycloalkyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R5is(1) hydrogen,(2) halogen,(3) -C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents, or(4) -O-C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents;.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R6is(1) hydrogen,(2) halogen,(3) -C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents, or(4) -O-Ci-3alkyl, unsubstituted or substituted with 1-3 halogen substituents.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R7is(1) hydrogen,(2) halo,(3) -C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents, or(4) -O-C1-3alkyl unsubstituted or substituted with 1-3 halogen substituents.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R8is(1) hydrogen,(2) halo,(3) -C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents, or(4) -O-C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R9is(1) hydrogen,(2) halo,(3) -C1-3alkyl , unsubstituted or substituted with 1-3 halogen substituents, or(4) -O-C1-3alkyl, unsubstituted or substituted with 1-3 halogen substituents.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X1is - CR5-; X2is -CR6-; X3is -CR7-; X4is -N-; and X5is -CR9-.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X1is - CR5-; X2is -CR6-: X3is -N-; X4is -N-; and X5is -CR9-.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X1is: - CR5-; X2is: -N-; X3is: -CR7-; X4is: -N-; and X5is: -CR9-.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X1is - CR5-; X2is -N-; X3is -N-; X4is -N-; and X5is -CR9-.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X1is: - CR5-; X2is: -CR6-; X3is: -N-: X4is: -CR8-; and X5is: -CR9-.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X1is: - N-; X2is: -CR6-; X3is: -N-; X4is: -N-; and X5is: -CR9-.

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X1is: - CR5-; X2is: -CR6-; X3is: -N-; X4is: -N-; and X5is: -N-.

18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, or a pharmaceutically acceptable salt thereof, which is:N-(6-(2-Fluoro-5-((3-fluorobenzyl)oxy)phenyl)-3-methoxypyridazin-4-yl)methanesulfonamide,2,2,2-Trifluoro-N-(5-(2-fluoro-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-2- methoxypyridin-3-yl)ethane-1-sulfonamide,N-(6-(5-((3-Chlorobenzyl)oxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(5-((3-Chloro-4-fluorobenzyl)oxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(5-((3,5-Dichlorobenzyl)oxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(2-Fluoro-5-((4-fluoro-3-methylbenzyl)oxy)phenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(5-((4,4-Difluorocyclohexyl)oxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(5-((4,4-Dimethylcyclohexyl)oxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(2-Fluoro-5-((6-(trifluoromethyl)pyridin-2-yl)methoxy)phenyl)-3- methoxypyridazin-4-yl)methanesulfonamide,N-(6-(5-(Cyclopropylmethoxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(5-((2,2-Dimethylcyclopropyl)methoxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide.N-(6-(5-((2,2-Difluorocyclopropyl)methoxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(5-((5-Cyclopropylisoxazol-3-yl)methoxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(2-Fluoro-5-((5-methylisoxazol-3-yl)methoxy)phenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(5-((4,5-Dimethylthiazol-2-yl)methoxy)-2-fluorophenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(2-Fluoro-5-(thiazol-2-ylmethoxy)phenyl)-3-methoxypyridazin-4- yl)methanesulfonamideN-(6-(5-((5-Cyclopropyl-1-methyl-1H-pyrazol-3-yl)methoxy)-2-fluorophenyl)-3- methoxypyridazin-4-yl)methanesulfonamide,N-(6-(5-((1,4-Dimethyl- 