3-sulfamoyl benzoate ester and benzamide compounds as tead modulators

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 and pharmaceutically acceptable salts thereof.

Description

3-SULFAMOYL BENZOATE ESTER AND BENZAMIDE COMPOUNDS AS TEADMODULATORSCROSS-REERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 562,996, filed March 8, 2024, the disclosure of which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Y es-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] The present disclosure is directed to compounds having structural Formula I:or a pharmaceutically acceptable salt thereof wherein:A is -CH- or -N-;X is -NH- or -O-;Y is -NH- or -O-;R1is(1) -C1-6alkyl, unsubstituted or substituted with 1-3 substituents independently selected from R3.(2) -C1-6alkyl-OH,(3) -C1-6alkyl-O-C1-3alkyl,(4) -C3-6Cycloalkyl. unsubstituted or substituted with 1-3 substituents independently selected from R3,(5) -C1-6alkyl-C3-6cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R3,(6) -C1-6alkyl-monocylic heteroaryl wherein the heteroaryl is a 5-6 membered heteroaryl ring having 1, 2 or 3 heteroatoms independently selected from N, O and S. wherein the heteroaryl is unsubstituted or substituted with 1-3 substituents independently selected from R3,(7) -C1-6haloalkyl,(8) -C1-6alkyl- 8-10 membered fused bicyclic heteroaryl having 1. 2 or 3 heteroatoms independently selected from N, O and S and wherein the bicyclic heteroaryl is optionally substituted with 1-3 substituents independently selected from R3, or(9) hydrogen;R2is(1) phenyl unsubstituted or substituted with 1-3 substituents independently selected from R4,(2) -C1-6alkyl-C3-10monocyclic cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from R4,(3) -C1-8alkyl unsubstituted or substituted with 1-3 substituents independently selected from R4,(4) monocyclic -C3-6cycloalkyl unsubstituted or substituted with 1-3 substituents independently selected from R4,(5) 5-6 membered heterocyclyl having 1, 2 or 3 heteroatoms independently selected from N, S or O, wherein the heterocycle is unsubstituted or substituted with 1-3 substituents independently selected from R4,(6) -C1-6alky 1-ary 1 wherein the alky l and aryl are independently unsubstituted or substituted with 1-3 substituents independently selected from R4,(7) 5-10 membered fused bicyclic cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R4,(8) -C1-6alkyl- 5-10 membered bridged cycloalky l, unsubstituted or substituted with 1- 3 substituents independently selected from R4,(9) 5-10 membered bridged cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R4,(10) -C1-6alkyl- 5-10 membered bridged heterocycle having 1, 2 or 3 heteroatoms independently selected from N, S or O, wherein the bridged heterocycle is unsubstituted or substituted with 1-3 substituents independently selected from R4,(11) C1-6haloalkyl,(12) -C1-6alkyl-O-C1-6haloalkyl,(13) 5-8 membered spiro bicyclic cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R4, or(14) C1-6alkyl- 5-8 membered spiro bicyclic cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R4. when present, each R3is independent!(1) halogen,(2) -C1-6haloalkyl,(3) -C1-6alkyl,(4) -C3-6cycloalkyl,(5) -OC1-6alkyl,(6) -OH,(7) -N(CH3)2,(8) -C1-6alkyl-OH,(9) cyano,(10) -C1-6alkyl-O-C1-3alkyl, or(11) -C1-6alkyl-C3-6Cycloalkyl, when present, each R4is independently(1) halogen,(2) -C1-6haloalkyl,(3) -C1-3alkyl,(4) -SF5,(5) -O-C1-6haloalkyl,(6) -S-C1-6haloalkyl, or(7) C1-6cycloalkyl.

[0005] In Embodiment 2 of this disclosure are the compounds of Formula I, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is(1) -C1-6alkyl, unsubstituted or substituted with 1-3 substituents independently selected from R3.(2) -C1-6alkyl-OH,(3) -C1-6alkyl-O-C1-3alkyl,(4) -C3-6Cycloalkyl. unsubstituted or substituted with 1-3 substituents independently selected from R3,(5) -C1-3alkyl-C3-6cycloalkyl unsubstituted or substituted with 1-3 substituents independently selected from R3,(6) -C1-3alkyl-monocylic heteroaryl wherein the heteroaryl is a 5-6 membered heteroaryl ring having 1, 2 or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or substituted with 1-3 substituents independently selected from R3,(7) -C1-6haloalkyl,(8) -C1-3alkyl-8-10 membered fused bicyclic heteroaryl, wherein the fused bicyclic heteroaryl ring system having 1, 2 or 3 heteroatoms independently selected from N, O and S and wherein the fused bicyclic heteroaryl is optionally substituted with 1-3 substituents independently selected from R3, or(9) hydrogen;

[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) -C1-3alkyl, unsubstituted or substituted with -N(CH3)2,(2) -C1-3alkyl-OH,(3) -C1-3alkyl-O-C1-3alkyl,(4) -C3-6Cycloalkyl unsubstituted or substituted with 1 -3 substituents independently selected from -OCH3, halo, -CH3, -OH, -CH2OH, and C1-6haloalkyl,(5) -C1-3alkyl-C3-6cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from halo, methyl, -OH, -CH2OH, cyano, and -CH2OCH3,(6) -C1-3alkyl-monocyclic heteroaryl, wherein the heteroaryl is a 5-6 membered heteroaryl ring having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or substituted with 1-2 substituents independently selected from methyl, cyclopropyl, and -CH2-cyclopropyl,(7) -C1-2haloalkyl,(8) -C1-3alkyl- 8-10 membered fused bicyclic heteroaryl, wherein the fused bicyclic heteroaryl ring system having 1 or 2 nitrogen atoms, or(9) hydrogen.

[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:(1) -CH3,(2) -CH2CH3,(3) -CH2CH2CH3,(4) -CH2CH2N(CH3)2,(5) -CH2CH2OH,(6) -CH2CH2CH2OH,(7) -CH2CH2OCH3,(8) -CH2CH2CH2OCH3,(9) 3-4 membered cycloalkyl, unsubstituted or substituted with 1-2 substituents independently selected from -OCH3, -F, -CH3, -OH, -CH2OH, and -CF3,(10) -CH2-cycloalkyl, wherein the cycloalkyl is cyclopropyl, cyclobutyl or cyclohexyl, unsubstituted or substituted with 1-2 substituents independently selected from -F. methyl, -OH, -CH2OH, cyano, and -CH2OCH3,(11) -C1-3alkyl- monocyclic heteroaryl, wherein the heteroaryl is a 5-6 membered heteroaryl ring having 1 or 2 nitrogen atoms wherein the heteroaryl is unsubstituted or substituted with 1-2 substituents independently selected from methyl, cyclopropyl, and -CH2-cyclopropyl,(12) -CH2CH2F,(13) -CH2-quinoline,(14) -CH2-isoquinoline.(15) -CH2-quinoxaline, or(16) hydrogen.

[0008] In Embodiment 5 of this disclosure are compounds of Formula I, or Embodiments 1 -4, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -C1-3alkyl, unsubstituted or substituted with -N(CH3)2.

[0009] In Embodiment 6 of this disclosure are compounds of Formula I, or Embodiments 1-, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -CH3, -CH2CH3, - CH2CH2CH3, or -CH2CH2N(CH3)2.

[0010] In Embodiment 7 of this disclosure are compounds of Formula I, or Embodiments 1-, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -C1-3alkyl-OH.

[0011] In Embodiment 8 of this disclosure are compounds of Formula l, or Embodiments 1-4 or, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -CH2CH2OH, or - CH2CH2CH2OH.

[0012] In Embodiment 9 of this disclosure are compounds of Formula I, or Embodiments 1 -, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -C1-3alkyl-O-C1-3alkyl.

[0013] In Embodiment 10 of this disclosure are compounds of Formula I, or Embodiments 1-4 or, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -CH2CH2OCH3, or -CH2CH2CH2OCH3.

[0014] In Embodiment 11 of this disclosure are compounds of Formula I, or Embodiments 1, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -C3-6cycloalkyl unsubstituted or substituted with 1-3 substituents independently selected from -OCH3, halo, - CH3, -OH, -CH2OH, and C1-6haloalkyl.

[0015] In Embodiment 12 of this disclosure are compounds of Formula I, or Embodiments 1-4 or 11, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is 3-4 membered cycloalkyl, unsubstituted or substituted with 1-2 substituents independently selected from -OCH3, -F, -CH3, -OH, -CH2OH, and -CF3.

[0016] In Embodiment 13 of this disclosure are compounds of Formula I, or Embodiments 1, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -C1-3alkyl-C3-6cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, methyl, -OH, -CH2OH, cyano, and -CH2OCH3.

[0017] In Embodiment 14 of this disclosure are compounds of Formula I, or Embodiments 1-4 or, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -CH2-cyclopropyl, CH2-cyclobutyl or CH2-cyclohexyl, wherein the cyclopropyl. cyclobutyl, or cyclohexyl is unsubstituted or substituted with 1-2 substituents independently selected from -F, methyl, -OH, -CH2OH, cyano, and -CH2OCH3.

[0018] In Embodiment 15 of this disclosure are compounds of Formula I, or Embodiments 1, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -C1-3alkyl- monocyclic heteroaryl, wherein the heteroaryl is a 5-6 membered heteroaryl ring having 1 or 2 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or substituted with 1-3 substituents independently selected from methyl, cyclopropyl, and -CH2- cyclopropyl.

[0019] In Embodiment 16 of this disclosure are compounds of Formula I, or Embodiments 1-4 or 15, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -Ci salkyl- monocyclic heteroaryl, wherein the heteroaryl is a 5-6 membered heteroaryl ring having 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 1-2 substituents independently selected from methyl, cyclopropyl. and -CH2-cyclopropyl.

[0020] In Embodiment 17 of this disclosure are compounds of Formula I, or Embodiments 1- 4, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -C1-2haloalkyl.

[0021] In Embodiment 18 of this disclosure are compounds of Formula I, or Embodiments 1-4 or 17, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -(CH2)2F.

[0022] In Embodiment 19 of this disclosure are compounds of Formula I, or Embodiments 1- 4, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -C1-3alkyl- 8-10 membered fused bicyclic heteroaryl comprising 1 or 2 nitrogen atoms.

[0023] In Embodiment 20 of this disclosure are compounds of Formula I, or Embodiments 1-4 or 19, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -CH2- quinolinyl, -CH2-isoquinolyl, and -CH2-quinoxalinyl.

[0024] In Embodiment 21 of this disclosure are compounds of Formula I, or Embodiments 1- 4, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is hydrogen.

