NILSEN AARON (US)
DOGGETT J (US)
ALDAY HOLLAND (US)
US GOV VETERANS AFFAIRS (US)
| US20200157053A1 | 2020-05-21 | |||
| US20200283391A1 | 2020-09-10 | |||
| US8877752B2 | 2014-11-04 | |||
| US20140045888A1 | 2014-02-13 |
| What is claimed: 1. A compound of Formula (I): wherein: each of R1a, R1b, and R1c is independently selected from the group of H, halogen, CN, C1‐C6 alkyl, and C1‐C6 alkoxy; R2 is selected from the group of: n) oxo (=O); o) ‐OH; p) –O‐CH2‐O‐C(=O)‐O‐R6; q) –O‐CH2‐CH2‐O‐C(=O)‐O‐R6; r) –O‐CH2(CH3)‐O‐C(=O)‐O‐R6; s) –O‐C(=O)‐CH2‐CH2‐C(=O)‐O‐R6; t) –O‐CH2‐O‐C(=O)‐R6; u) –O‐(C=O)‐R7; v) –O‐(C=O)‐O‐R7; w) –O‐C(O)‐NR8R9; x) –O‐CH2‐O‐C(O)‐O‐(CH2)n1‐NR8R9; y) –O‐CH2‐O‐C(O)‐O‐(CH2)n1‐NR8‐C(=O)‐O‐R9; and z) –O‐(CH2)‐O‐PO3; the dashed lines (‐‐‐‐‐) in each instance represent an optional single or double bond; Z is selected from the group of N and C; and R3, R4, and R5 are each independently selected from the group of H, halogen, C1‐C4 alkyl, ‐O‐C1‐C4 alkyl, ‐S‐C1‐C4 alkyl, ‐SO2‐C1‐C4 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, ‐S‐C1‐C4 haloalkyl, SF3, ‐SF5, CN, 2‐ pyrrolidinone, NO2, ‐SO2‐NH2, ‐SO2‐NH(C1‐C4 alkyl), ‐SO2‐N(C1‐C4 alkyl)2, ‐C(O)NH2, ‐C(O)NH(C1‐C4 alkyl), , ‐ C(O)N(C1‐C4 alkyl)2, ‐C(O)NH(C3‐C6 cycloalkyl), ‐C(O)NH(‐CH2‐C3‐C6 cycloalkyl), C3‐C6 cycloalkyl, ‐O‐C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl, wherein the cycloalkyl rings of the ‐C(O)NH(C3‐C6 cycloalkyl), ‐C(O)NH(‐ CH2‐C3‐C6 cycloalkyl), C3‐C6 cycloalkyl, ‐O‐C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl groups are further substituted by 0, 1, 2, or 3 substituents selected from the group of H, OH, oxo (=O), halogen, C1‐C4 alkyl, ‐O‐C1‐C4 alkyl, ‐S‐C1‐C4 alkyl, ‐SO2‐C1‐C4 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, ‐S‐C1‐C4 haloalkyl, SF3, ‐ SF5, CN, NO2, ‐SO2‐NH2, ‐SO2‐NH(C1‐C4 alkyl), ‐SO2‐N(C1‐C4 alkyl)2, ‐C(O)NH2, ‐C(O)NH(C1‐C4 alkyl), , and ‐ C(O)N(C1‐C4 alkyl)2; R6 is selected from the group of C1‐C10 alkyl, C2‐C10 alkenyl, C2‐C10 alkynyl, C3‐C6 cycloalkyl, ‐ (CH2)n1‐C3‐C6 cycloalkyl, 3‐6‐membered heterocyclyl, ‐(CH2)n1‐3‐6‐membered heterocyclyl, phenyl, ‐ (CH2)n1‐phenyl, and ‐(CH2)n1‐NR8R9; R7 is selected from the group of C1‐C10 alkyl, C2‐C10 alkenyl, C2‐C10 alkynyl, C3‐C6 cycloalkyl, ‐ (CH2)n3‐(C3‐C6 cycloalkyl), ‐(CH2)n3‐(3‐6 membered heterocyclyl), phenyl, ‐(CH2)n1‐phenyl, –(CH2)n1‐O‐ (CH2)n2‐C1‐C2 alkyl,–(CH2‐CH2‐O)n1‐C1‐C2 alkyl, and ‐(CH2)n1‐NR8R9; R8 and R9 are each independently selected from the group of H and C1‐C6 alkyl; R10 is selected from the group of H, halogen, C1‐C6 alkyl, ‐O‐C1‐C6 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, and ‐S‐C1‐C4 haloalkyl; R11 is selected from the group of H, OH, and O‐; n1 and n2 are each integers independently selected from the group of 1, 2, 3, 4, 5, and 6; and n3 is an integer selected from the group of 0, 1, 2, 3, 4, 5, and 6; with the proviso that the compound is not a compound selected from the group of 3‐[1,1′‐ Biphenyl]‐4‐yl‐2‐methyl‐4(1H)‐quinolinone (CAS Reg. No. 1354745‐30‐4), 3‐[1,1′‐Biphenyl]‐4‐yl‐7‐ methoxy‐2‐methyl‐4(1H)‐quinolinone (CAS Reg. No. 1354745‐39‐3), 3‐[1,1′‐Biphenyl]‐4‐yl‐6‐chloro‐2‐ methyl‐4(1H)‐quinolinone (CAS Reg. No. 1354745‐40‐6), 3‐[1,1′‐Biphenyl]‐4‐yl‐6‐fluoro‐2‐methyl‐4(1H)‐ quinolinone (CAS Reg. No. 1354745‐28‐0), 3‐[1,1′‐Biphenyl]‐4‐yl‐5,7‐difluoro‐2‐methyl‐4(1H)‐ quinolinone (CAS Reg. No. 2251119‐93‐2), 3‐[1,1′‐Biphenyl]‐4‐yl‐6‐fluoro‐7‐methoxy‐2‐methyl‐4(1H)‐ quinolinone (CAS Reg. No. 1354745‐27‐9), 3‐[1,1′‐Biphenyl]‐4‐yl‐6‐chloro‐7‐methoxy‐2‐methyl‐4(1H)‐ quinolinone (CAS Reg. No. 1636139‐73‐5), and 6‐fluoro‐7‐methoxy‐2‐methyl‐3‐(3''‐(trifluoromethyl)‐ [1,1':4',1''‐terphenyl]‐4‐yl)quinolin‐4(1H)‐one (CAS Reg. No. 1374758‐04‐9); or a pharmaceutically acceptable salt, co‐crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. 2. The compound of Claim 1, wherein R2 is selected from the group of: f) oxo (=O); g) ‐OH; h) –O‐CH2‐O‐C(=O)‐O‐R6; i) –O‐CH2‐CH2‐O‐C(=O)‐O‐R6; and j) –O‐CH2(CH3)‐O‐C(=O)‐O‐R6; or a pharmaceutically acceptable salt, co‐crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. 3. The compound of Claim 1, wherein: R2 is selected from the group of oxo (=O) and a moiety of the formula –O‐CH2‐O‐C(=O)‐O‐(C1‐C6 alkyl); and R3, R4, and R5 are each independently selected from the group of H, halogen, C1‐C3 alkyl, ‐O‐C1‐C3 alkyl, C1‐C3 haloalkyl, ‐O‐C1‐C3 haloalkyl, ‐S‐CF3, ‐SF5, CN, 2‐pyrrolidinone, ‐C(O)NH2, ‐C(O)NH(C1‐C3 alkyl), ‐C(O)N(C1‐C3 alkyl)2, ‐C(O)NH(C3‐C6 cycloalkyl), ‐C(O)NH(‐CH2‐C3‐C6 cycloalkyl), C3‐C6 cycloalkyl, ‐O‐C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl, wherein the cycloalkyl rings of the ‐C(O)NH(C3‐C6 cycloalkyl), ‐C(O)NH(‐ CH2‐C3‐C6 cycloalkyl), C3‐C6 cycloalkyl, ‐O‐C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl groups are further substituted by 0, 1, 2, or 3 substituents selected from the group of H, OH, oxo (=O), halogen, C1‐C4 alkyl, ‐O‐C1‐C4 alkyl, ‐S‐C1‐C4 alkyl, ‐SO2‐C1‐C4 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, ‐S‐C1‐C4 haloalkyl, SF3, ‐ SF5, CN, NO2, ‐SO2‐NH2, ‐SO2‐NH(C1‐C4 alkyl), ‐SO2‐N(C1‐C4 alkyl)2, ‐C(O)NH2, ‐C(O)NH(C1‐C4 alkyl), , and ‐ C(O)N(C1‐C4 alkyl)2; and R6, R7, R8, R9, R10, and R11 are as defined for Formula (I), above; and with the proviso that, when R2 is selected from the group of oxo (=O), then at least one of R3, R4, and R5 is not H; or a pharmaceutically acceptable salt, co‐crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. 4. The compound of Claim 4, wherein R2 is selected from the group of oxo (=O) and a moiety of the formula –O‐CH2‐O‐C(=O)‐O‐(C1‐C3 alkyl); or a pharmaceutically acceptable salt, co‐crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. 5. The compound of Claim 1 of Formula (II): wherein: R1 is selected from the group of H, F, and Cl; R2 is selected from the group of oxo (=O) and a moiety of the formula –O‐CH2‐O‐C(=O)‐O‐(C1‐C10 alkyl); R3, R4, and R5 are each independently selected from the group of H, halogen, C1‐C4 alkyl, ‐O‐C1‐C4 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, ‐S‐CF3, ‐SF5, CN, 2‐pyrrolidinone, ‐C(O)NH2, ‐C(O)NH(C1‐C4 alkyl), , ‐C(O)N(C1‐C4 alkyl)2, ‐C(O)NH(C3‐C6 cycloalkyl), ‐C(O)NH(‐CH2‐C3‐C6 cycloalkyl) ), C3‐C6 cycloalkyl, ‐O‐C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl, wherein the cycloalkyl rings of the ‐C(O)NH(C3‐C6 cycloalkyl), ‐C(O)NH(‐ CH2‐C3‐C6 cycloalkyl), C3‐C6 cycloalkyl, ‐O‐C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl groups are further substituted by 0, 1, 2, or 3 substituents selected from the group of H, OH, oxo (=O), halogen, C1‐C4 alkyl, ‐O‐C1‐C4 alkyl, ‐S‐C1‐C4 alkyl, ‐SO2‐C1‐C4 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, ‐S‐C1‐C4 haloalkyl, SF3, ‐ SF5, CN, NO2, ‐SO2‐NH2, ‐SO2‐NH(C1‐C4 alkyl), ‐SO2‐N(C1‐C4 alkyl)2, ‐C(O)NH2, ‐C(O)NH(C1‐C4 alkyl), , and ‐ C(O)N(C1‐C4 alkyl)2; R10 is selected from the group of H, C1‐C6 alkyl, ‐O‐C1‐C6 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, and ‐S‐C1‐C4 haloalkyl; and the dashed lines (‐‐‐‐‐) in each instance represent an optional single or double bond; with the proviso that, when R2 is selected from the group of oxo (=O), then at least one of R3, R4, and R5 is not H; or a pharmaceutically acceptable salt thereof. A further embodiment provides a compound of Formula (II), wherein: R1 is selected from the group of H, F, and Cl; R2 is selected from the group of oxo (=O) and a moiety of the formula –O‐CH2‐O‐C(=O)‐O‐(C1‐C6 alkyl); R3, R4, and R5 are each independently selected from the group of H, halogen, C1‐C3 alkyl, ‐O‐C1‐C3 alkyl, C1‐C3 haloalkyl, ‐O‐C1‐C3 haloalkyl, ‐S‐CF3, ‐SF5, CN, 2‐pyrrolidinone, ‐C(O)NH2, ‐C(O)NH(C1‐C3 alkyl), , ‐C(O)N(C1‐C3 alkyl)2, ‐C(O)NH(C3‐C6 cycloalkyl), ‐C(O)NH(‐CH2‐C3‐C6 cycloalkyl) , C3‐C6 cycloalkyl, ‐O‐C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl, wherein the cycloalkyl rings of the ‐C(O)NH(C3‐C6 cycloalkyl), ‐C(O)NH(‐ CH2‐C3‐C6 cycloalkyl), C3‐C6 cycloalkyl, ‐O‐C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl groups are further substituted by 0, 1, 2, or 3 substituents selected from the group of H, OH, oxo (=O), halogen, C1‐C4 alkyl, ‐O‐C1‐C4 alkyl, ‐S‐C1‐C4 alkyl, ‐SO2‐C1‐C4 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, ‐S‐C1‐C4 haloalkyl, SF3, ‐ SF5, CN, NO2, ‐SO2‐NH2, ‐SO2‐NH(C1‐C4 alkyl), ‐SO2‐N(C1‐C4 alkyl)2, ‐C(O)NH2, ‐C(O)NH(C1‐C4 alkyl), , and ‐ C(O)N(C1‐C4 alkyl)2; and the dashed lines (‐‐‐‐‐) in each instance represent an optional single or double bond; R10 is selected from the group of H, C1‐C6 alkyl, ‐O‐C1‐C6 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, and ‐S‐C1‐C4 haloalkyl; with the proviso that, when R2 is selected from the group of oxo (=O), then at least one of R3, R4, and R5 is not H; or a pharmaceutically acceptable salt, co‐crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. 6. The compound of Claim 5, wherein: R1 is selected from the group of H, F, and Cl; R2 is selected from the group of oxo (=O) and a moiety of the formula –O‐CH2‐O‐C(=O)‐O‐(C1‐C4 alkyl); and R3, R4, and R5 are each independently selected from the group of H, halogen, C1‐C2 alkyl, ‐O‐C1‐C2 alkyl, C1‐C2 haloalkyl, ‐O‐C1‐C2 haloalkyl, ‐S‐CF3, ‐SF5, CN, 2‐pyrrolidinone, ‐C(O)NH2, ‐C(O)NH(C1‐C2 alkyl), , ‐C(O)N(C1‐C2 alkyl)2, ‐C(O)NH(C3‐C6 cycloalkyl), ‐C(O)NH(‐CH2‐C3‐C6 cycloalkyl), C3‐C6 cycloalkyl, ‐O‐C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl, wherein the cycloalkyl rings of the ‐C(O)NH(C3‐C6 cycloalkyl), ‐C(O)NH(‐ CH2‐C3‐C6 cycloalkyl), C3‐C6 cycloalkyl, ‐O‐C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl groups are further substituted by 0, 1, 2, or 3 substituents selected from the group of H, OH, oxo (=O), halogen, C1‐C4 alkyl, ‐O‐C1‐C4 alkyl, ‐S‐C1‐C4 alkyl, ‐SO2‐C1‐C4 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, ‐S‐C1‐C4 haloalkyl, SF3, ‐ SF5, CN, NO2, ‐SO2‐NH2, ‐SO2‐NH(C1‐C4 alkyl), ‐SO2‐N(C1‐C4 alkyl)2, ‐C(O)NH2, ‐C(O)NH(C1‐C4 alkyl), , and ‐ C(O)N(C1‐C4 alkyl)2; R10 is selected from the group of H, C1‐C6 alkyl, ‐O‐C1‐C6 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, and ‐S‐C1‐C4 haloalkyl; and the dashed lines (‐‐‐‐‐) in each instance represent an optional single or double bond; with the proviso that, when R2 is selected from the group of oxo (=O), then at least one of R3, R4, and R5 is not H; or a pharmaceutically acceptable salt, co‐crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. 7. The compound of Claim 5, wherein: R1 is selected from the group of H, F, and Cl; R2 is selected from the group of oxo (=O) and a moiety of the formula –O‐CH2‐O‐C(=O)‐O‐(C1‐C3 alkyl); and R3, R4, and R5 are each independently selected from the group of H, halogen, methyl, methoxy, CH2F, CHF2, CF3, ‐O‐CH2F, ‐O‐CHF2, ‐O‐CF3, ‐S‐CF3, ‐SF5, CN, 2‐pyrrolidinone, ‐C(O)NH2, ‐C(O)NH(C1‐C2 alkyl), , ‐C(O)N(C1‐C2 alkyl)2, ‐C(O)NH(C3‐C6 cycloalkyl), ‐C(O)NH(‐CH2‐C3‐C6 cycloalkyl), C3‐C6 cycloalkyl, ‐O‐ C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl, wherein the cycloalkyl rings of the ‐C(O)NH(C3‐C6 cycloalkyl), ‐ C(O)NH(‐CH2‐C3‐C6 cycloalkyl), C3‐C6 cycloalkyl, ‐O‐C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl groups are further substituted by 0, 1, 2, or 3 substituents selected from the group of H, OH, oxo (=O), halogen, C1‐ C4 alkyl, ‐O‐C1‐C4 alkyl, ‐S‐C1‐C4 alkyl, ‐SO2‐C1‐C4 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, ‐S‐C1‐C4 haloalkyl, SF3, ‐SF5, CN, NO2, ‐SO2‐NH2, ‐SO2‐NH(C1‐C4 alkyl), ‐SO2‐N(C1‐C4 alkyl)2, ‐C(O)NH2, ‐C(O)NH(C1‐C4 alkyl), , and ‐C(O)N(C1‐C4 alkyl)2; R10 is selected from the group of H, halogen, C1‐C6 alkyl, ‐O‐C1‐C6 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, and ‐S‐C1‐C4 haloalkyl; and the dashed lines (‐‐‐‐‐) in each instance represent an optional single or double bond; with the proviso that, when R2 is selected from the group of oxo (=O), then at least one of R3, R4, and R5 is not H; or a pharmaceutically acceptable salt, co‐crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. 8. The compound of Claim 1 of Formula (III): wherein: R1 is selected from the group of H, F, and Cl; R3, R4, and R5 are each independently selected from the group of H, halogen, C1‐C4 alkyl, ‐O‐C1‐C4 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, ‐S‐CF3, ‐SF5, CN, 2‐pyrrolidinone, ‐C(O)NH2, ‐C(O)NH(C1‐C4 alkyl), , ‐C(O)N(C1‐C4 alkyl)2, ‐C(O)NH(C3‐C6 cycloalkyl), ‐C(O)NH(‐CH2‐C3‐C6 cycloalkyl), C3‐C6 cycloalkyl, ‐O‐C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl, wherein the cycloalkyl rings of the ‐C(O)NH(C3‐C6 cycloalkyl), ‐C(O)NH(‐ CH2‐C3‐C6 cycloalkyl), C3‐C6 cycloalkyl, ‐O‐C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl groups are further substituted by 0, 1, 2, or 3 substituents selected from the group of H, OH, oxo (=O), halogen, C1‐C4 alkyl, ‐O‐C1‐C4 alkyl, ‐S‐C1‐C4 alkyl, ‐SO2‐C1‐C4 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, ‐S‐C1‐C4 haloalkyl, SF3, ‐ SF5, CN, NO2, ‐SO2‐NH2, ‐SO2‐NH(C1‐C4 alkyl), ‐SO2‐N(C1‐C4 alkyl)2, ‐C(O)NH2, ‐C(O)NH(C1‐C4 alkyl), , and ‐ C(O)N(C1‐C4 alkyl)2; R10 is selected from the group of H, halogen, C1‐C6 alkyl, ‐O‐C1‐C6 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, and ‐S‐C1‐C4 haloalkyl; and the dashed lines (‐‐‐‐‐) in each instance represent an optional single or double bond; with the proviso that, when R10 is H, at least one of R3, R4, and R5 is not H; or a pharmaceutically acceptable salt, co‐crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. 9. The compound of Claim 8, wherein: R1 is selected from the group of H, F, and Cl; R3, R4, and R5 are each independently selected from the group of H, halogen, C1‐C3 alkyl, ‐O‐C1‐C3 alkyl, C1‐C3 haloalkyl, ‐O‐C1‐C3 haloalkyl, ‐S‐CF3, ‐SF5, CN, 2‐pyrrolidinone, ‐C(O)NH2, ‐C(O)NH(C1‐C3 alkyl), , ‐C(O)N(C1‐C3 alkyl)2, ‐C(O)NH(C3‐C6 cycloalkyl), ‐C(O)NH(‐CH2‐C3‐C6 cycloalkyl) , C3‐C6 cycloalkyl, ‐O‐C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl, wherein the cycloalkyl rings of the ‐C(O)NH(C3‐C6 cycloalkyl), ‐C(O)NH(‐ CH2‐C3‐C6 cycloalkyl), C3‐C6 cycloalkyl, ‐O‐C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl groups are further substituted by 0, 1, 2, or 3 substituents selected from the group of H, OH, oxo (=O), halogen, C1‐C4 alkyl, ‐O‐C1‐C4 alkyl, ‐S‐C1‐C4 alkyl, ‐SO2‐C1‐C4 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, ‐S‐C1‐C4 haloalkyl, SF3, ‐ SF5, CN, NO2, ‐SO2‐NH2, ‐SO2‐NH(C1‐C4 alkyl), ‐SO2‐N(C1‐C4 alkyl)2, ‐C(O)NH2, ‐C(O)NH(C1‐C4 alkyl), , and ‐ C(O)N(C1‐C4 alkyl)2; and R10 is selected from the group of H, halogen, C1‐C6 alkyl, ‐O‐C1‐C6 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, and ‐S‐C1‐C4 haloalkyl; and the dashed lines (‐‐‐‐‐) in each instance represent an optional single or double bond; with the proviso that, when R10 is H, at least one of R3, R4, and R5 is not H; or a pharmaceutically acceptable salt, co‐crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. 10. The compound of Claim 8, wherein: R1 is selected from the group of H, F, and Cl; and R3, R4, and R5 are each independently selected from the group of H, halogen, C1‐C2 alkyl, ‐O‐C1‐C2 alkyl, C1‐C2 haloalkyl, ‐O‐C1‐C2 haloalkyl, ‐S‐CF3, ‐SF5, CN, 2‐pyrrolidinone, ‐C(O)NH2, ‐C(O)NH(C1‐C2 alkyl), , ‐C(O)N(C1‐C2 alkyl)2, ‐C(O)NH(C3‐C6 cycloalkyl), ‐C(O)NH(‐CH2‐C3‐C6 cycloalkyl), C3‐C6 cycloalkyl, ‐O‐C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl, wherein the cycloalkyl rings of the ‐C(O)NH(C3‐C6 cycloalkyl), ‐C(O)NH(‐ CH2‐C3‐C6 cycloalkyl), C3‐C6 cycloalkyl, ‐O‐C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl groups are further substituted by 0, 1, 2, or 3 substituents selected from the group of H, OH, oxo (=O), halogen, C1‐C4 alkyl, ‐O‐C1‐C4 alkyl, ‐S‐C1‐C4 alkyl, ‐SO2‐C1‐C4 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, ‐S‐C1‐C4 haloalkyl, SF3, ‐ SF5, CN, NO2, ‐SO2‐NH2, ‐SO2‐NH(C1‐C4 alkyl), ‐SO2‐N(C1‐C4 alkyl)2, ‐C(O)NH2, ‐C(O)NH(C1‐C4 alkyl), , and ‐ C(O)N(C1‐C4 alkyl)2; R10 is selected from the group of H, halogen, C1‐C6 alkyl, ‐O‐C1‐C6 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, and ‐S‐C1‐C4 haloalkyl; and the dashed lines (‐‐‐‐‐) in each instance represent an optional single or double bond; with the proviso that, when R10 is H, at least one of R3, R4, and R5 is not H; or a pharmaceutically acceptable salt, co‐crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. 11. The compound of Claim 8, wherein: R1 is selected from the group of H, F, and Cl; and R3, R4, and R5 are each independently selected from the group of H, halogen, methyl, methoxy, CH2F, CHF2, CF3, ‐O‐CH2F, ‐O‐CHF2, ‐O‐CF3, ‐S‐CF3, ‐SF5, CN, 2‐pyrrolidinone, ‐C(O)NH2, ‐C(O)NH(C1‐C2 alkyl), , ‐C(O)N(C1‐C2 alkyl)2, ‐C(O)NH(C3‐C6 cycloalkyl), ‐C(O)NH(‐CH2‐C3‐C6 cycloalkyl), C3‐C6 cycloalkyl, ‐O‐ C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl, wherein the cycloalkyl rings of the ‐C(O)NH(C3‐C6 cycloalkyl), ‐ C(O)NH(‐CH2‐C3‐C6 cycloalkyl), C3‐C6 cycloalkyl, ‐O‐C3‐C6 cycloalkyl, and ‐S‐C3‐C6 cycloalkyl groups are further substituted by 0, 1, 2, or 3 substituents selected from the group of H, OH, oxo (=O), halogen, C1‐ C4 alkyl, ‐O‐C1‐C4 alkyl, ‐S‐C1‐C4 alkyl, ‐SO2‐C1‐C4 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, ‐S‐C1‐C4 haloalkyl, SF3, ‐SF5, CN, NO2, ‐SO2‐NH2, ‐SO2‐NH(C1‐C4 alkyl), ‐SO2‐N(C1‐C4 alkyl)2, ‐C(O)NH2, ‐C(O)NH(C1‐C4 alkyl), , and ‐C(O)N(C1‐C4 alkyl)2; R10 is selected from the group of H, halogen, C1‐C6 alkyl, ‐O‐C1‐C6 alkyl, C1‐C4 haloalkyl, ‐O‐C1‐C4 haloalkyl, and ‐S‐C1‐C4 haloalkyl; and the dashed lines (‐‐‐‐‐) in each instance represent an optional single or double bond; with the proviso that, when R10 is H, at least one of R3, R4, and R5 is not H; or a pharmaceutically acceptable salt, co‐crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. 12. The compound of Claim 1, which is selected from the group of: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
; ; ; ; ; ; or a pharmaceutically acceptable salt, co‐crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. 13. A pharmaceutical composition comprising a pharmaceutically or therapeutically effective amount of a compound selected from any of Claims 1‐12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 14. The use in the preparation of a medicament of a compound of any of Claims 1‐12, or a pharmaceutically acceptable salt, co‐crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof. |
Table 2. Structure activity profile of 3‐biaryl‐EL Qs vs. drug sensitive (D6) and drug resistant (Dd2, C2B, and D1) strains of Plasmodium falciparum. IC 50 values represent the concentration of drug tha t suppresses parasite growth by 50% relative to control s without addition of drug.
