Substituted biaryl endochin-like quinolones having enhanced anti-parasitic activity

Abstract

Provided herein are endochin-like quinolone (ELQ) compounds of formula (I), or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them, and methods for their use in the treatment or prevention of parasitic diseases including malaria, toxoplasmosis, and babesiosis. TIFF2025524371000356.tif48128

Description

Technical Field

[0001] Field of the Invention The present invention relates to novel biaryl endothion-like quinolone (ELQ) compounds useful in the treatment or prevention of parasitic diseases, including malaria, toxoplasmosis, and babesiosis.

[0002] Statement of Government Support This invention was made with government support under R01 AI100569 and R01 AI141412 awarded by the National Institutes of Health, and W81XWH-19-2-0031 awarded by the Department of Defense. The government has certain rights in this invention.

Background Art

[0003] Background of the Invention In 2020, an estimated 241 million cases of malaria occurred worldwide, with approximately 93% of them occurring in the African continent. In the same year, the worldwide malaria-related deaths were estimated to be 627,000 cases, and children accounted for approximately 77% of all malaria-related deaths worldwide. These figures represent an increase in the number of cases and deaths compared to the previous few years due to the interruption of medical services caused by the ongoing COVID pandemic. 1 Over the past 20 years before the pandemic, the World Health Organization noted that the number of cases and deaths worldwide had steadily decreased mainly due to the increased use of vector control measures and mosquito nets, as well as the introduction of artemisinin combination therapy (ACT). Currently, the situation is not only the rapidly increasing COVID-19 pandemic, but also Asia 2 and Africa 3 where resistance to first-line antimalarial drugs such as chloroquine, mefloquine, amodiaquine, folate antagonists, and quinine has already become established, and is further complicated by the emerging resistance to ACT. Therefore, although malaria-related deaths generally tend to decrease, there is an urgent need for new drugs to address multidrug resistance and contribute to the global efforts towards the eradication of the disease.

[0004] To address the challenges of today's dynamic antimalarial drug resistance situation and move towards the global goal of malaria eradication, Medicines for Malaria Venture (MMV) has created a list of desirable Target Product Profiles (TPPs) and related Target Candidate Profiles (TCPs) that provide useful guidance (or "roadmaps") on what is needed to achieve the ultimate goal of eradication. 4、5 This list is comprehensive and includes new oral drugs for the treatment of uncomplicated acute malaria and for use in severe and complicated diseases where rapid-acting parenteral formulations are appropriate. There are also TPPs for drugs that can be used for chemoprevention, for individuals entering areas with high malaria endemicity or during an epidemic, or for particularly vulnerable groups such as pregnant women and children. Among these TPPs are described drug molecules with TCPs that fill specific niches in the treatment and / or prophylaxis pharmacopoeia of currently available drugs. Such TCPs include molecules that target asexual blood-stage parasites (TCP-1) or latent liver-stage hypnozoites of Plasmodium vivax and Plasmodium ovale (TCP-3) or replicating liver schizonts of all Plasmodium species (TCP-4), as well as drugs that interfere with transmission in the blood or in the insect vector (TCP-5). More recently, MMV has reported a new TPP for long-acting injectables (LAI-C) for 2 - 4 months of protection against seasonal malaria or for use in treatment and chemoprevention during malaria epidemics. 5 .

[0005] TIFF2025524371000002.tif49155Figure 1. Structures of coenzyme Q10, endothelin, ELQ-300, ELQ-331, ELQ-596 and ELQ-598.

[0006] Over 10 years ago, ELQ-300 (Figure 1) was discovered as part of a research consortium with MMV to optimize the historical lead compound endochin for human use 6 Like all known cytochrome bc1 inhibitors, ELQ-300 is an analogue of coenzyme Q 10 , a natural ligand of the electron transport system enzyme. Since its discovery, almost everything we have learned about ELQ-300 indicates that ELQ-300 is a very useful tool for the prevention and treatment of malaria, as well as for addition to the anti-malaria toolbox for transmission blocking 6 . Identification of the characteristics of this drug includes low nM IC 50 against multidrug-resistant strains of Plasmodium falciparum, including field isolates, broad anti-malaria activity against various Plasmodium species infecting humans 7 , in the liver 6 , in the blood, and in the vector stage of infection, strong activity against replicating parasites 6 , novel and selective targeting of the Q i site of the Plasmodium falciparum cytochrome bc1 complex 8 , excellent metabolic stability and long-term pharmacokinetics in preclinical species (mice, rats, and dogs), and a complete safety profile 6 . This was sufficient for ELQ-300 to be selected as a preclinical candidate by MMV in 2012, but further development stalled in 2014 and it dropped out of the pipeline due to high crystallinity that limited absorption and hindered determination of the in vivo therapeutic index required for regulatory approval. Fortunately, the inventors were able to address this problem and revive interest in ELQ-300 by introducing a prodrug (ELQ-331, Figure 1) with significantly low crystallinity that improves oral bioavailability and enhances overall anti-malaria performance 9。ELQ-331 was approved as a preclinical candidate by MMV in October 2020. Since then, an oral formulation of ELQ-331 has been developed by MMV, and the inventors have recently reported a low-cost and scalable synthetic route for the core molecule ELQ-300, in addition to the development potential of this drug for human use. 10 。Therefore, the prodrug ELQ-331 continues to progress through MMV's clinical development pipeline.

[0007] There is still a need to discover and develop new ELQ compounds with improved essential potency, selectivity, pharmacokinetic properties and / or efficacy.