[0025] In Embodiment 22 of this disclosure are the compounds of Formula I, or Embodiments 1-21, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is(1) phenyl unsubstituted or substituted with 1-3 substituents independently selected from R4,(2) -C1-6alkyl-C3-10cycloalkyl unsubstituted or substituted with 1-3 substituents independently selected from R4,(3) -C1-8alkyl unsubstituted or substituted with 1-3 substituents independently selected from R4,(4) monocyclic -C3-6cycloalkyl unsubstituted or substituted with 1-3 substituents independently selected from R4,(5) 5-6 membered heterocyclyl ring having 1, 2 or 3 heteroatoms independently selected fromN, S or O, wherein the heterocycle is unsubstituted or substituted with 1-3 substituents independently selected from R4,(6) -C1-6alkyl-aryl wherein the alkyl and aryl are independently unsubstituted or substituted with 1-3 substituents independently selected from R4,(7) 5-10 membered fused bicyclic cy cloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R4.(8) -C1-6alkyl- 5-10 membered bridged cycloalkyl, unsubstituted or substituted with 1- 3 substituents independently selected from R4,(9) 5-10 membered bridged cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R4,(10) -C1-6alkyl-5-10 membered bridged heterocycle having 1, 2 or 3 heteroatoms independently selected from N, S or O, wherein the bridged heterocycle is unsubstituted or substituted with 1-3 substituents independently selected from R4,(11) C1-6haloalkyl,(12) -C1-6alkyl-O-C1-6haloalkyl.(13) 5-8 membered spiro bicyclic cycloalkyd, unsubstituted or substituted with 1-3 substituents independently selected from R4, or(14) C1-6alkyl- 5-8 membered spiro bicyclic cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R4.

[0026] In Embodiment 23 of this disclosure are the compounds of Formula 1, or Embodiments 1-22, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is(1) phenyl unsubstituted or substituted with 1-3 substituents independently selected from -C1-6haloalkyl,(2) -C1-6alkyl-C3-10cycloalkyl unsubstituted or substituted with 1-3 substituents independently selected from C1-6alkyl, halo, and -C1-6haloalkyl,(3) -C1-8alkyl unsubstituted or substituted with 1-3 substituents independently selected from -C1-3alkyl,(4) monocyclic -C3-6cycloalkyl unsubstituted or substituted with 1-3 substituents independently selected from -C1-6haloalkyl and C1-6cycloalkyl,(5) 5-6 membered heterocyclyl having 1, 2 or 3 heteroatoms independently selected from N, S or O, wherein the heterocycle is unsubstituted or substituted with 1-3 substituents independently selected from -C1-6haloalkyl,(6) -C1-6alkyl-aryl wherein the alkyl and aryl are independently unsubstituted or substituted with 1-3 substituents independently selected from -C1-6haloalkyl, halo, -S-C1-6haloalkyl, -O-C1-6haloalkyl, and -SF5,(7) 5-10 membered fused bicyclic cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from halo,(8) -C1-6alkyl- 5-10 membered bridged cycloalkyl, unsubstituted or substituted with 1- 3 substituents independently selected from halo,(9) 5-10 membered bridged cycloalkyl,(10) -C1-6alkyl- 5-10 membered bridged heterocycle having 1, 2 or 3 ring heteroatoms independently selected from N, S or O, wherein the bridged heterocycle is unsubstituted or substituted with 1-3 substituents independently selected from -C1-3alkyl,(11) -C1-6haloalkyl,(12) -C1-6alkyl-O-C1-6haloalkyl,(13) 5-8 membered spiro bicyclic cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from halo, or(14) -C1-6alkyl- 5-8 membered spiro bicyclic cycloalkyl.

[0027] In Embodiment 24 of this disclosure are the compounds of Formula I, or Embodiments 1-23, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is(1) -phenyl -CF3,(2) -C1-3alkyl-C3-7Cycloalkyl unsubstituted or substituted with 1-3 substituents independently selected from methyl, -F, and -CF3,(3) -C1-5alkyl,(4) cyclohexyl, unsubstituted or substituted with 1-2 substituents independently- selected from methyl, -CF3and cyclopentyl,(5) cyclobutyl, unsubstituted or substituted with 1-2 substituents independently selected from methyl, -CF3and cyclopentyl,(6) cyclopropyl, unsubstituted or substituted with 1-2 substituents independently selected from methyl, -CF3and cyclopentyl,(7) pyrrolidine-CH2CF3,(8) azetidine-CH2CF3,(9) piperidine-CH(CH3)CF3.(10) C1-2alkyl-phenyl, wherein alkyl and phenyl are unsubstituted or substituted with 1- 2 substituents independently selected from -CF3, -F, -SCF3, -OCF3, and -SF5,(11) tetrahydronaphthyl unsubstituted or substituted with 1-2 fluoro substituents,(12) bi cyclohexyl, unsubstituted or substituted with 1-2 fluoro substituents,(13) -CH2-adamantyl, unsubstituted or substituted with a fluoro- substituent,(14) -CH2-bicyclopentyl, unsubstituted or substituted with a fluoro- substituent,(15) bi cyclopentyl,(16) -CH2-oxabicyclohexyl substituted with methyl,(17) -C4-5haloalkyl,(18) -C1-2alkyl-O-C1-2haloalkyl,(19) 5-7 membered spiro bicyclic cycloalkyl, unsubstituted or substituted with 2 fluoro substituents, or(20) -CH2- 5-8 membered spiro bicyclic cycloalkyl.

[0028] In Embodiment 25 of this disclosure are the compounds of Formula I, or Embodiments 1-24, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is phenyl unsubstituted or substituted with 1-3 substituents independently selected from -C1-6haloalkyl

[0029] In Embodiment 26 of this disclosure are the compounds of Formula I, or Embodiments 1-25, or a pharmaceutically acceptable salt of any of the foregoing, w herein R2is phenyl-CF3.

[0030] In Embodiment 27 of this disclosure are the compounds of Formula I, or Embodiments 1-24, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is -C1-6alkyl-C3-locycloalkyl unsubstituted or substituted with 1-3 substituents independently selected from Ci-6alkyl, halo, and -C1-6haloalkyl.

[0031] In Embodiment 28 of this disclosure are the compounds of Formula I, or Embodiments 1-24 or 27, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is -C1-3alkyl-C3-7cycloalkyl unsubstituted or substituted with 1-3 substituents independently selected from methyl. -F, and -CF3.

[0032] In Embodiment 29 of this disclosure are the compounds of Formula I, or Embodiments 1-24, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is -C1-8alkyl unsubstituted or substituted with 1-3 substituents independently selected from -C1-3alkyl.

[0033] In Embodiment 30 of this disclosure are the compounds of Formula I, or Embodiments 1-24 or 29, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is -C1-5alkyl.

[0034] In Embodiment 31 of this disclosure are the compounds of Formula 1, or Embodiments 1-24, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is monocyclic - C3-6cycloalkyl unsubstituted or substituted with 1-3 substituents independently selected from -C1-6haloalkyl and C1-6cycloalkyl.

[0035] In Embodiment 32 of this disclosure are the compounds of Formula I, or Embodiments 1-24 or 31, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is cyclohexyl, cyclobutyl, or cyclopropyl unsubstituted or substituted with 1-2 substituents independently selected from methyl, -CF3and cyclopentyl.

[0036] In Embodiment 33 of this disclosure are the compounds of Formula I, or Embodiments 1-24, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is a 5-6 membered heterocyclyl having 1, 2 or 3 heteroatoms independently selected from N, S or O, wherein the heterocycle is unsubstituted or substituted with 1-3 substituents independently- selected from -C1-6haloalkyl.

[0037] In Embodiment 34 of this disclosure are the compounds of Formula I, or Embodiments 1-24 or 33, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is pyrrolidine-CH2CF3, azetidine-CH2CF3, or piperidine-CH(CH3)CF3.

[0038] In Embodiment 35 of this disclosure are the compounds of Formula I, or Embodiments 1-24. or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is-C1-6al ky l-ary l wherein the alkyl and aryl are independently unsubstituted or substituted with 1-3 substituents independently selected from -C1-6haloalkyl, halo, -S-C1-6haloalkyl, -O-C1-6haloalkyl, and -SF5.

[0039] In Embodiment 36 of this disclosure are the compounds of Formula I, or Embodiments 1-24 or 35, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is C1-2alkyl- phenyl. wherein alkyl and phenyl are unsubstituted or substituted with 1-2 substituents independently selected from -CF3, -F, -SCF3, -OCF3, and -SF5.

[0040] In Embodiment 37 of this disclosure are the compounds of Formula I, or Embodiments 1-24, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is 5-10 membered fused bicyclic cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from halo.

[0041] In Embodiment 38 of this disclosure are the compounds of Formula I, or Embodiments 1-24 or 37, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is tetrahydronaphthyl or bicyclohexyl wherein the tetrahydronaphthyl or bicyclohexyl is unsubstituted or substituted with 2 substituents selected from -F.

[0042] In Embodiment 39 of this disclosure are the compounds of Formula 1, or Embodiments 1-24, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is -C1-6alkyl- 5-10 membered bridged cycloalkyl, unsubstituted or substituted with 1-3 halo substituents.

[0043] In Embodiment 40 of this disclosure are the compounds of Formula I, or Embodiments 1-24 or 39. or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is -CH2- adamantyl, or -CH2-bicyclopentyl, wherein the -CH2-adamantyl or -CH2-bicyclopentyl is unsubstituted or substituted with 1 substituent selected from -F.

[0044] In Embodiment 41 of this disclosure are the compounds of Formula I, or Embodiments 1-24, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is 5-10 membered bridged cycloalkyl.

[0045] In Embodiment 42 of this disclosure are the compounds of Formula I, or Embodiments 1-24 or 41, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is bicyclopentyl.

[0046] In Embodiment43 of this disclosure are the compounds of Formula I. or Embodiments 1-24, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is -C1-6alkyl- 5-10 membered bridged heterocycle ring having 1 , 2 or 3 heteroatoms independently selected from N, S or O, wherein the bridged heterocycle is unsubstituted or substituted with 1-3 substituents independently selected from -C1-3alkyl.

[0047] In Embodiment 44 of this disclosure are the compounds of Formula I, or Embodiments 1-24 or 43, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is -CH2- oxabicyclohexyl substituted with methyl.

[0048] In Embodiment 45 of this disclosure are the compounds of Formula I, or Embodiments 1-24. or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is C1-6haloalkyl.

[0049] In Embodiment 46 of this disclosure are the compounds of Formula I, or Embodiments 1-24 or 45, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is

[0050] In Embodiment 47 of this disclosure are the compounds of Formula I, or Embodiments 1-24, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is -C1-6alkyl-O- C1-6haloalkyl.

[0051] In Embodiment 48 of this disclosure are the compounds of Formula 1, or Embodiments1-24 or 47. or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is

[0052] In Embodiment 49 of this disclosure are the compounds of Formula I, or Embodiments 1-24, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is a 5-8 membered spiro bicyclic cycloalkyl, unsubstituted or substituted with 1-3 halo substituents.

[0053] In Embodiment 50 of this disclosure are the compounds of Formula I, or Embodiments 1-24 or 49, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is a 5-7 membered spiro bicyclic cycloalkyl, unsubstituted or substituted with 2 fluoro substituents.

[0054] In Embodiment 51 of this disclosure are the compounds of Formula I, or Embodiments 1-24, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is C1-6alky I- 5-8 membered spiro bicyclic cycloalkyl.

[0055] In Embodiment 52 of this disclosure are the compounds of Formula I, or Embodiments 1-24 or 51, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is -CH2- 5-8 membered spiro bicyclic cycloalkyl.

[0056] In Embodiment 53 of this disclosure are the compounds of Formula I, or Embodiments 1-52, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, each R3is independently selected from halogen, -C1-6alkyl, -C1-6haloalkyl, -C3-6cycloalkyl, -OC1-6alkyl, -OH, -N(CH3)2, -C1-6alkyl-OH, cyano, -C1-6alkyl-O-C1-3alkyl, and -C1-6alkyl-C3-6cycloalkyl.