In vitro Activities of Selected 3‐Biaryl‐ELQs vs. P. falciparum strains. IC 50 values are shown in Tables 1 and 2 together with 95% confidence intervals for a single experiment performed in quadruplicate. (Assays were repeated at least two times.). We also prepared ELQ‐598, the a lkoxy‐carbonate ester prodrug of ELQ‐596, and included it in the assays along with historical controls atovaquone (ATV), ELQ‐300 and E LQ‐ 400. The latter is a drug that, like ATV, targets the Q o site of the Pf cyt bc 1 complex. Notice that the IC 50 values for ELQ‐596 were improved over ELQ‐300 by 8‐ to 10‐fold for the D6 and Dd2 strains as w ell as the ATV r C2B (Table 1) while they were higher for the ELQ‐300 r D1 clone. We interpret these results to sugge st higher inhibitory action by ELQ‐596 vs. the wild t ype Pf cyt bc 1 as well as the mutated cyt bc 1 complex of the clinical isolate Tm90‐C2B. ELQ‐596 Metabolic Stability. We then evaluated ELQ 596 for metabolic stability in the presence of pool ed murine hepatic derived microsomes. Because of its clo se structural similarity to ELQ‐300, we expected th e new analog to be stable under the conditions of the assay. The drug was incubated in the presence of pooled murine liver microsomes (0.5 mg/ml) at 37 ^C in the presence of NADPH to test for P450 drug dependent metabolism. Samples were taken over the int erval of 45 minutes and analyzed by LC‐MS/MS for the presence of test compound. Ketanserin served as an internal standard for the metabolic rate of a known drug with known intermediate stability. As show n in Table 3, tests demonstrated extreme stability of ELQ‐596 to microsomal attack with negligible bre akdown over the course of 45 minutes of incubation yielding an estimated T 1/2 in this in vitro assay of >4,000 minutes. Table 3. Metabolic stability of ELQ‐596 in the pre sence of murine microsomes. T K E In Vivo Efficacy of ELQ‐596 and Alkoxycarbonate Est er Prodrug ELQ‐598 against Murine Malaria. Next, we were interested in testing ELQ‐596 in vivo. Because it is a highly crystalline compound like ELQ‐300 we prepared an alkoxycarbonate ester prodrug, ELQ‐598. And, like ELQ‐331, ELQ‐598 exhibits significantly reduced crystal lattice energy as evidenced by a 229 °C decrease in melting point (Table 3). We tested ELQ‐ 598 in the 4‐day test using a modified Peters pro tocol in which all test animals are first inoculated with 35,000 infected red cells from a donor mouse infecte d with P. yoelii via tail vein injection (Day 0). Animals were then dosed with ELQ‐598 dissolved in PEG400 ( 100 µl) by oral gavage on Days 1, 2, 3 and 4. On Day 5 a drop of blood was taken from the tail and a blood smear was prepared, fixed with methanol, and stained with Giemsa. The operator then examined the stained smear microscopically to determine percent parasitemia. Dosages of 0.0025, 0.005, 0.01, 0.03, 0.1, 0.3, 1.0 and 10 mg/kg/day were used for the experiment. From two separate studies (4 mice pe r group) the average estimates for ED 50 and ED 90 were 0.006 and 0.01 mg/kg/day, respectively, with a non‐recrudescence dose (NRD) of 0.1 mg/kg/day (Table 4). These values are roughly 3‐fold lower than for ELQ‐300 and ELQ‐331. Gratifyingly, the superiority of ELQ‐596 carried over to single dose cures (SDC) for prodrug ELQ‐598. In this model an imals were inoculated exactly as for the 4‐day test on Day 0 however drug was administered only on Day 1 while the operator made smears on Day 5 and again weekly thereafter for animals that remained aparasitemic. Animals that remained aparasitemic out to Day 30 wer e scored as cures. In this latter experiment the lowest fully protective single dose cure was at 0.5 mg/kg (0.6 mg/kg of prodrug) – the lowest dose t ested to date. Thus, prodrug ELQ‐598 is at least 6 time s more effective as a single dose cure against bloo d stage malaria infections in mice compared directly to ELQ 331. Table 4. Comparison of ELQ‐300, prodrug ELQ‐331, and ELQ‐596 and prodrug ELQ‐598. MP = melting point; ED 50 – dose required to suppress parasitemia by 50% relative to untreated controls (4‐day Peters test), ED 90 ‐ dose required to suppress parasitemia by 90% relative to untreated controls (4‐day Peters test, P. yoelii Ke nya Strain), NRD – non‐recrudescence dose (4‐day Peters test), and SDC – single dose cure (lowest single dose that provides complete cures of all 4 mice in the group). NT = not tested. ND = Not d etermined. Note: Prodrugs were dosed based on molar equivalency to the parent drug. Selective Inhibition of Parasite Cytochrome bc 1 complex by ELQ‐596. The ability of ELQ‐596 to inhibit cytochrome bc 1 activity from P. falciparum mitochondria was assessed. As shown in Table 5, ELQ‐596 showed potent inhibitory action of the P. falciparum cytochrome bc 1 complex, with an IC 50 value of 0.1 nM. This value is much lower than IC 50 values previously cited for either atovaquone or ELQ‐300. Notice that the prodrug ELQ‐598 exhibits only feeble inhibitory activity against the parasite enzyme. We a lso evaluated ELQ‐596 for inhibition of the human host cytochrome bc 1 complex isolated from human liver tissue and found no detectable inhibition at a conce ntration of 10,000 nM. Together, our data show that ELQ‐596 is a highly selective inhibitor of plasmodial cytochrome bc 1 complexes with a selectivity index that is ^ ^18,000‐fold based on enzyme inhibitory activity. Su ch a high level of selectivity suggests a low potential for side effects in humans due to inhibiti on of the host enzyme complex. Table 5. Comparative inhibition of P. falciparum (par asite) and human (host) cytochrome bc1 complex. aData taken from Nilsen et al., 2013. b Data taken from Frueh et al., 2017. Assay conditions are presented in the Methods section . Safety and Mitochondrial Toxicity of ELQ‐596 and Pr odrug ELQ‐598. Of course, enhanced potency is desirable only if unaccompanied by enhanced toxicity. Although our in vivo efficacy‐testing model is not intended as a formal toxicity assessment, there were no appearance, behavioral or weight changes observed after dosing with ELQ‐598 at any dose lev el. We also evaluated ELQ‐596 for cytotoxicity usin g the TiterGlo luminescence assay kit, which determines cell viability by measuring cellular ATP. In the as say, ATP is consumed as a co‐substrate of luciferase on reaction with its substrate luciferin with release of light. Using the human HepG2 cell line in culture m edium in which glucose was replaced by galactose to promote reliance upon oxidative phosphorylation processes and to reverse the so‐called “Crabtree effect”, we observed an EC 50 of >10µM for ELQ‐596 while the control drug, rotenone, proved quite cytotoxic under these conditions (EC 50 = ?) (Table 6). The incubation period for th ese experiments was 48 hours. Table 6. Comparative inhibition of P. falciparum (par asite) and human (host) cytochrome bc 1 complex. Cytotoxicity experiments were performed in medium in which glucose was substituted by galactose to reverse the Crabtree effect. Cyt bc 1 assay conditions are presented in the Methods section. NT = Not tested. Based on pharmacokinetics experiments that were performed previously in mice, rats, and dogs, pharmacology experts predict that a single 30 mg ora l dose of formulated ELQ‐331 will protect adults f rom malaria infection if taken weekly. We feel that our “backup plan” could deliver a more potent drug, perhaps prodrug ELQ‐598 or variant thereof, that co uld provide the same degree of long‐term protection but at a significantly lower dose, perhaps 5 to 10 mg on a weekly or biweekly schedule. Materials and Methods Chemical synthesis procedures. Unless otherwise stated all chemicals and reagents we re from Sigma‐Aldrich Chemical Company in St. Louis, MO (USA), Combi‐Blocks, San Diego (CA), or TCI America, Portland (OR) and were used as received . Quinolone 1 and 4,4,5,5‐tetramethyl‐2‐(4‐(4‐(trifluoromethoxy)phen oxy)phenyl)‐1,3,2‐dioxaborolane (14k) were obtained as previously reported 12 . Melting points were obtained in the Optimel t Automated Melting point system from Stanford Research Systems, Sunnyvale, CA (USA). Analytical TLC utilized Merck 60F‐254 250 micron precoated silica gel plates and spots were visualized under 254 nm UV light. GC‐M S was obtained using an Agilent Technologies 7890B gas chromatograph (30 m, DBS column set at either 100°C or 200°C for 2 min, then at 30°C/min to 3 00°C with inlet temperature set at 250°C) with an Agilent Technologies 5977A mass‐selective detector operating at 70 eV. Flash chromatography over silica gel column was performed using an Isolera One flash chromatography system from Biotage, Uppsala, Sweden. 1 H‐NMR spectra were obtained using a Bruker 400 MHz Avance NEO NanoBay NMR spectrometer operating at 400.14 MHz. The NMR raw data were analyzed using the iNMR Spectrum Analyst software. 1 H chemical shifts are reported in parts per million (ppm) relative to internal tetramethylsilane (TMS) standard or residual solvent p eak. Coupling constant values (J) are reported in hertz (Hz). Decoupled 19 F operating at 376 MHz was also obtained for compounds containing fluorine (data not shown). HPLC analyses were performed usin g an Agilent 1260 Infinity instrument with detection at 254 nm and a Phenomenex, Luna® 5 µm C8(2) 100 Å reverse phase LC column 150 x 4.6 mm at 40°C , and eluted with a gradient of A/B at 25%/75% to A/ B at 25% to 90% (A:0.05% formic acid in milliQ wat er, B: 0.05% formic acid in methanol). All compounds wer e >95% pure for in vitro testing and >98% pur e for in vivo testing as determined by GC‐MS, 1 H‐NMR and HPLC. 4,6‐dichloro‐3‐iodo‐7‐methoxy‐2‐methylquinolin e (2). A stirred solution of 4(1H)‐Quinolone 1 (10.0 g, 28.6 mmol, 1 eq) and POCl 3 (14 ml, 146 mmol, 5.1 eq) in DCM (100 ml) was refluxed for 72 h. After cooling to room temperature, the mixture was filtered and th e precipitate washed with DCM (3X5ml) and air dried to give pure 2 (9.8 g, 93 % yield) as a white po wder. GC‐MS shows one peak M + = 366.9 (100%). 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 8.23 (s, 1H), 7.70 (s, H), 7.08 (s, 1H ), 4.07 (s, 3H), 2.42 (s, 3H). 4,4,5,5‐tetramethyl‐2‐(4'‐(trifluoromethoxy)‐[1,1' ‐biphenyl]‐4‐yl)‐1,3,2‐dioxaborolane (4). 6‐chloro‐7‐methoxy‐2‐methyl‐3‐(4'‐(trifluoro methoxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐one (ELQ‐596). Ethyl 2‐(4'‐(trifluoromethoxy)‐[1,1'‐biphenyl]‐4‐yl)ac etate (6). A stirred mixture of ethyl 2‐(4‐ bromophenyl)‐acetate 5 (24.3 g, 100.0 mmol, 1.0 e q), (4‐(trifluoromethoxy)phenyl)boronic acid (24.72 g, 120.0 mmol, 1.2 eq), K 2 CO 3 (27.6 g, 200.0 mmol, 1.2 eq) and (Pd(dppf)Cl 2 ) (3.65 g, 5.0 mmol, 0.05 eq) in DMF (250 ml) was deoxygenated by bubbling argon thro ugh the reaction mixture for 15 minutes. The stirred reaction mixture was then heated at 80 °C under argon for 18 hours, until no more starting ma terial 5 remained as determined by GC‐MS. The reaction wa s cooled to room temperature and filtered through celite, and DMF was removed in vacuo. The resulting black, oily solid was resuspended in DCM (500 ml) and stirred vigorously at room temperature for 30 minutes, filtered through celite, concentrated to dryness and purified by flash chromatography over sil ica gel using a gradient of ethyl acetate / hexane (1/9) as the eluting solvent mixture to give 6 (18. 7 g, 58 % yield) as a white solid. GC‐MS shows one peak M + = 324.1 (42%); 251.2 (100%). 1 H‐NMR (400 MHz; CDCl 3 ): δ 7.63‐7.59 (m, 2H), 7.56‐7.53 (m, 2H ), 7.41‐ 7.38 (m, 2H), 7.32‐7.29 (m, 2H), 4.21 (q, J = 7. 1 Hz, 2H), 3.69 (s, 2H), 1.32‐1.29 (t, J = 7.1 Hz, 3H). Ethyl 3‐acetoxy‐2‐(4‐bromophenyl)but‐2‐enoate (7a). Temperatures given were recorded by an intern al thermometer. A stirred solution of dry THF (50 ml) and HMDS (41.5 g, 257.0 mmol, 2.5 eq) under Ar w as cooled to ‐20 °C in an 75% ethylene glycol, 25% ethanol and dry ice bath. While monitoring the temperature to ensure that it did not exceed ‐10° C, n‐butyl‐lithium (2.5 M) in hexane (n‐BuLi) ( 98.8 mL, 247.0 mol, 2.4 eq) was added. The temperature of th e mixture was then lowered to ‐30 o C and a solution of 5 (25.0 g, 103.0 mol, 1.0 eq) in THF (50 ml) was slowly added. The mixture was allowed to warm u p to ‐10 o C and stirred for 35 min while maintaining thi s temperature. Next, acetic anhydride (31.5 g, 309.0 mmol, 3.0 eq) was added dropwise, then the mixture was allowed to slowly warm up to room temperature. The mixture turned cloudy as it warmed up, but did not jellify. The reaction progress was monitored by GC‐MS, and after 1 h at 25 o C there was still 25% starting material present . An additional acetic anhydride (3.15 g, 30.0 mmol, 0.3 eq) was ad ded. After stirring at room temperature for 72 hours 19% of starting material was still present as determ ined by GC‐MS. The reaction was stopped and the mixture was poured into saturated ammonium chloride solution (100 ml), e xtracted with ethyl acetate (3x100ml), then the organic layers were combined and concentrated to give 35.0 g of a brown oil. GC‐M S analysis showed one major peak (100 %) with M + = 326 (2%), 238 (100%), one minor peak (27 %) with M + = 326 (2%), 238 (100%) and another minor peak (19%, corresponding to 5) with M + = 242 (25%), 168.9 (100 %). The peaks with M + = 326 correspond to the stereoisomers E and Z of the desired product 7a. Two D NOESY NMR did not provide unambiguous assignment o f the two stereoisomers. The percent of the major stereoisomer relative to the minor stereoisomer was estimated to be 80 % by GC‐MS. The product can be used without further purification in the next step. For analysis and characterization purpose the two ste reoisomers were purified by flash chromatography using hexane and ethyl acetate (5 to 15 %gradient). NMR of the major stereoisomer of 7a: 1 H‐NMR (400 MHz; CDCl 3 ): δ 7.51‐7.48 (m, 2H), 7.18‐7.15 (m, 2H ), 4.14 (q, J = 7.1 Hz, 2H), 2.23 (s, 3H), 1.88 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H). NMR of the minor stereoisomer of 7a: 1 H‐NMR (400 MHz; CDCl 3 ): δ 7.47‐7.44 (m, 2H), 7.08‐7.05 (m, 2H ), 4.20 (q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 1.88 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H). Ethyl 3‐acetoxy‐2‐(4'‐(trifluoromethoxy)‐[1,1'‐ biphenyl]‐4‐yl)but‐2‐enoate (7b). Temperatures gi ven were recorded by an internal thermometer. A stirred soluti on of dry THF (50 ml) and HMDS (16.6 g, 102.9 mmo l, 2.3 eq) under Ar was cooled to ‐20 °C in 75% ethylene glycol, 25% ethanol and dry ice bath. While monitoring the temperature to ensure that it did not exceed ‐10°C, n‐butyl‐lithium (2.5 M) in hexa ne (n‐ BuLi) (39.4 mL, 98.5 mmol, 2.2 eq), followed by a solution of 6 (14.5 g, 44.75 mmol, 1.0 eq) in THF (50 ml) were added dropwise. After stirring for 35 minutes a t ‐15 °C to ‐10 °C, acetic anhydride (10.05 g , 11.3 ml, 98.5 mmol, 2.2 eq) was added dropwise while monitori ng the temperature not to exceed ‐10 °C. The solution was then allowed to gradually warm to room temperature, when it turned into a light‐yellow ge l. After stirring 20 h at room temperature, the mixture was poured into saturated ammonium chloride solution (200 ml), extracted with ethyl acetate (3x10 0ml), then the organic layers were combined and concentrated to give 17.3 g of a brown oil. GC‐MS analysis showed one major peak (100 %) with M + = 408 (3%), 320 (100%), one minor peak (5 %) with M + = 408 (3%), 320 (100%), and another minor pe ak (5% corresponding to the starting material 6) with M + = 324 (42%), 251 (100%). The peaks with M + = 408 correspond to the mixture of the stereoisomers E and Z of the desired product 7b. Two D NOESY NMR did not provide unambiguous assignment of the two stereoi somers. The percent of the major stereoisomer relative to the minor stereoisomer was estimated to be 95 % by GC‐MS. The product can be used withou t further purification in the next step. For analysis and characterization purpose the two ste reoisomers were purified by flash chromatography using hexane and ethyl acetate (5 to 50 %gradient). NMR of the major stereoisomer of 7b: 1 H‐NMR (400 MHz; CDCl 3 ): δ 7.66‐7.62 (m, 2H), 7.60‐7.57 (m, 2H ), 7.41‐7.38 (m, 2H), 7.32‐7.30 (m, 2H), 4.20 (q, J = 7.1 Hz, 2H), 2.27 (s, 3H), 1.98 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). NMR of the minor stereoisomer of 7b: 1 H‐NMR (400 MHz; CDCl 3 ): δ 7.66‐7.62 (m, 2H), 7.57‐7.54 (m, 2H ), 7.32‐7.29 (m, 4H), 4.25 (q, J = 7.1 Hz, 2H), 2.4 4 (s, 3H), 1.90 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H ). Ethyl 2‐(4‐bromophenyl)‐3‐oxobutanoate (8a). A s tirred solution of the bis‐acylated 7a (32.6 g, 0. 10 mol, 1 eq) in glacial acetic acid (100 ml) and p‐TsOH monohydrate 98% (1.9 g, 0.1 mol, 0.1 eq) was heate d at 100 °C. After 2 hours no more, starting material 7 a was detected by TLC and GC‐MS. The dark brown solution was cooled to room temperature and concentra ted under vacuum. After most of the acetic acid was eliminated, cyclohexane (2x100ml) was added to th e brown oil and concentrated again to give 30.5 g of 8a as a dark brown oil. Because this material still contained 1.9 g of p‐TsOH, the yield of 8 a was 28.6 g (100 % yield). The product can be used without p urification in the following Conrad‐Limpach reaction. Both the keto and enol forms can be detected by 1 H‐NMR. Ethyl 3‐hydroxy‐2‐(4'‐(trifluoromethoxy)‐[1,1'‐ biphenyl]‐4‐yl)but‐2‐enoate (8b). A stirred solu tion of the bis‐acylated 7b (11.8 g, 0.29 mol, 1 eq) in glaci al acetic acid (25 ml) and p‐TsOH monohydrate 98% (549 mg, 0.29 mol, 0.1 eq) was heated at 100 °C. After 16 hours no more, starting material 7b was detecte d by TLC and GC‐MS. Of note the β‐keto ester 8b dec omposed in injection port of the mass spectrometer t o give a major peak with M + = 294 (32%), 251 (100%). The dark brown solution was cooled to room temperature and concentrated under vacuum. After most of the acetic acid was eliminated, cyclohexane (2x50ml) was added to the brown oil and concentrated again to give 10.0 g of 10b as a dark brown oil . Because this material still contained 549 mg of p‐ TsOH, the yield of 5 was 9.45 g (89 % yield). The product can be used without purification in the following Co nrad‐Limpach reaction. Both the keto and enol forms can be detected by 1 H‐NMR. General procedure for the preparation of Schiff bases (10a‐d and 11). A stock solution of β‐keto es ter 8a or 8b containing 0.1 eq of p‐TsOH (0.25 mM) in b enzene was prepared (0.92 g/10 ml = 2.5 mM) and ke pt. A stirred solution of a substituted aniline (9a‐d) in benzene and an aliquot of the β‐keto ester 8 a or 8b was heated at reflux for 24‐72 h using a Dean‐Stark trap to continuou sly remove water azeotropically and monitored for the disappearance of β‐keto ester 8a or 8b by GC‐MS. The solution was then concentrat ed in vacuo to give the product Schiff bases (10a‐d and 11) as a yellow‐brown, highly viscous oil. General procedure for the Conrad‐Limpach reaction (E LQ). The intermediate Schiff base (10a‐d and 11) was diluted with 5 ml of warm Dowtherm A and added to 65 ml of boiling Dowtherm A (250°C) in portio ns over approximately 5 minutes with vigorous stirring t o maintain the boiling of Dowtherm A. The mixture was kept at boiling for another 5 minutes, then all owed to cool to room temperature and diluted with hexane (250 ml) resulting in the formation of a precipitate which was filtered and washed with ethyl acetate and acetone until a colorless filtrate was o btained. 2‐methyl‐3‐(4'‐(trifluoromethoxy)‐[1,1'‐biphenyl ]‐4‐yl)quinolin‐4(1H)‐one (ELQ‐649). Following the general procedure for the preparation o f the Schiff base, a mixture of aniline 9a (0.47 g , 5.0 mol, 1 eq), benzene (125 ml), β‐keto ester 8b (5 .0 mmol, 1eq) containing p‐TsOH (0.5 mmol, 0.1eq) was heated at reflux for 24 h. Then following the gener al procedure of the Conrad‐Limpach reaction to give ELQ‐649 (0.64 g, 32% yield) after crystallization u sing DMF as a white powder. 1 H‐NMR (400 MHz; DMSO‐ d 6 ): δ 11.68 (s, 1H), 8.10 (dd, J = 8.1, 1. 5 Hz, 1H), 7.87‐7.83 (m, 2H), 7.73‐7.70 (m, 2H), 7.65 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.56‐7.54 (m, 1H), 7.49‐7.46 ( m, 2H), 7.39‐7.36 (m, 2H), 7.30 (ddd, J = 8.1, 6 .9, 1.1 Hz, 1H), 2.29 (s, 3H). The product is >98 % pure by HP LC and 1 H‐NMR. 6‐chloro‐7‐methoxy‐2‐methyl‐3‐(4'‐(trifluoro methoxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐one (ELQ‐596). Following the general procedure for the preparation o f the Schiff base, a mixture of aniline 9b (0.78 g , 5.0 mmol, 1 eq), benzene (125 ml), β‐keto ester 8b ( 5.0 mmol, 1eq) containing p‐TsOH (0.5 mmol, 0.1 eq ) was heated at reflux for 72 h. Then following the gener al procedure of the Conrad‐Limpach reaction to give ELQ‐596 (0.77 g, 34% yield) as a white powder. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.69 (s, 1H), 8.01 (s, 1H), 7.87‐7.83 (m, 2H), 7.72‐7.69 (m, 2H), 7.50‐7.44 (m, 2H), 7.38‐7.35 (m, 2H), 7.09 (s, 1H), 3.97 ( s, 3H), 2.26 (s, 3H). The product is >98 % pure by HPLC and 1 H‐NMR. 6‐fluoro‐7‐methoxy‐2‐methyl‐3‐(4'‐(trifluoro methoxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐one (ELQ‐650). Following the general procedure for the preparation o f the Schiff base, a mixture of aniline 9c (0.71 g , 5.0 mmol, 1 eq), benzene (125 ml), β‐keto ester 8b ( 5.0 mmol, 1eq) containing p‐TsOH (0.5 mmol, 0.1 eq ) was heated at reflux for 46 h. Then following the gener al procedure of the Conrad‐Limpach reaction to give ELQ‐650 (0.61 g, 28% yield) as a white powder. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.66 (s, 1H), 7.86‐7.83 (m, 2H), 7.73‐7.69 (m, 3H), 7.50‐7.44 (m, 2H), 7 .37‐7.35 (m, 2H), 7.11 (d, J = 7.4 Hz, 1H), 3.96 (s, 3H), 2.26 (s, 3H). The product is >98 % pure by HPLC an d 1 H‐NMR. 5,7‐difluoro‐2‐methyl‐3‐(4'‐(trifluoromethoxy) [1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐one (ELQ‐6 01). Following the general procedure for the preparation o f the Schiff base, a mixture of aniline 9d (0.71 g , 5.0 mmol, 1 eq), benzene (125 ml), β‐keto ester 8b ( 5.0 mmol, 1eq) containing p‐TsOH (0.5 mmol, 0.1eq) was heated at reflux for 72 h. Then following the gener al procedure of the Conrad‐Limpach reaction to give ELQ‐601 (0.80 g, 37% yield) as a white powder. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.76 (s, 1H), 7.87‐7.83 (m, 2H), 7.73‐7.69 (m, 2H), 7.48‐7.46 (m, 2H), 7 .36‐7.32 (m, 2H), 7.11‐7.08 (m, 1H), 7.04 (ddd, J = 11.9, 9.6, 2.4 Hz, 1H), 2.22 (s, 3H). The product is >98 % pure by HPLC and 1 H‐NMR. 3‐(4‐bromophenyl)‐6‐chloro‐7‐methoxy‐2‐methy lquinolin‐4(1H)‐one (12) Following the general procedure for the preparation of the Schiff base, a mixture of aniline 9b (13.0 g, 83.0 mmol, 1eq), be nzene (150 ml), β‐keto ester 8a (23.7 g, 83.0 mmol, 1e q) containing p‐TsOH (8.3 mmol, 0.1 eq) was heated at reflux for 21 h. Then following the general procedur e of the Conrad‐Limpach reaction, using Dowtherm A (30 ml) to dilute the Schiff base and added to boi ling Dowtherm A (200 ml). Upon cooling while stirrin g a precipitate was formed. Hexane (800 ml) was added re sulting in the formation of a sticky solid which wa s filtered and stirred for 15 minutes with acetone (15 0 ml), filtered, washed with acetone (3 x 25 ml) a nd air dried to give pure 12 (14.7 g, 49.5% yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.70 (s, 1H), 7.99 (s, 1H), 7.58‐7.56 (m, 2H), 7.24‐7.18 (m, 2H), 7.07 (s, 1H), 3.96 (s, 3H), 2.21 (s, 3H). 3‐(4‐bromophenyl)‐4,6‐dichloro‐7‐methoxy‐2‐m ethylquinoline (13). 4(1H)‐Quinolone 12 (14.7 g, 39.0 mmol) was refluxed with POCl 3, (70 ml) for 45 minutes. After cooling to room temperature, the solution was poured slowly over 10 minutes in vigorously stirred water (800 ml) and stirred for an additional 5 minutes. The formed precipitate was washed with water (50 ml), acetone (2 x 25 ml) and air dried to g ive pure 13 (15.7 g, 100 % yield). GC‐MS shows one p eak M + = 395 (63 %), 397 (100%), 399 (47 %), 401 (10%). 1 H‐NMR (400 MHz; DMSO‐d 6 ): 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 8.18 (s, 1H), 7.76‐7.73 (m, 2H), 7.6 4 (s, 1H), 7.37‐7.34 (m, 2H), 4.05 (s, 3H), 2.38 (s, 3H ). General Procedure for the preparation of the biphenyl quinolines (15a‐k). A stirred mixture of quinoline 13, substituted phenyl boronic acids 14a‐g, 14i and 14j or pinacol esters 14h and 14k, K 2 CO 3 and Pd(dppf)Cl 2, in DMF was deoxygenated by bubbling argon through the s olution for 15 minutes. The stirred reaction mixture was then heated at 80 °C under ar gon until almost no more starting material 13 remain ed as determined by GC‐MS. The reaction was cooled to room temperature and filtered through celite, and DMF was removed in vacuo. The resulting black oily solid was resuspended in DCM and stirred vigorously at room temperature for 30 minutes, filtered through celite, and concentrated to dryness. The residue was taken up with 3‐5 ml of DCM, if all the solid was dissolved then the product was purified by flash chromatography. In some instance the products were not soluble in methylene chloride they were filtered, washed with DCM and the filtrates were further purified by flash chromatography to give additional products. General Procedure for the hydrolysis of the 4‐chloro quinolines. A stirred mixture of the 4‐chloro quinolines, potassium acetate (KOAc) and glacial acetic acid was heated at 120°C in a loosely capped reaction vial for 16‐26 h. 4,6‐dichloro‐3‐(4'‐chloro‐[1,1'‐biphenyl]‐4‐ yl)‐7‐methoxy‐2‐methylquinoline (15a). Following the general procedure for the preparation of biphenyl quinolines, a mixture of 13 (740 mg, 1.86 mmol, 1 eq), 14a (435 mg, 2.79 mmol, 1.5 eq), K 2 CO 3 (513 mg, 3.72 mmol, 2 eq) and Pd(dppf)Cl 2 (68 mg, 0.093 mmol, 0.05 eq) and DMF (75 ml) was heated for 16 h to give crude 25 (911 mg) as a black solid. DCM (5ml) was added and the precipitate was filtered washed with m ethylene chloride (2 x 5 ml) to give pure 15a (158 mg) as a white solid. The filtrate was further puri fied by flash chromatography using a gradient of eth yl acetate/hexane (3/7) as the eluting solvent to yield additional 15a (99 mg) for a combined yield of 15a (257 mg, 32% yield). GC‐MS shows one peak M + = 427 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.27 (s, 1H), 7.74‐7.71 (m, 2H), 7.65‐7.62 (m, 2H), 7.49‐7.46 (m, 3H), 7.39‐7.36 (m, 2H), 4.10 (s, 3H), 2.52 ( s, 3H). 4,6‐dichloro‐7‐methoxy‐2‐methyl‐3‐(4'‐methyl ‐[1,1'‐biphenyl]‐4‐yl)quinoline (15b). Following the general procedure for the preparation of biphenyl quinolines, a mixture 13 (794 mg, 2.0 mmol, 1 eq), 14b (326 mg, 2.4 mmol, 1.2 eq), K 2 CO 3 (552 mg, 4.0 mmol, 2 eq) and Pd(dppf)Cl 2 (73 mg, 0.10 mmol, 0.05 eq) and DMF (75 ml) was heated for 16 h to give crude 15b (898 mg) as a black solid. The product was solubl e in DCM and was purified by flash chromatography using a gradient of ethyl acetat e/hexane (3/7) as the eluting solvent to give pure 15b (328 mg, 40% yield ) as a white solid. GC‐MS shows one peak M + = 407 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.27 (s, 1H), 7.76‐7.73 (m, 2H), 7.62 ‐7.59 (m, 2H), 7.49 (s, 1H), 7.37‐ 7.30 (m, 4H), 4.09 (s, 3H), 2.53 (s, 3H), 2.45 (s, 3H). 