Summary of the Invention

[0008] One aspect is a compound of formula (I): TIFF2025524371000003.tif47128, wherein: R 1a 、R 1b 、and R 1c each is independently selected from the group consisting of H, halogen, CN, C1-C6 alkyl, and C1-C6 alkoxy; R2 is a) oxo (=O), b) -OH, c) -O-CH2-O-C(=O)-O-R6, d) -O-CH2-CH2-O-C(=O)-O-R6, e) -O-CH2(CH3)-O-C(=O)-O-R6, f) -O-C(=O)-CH2-CH2-C(=O)-O-R6, g) -O-CH2-O-C(=O)-R6, h) -O-(C=O)-R7, i) -O-(C=O)-O-R7, j) -O-C(O)-NR^8R^9, k) -O-CH2-O-C(O)-O-(CH2) n1 -NR^8R^9, l) -O-CH2-O-C(O)-O-(CH2) n1-NR8-C(=O)-O-R9, and m)-O-(CH2)-O-PO3 is selected from the group of; The dashed line (-----) in each case represents any single or double bond; Z is selected from the group of N and C; and R3, R4, and R5 are each independently 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, 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, 2-pyrrolidinone, -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, where the cycloalkyl ring 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 is further substituted with 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 C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C6 cycloalkyl, -(CH2) n1-C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, -(CH2) n1 -3- to 6-membered heterocyclyl, phenyl, -(CH2) n1 -phenyl, and -(CH2) n1 selected from the group of -NR8R9; R7 is, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C6 cycloalkyl, -(CH2) n3 -(C3-C6 cycloalkyl), -(CH2) n3 -(3- to 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 selected from the group of -NR8R9; R8 and R9 are each independently selected from the group of H and C1-C6 alkyl; R 10 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; R 11 is selected from the group of H, OH, and O - ; n1 and n2 are each independently an integer 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; Provided that the compound is not a compound selected from the group consisting 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). There is provided a compound, 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.

Mode for Carrying Out the Invention

[0009] Detailed Description of the Invention One aspect is that R2 is a) oxo (=O), b) -OH, c) -O-CH2-O-C(=O)-O-R6, d) —O—CH2—CH2—OC(═O)—O—R6, e) -O-CH2(CH3)-OC(=O)-O-R6, f) -OC(=O)-CH2-CH2-C(=O)-O-R6, and g) -O-CH2-OC(=O)-R6 and R 1a , R 1b , R 1c , R3, R4, R5, R6, R8, R9, R 10 , and R 11 is as defined above for formula (I), Provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0010] formula: Wavy line in X variable of TIFF2025524371000004.tif24128: A dangling bond crossing TIFF2025524371000005.tif4128 is understood to represent a phenyl ring, a pyridine ring, or a pyridazine ring bonded to an adjacent phenyl ring through one of its five available carbon atoms, as seen in the following example: TIFF2025524371000006.tif25128.

[0011] It is also understood that the dashed lines between the ring nitrogen and the 2-carbon atom, between the 2-carbon and 3-carbon atoms, and between the 3-carbon and 4-carbon atoms of the quinoline ring represent, in each case, an optional single bond or an optional double bond, depending on the valence of the R2 substituent, as illustrated by the oxo and hydroxy groups in the following non-limiting exemplary structures: TIFF2025524371000007.tif91157

[0012] Another aspect is R2, a) oxo (=O), b) -OH, c) —O—CH2—OC(═O)—O—R6, d) -O-CH2-CH2-O-C(=O)-O-R6, and e) -O-CH2(CH3)-O-C(=O)-O-R6 selected from the group of; and R1, R3, R4, R5, R6, R8, R9, R 10 , and R 11 is as defined above for formula (I), provide a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0013] A further aspect is that R1 is selected from the group of H, F, and Cl; R2 is selected from the group of oxo (=O) and the moiety of formula -O-CH2-O-C(=O)-O-(C1-C6 alkyl); Z is selected from the group of N and C; and R3, R4, and R5 are each independently selected from the group consisting 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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, R 10 , and R 11 are as defined for formula (I) above; provided that when R2 is selected from the group consisting of oxo(=O), at least one of R3, R4, and R5 is not H, There is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0014] Another aspect is R1 is selected from the group consisting of H, F, and Cl; R2 is selected from the group consisting of oxo(=O) and the moiety of the formula -O-CH2-O-C(=O)-O-(C1-C4 alkyl); Z is selected from the group consisting of N and C; R3, R4, and R5 are each independently selected from the group consisting 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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, R 10 , and R 11 are as defined for formula (I) above; provided that when R2 is selected from the group consisting of oxo (=O), at least one of R3, R4, and R5 is not H, provided a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0015] Another aspect is R1 is selected from the group consisting of H, F, and Cl; R2 is selected from the group consisting of oxo (=O) and the moiety of formula -O-CH2-O-C(=O)-O-(C1-C3 alkyl); 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, methyl, methoxy (-O-CH3), 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, where the cycloalkyl ring 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 is further substituted with 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, R 10 and R 11 are as defined for formula (I) above; provided that when R2 is selected from the group of oxo (=O), at least one of R3, R4, and R5 is not H, There is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0016] An additional aspect is a compound of formula (II): TIFF2025524371000008.tif41128 wherein: R1 is selected from the group of H, F, and Cl; R2 is selected from the group consisting of oxo (=O) and the moiety of the formula -O-CH2-O-C(=O)-O-(C1-C 10 alkyl); R3, R4, and R5 are each independently selected from the group consisting 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; and the dashed line (-----) in each case represents an optional single or double bond; provided that when R2 is selected from the group consisting of oxo (=O), at least one of R3, R4, and R5 is not H, there is provided a compound, or a pharmaceutically acceptable salt thereof.

[0017] A further aspect is that R1 is selected from the group of H, F, and Cl; R2 is selected from the group of oxo (=O) and the 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, where the cycloalkyl ring 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 is further substituted with 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 line (-----) in each case represents any single or double bond; R 10 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; provided that when R2 is selected from the group of oxo (=O), at least one of R3, R4, and R5 is not H, Provided is a compound of formula (II), or a pharmaceutically acceptable salt thereof.