1H-pyrazol-3-y l)methoxy)-2-fluorophenyl)-3 -methoxypyridazin- 4-yl)methanesulfonamide,N-(6-(2-Fluoro-5-((3-methyl-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-3-methoxypyridazin-4-yl)methanesulfonamide,N-(6-(2-Fluoro-5-((3-methylbenzyl)oxy)phenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(3-((3-Oxaspiro[5.5]undecan-9-yl)oxy)phenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(2-Fluoro-3-((3-(trifluoromethyl)benzyl)oxy)phenyl)-3-rnethoxypyridazin-4- yl)methanesulfonamide,N-(3-Methoxy-6-(6-((3-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)pyridazin-4- yl)methanesulfonamide,N-(6-(6-((3-Fluorobenzyl)oxy)pyridin-2-yl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(3-Methoxy-6-(6-((3-methylbenzyl)oxy)pyridin-2-yl)pyridazin-4- yl)methanesulfonamide,N-(6-(6-((3-Chlorobenzyl)oxy)pyridin-2-yl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(6-((4,4-Difluorocyclohexyl)methoxy)pyridin-2-yl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(6-((8,8-Difluorobicyclo[3.2.1]octan-3-yl)methoxy)pyridin-2-yl)-3- methoxypyridazin-4-yl)methanesulfonamide,N-(3-Methoxy-6-(6-((4-(trifluoromethyl)cyclohexyl)oxy)pyridin-2-yl)pyridazin-4- yl)methanesulfonamide,N-(6-(6-((4,4-Difluorocyclohexyl)oxy)pyridin-2-yl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(6-((4,4-Dirnethylcyclohexyl)oxy)pyridin-2-yl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(3-Methoxy-6-(6-((5-(trifluoromethyl)furan-2-yl)methoxy)pyridin-2-yl)pyridazin-4- yl)methanesulfonamide,N-(3-Methoxy-6-(6-((1-(trifluoromethyl)cyclopropyl)methoxy)pyridin-2-yl)pyridazin-4- yl)methanesulfonamide,N-(6-(6-((3-Cyanobicyclo[1.1.1]pentan-1-yl)methoxy)pyridin-2-yl)-3-methoxypyridazin-4-yl)methanesulfonamide,N-(6-(6-((3,3-Difluorocyclobutyl)methoxy)pyri din-2 -yl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(6-(6-((1-(Difluoromethyl)-1H-pyrazol-3-yl)methoxy)pyridin-2-yl)-3- methoxypyridazin-4-yl)methanesulfonamide,N-(3-Methoxy-6-(6-((1-(2.2.2-trifluoroethyl)piperidin-4-yl)methoxy)pyridin-2- yl)pyridazin-4-yl)methanesulfonamide,N-(3-Methoxy-6-(6-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)pyridin-2-yl)pyridazin-4- yl)methanesulfonamide,N-(6-(6-((3-Fluorobenzyl)oxy)pyridin-2-yl)-3-methoxypyridazin-4-yl)ethanesulfonamide,N-(6-(3-((3-Fluorobenzyl)oxy)phenyl)-3-methoxypyridazin-4-yl)ethanesulfonamide,N-(3,5-Difluoro-6'-methoxy-6-((3-(trifluoromethyl)benzyl)oxy)-[2,3'-bipyridin]-5'- yl)methanesulfonamide,N-(3-Fluoro-6,-methoxy-6-((3-(trifluoromethyl)benzyl)oxy)-[2.3,-bipyridin]-5'- yl)methanesulfonamide,N-(5-(2-Fluoro-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-2-methoxypyridin-3- yl)methanesulfonamide,N-(3,6'-Dimethoxy-6-((4-(trifluoromethyl)benzyl)oxy)-[2,3'-bipyridin]-5'- yl)methanesulfonamide,N-(3-Fluoro-6'-methoxy-6-((6-(trifluoromethyl)pyridin-2-yl)methoxy)-[2,3'-bipyridin]-5'- yl)methanesulfonamide,2.2.2-Trifluoro-N-(5-(2-fluoro-3-((3-(trifluoromethyl)benzyl)oxy)phenyl)-2- methoxypyridin-3-yl)ethane-1-sulfonamide.N-(5-(2,6-Difluoro-3-((3-(trifluoromethyl)benzyl)oxy)phenyl)-2-rnethoxypyridin-3-yl)-2,2,2-trifluoroethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-((2-(2,2,2-trifluoroethyl)-2-azaspiro[4.5]decan- 