[0057] In Embodiment 54 of this disclosure are the compounds of Formula I, or Embodiments 1 or 53, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, each R3is independently selected from -F, -CF3, methyl, cyclopropyl, -OCH3, -OH, -N(CH3)2, - CH2-OH, cyano, -CH2OCH3, and -CH2-cyclopropyl.

[0058] In Embodiment 55 of this disclosure are the compounds of Formula I, or Embodiment 1 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, each R4is independently selected from halogen, -C1-3alkyl, -SF5, -O-C1-6haloalkyl, -S- C1-6haloalkyl, C1-6cycloalkyl and -C1-6haloalkyl.

[0059] In Embodiment 56 of this disclosure are the compounds of Formula I, or Embodiments 1-52 or 55, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present,each R4is independently selected from methyl, -CH2CH3. -CH2CF3, -CF3, -F, -SCF3. -OCF3. cyclopentyl, and -SF5.

[0060] In Embodiment 57 of this disclosure are the compounds of Formula I, or Embodiments 1-56, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is -N-, X is -NH-,Y is -NH-.

[0061] In Embodiment 58 of this disclosure are the compounds of Formula I, or Embodiments 1-56, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is -CH-, X is -NH- , Y is -NH-.

[0062] In Embodiment 59 of this disclosure are the compounds of Formula I, or Embodiments 1-56, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is -CH-, X is -O-,Y is -NH-.

[0063] In Embodiment 60 of this disclosure are the compounds of Formula I, or Embodiments 1-56, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is -CH-. X is -O-,Y is -O-.

[0064] In Embodiment 61 of this disclosure are the compounds of Formula I, or Embodiments 1-56, or a pharmaceutically acceptable salt of any of the foregoing, wherein A is -CH-, X is -NH- , Y is -O-.

[0065] In Embodiment 62, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is: methyl-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((l-(2,2,2-trifluoroethoxy)propan-2-yl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((6,6,6-trifluorohexan-3-yl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((5,5,5-trifluoro-4-methylpentan-2-yl)amino)benzoate. methyl-5-(N-methylsulfamoyl)-2-((5, 5, 5-tri fluoropentan-2 -yl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((4,4,4-trifluoro-3-methylbutyl)amino)benzoate, methyl-2-(cyclohexylamino)-5-(N-methylsulfamoyl)benzoate, methyl-5-(N-methylsulfamoyl)-2-((4,4,4-trifluorobutyl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((3,3,4,4,4-pentafluorobutyl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((l-(2,2,2-trifluoroethyl)azetidin-3-yl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((3-(trifluoromethyl)benzyl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((4,4,5,5,5-pentafluoropentyl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)benzyl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((2-(trifluoromethyl)benzyl)amino)benzoate,methyl-5-(N-methylsulfamoyl)-2-((2-(trifluoromethyl)cyclopropyl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((2-(trifluoromethyl)phenethyl)amino)benzoate, methyl-2-(bicyclo[l.l.l]pentan-l-ylamino)-5-(N-methylsulfamoyl)benzoate, methyl-5-(N-methylsulfamoyl)-2-((2-(2.2.2-trifluoroethoxy)ethyl)amino)benzoate, methyl-2-(((lR,3r and 3s,5S)-bicyclo[3.1.0]hexan-3-yl)amino)-5-(N-methylsulfamoyl)benzoate. methyl-2-(cyclohexylamino)-5-sulfamoylbenzoate, N-methyl-5-(N-methylsulfamoyl)-2-((4,4,5,5,5-pentafluoropentyl)amino)benzamide, 2-(( 1 -cyclohexyl ethyl )amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, 2-((2-cyclohexylethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, N-methyl-2-(((l-methylcyclobutyl)methyl)amino)-5-(N-methylsulfamoyl)benzamide, N-methyl-2-((5-methylhexan-2-yl)amino)-5-(N-methylsulfamoyl)benzamide.2-(((adamantan-2-yl)methyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, (R)-2-((l-cyclobutylethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, 2-((cyclopentylrnethyl)arnino)-N-methyl-5-(N-rnethylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((3,3,3-trifluoro-2-methylpropyl)amino)benzamide, 2-(((2.2-dimethylcyclopropyl)methyl)amino)-N-melhyl-5-( / V-methylsulfamoyl)benzamide. N-methyl-5-(N-methylsulfamoyl)-2-((4,4,4-trifluorobutyl)amino)benzamide, 2-((3,3-dimethylbutyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, 2-((cyclobutylmethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, 2-((2-cyclopentjdethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, 2-((cyclohexylmethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide. 2-((cycloheptylmethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-(phenethylamino)benzamide. 2-((4,4-dimethylpentyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, 2-(((adamantan-l-yl)methyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((((cis or trans)-4 (trifluoromethyl)cyclohexyl)methyl)amino)benzamide, A''-methyl-5-(N-methy lsulfamoyl)-2 -((((trans or cis)-4 (trifluoromethyl)cyclohexyl)methyl)amino)benzamide, 2-((2,2-difluoro-2-phenylethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenethyl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((3-(trifluoromethyl)phenethyl)amino)benzamide, 2-(cyclohexylamino)-N-methyl-5-(N-methylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzamide,(R or S)-N-methyl-5-(N-methylsulfamoyl)-2-((4,4,4-trifluoro-3-methylbutyl)amino)benzamide, (S or R)-N-methyl-5-(N-methylsulfamoyl)-2-((4,4,4-trifluoro-3-methylbutyl)amino)benzamide, N-methyl-2-((2-methylbutyl)amino)-5-(N-methylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-(spiro[2.4]heptan-l-ylamino)benzamide, (R)-2-((l-(4,4-difluorocyclohexyl)ethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, 2-((((lr,3s,5R,7S)-3-fluoroadamantan-l-yl)methyl)amino)-N-methyl-5-(N- methylsulfamoyl)benzamide, 2-(((3,3-difluorocyclobutyl)methyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, 2-((2-fluorophenethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, 2-((3-fluorophenethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, 2-((6-fluoro- 1,2,3, 4-tetrahy dronaphthalen-2-yl)amino)-N-methyl-5-(N- methylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((3,3,3-trifluoro-2,2-dimethylpropyl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-(( 1 -(1 , 1 , 1 -trifluoropropan-2-yl)piperidin-4- yl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((3-(trifluoromethyl)benzyl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((2-(trifluoromethyl)benzyl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((2-(trifluoromethyl)phenethyl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((2-((trifluoromethyl)thio)benzyl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((3-(trifluoromethoxy)benzyl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((5,5,5-trifluoro-4-methylpentan-2-yl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((5,5,5-trifluoropentan-2-yl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((2-(trifluoromethoxy)phenethyl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((spiro[2.5]octan-l-ylmethyl)amino)benzamide, 2-((l-cyclopentylcyclopropyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((3,3,4,4,4-pentafluorobutyl)amino)benzamide, N-methyl-2-(((4-methyl-2-oxabicyclo[2.1.1]hexan-l-yl)methyl)amino)-5-(N- methylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((spiro[2.2]pentan-l-ylmethyl)amino)benzamide, 2-((2-(3,3-difluorocyclobutyl)ethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, 2-((l,l-difluorospiro[2.3]hexan-5-yl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((spiro[3.3]heptan-2-ylmethyl)amino)benzamide, 2-(((lR,3r or 3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)amino)-N-methyl-5-(N- methylsulfamoyl)benzamide,2-(((lR,3s or 3r,5S)-6.6-difluorobicyclo[3.1.0]hexan-3-yl)amino)-N-methyl-5-(N- methylsulfamoyl)benzamide, 2-((bicyclo[l.l.l]pentan-l-ylmethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide N-methyl-5-(N-methylsulfamoyl)-2-(spiro[2.3]hexan-5-ylamino)benzamide, 2-(((lR,3r and 3s,5S)-bicyclo[3.1.0]hexan-3-yl)amino)-N-methyl-5-(N- methylsulfamoyl)benzamide, 2-(((4,4-difluorocyclohexyl)methyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((2-((trifluoromethyl)thio)ethyl)amino)benzamide,(R)-2-((l-cyclohexylethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide,(S)-2-((l-cyclohexylethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, 2-(((3,3-difluoro-l-methylcyclobutyl)methyl)amino)-N-methyl-5-(N methylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((4-(pentafluoro-16-sulfaneyl)benzyl)amino)benzamide, 2-((6,6-difluorospiro[3.3]heptan-2-yl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide. (S)-2-(((3,3-difluorocyclopentyl)methyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, N-(2-hydroxyethyl)-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzamide, N-(2-methoxyethyl)-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzamide, N-(3-methoxypropyl)-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzamide, N-cyclobutyl-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzamide, N-(2-(dimethylamino)ethyl)-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzamide, N-(cyclopropylmethyl)-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzamide, N-cyclopropyl-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzamide, N-ethyl-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzamide. N-(3-hydroxypropyl)-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzamide, Methyl-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzoate, Methyl-5-(N-methylsulfamoyl)-2-(4-(trifluoromethyl)phenoxy)benzoate, N-Methyl-5-(N-methylsulfamoyl)-2-(4-(trifluoromethyl)phenoxy)benzamide, Methyl 5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzoate, 5-(N-Methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzoic acid, N-Methyl-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide, N-(2-methoxyethyl)-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide, N-(3,3-difluorocyclobutyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide,N-(3-methoxycyclobutyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-(3-methoxycyclobutyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-(l-methylcyclobutyl)-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide, N-( 1 -(hydroxymethyl)cyclobutyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-(cyclobutylmethyl)-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide, N-((l-(hydroxymethyl)cyclobutyl)methyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-((l -hydroxy cyclobutyl)methyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-((3,3-difluorocyclobutyl)methyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-(2-fluoroethyl)-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide, 5-(N-methylsulfamoyl)-N-(l-(trifluoromethyl)cyclobutyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-((2,2-dimethylcyclopropyl)methyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-((l-cyanocyclopropyl)methyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-((5-cyclopropyl-lH-pyrazol-3-yl)methyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-((l-(cyclopropylmethyl)-lH-imidazol-5-yl)methyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, 5-(N-methylsulfamoyl)-N-propyl-2-((4-(trifluoromethyl)phenyl)amino)benzamide, N-(3-methoxypropyl)-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide, 5-(N-methylsulfamoyl)-N-(pyridin-4-ylmethyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide, 5-(N-methylsulfamoyl)-N-(2-(pyridin-4-yl)ethyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, 5-(N-methylsulfamoyl)-N-(pyridin-3-ylmethyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide, 5-(N-methylsulfamoyl)-N-(3-(pyridin-4-yl)propyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide,5-(N-methylsulfamoyl)-N-(quinolin-7-ylmethyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, 5-(N-methylsulfamoyl)-N-(quinoxalin-6-ylmethyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-(isoquinolin-7-ylmethyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-(isoquinolin-4-ylmethyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, 5-(N-methylsulfamoyl)-N-(quinolin-5-ylmethyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-(isoquinolin-6-ylmethyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-(isoquinolin-5-ylmethyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-((l,5-dimethyl-lH-pyrazol-3-yl)methyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, 5-(N-methylsulfamoyl)-N-(pyridazin-3-ylmethyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-(( l-(cyclopropylmethyl)-l H-imidazol-4-yl)methyl)-5-( / V-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-((l,4-dimethyl-lH-imidazol-2-yl)methyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-((lS.2R)-2-methoxy-2-methylcyclopropyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-(( l-(methoxymethyl)cyclopropyl)methyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-(2.2-difluorocyclopropyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, or 3-((2-Cyclohexylethyl)amino)-N-methyl-6-(N-methylsulfamoyl)picolinamide.