[0018] Another aspect is 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, where the cycloalkyl ring 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 is further substituted with 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; R 10 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; In each case, the dashed line (-----) represents any single or double bond; However, when R2 is selected from the group of oxo (=O), at least one of R3, R4, and R5 is not H. Provided is a compound of formula (II), or a pharmaceutically acceptable salt thereof.

[0019] Another aspect is R1 is selected from the group of H, F, and Cl; R2 is selected from the group of oxo (=O) and the moiety of 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, where the cycloalkyl ring 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 is further substituted with 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; R 10 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; The dashed line (-----) in each instance represents any single or double bond; provided that when R2 is selected from the group of oxo (=O), at least one of R3, R4, and R5 is not H, There is provided a compound of formula (II), or a pharmaceutically acceptable salt thereof.

[0020] A different embodiment is a compound of formula (III): TIFF2025524371000009.tif42128, 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, where the cycloalkyl ring 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 is further substituted with 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; R 10is selected from the group consisting 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 line (-----) in each case represents an optional single or double bond; provided that when R 10 is H, at least one of R3, R4, and R5 is not H, there is provided a compound, or a pharmaceutically acceptable salt thereof.

[0021] A further aspect is R1 is selected from the group consisting of H, F, and Cl; R3, R4, and R5 are each independently selected from the group consisting 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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 R 10is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; the dashed line (-----) in each case represents any single or double bond; provided that when R 10 is H, at least one of R3, R4, and R5 is not H, There is provided a compound of formula (III), or a pharmaceutically acceptable salt thereof.

[0022] Another embodiment is R1 is selected from the group consisting of H, F, and Cl; and R3, R4, and R5 are each independently selected from the group consisting 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; the dashed line (-----) in each case represents any single or double bond; provided that when R 10 is H, at least one of R3, R4, and R5 is not H, There is provided a compound of formula (III), or a pharmaceutically acceptable salt thereof.

[0023] Another aspect is R1 is selected from the group consisting of H, F, and Cl; and R3, R4, and R5 are each independently selected from the group consisting 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-Cz 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; the dashed line (-----) in each case represents any single or double bond; provided that when R 10 is H, at least one of R3, R4, and R5 is not H, There is provided a compound of formula (III), or a pharmaceutically acceptable salt thereof.

[0024] Two further distinct aspects each provide a compound of formula (III-A) and a compound of formula (III-B), or a pharmaceutically acceptable salt thereof: TIFF2025524371000010.tif44160In each distinct aspect, wherein: R1 is selected from the group consisting of H, F, and Cl; R3 and R4 are each independently selected from the group consisting of 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 ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; provided that when R 10 is H, at least one of R3 and R4 is not H.

[0025] Two further aspects are, in each separate aspect, R1 is selected from the group consisting of H, F, and Cl; R3 and R4 are each independently selected from the group consisting 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, where 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 with 0, 1, 2, or 3 substituents selected from the group consisting 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 R 10 is selected from the group consisting of H, halogen, C1-C3 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; provided that when 10 R is H, at least one of R3 and R4 is not H, There are provided compounds of formula (III-A) and compounds of formula (III-B), or pharmaceutically acceptable salts thereof.

[0026] Two further aspects are, each in a separate aspect, R1 is selected from the group consisting of H, F, and Cl; and R3 and R4 are each independently selected from the group consisting 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, halogen, C1-C2 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; provided that when R 10 is H, at least one of R3 and R4 is not H, There are provided compounds of formula (III-A) and compounds of formula (III-B), or pharmaceutically acceptable salts thereof.

[0027] Two further aspects are, in each separate aspect, R1 is selected from the group consisting of H, F, and Cl; and R3 and R4 are each independently selected from the group consisting 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; R 10 is selected from the group consisting of H, F, methyl, methoxy, CH2F, CHF2, CF3, -O-CH2F, -O-CHF2, -O-CF3, and -S-CF3; provided that when R 10 is H, at least one of R3 and R4 is not H, There is provided a compound of formula (III-A) and a compound of formula (III-B), or a pharmaceutically acceptable salt thereof.

[0028] Two further embodiments are, in each separate embodiment, R1 is selected from the group consisting of H, F, and Cl; and R3 and R4 are each independently selected from the group consisting of H, halogen, CH2F, CHF2, CF3, -O-CH2F, -O-CHF2, -O-CF3, and -S-CF3; R 10 is selected from the group consisting of H, F, methyl, methoxy, CH2F, CHF2, CF3, -O-CH2F, -O-CHF2, -O-CF3, and -S-CF3; provided that when R 10 is H, at least one of R3 and R4 is not H, There is provided a compound of formula (III-A) and a compound of formula (III-B), or a pharmaceutically acceptable salt thereof.

[0029] Two additional embodiments are, in each separate embodiment, R1 is selected from the group consisting of H, F, and Cl; and R3 and R4 are each independently selected from the group consisting of F, CH2F, CHF2, CF3, -O-CH2F, -O-CHF2, -O-CF3, and -S-CF3; R 10 is selected from the group consisting of H, F, methyl, methoxy, CH2F, CHF2, CF3, -O-CH2F, -O-CHF2, -O-CF3, and -S-CF3; provided that when R 10 is H, at least one of R3 and R4 is not H, There are provided compounds of formula (III-A) and compounds of formula (III-B), or pharmaceutically acceptable salts thereof.