8-yl)oxy)-[2.3'-bipyridin]-5'-yl)ethane-1-sulfonamide,N-(6-((1-Cyclopentyl-1H-indazol-3-yl)methoxy)-3-fluoro-6,-methoxy-[2,3,-bipyridin]-5'- yl)-2,2,2-trifluoroethane-1-sulfonamide,N-(3-Fluoro-6'-(pyridin-4-ylmethoxy)-6-((1-(2,2,2-trifluoroethyl)piperidin-4- yl)methoxy)-[2,3'-bipyridin]-5'-yl)methanesulfonamide,N-(3-Fluoro-6'-(pyridin-4-ylmethoxy)-6-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)- [2,3'-bipyridin]-5'-yl)methanesulfonamide,N-(3-Fluoro-6'-(pyridin-2-ylmethoxy)-6-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)- [2,3'-bipyridin]-5'-yl)methanesulfonamide,N-(3-Fluoro-6'-(pyridin-4-ylmethoxy)-6-((1-(2,2,2-trifluoroethyl)piperidin-3- yl)methoxy)-[2,3'-bipyridin]-5,-yl)methanesulfonamide,N-(3-Fluoro-6'-(pyridin-2-ylmethoxy)-6-((1-(2,2,2-trifluoroethyl)piperidin-3- yl)methoxy)-[2,3'-bipyridin]-5'-yl)methanesulfonamide,N-(5-Methoxy-2-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-4- yl)methanesulfonamide,N-(2-Methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,3-Fluoro-N-(3-methoxy-6-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridazin-4- yl)propane- 1 -sulfonamide,N-(3-Methoxy-6-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridazin-4- yl)ethanesulfonamide,N-(3-Methoxy-6-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridazin-4-yl)propane-1- sulfonamide,N-(3-Methoxy-6-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridazin-4- yl)cyclopropanesulfonamide, 1-Cyclopropyl-N-(6-(3-fluoro-6-((3-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-3- methoxypyridazin-4-yl)methanesulfonamide,2.2.2-Trifluoro-N-[5-[3-fluoro-6-(4-methyl-4-phenyl-cyclohexoxy)-2-pyridyl]-2- methoxy-3-pyridyl]ethanesulfonamide,1-Fluoro-N-(3-fluoro-6'-methoxy-6-((3-(trifluoromethyl)benzyl)oxy)-[2,3'-bipyridin]-5'- yl)methanesulfonamide,N-(6-(3,4-Dichlorophenoxy)-6,-methoxy-[2,3,-bipyridin]-5'-yl)methanesulfonamide, tert-Butyl 8-[[5-fluoro-6-[6-methoxy-5-(2,2,2-trifluoroethylsulfonylamino)-3-pyridyl]-2- pyridyl]oxy]-2-azaspiro[4.5]decane-2-carboxylate,2.2.2-Trifluoro-N-[5-(3fluoro-6-spiro[cyclohexane-4,1,-indane]-1-yloxy-2-pyridyl)-2- methoxy-3-pyridyl]ethanesulfonamide, diastereomer 1,2.2.2-Trifluoro-N-[5-(3-fluoro-6-spiro[cyclohexane-4,1'-indane]-1-yloxy-2-pyridyl)-2- methoxy-3 -pyridyl] ethanesulfonamide, diastereomer 2,2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-((6-(trifluoromethyl)pyridin-2-yl)methoxy)- [2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide.2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-((3-(trifluoromethyl)benzyl)oxy)-[2,3'- bipyridin] -5 '-yl)ethane-1-sulfonamide,N-(6'-Methoxy-6-((3-(trifluoromethyl)benzyl)oxy)-[2.3'-bipyridin]-5'- yl)methanesulfonamide,N-(6'-Methoxy-5-methyl-6-((3-(trifluoromethyl)benzyl)oxy)-[2,3,-bipyridin]-5,- yl)methanesulfonamide, 