[0066] In Embodiment 63, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is:

[0067] In one embodiment the present disclosure provides pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0068] 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, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In a further embodiment, the cancer is associated with increased YAP1 and / or TAZ expression.

[0069] 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, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0070] 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, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In a further embodiment, the disease or disorder is a cellular proliferative disorder. In a further embodiment, the cellular proliferative disorder is cancer.

[0071] 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 comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for treating cancer in a patient.

[0072] 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 comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for the preparation of a medicament useful for the prevention of a cell proliferative disorder.

[0073] In the description that follows conventional structural representation is employed and includes conventional stereochemical notation for certain asymmetric carbon centers.

[0074] Thus, structural representation of compounds of Formula I includes conventional stereochemical notation for some asymmetric carbon centers show n 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.

[0075] 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 crystallography) 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 otherwise noted in the data 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 (S)-. 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.

[0076] 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.

[0077] 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 carried out at an intermediate step during the synthesis of a compound of Formula I or it can be done on a final racemic product.

[0078] Where indicated herein, absolute stereochemistry is determined by X-ray crystallography of cry stalline products or cry stalline intermediates which are derivatized, ifnecessary, 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.

[0079] 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.

[0080] 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.

[0081] 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., 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.

[0082] 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.

[0083] 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).

[0084] It is understood that reference to ’‘Formula I” also encompasses compounds of Formula IA, unless indicated otherwise.

[0085] 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 dictates otherwise. 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.

[0086] 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.

[0087] "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 alkyl radicals and alkyl radicals having no substitution.

[0088] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation. Alky l may contain one to fifteen carbon atoms (e.g., C1-15 alkyl), unless otherwise stated. In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C18alkyl). In other embodiments, an alkyl comprises one to six carbon atoms (e.g., C1-6alkyl). In other embodiments, an alky l comprises one to four carbon atoms (e.g, C1-4alky l). 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 alkyl group is selected from methyl, ethyl, 1 -propyl (n-propyl), 1 -methylethyl (iso- propyl). 1 -butyl (n-butyl), 1 -methylpropyl (sec butyl), 2-methylpropyl (iso-butyl), 1,1- dimethylethyl (tert-butyl), 1 -pentyl (n-pentyl). In other embodiments, the alkyl group is methyl. The alkyl is attached to the rest of the molecule by a single bond.

[0089] ‘‘Alkylenyl” 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 orbranched 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.

[0090] "Halogen" or "halo" as used herein refers to fluoro, chloro, bromo and iodo.

[0091] " Haloalkvf refers to an alkyl group as defined above, wherein one or more of the alkyl group’s hydrogen atoms has been replaced with a halogen. In one embodiment, a haloalkyl group has from 1 to 10 carbon atoms. In another embodiment, a haloalkyl group has from 1 to 6 carbon atoms. In another embodiment, a haloalkyl group is substituted with from 1 to 6 F atoms. In a class of this embodiment, the haloalkyl group is substituted with from 1 to 3 F atoms. Nonlimiting examples of haloalkyl groups include -CH2CF3, -CF2CH3, -CH(CH3)CF3, -CH2CHF2, - CH2CH2F, -CH2F, -CHF2, -CF3, -CH2CI, -CCl3, -CH2CH2CH2CF3, -CH2CH2CH2CH2CF3, - CH(CH3)CH2CH2CF3, -CH(CH2CH3)CH2CH2CF3, -CH(CH3)CH2CH(CH3)CF3, - CH2CH2CH(CH3)CF3, -CH2CH2CF2CF3, CH2C(CH3)2CF3, CH2CH2CH2CF2CF3.CH2CH(CH3)CF3, -CH2CH2CF(CH3)2, and -CH2CH2CH2CF2CF3.

[0092] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic hydrocarbon substituent group having 3 to 10 carbon atoms. In subclasses of monocyclic cycloalkyl, cycloalkyl has 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Bicyclic cycloalkyl includes a cycloalkyl having a spiro ring, bridged ring, or a fused ring, including fused to an aryl ring. Non-limiting examples of bicyclic cycloalkyl include adamantyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.1]octanyl, bicyclofl. l. l]pentyl, indanyl, spiro[4.5]decanyl, spiro[2.4]heptyl, spiro[3.3]heptyl, spiro[2.3]hexyl. spiro[2.5]octyl, spiro[2.2]pentyl. tetrahydronaphthyl.

[0093] As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring of 6 to 10 members, wherein the ring system is aromatic. In an embodiment, aryl is phenyl or naphthyl. In a further embodiment, aryl is phenyl.

[0094] 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 independently 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 aryl or heteroaryl ring. Atoms forming the heterocyclic ring(s) are referred to as “members” of the heterocyclic ring or ring system. Bicyclic ring moieties also include spirocyclic and bridged bicyclic rings and may comprise one or more heteroatoms in either of the rings. The heterocyclicring may be atached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of heterocyclic elements include, but are not limited to azetidinyl, dihydroisobenzofuranyl, imidazolidinyl, indolinyl, isoindolinyl, morpholinyl, oxabicyclohexyl, oxetanyl, piperidinyl, pyrrolidinyl. and tetrahydropyranyl.

[0095] The term "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 having 1, 2, or 3 heteroatoms independently selected from N. O, and S. Examples of such heteroaryl groups include, but are not limited to, furyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isothiazolyl, isoquinolyl, oxazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thienyl, triazolyl and the like.

[0096] 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 of Formula I or of their pharmaceutically acceptable salts. '‘Pharmaceutically acceptable salts" 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.

[0097] "Pharmaceutically acceptable acid addition salts" 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, isobuty rates, oxalates, malonates, succinate suberates, sebacates,fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dimtrobenzoates, 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).

[0098] In some embodiments, acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0099] 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'-dibenzylethylenediamine. 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.

[0100] 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.

[0101] 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. Set., 1977:66: 1-19.

[0102] If the compounds of Formula 1 simultaneously contain acidic and basic groups in the molecule. Formula I also includes zwitterions, in addition to the salt forms described above.Pharmaceutical Compositions

[0103] 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.

[0104] 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, distintegrating 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 sulfate, 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, elixirs); 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.

[0105] 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 ormore of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.

[0106] 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.

[0107] 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 of the particular compound being used. For example, disclosed compositions are formulated as a unit dose, and / or are formulated for oral or subcutaneous administration.

[0108] 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.

[0109] 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.

[0110] 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 type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0111] 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.

[0112] 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, benzyl 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.

[0113] 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.

[0114] 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.

[0115] 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 acceptable carrier, and with any preservatives, buffers, or propellants which are required in some embodiments.

[0116] 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.

[0117] 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.

[0118] 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, orpolyethylene 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.

[0119] 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 with the blood of the intended recipient or suspending or thickening agents.

[0120] 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, proper fluidity 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.

[0121] 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.

[0122] 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.

[0123] 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 to100 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.

[0124] 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 a compound of Formula I means providing the compound, or a pharmaceutically acceptable salt thereof, to a subject in need of treatment.

[0125] As used herein, "treatment" and "treating" are used interchangeably herein. These terms refer 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 compounds

[0126] 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 hydrogenisotope 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,18O,17O,31P,32P,35S,18F, and36Cl, 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 are particularly 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.

[0127] 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

[0128] The Hippo signaling network (also known as the Salvador / Warts / Hippo (SWH) pathw ay) is a master regulator of cell proliferation, death, and differentiation. In some embodiments, the main function of the Hippo signaling pathw ay is to regulate negatively the transcriptional co activators Yes-associated protein (YAP) 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, andanti-apoptosis leads to development of cancer. In some instances, overexpression of YAP / TAZ is associated with cancer.

[0129] Additional core members of the Hippo signaling pathway comprise the serine / threonine kinases MST1 / 2 (homologues of Hippo / Hpo in Drosophila). Latsl / 2 (homologues of Warts / Wts), and their adaptor proteins Savl (homologue of Salvador / Sav) and Mob (MOBKL1A and MOBKL1B; homologues of Mats), respectively. In general, MST1 / 2 kinase complexes with the scaffold protein Savl, which in turn ph os ph ory 1 ates and activates Latsl / 2 kinase. Latsl / 2 is also activated by the scaffold protein Mob. The activated Latsl / 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.

[0130] In some instances, Latsl / 2 phosphory lates YAP at the [HXRXXS] consensus motifs. YAP comprises five [HXRXXS] consensus motifs, wherein X denotes any amino acid residue. In some instances, Latsl / 2 phosphorylates YAP at one or more of the consensus motifs. In some instances, Latsl / 2 phosphory lates YAP at all five of the consensus motifs. In some instances, Latsl / 2 phosphorylate at the SI 27 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 SI 27 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.

[0131] 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.

[0132] In some instances, Latsl / 2 phosphorylates TAZ at the [HXRXXS] consensus motifs. TAZ comprises four [HXRXXS] consensus motifs, wherein X denotes any amino acid residue. In some instances, Latsl / 2 phosphorylates TAZ at one or more of the consensus motifs. In some instances, Latsl / 2 phosphorylates TAZ at all four of the consensus motifs. In some instances, Latsl / 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.

[0133] In some embodiments, phosphorylated YAP / TAZ accumulates in the cytoplasm, and undergoes SCFβ-TRCP-mediated ubiquitination and subsequent proteasomal degradation. In some instances, the Skp, Cullin, F-box containing complex (SCF complex) is a multi-protein E3ubiquitin ligase complex that comprises a F-box family member protein (e.g., Cdc4). SkpL 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 I A (FBXWIA. βTrCPl, Fbxwl, hsSlimb, plkappaBalpha-E3 receptor subunit) and S-phase kinase- associated proteins 2 (SKP2). In some embodiments, the SCF complex (e.g., SCPβTrCPl) interacts with an El ubiquitin-activating enzy me and an E2 ubiquitin-conjugating enzyme to catalyze the transfer of ubiquitin to the YAP / TAZ substrate. Exemplary El 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, UBE2QI. UBE2Q2, UBE2RI, UBE2R2, UBE2 UBE2T, UBE2U, UBE2VI, UBE2V2, UBE2ZATG2, BIRC5. and UFCI. In some embodiments, the ubiquitinated YAP / TAZ further undergoes the degradation process through the 26S proteasome.

[0134] In some embodiments, the Hippo pathway is regulated upstream by several different families of regulators. In some instances, the Hippo pathw ay 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

[0135] 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.

[0136] 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.

[0137] Also provided is a method for the synthesis of compounds useful as intermediates in the preparation of compounds of Formula I.