[0030] Two further distinct aspects each provide a compound of formula (III-A2) and a compound of formula (III-B2), or a pharmaceutically acceptable salt thereof: TIFF2025524371000011.tif49160In each distinct aspect, wherein: R1 is selected from the group consisting of H, F, and Cl; R2 is a) oxo (=O), b) -OH, c) -O-CH2-O-C(=O)-O-R6, d) -O-CH2-CH2-O-C(=O)-O-R6, e) -O-CH2(CH3)-O-C(=O)-O-R6, f) -O-C(=O)-CH2-CH2-C(=O)-O-R6, g) -O-CH2-O-C(=O)-R6, h) -O-(C=O)-R7, i) -O-(C=O)-O-R7, j) -O-C(O)-NR8R9, k) -O-CH2-O-C(O)-O-(CH2) n1 -NR8R9, l) -O-CH2-O-C(O)-O-(CH2) n1 -NR8-C(=O)-O-R9, and m) -O-(CH2)-O-PO3 is selected from the group of; The dashed line (-----) in each example represents an optional single or double bond; R3 and R4 are each independently selected from the group consisting of 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 ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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 C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C6 cycloalkyl, -(CH2) n1 -C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, -(CH2) n1 -3- to 6-membered heterocyclyl, phenyl, -(CH2) n1 -phenyl, and -(CH2) n1 -NR8R9; R7 is C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10Alkynyl, C3-C6 cycloalkyl, -(CH2) n3 -(C3-C6 cycloalkyl), -(CH2) n3 -(3- to 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 selected from the group of -(CH2)-NR8R9; R8 and R9 are each independently selected from the group of H and C1-C6 alkyl; R 10 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; R 11 is selected from the group of H, OH, and O - ; n1 and n2 are each independently an integer 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.

[0031] Two further aspects are, respectively, in each separate aspect, R1, R2, R6, R7, R8, R9, R 10 , R 11 , n1, n2, n3, and the dashed line are each as defined above for formulas (III-A2) and (III-B2); R3 and R4 are each independently selected from the group consisting 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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 R 10 is selected from the group consisting of H, halogen, C1-C3 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; provided that when R 10 is H, at least one of R3 and R4 is not H, There is provided a compound of formula (III-A2) and a compound of formula (III-B2), or a pharmaceutically acceptable salt thereof.

[0032] Two further aspects are, in each separate aspect, R1, R2, R6, R7, R8, R9, R 10 、R 11, n1, n2, n3, and each of the dashed lines is as defined above for formulas (III-A2) and (III-B2); R3 and R4 are each independently selected from the group consisting 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, halogen, C1-C2 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; provided that when R 10 is H, at least one of R3 and R4 is not H, There are provided compounds of formula (III-A2) and compounds of formula (III-B2), or pharmaceutically acceptable salts thereof.

[0033] Two further aspects are, each in a separate aspect, R1, R2, R6, R7, R8, R9, R 10 , R 11 , n1, n2, n3, and each of the dashed lines is as defined above for formulas (III-A2) and (III-B2); R3 and R4 are each independently selected from the group consisting 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, F, methyl, methoxy, CH2F, CHF2, CF3, -O-CH2F, -O-CHF2, -O-CF3, and -S-CF3; provided that when R 10 is H, at least one of R3 and R4 is not H, There is provided a compound of formula (III-A2) and a compound of formula (III-B2), or a pharmaceutically acceptable salt thereof.

[0034] Two further aspects are, in each separate aspect, R1, R2, R6, R7, R8, R9, R 10 , R 11 , n1, n2, n3, and each of the dashed lines is as defined above for formulas (III-A2) and (III-B2); R3 and R4 are each independently selected from the group consisting of H, halogen, CH2F, CHF2, CF3, -O-CH2F, -O-CHF2, -O-CF3, and -S-CF3; R 10 is selected from the group consisting of H, F, methyl, methoxy, CH2F, CHF2, CF3, -O-CH2F, -O-CHF2, -O-CF3, and -S-CF3; provided that when R 10 is H, at least one of R3 and R4 is not H, providing a compound of formula (III-A2) and a compound of formula (III-B2), or a pharmaceutically acceptable salt thereof.

[0035] Two additional aspects are, in each separate aspect, R1, R2, R6, R7, R8, R9, R 10 , R 11 , n1, n2, n3, and each of the dashed lines is as defined above for formulas (III-A2) and (III-B2); R3 and R4 are each independently selected from the group consisting of F, CH2F, CHF2, CF3, -O-CH2F, -O-CHF2, -O-CF3, and -S-CF3; R 10 is selected from the group consisting of H, F, methyl, methoxy, CH2F, CHF2, CF3, -O-CH2F, -O-CHF2, -O-CF3, and -S-CF3; provided that when R 10 is H, at least one of R3 and R4 is not H, providing a compound of formula (III-A2) and a compound of formula (III-B2), or a pharmaceutically acceptable salt thereof.

[0036] A further aspect is a compound of formula (IV): TIFF2025524371000012.tif40128 wherein: R1 is selected from the group consisting of H, F, and Cl; and R3 is selected from the group consisting of 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 ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, providing a compound, or a pharmaceutically acceptable salt thereof.

[0037] A further aspect is R1 is selected from the group consisting of H, F, and Cl; and R3 is selected from the group consisting of 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-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 ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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, There is provided a compound of formula (IV), or a pharmaceutically acceptable salt thereof.

[0038] A further aspect is R1 is selected from the group consisting of H, F, and Cl; and R3 is selected from the group consisting of 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-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 ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; There is provided a compound of formula (IV), or a pharmaceutically acceptable salt thereof.

[0039] Another further aspect is R1 is Cl; and R3 is selected from the group consisting of 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-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 ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, There is provided a compound of formula (IV), or a pharmaceutically acceptable salt thereof.

[0040] Another aspect further provides that R1 is Cl; and R3 is selected from the group consisting of halogen, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 haloalkyl, -SF5, and CN; R 10is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof.

[0041] An additional aspect is R1 is Cl; and R3 is selected from the group consisting of F, Cl, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 haloalkyl, -SF5, and CN; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof.