3‐(4'‐(tert‐butyl)‐[1,1'‐biphenyl]‐4‐yl)‐4,6 ‐dichloro‐7‐methoxy‐2‐methylquinoline (15c). Following the general procedure for the preparation of biphenyl qui nolines, a mixture 13 (794 mg, 2.0 mmol, 1 eq), 14 c (427 mg, 2.4 mmol, 1.2 eq), K 2 CO 3 (552 mg, 4.0 mmol, 2 eq) and Pd(dppf)Cl 2 (73 mg, 0.10 mmol, 0.05 eq) and DMF (75 ml) was heated for 16 h to give crude 15c (1.032 g) as a black solid. The product was soluble in DCM and was purified by flash chromatography usin g a gradient of ethyl acetate/hexane (3/7) as the eluting solvent to give pure 15c (331 mg, 37 % yie ld) as a white solid. GC‐MS shows one peak M + = 450 (63%), 434 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.28 (s, 1H), 7.77‐7.74 (m, 2H), 7.66 ‐7.64 (m, 2H), 7.55‐ 7.52 (m, 2H), 7.50 (s, 1H), 7.37‐7.33 (m, 2H), 4. 10 (s, 3H), 2.53 (s, 3H), 1.41 (s, 9H). 4,6‐dichloro‐7‐methoxy‐2‐methyl‐3‐(4'‐(trifl uoromethyl)‐[1,1'‐biphenyl]‐4‐yl)quinoline (15d). Following the general procedure for the preparation of biphenyl quinolines, a mixture 13 (794 mg, 2.0 mmol, 1 eq) , 14d (456 mg, 2.4 mmol, 1.2 eq), K 2 CO 3 (552 mg, 4.0 mmol, 2 eq) and Pd(dppf)Cl 2 (73 mg, 0.10 mmol, 0.05 eq) and DMF (75 ml) was heated for 36 h to give crude 15d (1.12 g) as a reddish black solid. DCM ( 5ml) was added and the precipitate was filtered washed wi th methylene chloride (2 x 5 ml) to give pure 15d (320 mg, 35% yield) as a white solid. GC‐MS shows one peak M+ = 461 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.28 (s, 1H), 7.83‐7.80 (m, 2H), 7.78‐7.76 (m, 4H), 7.50 (s, 1H), 7.42‐7.40 (m, 2H), 4.10 (s , 3H), 2.53 (s, 3H). 4'‐(4,6‐dichloro‐7‐methoxy‐2‐methylquinolin‐3 yl)‐[1,1'‐biphenyl]‐4‐carbonitrile (15e). Following the general procedure for the preparation of biphenyl qui nolines, a mixture 13 (794 mg, 2.0 mmol, 1eq), 14e (353 mg, 2.4 mmol, 1.2 eq), K 2 CO 3 (552 mg, 4.0 mmol, 2 eq) and Pd(dppf)Cl 2 (73 mg, 0.10 mmol, 0.05 eq) and DMF (75 ml) was heated for 36 h to give crude 15e (769 mg) as a black solid. DCM (5ml) was ad ded and the precipitate was filtered washed with DCM (2 x 5 ml) to give 15e (384 mg) as a white solid. The product was further recrystallized from DMF to give pure 15e (290 mg) as a white solid. The filtrate was further purified by flash chromatography using a grad ient of ethyl acetate/hexane (3/7) as the eluting solvent to yield an additional 29 (90 mg) for a co mbined yield of 15e (380 mg, 45% yield). GC‐MS shows one peak M + = 418 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.26 (s, 1H), 7.82‐7.79 (m, 4H), 7.77 7.75 (m, 2H), 7.49 (s, 1H), 7.44‐7.41 (m, 2H), 4.09 (s, 3H), 2. 51 (s, 3H). 4,6‐dichloro‐3‐(4'‐(difluoromethyl)‐[1,1'‐biphen yl]‐4‐yl)‐7‐methoxy‐2‐methylquinoline (15f). Following the general procedure for the preparation of biphenyl quinolines, a mixture 13 (397 mg, 1.0 mmol, 1 eq) , 14f (206 mg, 1.2 mmol, 1.2 eq), K 2 CO 3 (276 mg, 2.0 mmol, 2 eq) and Pd(dppf)Cl 2 (73 mg, 0.10 mmol, 0.1 eq) and DMF (3 ml) was heated for 36 h to give c rude 15f as a brown solid. DCM (5ml) was added and t he precipitate was filtered washed with DCM (2 x 5 ml) to give 15f as a white solid. The product was further recrystallized from DMF to give pure 15f (220 mg, 50% yield) as a white solid. GC‐M S shows one peak M + = 443.1 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.26 (s, 1H), 7.79‐7.73 (m, 4H), 7.66 7.61 (m, 2H), 7.48 (s, 1H), 7.40‐7.35 (m, 2H), 6.73 (t, 1H, J = 57 Hz), 4.08 (s, 3H), 2.51 (s, 3H). 4,6‐dichloro‐7‐methoxy‐3‐(4'‐methoxy‐[1,1'‐b iphenyl]‐4‐yl)‐2‐methylquinoline (15g). Following the general procedure for the preparation of biphenyl qui nolines, a mixture 13 (794 mg, 2.0 mmol, 1 eq), 14 g (365 mg, 2.4 mmol, 1.2 eq), K 2 CO 3 (552 mg, 4.0 mmol, 2 eq) and Pd(dppf)Cl 2 (73 mg, 0.10 mmol, 0.05 eq) and DMF (75 ml) was heated for 16 h to give crude 15g (1.29 g) as a black solid. DCM (5ml) was ad ded and the precipitate was filtered washed with DCM (2 x 5 ml) to give pure 15g (255 mg) as a white solid. The filtrate was further purified by flash chromatography using a gradient of DCM/ethyl acetate (95/5) as the eluting solvent to yield an additional 15g (143 mg) for a combined yield of 15g (398 mg, 47% yield). GC‐ MS shows one peak M + = 423 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.27 (s, 1H), 7.73‐7.71 (m, 2H), 7.66 7.64 (m, 2H), 7.49 (s, 1H), 7.35‐7.33 (m, 2H), 7. 05‐7.03 (m, 2H), 4.09 (s, 3H), 3.90 (s, 3H), 2.53 (s, 3H). 4,6‐dichloro‐3‐(4'‐(difluoromethoxy)‐[1,1'‐biphe nyl]‐4‐yl)‐7‐methoxy‐2‐methylquinoline (15h). Following the general procedure for the preparation the bipheny l quinolines, a mixture 13 (794 mg, 2.0 mmol, 1eq), 14h (648 mg, 2.4 mmol, 1.2 eq), K 2 CO 3 (552 mg, 4.0 mmol, 2 eq) and Pd(dppf)Cl 2 (73 mg, 0.10 mmol, 0.05 eq) and DMF (75 ml) was heated for 16 h to give crude 15h (1.073 g) as a black solid. DCM (5ml) was a dded and the precipitate was filtered washed with DCM (2 x 5 ml) and then crystallize from DCM to give pur e 15h (412 mg) as a white solid. The filtrate was further purified by flash chromatography using a gra dient of ethyl acetate/hexane (3/7) as the eluting solvent to yield an additional 15h (140 mg) for a combined yield of 15h (552 mg, 60 % yield). GC‐MS sho ws one peak M + = 459 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.27 (s, 1H), 7.74‐7.68 (m, 4H), 7.49 (s, 1H), 7. 39‐7.36 (m, 2H), 7.28‐7.24 (m, 2H), 6.60 (t, J = 73.8 Hz, 1H), 4.10 (s, 3H), 2.52 (d, J = 2.9 Hz, 3H). 4,6‐dichloro‐7‐methoxy‐2‐methyl‐3‐(3'‐(trifl uoromethyl)‐[1,1'‐biphenyl]‐4‐yl)quinoline (15i). Following the general procedure for the preparation the bipheny l quinolines, a mixture 13 (794 mg, 2.0 mmol, 1eq), 14i (456 mg, 2.4 mmol, 1.2 eq), K 2 CO 3 (552 mg, 4.0 mmol, 2 eq) and Pd(dppf)Cl 2 (73 mg, 0.10 mmol, 0.05 eq) and DMF (75 ml) was heated at 120 0 C for 36 h to give crude 15i (932 mg) as a black solid. The product was soluble in DCM and was purified by flash chroma tography using a gradient of ethyl acetate/hexane (6/4) as the eluting solvent to give about 95% pure 15i (100 mg, 11 % yield) as a white solid. GC MS shows one major peak M + = 461 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.28 (s, 1H), 7.96‐7.88 (m, 2H), 7.79 ‐7.76 (m, 2H), 7.69‐7.63 (m, 2H), 7.50 (s, 1H), 7.43‐7 .40 (m, 2H), 4.10 (s, 3H), 2.53 (s, 3H). 4,6‐dichloro‐7‐methoxy‐2‐methyl‐3‐(3'‐(trifl uoromethoxy)‐[1,1'‐biphenyl]‐4‐yl)quinoline (15j). Following the general procedure for the preparation the bipheny l quinolines, a mixture 13 (794 mg, 2.0 mmol, 1eq), 14j (494 mg, 2.4 mmol, 1.2 eq), K 2 CO 3 (552 mg, 4.0 mmol, 2 eq) and Pd(dppf)Cl 2 (73 mg, 0.10 mmol, 0.05 eq) and DMF (75 ml) was heated for 16 h to give crude 15j (1.249 g) as a black solid. The product was soluble in DCM and was purified by flash chromatogra phy using a gradient of ethyl acetate/hexane (3/7) as the eluting solvent to give 15j (639 mg, 67 % yield) as a white solid. GC MS shows one peak M + = 477 (100%) and one minor peak M + = 397 (100%) corresponding to the starting ma terial 13. GC‐MS and NMR indicated that 15j is pure (~95%) enough to use for the next st ep. 4,6‐dichloro‐7‐methoxy‐2‐methyl‐3‐(4'‐(4‐( trifluoromethoxy)phenoxy)‐[1,1'‐biphenyl]‐4‐yl)quino line (15k). Following the general procedure for the prepar ation the biphenyl quinolines, a mixture 13 (794 mg, 2.0 mmol, 1eq), 14k (1.18 g, 3 mmol, 1.5 eq), K 2 CO 3 (552 mg, 4.0 mmol, 2 eq) and Pd(dppf)Cl 2 (73 mg, 0.10 mmol, 0.05 eq) and DMF (75 ml) was heated for 48 h to give crude 15k (1.42 g) as a black solid. DCM (5ml) was added and the precipitate was filtered washed wi th DCM (2 x 5 ml) to give pure 15k (110 mg) as a white solid. The filtrate was further purified by flash chromatography using a gradient of ethyl acetate/hexane (3/7) as the eluting solvent to yield an additional 15k (489 mg) for a combined yield of 15k (599 mg, 53 % yield). GC‐MS shows one peak M + = 569 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.28 (s, 1H), 7.75‐7.72 (m, 2H), 7.71‐7.69 (m, 2H), 7.50 (s, 1H), 7.39‐7.35 (m, 2H), 7.26‐7.23 (m, 2H), 7 .17‐7.13 (m, 2H), 7.12‐7.08 (m, 2H), 4.10 (s, 3H), 2.53 (s, 3H ). 6‐chloro‐3‐(4'‐chloro‐[1,1'‐biphenyl]‐4‐yl) 7‐methoxy‐2‐methylquinolin‐4(1H)‐one (ELQ‐637 ). Following the general procedure for the hydrolysis of the 4‐chloro quinolines, a mixture of 15a (157 m g, 0.3 mmol, 1 eq), KOAc (360 mg, 3.7 mmol, 10 eq) a nd glacial acetic acid (10 ml) was heated for 26 h . After cooling to room temperature, the reaction mixture was further cooled to 4 o C. The resulting solid was recovered by vacuum filtration, rinsing with excess w ater followed by acetone (3 x 5 ml) and airdried t o give ELQ‐637 as a pale taupe powder (0.104 g, yie ld 69%). 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.70 (s, 1H), 8.01 (s, 1H), 7.78‐7.73 (m, 2H), 7.72‐7.66 (m, 2 H), 7.57‐7.51 (m, 2H), 7.38‐7.32 (m, 2H), 7.08 ( s, 1H), 3.97 (s, 3H), 2.26 (s, 3H). 6‐chloro‐7‐methoxy‐2‐methyl‐3‐(4'‐methyl‐[ 1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐one (ELQ‐603 ). Following the general procedure for the hydrolysis of the 4‐chloro quinolines, a mixture of 15b (204 m g, 0.5 mmol, 1 eq), KOAc (490 mg, 5.0 mmol, 10 eq) a nd glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was poured into ice water (20 ml). The resulting precipitate was filtered washed with water (3x10 ml), acetone (2x10 ml), DCM (2x10 ml), hexane (10 ml) and airdried to give pure ELQ‐603 (170 mg, 87 % yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.69‐11.67 (s, 1H), 8.02 (s, 1H), 7.66‐7.60 (m, 4H), 7.32‐7.28 (m, 4H), 7.08 (s, 1H), 3.97 (s, 3 H), 2.36‐2.33 (s, 3H), 2.25 (s, 3H). 3‐(4'‐(tert‐butyl)‐[1,1'‐biphenyl]‐4‐yl)‐6 chloro‐7‐methoxy‐2‐methylquinolin‐4(1H)‐one (E LQ‐651). Following the general procedure for the hydrolysis of the 4‐chloro quinolines, a mixture of 15c (225 m g, 0.5 mmol, 1 eq), KOAc (490 mg, 5.0 mmol, 10 eq) a nd glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was poured into ice water (20 ml). The resulting precipitate was filtered washed with water (3x10 ml), acetone (2x10 ml), DCM (2x10 ml), hexane (10 ml) and airdried to give pure ELQ‐651 (184 mg, 85 % yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.68 (s, 1H), 8.02 (s, 1H), 7.67‐7.64 (m, 4H), 7 .51 (m, 2H), 7.34‐7.32 (m, 2H), 7.09 (s, 1H), 3.9 8 (s, 3H), 2.27 (s, 3H), 1.34 (s, 9H). 6‐chloro‐7‐methoxy‐2‐methyl‐3‐(4'‐(trifluoro methyl)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐one (ELQ‐647). H Following the general procedure for the hydrolysis of the 4‐chloro quinolines, a mixture of 15d (231 m g, 0.5 mmol, 1 eq), KOAc (490 mg, 5.0 mmol, 10 eq) a nd glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was poured into ice water (20 ml). The resulting precipitate was filtered washed with water (3x10 ml), acetone (2x10 ml), DCM (2x10 ml), hexane (10 ml) and airdried to give pure ELQ‐647 (180 mg, 81 % yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.71 (s, J = 0.2 Hz, 1H), 8.02 (s, J = 1.7 Hz, 1H), 7.98‐7.95 (m, 2H), 7.85‐7.83 (m, 2H), 7.79 7.77 (m, 2H), 7.41‐7.39 (m, 2H), 7.10 (s, 1H), 3.98 (s, 3H), 2. 27 (s, 3H). 4'‐(6‐chloro‐7‐methoxy‐2‐methyl‐4‐oxo‐1,4 dihydroquinolin‐3‐yl)‐[1,1'‐biphenyl]‐4‐carbon itrile (ELQ‐ 602). Following the general procedure for the hydrolysis of the 4‐chloro quinolines, a mixture of 15e (231 m g, 0.5 mmol, 1 eq), KOAc (490 mg, 5.0 mmol, 10 eq) a nd glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was poured into ice water (20 ml). The resulting precipitate was filtered washed with water (3x10 ml), acetone (2x10 ml), DCM (2x10 ml), hexane (10 ml) and airdried to give pure ELQ‐602 (172 mg, 86 % yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.70 (s, 1H), 7.96 (broad d, J = 32.4 Hz, 4H), 7 .77 (broad d, J = 7.9 Hz, 2H), 7.39 (broad d, J = 7.8 Hz, 2H), 7.07 (s, 1H), 3.97 (s, 3H), 2.26 (s, 3H). 6‐chloro‐3‐(4'‐(difluoromethyl)‐[1,1'‐biphenyl] 4‐yl)‐7‐methoxy‐2‐methylquinolin‐4(1H)‐one (ELQ‐659). Following the general procedure for the hydrolysis of the 4‐chloro quinolines, a mixture of 15f (210 m g, 0.5 mmol, 1 eq), KOAc (490 mg, 5.0 mmol, 10 eq) a nd glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was poured into ice water (10 ml). The resulting precipitate was filtered washed with water (3 x 3 m l), acetone (2 x 3 ml), methylene chloride (2 x 3 ml), hexane (20 ml) and air‐dried to give pure ELQ‐65 9 (105 mg, 52% yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.70 (s, 1H), 8.02 (s, 1H), 7.87 (d, J = 7.9 Hz, 2H), 7.74 (d, J = 7.9 Hz, 2H), 7.68 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 7.9 Hz, 2H), 7.10 (t, J = 56.3 Hz, 1H), 7.09 (s, 1H), 3.98 (s, 3H), 2.27 (s, 3H ). 6‐chloro‐7‐methoxy‐3‐(4'‐methoxy‐[1,1'‐biphe nyl]‐4‐yl)‐2‐methylquinolin‐4(1H)‐one (ELQ‐64 5). Following the general procedure for the hydrolysis of the 4‐chloro quinolines, a mixture of 15g (212 m g, 0.5 mmol, 1 eq), KOAc (490 mg, 5.0 mmol, 10 eq) a nd glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was poured into ice water (20 ml). The resulting precipitate was filtered washed with water (3x10 ml), acetone (2x10 ml), DCM (2x10 ml), hexane (10 ml) and airdried to give pure ELQ‐645 (160 mg, 79 % yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.67 (s, 1H), 8.02 (s, 1H), 7.68‐7.62 (m, 3H), 7 .32‐7.29 (m, 2H), 7.09‐7.04 (m, 2H), 3.98 (s, 3H ), 3.82 (s, 3H), 2.26 (s, 2H). 6‐chloro‐3‐(4'‐(difluoromethoxy)‐[1,1'‐biphenyl] ‐4‐yl)‐7‐methoxy‐2‐methylquinolin‐4(1H)‐one (ELQ‐600). Following the general procedure for the hydrolysis of the 4‐chloro quinolines, a mixture of 15h (230 m g, 0.5 mmol, 1 eq), KOAc (490 mg, 5.0 mmol, 10 eq) a nd glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was poured into ice water (20 ml). The resulting precipitate was filtered washed with water (3x10 ml), acetone (2x10 ml), DCM (2x10 ml), hexane (10 ml) and airdried to give pure ELQ‐600 (165 mg, 75 % yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.74 (s, 1H), 8.02 (s, 1H), 7.77 (broad d, J = 8 .7 Hz, 2H), 7.67 (broad d, J = 8.3 Hz, 2H), 7.31 (t, J = 73.8 Hz, 1H) ), 7.34 (broad d, J = 8.3 Hz, 2H), 7.29 (broa d d, J = 8.6 Hz, 2H), 7.07 (s, 1H), 3.96 (s, 3H) , 2.25 (s, 3H). 6‐chloro‐7‐methoxy‐2‐methyl‐3‐(3'‐(trifluoro methyl)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐one (ELQ‐646). Following the general procedure for the hydrolysis of the 4‐chloro quinolines, a mixture of 15i (87 mg , 0.188 mmol, 1 eq), KOAc (184 mg, 1.82 mmol, 10 eq) and glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixtu re was poured into ice water (20 ml). The resulting precipitate was filtered washed with water (3x10 ml), acetone (2x10 ml), DCM (2x10 ml), hexane (10 ml) and airdried to give ELQ‐646 (30 mg, 36 % yield) as a white solid. The product is 95‐98% by NMR and HPLC. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.70 (s, 1H), 8.07‐8.04 (m, 1H), 8. 02 (s, 2H), 7.80‐7.73 (m, 4H), 7.41‐7.37 (m, 2H), 7.10 (s, 1H), 3.98 (s, 3H), 2.28 (s, 3H). 6‐chloro‐7‐methoxy‐2‐methyl‐3‐(3'‐(trifluoro methoxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐one (ELQ‐604). Following the general procedure for the hydrolysis of the 4‐chloro quinolines, a mixture of 15j (476 m g, 1.0 mmol, 1 eq), KOAc (980 mg, 10.0 mmol, 10 eq) and glacial acetic acid (5 ml) was heated for 16 h . After cooling to room temperature, the reaction mixture was poured into ice water (20 ml). The resulting precipitate was filtered washed with water (3x10 ml), acetone (2x10 ml), DCM (2x10 ml), hexane (10 ml) and airdried to give crude ELQ‐604 (350 mg). The product was crystallized from DMF to give ELQ‐604 (200 mg, 43 % yield). NMR and HPLC indicated that the product was about 95‐98% pure. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.70 (s, 1H), 8.02 (s, 1H), 7.79 (dd d, J = 7.9, 1.7, 0.9 Hz, 1H), 7.76‐7.73 (m, 2H), 7.69 (s, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.40‐7.36 (m, 3H), 7.0 9 (s, 1H), 3.98 (s, 3H), 2.27 (s, 3H). ((6‐chloro‐7‐methoxy‐2‐methyl‐3‐(4'‐(trifl uoromethoxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4‐yl) oxy)methyl ethyl carbonate (ELQ‐598). A stirred mixture of ELQ‐596 (460 mg, 1.0 mmol, 1 eq), tetra butyl ammonium iodide (742 mg, 2.0 mmol , 2 eq), chloromethyl ethylcarbonate (278 mg, 2.0 mmol, 2 eq) and dried K 2 CO 3 (278 mg, 2.0 mmol, 2 eq) in DMF (25 ml) was heated at 60 o C for 24 hours when TLC showed no more starti ng material remained. The mixture was cooled to room temperature, filtered and the filtrate concentrated to dryness to give 700 mg of brown oil. The resulting residue was stirred with ethyl acetate (50 ml) for 30 minutes and the inso luble tetra butyl ammonium iodide filtered and wash with e thyl acetate (3x10 ml). The filtrate was concentrated to dryness and purified by flash chromatography using a gradient of ethyl acetate/hexane (1/1) as eluent to give pure ELQ‐598 (412 mg, 73 % yield) as a white solid. HPLC shows 1 peak with a purity grea ter than 98 %. GC‐MS shows 1 peak M + = 561 (53%), 459 (100 %). 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.08 (s, 1H), 7.74‐ 7.70 (m, 4H), 7.51‐7.48 (m, 2H), 7.46 (s, 1H), 7. 37‐7.34 (m, 2H), 5.31 (s, 2H), 4.13 (q, J = 7.1 Hz, 2H), 4.07 (s, 3H), 2.56 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H). 6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(4‐(4,4,5,5 tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)phenyl)quinoli ne: A mixture of 3‐(4‐bromophenyl)‐4,6‐dichloro‐7 methoxy‐2‐methylquinoline (7.08 g, 0.18 mol), bis(pinacolato)diboron (1.4 eq, 6.34 g, 0.025 mol), a nd potassium acetate (3.0 eq, 5.24 g, 0.0534 mol) i n 250 mL N,N‐dimethylformamide was degassed by bubblin g argon through a glass tube inserted under the liquid surface for 20 minutes at room temperatur e. [1,1’‐Bis(diphenylphosphino)ferrocene]‐ dichloropalladium (II) (5 mol %, 0.65 g, 0.00089 mol ) was added, followed by heating at 80°C under an atmosphere of argon. After 72 hours, TLC and GC/MS indicated that unreacted quinoline starting material was still present. The reaction was cooled to room temperature and again degassed, followed by the addition of further [1,1’‐bis(diphenylphosph ino)ferrocene]‐dichloropalladium (II) (2.4 mol %, 0.3 2 g, 0.00044 mol). The reaction was again heated at 80°C under an atmosphere of argon for 72 hours. Although TLC and GC/MS showed that a small amount o f unreacted 3‐(4‐bromophenyl)‐4,6‐dichloro‐7‐ methoxy‐2‐methylquinoline still remained, the reacti on was removed from the heat, filtered through Celite, and concentrated under reduced pressure with heating. The resulting black residue was taken up in dichloromethane (250 mL) and filtered through Celi te. The dark filtrate was concentrated under reduced pressure with heating, affording a black slud ge. This material was again taken up in dichloromethane (300 mL) and washed with 5% brine (2 x 100 mL), then 10% brine (100 mL). The pooled organic layers were dried (MgSO 4 ) and evaporated under reduced pressure with wa rming, affording a black solid (11.44 g). This material w as taken up in 15 mL dichloromethane and filtered through a plug of silica gel (100 g, pre‐wetted w ith dichloromethane), washing with 98/2 v/v dichloromethane/ethyl acetate until no more product el uted by TLC. Evaporation of the filtrate afforded a pale greenish gray solid (7.22 g). Auto mated flash chromatography on silica, eluting with a gradient of 100% dichloromethane to 98/2 v/v dichloro methane/ethyl acetate, afforded the desired product (R f = 0.21, 98/2 v/v dichloromethane/ethyl acetate) as an off‐white solid (3.66 g, 46%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.23 (s, 1H), 7.97‐7.94 (m, 2H), 7.4 6 (s, 1H), 7.30‐7.27 (m, 2H), 4.06 (s, 3H), 2.43 (s, 3H), 1.38 (s, 12H).) 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(3'‐(penta fluorosulfanyl)‐[1,1'‐biphenyl]‐4‐yl)quinoline: A mixture of 4,6‐dichloro‐7‐methoxy‐2‐methyl‐ 3‐(4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2 yl)phenyl)quinoline (0.46 g, 0.0010 mol), anhydrous po tassium carbonate (2.0 eq, 0.0021 mol, 0.29 g), and meta‐bromophenylsulfur pentafluoride (1.3 eq, 0.0 013 mol, 0.38 g) in N,N‐dimethylformamide (55 mL) was degassed by bubbling argon through a glass tube under the liquid surface for 20 minutes at room temperature. [1,1’‐Bis(diphenylphosphino)ferroc ene]‐dichloropalladium (II) (5 mol %, 0.038 g, 0.000052 mol) was added, followed by heating at 80° C under an atmosphere of argon for 22 hours. The cooled reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was taken up in dichloromethane (125 mL) and again filtered through Celite. The filtrate was adsorbed onto silica and purified by flash chromatography, eluting with a gradient of 95/5 to 77/23 v/v hexane s/ethyl acetate. The desired product (R f = 0.41 (3/2 v/v hexanes/ethyl acetate, silica) was obtained as a white solid (0.45 g, 70%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.26 (s, 1H), 8.06‐8.04 (m, 1H), 7.83‐7.81 (m, 1H), 7.78 (ddd, J = 8.3, 2.2, 1.0 Hz, 1H), 7. 74‐7.71 (m, 2H), 7.61‐7.57 (m, 1H), 7.48 (s, 1H), 7.42‐7.38 (m, 2 H), 4.08 (s, 3H), 2.50 (s, 3H)). 6‐Chloro‐7‐methoxy‐2‐methyl‐3‐(3'‐(pentafluo rosulfanyl)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐ one (ELQ‐ 662): 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(3'‐(penta fluorosulfanyl)‐[1,1'‐biphenyl]‐4‐yl)quinoline (0.4 5 g, 0.00086 mol) and potassium acetate (10 eq, 0.0086 mo l, 0.85 g) were heated in glacial acetic acid (9 m L) at 120°C for 6 hours. After cooling, the reaction mixture was chilled at 5°C for 30 minutes. Vacu um filtration, rinsing with excess water followed by ace tone (5 x 1.5 mL), afforded the desired product as fine white crystals (0.21 g, 48%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.75 (s, 1H), 8.14‐8.11 (m, 1H), 8. 05‐ 8.02 (m, 2H), 7.92 (ddd, J = 8.3, 2.3, 0.8 Hz, 1H ), 7.77‐7.72 (m, 3H), 7.41‐7.38 (m, 2H), 7.09 (s , 1H), 3.97 (s, 3H), 2.26 (s, 3H)). ((6‐Chloro‐7‐methoxy‐2‐methyl‐3‐(3'‐(penta fluoro‐λ 6 ‐sulfaneyl)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐ 4‐ yl)oxy)methyl ethyl carbonate (ELQ‐674) 6‐Chloro‐7‐methoxy‐2‐methyl‐3‐(3'‐(pentafluo ro‐λ 6 ‐sulfaneyl)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐ 4(1H)‐one (0.173g, 0.00034 mol) was combined with tetrabutyl am monium iodide (2.0 eq, 0.00069 mol, 0.25 g) and anhydrous potassium carbonate (2.0 eq, 0.00069 mo l, 0.095 g) in 15 mL DMF. After stirring briefly at room temperature, chloromethyl ethyl carbonate (2.0 eq, 0.00069 mol, 0.095 g) was added as a solution in 1mL DMF. The reaction was allowed to stir at 60°C, sealed with a needle vented septum, for 24 hours, whereupon TLC indicated that reaction was complete. The cooled reaction mixture was vacuum filtered to remove solids, and the solvent wa s removed from the filtrate under reduced pressure with heating. The residue was taken up in 50 mL ethyl acetate and stirred, resulting in precipitation of tetrabutyl ammonium iodide; this was removed by vacuum filtration, and the solvent was removed from the filtrate under reduced pressure with warming. Automated flash chromatography of the residue on silica, eluting with a gradient o f 90:10 to 65:35 v:v hexanes:ethyl acetate afforded the desired product (R F = 0.40, 1:1 v:v hexanes:ethyl acetate) as a white solid (90 mg, 44%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.06 (s, 1H), 8.06‐8.04 (m, 1H), 7.8 2‐7.77 (m, 2H), 7.74‐7.71 (m, 2H), 7.62‐7.56 (m , 1H), 7.53‐7.50 (m, 2H), 7.45 (s, 1H), 5.30 (s, 2H), 4. 11 (q, J = 7.1 Hz, 2H), 4.06 (s, 3H), 2.54 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3H)). 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(4'‐(penta fluorosulfanyl)‐[1,1'‐biphenyl]‐4‐yl)quinoline: A mixture of 4,6‐dichloro‐7‐methoxy‐2‐methyl‐ 3‐(4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2 yl)phenyl)quinoline (0.46 g, 0.0010 mol), anhydrous po tassium carbonate (2.0 eq, 0.0021 mol, 0.29 g), and para‐bromophenylsulfur pentafluoride (1.3 eq, 0.0 013 mol, 0.38 g) in N,N‐dimethylformamide (75 mL) was degassed by bubbling argon through a glass tube under the liquid surface for 20 minutes at room temperature. [1,1’‐Bis(diphenylphosphino)ferroc ene]‐dichloropalladium (II) (5 mol %, 0.038 g, 0.000052 mol) was added, followed by heating at 80° C under an atmosphere of argon for 22 hours. The cooled reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was taken up in dichloromethane (125 mL) and again filtered through Celite. The filtrate was adsorbed onto silica and purified by flash chromatography, eluting with a gradient of 95/5 to 75/25 v/v hexane s/ethyl acetate. This afforded the desired product (R f = 0.43 (3/2 v/v hexanes/ethyl acetate, silica) as an off‐white solid (0.38 g, 83%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.25 (s, 1H), 7.89‐7.86 (m, 2H), 7.7 7‐7.72 (m, 4H), 7.48 (s, 1H), 7.41‐7.38 (m, 2H), 4.08 (s, 3H), 2.50 (s, 3H)). 6‐Chloro‐7‐methoxy‐2‐methyl‐3‐(4'‐(pentafluo rosulfanyl)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐ one (ELQ‐ 663): 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(4'‐(penta fluorosulfanyl)‐[1,1'‐biphenyl]‐4‐yl)quinoline (0.3 8 g, 0.00073 mol) and potassium acetate (10 eq, 0.0073 mo l, 0.72 g) were heated in glacial acetic acid (12 mL) at 120°C for 6 hours. After cooling, the rea ction mixture was chilled at 5°C for 30 minutes. Vacuum filtration, rinsing with excess water followed by ace tone (5 x 1.5 mL), afforded the desired product as silver crystals (0.26 g, 72%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.71 (s, 1H), 8.02 (s, 1H), 8.01‐7. 98 (m, 2H), 7.97‐7.93 (m, 2H), 7.78‐7.75 (m, 2H), 7.42 7.39 (m, 2H), 7.09 (s, 1H), 3.97 (s, 3H), 2.27 (s , 3H)). ((6‐Chloro‐7‐methoxy‐2‐methyl‐3‐(4'‐(pe ntafluoro‐λ 6 ‐sulfaneyl)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4 ‐ yl)oxy)methyl ethyl carbonate (ELQ‐674) 6‐Chloro‐7‐methoxy‐2‐methyl‐3‐(4'‐(pentafluo ro‐λ 6 ‐sulfaneyl)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐ 4(1H)‐one (0.166g, 0.00033 mol) was combined with tetrabutyl am monium iodide (2.0 eq, 0.00066 mol, 0.24 g) and anhydrous potassium carbonate (1.0 eq, 0.00033 mo l, 0.046 g) in 15 mL DMF. After stirring briefly at room temperature, chloromethyl ethyl carbonate (1.0 eq, 0.00033 mol, 0.046 g) was added as a solution in 1 mL DMF. The reaction was allowed to stir at 60°C, sealed with a needle vented septum, for 24 hours. Although a small amount of unreacted sta rting material was still present by TLC, the reactio n mixture was cooled, vacuum filtered to remove solids, and the solvent was removed from the filtrate under reduced pressure with heating. The residue wa s taken up in 40 mL ethyl acetate and stirred, resulting in precipitation of tetrabutyl ammonium iodi de; this was removed by vacuum filtration, and the solvent was removed from the filtrate under redu ced pressure with warming. Automated flash chromatography of the residue on silica, eluting with a gradient of 9:1 to 7:3 v:v hexanes:ethyl acetate afforded the desired product as a white solid (0.17g , 86%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.06 (s, 1H), 7.90‐7.86 (m, 2H), 7.76‐7.72 (m, 4H), 7.52‐7.49 (m, 2H), 7.45 (s, 1H), 5.30 (s, 2H), 4.10 (q, J = 7.1 Hz, 2H), 4.06 (s, 3H), 2.54 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H)). 