[0138] 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).1H NMR spectra were recorded at 300-500 MHz.SCHEMES AND EXAMPLES

[0139] 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 aqueous°C degree CelsiusDCE 1,2-di chloroethaneDCM dichloromethaneDIPEA N,N-di isopropyl ethyl amineDMA N,N-dimethyl acetamideDMF N,N-di methyl formamideDMSO dimethyl sulfoxideESI electrospray ionizationEtOAc ethyl acetate g gram h hour(s)HATU l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3- oxid hexafluorophosphateHPLC high performance liquid chromatographyM molar mg milligrammin minutes mL milliliter mmol millimoleMS mass spectrometry nM nanomolarNMP N-methyl-2-pyrrolidoneN normalNaOAc sodium acetateNaBH(OAc)3sodium triacetoxyborohydride NEt3triethylamineNMR nuclear magnetic resonance PdCl2(dppf) [1,1 -bis(diphenylphosphine)ferrocene] dichloropalladium(II) Pd2(dba)3tris(dibenzylideneacetone)dipalladium(0) pet. ether petroleum ether PyAOP ((7-Azabenzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate)RT room temperatureSFC supercritical fluid chromatographyTBD triazabicyclodeceneTFA trifluoroacetic acidTHF tetrahydrofuranTLC thin layer chromatography μL microliter μmol micromolXantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxantheneXPhos-Pd-G4 (2-Dicyclohexylphosphino-2',4’,6'-triisopropyl-l,l '-biphenyl)[2-(2’- methylamino-1 , 1'-biphenyl)]palladium(II) methanesulfonateINTERMEDIATESIntermediate A: Methyl 2-fluoro-5-(N-methylsuIfamoyl)benzoate (Int-A)

[0140] To a stirred solution of methyl 5-(chlorosulfonyl)-2-fluorobenzoate (1.52 g. 6.02 mmol) in DCM (50 mL) at 0 °C was added water (30 mL). Carefully, CH3NH2(40 wt% in water, 0.57 mL, 6.6 mmol) was added to the water layer. Finally, K2CO3(2.50 g, 18.1 mmol) was added, and the mixture was vigorously stirred. The resulting mixture was stirred at RT overnight, diluted with DCM. and quenched with saf d NH4CI. The layers were separated, and the organic layer was dried over MgSO4. filtered, and concentrated in vacuo to afford the title compound, which was used without further purification. MS (ESI) m / z calc’d for C9H11FNO4S [M+H]+: 248; found: 248.1H NMR (400 MHz, CDCl3) δ 8.45 (dd, J= 6.65, 2.35 Hz, 1H), 8.03 (ddd, J= 8.71, 4.21, 2.35 Hz, 1H), 7.36 - 7.22 (m, 1H), 3.95 (s, 2H). 2.71 - 2.60 (m, 3H), 1.09 (t, J= 7.24 Hz, 1H).Intermediate B: 3-Bromo-N-methyl-4-((4-(trifluoromethyl)phenyl)amino)benzenesulfonamide (Int-B)Step 1: 4-Amino-3-bromo-N-methylbenzenesulfonamide

[0141] To a stirred solution of 4-amino-3 -bromobenzenesulfonyl fluoride (2.50 g, 9.84 mmol), in ethanol (33 mL) were added CH3NH2(40 wt% in water, 1.70 rnL, 19.7 mmol) and NEts (5.49 mL, 39.4 mmol). The resulting mixture was heated to 80 °C for 3 h, cooled to RT, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel. 0-10% CH3OH / DCM) to afford the title compound. MS (ESI) m / z calc’d for C7H9BrN2NaO2S [M+Na]+: 287; found: 287.Step 2: 3-Bromo-N-methyl-4-((4-(trifluoromethyl)phenyl)amino)benzenesulfonamide (Int-B)

[0142] To a stirred solution of 4-amino-3-bromo-N-methylbenzenesulfonamide (1.00 g, 3.77 mmol) in dioxane were added l-bromo-4-(trifluoromethyl)benzene (1.02 g, 4.53 mmol), Xantphos (349 mg, 0.603 mmol), Pd2(dba)3 (276 mg, 0.302 mmol), and Cs2CO3(2.46 g, 7.54 mmol). The resulting mixture was heated to 100 °C for 2 h, cooled to RT, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc / pet. ether) to afford the title compound.EXAMPLESExample 1-01: Methyl 5-(N-inethylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzoate

[0143] To a stirred solution of methyl 2-fluoro-5-(N-methylsulfamoyl)benzoate (Int-A, 25 mg, 0.10 mmol) in DMF (1 mL) was added DIPEA (52 μL. 0.30 mmol). The resulting solution was added to spiro[3.3]heptan-2-amine hydrochloride (18 mg, 0.12 mmol). The resulting mixture was heated to 80 °C overnight, cooled to RT, filtered, and then purified by preparative HPLC (relse phase, C18, ACN / water with 0. 1% TFA modifier) to afford the title compound. MS (ESI) m / z calc’d for C16H23N2O4S [M+H]’: 339; found: 339.Table Ex-01: The following compounds were prepared using a similar procedure as the above example with the corresponding amine. Note, alternatively, methyl 2-fluoro-5-sulfamoylbenzoate may be used as the aryl fluoride, K2CO3as the base, DMSO as the solvent, and 50 °C as the reaction temperature.Example 2-01: N-Methyl-5-(N-methylsulfamoyl)-2-((4,4,5,5,5- pentafluoropentyl)amino)benzamide (Ex. 2-01)

[0144] To a stirred solution of methyl 2-fluoro-5-(N-methylsulfamoyl)benzoate (Int-A, 32 mg, 0. 13 mmol) in DMF (1.3 mL) was added DIPEA (68 μL, 0.39 mmol). The resulting solution was added to 4,4,5,5,5-pentafluoropentan-l-amine hydrochloride (33 mg, 0.16 mmol). The resulting mixture was heated to 50 °C overnight and then cooled to RT as a solution of the crude ester.

[0145] To the solution of the crude ester was added CH3NH2(40 wt% in water, 1.0 mL, 12 mmol). The resulting mixture was heated to 80 °C overnight, cooled to RT, filtered, and then purified by reverse preparative HPLC (reverse phase. C18, ACN / water with 0.1% TFA modifier) to afford the title compound. MS (ESI) m / z calc’d for C14H19F5N3O3S [M+H]+: 404; found: 404.

[0146] Table Ex-02: The following compounds were prepared using a similar procedure as the above example with the corresponding amine. Note, alternatively, TBD may be used as a base in the presence of an appropriate amine nucleophile, and dioxane may be used as a co-solvent. Also, if containing a mixture of isomers, the final compound may be further separated by chiral SFC such as with an AD-H column.Example 3-01: Methyl 5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzoate (Ex.3-01)Step 1 : 3-Cyano-N-methyl-4-((4-(trifluoromethyl)phenyl)amino)benzenesulfonamide

[0147] A stirred solution of 3-bromo-N-methyl-4-((4-(trifluoromethyl)phenyl)amino)benzenesulfonamide (Int-B, 700 mg, 1.71 mmol), zinc cyanide(110 mg, 0.941 mmol), XPhos-Pd-G4 (147 mg, 0.171 mmol) and zinc (11.2 mg, 0.171 mmol) inDMA (6.8 mL) was heated to 80 °C for 2 h. cooled to RT, and concentrated in vacuo. The residue was re-dissolved in DCM and purified by flash chromatography (silica gel, 25% CH3OH / EtOAc) to afford the title compound (559 mg). A sample of the title compound was further purified by preparative HPLC (reverse phase, C18, ACN / water with 0.1% TFA modifier). MS (ESI) m / z calc’d for C15H13F3N3O2S [M+H] ' : 356; found: 356.1H NMR (600 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.04 (d, J= 2.2 Hz, 1H), 7.85 (dd, J= 8.9, 2.2 Hz, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.52 (d, J= 8.9 Hz, 1H), 7.48 (q, J= 5.0 Hz, 1H), 7.41 (d, J= 8.5 Hz, 2H), 2.45 (d, J= 5.0 Hz, 3H).Step 2: 5-(N-Methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide (Ex. 3-01)

[0148] To a stirred solution of 3-cyano-N-methyl-4-((4- (trifluoromethyl)phenyl)amino)benzenesulfonamide (22 mg, 0.062 mmol) in DMSO (0.12 mL) was added K2CO3(1.3 mg, 9.3 μmol), followed by H2O2(30 wt% in water, 8.9 μL, 0.087 mmol). The resulting mixture was stirred at RT overnight and then purified by preparative HPLC (reverse phase. C18, ACN / water with 0.05% NH4OH) to afford the title compound. MS (ESI) m / z calc’d for C15H15F3N3O3S [M+H]+: 374; found: 374.1H NMR (499 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.39 (s, 1H), 8.09 (d, J= 2.1 Hz, 1H), 7.72 (dd, J= 8.8, 2.1 Hz, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.54 (d, J= 8.8 Hz, 1H), 7.41 (d, J= 8.5 Hz, 2H), 7.25 (q, J= 5.0 Hz, 1H), 2.43 (d, J= 5.0 Hz. 2H).Example 4-01: Methyl 5-(N-methylsulfamoyl)-2-(4-(trifluoromethyl)phenoxy)benzoate (Ex.4-01)Step 1: 3-Bromo-4-fluoro-N-methylbenzenesulfonamide

[0149] To a stirred solution of 3-bromo-4-fluorobenzene-l -sulfonyl chloride (5.00 g. 18.3 mmol) in DCM (50 mL) at 0 °C was added CH3NH2(2 M in THF, 13.7 mL, 27.4 mmol). The resulting mixture was warmed to RT and stirred for 1 h and then quenched with water. The layers were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with w ater and brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound, which was used without further purification. MS (ESI) m / z calc’dfor C7H8BrFNO2S [M+H]+: 268; found: 268.1H NMR (400 MHz. DMSO-d6) δ 8.02 (dd. J = 2.20, 6.36 Hz, 1H), 8.05 - 8.00 (m, 1H), 7.80 (ddd, J= 2.20, 4.59, 8.62 Hz, 1H), 7.64 - 7.55 (m, 2H), 2.40 (d, J= 5.14 Hz, 3H).Step 2: 3-Bromo-N-methyl-4-(4-(trifluoromethyl)phenoxy)benzenesulfonamide

[0150] To a stirred solution of 4-(trifluoromethyl)phenol (2.42 g, 14.9 mmol) in DMSO (5 mL) was added K2CO3(3.09 g, 22.4 mmol) portionwise. The resulting mixture was stirred at RT for 1 min. Then 3-bromo-4-fluoro-N-methylbenzenesulfonamide (2.00 g, 7.46 mmol) was added. The resulting mixture was heated to 60 °C for 14 h, cooled to RT, diluted with EtOAc, and quenched with water. The layers were separated, and the organic layer was washed with brine (3x), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc / pet. ether) to afford the title compound.1H NMR (400 MHz, CDCl3) 8 8.18 (d, J= 1.96 Hz, 1H), 7.79 (dd, J= 8.61, 2.35 Hz, 1H), 7.67 (br d, J= 8.61 Hz. 2H), 7.11 (d. J = 8.22 Hz, 2H), 7.04 (d, J = 8.61 Hz, 1H), 4.50 (br d, J= 5.09 Hz, 1H), 2.73 (d, J = 5.09 Hz, 3H).Step C: Methyl 5-(N-methylsulfamoyl)-2-(4-(trifluoromethyl)phenoxy)benzoate (Ex. 4-01)