[0042] A further aspect is a compound of formula (V): TIFF2025524371000013.tif39128, wherein: R1 is selected from the group consisting of H, F, and Cl; and R3 is selected from the group consisting of 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, to provide a compound, or a pharmaceutically acceptable salt thereof.

[0043] A further aspect is R1 is selected from the group consisting of H, F, and Cl; and R3 is selected from the group consisting of 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-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 ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, There is provided a compound of formula (V), or a pharmaceutically acceptable salt thereof.

[0044] A further aspect is R1 is selected from the group consisting of H, F, and Cl; and R3 is selected from the group consisting of 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-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 ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, There is provided a compound of formula (V), or a pharmaceutically acceptable salt thereof.

[0045] Another further aspect is R1 is Cl; and R3 is selected from the group consisting of 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-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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, There is provided a compound of formula (V), or a pharmaceutically acceptable salt thereof.

[0046] Another aspect further is R1 is Cl; and R3 is selected from the group consisting of halogen, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 haloalkyl, -SF5, and CN; R 10is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; To provide a compound of formula (V), or a pharmaceutically acceptable salt thereof.

[0047] Additional embodiments are, R1 is Cl; and R3 is selected from the group consisting of F, Cl, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 haloalkyl, -SF5, and CN; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; To provide a compound of formula (V), or a pharmaceutically acceptable salt thereof.

[0048] Different embodiments are compounds of formula (VI): TIFF2025524371000014.tif41128, wherein: R1 is selected from the group consisting of H, F, and Cl; R3, R4, and R5 are each independently selected from the group consisting 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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 a C1-C 10 alkyl; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, to provide a compound, or a pharmaceutically acceptable salt thereof.

[0049] A further aspect is R1 is selected from the group consisting of H, F, and Cl; and R3, R4, and R5 are each independently selected from the group consisting 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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 C1-C6 alkyl; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, To provide a compound of formula (VI), or a pharmaceutically acceptable salt thereof.

[0050] Another aspect is R1 is selected from the group consisting of H, F, and Cl; and R3, R4, and R5 are each independently selected from the group consisting 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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 C1-C4 alkyl; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, To provide a compound of formula (VI), or a pharmaceutically acceptable salt thereof.

[0051] Another aspect is, R1 is selected from the group consisting of H, F, and Cl; R3, R4, and R5 are each independently selected from the group consisting 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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 C1-C3 alkyl; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, provide a compound of formula (VI), or a pharmaceutically acceptable salt thereof.

[0052] Different embodiments are compounds of formula (VII): TIFF2025524371000015.tif41128, wherein: R1 is selected from the group consisting of H, F, and Cl; and R3, R4, and R5 are each independently selected from the group consisting 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, to provide a compound, or a pharmaceutically acceptable salt thereof.

[0053] Another aspect is R1 is Cl; and R3, R4, and R5 are each independently selected from the group consisting 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 ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, to provide a compound of formula (VII), or a pharmaceutically acceptable salt thereof.

[0054] A further aspect is R1 is selected from the group consisting of H, F, and Cl; and R3, R4, and R5 are each independently selected from the group consisting 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 ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, provides a compound of formula (VII), or a pharmaceutically acceptable salt thereof.

[0055] Another aspect is R1 is Cl; and R3, R4, and R5 are each independently selected from the group consisting 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 with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, provided is a compound of formula (VII), or a pharmaceutically acceptable salt thereof.

[0056] Another aspect is R1 is selected from the group consisting of H, F, and Cl; and R3, R4, and R5 are each independently selected from the group consisting 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 ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; There is provided a compound of formula (VII), or a pharmaceutically acceptable salt thereof.

[0057] Another aspect is R1 is Cl; and R3, R4, and R5 are each independently selected from the group consisting 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; Provide a compound of formula (VII), or a pharmaceutically acceptable salt thereof.

[0058] Another aspect is R1 is selected from the group consisting of H, F, and Cl; and R3, R4, and R5 are each independently selected from the group consisting 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 ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, to provide a compound of formula (VII), or a pharmaceutically acceptable salt thereof.

[0059] Another aspect is R1 is Cl; and R3, R4, and R5 are each independently selected from the group consisting 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; There is provided a compound of formula (VII), or a pharmaceutically acceptable salt thereof.

[0060] Additional embodiments are R1 is Cl; and R3 is selected from the group consisting of F, Cl, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 haloalkyl, -SF5, and CN; R 10is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; provides a compound of formula (VII), or a pharmaceutically acceptable salt thereof.

[0061] Different embodiments are compounds of formula (VIII): TIFF2025524371000016.tif38128, wherein: R1 is selected from the group consisting of H, F, and Cl; R3 is selected from the group consisting 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 ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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 is C1-C 10 alkyl; R 10is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; There is provided a compound, or a pharmaceutically acceptable salt thereof.

[0062] A further aspect is that R1 is selected from the group consisting of H, F, and Cl; R3 is selected from the group consisting of 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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 is C1-C6 alkyl; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; Provided is a compound of formula (VIII) or a pharmaceutically acceptable salt thereof.

[0063] A further aspect is that R1 is selected from the group of H, F, and Cl; R3 is selected from the group of 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-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, where the cycloalkyl ring 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 is further substituted with 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 is C1-C6 alkyl; R 10 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, Provided is a compound of formula (VIII) or a pharmaceutically acceptable salt thereof.

[0064] Another aspect is that R1 is selected from the group consisting of H, F, and Cl; and R3 is selected from the group consisting of halogen, C1-C3 alkyl, -O-C1-C3 alkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -SF5, and CN; R6 is C1-C6 alkyl; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, There is provided a compound of formula (VIII), or a pharmaceutically acceptable salt thereof.