1-Fluoro-N-(5-(2-fluoro-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-2-methoxypyridin-3- yl)methanesulfonamide,1-Fluoro-N-(2-methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-Methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)ethanesulfonamide,N-(2-Methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)propane-1- sulfonamide,N-(2-Methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)cyclopropanesulfonamide,N-(2-Methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)benzenesulfonamide,N-(2-Methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)propane-2- sulfonamide,N-(2-Methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)oxetane-3- sulfonamide,2.2-Difluoro-N-(2-methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)ethane- 1 -sulfonamide,3,3,3-Trifluoro-N-(2-methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)propane- 1 -sulfonamide,3-Fluoro-N-(2-methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)propane- 1 -sulfonamide.N-(2-Methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)-1- methylcyclopropane- 1 -sulfonamide,2-Fluoro-N-(2-methoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)ethane- 1 -sulfonamide,2.2.2-Trifluoro-N-[5-[3-fluoro-6-[[l-(2,2,2-trifluoroethyl)-4-piperidyl]methoxy]-2- pyridyl]-2-(4- pyridylmethoxy )-3-pyridyl]ethanesulfonamide,2.2.2-Trifluoro-N-[5-[3-fluoro-6-[[3-(trifluoromethyl)phenyl]methoxy]-2 pyridyl]-2- (oxazol-5-ylmethoxy)-3-pyridyl]ethanesulfonamide,2.2.2-Trifluoro-N-[5-f3-fluoro-6-[[l-(2,2,2-trifluoroethyl)-4-piperidyl]oxy]-2-pyridyl]-2- (2-pyridylmethoxy)-3-pyridyl]ethanesulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-(pyridin-4-ylmethoxy)-6-((4-(2,2,2- trifluoroethyl)cyclohexyl)oxy)-[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6,-(pyridin-3-ylmethoxy)-6-((3-(trifluoromethyl)benzyl)oxy)- [2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-(pyridin-4-ylmethoxy)-6-((3-(trifluoromethyl)benzyl)oxy)- [2, 3'-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6,-(pyrimidin-5-yloxy)-6-((3-(trifluoromethyl)benzyl)oxy)- [2, 3'-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-(pyridin-2-ylmethoxy)-6-((1-(2,2,2- trifluoroethyl)piperidin-4-yl)oxy)-[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6,-(pyrimidin-5-ylmethoxy)-6-((3- (trifluoromethyl)benzyl)oxy)-[2,3,-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-(pyrimidin-2-ylmethoxy)-6-((3- (trifluoromethyl)benzyl)oxy)-[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6,-(pyrimidin-4-ylmethoxy)-6-((3- (trifluoromethyl)benzyl)oxy)-[2,3,-bipyridin]-5,-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(2-methoxy-6-methyl-5-(3-((3- (trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)ethane-1-sulfonamide,N-(5-(2-Fluoro-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-2-(pyridin-4- ylmethoxy)pyridin-3-yl)methanesulfonamide.2.2.2-Trifluoro-N-(5-(2-fluoro-5-((3-(trifluoromethyl)benzyl)oxy)phenyl)-2-(pyridin-4- ylmethoxy)pyridin-3-yl)ethane- 1 -sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-(spiro[4.5]decan-8-yloxy)-[2,3'-bipyridin]-5'- yl)ethane-1-sulfonamide ,N-(6-((l,5-Diphenyl-1H-pyrazol-4-yl)methoxy)-3-fluoro-6,-methoxy-[2,3,-bipyridin]-5,- yl)-2,2,2-trifluoroethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-((5-phenyl-1-(tetrahydro-2H-pyran-4-yl)-1H- pyrazol-4-yl)methoxy)-[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide.N-(6-((1-Cyclobutyl-3-phenyl-1H-pyrazol-4-yl)methoxy)-3-fluoro-6'-methoxy-[2,3'- bipyridin] -5 '-yl)-2,2,2-trifluoroethane- 1 -sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-((6-(trifluoromethyl)-2,3-dihydro-1H-inden-1- yl)oxy)-[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide.2.2.2-Trifluoro-N-(3-fluoro-6,-methoxy-6-((7-methoxy-1.2.3.4-tetrahydronaphthalen-2- yl)oxy)-[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-((4-(naphthalen-2-yl)-2,3-dihydro-1H-inden-2- yl)oxy)-[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide,N-(6-((4,4-Dimethyl-1,2.3.4-tetrahydronaphthalen-1-yl)methoxy)-3-fluoro-6'-methoxy- [2,3'-bipyridin]-5,-yl)-2,2,2-trifluoroethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-((7-phenyl-1,2,3,4-tetrahydronaphthalen-2- yl)oxy)-[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6,-methoxy-6-((1-methyl-1H-indazol-3-yl)methoxy)-[2,3'- bipyridin] -5 '-y l)ethane- 1 -sulfonamide,N-(3-(Difluoromethyl)-6'-methoxy-6-((3-(trifluoromethyl)benzyl)oxy)-[2,3'-bipyridin]-5'- yl)methanesulfonamide,N-(3-Methoxy-6-(5-((3-(trifluoromethyl)benzyl)oxy)pyridin-3-yl)pyridazin-4- yl)methanesulfonamide,N-(6-(3-((3-Fluorobenzyl)oxy)phenyl)-3-methoxypyridazin-4-yl)methanesulfonamide,N-(6-(2-Fluoro-3-((3-fluorobenzyl)oxy)phenyl)-3-methoxypyridazin-4- yl)methanesulfonamide,N-(5-(2-Fluoro-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)phenyl)-2-(pyridin-3- ylmethoxy)pyridin-3-yl)ethanesulfonamid,N-(3-Methoxy-6-(4-((3-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)pyridazin-4- yl)methanesulfonamide,N-(2-Phenoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-(Pyrimidin-5-yloxy)-5-(3-((3-(trifluoroniethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-(Pyridin-3-yloxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-((5-Methyl-l,2,4-oxadiazol-3-yl)methoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)methanesulfonamide,N-(2-((1-Methyl-1H-pyrazol-4-yl)methoxy)-5-(3-((3- (trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)methanesulfonamide.N-(2-(2-Methoxyethoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-(2-(2-Oxopyrrolidin-1-yl)ethoxy)-5-(3-((3- (trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)methanesulfonamide.N-(2-(Pyridin-2-ylmethoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-(Pyridin-3-ylmethoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-(Pyridin-4-ylmethoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-(Oxazol-5-ylmethoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-((Tetrahydro-2H-pyran-4-yl)oxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)methanesulfonamide,N-(2-(Benzyloxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-Cyclobutoxy-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-(Isoxazol-3-ylmethoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-(Pyrimidin-5-ylmethoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-((Tetrahydro-2H-pyran-4-yl)methoxy)-5-(3-((3- (trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)methanesulfonamide.N-(2-(2,2-Difluoroethoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-((1,3-Dimethoxypropan-2-yl)oxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)methanesulfonamide,N-(2-(Pyridazin-4-ylmethoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3- yl)methanesulfonamide,N-(2-((3-Methyloxetan-3-yl)methoxy)-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)pyridin-3-yl)methanesulfonamide,N-(6-(3-((4,4-Dimethylcyclohexyl)oxy)phenyl)-3-methoxypyridazin-4- yl)methanesulfonamide ,N-(6-{3-[(1-Cyclopentyl-5-phenyl-1H-pyrazol-4-yl)methoxy]phenyl}-3- methoxypyridazin-4-yl)methanesulfonamide,N-(6-((1-Cyanocyclopropyl)methoxy)-3-fluoro-6,-methoxy-f2,3'-bipyridin]-5'-yl)-2,2,2- trifluoroethane- 1 -sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-(3-(trifluoromethyl)phenoxy)-[2,3'-bipyridin]- 5'-yl)ethane-1-sulfonamide,N- {6-[(3-Bromophenyl)methoxy] -3-fluoro-6'-methoxy [2,3'-bipyridin] -5'-yl } -2.2.2- trifluoroethane- 1 -sulfonamide,2.2.2-Trifluoro-N-{3-fluoro-6'-methoxy-6-[(oxan-4-yl)methoxy][2,3'-bipyridin]-5'- y 1 } ethane- 1 -sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6,-methoxy-6-{[4-(2,2,2-trifluoroethyl)morpholin-2- yl]methoxy}[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-{[l-(2,2,2-trifluoroethyl)-1H-pyrazol-4- yl]methoxy} [2, 3'-bipyridin]-5'-yl)ethane-1-sulfonamide,2.2.2-Trifluoro-N-{3-fluoro-6,-methoxy-6-[(oxan-3-yl)methoxy][2.3,-bipyridin]-5,- yl} ethane- 1 -sulfonamide,N-{6-[(3-Cyanophenyl)methoxy]-3-fluoro-6'-methoxy[2,3'-bipyridin]-5'-yl}-2,2,2- trifluoroethane-1 -sulfonamide.2.2.2-Trifluoro-N-{3-fluoro-6'-methoxy-6-[(naphthalen-1-yl)methoxy] [2.3'-bipyridin]-5'- yl} ethane- 1 -sulfonami de,2.2.2-Trifluoro-N-{3-fluoro-6'-methoxy-6-[(oxan-2-yl)methoxy][2,3'-bipyridin]-5'- yl} ethane- 1 -sulfonamide,N-(6-{[l-(Cyanomethyl)piperidin-3-yl]methoxy}-3-fluoro-6'-methoxy[2,3'-bipyridin]-5'- yl)-2.2.2-trifluoroethane-1-sulfonamide.2.2.2-Trifluoro-N-{3-fluoro-6'-methoxy-6-[(3-methyloxetan-3-yl)methoxy][2,3,- bipyridin] -5 '-y 1 } ethane- 1 -sulfonamide,2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-{[(3-endo)-8-oxabicyclo[3.2.1]octan-3- yl]oxy}[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide,N-[6-(3,4-Dichlorophenoxy)-3-fluoro-6'-methoxy[2,3'-bipyridin]-5'-yl]-2,2,2- trifluoroethane- 1 -sulfonamide,N-{6-[3-Bromo-5-(trifluoromethyl)phenoxy]-3-fluoro-6'-methoxy[2,3'-bipyridin]-5'-yl}-2,2,2-trifluoroethane-1-sulfonamide.2.2.2-Trifluoro-N-(3-fluoro-6'-methoxy-6-{[1-(2,2,2-trifluoroethy1)-1H-1,2,4-triazol-3- yl]methoxy}[2,3'-bipyridin]-5'-yl)ethane-1-sulfonamide,N-(6-(((1r,4r)-4-Cyanocyclohexyl)oxy)-3-fluoro-6'-methoxy-[2,3'-bipyridin]-5'-yl)-2,2,2- trifluoroethane-1 -sulfonamide, orN-(6-((4,4-Dimethylcyclohexyl)oxy)-6'-methoxy-[2,3'-bipyridin]-5'- yl)methanesulfonamide.

19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is:

20. A method for treating cancer in a patient, comprising administering to the patient a compound of any of one of Claims 1-19, or a pharmaceutically acceptable salt thereof.

21. A method of treating a disease or disorder in which Hippo pathway inhibition is beneficial comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of any of Claims 1-19, or a pharmaceutically acceptable salt thereof.

22. A composition for treating cancer associated with increased YAP1 and / or TAZ expression comprising a compound of any of claims 1-19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically carrier.

23. A composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1-19, or a pharmaceutically acceptable salt thereof.

24. Use of a compound of any of claims 1-19, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cancer associated with increased YAP1 and / or TAZ expression.

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