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(4'‐(trifl uoroethoxy)‐[1,1'‐biphenyl]‐4‐yl)quinoline: A mixture of 4,6‐dichloro‐7‐methoxy‐2‐methyl‐ 3‐(4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2 yl)phenyl)quinoline (0.48 g, 0.0011 mol), anhydrous po tassium carbonate (2.0 eq, 0.0022 mol, 0.30 g), and 1‐bromo‐4‐(2,2,2‐trifluoroethoxy)benzene (1.3 eq., 0.0014 mol, 0.36 g) in N,N‐dimethylformamide (80 mL) was degassed by bubbling argon through a gl ass tube under the liquid surface for 20 minutes at room temperature. [1,1’‐Bis(diphenylphosphino)ferrocen e]‐dichloropalladium (II) (5 mol %, 0.040 g, 0.000055 mol) was added, followed by heating at 80° C under an atmosphere of argon for 16 hours. The cooled reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was taken up in dichloromethane (125 mL) and again filtered through Celite. The filtrate was adsorbed on to silica and purified by flash chromatography, eluting with a gradient of 100/0 to 75/25 v/v hexan es/ethyl acetate. Concentrated fractions were combined and taken up in ethyl acetate (50 mL) and dichloromethane (50 mL). The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was adsorbed onto silica and purified by flash chromatography again, eluting w ith a gradient of 100/0 to 80/20 v/v hexanes/ethyl acetate. This afforded the desired product (R f = 0.39 (3/2 v/v hexanes/ethyl acetate, silica) as an off‐ white solid (0.39 g, 72%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.25 (s, 1H), 7.71‐7.68 (m, 2H), 7.6 7‐7.64 (m, 2H), 7.47 (s, 1H), 7.35‐7.32 (m, 2H), 7.08‐7.05 (m, 2 H), 4.43 (q, J = 8.1 Hz, 2H), 4.07 (s, 3H), 2.50 (s, 3H)). 6‐Chloro‐7‐methoxy‐2‐methyl‐3‐(4'(trifluoroeth oxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐one (ELQ‐670): 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(4'‐(trifl uoroethoxy)‐[1,1'‐biphenyl]‐4‐yl)quinoline (0.39 g , 0.00079 mol) and potassium acetate (10 eq., 0.0079 mol, 0.78 g) were heated in glacial acetic acid (18 mL) at 120°C for 20 hours. After cooling, the reaction mix ture was chilled at 5°C for one hour. Vacuum filtration, rinsing with excess water followed by ace tone (3 x 1.5 mL), afforded the desired product as an off‐white solid (0.06 g, 11.5%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.67 (s, 1H), 8.01 (s, 1H), 7.71‐7. 69 (m, 2H), 7.66‐7.64 (m, J = 8.3 Hz, 2H), 7.33‐7.30 ( m, J = 8.2 Hz, 2H), 7.18‐7.16 (m, 2H), 7.08 (s, 1H), 4.83 (q, J = 8.9 Hz, 2H), 3.97 (s, 3H), 2.26 (s, 3H)). 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(4'‐((trif luoromethyl)thio)‐[1,1'‐biphenyl]‐4‐yl)quinoline A mixture of 4,6‐dichloro‐7‐methoxy‐2‐methyl‐ 3‐(4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2 yl)phenyl)quinoline (0.54 g, 0.0012 mol), anhydrous po tassium carbonate (2.0 eq, 0.0024 mol, 0.33 g), and 4‐bromo‐(trifluoromethylthio)benzene (1.3 eq, 0. 0013 mol, 0.38 g) in N,N‐dimethylformamide (80 mL) was degassed by bubbling argon through a glass tube under the liquid surface for 30 minutes at room temperature. [1,1’‐Bis(diphenylphosphino)ferroc ene]‐dichloropalladium (II) (5 mol %, 0.044 g, 0.000060 mol) was added, followed by heating at 80° C under an atmosphere of argon for 24 hours. The cooled reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was taken up in dichloromethane (300 mL) and again filtered through Celite. The filtrate was adsorbed onto silica and purified by flash chromatography, eluting with a gradient of 100% dichloromethane to 9 8/2 v/v dichloromethane/ethyl acetate. This afforded the desired product (R f = 0.47, 98/2 v/v dichloromethane/ethyl acetate, silica) as a white solid (0.47 g, 79%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.25 (s, 1H), 7.78‐7.72 (m, 6H), 7.4 7 (s, 1H), 7.40‐7.37 (m, 2H), 4.07 (s, 3H), 2.50 (s, 3H), 19 F NMR (376 MHz; CDCl 3 ): δ ‐42.7). 6‐Chloro‐7‐methoxy‐2‐methyl‐3‐(4'‐((trifluor omethyl)thio)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H) one 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐4‐(4'‐(trifl uoromethylthio)‐[1,1'‐biphenyl]‐4‐yl)quinoline (0.4 7 g, 0.00095 mol) and potassium acetate (10 eq, 0.0095 mo l, 0.93 g) were heated in glacial acetic acid (10 mL) at 120°C for 2 hours. After cooling, the rea ction mixture was chilled at 5°C for 20 minutes. Vacuum filtration, rinsing with excess water followed by ace tone (3 x 2 mL), afforded the desired product as cream crystals (0.31 g, 69%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.71 (s, 1H), 8.02 (s, 1H), 7.91‐7. 89 (m, 2H), 7.85‐7.80 (m, 2H), 7.77‐7.75 (m, 2H), 7.40 7.38 (m, 2H), 7.09 (s, 1H), 3.98 (s, 3H), 2.27 (s , 3H). 19 F NMR (376 MHz; DMSO): δ ‐42.0). 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(3’((trifl uoromethyl)thio)‐[1,1’‐biphenyl]‐4‐yl)quinoline: A mixture of 4,6‐dichloro‐7‐methoxy‐2‐methyl‐ 3‐(4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaboroian‐2 yl)phenyl)quinoline (0.57 g, 0.0013 mol), anhydrous po tassium carbonate (2.0 eq, 0.0026 mol, 0.36 g), and 3‐bromophenyltrifluoromethyl sulfide (1.3 eq., 0. 0017 mol, 0.43 g) in N,N‐dimethylformamide (80 mL) was degassed by bubbling argon through a glass tube under the liquid surface for 20 minutes at room temperature. [1,1’‐Bis(diphenylphosphino)ferrocen e]‐dichloropalladium (II) (5 mol %, 0.047 g, 0.00006 mol) was added, followed by heating at 80°C under an atmosphere of argon for 23 hours. The cooled reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was taken up in dichloromethane (125 mL) and again filtered through Celite. The filtrate was adsorbed on to silica and purified by flash chromatography, eluting with a gradient of 100/0 to 92/8 v/v dichlo romethane/ethyl acetate. This afforded the desired product (R f = 0.61 (98/2 v/v dichloromethane/ethyl acetate, silica) as an off‐white solid (1.0 g, containing residual solvent) that was used without drying in th e following step. 6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(3’((trifluo romethyl)thio)‐[1,1’‐biphenyl]‐4‐yl)quinolin‐4(1 H)‐one (ELQ‐678): 4,6‐dichloro‐7‐methoxy‐2‐methyl‐3‐(3’((trifl uoromethyl)thio)‐[1,1’‐biphenyl]‐4‐yl)quinoline ( 1.0 g, containing residual solvent) and potassium acetate (0. 02 mol, 1.99 g) were heated in glacial acetic acid (15 mL) at 120°C for 28 hours. After cooling, the reaction mixture was chilled at 5°C for 1.5 hours. Vacuum filtration, rinsing with excess water followed by acetone (4 x 1.5 mL), afforded the desired product as grey crystals (0.40 g, 65% over two step s; 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.70 (s, 1H), 8.04 ‐8.02 (m, 1H), 8.02 (s, 1H), 7.99‐7.96 (m, 1H), 7.76‐7.72 (m, 3H), 7.69‐7.64 (m, 1H), 7.40‐7.37 (m, 2H), 7.09 (s, 1H), 3.98 (s, 3H), 2.27 (s, 3H).; 19 F NMR (376 MHz; DMSO): δ ‐41.9). 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(4'‐(methy lsulfonyl)‐[1,1'‐biphenyl]‐4‐yl)quinoline A mixture of 3‐(4‐bromophenyl)‐4,6‐dichloro‐7 methoxy‐2‐methylquinoline (1.00 g, 0.0025 mol), 4 (methylsulfonyl)boronic acid (0.60 g, 0.0030 mol, 1.2 eq), and anhydrous potassium carbonate (2.0 eq, 0.0050 mol, 0.69 g), in N,N‐dimethylformamide (130 mL) was degassed by bubbling argon through a glass tube under the liquid surface for 25 minutes at room temperature. [1,1’‐ Bis(diphenylphosphino)ferrocene]‐dichloropalladium (II) (5 mol %, 0.091 g, 0.000125 mol) was added, followed by heating at 80°C under an atmosphere of argon for 4 days. The cooled reaction mixture was filtered through Celite. The filtrate was concentrat ed under reduced pressure with heating, and the resulting dark solid was taken up in dichloromethane (150 mL) and again filtered through Celite. The filtrate was adsorbed onto silica and purified by fl ash chromatography, eluting with a gradient of 85/15 to 30/70 v/v hexanes/ethyl acetate. This afforded t he desired product (R f = 0.25 (3/2 v/v hexanes/ethyl acetate, silica) as a white solid (0.42 g, 36%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 8.20 (s, 1H), 8.08‐8.03 (m, 4H), 7.96‐7.93 (m, 2H), 7.66 (s, 1H), 7.56‐7.53 (m, 2H), 4.07 (s, 3H), 3.29 (s, 3H), 2.43 (s, 3H)) . 6‐Chloro‐7‐methoxy‐2‐methyl‐3‐(4'‐(methylsul fonyl)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐one (ELQ‐658) 4,6‐dichloro‐7‐methoxy‐2‐methyl‐3‐(4'‐(methy lsulfonyl)‐[1,1'‐biphenyl]‐4‐yl)quinoline (0.42 g, 0.00090 mol) and potassium acetate (10 eq, 0.0090 mol, 0.88 g) were heated in glacial acetic acid (10 mL) at 120°C for 3 hours. After cooling, the reaction mi xture was chilled at 5°C for 1h. Vacuum filtratio n, rinsing with excess water followed by acetone (3 x 2 mL), afforded the desired product as fine, white crystals (0.24 g, 59%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.71 (s, 1H), 8.04‐7.99 (m, 5H), 7. 80‐7.78 (m, 2H), 7.42‐7.40 (m, 2H), 7.09 (s, 1H), 3.97 (s, 3H ), 3.27 (s, 3H), 2.27 (s, 3H)). 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(3'‐(2,2,2 ‐trifluoroethoxy)‐[1,1'‐biphenyl]‐4‐yl)quinoline: A mixture of 4,6‐dichloro‐7‐methoxy‐2‐methyl‐ 3‐(4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2 yl)phenyl)quinoline (0.48 g, 0.0011 mol), anhydrous po tassium carbonate (2.0 eq, 0.0022 mol, 0.30 g), and 1‐bromo‐4‐(2,2,2‐trifluoroethoxy)benzene (1.3 eq., 0.0014 mol, 0.36 g) in N,N‐dimethylformamide (50 mL) was degassed by bubbling argon through a gl ass tube under the liquid surface for 20 minutes at room temperature. [1,1’‐Bis(diphenylphosphino)ferrocen e]‐dichloropalladium (II) (5 mol %, 0.040 g, 0.000055 mol) was added, followed by heating at 80° C under an atmosphere of argon for 23 hours. The cooled reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was taken up in dichloromethane (125 mL) and again filtered through Celite. The filtrate was adsorbed on to silica and purified by flash chromatography, eluting with a gradient of 95/5 to 72/28 v/v hexane s/ethyl acetate. The desired product was obtained as a white solid (R f = 0.38 (7/3 v/v hexanes/ethyl acetate, silica) , 0.30 g, 55%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.25 (s, 1H), 7.71‐7.68 (m, 2H), 7.67‐7.64 (m, 2 H), 7.47 (s, 1H), 7.35‐7.32 (m, 2H), 7.08‐7.05 ( m, 2H), 4.43 (q, J = 8.1 Hz, 2H), 4.07 (s, 3H), 2.50 (s, 3H)). 6‐Chloro‐7‐methoxy‐2‐methyl‐3‐(3'‐(2,2,2‐t rifluoroethoxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H )‐one (ELQ‐ 673): 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(3'‐(2,2,2 ‐trifluoroethoxy)‐[1,1'‐biphenyl]‐4‐yl)quinoline (0.30 g, 0.00061 mol) and potassium acetate (10 eq., 0.0061 m ol, 0.59 g) were heated in glacial acetic acid (10 mL) at 120°C for 22 hours. After cooling, the reac tion mixture was poured into 60 mL water. After stirring 3 minutes, the resulting solid was recovered by vacuum filtration, rinsing with excess water followed by acetone (2 x 2 mL). This afforded the desired product as a white solid (0.14 g, 47%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.67 (s, 1H), 8.01 (s, 1H), 7.71‐7. 69 (m, 2H), 7.66‐7.64 (m, J = 8.3 Hz, 2H), 7.33 7.30 (m, J = 8.2 Hz, 2H), 7.18‐7.16 (m, 2H), 7.0 8 (s, 1H), 4.83 (q, J = 8.9 Hz, 2H), 3.97 (s, 3H ), 2.26 (s, 3H)). 4'‐(4,6‐Dichloro‐7‐methoxy‐2‐methylquinolin‐3 yl)‐[1,1'‐biphenyl]‐4‐sulfonamide A mixture of 3‐(4‐bromophenyl)‐4,6‐dichloro‐7 methoxy‐2‐methylquinoline (1.00 g, 0.0025 mol), 4 aminosulfonylphenylboronic acid (0.66 g, 0.0033 mol, 1 .3 eq), and anhydrous potassium carbonate (2.0 eq, 0.0050 mol, 0.69 g), in N,N‐dimethylformamide ( 130 mL) was degassed by bubbling argon through a glass tube under the liquid surface for 20 minutes at room temperature. [1,1’‐ Bis(diphenylphosphino)ferrocene]‐dichloropalladium (II) (5 mol %, 0.091 g, 0.000125 mol) was added, followed by heating at 80°C under an atmosphere of argon for 24 hours. The cooled reaction mixture was filtered through Celite. The filtrate was conce ntrated under reduced pressure with heating, and the resulting dark solid was swirled in dichloromethane ( 125 mL) and vacuum filtered. Because precipitation was observed in the filtrate, this was concentrated to 90 mL and again vacuum filtered. The resulting pale tan solid was the desired product in sufficient purity for the next reaction (0.30 g , 26%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 8.20 (s, 1H), 8.00‐7.90 (m, 6H), 7.6 5 (s, 1H), 7.54‐7.51 (m, 2H), 7.44 (br s, 2H), 4.07 (s, 3H), 2.43 (s, 3H).). 4'‐(6‐Chloro‐7‐methoxy‐2‐methyl‐4‐oxo‐1,4 dihydroquinolin‐3‐yl)‐[1,1'‐biphenyl]‐4‐sulfon amide (ELQ‐ 680) 4'‐(4,6‐Dichloro‐7‐methoxy‐2‐methylquinolin‐3 yl)‐[1,1'‐biphenyl]‐4‐sulfonamide (0.30 g, 0.00 064 mol) and potassium acetate (10 eq, 0.0064 mol, 0.63 g) w ere heated in glacial acetic acid (10 mL) at 120°C for 20 hours. After cooling, the reaction mixture was chilled at 5°C for 20 minutes. Vacuum filtration, rinsing with excess water followed by acetone (3 x 1.5 mL), afforded the desired product as a grayish beige powder (0.21 g, 71%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.70 (s, 1H), 8.02 (s, 1H), 7.94‐7. 92 (m, 4H), 7.77‐7.75 (m, 2H), 7.40‐7.38 (m, 4H), 7.09 (s, 1H), 3.97 (s, 3H), 2.27 (s, 3H).). 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(4‐(6‐(t rifluoromethyl)pyridin‐3‐yl)phenyl)quinoline A mixture of 3‐(4‐bromophenyl)‐4,6‐dichloro‐7 methoxy‐2‐methylquinoline (0.85 g, 0.0021 mol), 2 (trifluoromethyl)pyridyl‐5‐boronic acid (1.3 eq., 0. 0028 mol, 0.53 g), and anhydrous potassium carbonate (2.0 eq, 0.0042 mol, 0.58g) in N,N‐dimeth ylformamide (100 mL) was stirred at room temperature for 20 minutes while degassing by bubblin g argon through a glass tube under the liquid surface. [1,1’‐bis(diphenylphosphino)ferrocene]‐dichl oropalladium (II) (5 mol %, 0.077 g, 0.00011 mol) was added and the reaction was allowed to heat at 80°C under argon for 19 hours. The cooled reaction mixture was filtered through Celite, followed by conc entration of the filtrate under reduced pressure with heating. The resulting solid was taken up in 1 10 mL DCM, followed by vacuum filtration. Automated flash chromatography of the evaporated filtr ate on silica, eluting with a gradient of 9:1 to 72:28 v:v hexanes:ethyl acetate, afforded the desired product (R f = 0.35, 6:4 v:v hexanes:ethyl acetate on silica) as a white powder (0.37 g, 38%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 9.07‐9.03 (m, 1H), 8.26 (s, 1H), 8.16‐8.13 (m, 1H), 7.83‐7.80 (m, 1H), 7.78‐7.75 (m, 2H), 7.48 (s, 1H), 7.46‐7.43 (m, 2H), 4.08 ( s, 3H), 2.50 (s, 3H). 19 F NMR (376 MHz; CDCl3): δ ‐67.7). 6‐Chloro‐7‐methoxy‐2‐methyl‐3‐(4‐(6‐(trifl uoromethyl)pyridin‐3‐yl)phenyl)quinolin‐4(1H)‐one ( ELQ‐683) 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(4‐(6‐(t rifluoromethyl)pyridin‐3‐yl)phenyl)quinoline (0.37 g, 0.00080 mol) and anhydrous potassium acetate (10 eq, 0.0080 mol, 0.79g) were stirred in glacial acetic acid (15 mL) at 120°C for 20 hours. After cooling, the re action mixture was additionally chilled at 5°C for 20 minutes, followed by vacuum filtration, rinsing with excess water followed by acetone (3 x 1.5 mL). Th e desired product was obtained as a cream powder (0.23 g, 65%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.72 (s, 1H), 9.18‐9.14 (m, 1H), 8.44‐8.41 (m, 1H), 8 .02 (s, 1H), 8.02‐7.99 (m, 1H), 7.87‐7.85 (m, 2H ), 7.45‐7.43 (m, 2H), 7.09 (s, 1H), 3.98 (s, 3H), 2.28 (s, 3H). 19‐F NMR (376 MHz; DMSO): δ ‐66.2). 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(4‐(5‐(t rifluoromethoxy)pyridin‐2‐yl)phenyl)quinoline A mixture of 4,6‐dichloro‐7‐methoxy‐2‐methyl‐ 3‐(4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2 yl)phenyl)quinoline (0.50 g, 0.0011 mol), anhydrous po tassium carbonate (2.0 eq, 0.0022 mol, 0.30 g), and 2‐bromo‐5‐(trifluoromethoxy)benzene (1.3 eq., 0.0015 mol, 0.35 g) in N,N‐dimethylformamide (80 mL) was degassed by bubbling argon through a glass tube inserted under the liquid surface for 20 minutes at room temperature. [1,1’‐Bis(diphenylphosp hino)ferrocene]‐dichloropalladium (II) (5 mol %, 0.040 g, 0.000055 mol) was added, followed by heatin g at 80°C under an atmosphere of argon for 4 days. The cooled reaction mixture was filtered throug h Celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was taken up in dichloromethane (100 mL) and again filtered through Celite. After evaporation of the filtrate, the residue was purified by automated flash chromatography on silica, eluting with a gradient of 1:0 to 6:4 v:v hexanes:ethyl acetate, followed by a second flash chromatography on the same silica gel column, eluting with a gradient of 1:0 to 75:25 v:v hexanes:ethyl acetate. The desired product (R f = 15, 8:2 v:v hexanes:ethyl acetate on silica) was obtained as a white powder ( 0.29 g, 55%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.67‐8.66 (m, 1H), 8.25 (s, 1H), 8.14‐8.11 (m, 2H), 7.88‐7 .86 (m, 1H), 7.70‐7.67 (m, 1H), 7.48 (s, 1H), 7.4 2‐7.39 (m, 2H), 4.07 (s, 3H), 2.49 (s, 3H).); 19‐F NMR (376 MHz; CDCl3): δ ‐58.1). 6‐Chloro‐7‐methoxy‐2‐methyl‐3‐(4‐(5‐(trifl uoromethoxy)pyridin‐2‐yl)phenyl)quinolin‐4(1H)‐one (ELQ‐ 681) 4,6‐dichloro‐7‐methoxy‐2‐methyl‐3‐(4‐(5‐(t rifluoromethoxy)pyridin‐2‐yl)phenyl)quinoline (0.29 g, 0.00061 mol) and anhydrous potassium acetate (10 eq, 0.0061 mol, 0.60 g) were heated at 120°C in 10 mL glacial acetic acid for 20 hours. The cooled r eaction mixture was chilled at 5°C for 14 hours. Vacuum filtration, rinsing with excess water followed by acetone (3 x 1.5 mL), afforded the desired product as a white powder (0.17 g, 60% 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.72 (s, 1H), 8.77‐8.77 (m, 1H), 8.18‐8.16 (m, 1H), 8.13‐8.10 (m, 2H), 8.02 (s, 1H), 8.02‐7.99 (m, 1H), 7.42‐7.39 (m, 2H), 7 .10 (s, 1H), 3.98 (s, 3H), 2.27 (s, 3H). 19‐F NMR (376 MHz; D MSO): δ ‐57.1). 4,6‐Dichloro‐3‐(3'‐ethoxy‐[1,1'‐biphenyl]‐4‐ yl)‐7‐methoxy‐2‐methylquinoline A mixture of 3‐(4‐bromophenyl)‐4,6‐dichloro‐7 methoxy‐2‐methylquinoline (0.70 g, 0.0018 mol), 3 ethoxyphenylboronic acid (1.2 eq, 0.0022 mol, 0.37 g), and aqueous potassium carbonate (2.0 eq, 0.0036 mol, 0.50 g of anhydrous potassium carbonate dissolved in 1.8 mL water) in N,N‐ dimethylformamide (100 mL) was degassed by bubbling a rgon through a glass tube under the liquid surface for 20 minutes at room temperature. [1,1’ ‐Bis(diphenylphosphino)ferrocene]‐dichloropalladium (II) (5 mol %, 0.066 g, 0.000090 mol) was added, f ollowed by heating at 80°C under an atmosphere of argon for 20 hours. The cooled reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was taken up in dichloromethane (100 mL), vacuum filtered, and purifie d by flash chromatography, eluting with a gradient of 1:0 to 75:25 v:v hexanes:ethyl acetate. This afforded the desired product (R f = 0.35, 7:3 v:v hexanes:ethyl acetate, silica) as a white solid (0.34 g, 43%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.28 (s, 1H), 7.77‐7.74 (m, 2H), 7.50 (s, 1H), 7.41 (t, J = 7. 9 Hz, 1H), 7.37‐7.34 (m, 2H), 7.28 (ddd, J = 7.6 , 1.7, 1.0 Hz, 3H), 7.24 (t, J = 2.0 Hz, 1H), 6.95 (ddd, J = 8. 2, 2.5, 0.9 Hz, 1H), 4.17 (t, J = 7.0 Hz, 3H), 4 .10 (s, 3H), 2.53 (s, 3H), 1.49 (t, J = 7.0 Hz, 3H).) 6‐Chloro‐3‐(3'‐ethoxy‐[1,1'‐biphenyl]‐4‐yl) 7‐methoxy‐2‐methylquinolin‐4(1H)‐one (ELQ‐691 ) 4,6‐dichloro‐3‐(3'‐ethoxy‐[1,1'‐biphenyl]‐4‐ yl)‐7‐methoxy‐2‐methylquinoline (0.34 g, 0.00078 mol) and anhydrous potassium acetate (10 eq, 0.77 g, 0.0078 m ol) were heated at 120°C in glacial acetic acid (1 0 mL) for 23 hours. The cooled reaction mixture was further chilled at 5°C overnight, then vacuum filtered, rinsing with excess water followed by aceto ne (3 x 1 mL), affording a white solid (the desire d product; 0.20g, 61%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.68 (s, 1H), 8.01 (s, 1H), 7.70‐7. 67 (m, 2H), 7.41‐ 7.35 (m, 1H), 7.34‐7.31 (m, 2H), 7.26 (ddd, J = 7.7, 1.6, 1.0 Hz, 1H), 7.23‐7.20 (m, 1H), 7.08 (s , 1H), 6.93 (ddd, J = 8.2, 2.5, 0.9 Hz, 1H), 4.12 (q, J = 7. 0 Hz, 2H), 3.97 (s, 3H), 2.26 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H).) 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(4‐(pyridi n‐4‐yl)phenyl)quinoline A mixture of 3‐(4‐bromophenyl)‐4,6‐dichloro‐7 methoxy‐2‐methylquinoline (0.71 g, 0.0018 mol), pyridine‐4‐boronic acid (1.3 eq, 0.0024 mol, 0.2 9 g), and aqueous potassium carbonate (2.0 eq, 0.003 6 mol, 0.50 g of anhydrous potassium carbonate dissolve d in 1.3 mL water) in N,N‐dimethylformamide (80 mL) was degassed by bubbling argon through a glass tube under the liquid surface for 20 minutes at room temperature. [1,1’‐Bis(diphenylphosphino)ferroc ene]‐dichloropalladium (II) (5 mol %, 0.066 g, 0.000090 mol) was added, followed by heating at 80° C under an atmosphere of argon for 20 hours. The cooled reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was taken up in dichloromethane (100 mL) and vacuum filtered. The evaporated filtrate was purified by flash chromatography, eluting with a gradient of 85:15 to 0:100 v:v hexanes:ethyl acetate. This afforded the desired product (R f = 0.3, 100% ethyl acetate, silica) as a white solid (0.17 g, 24%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.73‐8.71 (m, 2H), 8.25 (s, 1H), 7.81‐7.78 (m, 2H), 7.61‐7.59 (m, 2H), 7.47 (s, 1 H), 7.43‐7.40 (m, 2H), 4.08 (s, 3H), 2.50 (s, 3H) ). 6‐Chloro‐7‐methoxy‐2‐methyl‐3‐(4‐(pyridin‐ 4‐yl)phenyl)quinolin‐4(1H)‐one (ELQ‐714) 4,6‐dichloro‐7‐methoxy‐2‐methyl‐3‐(4‐(pyridi n‐4‐yl)phenyl)quinoline (0.17 g, 0.00043 mol) and anhydrous potassium acetate (10 eq, 0.0043 mol, 0.42 g) were heated at 120°C in glacial acetic acid (1 0 mL) for 24 hours. After cooling to room temperatur e, the reaction mixture was chilled overnight at 5° C, followed by vacuum filtration, rinsing with excess wa ter followed by acetone (3 x 0.75 mL). The desire d product was obtained as a pale yellow solid (50 mg) . Additional clean product was recovered from the filtrate (27 mg) for a total of 77 mg desired prod uct (48%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.79 (s, 1H), 8.76‐8.74 (m, 2H), 8.02 (s, 1H), 8.00‐7.98 (m, 2 H), 7.92‐7.90 (m, 2H), 7.46‐7.44 (m, 2H), 7.11 ( s, 1H), 3.98 (s, 3H), 2.27 (s, 3H)). 4,6‐Dichloro‐3‐(2'‐chloro‐[1,1'‐biphenyl]‐4‐ yl)‐7‐methoxy‐2‐methylquinoline A mixture of 3‐(4‐bromophenyl)‐4,6‐dichloro‐7 methoxy‐2‐methylquinoline (0.70 g, 0.0018 mol), 2 chlorophenylboronic acid pinacol ester (1.3 eq, 0.00 23 mol, 0.55 g), and aqueous potassium carbonate (2.0 eq, 0.0032 mol, 0.44 g of anhydrous potassium carbonate dissolved in 1.6 mL water) in N,N‐ dimethylformamide (80 mL) was degassed by bubbling ar gon through a glass tube under the liquid surface for 20 minutes at room temperature. [1,1’ ‐Bis(diphenylphosphino)ferrocene]‐dichloropalladium (II) (5 mol %, 0.066 g, 0.000090 mol) was added, f ollowed by heating at 80°C under an atmosphere of argon for 24 hours. The cooled reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was taken up in dichloromethane (150 mL) and vacuum filtered. Automa ted flash chromatography of the residue from evaporation of the filtrate, eluting with a gradient of 95:5 to 82:18 v:v hexanes:ethyl acetate, did not effectively separate the desired product (R F = 0.24, 8:2 v:v hexanes:ethyl acetate) from a significant side product (R F = 0.21, 8:2 v:v hexanes:ethyl acetate) resulti ng from double addition of the boronic ester to the quinoline (replacing chlorine); this side product was observed by GC/MS with m/z = 503, t R = 21 minutes (temperature program: 250°C for 2 minutes fo llowed by temperature increase of 30°C/minute to 300°C, DB5 column). The impure mixture (0.45g) w as used without further purification in the following reaction. 6‐Chloro‐3‐(2'‐chloro‐[1,1'‐biphenyl]‐4‐yl) 7‐methoxy‐2‐methylquinolin‐4(1H)‐one (ELQ‐713 ) 4,6‐Dichloro‐3‐(2'‐chloro‐[1,1'‐biphenyl]‐4‐ yl)‐7‐methoxy‐2‐methylquinoline (0.15 g of impur e material, see above) was heated at 110°C in 10 mL glacial a cetic acid with anhydrous potassium acetate (0.34g, 0.0035 mol) for 24 hours. After cooling, the react ion mixture was chilled at 5°C, then vacuum filtere d, rinsing with excess water followed by acetone (2 x 1.5 mL). The desired product was afforded as a wh ite solid (0.0668g). Separately, another portion of 4,6 dichloro‐3‐(2'‐chloro‐[1,1'‐biphenyl]‐4‐yl) 7‐methoxy‐ 2‐methylquinoline (0.30 g of impure material from t he same reaction, above) was treated in the same manner with anhydrous potassium acetate (0.69 g) and glacial acetic acid (10 mL), obtaining 0.116 g of a cream solid that was also the desired product (total yield 0.18 g, 23% over two steps from 3‐(4‐ bromophenyl)‐4,6‐dichloro‐7‐methoxy‐2‐methylquin oline, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.70 (s, 1H), 8.02 (s, 1H), 7.60‐7.58 (m, 1H), 7.50‐7.39 (m, 5H), 7.36‐7.33 (m, 2H), 7.09 (s, 1H), 3.97 (s , 3H), 2.27 (s, 3H)). 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(4'‐nitro [1,1'‐biphenyl]‐4‐yl)quinoline A mixture of 3‐(4‐bromophenyl)‐4,6‐dichloro‐7 methoxy‐2‐methylquinoline (0.70 g, 0.0018 mol), 4 nitrophenylboronic acid pinacol ester (1.3 eq, 0.002 3 mol, 0.57 g), and aqueous potassium carbonate (2.0 eq, 0.0036 mol, 0.50 g of anhydrous potassium carbonate dissolved in 1.8 mL water) in N,N‐ dimethylformamide (80 mL) was degassed by bubbling ar gon through a glass tube under the liquid surface for 20 minutes at room temperature. [1,1’ ‐Bis(diphenylphosphino)ferrocene]‐dichloropalladium (II) (5 mol %, 0.066 g, 0.000090 mol) was added, f ollowed by heating at 80°C under an atmosphere of argon for 21 hours. The cooled reaction mixture was vacuum filtered, and the filtrate was concentrated under reduced pressure with heating. The residue wa s taken up in dichloromethane (125 mL) and vacuum filtered. Automated flash chromatography of t he evaporated filtrate on silica, eluting with a gradient of 9:1 to 1:1 v:v hexanes:ethyl acetate, af forded the desired product as an off‐white solid (0.07g, 9%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.37‐8.34 (m, 2H), 8.26 (s, 1H), 7.8 6‐7.83 (m, 2H), 7.80‐7.77 (m, 2H), 7.48 (s, 1H), 7.44‐7.41 (m, 2H), 4.08 (s, 3H ), 2.50 (s, 3H)). 6‐Chloro‐7‐methoxy‐2‐methyl‐3‐(4'‐nitro‐[1 ,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐one (ELQ‐715) 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(4'‐nitro [1,1'‐biphenyl]‐4‐yl)quinoline (0.07g, 0.00016 mo l) and anhydrous potassium acetate (10 eq, 0.00016 mol, 0.01 6 g) were heated in glacial acetic acid (10 mL) at 120°C for 21 hours. The cooled reaction was chill ed at 5°C overnight, then vacuum filtered, rinsing with excess water followed by acetone (3 x 3 mL) to obt ain the desired product as a beige powder (14 mg, 21%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.72 (s, 1H), 8.35‐8.32 (m, 2H), 8. 05‐8.02 (m, 3H), 7.85‐7.81 (m, 2H), 7.44‐7.41 (m, 2H), 7.09 (s, 1H), 3.98 (s, 3H ), 2.28 (s, 3H)). 