[0065] Another aspect is R1 is selected from the group consisting of H, F, and Cl; and R3 is selected from the group consisting of halogen, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 haloalkyl, -SF5, and CN; R6 is C1-C6 alkyl; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, There is provided a compound of formula (VIII), or a pharmaceutically acceptable salt thereof.

[0066] Another aspect is R1 is Cl; R3 is selected from the group consisting of halogen, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 haloalkyl, -SF5, and CN; and R6 is C1-C6 alkyl; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, Provided is a compound of formula (VIII), or a pharmaceutically acceptable salt thereof.

[0067] Another embodiment is R1 is Cl; R3 is selected from the group consisting of halogen, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 haloalkyl, -SF5, and CN; and R6 is C1-C4 alkyl; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, Provided is a compound of formula (VIII), or a pharmaceutically acceptable salt thereof.

[0068] Another embodiment is R1 is Cl; R3 is selected from the group consisting of halogen, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 haloalkyl, -SF5, and CN; and R6 is ethyl; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, Provided is a compound of formula (VIII), or a pharmaceutically acceptable salt thereof.

[0069] A different embodiment is a compound of formula (IX): TIFF2025524371000017.tif38128 wherein: R1 is selected from the group consisting of H, F, and Cl; R3 is selected from the group consisting 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 ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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 is C1-C 10 alkyl; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, and provides a compound, or a pharmaceutically acceptable salt thereof.

[0070] A further aspect is R1 is selected from the group consisting of H, F, and Cl; R3 is selected from the group consisting of 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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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 is C1-C6 alkyl; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, There is provided a compound of formula (IX), or a pharmaceutically acceptable salt thereof.

[0071] A further aspect is R1 is selected from the group consisting of H, F, and Cl; R3 is selected from the group consisting of 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-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, where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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 is C1-C6 alkyl, There is provided a compound of formula (IX), or a pharmaceutically acceptable salt thereof.

[0072] Another aspect is R1 is selected from the group consisting of H, F, and Cl; and R3 is selected from the group consisting of halogen, C1-C3 alkyl, -O-C1-C3 alkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -SF5, and CN; R6 is C1-C6 alkyl; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, Provided is a compound of formula (IX), or a pharmaceutically acceptable salt thereof.

[0073] Another aspect is R1 is selected from the group consisting of H, F, and Cl; and R3 is selected from the group consisting of halogen, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 haloalkyl, -SF5, and CN; R6 is C1-C6 alkyl; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, Provided is a compound of formula (IX), or a pharmaceutically acceptable salt thereof.

[0074] Another aspect is R1 is Cl; R3 is selected from the group consisting of halogen, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 haloalkyl, -SF5, and CN; and R6 is C1-C6 alkyl; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, Provided is a compound of formula (IX), or a pharmaceutically acceptable salt thereof.

[0075] Another aspect is R1 is Cl; R3 is selected from the group consisting of halogen, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 haloalkyl, -SF5, and CN; and R6 is C1-C4 alkyl; R 10is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, to provide a compound of formula (IX), or a pharmaceutically acceptable salt thereof.

[0076] Another aspect is R1 is Cl; R3 is selected from the group consisting of halogen, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 haloalkyl, -SF5, and CN; and R6 is ethyl; R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl, to provide a compound of formula (IX), or a pharmaceutically acceptable salt thereof.

[0077] Another aspect is a compound of formula (X): TIFF2025524371000018.tif48128 wherein: R2 is a) oxo (=O), b) -OH, c) -O-CH2-O-C(=O)-O-R6, d) -O-CH2-CH2-O-C(=O)-O-R6, e) -O-CH2(CH3)-O-C(=O)-O-R6, f) -O-C(=O)-CH2-CH2-C(=O)-O-R6, g) -O-CH2-O-C(=O)-R6, h) -O-(C=O)-R7, i) -O-(C=O)-O-R7, j) -O-C(O)-NR8R9, k) -O-CH2-O-C(O)-O-(CH2) n1 -NR8R9, l)-O-CH2-O-C(O)-O-(CH2) n1 -NR8-C(=O)-O-R9, and m)-O-(CH2)-O-PO3 selected from the group of; The dashed line (-----) in each case represents any single or double bond; 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, where the cycloalkyl ring 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 is further substituted with 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, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 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 - selected from the group of -NR8R9; R7 is, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C6 cycloalkyl, -(CH2) n3 -(C3-C6 cycloalkyl), -(CH2) n3 -(3- to 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 - selected from the group of -NR8R9; R8 and R9 are each independently selected from the group of H and C1-C6 alkyl; R 11 is selected from the group of H, OH, and O - ; n1 and n2 are each independently an integer 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, to provide a compound, or a pharmaceutically acceptable salt thereof.

[0078] Additional aspects are, R2 is, a) oxo (=O); b) OH; and c) -O-CH2-O-C(=O)-O-R6 selected from the group of; 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, and -SF5; R6 is, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C6 cycloalkyl, and -(CH2)n1 -selected from the group of C3-C6 cycloalkyl; and R 11 is selected from the group of H, OH, and O - ; a compound of formula (X), or a pharmaceutically acceptable salt thereof. contains.

[0079] A further aspect is R2 is d) oxo (=O); e) -OH; and f) selected from the group of -O-CH2-O-C(=O)-O-R6; R3, R4, and R5 are each independently selected from the group of H, halogen, C1-C3 alkyl, -O-C1-C3 alkyl, C1-C3 haloalkyl, and -O-C1-C3 haloalkyl; R6 is 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C6 cycloalkyl, and -(CH2) n1 -C3-C6 cycloalkyl; and R 11 is selected from the group of H, OH, and O - ; a compound of formula (X), or a pharmaceutically acceptable salt thereof. contains.