[0151] To a stirred solution of 3-bromo-N-methyl-4-(4- (trifluoromethyl)phenoxy)benzenesulfonamide (1.00 g, 2.44 mmol) in CH3OH (30 mL) were added PdCl2(dppl) (535 mg, 0.731 mmol) and NaOAc (400 mg, 4.88 mmol). The reaction vessel was degassed and backfilled with an atmosphere of CO (3x). The resulting mixture was heated to 80 °C under an atmosphere of CO (45 psi) for 16 h, cooled to RT, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc / pet. ether) to afford the title compound. MS (ESI) m / z calc'd for C16H15F3NO5S [M+H]+: 390; found: 390.1H NMR (400 MHz. CDCl3) δ 8.45 (d, J = 2.35 Hz. 1H), 7.97 (dd, J = 8.61, 2.35 Hz. 1H). 7.66 (d, J= 8.61 Hz, 2H), 7.10 (d, J= 8.61 Hz, 3H), 4.44 (q, J= 4.96 Hz, 1H), 3.87 (s, 3H), 2.74 (d, J = 5.09 Hz, 3H).Example 5-01 : N-Methyl-5-(N-methylsulfamoyl)-2-(4-(trifluoromethyl)phenoxy)benzamide(Ex. 5-01)Step 1: 5-(N-Methylsulfamoyl)-2-(4-(trifluoromethyl)phenoxy (benzoic acid

[0152] To a stirred solution of methyl 5-(N-methylsulfamoyl)-2-(4- (trifluoromethyl)phenoxy)benzoate (Ex. 4-01, 870 mg, 2.24 mmol) in THF (10 mL) and water (1 mL) at 0 °C was added LiOH·H2O (281 mg, 6.70 mmol). The resulting mixture was warmed to RT and stirred for 1 h and then quenched with aq. HC1 (I M) until pH = 3. The resulting suspension was extracted with EtOAc. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound.1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.00 (br d, J= 8.61 Hz, 1H), 7.70 (d, J = 8.61 Hz, 2H), 7.17 (br d. J= 8.61 Hz, 2H), 7.06 (d, J = 9.00 Hz, 1H). 2.74 (d, J= 4.70 Hz. 3H). Step B: N-Methyl-5-(N-methylsulfamoyl)-2-(4-(trifluoromethyl)phenoxy (benzamide (Ex. 5-01)

[0153] To a stirred solution of 5-(N-methylsulfamoyl)-2-(4-(trifluoromethyl)phenoxy)benzoic acid (150 mg, 0.400 mmol) in DMF (8 mL) was added methylamine hydrochloride (54.0 mg, 0.799 mmol), HATU (228 mg, 0.599 mmol) and DIPEA (279 μL, 1.60 mmol). The resulting mixture was stirred at RT for 14 h and then diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc / pet. ether) to afford the title compound. MS (ESI) m / z calc'd for C16H16F3N2O4S [M+H]+: 390; found: 390. 'H NMR (400 MHz, CDCl3) δ 8.72 (d, J= 2.35 Hz, 1H), 7.90 (dd, J= 8.80, 2.54 Hz. 1H), 7.75 (d. J= 8.61 Hz, 2H), 7.40 (br s. 1H), 7.23 (d, J= 8.22 Hz, 2H), 6.91 (d, J= 8.61 Hz, 1H), 4.56 (br d, J= 5.09 Hz, 1H), 3.04 (d, J = 4.70 Hz, 3H), 2.71 (d, J = 5.09 Hz, 3 H).Example 6-01: Methyl 5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzoate (Ex. 6-01)

[0154] To a solution of 3-bromo-N-methyl-4-((4- (trifluoromethyl)phenyl)amino)benzenesulfonamide (Int-B, 2.00 g, 4.89 mmol) in CH3OH (20 mL) were added PdCl2(dppf) (1.00 g, 1.37 mmol) and NaOAc (802 mg, 9.77 mmol). The reaction vessel was degassed and backfilled with an atmosphere of CO (3x). The resulting mixture was heated to 80 °C under an atmosphere of CO (45 psi) for 16 h, cooled to RT. filtered,and concentrated in vacuo. The residue was purified by flash chromatography (sihca gel. 0-20% EtOAc / pet. ether) to afford the title compound. MS (ESI) m / z calc’d for C16H16F3N2O4S [M+H]+: 389; found: 389.1H NMR (500 MHz, CDCl3) δ 10.11 (s, 1H), 8.53 (d, J= 2.3 Hz, 1H), 7.78 (dd, J= 2.3. 9.0 Hz, 1H), 7.66 (d. J= 8.4 Hz, 2H), 7.36 (t, J= 9. 1 Hz, 3H), 4.29 (q, J= 5.3 Hz. 1H), 3.96 (s. 3H), 2.69 (d, J= 5.5 Hz. 3H)Example 7-01: 5-(N-Methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzoic acid(Ex. 7-01)

[0155] To a stirred solution of methyl 5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzoate (Ex. 6-01, 2.72 g, 7.00 mmol) in THF (20 mL) were added Li OH (671 mg, 28.0 mmol), water (10 mL), and CH3OH (20 mL). The resulting mixture was stirred at RT for 2 h and then quenched with aq. HC1 (I N) until pH < 3. The resulting suspension was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was suspended in H2O and CH3OH, and the suspension was filtered. The filtrate was concentrated in vacuo to afford the title compound. MS (ESI) m / z calc'd for C15H14F3N2O4S [M+H]+: 375; found: 375.1H NMR (500 MHz, DMSO-d6) δ 10.20 (br s, 1H), 8.32 (d, J= 2.4 Hz, 1H), 7.79 - 7.66 (m. 3H), 7.54 - 7.48 (m, 3H), 7.38 (q, J= 5.0 Hz, 1H). 2.40 (d, J= 5.0 Hz, 3H).Example 8-01: N-Methyl-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide (Ex. 8-01)

[0156] To a stirred solution of methylamine hydrochloride (43.3 mg, 0.641 mmol). HATU (122 mg, 0.321 mmol), DIPEA (0.149 μL, 0.855 mmol) in DMF (3 mL) was added (N- methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzoic acid (Ex. 7-01, 80.0 mg, 0.220 mmol). The resulting mixture was stirred at RT for 18 h and then purified by preparative HPLC (C18, ACN / water with 0.1% TFA modifier) to afford the title compound. MS (ESI) m / z calc’d for C16H17F3N3O3S [M+H]+: 388; found: 388.1H NMR (400 MHz, CDCl3) δ 7.96 (d, J= 1.96 Hz, 1H), 7.74 - 7.74 (m, 1H), 7.74 - 7.68 (m, 1H), 7.64 - 7.63 (m, 1H), 7.60 (d, J= 8.61 Hz, 1H), 7.43 (d, J= 9.00 Hz, 1H), 7.29 (s, 1H), 7.31 - 7.27 (m, 1H), 7.32 (s, 1H), 6.41 (br s, 1H), 3.02 (d, J= 4.70 Hz, 3H), 2.67 (d, J= 5.48 Hz, 3H).

[0157] Table Ex-08; The following compounds were prepared using a similar procedure as the above example with the corresponding amine. Note, alternatively, PyAOP may be used as the coupling agent and NMP may be used as the solvent.Example 9-01: 3-((2-Cyclohexylethyl)amino)-N-methyl-6-(N-methylsulfamoyl)picolinamide(Ex. 9-01)Step 1 : 6-(Benzylthio)-2-chloropyridin-3-amine

[0158] To a stirred solution of sodium ethoxide (1.31 g. 19.3 mmol) and benzyl mercaptan (1.32 g, 10.6 mmol) in DMF (40 mL) was added 6-bromo-2-chloropyridin-3-amine (2.00 g, 9.64 mmol). The resulting mixture was stirred at RT for 1 h and then quenched with brine. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organiclayers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 33% EtOAc / pet. ether) to afford the title compound. MS (ESI) m / z calc’d for C12H12C1N2S [M+H]+: 251; found: 251.Step 2: 5-Amino-6-chloropyridine-2-sulfonyl chloride

[0159] To a stirred solution of 6-(benzylthio)-2-chloropyridin-3-amine (700 mg, 2.79 mmol) in DCM (12 mL) was added water (1.2 mL). The resulting mixture was cooled to -5 °C, and sulfuryl chloride (2.71 mL, 33.5 mmol) was added. The resulting mixture was stirred at -5 °C for 2 h and then quenched with ice water. The layers were separated, and the organic layer was concentrated in vacuo to afford the title compound, which was used without further purification. MS (ESI) m / z calc’d for C5H5C12N2O2S [M+H]+: 227; found: 227.Step 3: 5-Amino-6-chloro-N-methylpyridine-2-sulfonamide

[0160] To a stirred solution of 5-amino-6-chloropyridine-2-sulfonyl chloride (600 mg, 2.64 mmol) in DCM (15 mL) at 0 °C was added methyl amine (30 wt% in EtOH, 1.09 g, 10.6 mmol) in DCM (23 mL). The resulting mixture was warmed to RT, stirred for 1 h. and then quenched with water. The layers were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, 65% EtOAc / pet. ether) to afford the title compound. MS (ESI) m / z calc’d for C6H9C1N3O2S [M+H]+: 222; found: 222. Step 4: Methyl 3-amino-6-(N-methylsulfamoyl)picolinate

[0161] To a stirred solution of 5-amino-6-chloro-N-methylpyridine-2-sulfonamide (200 mg, 0.902 mmol) in CH3OH (10 mL) was added PdCl3(dppl) (33 mg, 0.045 mmol) and NaOAc (148 mg, 1.81 mmol). The reaction vessel was degassed and backfilled with an atmosphere of CO (3x). The resulting mixture was heated to 80 °C under an atmosphere of CO (45 psi) for 18 h, cooled to RT, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 50% EtOAc / pet. ether) to afford the title compound. MS (ESI) m / z calc’d for C8H12N3O4S [M+H]+: 246; found: 246.Step 5: 3-Amino-6-(N-methylsulfamoyl)picolinic acid

[0162] To a stirred solution of methyl 3-amino-6-(N-methylsulfamoyl)picolinate (100 mg, 0.408 mmol) in THF (1 mL), water (1 mL), and CH3OH (1 mL) was added LiOH·H2O (30.0 mg, 0.715 mmol). The resulting mixture was stirred at RT for 1 h and then concentrated in vacuo to afford the title compound, which was used without further purification. MS (ESI) m / z calc’d for C7H10N3O4S [M+H]+: 232; found: 232.Step 6: 3-Amino-N-methyl-6-(N-methylsulfamoyl)picolinamide

[0163] To a stirred solution of 3-amino-6-(N-methylsulfamoyl)picolinic acid (150 mg, 0.649 mmol) from multiple batches, HATU (370 mg, 0.973 mmol), and DIPEA (340 μL, 1.95 mmol) in DMF (3 mL) was added methylamine hydrochloride (53.0 mg, 0.785 mmol). The resulting mixture was stirred at RT for 2 h and then quenched with brine. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound, which was used without further purification. MS (ESI) m / z calc’d for C8H13N4O3S [M+H]+: 245; found: 245.Step 7: 3-((2-Cvclohexylethyl)amino)-N-methyl-6-(N-methylsulfamoyl)picolinamide (Ex. 9-01)

[0164] To a stirred solution of 3-amino-N-methyl-6-(N-methylsulfamoyl)picolinamide (100 mg, 0.409 mmol), 2-cyclohexylacetaldehyde (58.0 mg, 0.460 mmol), and 4Å molecular sieves in DCE (2 mL) at 0 °C was added NaBH(OAc)3 (434 mg, 2.05 mmol). The resulting mixture was warmed to RT. stirred for 2 h, and then filtered (washing with DCM). The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (revere phase, C18, ACN / water with 0.1% TFA modifier) to afford the title compound. MS (ESI) m / z calc'd for C16H27N4O3S [M+H]+: 355; found: 355.1H NMR (400 MHz, CD3OD) δ 7 83 (d, J= 9.00 Hz, 1H), 7.27 (d, J= 8.61 Hz, 1H), 3.27 (t, J= 7.24 Hz, 2 H), 2.91 (s. 3H), 2.52 (s, 3H), 1.83 - 1.64 (m, 5H), 1.59 (q, J= 6.91 Hz, 2H), 1.46 (ddd, J= 10.56, 7.04, 3.52 Hz, 1H), 1.34 - 1.18 (m, 3H), 1.06 - 0.94 (m, 2H).Reverse Phase prep-HPLC Methods:TFA modifier

[0165] 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

[0166] Reverse-phase preparative-HPLC [Waters XBridge OBD C18, 19 mm X 150 mm(5 μm); 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.