4,6‐Dichloro‐3‐(2',6'‐dimethyl‐[1,1'‐biphenyl] 4‐yl)‐7‐methoxy‐2‐methylquinoline A mixture of 3‐(4‐bromophenyl)‐4,6‐dichloro‐7 methoxy‐2‐methylquinoline (0.70 g, 0.0018 mol), 2, 6‐ dimethylphenylboronic acid (2.0 eq, 0.0036 mol, 0.54 g), and aqueous potassium carbonate (2.0 eq, 0.0036 mol, 0.50 g of anhydrous potassium carbonate dissolved in 1.8 mL water) in N,N‐ dimethylformamide (80 mL) was degassed by bubbling ar gon through a glass tube under the liquid surface for 20 minutes at room temperature. [1,1’ ‐Bis(diphenylphosphino)ferrocene]‐dichloropalladium (II) (5 mol %, 0.066 g, 0.000090 mol) was added, f ollowed by heating at 80°C under an atmosphere of argon for 12 days. Although the reaction was not complete, it was removed from the heat. The cooled reaction mixture was vacuum filtered, and the solid obtained was rinsed with DMF followed by excess water and finally, acetone (5 mL). The resulting a sh‐gray solid (0.33 g) was boiled in 35 mL DMF a nd allowed to cool slowly, resulting in the formation o f white crystals as well as a small amount of dark precipitate that sinks. Vacuum filtration afforded w hite crystals mixed with a small amount of dark precipitate. GC/MS shows only the m/z of the desir ed product (421.1) at t R = 12.659 min, 200°C for 2 minutes, then 30°C/minute increase to 300°C, DB5 co lumn. This material (0.19 g) was used without further analysis or purification in the next reaction . 6‐Chloro‐3‐(2',6'‐dimethyl‐[1,1'‐biphenyl]‐4 yl)‐7‐methoxy‐2‐methylquinolin‐4(1H)‐one (ELQ 729) 4,6‐Dichloro‐3‐(2',6'‐dimethyl‐[1,1'‐biphenyl] 4‐yl)‐7‐methoxy‐2‐methylquinoline (0.19 g of crude crystallized material from the preceeding reaction, 0. 19 g) and anhydrous potassium acetate (0.44g, 0.0045 mol) were heated at 110°C in glacial acetic acid (15 mL) for 5 days. The hot reaction mixtur e was vacuum filtered to remove a small amount of gray so lid, and the cooled filtrate was chilled at 5°C, t hen vacuum filtered, rinsing with excess water followed b y acetone (3 x 1 mL). The resulting solid (79 mg ) was recrystallized from 1.5 mL DMF to afford the de sired product as sparkling off‐white crystals (63 m g, 9% over two steps from 3‐(4‐bromophenyl)‐4,6‐di chloro‐7‐methoxy‐2‐methylquinoline, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.68 (s, 1H), 8.02 (s, 1H), 7.34‐7. 31 (m, 2H), 7.19‐7.12 (m, 5H), 7.09 (s, 1H), 3.97 (s, 3H), 2.27 (s, 3H), 2.04 (s, 6H)). 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(2'‐methyl ‐[1,1'‐biphenyl]‐4‐yl)quinoline A mixture of 3‐(4‐bromophenyl)‐4,6‐dichloro‐7 methoxy‐2‐methylquinoline (1.00 g, 0.0025 mol), 2 methylphenylboronic acid pinacol ester (1.4 eq, 0.0035 mol, 0.77 g), and aqueous potassium carbonate (2.0 eq, 0.0050 mol, 0.69 g of anhydrous potassium carbonate dissolved in 2.5 mL water) in N,N‐ dimethylformamide (80 mL) was degassed by bubbling ar gon through a glass tube under the liquid surface for 20 minutes at room temperature. [1,1’ ‐Bis(diphenylphosphino)ferrocene]‐dichloropalladium (II) (5 mol %, 0.091 g, 0.000125 mol) was added, f ollowed by heating at 80°C under an atmosphere of argon for 1 day. The cooled reaction mixture was vacuum filtered through Celite, and the filtrate was concentrated under reduced pressure with heating. The residue was taken up in 125 mL dichloromethane and vacuum filtered, and the evaporate d filtrate was purified by automated flash chromatography on silica gel, eluting with a gradient of 95:5 to 81:19 v:v hexanes:ethyl acetate to affo rd the desired product as a solid (R f = 0.31, 7:3 v:v hexanes:ethyl acetate, silica, 0.08 g, 80%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.26 (s, 1H), 7.48‐7.45 (m, 3H), 7.3 5‐7.28 (m, 6H), 4.07 (s, 3H), 2.52 (s, 3H), 2.36 (s, 3H)). 6‐Chloro‐7‐methoxy‐2‐methyl‐3‐(2'‐methyl‐[ 1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐one (ELQ‐718 ) 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(2'‐methyl ‐[1,1'‐biphenyl]‐4‐yl)quinoline (0.08g, 0.00020 m ol) and anhydrous potassium acetate (10 eq, 0.0020 mol, 0.19g ) were heated at 120°C in glacial acetic acid (10 mL) for 21 hours. After cooling to room temperatur e, the reaction mixture was chilled for 30 minutes at 5°C. The desired product was recovered by vacuum filtration, rinsing with excess water followed by 2 x 3 mL acetone. The resulting solid (34 mg) was rec rystallized from N,N‐dimethylformamide (2 mL). The desired product was obtained as a gray powder (17 m g, 22%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.68 (s, 1H), 8.02 (s, 1H), 7.38‐7.26 (m, 8H), 7.09 (s, 1H ), 3.97 (s, 3H), 2.31 (s, 3H), 2.27 (s, 3H)). 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(2',3',4'‐ trifluoro‐[1,1'‐biphenyl]‐4‐yl)quinoline A mixture of 3‐(4‐bromophenyl)‐4,6‐dichloro‐7 methoxy‐2‐methylquinoline (0.70 g, 0.0018 mol), 2, 3,4‐ trifluorophenylboronic acid (1.2 eq, 0.0022 mol, 0.39 g), and aqueous potassium carbonate (2.0 eq, 0.0036 mol, 0.50 g of anhydrous potassium carbonate dissolved in 1.8 mL water) in N,N‐ dimethylformamide (80 mL) was degassed by bubbling ar gon through a glass tube under the liquid surface for 20 minutes at room temperature. [1,1’ ‐Bis(diphenylphosphino)ferrocene]‐dichloropalladium (II) (5 mol %, 0.065 g, 0.000090 mol) was added, f ollowed by heating at 80°C under an atmosphere of argon for 20 hours. The cooled reaction mixture wa s vacuum filtered, and the resulting solid was rinse d with additional DMF followed by water. After air d rying, the white solid thus obtained was taken up i n boiling DMF (50 mL) and vacuum filtered while hot, and the filtrate was then concentrated by boiling to 30 mL followed by slow cooling. Vacuum filtration afforded the desired product as tan crystals (0.39g, 48%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.25 (s, 1H), 7.66‐7.64 (m, 2H), 7.4 7 (s, 1H), 7.38‐7.36 (m, 2H), 7.27‐ 7.23 (m, ~1H, overlaps CDCl 3 solvent residual peak), 7.12‐7.06 (m, 1H), 4 .07 (s, 3H), 2.50 (s, 3H). 19‐F NMR (376 MHz; CDCl3): δ ‐135.1, ‐138.4, ‐159.7). 6‐Chloro‐7‐methoxy‐2‐methyl‐3‐(2',3',4'‐trif luoro‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐one ( ELQ‐747) 4,6‐Dichloro‐7‐methoxy‐2‐methyl‐3‐(2',3',4'‐ trifluoro‐[1,1'‐biphenyl]‐4‐yl)quinoline (0.39 g, 0.00087 mol) and anhydrous potassium acetate (10 eq, 0.0087 mol, 0.86 g) were heated at 120°C in glacial acetic aci d (10 mL) for 2 days. After cooling to room tempera ture, the reaction mixture was chilled at 5°C for 2 hours. Vacuum filtration, rinsing with excess water followed by acetone (3 x 1.5 mL), afforded the desired product as a beige powder (0.28g, 76%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.71 (s, 1H), 8.01 (s, 1H), 7.59‐7.56 (m, 2H), 7.50‐7.42 (m, 2H), 7.40 7.37 (m, 2H), 7.09 (s, 1H), 3.97 (s, 3H), 2.27 (s , 3H). 19 F NMR (376 MHz; DMSO): δ ‐136.4, ‐139.6, ‐161.0). 4‐Chloro‐6‐fluoro‐7‐methoxy‐2‐methyl‐3‐(2' ,3',4'‐trifluoro‐[1,1'‐biphenyl]‐4‐yl)quinoline A mixture of 3‐(4‐bromophenyl)‐4‐chloro‐6‐flu oro‐7‐methoxy‐2‐methylquinoline (0.70 g, 0.0018 mol), 2,3,4‐trifluorophenylboronic acid (1.2 eq, 0.0022 mol , 0.39 g), and aqueous potassium carbonate (2.0 eq, 0.0036 mol, 0.50 g of anhydrous potassium carbon ate dissolved in 1.8 mL water) in N,N‐ dimethylformamide (80 mL) was degassed by bubbling ar gon through a glass tube under the liquid surface for 20 minutes at room temperature. [1,1’ ‐Bis(diphenylphosphino)ferrocene]‐dichloropalladium (II) (5 mol %, 0.065 g, 0.000090 mol) was added, f ollowed by heating at 80°C under an atmosphere of argon for 20 hours. The cooled reaction mixture wa s vacuum filtered, and the resulting solid was rinse d with additional DMF followed by water. After air d rying, the cream crystals thus obtained (0.89 g) was taken up in boiling DMF (60 mL) and vacuum filtered while hot, and the filtrate was then concentrated by boiling to 40 mL followed by slow cooling. Vac uum filtration, rinsing with DMF (10 mL) followed by acetone (15 mL), afforded the desired product as whi te crystals (0.41 g). Meanwhile, the filtrate from initial filtration of the reaction mixture was concen trated under reduced pressure with heating. The residue was taken up in 125 mL dichloromethane and vacuum filtered, followed by automated flash chromatography of the evaporated filtrate on silica g el, eluting with a gradient of 93:7 to 70:30 v:v hexanes:ethyl acetate; this also afforded the desired product (R f = 0.24, 7:3 v:v hexanes:ethyl acetate, silica) as a white solid (0.23 g, total yield from crystallization and chromatography 0.64g, 82%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 7.86 (d, J F = 11.8 Hz, 1H), 7.66‐7.63 (m, 2H), 7.50 (d , J F = 8.1 Hz, 1H), 7.39‐7.36 (m, 2H), 7.29‐7.23 (m, ~1H, overlaps CDCl 3 solvent residual peak), 7.12‐7.06 (m, 1H), 4 .06 (s, 3H), 2.50 (s, 3H), 19 F NMR (376 MHz; CDCl3): δ ‐131.3, ‐135.1, ‐138.4, ‐159.8). 6‐Fluoro‐7‐methoxy‐2‐methyl‐3‐(2',3',4'‐trif luoro‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐one ( ELQ‐748) 4‐Chloro‐6‐fluoro‐7‐methoxy‐2‐methyl‐3‐(2' ,3',4'‐trifluoro‐[1,1'‐biphenyl]‐4‐yl)quinoline ( 0.41 g, 0.00095 mol) and anhydrous potassium acetate (10 eq, 0.0095 mol, 0.93 g) were heated at 120°C in glacial aceti c acid (10 mL) for 2 days. After cooling to room t emperature, the reaction mixture was chilled at 5°C for 2 hours. Vacuum filtration, rinsing with excess water followed by acetone (3 x 1.5 mL), afforded the desired product as a beige powder (0.34 g, 82%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.69 (s, 1H), 7.72 (d, J F = 11.7 Hz, 1H), 7.59‐7.56 (m, 2H), 7.51‐7 .42 (m, 2H), 7.40‐7.37 (m, 2H), 7.12 (d, J F = 7.3 Hz, 1H), 3.96 (s, 3H), 2.26 (s, 3H), 19 F NMR (376 MHz; DMSO): δ ‐136.4, ‐139.4, ‐139.6, ‐161.0). 4‐Chloro‐6‐fluoro‐7‐methoxy‐2‐methyl‐3‐(4 (6‐(trifluoromethyl)pyridin‐3‐yl)phenyl)quinoline A mixture of 3‐(4‐bromophenyl)‐4‐chloro‐6‐flu oro‐7‐methoxy‐2‐methylquinoline (0.57 g, 0.0015 mol), 2‐ (trifluoromethyl)pyridine‐5‐boronic acid (1.2 eq, 0. 0018 mol, 0.34 g), and aqueous potassium carbonate (2.0 eq, 0.0030 mol, 0.41 g of anhydrous potassium carbonate dissolved in 1.5 mL water) in N,N‐ dimethylformamide (60 mL) was degassed by bubbling ar gon through a glass tube under the liquid surface for 20 minutes at room temperature. [1,1’ ‐Bis(diphenylphosphino)ferrocene]‐dichloropalladium (II) (5 mol %, 0.055 g, 0.000075 mol) was added, f ollowed by heating at 80°C under an atmosphere of argon for 4 days. The cooled reaction mixture was vacuum filtered, and the filtrate was evaporated under reduced pressure with heating. The residue wa s taken up in dichloromethane (125 mL) and vacuum filtered. Automated flash chromatography of t he evaporated filtrate on silica gel, eluting with a gradient of 85:15 to 63:37 v:v hexanes:ethyl acetate. The desired product was obtained as a white, crystalline solid (0.43 g, 64%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 9.07‐9.04 (m, 1H), 8.16‐8.13 (m, 1H ), 7.86 (d, J F = 11.8 Hz, 1H), 7.82‐7.80 (m, 1H), 7.78‐7 .75 (m, 2H), 7.51 (d, J F = 8.1 Hz, 1H), 7.46‐7.43 (m, 2H), 4.07 (s, 3H), 2.50 (s, 3H), 19 F NMR (376 MHz; CDCl3): δ ‐67.7, ‐131.1). 6‐Fluoro‐7‐methoxy‐2‐methyl‐3‐(4‐(6‐(trifl uoromethyl)pyridin‐3‐yl)phenyl)quinolin‐4(1H)‐one ( ELQ‐758) 4‐chloro‐6‐fluoro‐7‐methoxy‐2‐methyl‐3‐(4 (6‐(trifluoromethyl)pyridin‐3‐yl)phenyl)quinoline ( 0.43 g, 0.00096 mol) and anhydrous potassium acetate (10 eq, 0.0096 mol, 0.94g) were heated at 120°C in glacial acetic acid (10 mL) for 1 day. After cool ing, the reaction mixture was chilled at 5°C overni ght. Vacuum filtration, rinsing with excess water followed by acetone (3 x 1.5 mL), afforded the desired product as beige crystals (0.32 g, 78%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.69 (s, 1H), 9.17‐9.15 (m, 1H), 8.44‐8.41 (m, 1H), 8.03‐7.98 (m, 1H), 7.87‐7.84 (m, 2H), 7.72 (d, J F = 11.7 Hz, 1H), 7.45‐7.42 (m, 2H), 7.12 (d, J F = 7.3 Hz, 1H), 3.97 (s, 3H), 2.27 (s, 3H), 19 F NMR (376 MHz; DMSO): δ ‐66.2, ‐139.4). SYNTHESIS OF ELQ BIPHENYLS Compounds of Formula (I) may be prepared as illustra ted in Scheme 8, below. Scheme 8: Synthesis of a series of 6‐chloro 7‐methoxy 3‐biaryl‐ELQs with structural variation at the terminal benzene ring and ELQ‐687. a Reaction (a): Pd(dppf)Cl 2 , K 2 CO 3 , DMF, 80°C, 19‐98%; (b): KOAc, AcOH, 16‐2 4 h, 57‐91%. Scheme 9: Synthesis of a series of 6‐chloro 7‐me thoxy 3‐biaryl‐ELQs with structural variation at t he inner benzene ring. a Reaction (a): Pd(dppf)Cl 2 , K 2 CO 3 , DMF, 80°C, 60 %; (b): KOAc, AcOH, 16‐24 h, 99%. Scheme 10 Scheme 11: Synthesis of a series of 7‐fluoro 7‐m ethoxy 3‐biaryl‐ELQs with structural variation at the outer benzene ring and ELQ‐688. a Reaction (a): Pd(dppf)Cl 2 , K 2 CO 3 , DMF, 80°C, 15‐51%; (b): KOAc, AcOH, 16‐2 4 h, 88‐93%. Scheme 12: Synthesis of a series of 6‐chloro 7‐m ethoxy 3‐biaryl‐ELQs alkoxy carbonate prodrugs. a Reaction (a) TBAI, K 2 CO 3 and DMF, 60°C, 24 h, 54‐70 %. Scheme 13: Synthesis of pivaloyl prodrug of ELQ‐596 . a Reaction (a) NaH and THF, 60°C, 2 h 55 %. Scheme 14: Synthesis of a series of 7‐fluoro 7‐m ethoxy 3‐biaryl‐ELQs alkoxy carbonate prodrugs. a Reaction (a) TBAI, K 2 CO 3 and DMF, 60°C, 24 h, 74‐77 %. Scheme 15: Synthesis of ELQ‐601 alkoxy carbonate pr odrug. a Reaction (a) TBAI, K 2 CO 3 and DMF, 60°C, 24 h. 72%. OCF3 O OCF3 O OCF3 O O O O O O O X (a) X (b) O O O + X H 3 CO N H 3 CO N H O - H 3 CO N X=Cl, ELQ-708 X=Cl, ELQ-598 X =F, ELQ-672 X=Cl, ELQ-707 OH X=F, ELQ-710 X=F, ELQ-709 Scheme 16: Synthesis of a series ELQ N‐oxide and ELQ‐N‐hydroxy a Reaction (a) MCPBA and CHCl 3 , 80°C, 24 h, 48‐70%. (b) EtOH/10% aqueous NaOH (4/1), 2 h, 48‐87%. Chemical synthesis procedures. Unless otherwise stated all chemicals and reagents we re from Sigma‐Aldrich Chemical Company in St. Louis, MO (USA), Combi‐Blocks, San Diego (CA), or TCI America, Portland (OR) and were used as received . 3‐(4‐bromophenyl)‐4,6‐dichloro‐7‐methoxy‐2‐m ethylquinoline (1), 3‐bromo‐4,6‐dichloro‐7‐methoxy‐2‐ methylquinoline (4), 3‐(4‐bromophenyl)‐4‐chloro‐6‐fluoro‐7‐methox y‐2‐methylquinoline (5), 3‐(4‐ bromophenyl)‐4‐chloro‐6‐fluoro‐7‐methoxy‐2‐m ethylquinoline (7), ELQ‐596, ELQ‐598, ELQ‐650 and ELQ‐ 601 were obtained as previously reported. Melting points were obtained in the Optimelt Automated Melting point system from Stanford Research Systems, Sunnyvale, CA (USA). Analytical TLC utilized Merck 60F‐254 250 micron precoated silica gel plates and spots were visualized under 254 nm UV light. GC‐M S was obtained using an Agilent Technologies 7890B gas chromatograph (30 m, DBS column set at either 100°C or 200°C for 2 min, then at 30°C/min to 3 00°C with inlet temperature set at 250°C) with an Agilent Technologies 5977A mass‐selective detector operating at 70 eV. Flash chromatography over silica gel column was performed using an Isolera One flash chromatography system from Biotage, Uppsala, Sweden. 1 H‐NMR spectra were obtained using a Bruker 400 MHz Avance NEO NanoBay NMR spectrometer operating at 400.14 MHz. The NMR raw data were analyzed using the iNMR Spectrum Analyst software. 1 H chemical shifts are reported in parts per million (ppm) relative to internal tetramethylsilane (TMS) standard or residual solvent p eak. Coupling constant values (J) are reported in hertz (Hz). Decoupled 19 F operating at 376 MHz was also obtained for compounds containing fluorine (data not shown). HPLC analyses were performed usin g an Agilent 1260 Infinity instrument with detection at 254 nm and a Phenomenex, Luna® 5 µm C8(2) 100 Å reverse phase LC column 150 x 4.6 mm at 40°C , and eluted with a gradient of A/B at 25% : 75% to A/B at 10% : 90% (A:0.05% formic acid in milliQ water, B: 0.05% formic acid in methanol). All compounds wer e at least >95% pure for in vitro testing and & gt;98% pure for in vivo testing as determined by GC‐MS, 1 H‐NMR and HPLC. General Procedure A for the synthesis of the bipheny l quinolines (3a‐p). A stirred mixture of quinoline 1(1eq), substituted phenyl boronic acids (1.1‐1.2 eq ) 2a, 2c, 2e‐2g, 2j‐2m, 15g, or pinacol esters 2b, 2d, 2h, 2i, 2n and 2o, aqueous 2M K 2 CO 3 (2 eq) and Pd(dppf)Cl 2 (0.05 eq), in DMF was deoxygenated by bubbling argon through the solution for 15 minutes. The stirred reaction mixture was then heated at 80° C under argon until no more starting material 1 remain ed as determined by GC‐MS. The reaction was cooled to room temperature and filtered through celite, and DMF was removed in vacuo. The resulting black oily solid was resuspended in DCM and stirred vigorously at room temperature for 30 minutes, filtered through celite, and concentrated to dryness. The resi due was taken up with 3‐5 ml of DCM, if all the solid was dissolved then the product was purified by flash chromatography. In instances where the products were not soluble in methylene chloride, they were filtered, washed with DCM and the filtrates were further purified by flash chomatography to give addit ional material. General Procedure B for the hydrolysis of the 4‐chloro quinolines. A stirred mixture of the 4‐chloro quinolines (3a‐o, 1eq), potassium acetate (KOAc, 10 eq) and glacial acetic acid was heated at 120°C in a loosely capped reaction vial for 16‐24 h. After co oling to room temperature, the reaction mixture was poured into ice water (20‐30 ml). The resulting precipitate was filtered washed with water (3x15 ml), acetone (3x10 ml), DCM (3x10 ml), hexane (3x10 ml) and air‐dried to give the desired product. If the products were less than 98% pure by NMR and HPLC t hey can be obtained in pure form by crystallization from DMF. General Procedure C for the synthesis of the alkoxy carbonate pro‐drug: A stirred mixture of 4‐(1H) quinolone ELQ (1 eq), tetrabutylammonium iodide (TBAI) (2 eq), dry K 2 CO 3 (2 eq) and chloromethyl ethylcarbonate (2 eq) in DMF was heated at 60°C fo r 24 h. The mixture was cooled to room temperature, filtered and the filtrate concentrated to dryness to give an oil. The resulting residue was stirred with ethyl acetate for 30 minutes and the i nsoluble TBAI filtered and washed with ethyl acetate. The filtrate was concentrated to dryness and purified by flash chromatography using a gradient of ethyl acetate/hexane as eluent to give the desired prodrug. If the resulting prodrugs were less than 98 % b y GM‐MS and NMR they can be obtained in pure form by crystallization from hexane/ethyl acetate. General procedure D for the synthesis the N‐oxide prodrugs: To a stirred solution of ELQ alkoxy carbonate (1 eq ) in chloroform was added MCPBA (1.5 eq) and the solution was heated to 90 o C for 24 hours. After cooling to room temper ature, the yellow solution was concentrated to dryness under vacuo and was purified by flash chromatography over silica gel. General procedure E for the hydrolysis of the N‐ox ide prodrugs: A solution of the alkoxy carbonate nitrone in ethano l/aqueous 10 % NaOH (4/1) was heated for 2 h at 6 0 o C some white precipitate was formed. The solu tion was concentrated to dryness. The resulting solid was then washed with water (3 x10 ml) , DCM (3 x1 0 ml) and air dried to give the desired N‐hydro xy ELQ. 3‐(3',5'‐bis(trifluoromethyl)‐[1,1'‐biphenyl]‐4‐ yl)‐4,6‐dichloro‐7‐methoxy‐2‐methylquinoline (3 a): Following the general procedure A, a mixture of 1 ( 794 mg, 2.0 mmol, 1 eq), 2a (568 mg, 2.2 mmol, 1. 1 eq), aqueous K 2 CO 3 (2 ml, 2 eq), Pd(dppf)Cl 2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 16 h to give crude 3a (1.09 gm) as a black solid. DCM (15ml) was added and the precipitate was filte red washed with methylene chloride (2 x 5 ml) to give pure 3a (305 mg) as a white solid, second crop fro m DCM give another pure 3a (126 mg). The mother liquo r was further purified by flash chromatography using a gradient of ethyl acetate/hexane (3/7) as th e eluting solvent to yield additional 3a (48 mg) fo r a combined yield of 3a (479 mg, 45% yield). GC‐ MS shows one peak M + = 529 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.25 (s, 1H), 8.12‐8.11 (m, 2H), 7.9 1‐7.90 (m, 1H), 7.78‐7.75 (m, 2H), 7.48 (s, 1H), 7.45‐7.42 (m, 2H), 4.08 (s, 3H), 2.50 (s, 3H). 4,6‐dichloro‐3‐(4'‐cyclohexyl‐[1,1'‐biphenyl]‐ 4‐yl)‐7‐methoxy‐2‐methylquinoline (3b): Following the general procedure A, a mixture of 1 (794 mg, 2.0 m mol, 1 eq), 2b (630 mg, 2.2 mmol, 1.1 eq), aqueous K 2 CO 3 (2 ml, 2 eq), Pd(dppf)Cl 2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 48 h to give crude 3a (1.03 gm) as a black solid. The product was purified twice by flash chromatography using a gradient of ethyl acetate/hexane (1/9) as the eluting solvent to give 3b (529 mg). The product was crystallized in ethyl acetate/hexane to give pure 3b (400 mg, 42 % yield) as a light yellow solid. GC‐MS shows one peak M + = 475 (42%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.24 (s, 1H), 7.72 (d, J = 8.1 Hz, 2 H), 7.61 (d, J = 8.1 Hz, 2H), 7.46 (s, 1H), 7.33‐7.31 (m, 4H) , 4.07 (s, 3H), 2.60‐2.53 (m, 1H), 2.50 (s, 3H), 1.95‐1.86 (m, 4H), 1.79‐1.76 (m, 1H), 1.53‐1.36 (m, 4H), 1.35 1.24 (m, 1H). 4,6‐dichloro‐3‐(2'‐chloro‐4'‐(trifluoromethoxy) [1,1'‐biphenyl]‐4‐yl)‐7‐methoxy‐2‐methylquin oline (3c): Following the general procedure A, a mixture of 1 ( 794 mg, 2.0 mmol, 1 eq), 2c (528 mg, 2.2 mmol, 1. 1 eq), aqueous K 2 CO 3 (2 ml, 2 eq), Pd(dppf)Cl 2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 48 h to give crude 3c (1.0 gm) as a black solid. The product was purified by flash chromatography usi ng a gradient of ethyl acetate/hexane (2/8) as the eluting solvent to give ~98% pure as determine by GC‐MS and NMR 3c (190 mg, 19% yield) as a white sol id. GC‐MS shows one peak M + = 511 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.26 (s, 1H), 7.57‐7.55 (m, 2H), 7.5 0‐7.46 (m, 2H), 7.41 (s, 1H), 7.36‐7.34 (m, 2H), 7.26‐7.23 (m, 2H), 4.08 (s, 3H), 2.51 (s, 3H). 4,6‐dichloro‐7‐methoxy‐2‐methyl‐3‐(2'‐methyl ‐4'‐(trifluoromethoxy)‐[1,1'‐biphenyl]‐4‐yl)quin oline (3d): Following the general procedure A, a mixture of 1 ( 794 mg, 2.0 mmol, 1 eq), 2d (664 mg, 2.2 mmol, 1. 1 eq), aqueous K 2 CO 3 (2 ml, 2 eq), Pd(dppf)Cl 2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 16 h to give crude 3d (1.26 gm) as a black solid. The product was purified by flash chromatography us ing a gradient of ethyl acetate/hexane (2/8) as the elut ing solvent to give 3d (654 mg) as a white solid. The product was crystallized in ethyl acetate to give pu re 3d (431 mg, 44% yield). GC‐MS shows one peak M + = 491 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.26 (s, 1H), 7.48 (s, 1H), 7.45‐7.44 (m, 1H), 7.43‐7.42 (t, 1H), 7.34‐7.31 (m, 3H), 7.17‐7.12 (m, 2H), 4.08 (s, 3 H), 2.51 (s, 3H), 2.36 (s, 3H). 4,6‐dichloro‐7‐methoxy‐2‐methyl‐3‐(2'‐(trifl uoromethoxy)‐[1,1'‐biphenyl]‐4‐yl)quinoline (3e): Following the general procedure A, a mixture of 1 (794 mg, 2 .0 mmol, 1 eq), 2e (494 mg, 2.4 mmol, 1.2 eq), aq ueous K 2 CO 3 (2 ml, 2 eq), Pd(dppf)Cl 2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 24 h to give crude 3e (2.65 gm) as a black solid. The product w as purified by flash chromatography using a gradient of ethyl acetate/hexane (2/8) as the eluting solvent to give 3e (638 mg, 67% yield ) as a white solid. G C‐MS shows one peak M + = 477 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.25 (s, 1H), 7.62‐7.59 (m, 2H), 7.57 ‐7.54 (m, 1H), 7.48 (s, 1H), 7.46‐7.39 (m, 3H), 7.36‐7 .33 (m, 2H), 4.08 (s, 3H), 2.50 (s, 3H). 4,6‐dichloro‐3‐(2'‐fluoro‐[1,1'‐biphenyl]‐4‐ yl)‐7‐methoxy‐2‐methylquinoline (3f): Following the general procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 eq), 2f (494 mg, 2.4 mmol, 1.2 eq), aqueous K 2 CO 3 (2 ml, 2 eq), Pd(dppf)Cl 2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 24 h to give crude 3f (738 mg) as a black solid. The product was purified by flash chromatography using a gradient of ethyl acetate/hexane (2/8) as the eluting solvent to give 3f (369 mg, 45% yield) as a white solid. GC‐MS s hows one peak M + = 411 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.25 (s, 1H), 7.72‐7.69 (m, 2H), 7.55 (td, J = 7.8, 1.8 Hz, 1H), 7.47 (s, 1H), 7.37‐7.34 (m, 3H inclu ding CDCl3), 7.28‐7.18 (m, 3H), 4.07 (s, 3H), 2.51 (s, 3H). 4,6‐dichloro‐7‐methoxy‐2‐methyl‐3‐(2'‐(trifl uoromethyl)‐[1,1'‐biphenyl]‐4‐yl)quinoline (3g): Following the general procedure A, a mixture of 1 (794 mg, 2 .0 mmol, 1 eq), 2g (456 mg, 2.4 mmol, 1.2 eq), aq ueous K 2 CO 3 (2 ml, 2 eq), Pd(dppf)Cl 2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 10 days to give crude 3g (1.65 g) as a black solid. The product wa s purified by flash chromatography using a gradient of ethyl acetate/hexane (2/8) as the eluting solvent to give 3g (41 mg) as a white solid. The overlap fra ction was concentrated in vacuo and the solid was crystall ized in ethyl acetate and hexane to give an additio nal 3g (200 mg) for a combined 3g (241 mg, 22 % yield). GC‐MS shows one peak M + = 461 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.26 (s, 1H), 7.79 (dd, J = 7.8, 0.5 Hz, 1H), 7.64‐7.60 (m, 1H), 7.53‐7.50 (m, 1H), 7.48‐ 7.46 (m, 4H), 7.32‐7.29 (m, 2H), 4.07 (s, 3H), 2. 50 (s, 3H). 4,6‐dichloro‐3‐(3',5'‐difluoro‐4'‐(trifluorometh oxy)‐[1,1'‐biphenyl]‐4‐yl)‐7‐methoxy‐2‐methy lquinoline (3h): Following the general procedure A, a mixture o f 1 (794 mg, 2.0 mmol, 1 eq), 2h (778 mg, 2.4 mm ol, 1.2 eq), aqueous K 2 CO 3 (2 ml, 2 eq), Pd(dppf)Cl 2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 24 h to give crude 3h (1.55 gm) as a black s olid. The product was purified by flash chromatograph y using a gradient of ethyl acetate/hexane (2/8) as th e eluting solvent to give ~95% pure as determine by GC‐MS and NMR 3h (677 mg, 66% yield) as a white solid. GC‐MS shows one peak M + = 513 (100%). 1H‐ NMR (400 MHz; CDCl 3 ): δ 8.25 (s, 1H), 7.69‐7.66 (m, 2H), 7.4 7 (s, 1H), 7.41‐7.38 (m, 2H), 7.34‐7.31 (m, 2H), 4.07 (s, 3H), 2.48 (s, 3H). 4,6‐dichloro‐3‐(3',5'‐difluoro‐4'‐methoxy‐[1,1 '‐biphenyl]‐4‐yl)‐7‐methoxy‐2‐methylquinoline (3i): Following the general procedure A, a mixture of 1 ( 794 mg, 2.0 mmol, 1 eq), 2i (648 mg, 2.4 mmol, 1. 2 eq), aqueous K 2 CO 3 (2 ml, 2 eq), Pd(dppf)Cl 2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 24 h to give crude 3i (1.48 gm) as a black solid. The product was purified by flash chromatography us ing a gradient of ethyl acetate/hexane (2/8) as the eluting solvent to give ~95% pure as determine by GC‐MS and NMR 3i (903 mg, 98% yield) as a white sol id. GC‐MS shows one peak M + = 459 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.25 (s, 1H), 7.67‐7.63 (m, 2H), 7.4 7 (s, 1H), 7.37‐7.33 (m, 2H), 7.24‐7.22 (m, 2H), 4.07‐4.06 (m, 6H), 2.49 (s, 3H). 4,6‐dichloro‐7‐methoxy‐3‐(2'‐methoxy‐5'‐(tri fluoromethoxy)‐[1,1'‐biphenyl]‐4‐yl)‐2‐methylqui noline (3j): Following the general procedure A, a mixture of 1 ( 1.19 gm, 3.0 mmol, 1 eq), 2j (850 mg, 3.6 mmol, 1 .2 eq), aqueous K 2 CO 3 (3ml, 6.0 mmol, 2 eq), Pd(dppf)Cl 2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (150 ml ) was heated for 18 h to give crude 3j (2.1 gm) as a b lack solid. The product was purified by flash chroma tography using a gradient of ethyl acetate/hexane (2/8) as th e eluting solvent to give 3j (976 mg, 64% yield) a s a white solid. GC‐MS shows one peak M + = 507 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.26 (s, 1H), 7.68‐7.65 (m, 2H), 7.47 (s, 1H), 7.34‐7.31 (m, 3H), 7.23‐7 .20 (m, 1H), 7.00 (d, J = 9.0 Hz, 1H), 4.07 (s, 3H), 3.88 (s, 3H), 2.52 (s, 3H). 4,6‐dichloro‐7‐methoxy‐3‐(2'‐methoxy‐[1,1'‐b iphenyl]‐4‐yl)‐2‐methylquinoline (3k): Following the general procedure A, a mixture of 1 (794 mg, 2.0 m mol, 1 eq), 2k (365 mg, 2.4 mmol, 1.2 eq), aqueous K 2 CO 3 (2 ml, 2 eq), Pd(dppf)Cl 2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (100 ml) was heated for 48 h to give crude 3k (1.2 gm) as a black solid. The product wa s purified by flash chromatography using a gradient of ethyl acetate/hexane (2/8) as the eluting solvent to give 3k (540 mg, 64 % yield) as a white solid. G C‐MS shows one peak M + = 423 (100%). (400 MHz; CDCl 3 ): δ 8.26 (s, 1H), 7.70‐7.67 (m, 2H), 7.47 (s, 1H), 7.43 (dd, J = 7.5, 1.7 Hz, 1H), 7.36 (ddd, J = 8.2, 7 .4, 1.8 Hz, 1H), 7.31‐7.28 (m, 2H), 7.09‐7.02 (m , 2H), 4.07 (s, 3H), 3.87 (s, 3H), 2.53 (s, 3H). 