[0080] A further aspect is R2 is g) oxo (=O); h) -OH; and j) selected from the group of -O-CH2-O-C(=O)-O-R6; R3 and R4 are each independently selected from the group of H, halogen, C1-C3 alkyl, -O-C1-C3 alkyl, CF3, and -O-CF3; R5 is H; R6 is C1-C6 alkyl; and R 11 is selected from the group of H, OH, and O - ; a compound of formula (X), or a pharmaceutically acceptable salt thereof. It contains a compound of formula (X) or a pharmaceutically acceptable salt thereof.

[0081] Another aspect further provides a compound of formula (XI): TIFF2025524371000019.tif48128 wherein: R2 is a) oxo (=O), b) -OH, c) -O-CH2-O-C(=O)-O-R6, d) -O-CH2-CH2-O-C(=O)-O-R6, e) -O-CH2(CH3)-O-C(=O)-O-R6, f) -O-C(=O)-CH2-CH2-C(=O)-O-R6, g) -O-CH2-O-C(=O)-R6, h) -O-(C=O)-R7, i) -O-(C=O)-O-R7, j) -O-C(O)-NR8R9, k) -O-CH2-O-C(O)-O-(CH2) n1 -NR8R9, l) -O-CH2-O-C(O)-O-(CH2) n1 -NR8-C(=O)-O-R9, and m) -O-(CH2)-O-PO3 selected from the group of; The dashed line (-----) in each case represents any single or double bond; R3, R4, and R5 are each independently selected from the group consisting 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), where 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 with 0, 1, 2, or 3 substituents selected from the group consisting 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 is selected from the group consisting of C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 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 consisting of C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 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 selected from the group of -NR8R9; R8 and R9 are each independently selected from the group of H and C1-C6 alkyl; R 11 is selected from the group of H, OH, and O - ; n1 and n2 are each independently an integer 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, to provide a compound, or a pharmaceutically acceptable salt thereof.

[0082] An additional aspect is R2 is a) oxo (=O); b) OH; and c) -O-CH2-O-C(=O)-O-R6 selected from the group of; 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, and -SF5; R6 is C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C6 cycloalkyl, and -(CH2) n1 -C3-C6 cycloalkyl; and R 11 is selected from the group of H, OH, and O - ; to include a compound of formula (XI), or a pharmaceutically acceptable salt thereof.

[0083] A further aspect is R2 is a) oxo (=O), b) -OH, and c) -O-CH2-O-C(=O)-O-R6 selected from the group of; R3, R4, and R5 are each independently selected from the group of H, halogen, C1-C3 alkyl, -O-C1-C3 alkyl, C1-C3 haloalkyl, and -O-C1-C3 haloalkyl; R6 is, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C6 cycloalkyl, and -(CH2) n1 -C3-C6 cycloalkyl; and R 11 is selected from the group of H, OH, and O - of, a compound of formula (XI), or a pharmaceutically acceptable salt thereof.

[0084] A further aspect is R2 is a) oxo (=O), b) -OH, and c) -O-CH2-O-C(=O)-O-R6 selected from the group of; R3 and R4 are each independently selected from the group of H, halogen, C1-C3 alkyl, -O-C1-C3 alkyl, CF3, and -O-CF3; R5 is H; R6 is C1-C6 alkyl; and R 11 is selected from the group of H, OH, and O - of, a compound of formula (XI), or a pharmaceutically acceptable salt thereof.

[0085] Another aspect is a compound of formula (XII): TIFF2025524371000020.tif48128 wherein: R2 is a) oxo (=O), b) -OH, c) -O-CH2-O-C(=O)-O-R6, d) -O-CH2-CH2-O-C(=O)-O-R6, e) -O-CH2(CH3)-O-C(=O)-O-R6, f) -O-C(=O)-CH2-CH2-C(=O)-O-R6, g) -O-CH2-O-C(=O)-R6, h) -O-(C=O)-R7, i) -O-(C=O)-O-R7, j) -O-C(O)-NR8R9, k) -O-CH2-O-C(O)-O-(CH2) n1 -NR8R9, l) -O-CH2-O-C(O)-O-(CH2) n1 -NR8-C(=O)-O-R9, and m) -O-(CH2)-O-PO3 selected from the group of; The dashed line (-----) in each case represents any single or double bond; R3, R4, and R5 are each independently selected from the group consisting 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), where the cycloalkyl ring 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 is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting 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 is selected from the group consisting of C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 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 consisting of C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 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 selected from the group of -NR8R9; R8 and R9 are each independently selected from the group of H and C1-C6 alkyl; R 11 is selected from the group of H, OH, and O - ; n1 and n2 are each independently an integer 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, provide a compound, or a pharmaceutically acceptable salt thereof.

[0086] Additional aspects are R2 is a) oxo (=O); b) OH; and c) -O-CH2-O-C(=O)-O-R6 selected from the group of; 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, and -SF5; R6 is C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C6 cycloalkyl, and -(CH2) n1 -C3-C6 cycloalkyl; and R 11 is selected from the group of H, OH, and O - ; include a compound of formula (XII), or a pharmaceutically acceptable salt thereof.

[0087] A further aspect is R2 is a) oxo (=O), b) -OH, and c) -O-CH2-O-C(=O)-O-R6 is selected from the group of; R3, R4, and R5 are each independently selected from the group of H, halogen, C1-C3 alkyl, -O-C1-C3 alkyl, C1-C3 haloalkyl, and -O-C1-C3 haloalkyl; R6 is, C1-C 10 [[ID=I2]]alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C6 cycloalkyl, and -(CH2) n1 -C3-C6 cycloalkyl is selected from the group of; and R 11 is selected from the group of H, OH, and O - of, a compound of formula (XII), or a pharmaceutically acceptable salt thereof.