[0167] 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 EC50values 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 / rnL 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 / rnL insulin (Sigma, #10516)400 μg / 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

[0168] The following table tabulates the biological data disclosed for the compounds of the Examples. 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;A is -CH- or -N-;X is -NH- or -O-;Y is -NH- or -O-;R1is(1) -C1-6alkyl, unsubstituted or substituted with 1-3 substituents independently- selected from R3.(2) -C1-6alkyl-OH(3) -C1-6alkyl-O-C1-3alkyl(4) -C3-6cycloalkyl. unsubstituted or substituted with 1-3 substituents independently- selected from R3,(5) -C1-6alkyl-C3-6cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R3,(6) -C1-6alkyl-monocylic heteroaryl wherein the heteroaryl is a 5-6 membered heteroaryl ring having 1 , 2 or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or substituted with 1-3 substituents independently selected from R3,(7) -C1-6haloalkyl(8) -C1-6alkyl- 8-10 membered fused bicyclic heteroaryl having 1. 2 or 3 heteroatoms independently selected from N, O and S and wherein the bicyclic heteroaryl is optionally substituted with 1-3 substituents independently selected from R3, or(9) hydrogen;R2is(1) phenyl unsubstituted or substituted with 1-3 substituents independently selected from R4,(2) -C1-6alkyl-C3-10monocyclic cycloalkyl unsubstituted or substituted with 1-3 substituents independently selected from R4,(3) -C1-8alkyl unsubstituted or substituted with 1-3 substituents independently selected from R4,(4) monocyclic -C3-6cycloalkyl unsubstituted or substituted with 1-3 substituents independently selected from R4,(5) 5-6 membered heterocyclyl having 1, 2 or 3 heteroatoms independently selected from N, S or O, wherein the heterocycle is unsubstituted or substituted with 1-3 substituents independently selected from R4,(6) -C1-6alkyl-aryl wherein the alky l and aryl are independently unsubstituted or substituted with 1-3 substituents independently selected from R4,(7) 5-10 membered fused bicyclic cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R4,(8) -C1-6alkyl- 5-10 membered bridged cycloalkyd, unsubstituted or substituted with 1- 3 substituents independently selected from R4,(9) 5-10 membered bridged cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R4,(10) -C1-6alkyl- 5-10 membered bridged heterocycle having 1, 2 or 3 heteroatoms independently selected from N, S or O, wherein the bridged heterocycle is unsubstituted or substituted with 1-3 substituents independently selected from R4,(11) C1-6haloalkyl,(12) -C1-6alkyl-O-C1-6haloalkyl,(13) 5-8 membered spiro bicyclic cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R4, or(14) C1-6alkyl- 5-8 membered spiro bicyclic cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from R4, when present, each R3is independently(1) halogen,(2) -C1-6haloalkyl,(3) -C1-6alkyl,(4) -C3-6cycloalkyl,(5) -OC1-6alkyl,(6) -OH,(7) -N(CH3)2,(8) -C1-6alkyl-OH,(9) cyano,(10) -C1-6alkyl-O-C1-3alkyl, or(11) -C1-6alkyl-C3-6cycloalkyl, when present, each R4is independently(1) halogen,(2) -C1-6haloalkyl,(3) -C1-3alkyl,(4) -SF5,(5) -O-C1-6haloalkyl,(6) -S-C1-6haloalkyl, or(7) C1-6cycloalkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is:(1) -C1-3alkyl,(2) -C1-3alkyl, substituted with -N(CH3)2,(3) -C1-3alkyl-OH,(4) -C1-3alkyl-O-C1-3alkyl,(5) -C3-6cycloalkyl unsubstituted or substituted with 1-3 substituents independently selected from -OCH3, halo. -CH3, -OH, -CH2OH, and haloalkyl.(6) -C1-3alkyl-C3-6Cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from halo, methyl, -OH, -CH2OH, cyano, and -CH2OCH3,(7) -C1-3alkyl-monocyclic heteroaryl, wherein the heteroaryl is a 5 or 6 membered heteroaryl ring having 1 or 2 heteroatoms independently selected from N. O, and S, wherein the heteroaryl is unsubstituted or substituted with 1-2 substituents independently selected from methyl, cyclopropyl, and -CH2-cyclopropyl,(8) -C1-2haloalkyl,(9) -C1-3alkyl- 8-10 membered fused bicyclic heteroaryl, wherein the fused bicyclic heteroaryl ring system having 1 or 2 nitrogen atoms, or(10) hydrogen.

3. The compound of any one of claims 1-2. or a pharmaceutically acceptable salt thereof, wherein R1is:(1) -CH3,(2) -CH2CH3,(3) -CH2CH2CH3,(4) -CH2CH2N(CH3)2,(5) -CH2CH2OH,(6) -CH2CH2CH2OH,(7) -CH2CH2OCH3,(8) -CH2CH2CH2OCH3,(9) 3-4 membered cycloalkyl, unsubstituted or substituted with 1-2 substituents independently selected from -OCH3, -F, -CH3, -OH, -CH2OH, and -CF3,(10) -CH2-cycloalkyl, wherein the cycloalkyl is cyclopropyl, cyclobutyl, or cyclohexyl, wherein the cycloalkyl is unsubstituted or substituted with 1-2 substituents independently selected from -F, methyl, -OH, -CH2OH, cyano, and -CH2OCH3,(11) -C1-3alkyl- monocyclic heteroaryl, wherein the heteroaryl is a 5-6 membered heteroaryl ring having 1 or 2 nitrogen atoms wherein the heteroaryl is unsubstituted or substituted with 1-2 substituents independently selected from methyl, cyclopropyl, and -CH2-cyclopropyl,(12) -CH2CH2F,(13) -CH2-quinoline,(14) -CH2-isoquinoline,(15) -CH2-quinoxaline, or(16) hydrogen.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R2is(1) phenyl unsubstituted or substituted with 1-3 substituents independently selected from -C1-6haloalkyl,(2) -C1-6alkyl-C3-10cycloalkyl unsubstituted or substituted with 1-3 substituents independently selected from C1-6alkyl, halo, and -C1-6haloalkyl,(3) -C1-8alkyl unsubstituted or substituted with 1-3 substituents independently selected from -C1-3alkyl,(4) monocyclic -C3-6cycloalkyl unsubstituted or substituted with 1-3 substituents independently selected from -C1-6haloalkyl and C1-6cycloalkyl,(5) 5-6 membered heterocyclyl having 1, 2 or 3 heteroatoms independently selected from N. S or O. wherein the heterocycle is unsubstituted or substituted with 1-3 substituents independently selected from -C1-6haloalkyl.(6) -C1-6alkyl-aryl wherein the alkyl and aryl are independently unsubstituted or substituted with 1-3 substituents independently selected from -C1-6haloalkyl. halo, -S-C1-6haloalkyl, -O-C1-6haloalkyl, and -SF5,(7) 5-10 membered fused bicyclic cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from halo,(8) -C1-6alkyl- 5-10 membered bridged cycloalkyl, unsubstituted or substituted with 1- 3 substituents independently selected from halo,(9) 5-10 membered bridged cycloalkyl,(10) -C1-6alkyl- 5-10 membered bridged heterocycle having 1, 2 or 3 ring heteroatoms independently selected from N, S or O, wherein the bridged heterocycle is unsubstituted or substituted with 1-3 substituents independently selected from -C1¬3alkyl,(11) -C1-6haloalkyl,(12) -C1-6alkyl-O-C1-6haloalkyl,(13) 5-8 membered spiro bicyclic cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from halo, or(14) -C1-6alkyl- 5-8 membered spiro bicyclic cycloalkyl.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R2is(1) -phenyl-CF3,(2) -C1-3alkyl-C3-7cycloalkyl unsubstituted or substituted with 1-3 substituents independently selected from methyl, -F, and -CF3,(3) -C1-5alkyl,(4) cyclohexyl, substituted with 1-2 substituents independently selected from methyl, -CF3and cyclopentyl,(5) cyclobutyl, substituted with 1-2 substituents independently selected from methyl, - CF3and cyclopentyl,(6) cyclopropyl, substituted with 1-2 substituents independently selected from methyl, -CF3and cyclopentyl,(7) pyrrolidine-CH2CF3,(8) azetidine-CH2CF3,(9) piperidine-CH(CH3)CF3.(10) C1-2alkyl-phenyl, wherein alkyl and phenyl are unsubstituted or substituted with 1- 2 substituents independently selected from -CF3, -F, -SCF3, -OCF3, and -SF5,(11) tetrahydronaphthyl unsubstituted or substituted with 1-2 fluoro substituents,(12) bicyclohexyl, unsubstituted or substituted with 1-2 fluoro substituents,(13) -CH2-adamantyl, unsubstituted or substituted with a fluoro- substituent,(14) -CH2-bicyclopentyl, unsubstituted or substituted with a fluoro- substituent,(15) bi cyclopenty l,(16) -CH2-oxabicyclohexyl substituted with methyl,(17) -C4-5haloalkyl,(18) -C1-2alkyl-O-C1-2haloalkyl,(19) 5-7 membered spiro bicyclic cycloalkyl, unsubstituted or substituted with 2 fluoro substituents, or(20) -CH2- 5-8 membered spiro bicyclic cycloalkyl.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein when present, each R3independently selected from -F, -CF3, methyl, cyclopropyl, -OCH3, -OH, -N(CH3)2, -CH2-OH, cyano, -CH2OCH3. and -CH2-cyclopropyl.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein when present, each R4independently selected from methyl, -CH2CH3, -CH2CF3, -CF3, -F, -SCF3, -OCF3, cyclopentyl, and -SF5.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein A is -N-, X is -NH-, and Y is -NH-.

9. The compound of any one of claims 1-7. or a pharmaceutically acceptable salt thereof, wherein A is -CH-, X is -NH-, and Y is -NH-.

10. The compound of any one of claims 1-7. or a pharmaceutically acceptable salt thereof, wherein A is -CH-, X is -O-, and Y is -NH-.

11. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein A is -CH-, X is -O-, and Y is -O-.

12. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein A is -CH-, X is -NH-, and Y is -O-.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is: methyl-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((l-(2,2,2-trifluoroethoxy)propan-2-yl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((6,6,6-trifluorohexan-3-yl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((5,5,5-trifluoro-4-methylpentan-2-yl)amino)benzoate. methyl-5-(N-methylsulfamoyl)-2-((5, 5, 5-tri fluoropentan-2 -yl)amino)benzoate, melhyl-5-(N-methylsulfamoyl)-2-((4.4.4-tri fl uoro-3-methyl butyl )amino)benzoate. methyl-2-(cyclohexylamino)-5-(N-methylsulfamoyl)benzoate, methyl-5-(N-methylsulfamoyl)-2-((4,4,4-trifluorobutyl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((3,3,4,4,4-pentafluorobutyl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-(( l-(2,2,2-trifluoroethyl)azetidin-3-yl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((3-(trifluoromethyl)benzyl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((4,4,5,5,5-pentafluoropentyl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)benzyl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((2-(trifluoromethyl)benzyl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((2-(trifluoromethyl)cyclopropyl)amino)benzoate, methyl-5-(N-methylsulfamoyl)-2-((2-(trifluoromethyl)phenethyl)amino)benzoate, methyl-2-(bicyclo[ 1.

1. l]pentan- l-ylamino)-5-(N-methylsulfamoyl)benzoate, methyl-5-(N-methylsulfamoyl)-2-((2-(2,2,2-trifluoroethoxy)ethyl)amino)benzoate, methyl-2-(((lR,3r and 3s,5S)-bicyclo[3.1.0]hexan-3-yl)amino)-5-(N methylsulfamoyl)benzoate, methyl-2-(cyclohexylamino)-5-sulfamoylbenzoate, A-methyl-5-(N-methylsulfamoyl)-2-((4,4,5,5,5-pentafluoropentyl)amino)benzamide,2-(( l-cyclohexylethyl)amino)-A-methyl-5-(N-methylsulfamoyl)benzamide,2-((2-cyclohexylethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, N-methyl-2-(((l-methylcyclobutyl)methyl)amino)-5-(N-methylsulfamoyl)benzamide, N-methyl-2-((5-methylhexan-2-yl)amino)-5-(N-methylsulfamoyl)benzamide, 2-(((adamantan-2-yl)methyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, (R)-2-((l-cyclobutylethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, 2-((cyclopentylmethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide,N-methyl-5-(N- methylsulfamoyl)-2-((3,3,3-trifluoro-2-methylpropyl)amino)benzamide, 2-(((2,2-dimethylcyclopropyl)methyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide. N-methyl-5-(N-methylsulfamoyl)-2-((4,4,4-trifluorobutyl)amino)benzamide, 2-((3,3-dimethylbutyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, 2-((cyclobutylmethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, 2-((2-cy cl openty lethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, 2-((cyclohexylmethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, 2-((cycloheptylmethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-(phenethylamino)benzamide, 2-((4,4-dimethylpentyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, 2-(((adamantan-l-yl)methyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((((cis or trans)-4- (trifluoromethyl)cyclohexyl)methyl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((((trans or cis)-4- (trifluoromethyl)cyclohexyl)methyl)amino)benzamide, 2-((2,2-difluoro-2-phenylethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenethyl)amino)benzamide. N-methyl-5-(N-methylsulfamoyl)-2-((3-(trifluoromethyl)phenethyl)amino)benzamide, 2-(cyclohexylamino)-N-methyl-5-(N-methylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzamide,(R or S)-N-methyl-5-(N-methylsulfamoyl)-2-((4,4,4-trifluoro-3-methylbutyl)amino)benzamide, (S or R)-N-methyl-5-(N-methylsulfamoyl)-2-((4,4,4-trifluoro-3-methylbutyl)amino)benzamide, N-methyl-2-((2-methylbutyl)amino)-5-(N-methylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-(spiro[2.4]heptan-l-ylamino)benzamide, (R)-2-((l-(4,4-difluorocyclohexyl)ethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, 2-((((lr,3s,5R,7S)-3-fluoroadamantan-l-yl)methyl)amino)-N-methyl-5-(N- methylsulfamoyl)benzamide, 2-(((3,3-difluorocyclobutyl)methyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide,2-((2-fluorophenethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide,2-((3-fluorophenethyl)amino)-N-rnethyl-5-(N-rnethylsulfarnoyl)benzarnide, 2-((6-fluoro-l,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-methyl-5-(N- methy Is ulfamoy l)benzami de, N-methyl-5-(N-methylsulfamoyl)-2-((3.3.3-trifluoro-2,2-dimethylpropyl)amino)benzamide,N-methyl-5-(N-methy Isulfamoy 1 )-2-(( 1 -(1 , 1 , 1 -trifluoropropan-2-yl)piperidin-4- yl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((3-(trifluoromethyl)benzyl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((2-(trifluoromethyl)benzyl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((2-(trifluoromethyl)phenethyl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((2-((trifluoromethyl)thio)benzyl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((3-(trifluoromethoxy)benzyl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((5,5,5-trifluoro-4-methylpentan-2-yl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((5.5.5-trifluoropentan-2-yl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((2-(trifluoromethoxy)phenethyl)amino)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((spiro[2.5]octan-l-ylmethyl)amino)benzamide, 2-((l-cyclopentylcyclopropyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((3,3,4,4,4-pentafluorobutyl)amino)benzamide, N-methyl-2-(((4-methyl-2-oxabicyclo[2.

1. l]hexan-l-yl)methyl)amino)-5-(N- methylsulfarnoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((spiro[2.2]pentan-l-ylmethyl)amino)benzamide, 2-((2-(3,3-difluorocyclobutyl)ethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide. 2-((l,l-difluorospiro[2.3]hexan-5-yl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((spiro[3.3]heptan-2-ylmethyl)amino)benzamide, 2-(((lR,3r or 3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)amino)-N-methyl-5-(N- methylsulfamoyl)benzamide,2-(((lR,3s or 3r,5S)-6.6-difluorobicyclo[3.1.0]hexan-3-yl)amino)-N-methyl-5-(N- methylsulfamoyl)benzamide,2-((bicyclo[l .1.1 ]pentan-l -ylmethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide N-methyl-5-(N-methylsulfamoyl)-2-(spiro[2.3]hexan-5-ylamino)benzamide,2-(((lR,3r and 3s,5S)-bicyclo[3.1.0]hexan-3-yl)amino)-N-methyl-5-(N- methylsulfamoyl)benzamide,2-(((4,4-difluorocyclohexyl)methyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, N-methyl-5-(N-methylsulfamoyl)-2-((2-((trifluoromethyl)thio)ethyl)amino)benzamide,(R)-2-((l-cyclohexylethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide,(S)-2-((l-cyclohexylethyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide,2-(((3,3-difluoro-l-methylcyclobutyl)methyl)amino)-N-methyl-5-(N- methy Is ulfamoy l)benzami de, N-methyl-5-(N-methylsulfamoyl)-2-((4-(pentafluoro-16-sulfaneyl)benzyl)amino)benzamide,2-((6,6-difluorospiro[3.3]heptan-2-yl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide,(S)-2-(((3,3-difluorocyclopentyl)methyl)amino)-N-methyl-5-(N-methylsulfamoyl)benzamide, N-(2-hydroxyethyl)-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzamide, N-(2-methoxyethyl)-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzamide, N-(3-methoxypropyl)-5-('N-methylsulfamoyl)-2-('spiro|3.3 |heptan-2-ylamino)benzamide. N-cyclobutyl-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzamide, N-(2-(dimethylamino)ethyl)-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzamide, N-(cyclopropylmethyl)-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzamide. N-cyclopropyl-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzamide, N-ethyl-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzamide, N-(3-hydroxypropyl)-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzamide,Methyl-5-(N-methylsulfamoyl)-2-(spiro[3.3]heptan-2-ylamino)benzoate,Methyl-5-(N-methylsulfamoyl)-2-(4-(trifluoromethyl)phenoxy)benzoate.N-Methyl-5-(N-methylsulfamoyl)-2-(4-(trifluoromethyl)phenoxy)benzamide,Methyl 5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzoate, 5-(N-Methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzoic acid, N-Methyl-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide, N-(2-methoxyethyl)-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide,N-(3,3-difluorocyclobutyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide,N-(3 -methoxy cy cl obutyl)-5 -(N-methy lsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide, N-(3-methoxycyclobutyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-(l-methylcyclobutyl)-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide, N-(l-(hydroxymethyl)cyclobutyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-(cyclobuty lmethyl)-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide,N-((l-(hydroxymethyl)cyclobutyl)methyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-((1 -hydroxy cyclobutyl)methyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-((3,3-difluorocyclobutyl)methyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-(2-fluoroethyl)-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide, 5-(N-methylsulfamoyl)-N-(l-(trifluoromethyl)cyclobutyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide, N-((2,2-dimethylcyclopropyl)methyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-((l-cyanocyclopropyl)methyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-((5-cyclopropyl-lH-pyrazol-3-yl)methyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-((l-(cyclopropylmethyl)-1H-imidazol-5-yl)methyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, 5-(N-methylsulfamoyl)-N-propyl-2-((4-(trifluoromethyl)phenyl)amino)benzamide. N-(3-methoxypropyl)-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide, 5-(N-methylsulfamoyl)-N-(pyridin-4-ylmethyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide, 5-(N-methylsulfamoyl)-N-(2-(pyridin-4-yl)ethyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide,5-(N-methylsulfamoyl)-N-(pyridin-3-ylmethyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide, 5-(N-methylsulfamoyl)-N-(3-(pyridin-4-yl)propyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, 5-(N-methylsulfamoyl)-N-(quinolin-7-ylmethyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide,5-(N-methylsulfamoyl)-N-(quinoxalin-6-ylmethyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-(isoquinolin-7-ylmethyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-(isoquinolin-4-ylmethyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide,5-(N-methylsulfamoyl)-N-(quinolin-5-ylmethyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-(isoquinolin-6-ylmethyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-(isoquinolin-5-ylmethyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N- (l,5-dimethyl-1H-pyrazol-3-yl)methyl)-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide, 5-(N-methylsulfamoyl)-N-(pyridazin-3-ylmethyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-((l-(cyclopropylmethyl)-1H-imidazol-4-yl)methyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-((l,4-dimethyl-lH-imidazol-2-yl)methyl)-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide, N-((lS,2R)-2-methoxy-2-methylcyclopropyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, N-((l-(methoxymethyl)cyclopropyl)methyl)-5-(N-methylsulfamoyl)-2-((4-(trifluoromethyl)phenyl)amino)benzamide, N-(2.2-difluorocyclopropyl)-5-(N-methylsulfamoyl)-2-((4- (trifluoromethyl)phenyl)amino)benzamide, or 3-((2-Cyclohexylethyl)amino)-N-methyl-6-(N-methylsulfamoyl)picolinamide.

14. The compound of claims 1, or a pharmaceutically acceptable salt thereof, which is:

15. A method for treating cancer in a patient, comprising administering to the patient a compound of any of one of Claims 1-14, or a pharmaceutically acceptable salt thereof.

16. 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 1-14, or a pharmaceutically acceptable salt thereof.

17. A composition for treating cancer associated with increased YAP1 and / or TAZ expression comprising a compound of any of claims 1-14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically carrier.

18. A composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1-14. or a pharmaceutically acceptable salt thereof.

19. Use of a compound of any of claims 1-14, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a cancer associated with increased YAP1 and / or TAZ expression.