4,6‐dichloro‐7‐methoxy‐3‐(2'‐methoxy‐4'‐(tri fluoromethyl)‐[1,1'‐biphenyl]‐4‐yl)‐2‐methylquin oline (3l): Following the general A, a mixture of 1 (794 mg, 2 .0 mmol, 1 eq), 2l (528 mg, 2.4 mmol, 1.2 eq), aq ueous K 2 CO 3 (2 ml, 2 eq), Pd(dppf)Cl 2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 18 h to give crude 3l (1.0 gm) as a yellow solid. The product w as purified by flash chromatography using a gradient of ethyl acetate/hexane (2/8) as the eluting solvent to give 3l (618 mg, 63 % yield) as a white solid. G C‐MS shows one peak M + = 491 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.26 (s, 1H), 7.69‐7.66 (m, 2H), 7.54 ‐7.52 (m, 1H), 7.47 (s, 1H), 7.35‐7.32 (m, 3H), 7.23 (s , 1H), 4.07 (s, 3H), 2.51 (s, 3H). 4,6‐dichloro‐3‐(4'‐fluoro‐2'‐methoxy‐[1,1'‐b iphenyl]‐4‐yl)‐7‐methoxy‐2‐methylquinoline (3m) : Following the general A, a mixture of 1 (794 mg, 2.0 mmol, 1 eq), 2m (408 mg, 2.4 mmol, 1.2 eq), aqueous K 2 CO 3 (2 ml, 2 eq), Pd(dppf)Cl 2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 18 h. When the mixture was filtered over celite, white insoluble sol id found on top of the celite was separated and airdried to give pure 3m (503 mg, 57% yield) as a white solid. GC‐MS shows one peak M + = 441 (100%). 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.25 (s, 1H), 7.65‐7.62 (m, 2H), 7.4 7 (s, 1H), 7.39‐7.35 (m, 1H), 7.31‐7.28 (m, 2H), 6.80‐6.74 (m, 2H), 4.07 (s, 3H), 3.86 (s , 3H), 2.52 (s, 3H). 4,6‐dichloro‐7‐methoxy‐3‐(2'‐methoxy‐4'‐(tri fluoromethoxy)‐[1,1'‐biphenyl]‐4‐yl)‐2‐methylqui noline (3n): Following the general procedure A, a mixture o f 1 (794 mg, 2.0 mmol, 1 eq), 2n (763 mg, 2.4 mm ol, 1.2 eq), aqueous K 2 CO 3 (2 ml, 2 eq), Pd(dppf)Cl 2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 36 h to give crude 3n (1.40 gm) as a black s olid. The product was purified by flash chromatograph y using a gradient of ethyl acetate/hexane (2/8) as th e eluting solvent to give 3n (597 mg) as a white solid. The product was crystallized in DCM/hexane to give p ure 3n (360 mg), second crop from the mother liquor give an additional as 3n (120 mg) for a total of pure 3n (480 mg, 47% yield) as a white solid. GC MS shows one peak M + = 445 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.26 (s, 1H), 7.66‐7.63 (m, 2H), 7.47 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.33‐7.29 (m, 2H), 6.96‐6. 93 (m, 1H), 6.86 (d, J = 1.7 Hz, 1H), 4.07 (s, 3 H), 3.88 (s, 3H), 2.52 (s, 3H). 4'‐(4,6‐dichloro‐7‐methoxy‐2‐methylquinolin‐3 yl)‐2‐methoxy‐[1,1'‐biphenyl]‐4‐carbonitrile (3o): Following the general procedure A, a mixture of 1 ( 794 mg, 2.0 mmol, 1 eq), 3o (622 mg, 2.4 mmol, 1. 2 eq), aqueous K 2 CO 3 (2 ml, 2 eq), Pd(dppf)Cl 2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 110 h to give crude 3o (1.0 g) as a black solid. The product was purified by flash chromatography u sing a gradient of ethyl acetate/hexane (3/7) as the eluting solvent to give 3o (581 mg) as a white solid. The product was crystallized in ethyl acetate/DCM to give pure 3o (485 mg, 54% yield) as a white solid. GC ‐MS shows one peak M + = 448 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.25 (s, 1H), 7.68‐7.65 (m, 2H), 7.51 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.39 (dd, J = 7.8, 1.5 Hz, 1H), 7.36‐7.32 (m, 2H), 7.25 (d, J = 1.5 Hz, 1H), 4.07 (s, 3H), 3.91 (s, 3H), 2.51 (s, 3H). 4,6‐dichloro‐3‐(4‐cyclohexylphenyl)‐7‐methoxy‐ 2‐methylquinoline (3p): Following the general procedu re A, a mixture of 4 (321 mg, 1.0 mmol, 1 eq), 2p ( 300 mg, 1.05 mmol, 1.05 eq), aqueous K 2 CO 3 (1 ml, 2 eq), Pd(dppf)Cl 2 (37 mg, 0.1 mmol, 0.05 eq) and DMF (25 ml) was heated for 16 h and kept at room temperature for 72 h. After the mixture was filtered over celite white solid on top of the celite was separated to give pure 3p (90 mg) as a white solid . The filtrate was concentrated in vacuo to drynes s and was purified by flash chromatography using a gradient of ethyl acetate/hexane (1/9) as the eluting solven t to give 3p (89 mg). The product was further cryst allized in DMF to give pure 3p (26 mg) for a comb ined total 3p (116 mg, 29% yield). GC‐MS shows o ne peak M + = 399 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.23 (s, 1H), 7.45 (s, 1H), 7.34‐7.31 (m, 2H), 7.18‐7 .16 (m, 2H), 4.06 (s, 3H), 2.62‐2.55 (m, 1H), 2.4 5 (s, 3H), 1.99‐ 1.96 (m, 2H), 1.90‐1.87 (m, 2H), 1.81‐1.76 (m, 1 H), 1.51‐1.25 (m, 6H). 3‐(3',5'‐bis(trifluoromethyl)‐[1,1'‐biphenyl]‐4‐ yl)‐4‐chloro‐6‐fluoro‐7‐methoxy‐2‐methylquin oline (6a): Following the general procedure A, a mixture of 5 ( 3.81 g, 10.0 mmol, 1 eq), 2a (2.84 g, 11.0 mmol, 1.1 eq), aqueous K 2 CO 3 (20 ml, 2 eq), Pd(dppf)Cl 2 (366 mg, 0.5 mmol, 0.05 eq) and DMF (200 ml ) was heated for 16 h to give crude 6a (5.82 g) as a black so lid. The product was purified by flash chromatograp hy using a gradient of ethyl acetate/hexane (3/7) as th e eluting solvent. During the evaporation of the solvent under vacuo of the combined fractions white precipitate was formed. The product was filtered and washed with cold hexane to give pure 6a (2.46 g, 48% yield) as a white solid. GC‐MS shows one peak M + = 513 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.14 (s, 2H), 7.93 (s, 1H), 7.87 (d, J = 11.8 Hz, 1H), 7.80‐ 7.78 (m, 2H), 7.52 (d, J = 8.1 Hz, 1H), 7.47‐7.4 5 (m, 2H), 4.08 (s, 3H), 2.52 (s, 3H). 4‐chloro‐3‐(4'‐cyclohexyl‐[1,1'‐biphenyl]‐4‐ yl)‐6‐fluoro‐7‐methoxy‐2‐methylquinoline (6b): Following the general procedure A, a mixture of 5 (3.81 g, 10 mm ol, 1 eq), 2b (3.43 g, 12.0 mmol, 1.2 eq), aqueous K 2 CO 3 (20 ml, 2 eq), Pd(dppf)Cl 2 (366 mg, 0.5 mmol, 0.05 eq) and DMF (200 ml ) was heated for 16 h to give crude 6b as a black solid. The product was purified by flash chromatography using a gradient of ethyl acetate/hexane (3/7) as the eluting solvent to give 6b (1.28 g). The product was further crystallized in ethyl acetate/hexane to give pure 6b (698 mg, 15% y ield) as white crystal. GC‐MS shows one peak M + = 459 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 7.88 (d, J = 11.9 Hz, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.1 Hz, 1H), 7.35 (dd, J = 8.3, 2.1 Hz, 4H), 4.08 (s, 3H), 2.62‐2.55 (m, 1 H), 2.52 (s, 3H), 1.98‐1.79 (m, 5H), 1.56‐1.26 (m, 5H). 4,6‐dichloro‐3‐(4'‐fluoro‐2‐(trifluoromethoxy) [1,1'‐biphenyl]‐4‐yl)‐7‐methoxy‐2‐methylquino line (9): Following the general procedure A, a mixture of 4 ( 386 mg, 1.05 mmol, 1 eq), 8 (440 mg, 1.15 mmol, 1 .1 eq), aqueous K 2 CO 3 (1.1 ml, 2 eq), Pd(dppf)Cl 2 (38 mg, 0.5 mmol, 0.05 eq) and DMF (25 ml) was heated for 48 h to give crude 9 (671 mg) as a black solid. The product was purified by flash chromatography us ing a gradient of ethyl acetate/hexane (2/8) as the eluting solvent to give 9 (401 mg) and was further crysta llized in ethyl acetate/hexane to give pure 9 (310 mg, 60 % yield) as white solid. GC‐MS shows one peak M + = 495 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.27 (s, 1H), 7.59‐7.54 (m, 3H), 7.50 (s, 1H), 7.32‐7.30 (m, 2H), 7.23‐7.18 (m, 2H), 4.10 (s, 3H), 2.54 (s, 3H). 4‐chloro‐3‐(4‐cyclohexylphenyl)‐6‐fluoro‐7‐m ethoxy‐2‐methylquinoline (6p): Following the general procedure A, a mixture of 5 ( 305 mg, 1.0 mmol, 1 eq), 2p (300 mg, 1.05 mmol, 1 .05 eq), aqueous K 2 CO 3 (1 ml, 2 eq), Pd(dppf)Cl 2 (37 mg, 0.05 mmol, 0.05 eq) and DMF (25 ml) was heated for 16 h and kept at room temperature for 72 h. After the mixture was filtered over celite white solid on top of the celite was separated to give pure 6p (97 mg ) as a white solid. The filtrate was concentrated in vacuo to dryness and was purified by flash chromatography using a gradient of ethyl acetate/hexane (1/9) as the eluting solvent to give 6p (228 mg). The prod uct was further crystallized in DMF to give pure 6p (97 mg) for a combined total 3p (194 mg, 51% yield ). GC‐MS shows one peak M + = 383 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 7.84 (d, J = 12.0 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.34‐7.31 (m, 2H), 7.18‐7.15 (m, 2H), 4.05 (s, 3H), 2.62‐2.55 (m, 1H), 1.99‐1.76 (m, 5H), 1 .54‐1.26 (m, 5H). 3‐(3',5'‐bis(trifluoromethyl)‐[1,1'‐biphenyl]‐4‐ yl)‐6‐chloro‐7‐methoxy‐2‐methylquinolin‐4(1H) one (ELQ‐ 689): Following the general procedure B, a mixture o f 3a (690 mg, 1.30 mmol, 1 eq), KOAc, (1.28 g, 13 mmol, 10 eq), glacial acetic acid (5ml) was heated for 16 h to give pure ELQ‐689 (532 mg, 80 % yie ld) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.73 (s, 1H), 8.39 (s, 2H), 8.10 (s, 1H), 8.03 (s, 1H), 7.92‐7.90 (m, 2H), 7.44‐7.42 (m, 2H), 7.10 (s, 1H), 3.98 (s , 3H), 2.28 (s, 3H).` 6‐chloro‐3‐(4'‐cyclohexyl‐[1,1'‐biphenyl]‐4‐ yl)‐7‐methoxy‐2‐methylquinolin‐4(1H)‐one (ELQ‐690): Following the general procedure B, a mixture of 3b (238 mg, 0.5 mmol, 1 eq), KOAc, (490 mg, 5 mmol, 10 eq), glacial acetic acid (2 ml) was heated for 18 h to give pure ELQ‐690 (207 mg, 90 % yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.72‐11.67 (m, 1H), 8.02 (s, 1H), 7 .67‐7.62 (m, 4H), 7.35‐7.31 (m, 4H), 7.09 (s, 1H), 3.98 (s, 3H), 2.69‐2.67 (m,0.5) , 2.35‐2.33 (m, 0.5), 2.25 (s, 3H), 1.86‐1.81 (m , 4H), 1.75‐ 1.70 (m, 1H), 1.48‐1.34 (m, 5H), 1.32‐1.23 (m, 1 H). 6‐chloro‐3‐(2'‐chloro‐4'‐(trifluoromethoxy)‐[1 ,1'‐biphenyl]‐4‐yl)‐7‐methoxy‐2‐methylquinolin ‐4(1H)‐one (ELQ‐692): Following the general procedure B, a mix ture of 3c (190 mg, 0.37 mmol, 1 eq), KOAc, (363 mg, 3.7 mmol, 10 eq), glacial acetic acid (5 ml) was h eated for 24 h to give pure ELQ‐692 (161 mg, 88 % yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.72 (s, 1H), 8.02 (s, 1H), 7.72‐7. 72 (m, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.50‐7.48 (m, 3H), 7.37 (d, J = 8.2 Hz, 2H), 7.09 (s, 1H), 3.98 (s, 3H), 2.28 (s, 3H ). M.P. 337.8‐ 338.9 o C with decomposition. 6‐chloro‐7‐methoxy‐2‐methyl‐3‐(2'‐methyl‐4 '‐(trifluoromethoxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin ‐4(1H)‐one (ELQ‐693): Following the general procedure B, a mix ture of 3d (430 mg, 0.87 mmol, 1 eq), KOAc, (853 mg, 8.7 mmol, 10 eq), glacial acetic acid (4 ml) was h eated for 24 h to give pure ELQ‐693 (334 mg, 81 % yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.69 (s, 1H), 8.02 (s, 1H), 7.40‐7. 33 (m, 6H), 7.28‐7.26 (m, 1H), 7.08 (s, 1H), 3.97 (s, 3H), 2.34 (s, 3H), 2.27 (s, 3H). M.P. 325.9‐327.1 o C with decomposition. 6‐chloro‐7‐methoxy‐2‐methyl‐3‐(2'‐(trifluoro methoxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐one (ELQ‐ 702): Following the general procedure B, a mixture o f 3e (638 mg, 1.33 mmol, 1 eq), KOAc, (1.30 g, 13 .3 mmol, 10 eq), glacial acetic acid (5 ml) for heated for 24 h to give pure ELQ‐702 (334 mg, 76 % y ield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.71 (s, 1H), 8.02 (s, 1H), 7.62‐7. 60 (m, 1H), 7.55‐7.48 (m, J = 2.3 Hz, 5H), 7.38‐7.35 (m, 2H), 7.09 (s, 1H), 3.98 (s, 3H), 2.26 (s, 3H). M.P. 293.1‐294.3 o C with decomposition. 6‐chloro‐3‐(2'‐fluoro‐[1,1'‐biphenyl]‐4‐yl) 7‐methoxy‐2‐methylquinolin‐4(1H)‐one (ELQ‐703): Following the general procedure B, a mixture of 3f (369 mg, 0.90 mmol, 1 eq), KOAc, (882 mg, 9.0 mmol, 10 eq), glacial acetic acid (5 ml) for 24 h to give pure ELQ‐703 (262 mg, 74 % yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.72 (s, 1H), 8.02 (s, 1H), 7.62‐7. 57 (m, 3H), 7.45‐7.32 (m, 5H), 7.08 (s, 1H), 3.97 (s, 3H), 2.27 (s, 3H). M.P. 370.4‐371 o C with decomposition. 6‐chloro‐7‐methoxy‐2‐methyl‐3‐(2'‐(trifluoro methyl)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐one (ELQ‐704): Following the general procedure B, a mixture of 3g (200 mg, 0.43 mmol, 1 eq), KOAc, (421 mg, 4.3 mmol , 10 eq), glacial acetic acid (5 ml) was heated for 24 h to give pure ELQ‐704 (152 mg, 80 % yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.74 (s, 1H), 8.02 (s, 1H), 7.87‐7. 85 (m, 1H), 7.77‐7.74 (m, 1H), 7.65‐7.62 (m, 1H), 7.49‐7.47 (m, 1H), 7.33 (s, 4 H), 7.09 (s, 1H), 3.98 (s, 3H), 2.26 (s, 3H). M.P. 350.7‐351.3 o C with decomposition. 6‐chloro‐3‐(3',5'‐difluoro‐4'‐(trifluoromethoxy) ‐[1,1'‐biphenyl]‐4‐yl)‐7‐methoxy‐2‐methylqui nolin‐4(1H)‐ one (ELQ‐717): Following the general procedure B, a mixture of 3h (677 mg, 1.3 mmol, 1 eq), KOAc, (1 .27 g, 13 mmol, 10 eq), glacial acetic acid (10 ml) wa s heated for 24 h to give pure ELQ‐717 (507 mg, 79 % yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.72 (s, 1H), 8.02 (s, 1H), 7.85‐7. 80 (m, J = 11.6, 9.0 Hz, 4H), 7.39 (d, J = 8.4 Hz, 2H), 7.09 (s, 1H), 3.98 (s, 3H), 2.26 (s, 3H). 6‐chloro‐3‐(3',5'‐difluoro‐4'‐methoxy‐[1,1'‐ biphenyl]‐4‐yl)‐7‐methoxy‐2‐methylquinolin‐4(1 H)‐one (ELQ‐ 716): Following the general procedure B, a mixture o f 3i (917 mg, 1.98 mmol, 1 eq), KOAc, (1.95 g, 19 .8 mmol, 10 eq), glacial acetic acid (15 ml) was heate d for 18 h to give pure ELQ‐716 (500 mg, 57 % yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 8.01 (s, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 9.8 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.08 (s, 1H), 3.98‐3.9 7(2s, 6H), 2.25 (s, 3H). 6‐chloro‐7‐methoxy‐3‐(2'‐methoxy‐5'‐(trifluo romethoxy)‐[1,1'‐biphenyl]‐4‐yl)‐2‐methylquinoli n‐4(1H)‐ one (ELQ‐727): Following the general B, a mixture of 3j (976 mg, 1.92 mmol, 1 eq), KOAc, (1.88 g, 1 9.2 mmol, 10 eq), glacial acetic acid (10 ml) for heate d for 18 h to give pure ELQ‐727 (697 mg, 74 % yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.69 (s, 1H), 8.02 (s, 1H), 7.54‐7. 52 (m, 2H), 7.38‐7.30 (m, 4H), 7.24‐7.22 (m, 1H), 7.09 (s, 1H), 3.96‐3.95 (m, 3H), 3.88‐3.82 (m, 3H), 2.31‐2.24 (m, 3H). M .P. 297.3‐ 298.1 o C with decomposition. 6‐chloro‐7‐methoxy‐3‐(2'‐methoxy‐[1,1'‐biphe nyl]‐4‐yl)‐2‐methylquinolin‐4(1H)‐one (ELQ‐728): Following the general procedure B, a mixture of 3k (540 mg, 1.27 mmol, 1 eq), KOAc, (1.24 g, 12.7 mmo l, 10 eq), glacial acetic acid (5 ml) was heated for 18 h to give pure ELQ‐728 (467 mg, 91 % yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.67 (s, 1H), 8.02 (s, 1H), 7.51‐7. 49 (m, 2H), 7.38‐7.34 (m, 2H), 7.29‐7.26 (m, 2H), 7.15‐7.13 (m, 1H), 7.09 (s, 1 H), 7.06 (td, J = 7.4, 1.0 Hz, 1H), 3.98 (s, 3H), 3.81 (s, 3H), 2.27 (s, 3H). M.P. 327.3‐327.9 o C with decomposition. 6‐chloro‐7‐methoxy‐3‐(2'‐methoxy‐4'‐(trifluo romethyl)‐[1,1'‐biphenyl]‐4‐yl)‐2‐methylquinolin ‐4(1H)‐one (ELQ‐742): Following the general procedure B, a mix ture of 3l (600 mg, 1.22 mmol, 1 eq), KOAc, (1.20 g, 12.2 mmol, 10 eq), glacial acetic acid (10 ml) was heated for 18 h to give pure ELQ‐742 (455 mg, 7 9 % yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.70 (s, 1H), 8.02 (s, 1H), 7.59‐7. 53 (m, 4H), 7.42‐ 7.40 (m, 2H), 7.34‐7.31 (m, 2H), 7.09 (s, 1H), 3. 98 (s, 3H), 3.90 (s, 3H), 2.27 (s, 3H). M.P. 350.7 ‐351.2 o C with decomposition. 6‐chloro‐3‐(4'‐fluoro‐2'‐methoxy‐[1,1'‐biphe nyl]‐4‐yl)‐7‐methoxy‐2‐methylquinolin‐4(1H)‐ one (ELQ‐743): Following the general procedure B, a mixture of 3m (500 mg, 1.13mmol, 1 eq), KOAc, (1.11 g, 11.3 mmol, 10 eq), glacial acetic acid (10 ml) was heated for 18 h to give ELQ‐743 (455 mg). The product was further crystallized from DMF to pure ELQ‐743 (290 mg, 50 % yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐ d 6 ): δ 11.67 (s, 1H), 8.02 (s, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.37 (dd, J = 8.4, 7.0 Hz, 1H ), 7.27 (d, J = 8.2 Hz, 2H), 7.08 (s, 1H), 7.04 (dd, J = 11.5, 2.4 Hz, 1H ), 6.88 (td, J = 8.4, 2.5 Hz, 1H), 3.97 (s, 3H), 3.83 (s, 3H), 2.26 (s, 3H). M.P. 360.7‐361.1 o C with decomposition. 6‐chloro‐7‐methoxy‐3‐(2'‐methoxy‐4'‐(trifluo romethoxy)‐[1,1'‐biphenyl]‐4‐yl)‐2‐methylquinoli n‐4(1H)‐ one (ELQ‐744): Following the general procedure B, a mixture of 3n (380 mg, 0.75 mmol, 1 eq), KOAc, (735 mg, 7.5 mmol, 10 eq), glacial acetic acid (10 ml) was for 18 h to give ELQ‐744 (314 mg, 85% yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 8.02 (s, 1H), 7.52‐7.49 (m, 2H), 7.4 7 (d, J = 8.4 Hz, 1H), 7.31‐7.28 (m, 2H), 7.13 (d, J = 2.0 Hz, 1H), 7.0 9 (s, 1H), 7.06‐7.03 (m, J = 1.2 Hz, 1H), 3.98 (s, 3H), 3.85 (s, 3H). M.P. 344.5‐345.1 o C with decomposition. 4'‐(6‐chloro‐7‐methoxy‐2‐methyl‐4‐oxo‐1,4 dihydroquinolin‐3‐yl)‐2‐methoxy‐[1,1'‐biphenyl ]‐4‐ carbonitrile (ELQ‐745): Following the general procedu re B, a mixture of 3o (449 mg, 1.0 mmol, 1 eq), KOAc, (980 mg, 10.0 mmol, 10 eq), glacial acetic ac id (10 ml) for 18 h to give ELQ‐745 (384 mg, 89 % yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.69 (s, 1H), 8.02 (s, 1H), 7.61 (d, J = 1.3 Hz, 1H), 7.57‐7.51 (m, 4H), 7.34‐7.31 (m, 2H), 7.09 (s, 1 H), 3.98 (s, 3H), 3.88 (s, 3H), 2.27 (s, 3H). M.P. 352.7‐353.2 o C with decomposition. 3‐(4'‐cyclohexyl‐[1,1'‐biphenyl]‐4‐yl)‐6‐flu oro‐7‐methoxy‐2‐methylquinolin‐4(1H)‐one (ELQ 694): Following the general procedure B, a mixture of 6a (2.05 g, 4.0 mmol, 1 eq), KOAc, (3.90 g, 40.0 mmol , 10 eq), glacial acetic acid (10 ml) was heated for 24 h to give ELQ‐694 (1.76 g, 89% yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.71 (s, 1H), 8.38 (s, 2H), 8.10 (s, 1H), 7.91‐7.88 (m, 2H), 7.73 (d, J = 11.7 Hz, 1H), 7.44‐7.40 (m, 2H), 7.11 (d, J = 7. 3 Hz, 1H), 3.96 (s, 3H), 2.27 (s, 3H). 3‐(3',5'‐bis(trifluoromethyl)‐[1,1'‐biphenyl]‐4‐ yl)‐6‐fluoro‐7‐methoxy‐2‐methylquinolin‐4(1H) one (ELQ‐ 697): Following the general procedure B, a mixture o f 6b (698 mg, 1.52 mmol, 1 eq), KOAc, (1.49 g, 15 .2 mmol, 10 eq), glacial acetic acid (10 ml) was heate d for 24 h to give ELQ‐697 (623 mg, 93% yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.68 (s, 1H), 7.72 (d, J = 11.7 Hz, 1H), 7.67‐7.61 (m, 4H), 7.34‐7.30 (m, 4H), 7.12 (d, J = 7.4 Hz, 1H), 3.9 7 (s, 3H), 2.59‐2.54 (m, 1H), 2.26 (s, 3H), 1.85 1.71 (m, 5H), 1.51‐1.24 (m, 5H). 6‐chloro‐3‐(4'‐fluoro‐2‐(trifluoromethoxy)‐[1, 1'‐biphenyl]‐4‐yl)‐7‐methoxy‐2‐methylquinolin 4(1H)‐one (ELQ‐762): Following the general procedure B, a mix ture of 9 (310 mg, 0.63 mmol, 1 eq), KOAc, (517 m g, 6.3 mmol, 10 eq), glacial acetic acid (5 ml) was h eated for 24 h to give ELQ‐762 (300 mg, 99% yiel d) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 12.21‐11.94 (m, 1H), 8.03 (s, 1H), 7 .60‐7.54 (m, 3H), 7.42‐ 7.33 (m, 4H), 7.18‐7.15 (m, 1H), 4.00‐3.95 (m, 3 H), 2.32‐2.32 (m, 3H). M.P. 300‐301 o C. ((6‐chloro‐7‐methoxy‐2‐methyl‐3‐(3'‐(trifluo romethoxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4‐yl)ox y)methyl ethyl carbonate (ELQ‐652): Following the general pro cedure C, using a mixture of ELQ‐604 (150 mg, 0.3 3 mmol, 1 eq), TBAI (244 mg, 0.66 mmol, 2 eq), dry K 2 CO 3 (92 mg, 0.66 mmol, 2 eq) and chloromethyl ethylcarbonate (91.7 mg, 0.66 mmol, 2 eq) in DMF (1 5 ml) to give crude ELQ‐652 (193 mg). The product was purified by flash chromatography using ethyl acet ate/hexane (3/7) followed by crystallization in ethyl acetate/hexane to give pure ELQ‐652 (100 mg, yield 54%) as a white solid. GC‐MS shows one pea k M + = 561 (45%), M + = 459 (100%). 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.08 (s, 1H), 7.76‐7.73 (m, 2H), 7.6 5‐7.63 (m, 1H), 7.56‐7.49 (m, 5H), 7.47 (s, 1H), 5.32 (s , 2H), 5.31 (s, ), 4.13 (q, J = 7.1 Hz, 2H), 4.0 8 (s, 3H), 2.56 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H). ((6‐chloro‐7‐methoxy‐2‐methyl‐3‐(3'‐(trifluo romethyl)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4‐yl)oxy )methyl ethyl carbonate (ELQ‐671): Following the general procedure C, using a mixture of ELQ‐646 (150 mg, 0.34 mmol, 1 eq), TBAI (251 mg, 0.68 mmol, 2 eq), dry K 2 CO 3 (95 mg, 0.68 mmol, 2 eq) and chloromethyl ethylcarbonate (95 mg, 0.68 mmol, 2 eq) in DMF (30 ml) to give crude ELQ‐671 (188 mg). The product was purified by flash chromatography using ethyl acet ate/hexane (3/7) followed by crystallization in ethyl acetate/hexane to give pure ELQ‐671 (91 mg) and a second crop (23 mg) for a total ELQ‐671 (1 14 mg, yield 61 %) as a white solid. GC‐MS shows on e peak M + = 545 (37 %), M + = 443 (100 %). 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.08 (s, 1H), 7.96‐7.95 (m, 1H), 7.9 0‐7.87 (m, 1H), 7.79‐7.76 (m, 2H), 7.70‐7.62 (m , 2H), 7.54‐7.51 (m, 2H), 7.47 (s, 1H), 5.32 (s, 2H), 4. 13 (q, J = 7.1 Hz, 2H), 4.08 (s, 3H), 2.57 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3H). ((3‐(3',5'‐bis(trifluoromethyl)‐[1,1'‐biphenyl]‐4 yl)‐6‐chloro‐7‐methoxy‐2‐methylquinolin‐4‐ yl)oxy)methyl ethyl carbonate (ELQ‐699): Following the general pro cedure C, using a mixture of ELQ‐689 (511 mg, 1.0 mmol, 1 eq), TBAI (738 mg, 2.0 mmol, 2 eq), dry K 2 CO 3 (278 mg, 2.0 mmol, 2 eq) and chloromethyl ethylcarbonate (278 mg, 2.0 mmol, 2 eq) in DMF (50 ml) to give crude ELQ‐699 (707 mg). The product was purified by flash chromatography using ethyl acet ate/hexane (2/8) followed by crystallization in ethyl acetate/hexane to give pure ELQ‐699 (400 mg, yield 65 %) as a white solid. GC‐MS shows one p eak M + = 613 (30 %), M + = 511 (100 %). 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.11 (s, 2H), 8.06 (s, 1H), 7.91 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 7.9 Hz, 2H), 7.45 (s, 1H), 5.30 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 4.06 (s, 3H), 2.54 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H). ((6‐chloro‐7‐methoxy‐2‐methyl‐3‐(2'‐(trifluo romethoxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4‐yl)ox y)methyl ethyl carbonate (ELQ‐711): Following the general pro cedure C, using a mixture of ELQ‐702 (230 mg, 0.5 mmol, 1 eq), TBAI (369 mg, 1.0 mmol, 2 eq), dry K 2 CO 3 (139 mg, 1.0 mmol, 2 eq) and chloromethyl ethylcarbonate (139 mg, 2.0 mmol, 2 eq) in DMF (25 ml) to give crude ELQ‐711 (737 mg). The product was purified by flash chromatography using ethyl acet ate/hexane (2/8) followed by crystallization in ethyl acetate/hexane to give pure ELQ‐711 (160 mg, yield 57 %) as a white solid. GC‐MS shows one p eak M + = 561 (33%), M + = 459 (100 %). 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.09 (s, 1H), 7.64‐7.61 (m, 2H), 7.5 7‐7.55 (m, 1H), 7.50‐7.40 (m, 5H), 5.27 (s, 2H), 4.16 (q , J = 7.1 Hz, 2H), 4.08 (s, 3H), 2.58 (s, 3H), 1 .25 (t, J = 7.1 Hz, 3H). ((6‐chloro‐7‐methoxy‐3‐(2'‐methoxy‐4'‐(trifl uoromethoxy)‐[1,1'‐biphenyl]‐4‐yl)‐2‐methylquino lin‐4‐ yl)oxy)methyl ethyl carbonate (ELQ‐749): Following th e general procedure C, using a mixture of ELQ‐744 (980 mg, 2.0 mmol, 1 eq), TBAI (1.48 g, 4.0 mmol, 2 eq), dry K 2 CO 3 (556 mg, 4.0 mmol, 2 eq) and chloromethyl ethylcarbonate (556 mg, 4.0 mmol, 2 eq) in DMF (100 ml) to give crude ELQ‐749 (737 mg). The product was purified by flash chromatography usin g ethyl acetate/hexane (4/6) followed by crystallization in ethyl acetate/hexane to give pure ELQ‐749 (830 mg, yield 70 %) as a light‐yellow crystal. GC‐MS shows one peak M + = 591 (48%), M + = 489 (100 %). 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.06 (s, 1H), 7.66‐7.63 (m, 2H), 7.44‐7.40 (m, 4H), 6.96‐6.93 (m, J = 1.1 Hz, 1H), 6.87‐6.86 (m, 1H), 5.29 (s , 2H), 4.13 (q, J = 7.1 Hz, 2H), 4.05 (s, 3H), 3.88 (s, 3H), 2.56 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H). 6‐chloro‐7‐methoxy‐2‐methyl‐3‐(4'‐(trifluoro methoxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4‐yl piv alate (ELQ‐ 753): A mixture of ELQ‐596 (1.84 g, 4.0 mmol, 1 eq) and sodium hydride 60% oil suspension (320 mg, 8.0 mmol, 2 eq) in dry THF (75 ml) was heated at 60 oC for 30 minutes. Then pivaloyl chloride (968 mg, 8.0 mmol, 2 eq) was added and the cloudy solution was heated for another 2 hours. After cooling to room temperature water (2 ml) was added resulting in a f ormation of yellow sticky solid. This was filtered a nd the sticky solid washed with ethyl acetate (3x10 ml) . The combined filtrate was concentrated in vaccuo to give crude ELQ‐753 (2.41 mg) as a yellow solid . The product was purified by flash chromatography using ethyl acetate/hexane (2/8) followed by crystalli zation ethyl acetate to give pure ELQ‐753 (1.20 g, yield 55%) as a white crystal. GC‐MS shows one pe ak M + = 543 (5%), M + = 57 (100 %). 1 H‐NMR (400 MHz; CDCl 3 ): δ 7.67 (s, 1H), 7.66‐7.65 (m, 2H), 7.6 4‐7.63 (m, 2H), 7.50 (s, 1H), 7.35‐7.33 (m, 2H), 7.32‐7.31 (m, 2H), 4.06 (s, 3H), 2.52 (s, 3H), 1.08 (s, 9H). Ethyl (((6‐fluoro‐7‐methoxy‐2‐methyl‐3‐(4'‐ (trifluoromethoxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4 ‐ yl)oxy)methyl) carbonate (ELQ‐672): Following the gen eral procedure C, using a mixture of ELQ‐650 (1.77 g, 4.0 mmol, 1 eq), TBAI (2.95 g, 8.0 mmol, 2 eq), dry K 2 CO 3 (1.11 g, 8.0 mmol, 2 eq) and chloromethyl ethylcarbonate (1.11 g, 8.0 mmol, 2 eq) in DMF (150 ml) to give crude ELQ‐672 (2.75 g). The product was purified by flash chromatography usin g ethyl acetate/hexane (2/8) followed by crystallization in ethyl acetate/hexane to give pure ELQ‐650 (1.62 g, yield 74%) as a white crystal. G C‐MS shows one peak M + = 545 (40%), M + = 443 (100 %). 1 H‐NMR (400 MHz; CDCl 3 ): δ 7.72‐7.66 (m, 5H), 7.49‐ 7.46 (m, 3H), 7.35‐7.33 (m, 2H), 5.29 (s, 2H), 4. 09 (q, J = 7.1 Hz, 2H), 4.04 (s, 3H), 2.54 (s, 3 H), 1.20 (t, J = 7.1 Hz, 3H). ((3‐(3',5'‐bis(trifluoromethyl)‐[1,1'‐biphenyl]‐4 yl)‐6‐fluoro‐7‐methoxy‐2‐methylquinolin‐4‐ yl)oxy)methyl ethyl carbonate (ELQ‐696): Following the general pro cedure C, using a mixture of ELQ‐694 (495 mg, 1.0 mmol, 1 eq), TBAI (738 g, 2.0 mmol, 2 eq), dry K 2 CO 3 (278 mg, 2.0 mmol, 2 eq) and chloromethyl ethylcarbonate (278 mg, 2.0 mmol, 2 eq) in DMF (50 ml) to give crude ELQ‐696 (816 mg) . The product was purified by flash chromatography using ethyl acet ate/hexane (2/8) followed by trituration with hexane and cool to 4 o C for 12 h to give pure ELQ‐696 (459 mg, y ield 77%) as a white solid. GC‐MS shows one peak M + = 597 (25%), M + = 495 (100 %). 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.12‐8.11 (m, 2H), 7.92‐7.91 (m, 1H), 7.78‐7.75 (m, 2H), 7.68 (d, J = 11.7 Hz , 1H), 7.57‐7.54 (m, 2H), 7.48 (d, J = 8.0 Hz, 1H), 5.30 (s, 2H), 4.09 (q, J = 7.1 Hz, 2H), 4.05 (s, 3H), 2.54 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). ((3‐(4'‐cyclohexyl‐[1,1'‐biphenyl]‐4‐yl)‐6‐f luoro‐7‐methoxy‐2‐methylquinolin‐4‐yl)oxy)methyl ethyl carbonate (ELQ‐698): Following the general procedure C, using a mixture of ELQ‐697 (442 mg, 1.0 mmol, 1 eq), TBAI (738 g, 2.0 mmol, 2 eq), dry K 2 CO 3 (278 mg, 2.0 mmol, 2 eq) and chloromethyl ethylcarbonate (278 mg, 2.0 mmol, 2 eq) in DMF (50 ml) to give crude ELQ‐698 (816 mg) . The product was purified by flash chromatography using ethyl acet ate/hexane (2/8) give pure ELQ‐698 (420 mg, yield 77%) as a white solid. GC‐MS shows one peak M + = 543 (50 %), M + = 207 (100 %). 1 H‐NMR (400 MHz; CDCl 3 ): δ 7.74‐7.70 (m, 2H), 7.67 (d, J = 11. 7 Hz, 1H), 7.63‐7.60 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.45‐7.42 (m, 2H), 7.35‐7.31 (m, 2H), 5.27 (s, 2H), 4.09 (q , J = 7.1 Hz, 2H), 4.04 (s, 3H), 2.60‐2.57 (m, 1H), 2.54 (s, 3H), 1.95‐1.75 (m, 5H), 1.53‐1.26 (m, 5H), 1.20 (t, J = 7.1 Hz, 3H). ((5,7‐difluoro‐2‐methyl‐3‐(4'‐(trifluoromethoxy) ‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4‐yl)oxy)methyl ethyl carbonate (ELQ‐761): Following the general procedure C, using a mixture of ELQ‐601 (431 mg, 1.0 mmol, 1 eq), TBAI (738 g, 2.0 mmol, 2 eq), dry K 2 CO 3 (278 mg, 2.0 mmol, 2 eq) and chloromethyl ethylcarbonate (278 mg, 2.0 mmol, 2 eq) in DMF (50 ml) to give crude ELQ‐761 (521 mg) . The product was purified by flash chromatography using ethyl acet ate/hexane (2/8) give pure ELQ‐761 (382 mg, yield 72%) as a white solid. GC‐MS shows one peak M + = 533 (25 %), M + = 431 (100 %). 1 H‐NMR (400 MHz; CDCl 3 ): δ 7.73‐7.70 (m, 4H), 7.56 (ddd, J = 9 .7, 2.5, 1.4 Hz, 1H), 7.49‐7.46 (m, 2H), 7.37‐7. 35 (m, 2H), 7.04 (ddd, J = 11.8, 9.0, 2.6 Hz, 1H), 5.41 (d, J = 1 .1 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 2.57 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3H). 6‐chloro‐4‐(((ethoxycarbonyl)oxy)methoxy)‐7‐methox y‐2‐methyl‐3‐(4'‐(trifluoromethoxy)‐[1,1'‐ biphenyl]‐4‐yl)quinoline 1‐oxide (ELQ‐707): Follo wing the general procedure D, using a solution of E LQ‐ 598 (562 mg, 1.0 mmol, 1 eq) and MCPBA (260 mg, 1 .5 mmol, 1.5 eq) in chloroform (25 ml) to give cru de ELQ‐707 (1.0 g). The crude ELQ‐707 was dissolved in DCM (5 ml) cooled at 4 o C for 12 h, filtered and the filtrate was purified by flash chromatography using e thyl acetate/DCM (6/4) followed by crystallization in ethyl acetate/hexane to give pure ELQ‐707 (397 mg, yield 69%) as a yellow crystal. 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.25 (s, 1H), 8.11 (s, 1H), 7.74‐7.6 7 (m, 4H), 7.48‐7.45 (m, 2H), 7.36‐7.33 (m, 2H), 5.25 (s, 2H), 4.13 (s, 3H), 4.08 (q, J = 7.1 Hz, 2H), 2.57 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H). 3‐(3',5'‐bis(trifluoromethyl)‐[1,1'‐biphenyl]‐4‐ yl)‐6‐chloro‐4‐(((ethoxycarbonyl)oxy)methoxy)‐7‐ methoxy‐ 2‐methylquinoline 1‐oxide (ELQ‐736): Following the general procedure D, using a solution of ELQ‐699 (250 mg, 0.41 mmol, 1 eq) and MCPBA (106 mg, 1.5 mmol, 1.5 eq) in chloroform (25 ml) to give crude ELQ‐707 (1.0 g). The product was purified by flash chromatography using ethyl acetate/DCM (6/4) followed by crystallization in ethyl acetate/hexane to give pure ELQ‐736 (180 mg, yield 70%) as a whit e solid. 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.27 (s, 1H), 8.14 (s, 1H), 8.13 (s, 2H), 7.95 (s, 1H), 7.83‐7.80 (m, 2H), 7.58‐7.56 (m, 2H), 5.28 (s, 2H), 4.16 (s, 3H), 4. 11 (q, J = 7.1 Hz, 2H), 2.59 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H). 4‐(((ethoxycarbonyl)oxy)methoxy)‐6‐fluoro‐7‐methox y‐2‐methyl‐3‐(4'‐(trifluoromethoxy)‐[1,1'‐ biphenyl]‐4‐yl)quinoline 1‐oxide (ELQ‐709): Follo wing the general procedure D, using a solution of E LQ‐ 672 (545 mg, 1.0 mmol, 1 eq) and MCPBA (260 mg, 1 .5 mmol, 1.5 eq) in chloroform (25 ml) to give cru de ELQ‐709 (898 mg). The product was purified by flas h chromatography using ethyl acetate/DCM (6/4) followed by crystallization in ethyl acetate/hexane to give pure ELQ‐709 (352 mg, yield 63%) as a whit e solid. 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.31 (d, J = 8.0 Hz, 1H), 7.77‐7.69 (m, 5H), 7.50‐7.48 (m, 2H), 7.38‐ 7.35 (m, 2H), 5.26 (s, 2H), 4.13 (s, 3H), 4.09 (q, J = 7.1 Hz, 2H), 2.59 (s, 3H), 1.20 (t, J = 7. 1 Hz, 3H). 3‐(3',5'‐bis(trifluoromethyl)‐[1,1'‐biphenyl]‐4‐ yl)‐4‐(((ethoxycarbonyl)oxy)methoxy)‐6‐fluoro‐7‐ methoxy‐ 2‐methylquinoline 1‐oxide (ELQ‐737): Following the general procedure D, using a solution of ELQ‐696 (245 mg, 0.41 mmol, 1 eq) and MCPBA (105 mg, 1.5 mmol, 1.5 eq) in chloroform (25 ml) to give crude ELQ‐709 (376 mg). The product was purified by flas h chromatography using ethyl acetate/DCM (6/4) followed by crystallization in ethyl acetate/hexane to give pure ELQ‐737 (121 mg, yield 48%) as a whit e crystal. 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.31 (d, J = 8.0 Hz, 1H), 8.13 (s, 2H), 7.95 (s, 1H), 7.82‐7.75 (m, 3H), 7.58‐7.56 (m, 2H), 5.28 (s, 2H), 4.14 (s, 3H), 4. 09 (q, J = 7.1 Hz, 2H), 2.58 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). 4‐(((ethoxycarbonyl)oxy)methoxy)‐5,7‐difluoro‐2‐me thyl‐3‐(4'‐(trifluoromethoxy)‐[1,1'‐biphenyl]‐4 yl)quinoline 1‐oxide (ELQ‐735): Following the gener al procedure D, using a solution of ELQ‐761 (382 mg, 0.72 mmol, 1 eq) and MCPBA (187 mg, 1.5 mmol, 1.5 eq) in chloroform (25 ml) to give crude ELQ‐735 (581 mg). The product was purified by flash chromato graphy using ethyl acetate/DCM (6/4) followed by crystallization in ethyl acetate/hexane to give pure ELQ‐735 (235 mg, yield 59 %) as a white crystal. 6‐chloro‐1‐hydroxy‐7‐methoxy‐2‐methyl‐3‐(4 '‐(trifluoromethoxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin ‐4(1H)‐one (ELQ‐708): Following the general procedure E, using a solution of ELQ‐707 (145 mg, 0.25 mmol, 1 eq) in ethanol/aqueous 10 % NaOH (10 ml) to give pure ELQ 708 (92 mg, yield 77%) as a brown solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 8.05 (s, 1H), 7.85‐7.83 (m, 2H), 7.7 4 (broad s, 1H), 7.66‐7.64 (m, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 3.88 (s, 3H), 2.28 (s, 3H). 3‐(3',5'‐bis(trifluoromethyl)‐[1,1'‐biphenyl]‐4‐ yl)‐6‐chloro‐1‐hydroxy‐7‐methoxy‐2‐methylqui nolin‐4(1H)‐ one (ELQ‐739): Following the general procedure E, u sing a solution of ELQ‐736 (100 mg, 0.16 mmol, 1 eq) in ethanol/aqueous 10 % NaOH (10 ml) to give p ure ELQ‐739 (72 mg, yield 86%) as a red solid. 1 H‐ NMR (400 MHz; DMSO‐d 6 ): δ 8.37 (s, 2H), 8.07‐8.06 (m, J = 4.9 Hz, 2H), 7.84 (d, J = 8.3 Hz, 2H), 7.77 (broad s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 3.90 (s, 3H), 2.29 (s, 3H). 6‐fluoro‐1‐hydroxy‐7‐methoxy‐2‐methyl‐3‐(4 '‐(trifluoromethoxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin ‐4(1H)‐one (ELQ‐710): Following the general procedure E, using a solution of ELQ‐709 (140 mg, 0.25 mmol, 1 eq) in ethanol/aqueous 10 % NaOH (10 ml) to give pure ELQ 710 (100 mg, yield 87%) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 7.84 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 12.0 Hz, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.53 (broad s, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 7.9 Hz, 2H), 3.77 (s, 3H), 2.24 (s, 3H). 3‐(3',5'‐bis(trifluoromethyl)‐[1,1'‐biphenyl]‐4‐ yl)‐6‐fluoro‐1‐hydroxy‐7‐methoxy‐2‐methylqui nolin‐4(1H)‐ one (ELQ‐740): Following the general procedure E, u sing a solution of ELQ‐737 (100 mg, 0.16 mmol, 1 eq) in ethanol/aqueous 10 % NaOH (10 ml) to give p ure ELQ‐740 (68 mg, yield 83%) as a white solid. 1 H‐ NMR (400 MHz; DMSO‐d 6 ): δ 12.06 (s, 1H), 8.39 (s, 2H), 8.11 (s, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 11.4 Hz, 1H), 7.46‐7.40 (m, 3H), 4.02 (s, 3H), 2. 35 (s, 3H). 5,7‐difluoro‐1‐hydroxy‐2‐methyl‐3‐(4'‐(trifl uoromethoxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H) one (ELQ‐ 738): Following the general procedure E, using a sol ution of ELQ‐735 (100 mg, 0.16 mmol, 1 eq) in ethanol/aqueous 10 % NaOH (10 ml) to give pure ELQ 738 (54 mg, yield 48 %) as a yellow solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 7.85‐7.79 (m, 3H), 7.67‐7.65 (m, 2H ), 7.47‐7.44 (m, 2H), 7.33‐7.31 (m, 2H), 6.82‐ 6.74 (m, 1H), 2.26 (s, 3H). Ethyl (Z)‐3‐((3‐methoxyphenyl)imino)‐2‐(4'‐(tri fluoromethoxy)‐[1,1'‐biphenyl]‐4‐yl)butanoate meta‐Anisidine (1.10 g, 0.0089 mol) was combined wi th ethyl 3‐oxo‐2‐(4'‐(trifluoromethoxy)‐[1,1'‐ biphenyl]‐4‐yl)butanoate (3.44 g of a 10:1 mol:mol mixture with para‐toluenesulfonic acid monohydrate, thus 3.27 g, 0.0089 mol of ethyl 3‐ox o‐2‐(4'‐(trifluoromethoxy)‐[1,1'‐biphenyl]‐4‐ yl)butanoate and 0.17 g, 0.00089 mol of para‐toluen esulfonic acid monohydrate). This mixture was allowed to reflux in benzene (75 mL) under Dean Sta rk conditions for three days. The solvent was removed under reduced pressure with warming, and the residue (a stiff, brown oil) was used without purification or analysis in the ensuing reaction. 7‐Methoxy‐2‐methyl‐3‐(4'‐(trifluoromethoxy)‐[1 ,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐one (ELQ‐685) Ethyl (Z)‐3‐((3‐methoxyphenyl)imino)‐2‐(4'‐(tri fluoromethoxy)‐[1,1'‐biphenyl]‐4‐yl)butanoate (the crude product of the preceding reaction) was taken up in hot Dowtherm A (8 mL followed by an additional 7 mL used to rinse the flask), and was added graduall y to boiling Dowtherm A (100 mL, 255°C) over the course of 8 minutes. After a total of 11 minute s’ heating, the mixture was allowed to cool, stirr ing, to room temperature. Hexanes (300 mL) were added with stirring, and the resulting solid was recovered by vacuum filtration, rinsing with excess hexanes fol lowed by acetone (50 mL). The crude product (a cream solid, 1.76 g) was recrystallized from N,N‐di methylformamide (15 mL), affording 1.25 g of the desired product; a second crop was also recovered fr om the mother liquor (0.23 g, a total of 1.48 g f ine, nearly white crystals; yield 39% over two steps from meta‐anisidine, mp: 389.8‐392.1°C (dec.), 1 H‐NMR (400 MHz; DMSO‐d6): δ 11.51 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.87‐7.83 (m, 2H), 7.71‐7.68 ( m, 2H), 7.48‐ 7.46 (m, 2H), 7.37‐7.34 (m, 2H), 6.93‐6.89 (m, 2 H), 3.87 (s, 3H), 2.25 (s, 3H); 19 F NMR (376 MHz; DMSO): δ ‐56.7). Ethyl (((7‐methoxy‐2‐methyl‐3‐(4'‐(trifluoromet hoxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4‐yl)oxy)met hyl) carbonate (ELQ‐695) To a stirred mixture of 7‐methoxy‐2‐methyl‐3‐ (4'‐(trifluoromethoxy)‐[1,1'‐biphenyl]‐4‐yl)quinol in‐4(1H)‐ one (ELQ‐685; 0.45 g, 0.0011 mol), tetrabutyl ammon ium iodide (2.0 eq., 0.0022 mol, 0.81 g), and anhydrous potassium carbonate (2.0 eq., 0.0022 mol, 0 .30 g) in N,N‐dimethylformamide (17 mL) was added chloromethyl ethyl carbonate (2.0 eq., 0.0022 m ol, 0.30 g). This mixture was allowed to heat at 60°C for 21 hours. The cooled reaction mixture wa s vacuum filtered to remove solids, and the filtrate was concentrated under reduced pressure with heating. The residue was taken up in ethyl acetate (25 mL), followed by vacuum filtration to remove precipit ate. The filtrate was adsorbed onto silica and purified by flash column chromatography on silica gel , eluting with a gradient of 100% hexanes to 68/32 v/v hexanes/ethyl acetate. The desired product was obtained as a pale yellow oil that crystallized to a white solid upon standing (0.20g, yield 34%, R f = 0.32, 6:4 v:v hexanes:ethyl acetate, silica; mp: 111.0‐ 112.0°C, 1 H‐NMR (400 MHz; CDCl 3 ): δ 7.96 (d, J = 9.2 Hz, 1H), 7.71‐7.68 (m, 4H), 7.50‐7.47 (m, 2H), 7.39 (d, J = 2.5 Hz, 1H), 7.35‐7.33 (m, 2H), 7.17 (dd , J = 9.1, 2.5 Hz, 1H), 5.33 (s, 2H), 4.04 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 2.55 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H).). Ethyl (Z)‐2‐(4‐bromophenyl)‐3‐((3‐methoxyphenyl )amino)but‐2‐enoate meta‐Anisidine (14.18 g, 0.115 mol) and ethyl 2‐( 4‐bromophenyl)‐3‐oxobutanoate (35.03 g of a 10:1 mol:mol mixture with para‐toluenesulfonic acid monohy drate, thus 32.82 g, 0.115 mol, 1 eq of ethyl 2‐ (4‐bromophenyl)‐3‐oxobutanoate and 2.19 g, 0.0115 mol, 0.1 eq of pTSA) were combined in benzene (150 mL) and heated at reflux under Dean & Star k conditions for 2 days. The solvent was then rem oved under reduced pressure with warming, and the resultin g crude material (a thick, reddish brown oil) was used without purification or analysis in the followin g reaction. 3‐(4‐Bromophenyl)‐7‐methoxy‐2‐methylquinolin‐4 (1H)‐one Ethyl (Z)‐2‐(4‐bromophenyl)‐3‐((3‐methoxyphenyl )amino)but‐2‐enoate was taken up in hot Dowtherm A (20 mL followed by an additional 10 mL used to rin se the flask), and was added gradually to boiling Dowtherm A (220 mL, 255°C) over the course of 8 minutes. After a total of 11 minutes’ heating, the mixture was allowed to cool, stirring, to room tempe rature. Hexanes (300 mL) were added and the resulting sticky, amber precipitate was recovered by vacuum filtration, rinsing with hexanes followed by ethyl acetate (20 mL) and finally, acetone (150 mL). This afforded the desired product as a beige powder (19.70 g, 50% over two steps from meta‐anis idine; 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.51 (s, 1H), 7.99‐7.96 (m, 1H), 7.58‐7.55 (m, 2H), 7.22 7.19 (m, 2H), 6.92‐6.89 (m, 2H), 3.86 (s, 3H), 2 .20 (s, 3H)). 3‐(4‐Bromophenyl)‐4‐chloro‐7‐methoxy‐2‐methy lquinoline To a mixture of 3‐(4‐Bromophenyl)‐7‐methoxy‐2 methylquinolin‐4(1H)‐one (19.70 g, 0.054 mol) and chloroform (125 mL) was added phosphorus oxychloride (3.0 eq, 0.162 mol, 15.1 mL). The reaction was stirred at reflux for 2 days. After cooling, the reaction was poured onto ice (total volume 500 mL) and stirred vigorously for 20 minutes. Additional chloro form (30 mL) and water (100 mL) were added to aid mixing and dissolve solid, and stirring was continued for a futher 10 minutes. The mixture was then made basic by the addition of 50% w/w aqueous sodiu m hydroxide followed by stirring for 30 minutes. The biphasic mixture was vacuum filtered and the fil trate (further diluted with water, 150 mL) was separated. The aqueous layer was further extracted with chloroform (100 mL, then 2 x 75 mL). The pooled organic layers were rinsed with brine (75 mL) , dried (MgSO 4 ) and evaporated under reduced pressure with warming, affording a greenish gray soli d (21.21 g). This material was recrystallized from ethyl acetate (125 mL), affording the desired product as grayish tan crystals (13.84 g); a second crop (2.92 g) and third crop (0.83 g) were also the des ired product (total yield 17.59 g, 90%; 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.10 (d, J = 9.2 Hz, 1H), 7.66‐7.62 (m, 2H), 7.39 (d, J = 2.5 Hz, 1H), 7.26‐7.23 ( m, overlaps solvent signal, estimated 1H), 7.18‐7.15 (m, 2H), 3 .97 (s, 3H), 2.45 (s, 3H).). 3‐(3',5'‐bis(Trifluoromethyl)‐[1,1'‐biphenyl]‐4‐ yl)‐4‐chloro‐7‐methoxy‐2‐methylquinoline A mixture of 3‐(4‐bromophenyl)‐4‐chloro‐7‐met hoxy‐2‐methylquinoline (1.00 g, 0.0028 mol), 3,5‐ bis(trifluoromethyl)phenylboronic acid (1.3 eq., 0.0036 mol, 0.92 g), and anhydrous potassium carbonate (2.0 eq, 0.0056 mol, 0.58g, dissolved in w ater, 3.6 mL) in N,N‐dimethylformamide (80 mL) was stirred at room temperature for 20 minutes while deg assing by bubbling argon through a glass tube under the liquid surface. [1,1’‐bis(Diphenylphosphin o)ferrocene]‐dichloropalladium (II) (5 mol %, 0.10 g , 0.00014 mol) was added and the reaction was allowed to heat at 80°C under argon for 3 days. The cooled reaction mixture was vacuum filtered, followed by concentration of the filtrate under reduced pressure with heating. The resulting solid was taken up in 125 mL DCM, followed by vacuum filtration. Automated flash chromatography of the evaporated filtr ate on silica, eluting with a gradient of 1:0 to 82:18 v:v hexanes:ethyl acetate, isolated the desired product (R f = 0.24, 5:2 v:v hexanes:ethyl acetate on silica) mixed with the major side product (3‐(3',5' ‐bis(trifluoromethyl)‐[1,1'‐biphenyl]‐4‐yl)‐4‐ (3,5‐ bis(trifluoromethyl)phenyl)‐6‐chloro‐7‐methoxy‐2 methylquinoline, resulting from double addition of 3,5‐bis(trifluoromethyl)phenylboronic acid); total 1.11 g. This mixture was used without further purification in the next reaction. 3‐(3',5'‐bis(trifluoromethyl)‐[1,1'‐biphenyl]‐4‐ yl)‐7‐methoxy‐2‐methylquinolin‐4(1H)‐one (ELQ 731) 3‐(3',5'‐bis(Trifluoromethyl)‐[1,1'‐biphenyl]‐4‐ yl)‐4‐chloro‐7‐methoxy‐2‐methylquinoline (1.11 g, containing both the desired starting material and its side product) and anhydrous potassium acetate (0.021 mol, 2.05 g) were combined in glacial acetic acid (15 mL) and allowed to heat, stirring, for 1 day at 110°C. After cooling to room temperature, the soli d that formed in the reaction mixture was recovered by vacuum filtration, rinsing with excess water follo wed by 3 mL acetone. This afforded the desired product as a white powder (0.84 g, 63% over two st eps from 3‐(4‐bromophenyl)‐4‐chloro‐7‐methoxy 2‐ methylquinoline, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.53 (s, 1H), 8.41‐8.37 (m, 2H), 8. 11‐8.08 (m, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.91‐7.88 (m, 2H), 7.4 3‐7.40 (m, 2H), 6.94‐6.90 (m, 2H), 3.88 (s, 3H), 2.26 (s, 3H); 19‐F NMR (376 MHz; DMSO): δ ‐61.2). 4‐Chloro‐7‐methoxy‐2‐methyl‐3‐(3'‐(trifluoro methyl)‐[1,1'‐biphenyl]‐4‐yl)quinoline A mixture of 3‐(4‐bromophenyl)‐4‐chloro‐7‐met hoxy‐2‐methylquinoline (1.00 g, 0.0028 mol), 3‐ (trifluoromethyl)phenylboronic acid (1.3 eq., 0.0036 mo l, 0.68 g), and anhydrous potassium carbonate (2.0 eq, 0.0056 mol, 0.58g, dissolved in water, 3.6 mL) in N,N‐dimethylformamide (80 mL) was stirred a t room temperature for 20 minutes while degassing by b ubbling argon through a glass tube under the liquid surface. [1,1’‐bis(Diphenylphosphino)ferrocene] ‐dichloropalladium (II) (5 mol %, 0.10 g, 0.00014 mol) was added and the reaction was allowed to heat at 80°C under argon for 3 days. The cooled reaction mixture was vacuum filtered, followed by con centration of the filtrate under reduced pressure with heating. The resulting solid was taken up in 1 25 mL DCM, followed by vacuum filtration. Automated flash chromatography of the evaporated filtr ate on silica, eluting with a gradient of 1:0 to 4:1 v:v hexanes:ethyl acetate, isolated the desired p roduct (R f = 0.42, 5:2 v:v hexanes:ethyl acetate on silica) as a white solid (0.79 g, 61%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.12 (d, J = 9.2 Hz, 1H), 7.95‐7.92 (m, 1H), 7.89‐7.84 (m, 1H), 7.76‐7.73 (m, 2H), 7.66 7.58 (m, 2H), 7.42‐7.38 (m, 3H), 7.28‐7.25 (m, 1H), 3.98 (s, 3H), 2.51 (s, 3H); 19‐F NMR (376 MHz; CDCl3): δ ‐62.6). 7‐Methoxy‐2‐methyl‐3‐(3'‐(trifluoromethyl)‐[1, 1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐one (ELQ‐730) 4‐Chloro‐7‐methoxy‐2‐methyl‐3‐(3'‐(trifluoro methyl)‐[1,1'‐biphenyl]‐4‐yl)quinoline (0.79 g, 0 .0017 mol) and anhydrous potassium acetate (10 eq, 0.017 mol, 1 .67 g) were combined in glacial acetic acid (15 mL) and allowed to heat, stirring, for 1 day at 110°C. After cooling to room temperature, the solid that formed in the reaction mixture was recovered by vacu um filtration, rinsing with excess water followed by 3 mL acetone. This afforded the desired product as a white powder (0.54 g, 78%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.52 (s, 1H), 8.06‐7.99 (m, 3H), 7. 78‐7.73 (m, 4H), 7.39‐7.37 (m, 2H), 6.94‐6.90 ( m, 2H), 3.87 (s, 3H), 2.26 (s, 3H); 19‐F NMR (376 MHz; D MSO): δ ‐61.0). 4‐chloro‐7‐methoxy‐2‐methyl‐3‐(3'‐(trifluoro methoxy)‐[1,1'‐biphenyl]‐4‐yl)quinoline A mixture of 3‐(4‐bromophenyl)‐4‐chloro‐7‐met hoxy‐2‐methylquinoline (0.70 g, 0.0019 mol), 3‐ (trifluoromethoxy)phenylboronic acid (1.3 eq., 0.0025 m ol, 0.52 g), and anhydrous potassium carbonate (2.0 eq, 0.0038 mol, 0.52g, dissolved in water, 1.9 mL) in N,N‐dimethylformamide (80 mL) was stirred a t room temperature for 20 minutes while degassing by b ubbling argon through a glass tube under the liquid surface. [1,1’‐bis(Diphenylphosphino)ferrocene] ‐dichloropalladium (II) (5 mol %, 0.070 g, 0.000095 mol) was added and the reaction was allowed to heat at 80°C under argon for 23 hours. The cooled reaction mixture was vacuum filtered, followed by con centration of the filtrate under reduced pressure with heating. The resulting solid was taken up in 1 00 mL DCM, followed by vacuum filtration. Automated flash chromatography of the evaporated filtr ate on silica, eluting with a gradient of 95:5 to 82:18 v:v hexanes:ethyl acetate, isolated the desired product (R f = 0.32, 7:3 v:v hexanes:ethyl acetate on silica) as a white solid (0.24 g, 28%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.13 (d, J = 9.2 Hz, 1H), 7.73‐7.70 (m, 2H), 7.62 (ddd, J = 7.8, 1.7, 1.0 Hz, 1H), 7.54‐ 7.48 (m, 2H), 7.41 (d, J = 2.5 Hz, 1H), 7.40‐7.3 7 (m, 2H), 7.28‐7.23 (m, overlaps residual solvent signal, esti mated 2H), 3.98 (s, 3H), 2.50 (s, 3H); 19‐F NMR (376 MHz; CDCl3): δ ‐57.7). 7‐methoxy‐2‐methyl‐3‐(3'‐(trifluoromethoxy)‐[1 ,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐one (ELQ‐732) 4‐Chloro‐7‐methoxy‐2‐methyl‐3‐(3'‐(trifluoro methoxy)‐[1,1'‐biphenyl]‐4‐yl)quinoline (0.24 g, 0.00054 mol) and anhydrous potassium acetate (10 eq, 0.0054 mol, 0.53 g) were combined in glacial acetic acid (11 mL) and allowed to heat, stirring, for 22 hours at 120°C. After cooling to room temperature, the solid that formed in the reaction mixture was recove red by vacuum filtration, rinsing with excess water followed by 3 mL acetone. This afforded the desire d product as white crystals (0.17 g, 74%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.51 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.78 (ddd, J = 7.9, 1.7, 0.9 Hz, 1H), 7.75 7.72 (m, 2H), 7.70‐7.67 (m, 1H), 7.65‐7.59 (m, 1 H), 7.39‐7.35 (m, 3H), 6.93‐6.89 (m, 2H), 3.87 ( s, 3H), 2.25 (s, 3H); 19‐F NMR (376 MHz; DMSO): δ ‐56. 6). 4‐chloro‐3‐(3',5'‐difluoro‐4'‐(trifluoromethoxy) ‐[1,1'‐biphenyl]‐4‐yl)‐7‐methoxy‐2‐methylqui noline A mixture of 3‐(4‐bromophenyl)‐4‐chloro‐7‐met hoxy‐2‐methylquinoline (0.70 g, 0.0019 mol), 2‐(3 ,5‐ difluoro‐4‐(trifluoromethoxy)phenyl)‐4,4,5,5‐tetrame thyl‐1,3,2‐dioxaborolane (1.2 eq., 0.0023 mol, 0.75 g), and anhydrous potassium carbonate (2.0 eq, 0.0038 mol, 0.53g, dissolved in water, 1.9 mL) in N,N‐ dimethylformamide (80 mL) was stirred at room tempera ture for 20 minutes while degassing by bubbling argon through a glass tube under the liquid surface. [1,1’‐bis(Diphenylphosphino)ferrocene]‐ dichloropalladium (II) (5 mol %, 0.070 g, 0.000095 m ol) was added and the reaction was allowed to heat at 80°C under argon for 4 days. The cooled reactio n mixture was vacuum filtered, followed by concentration of the filtrate under reduced pressure with heating. The resulting solid was taken up in 100 mL DCM, followed by vacuum filtration. Automate d flash chromatography of the evaporated filtrate on silica, eluting with a gradient of 95:5 to 83:17 v:v hexanes:ethyl acetate, isolated the des ired product (R f = 0.29, 7:3 v:v hexanes:ethyl acetate on sili ca) as a white, crystalline solid (0.67 g, 74%, 1 H‐ NMR (400 MHz; CDCl 3 ): δ 8.12 (d, J = 9.2 Hz, 1H), 7.68‐7.65 (m, 2H), 7.41‐7.38 (m, 3H), 7.35‐7.30 (m, 2H), 7.28‐7.25 (m, overlaps residual solvent signal, estimated 1H), 3.98 (s, 3H), 2.49 (s, 3H); 19‐F NMR (376 MHz; CDCl3): δ ‐124.2). 3‐(3',5'‐difluoro‐4'‐(trifluoromethoxy)‐[1,1'‐bi phenyl]‐4‐yl)‐7‐methoxy‐2‐methylquinolin‐4(1H) ‐one (ELQ‐ 733) 4‐Chloro‐3‐(3',5'‐difluoro‐4'‐(trifluoromethoxy) ‐[1,1'‐biphenyl]‐4‐yl)‐7‐methoxy‐2‐methylqui noline (0.67 g, 0.0014 mol) and anhydrous potassium acetate (10 e q, 0.014 mol, 1.37 g) were combined in glacial acetic acid (11 mL) and allowed to heat, stirring, for 22 hours at 120°C. After cooling to room temperature, the solid that formed in the reaction m ixture was recovered by vacuum filtration, rinsing with excess water followed by 3 mL acetone. This afforded the desired product as white crystals (0.52 g, 81%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.52 (s, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.85‐7.79 (m, 4H), 7.40‐7.37 (m, 2H), 6.93‐6.89 (m, 2H), 3.87 (s, 3H), 2.25 (s , 3H); 19‐F NMR (376 MHz; DMSO): δ ‐59.0). 4‐chloro‐3‐(3',5'‐difluoro‐4'‐methoxy‐[1,1'‐ biphenyl]‐4‐yl)‐7‐methoxy‐2‐methylquinoline A mixture of 3‐(4‐bromophenyl)‐4‐chloro‐7‐met hoxy‐2‐methylquinoline (0.70 g, 0.0019 mol), 2‐(3 ,5‐ difluoro‐4‐(methoxy)phenyl‐4,4,5,5‐tetramethyl‐1,3 ,2‐dioxaborolane (1.2 eq., 0.0023 mol, 0.62 g), and anhydrous potassium carbonate (2.0 eq, 0.0038 mol, 0. 53g, dissolved in water, 1.9 mL) in N,N‐ dimethylformamide (80 mL) was stirred at room tempera ture for 20 minutes while degassing by bubbling argon through a glass tube under the liquid surface. [1,1’‐bis(Diphenylphosphino)ferrocene]‐ dichloropalladium (II) (5 mol %, 0.070 g, 0.000095 m ol) was added and the reaction was allowed to heat at 80°C under argon for 4 days. The cooled reactio n mixture was vacuum filtered, followed by concentration of the filtrate under reduced pressure with heating. The resulting solid was taken up in 100 mL DCM, followed by vacuum filtration. Automate d flash chromatography of the evaporated filtrate on silica, eluting with a gradient of 95:5 to 82:18 v:v hexanes:ethyl acetate, isolated the des ired product (R f = 0.32, 7:3 v:v hexanes:ethyl acetate on sili ca) as a white, crystalline solid (0.72 g, 89%, 1 H‐ NMR (400 MHz; CDCl 3 ): δ 8.12 (d, J = 9.2 Hz, 1H), 7.66‐7.63 (m, 2H), 7.41 (d, J = 2.5 Hz, 1H), 7.37‐7.34 (m, 2H), 7.28‐7.20 (m, overlaps residual solvent si gnal, estimated 3H), 4.07 (s, 3H), 3.98 (s, 3H), 2. 49 (s, 3H); 19‐F NMR (376 MHz; CDCl3): δ ‐128.3). 3‐(3',5'‐difluoro‐4'‐methoxy‐[1,1'‐biphenyl]‐4 ‐yl)‐7‐methoxy‐2‐methylquinolin‐4(1H)‐one (EL Q‐734) 4‐Chloro‐3‐(3',5'‐difluoro‐4'‐methoxy‐[1,1'‐ biphenyl]‐4‐yl)‐7‐methoxy‐2‐methylquinoline (0. 72 g, 0.0017 mol) and anhydrous potassium acetate (10 eq, 0.017 m ol, 1.67 g) were combined in glacial acetic acid (11 mL) and allowed to heat, stirring, for 22 hours at 120°C. After cooling to room temperature, the solid that formed in the reaction mixture was recove red by vacuum filtration, rinsing with excess water followed by 3 mL acetone. This afforded the desire d product as white crystals (0.50 g, 71%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.50 (s, 1H), 8.00‐7.98 (m, 1H), 7. 73‐7.70 (m, 2H), 7.59‐7.53 (m, 2H), 7.35‐7.32 (m, 2H), 6.93‐6.89 (m, 2H), 3.97 (s, 3H), 3.87 (s , 3H), 2.24 (s, 3H); 19‐F NMR (376 MHz; DMSO): ‐128.4). 4‐chloro‐3‐(4'‐fluoro‐2'‐methoxy‐[1,1'‐biphe nyl]‐4‐yl)‐7‐methoxy‐2‐methylquinoline A mixture of 3‐(4‐bromophenyl)‐4‐chloro‐7‐met hoxy‐2‐methylquinoline (0.70 g, 0.0019 mol), 2‐ methoxy‐4‐(trifluoromethyl)phenylboronic acid (1.2 eq ., 0.0023 mol, 0.51 g), and anhydrous potassium carbonate (2.0 eq, 0.0038 mol, 0.53g, dissolved in w ater, 1.9 mL) in N,N‐dimethylformamide (80 mL) was stirred at room temperature for 20 minutes while deg assing by bubbling argon through a glass tube under the liquid surface. [1,1’‐bis(Diphenylphosphin o)ferrocene]‐dichloropalladium (II) (5 mol %, 0.070 g, 0.000095 mol) was added and the reaction was all owed to heat at 80°C under argon for 20 hours. Th e cooled reaction mixture was vacuum filtered, followed by concentration of the filtrate under reduced pressure with heating. The resulting solid was taken up in 120 mL DCM, followed by vacuum filtration. Automated flash chromatography of the evaporated filtr ate on silica, eluting with a gradient of 93:7 to 79:21 v:v hexanes:ethyl acetate, isolated the desired product (R f = 0.26, 7:3 v:v hexanes:ethyl acetate on silica) as a white, crystalline solid (0.70 g, 90%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.13 (d, J = 9.2 Hz, 1H), 7.64‐ 7.61 (m, 2H), 7.41 (d, J = 2.5 Hz, 1H), 7.40‐7.3 6 (m, 1H), 7.32‐7.29 (m, 2H), 7.27‐7.24 (m, over laps residual solvent signal, estimated 1H), 6.80‐6.73 (m , 2H), 3.98 (s, 3H), 3.86 (s, 3H), 2.52 (s, 3H); 19‐F NMR (376 MHz; CDCl3): δ ‐112.0). 3‐(4'‐Fluoro‐2'‐methoxy‐[1,1'‐biphenyl]‐4‐yl )‐7‐methoxy‐2‐methylquinolin‐4(1H)‐one (ELQ‐7 43) 4‐Chloro‐3‐(4'‐fluoro‐2'‐methoxy‐[1,1'‐biphe nyl]‐4‐yl)‐7‐methoxy‐2‐methylquinoline (0.70 g , 0.0017 mol) and anhydrous potassium acetate (10 eq, 0.017 mol, 1 .67 g) were combined in glacial acetic acid (10 mL) and allowed to heat, stirring, for 23 hours at 120 C. After cooling to room temperature, the solid t hat formed in the reaction mixture was recovered by vacu um filtration, rinsing with excess water followed by 3 x 1.5 mL acetone. This afforded the desired product as a white powder (0.57 g, 86%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.48 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.49‐7.43 (m, 2H), 7.40‐7.34 (m, 1H), 7.29 7.24 (m, 2H), 7.05‐7.02 (m, 1H), 6.95‐6.85 (m, 3H), 3 .87 (s, 3H), 3.82 (s, 3H), 2.25 (s, 3H); 19‐F NM R (376 MHz; DMSO): δ ‐112.3). 4‐Chloro‐7‐methoxy‐3‐(2'‐methoxy‐4'‐(trifluo romethyl)‐[1,1'‐biphenyl]‐4‐yl)‐2‐methylquinolin e A mixture of 3‐(4‐bromophenyl)‐4‐chloro‐7‐met hoxy‐2‐methylquinoline (0.70 g, 0.0019 mol), 2‐ methoxy‐4‐fluorophenylboronic acid (1.2 eq., 0.0023 mol, 0.39 g), and anhydrous potassium carbonate (2.0 eq, 0.0038 mol, 0.53g, dissolved in water, 1.9 mL) in N,N‐dimethylformamide (80 mL) was stirred a t room temperature for 20 minutes while degassing by b ubbling argon through a glass tube under the liquid surface. [1,1’‐bis(Diphenylphosphino)ferrocene] ‐dichloropalladium (II) (5 mol %, 0.070 g, 0.000095 mol) was added and the reaction was allowed to heat at 80°C under argon for 20 hours. The cooled reaction mixture was vacuum filtered, followed by con centration of the filtrate under reduced pressure with heating. The resulting solid was taken up in 1 20 mL DCM, followed by vacuum filtration. Automated flash chromatography of the evaporated filtr ate on silica, eluting with a gradient of 93:7 to 77:23 v:v hexanes:ethyl acetate, isolated the desired product (R f = 0.26, 7:3 v:v hexanes:ethyl acetate on silica) as a white, crystalline solid (0.64 g, 74%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.13 (d, J = 9.2 Hz, 1H), 7.68‐ 7.65 (m, 2H), 7.54‐7.52 (m, 1H), 7.41 (d, J = 2. 5 Hz, 1H), 7.36‐7.33 (m, 3H), 7.27‐7.25 (m, over laps solvent residual peak, 1H), 7.24‐7.21 (s, 1H), 3.98 (s, 3H ), 3.92 (s, 3H), 2.53 (s, 3H); 19‐F NMR (376 MHz ; CDCl3): δ ‐62.5). 4‐Chloro‐7‐methoxy‐3‐(2'‐methoxy‐4'‐(trifluo romethyl)‐[1,1'‐biphenyl]‐4‐yl)‐2‐methylquinolin e (ELQ‐ 744) 4‐Chloro‐7‐methoxy‐3‐(2'‐methoxy‐4'‐(trifluo romethyl)‐[1,1'‐biphenyl]‐4‐yl)‐2‐methylquinolin e (0.64 g, 0.0014 mol) and anhydrous potassium acetate (10 eq, 0.014 mol, 1.37 g) were combined in glacial acetic acid (10 mL) and allowed to heat, stirring, for 23 hours at 120°C. After cooling to room temperature , the solid that formed in the reaction mixture was recove red by vacuum filtration, rinsing with excess water followed by 3 x 1.5 mL acetone. This afforded the desired product as a white powder (0.55 g, 89%, 1 H‐ NMR (400 MHz; DMSO‐d 6 ): δ 11.51 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.60‐7.52 (m, 3H), 7.43‐7.40 (m, 2H), 7.32‐7.30 (m, 2H), 6.93‐6.89 (m, 2H), 3.90 (s, 3 H), 3.87 (s, 3H), 2.26 (s, 3H); 19‐F NMR (376 MH z; DMSO): δ ‐60.8). 4‐(((Ethoxycarbonyl)oxy)methoxy)‐7‐methoxy‐2‐methy l‐3‐(4'‐(trifluoromethoxy)‐[1,1'‐biphenyl]‐4‐ yl)quinoline 1‐oxide (ELQ‐754) To ethyl (((7‐methoxy‐2‐methyl‐3‐(4'‐(trifluor omethoxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4‐yl)oxy )methyl) carbonate (0.53 g, 0.0010 mol) in chloroform (50 mL) was added 3‐chloroperoxybenzoic acid (1.5 eq, 0.26 g, 0.0015 mol). The reaction was allowed to heat at reflux for 20 hours. After cooling, the r eaction was evaporated under reduced pressure with warming an d the residue was purified by chromatography on silica, eluting with a gradient of 88:12 to 0:10 0 v:v dichloromethane:ethyl acetate (product R f = 0.09, 100% ethyl acetate). The resulting white solid (0.4 3 g) was additionally recrystallized from a mixture of ethyl acetate (1.5 mL) and hexanes (3.5 mL). This afforded the desired product as off‐white needles (0.31 g, 57%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.18 (d, J = 2.5 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.73‐7.67 (m, 4H), 7.49‐7.46 (m, 2H), 7.36‐7.33 (m, 2H), 7.29 7.27 (m, overlaps solvent residual signal, estimated 1H), 5.28 (s, 2H), 4.05‐3.99 (m, 5H), 2.59 (s, 3H), 1. 14 (t, J = 7.1 Hz, 3H)). 1‐hydroxy‐7‐methoxy‐2‐methyl‐3‐(4'‐(trifluor omethoxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐on e (ELQ‐ 755) 4‐(((Ethoxycarbonyl)oxy)methoxy)‐7‐methoxy‐2‐methy l‐3‐(4'‐(trifluoromethoxy)‐[1,1'‐biphenyl]‐4‐ yl)quinoline 1‐oxide (0.28 g, 0.00066 mol) was diss olved by stirring in 10 mL of absolute ethanol. Aqueous sodium hydroxide (0.54 mL of a 10% solution, thus 3.3 eq, 0.0015 mol, 0.06 g NaOH) was added while stirring at room temperature. After 105 minutes, the reaction was concentrated to 2 mL, then poured into 80 mL of water. This mixture was allowed to stir overnight, followed by vacuum filtration; after rinsing with water and allowing to remain on suction for 1 hour, the resulting white powder was additionally rinsed with dichloromethane (3 x 0.5 mL). This afforded the desired product as an off‐white powder (0.17 g, 58%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.77 (s, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.86‐7.83 (m, 2H), 7.75‐7.68 (m, 2H), 7.51‐7.45 (m, 2H), 7.37‐7.33 (m, 2H), 7.25‐7.20 (m, 1H), 6.98 (dd, J = 8.9, 2.1 Hz, 1H), 3.92 (s, 3H), 2.33 (s, 3H); 1 9‐F NMR (376 MHz; DMSO): δ ‐56.7). Ethyl (Z)‐3‐((4‐chloro‐3,5‐difluorophenyl)amino) 2‐(4'‐(trifluoromethoxy)‐[1,1'‐biphenyl]‐4‐yl) but‐2‐ enoate 4‐Chloro‐3,5‐difluoroaniline (0.82 g, 0.0050 mol) was combined with a mixture of ethyl 3‐oxo‐2‐( 4'‐ (trifluoromethoxy)‐[1,1'‐biphenyl]‐4‐yl)butanoate ( 1.0 eq, 1.84 g, 0.0050 mol) and para‐toluenesulfoni c acid monohydrate (0.1 eq, 0.11 g, 0.00058 mol) in b enzene (70 mL). This mixture was allowed to reflux under Dean Stark conditions for two days. The solv ent was removed under reduced pressure with warming, and the residue (a reddish brown oil) was used without purification or analysis in the ensuing reaction. 6‐Chloro‐5,7‐difluoro‐2‐methyl‐3‐(4'‐(triflu oromethoxy)‐[1,1'‐biphenyl]‐4‐yl)quinolin‐4(1H)‐ one (ELQ‐ 648) Ethyl (Z)‐3‐((4‐chloro‐3,5‐difluorophenyl)amino) 2‐(4'‐(trifluoromethoxy)‐[1,1'‐biphenyl]‐4‐yl) but‐2‐ enoate (the crude product of the preceding reaction) was taken up in hot Dowtherm A (8 mL followed by an additional 7 mL used to rinse the flask), an d was added gradually to boiling Dowtherm A (80 mL, 255°C) over the course of 7 minutes. After a tot al of 10 minutes’ heating, the mixture was allowed to cool, stirring, to room temperature. Hexanes (300 m L) were added with stirring, and the resulting solid was recovered by vacuum filtration, rinsing with hexa nes (50 mL) followed by ethyl acetate (3 x 10 mL), additional hexanes (2 x 10 mL). The crude product (a pale pink, sparkling solid) was recrystallized fr om N,N‐dimethylformamide (5 mL), affording 0.31 g of t he desired product; a second crop afforded an additional 0.13 g (total yield over two steps from 4‐chloro‐3,5‐difluoroaniline 0.44 g, 19%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.91 (s, 1H), 7.87‐7.83 (m, 2H), 7. 73‐7.70 (m, 2H), 7.48‐7.45 (m, 2H), 7.36‐7.29 ( m, 3H), 2.23 (s, 3H), 19‐F NMR (376 MHz; DMSO): δ ‐56.7, ‐109.5, ‐112.4). 1‐(4'‐(4,6‐Dichloro‐7‐methoxy‐2‐methylquinolin ‐3‐yl)‐4‐(trifluoromethoxy)‐[1,1'‐biphenyl]‐2 yl)pyrrolidin‐2‐one A mixture of 4,6‐dichloro‐7‐methoxy‐2‐methyl‐ 3‐(4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2 yl)phenyl)quinoline (0.41 g, 0.00093 mol), 1‐[2‐bro mo‐5‐(trifluoromethoxy)phenyl]‐2‐pyrrolidinone (1.0 8 eq., 0.0010 mol, 0.33 g), and anhydrous potassium ca rbonate (2.0 eq, 0.0019 mol, 0.26 g, dissolved in water, 0.93 mL) in N,N‐dimethylformamide (50 mL) wa s stirred at room temperature for 20 minutes while degassing by bubbling argon through a glass tu be under the liquid surface. [1,1’‐ bis(Diphenylphosphino)ferrocene]‐dichloropalladium (II) (5 mol %, 0.034 g, 0.000047 mol) was added and the reaction was allowed to heat at 80°C under argon for 19 hours. The cooled reaction mixture wa s vacuum filtered, followed by concentration of the fil trate under reduced pressure with heating. The resulting solid was taken up in 100 mL DCM, followe d by vacuum filtration. Automated flash chromatography of the evaporated filtrate on silica, eluting with a gradient of 85:15 to 15:85 v:v hexanes:ethyl acetate, isolated the desired product (R f = 0.0.28, 3:7 v:v hexanes:ethyl acetate on si lica) as a white, crystalline solid (0.28 g, 54%, 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.27 (s, 1H), 7.56‐7.49 (m, 4H), 7.37‐7.29 (m, 4H), 4.10 (s, 3H), 3.34 (t, J = 6. 9 Hz, 2H), 2.51 (s, 3H), 2.47 (t, J = 8.1 Hz, 2H ), 1.99‐1.92 (m, 2H); 19‐F NMR (376 MHz; CDCl3): δ ‐57.7). 6‐chloro‐7‐methoxy‐2‐methyl‐3‐(2'‐(2‐oxopy rrolidin‐1‐yl)‐4'‐(trifluoromethoxy)‐[1,1'‐biphe nyl]‐4‐ yl)quinolin‐4(1H)‐one (ELQ‐787) 1‐(4'‐(4,6‐Dichloro‐7‐methoxy‐2‐methylquinolin ‐3‐yl)‐4‐(trifluoromethoxy)‐[1,1'‐biphenyl]‐2 yl)pyrrolidin‐2‐one (0.28 g, 0.00050 mol) and anhy drous potassium acetate (10 eq, 0.0050 mol, 0.49 g) were heated in glacial acetic acid (10 mL) for 22 hours at 120 ^C. After cooling to room temperature, the reaction mixture was poured into water (60 mL) and vacuum filtered, rinsing with excess water followed by 3 x 1.5 mL acetone. The resulting white powder was the desired product (0.16 g, 56%, 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.69 (s, 1H), 8.01 (s, 1H), 7.60 (dd , J = 8.2, 0.7 Hz, 1H), 7.47‐7.43 (m, 2H), 7.36 7.32 (m, 4H), 7.08 (s, 1H), 3.97 (s, 3H), 3.35‐3.33 (m , overlaps water signal, estimated 2H), 2.28 (t, J = 8.0 Hz, 2H), 2.24 (s, 3H), 1.91‐1.83 (m, 2H); 19‐F NMR (376 MHz; DMSO): δ ‐56.7). 3‐(3',4'‐bis(trifluoromethyl)‐[1,1'‐biphenyl]‐4‐ yl)‐4,6‐dichloro‐7‐methoxy‐2‐methylquinoline (3t): Following the general procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 eq), 2‐(3,4‐ bis(trifluoromethyl)phenyl)‐4,4,5,5‐tetramethyl‐1,3,2 dioxaborolane (748 mg, 2.2 mmol, 1.1 eq), aqueous K 2 CO 3 (2 ml, 2 eq), Pd(dppf)Cl 2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 18 h to give crude 3t (1.20 g) as a black solid. DCM (20 ml) was added, the precipitate was filtered washed with methylene chloride (2 x 5 ml) to give pure 3t (210 mg) as a white solid, second crop from DCM gives another pure 3t (420 mg) as a white solid for a c ombined yield of 3t (630 mg, 59% yield). GC‐MS shows one peak M + = 529 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.28 (s, 1H), 8.17 (s, 1H), 8.00‐7.99 (m, 2H), 7.81‐ 7.78 (m, 2H), 7.50 (s, 1H), 7.47‐7.44 (m, 2H), 4. 10 (s, 3H), 2.52 (s, 3H). 4,6‐dichloro‐3‐(2'‐fluoro‐4'‐(trifluoromethyl) [1,1'‐biphenyl]‐4‐yl)‐7‐methoxy‐2‐methylquino line (3u): Following the general procedure A, a mixture of 1 (1.59 gm, 4.0 mmol, 1 eq), (2‐fluoro‐4‐ (trifluoromethyl)phenyl)boronic acid (915 mg, 4.4 mmol, 1.1 eq), aqueous K 2 CO 3 (4 ml, 2 eq), Pd(dppf)Cl 2 (146 mg, 0.2 mmol, 0.05 eq) and DMF (150 ml) was heated for 24 h to give crude 3u (2.02 gm) as a yellow solid. DCM (20 ml) was added and the precipitate wa s filtered washed with methylene chloride (2 x 5 ml ) to give pure 3u (580 mg) as a white solid. The mo ther liquor was further purified by flash chromatogra phy using a gradient of ethyl acetate/hexane (3/7) as th e eluting solvent to yield additional 3u (802 mg). The combined product was further crystalized from DCM/ethy l acetate to 3u (1.10 gm, 57% yield) as a white solid. The product is pure enough for the next step (~ 95% pure by NMR). GC‐MS shows one peak M + = 479 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.28 (s, 1H), 7.75‐7.68 (m, 3H), 7.56 (dd, J = 8.1, 0.9 Hz, 1H), 7.52‐7.50 (m, 2H), 7.43‐7.41 (m, 2H), 4.10 (s, 3 H), 2.53 (s, 3H). 4,6‐dichloro‐3‐(2'‐fluoro‐5'‐(trifluoromethyl) [1,1'‐biphenyl]‐4‐yl)‐7‐methoxy‐2‐methylquino line (3v): Following the general procedure A, a mixture of 1 (1.59 gm, 4.0 mmol, 1 eq), (2‐fluoro‐5‐ (trifluoromethyl)phenyl)boronic acid (915 mg, 4.4 mmol, 1.1 eq), aqueous K 2 CO 3 (4 ml, 2 eq), Pd(dppf)Cl 2 (146 mg, 0.2 mmol, 0.05 eq) and DMF (150 ml) was heated for 24 h to give crude 3u (1.47 gm) as a yellow solid. The product was purified by flash chromatograp hy using a gradient of ethyl acetate/hexane (3/7) as the eluting solvent to give 3v (850 mg, 44 % yield ) as a white solid. The product is pure enough for the next step (~ 90% pure by NMR). GC‐MS shows o ne peak M + = 479 (100%). 1H‐NMR (400 MHz; CDCl 3 ): δ 8.28 (s, 1H), 7.87‐7.85 (m, 1H), 7.75‐7.72 (m, 2 H), 7.69‐7.65 (m, 1H), 7.50 (s, 1H), 7.43‐7.40 ( m, 2H), 7.37‐ 7.32 (m, 1H), 4.10 (s, 3H), 2.53 (s, 3H). 3‐(3',4'‐bis(trifluoromethyl)‐[1,1'‐biphenyl]‐4‐ yl)‐6‐chloro‐7‐methoxy‐2‐methylquinolin‐4(1H) one (ELQ‐ 750): Following the general procedure B, a mixture o f 3t (210 mg, 0.40 mmol, 1 eq), KOAc, (392 mg, 4. 0 mmol, 10 eq), glacial acetic acid (5 ml) was heated for 24 h to give pure ELQ‐750 (420 mg, 69% yie ld) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.74 (s, 1H), 8.29‐8.27 (m, 2H), 8. 16‐8.14 (m, 1H), 8.03 (s, 1H), 7.89‐7.86 (m, 2H), 7.46‐7.43 (m, 2H), 7.10 (s, 1H), 3.98 (s, 3H), 2.28 (s, 3H). 6‐chloro‐3‐(2'‐fluoro‐4'‐(trifluoromethyl)‐[1, 1'‐biphenyl]‐4‐yl)‐7‐methoxy‐2‐methylquinolin 4(1H)‐one (ELQ‐779): Following the general procedure B, a m ixture of 3u (1.10 gm, 2.3 mmol, 1 eq), KOAc, (2.2 5 gm, 23.0 mmol, 10 eq), glacial acetic acid (20 ml) was heated for 24 h to give ELQ‐750 (945 mg) as a white solid. The product was crystallized in DMF to give pure ELQ‐750 (820 mg, 77% yield) as a white solid. 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.72 (s, 1H), 8.02 (s, 1H), 7.87‐7. 82 (m, 2H), 7.73‐7.70 (m, 1H), 7.66‐7.63 (m, 2H), 7.43‐7.40 (m, 2H), 7.10 (s, 1 H), 3.98 (s, 3H), 2.28 (s, 3H). 6‐chloro‐3‐(2'‐fluoro‐5'‐(trifluoromethyl)‐[1, 1'‐biphenyl]‐4‐yl)‐7‐methoxy‐2‐methylquinolin 4(1H)‐one (ELQ‐780): Following the general procedure B, a mix ture of 3v (850 mg, 1.77 mmol, 1 eq), KOAc, (1.73 gm, 17.7 mmol, 10 eq), glacial acetic acid (20 ml) was heated for 24 h to give ELQ‐780 (650 mg) as a white solid. The product was crystallized from DMF t o give ELQ‐780 (431 mg, 47% yield, ~95 % pure by NMR). 1 H‐NMR (400 MHz; DMSO‐d 6 ): δ 11.72 (s, 1H), 8.02 (s, 1H), 7.96‐7. 93 (m, 1H), 7.86‐7.82 (m, 1H), 7.66‐7.59 (m, 3H), 7.42‐7.39 (m, 2H), 7.09 (s, 1 H), 3.98 (s, 3H), 2.28 (s, 3H). ((3‐(3',4'‐bis(trifluoromethyl)‐[1,1'‐biphenyl]‐4 yl)‐6‐chloro‐7‐methoxy‐2‐methylquinolin‐4‐ yl)oxy)methyl ethyl carbonate (ELQ‐773): Following the general pro cedure C, using a mixture of ELQ‐750 (256 mg, 0.5 mmol, 1 eq), TBAI (370 mg, 1.0 mmol, 2 eq), dry K 2 CO 3 (139 mg, 1.0 mmol, 2 eq) and chloromethyl ethylcarbonate (139 mg, 1.0 mmol, 2 eq) in DMF (25 ml) to give crude ELQ‐773 (370 mg). The product was purified by flash chromatography using ethyl acetate/h exane (1/1) to pure ELQ‐773 (247 mg, 80% yield). GC‐MS shows one peak M + = 613 (25%), M + = 511 (100 %). 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.14 (s, 1H), 8.06 (s, 1H), 7.97 (s, 2H), 7.78‐7.75 (m, 2H), 7.56‐7 .53 (m, 2H), 7.45 (s, 1H), 5.30 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 4.06 (s, 3H), 2.54 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H). ((3‐(2',4'‐bis(trifluoromethyl)‐[1,1'‐biphenyl]‐4 yl)‐6‐chloro‐7‐methoxy‐2‐methylquinolin‐4‐ yl)oxy)methyl ethyl carbonate (ELQ‐774): Following the general p rocedure C, using a mixture of ELQ‐763 (256 mg, 0 .5 mmol, 1 eq), TBAI (370 mg, 1.0 mmol, 2 eq), dry K 2 CO 3 (139 mg, 1.0 mmol, 2 eq) and chloromethyl ethylcarbonate (139 mg, 1.0 mmol, 2 eq) in DMF (25 ml) to give crude ELQ‐774 (305 mg). The product was purified by flash chromatography using ethyl acetate/h exane (1/1) to pure ELQ‐774 (237 mg, 77% yield). GC‐MS shows one peak M + = 613 (25%), M + = 511 (100 %). 1 H‐NMR (400 MHz; CDCl 3 ): δ 8.07 (s, 1H), 8.05 (s, 1H), 7.90‐7.88 (m, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.48‐7.45 (m, 5H), 5.26 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 4.06 (s, 3H), 2.56 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H). In Vitro Metabolic Stability Assay Murine Microsomal Stability. Metabolic stability studies of ELQ‐596 was performed at ChemPartner, Shanghai, China. The drug was incubated at 37 °C and 1 μM concentration in murine liver microsomes (Corning) for 45 minutes at a protein concentration of 0.5 mg/mL in potassium phosphate buffer at pH 7.4 containing 1.0 mM EDTA. The metabolic reaction w as initiated by addition of NADPH and quenched with ice‐cold acetonitrile at 0, 5, 15, 25, and 45 min utes. The progress of compound metabolism was followed by LC‐MS/ MS (ESI positive ion, LC‐MS/MS ‐034(API‐6500+) using a C 18 stationary phase (ACQUITY UPLC BEH C 18 (2.1 Å~ 50 mm, 1.7 μm)) and a MeOH/water mobile phase containing 0.25% FA and 1 mM NH4OAc. Imipramine or Osalmid were used as internal standards, and ketanserin was used as a control drug with intermediate stability. Concentration versus time data for each compound were fitted to an exponential decay function to determine the first‐or der rate constant for substrate depletion, which was then used to calculate the degradation half‐life (t 1/2 ) and predicted intrinsic clearance value Cl int ) from an assumed murine hepatic blood flow of 90 mL/min/kg. Plasmodium falciparum Culture. Laboratory strains o f P. falciparum were cultured in human erythrocytes by standard methods. The parasites were grown in culture medium with fresh human erythrocytes maintained at 2% hematocrit at 37 o C in low‐oxygen conditions (5% O 2 , 5% CO 2 , 90% and balance N 2 ). The culture medium used was RPMI‐1640 with 25 mg/L gentamicin sulfate, 45 mg/L Albumax II, 10 mM glucose, and 25 mM HEPES buffer. Cultures were maint ained at less than 10% parasitemia by transfer of infected cells to fresh erythrocytes and culture medi um every 3 or 4 days. The P. falciparum strains us ed in these experiments include the following: D6 (MRA 285/BEI Resources, deposited by Dr. Dennis Kyle) with modest resistance to mefloquine but generally drug sensitive; Dd2 (MRA‐150/BEI Resources, deposited by Dr. David Walliker) with resistance to chloroquine, mefloquine and pyrimethamine; D1 is a subclone of Dd2 that was selected for resistance to ELQ‐300; and Tm90‐C2B was isolated from a patien t enrolled in an atovaquone clinical trial in Thailand upon recrudescence after cessation of drug treatment (obtained from Drs. Dennis Kyle and Victor Melendez, WRAIR). In vitro drug susceptibility assays. SYBR green I assay. In vitro antiplasmodial activity was assessed using a published SYBR Green I fluorescence‐based method ( ). The drugs were added to 96‐well plates usi ng 2‐fold serial dilutions in complete medium. The i nitial range was from 2.5 µM to 2 nM. Asynchronous P. falciparum parasites were diluted with uninfected eryt hrocytes and added to the wells to give a final culture volume of 100µl at 2% hematocrit and 0.2% parasitemia. The plates were incubated for 72 h at 37 °C. The parasites were then lysed by adding 100µl of SYBR green I lysis buffer containing 0.2 µl/ml SYBR green I dye (10,000X) in 20mM Tris (pH 7.5), 5mM EDTA, 0.008% (wt/vol) saponin, and 0.08% (vol/vol) Triton X‐100. The plates were incubated at room temperature for an hour in the dark. The fluorescence signal, correlating to parasite DNA, was measured using a SpectraMax iD3 iD5 Multi‐Mode Microplate Reader, with excitation and emission wavelength bands centered at 497 and 520 nm, respectively. The 50% inhibitory concentrations (IC 50 ) were determined by non‐linear regression ana lysis using GraphPad Prism software. Drugs were assayed in quadruplicate and the results were averaged during analysis to give a final IC 50 value together with standard deviations and 95 % confidence intervals. Atovaquone and ELQ‐300 were used as internal controls to verify cross‐resistance and parasite strain integrity. If the IC 50 value fell outside of the initial tested rang e then the range was adjusted up or down and the assay was repeated. In Vivo Efficacy against Murine Malaria. The P. yo elii 4‐day test monitors suppression of patent infe ction in female CF1 mice. The test began with the inocula tion (iv) of parasitized erythrocytes (3.5 x 10 4 /P. yoelli) (from a donor animal) on the first day of the expe riment (D0). After 24 hr, test drugs (including ELQ 596 and prodrug ELQ‐598) were administered daily by gav age for 4 successive days. Initially the 3‐biaryl ELQs were tested at doses of 0.0025, 0.005, 0.01, 0.03, 0.1, 0.3, 1.0 and 10 mg/kg/day, including a vehicle only (PEG400) control. After completion of drug treatment, a blood sample was collected (by pricking the tail vein) for determination of parasite burden beginning on the day after the final dose (D5). Percent parasitemia is assessed by direct microscopic analysis of Giemsa‐stained blood smears. Drug activity was recorded as % suppression of parasite burden relative to drug‐free controls. Animals with observable parasitemia following the experiment were euthanized; animals cleared of parasites from the bloodstream were observed daily with assessment of pa rasitemia performed weekly until day 30, at which point the animal(s) were scored as cured of infectio n. Typically, the percentage parasitemia in untreated control animals on Day 5 of the “4‐day test” is between 20 and 25%. Non‐linear regression analys is is used for objective determination of ED 50 ’s and ED 90 ’s from the accumulated data as well as the Non‐ Recrudescence Dose (NRD). The 4‐day test protocol w as reviewed and approved by the local IACUC board at the Portland VA Medical Center. Experiments were performed with 4 mice per group to ensure statistical accuracy. Control drugs for these experime nts included ELQ‐300 and prodrug ELQ‐331. In Vivo Single‐Dose Efficacy against Murine Malaria. The effectiveness of selected 3‐biarylELQs and prodrugs was assessed vs. the blood stage infection for single dose cures. Mice are infected iv with 3. 5 x10 4 P. yoelii infected RBCs as described for the 4 ‐day test above. Drug administration occurred on th e day after inoculation (Day 1). Test agents were dissolved in PEG‐400 and administered ig once. On the 5th day blood films were prepared and % parasitemia was asse ssed. Animals remaining parasite‐free for 30 days after drug administration were considered cured. The initial dosing range was: 0.5, 1, 2.5, 5, 10 mg/kg, including a control. Experiments were performed with 4 mice per group to ensure statistical accuracy. The reported parameter for these studies is the lowest s ingle dose that provides a cure to all 4 animals i n the group. ELQ‐331 served as a positive control in the se studies to directly compare with prodrug ELQ‐598 . In Vivo Prophylaxis against Murine Malaria – whole animal bioluminescence. ELQ‐598 was evaluated for liver stage activity in vivo at the Portland VA wit h a Perkin‐Elmer IVIS instrument. This well‐charac terized assay uses in vivo imaging to demonstrate liver stag e activity in a murine model. In brief, luciferase/G FP expressing P. yoelii sporozoites were reared Anopheles stephensii at the OHSU insectary (Dr. Brandon Wilder). Mice were inoculated with 10,000 sporozoites via tail vein injection of CF1 mice treated with o r without drug (dissolved in PEG400) one hour after in oculation. In vivo imaging assessments were taken at 24‐, 48‐, and 72‐hours post‐injection and the luciferase signal from drug treated mice was compare d to the luciferase signal derived from vehicle treated mice. Imaging of any luciferase expressing liver stage parasites followed the administration of 150 mg/kg lu ciferin i.p. (150 µl volume) via a 25‐gauge needl e and syringe prior to each time point. At 3 to 5 minutes’ post luciferin administration the mice were anesthetized with isoflurane gas when imaging began. Additional monitoring of blood stage infection was conducted after IVIS assessment for a 30‐day period to confirm true causal prophylaxis against P. yoeli i challenge. Outcomes from this assay included full cau sal prophylaxis where all animals showed a negative liver stage signal, partial causal prophylaxis where less than 100% of the animals exhibited a negative liver signal, suppressive prophylaxis where a positive liver stage signal was observed followed by a negati ve blood stage signal, and a delay in patency where blood stage parasitemia was delayed in drug‐treated animals compared to vehicle animals. Testing involved the use of 4 animals per group for statistical accuracy. ELQ‐331 was used as a positive control. Isolation of Plasmodium falciparum Mitochondria and Ub iquinol‐Cytochrome c Oxidoreductase Assay. Human cytochrome bc 1 assays. Mitochondrial Toxicity of ELQ‐300 and ELQ‐331. A sub‐series of biphenyl ELQ compounds, having a 7 ‐methoxy‐6‐hydro substitution pattern on the quinolone ring system, have a positive attribute that distinguishes them from prior ELQs even within the 3‐biaryl‐ELQ series. This sub‐series is exempli fied by ELQ‐685. While ELQ‐596 exhibits cross resistance in the ELQ‐300 resistant P. falciparum clone D1 (which we infer to indicate targeting of the Q i site of cytochrome bc 1 complex, see Table A), and atovaquone exhibits cross resistance in the clinical isolate Tm90‐C2B of P. falciparum which contains a mutation in the distant Q o site of cytochrome bc 1 , ELQ‐685 and its analogs exhibit low nanomolar IC 50 values vs. drug sensitive and ELQ‐300 R and Atovaquone R P. falciparum strains. That ELQ‐685 is equipotent vs. multidrug resistant strains of P. falciparum (e.g., Dd2) as well as strains harboring resistance to ELQ‐300 (D1) and Atovaquone (Tm90‐C2B) suggests that it ma y be targeting both Q o and Q i sites in a docking orientation that is unique and not affected by mutated residues in either site. An advantage to such dual site targeting agents is that resistance is likely t o be very difficult to achieve, given that a parasite would ha ve to evolve with simultaneous mutations in both the Q o and Q i sites. Structure activity profile of selected 3‐biaryl‐ELQ s vs. drug sensitive (D6) and drug resistant (Dd2, C2B, and D1) strains of Plasmodium f alciparum. In vivo efficacy. Another positive attribute of ELQ ‐685 is that in vitro metabolism studies in the p resence of pooled murine hepatic microsomes shows complete me tabolic stability over the course of a 45‐minute incubation (t 1/2 = >4,000 minutes/performed by Chempartner). Given that ELQ‐685 exhibits impressive low nM IC 50 values vs. P. falciparum strains in vitro and excellent in vitro metabolic stability we tested it in vivo in a murine malaria model for efficacy usin g a standard 4‐day protocol with P. yoelii inocula tion via tail vein injection (Day 0). Animals (4/group) were then dosed with ELQ‐695 (in PEG‐400) by gavage o n Days 1, 2, 3 and 4. On Day 5, smears were prepare d from tail blood, stained and examined microscopical ly. A non‐recrudescence dose (NRD) of 3.7 mg/kg/day was determined for ELQ‐695. Efficacy of ELQ‐685 prodrug, ELQ‐695, in vivo in a mouse model of malaria infection. MP = melting point; ED 50 – dose required to suppress parasitemia by 50% relative to untreated controls (4‐day Peters test), ED 90 ‐ dose required to suppress parasitemia by 90% relative to untreated controls (4‐day Peters test, P. yoelii Kenya Strain ), NRD – non‐recrudescence dose (4‐day Peters t est), and SDC – single dose cure (lowest single dose th at provides complete cures of all 4 mice in the gr oup). UND = Experiments are currently underway. Note: Prodr ugs were dosed based on molar equivalency to the parent drug. References 1. World malaria report 2021; World Health Organization: Geneva, 2021. 2. Dondorp, A. 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