[0088] A further aspect is, R2 is, g) oxo (=O); h) -OH; and j) -O-CH2-O-C(=O)-O-R6 is selected from the group of; R3 and R4 are each independently selected from the group of H, halogen, C1-C3 alkyl, -O-C1-C3 alkyl, CF3, and -O-CF3; R5 is, H; R6 is, C1-C6 alkyl; and R 11 is selected from the group of H, OH, and O - of, a compound of formula (XII), or a pharmaceutically acceptable salt thereof.

[0089] Three additional aspects each provide a compound of formula (XIII), formula (XIV), and formula (XV), or a pharmaceutically acceptable salt thereof: TIFF2025524371000021.tif85156In each aspect, wherein: R1 is selected from the group of H, F, and Cl; R2 is a) oxo (=O), b) -OH, c) -O-CH2-O-C(=O)-O-R6, d) -O-CH2-CH2-O-C(=O)-O-R6, e) -O-CH2(CH3)-O-C(=O)-O-R6, f) -O-C(=O)-CH2-CH2-C(=O)-O-R6, g) -O-CH2-O-C(=O)-R6, h) -O-(C=O)-R7, i) -O-(C=O)-O-R7, j) -O-C(O)-NR8R9, k) -O-CH2-O-C(O)-O-(CH2) n1 -NR8R9, l) -O-CH2-O-C(O)-O-(CH2) n1 -NR8-C(=O)-O-R9, and m) -O-(CH2)-O-PO3 is selected from the group of; The dashed line (-----) in each case represents any single or double bond; R3, R4, and R5 are each independently selected from the group consisting 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), where 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 with 0, 1, 2, or 3 substituents selected from the group consisting 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 is selected from the group consisting of C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 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 consisting of C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C6 cycloalkyl, -(CH2) n3 -(C3-C6 cycloalkyl), -(CH2) n3 -(3-6 membered heterocyclyl), phenyl, -(CH)<2)n1 -phenyl, -(CH2) n1 -O-(CH2) n2 -C1-C2 alkyl, -(CH2-CH2-O) n1 -C1-C2 alkyl, and -(CH2) n1 selected from the group of -NR8R9; R8 and R9 are each independently selected from the group of H and C1-C6 alkyl; R 10 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; R 11 is selected from the group of H, OH, and O - ; n1 and n2 are each independently an integer 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.

[0090] Another aspect provides a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Additional aspects include different pharmaceutical compositions each comprising a pharmaceutically effective amount of a compound of formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), and formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV), and formula (XV), respectively, as well as each subgroup described herein that describes subsets of these formulas, and each individual ELQ compound described herein.

[0091] Also provided herein is a method of treating malaria in a human subject, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0092] Also provided herein is a method of inhibiting malaria in a human subject, the method comprising administering to a human in need thereof a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0093] Methods of treating or inhibiting malaria in a human subject include treating or inhibiting infections caused by Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, and Plasmodium malariae.

[0094] Also provided herein is a method of treating multidrug-resistant malaria in a human subject, the method comprising administering to a human in need thereof a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Multidrug-resistant malaria infections treatable using the compounds and methods herein include malaria resistant to treatment with one or more agents selected from the group consisting of chloroquine, sulfadoxine-pyrimethamine, quinine, piperaquine, mefloquine, artemisinin-based combination therapies (ACTs including artemether-lumefantrine (Coartem) and artesunate-mefloquine), pyrimethamine, dapsone, atovaquone, and Plasmodium falciparum dihydroorotate dehydrogenase (DHOD inhibitor or PfDHOD inhibitor). DHOD inhibitors include, but are not limited to, DSM265 (Coteron J M et al, J Med Chem 54, 5540-5561 (2011)).

[0095] Also provided herein is a method of treating chloroquine-resistant malaria in a human subject, the method comprising administering to a human in need thereof a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0096] Also provided herein is a method for treating latent malaria infection in a human subject, the method comprising administering to a human in need thereof a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0097] The method for treating malaria infection described herein may further comprise co-administering to a human in need thereof one or more compounds selected from the group consisting of quinine, chloroquine, atovaquone, proguanil, primaquine, amodiaquine, mefloquine, piperaquine, artemisinin, artesunate, methylene blue, pyrimethamine, sulfadoxine, artemether-lumefantrine, dapsone-chlorproguanil, artesunate, quinidine, clopidol, and dihydroartemisinin, or a pharmaceutically acceptable salt thereof, in a pharmaceutically effective amount, together with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0098] Also provided herein is a method for treating toxoplasmosis (Toxoplasma gondii infection) in a human subject, the method comprising administering to a human in need thereof a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0099] Also provided herein is a method for treating babesiosis in a human subject, the method comprising administering to a human in need thereof a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The method for treating babesiosis in a human subject includes a method for treating an infection caused by Babesia microti.

[0100] Also provided herein is a method of treating babesiosis in a non-human subject, the method comprising administering to the non-human subject in need thereof a pharmaceutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. Such methods include bovine babesiosis, including infections caused by Babesia bovis and B. bigemina, and equine babesiosis, including infections caused by B. caballi and Theileria equi.

[0101] Definitions The term "alkyl" refers to a straight or branched chain hydrocarbon. For example, alkyl groups can include those having from 1 to 4 carbon atoms (i.e., C1-C4 alkyl or C 1-4 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl (-CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), and 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3). Similarly, "alkenyl" refers to a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond, such as a prop-1-enyl or penta-1,3-dienyl group. The term "alkynyl" refers to a straight or branched chain hydrocarbon containing at least one carbon-carbon triple bond, such as a pent-3-ynyl group.

[0102] The term "alkoxy" refers to a group having the formula -O-alkyl, where the alkyl group is as defined above and is attached to the parent molecule through an oxygen atom, as seen with the variables R3, R4, and R5. Examples of the alkyl portion of an alkoxy group can have 1 to 4 carbon atoms (i.e., -O-C1-C4 alkyl or C1-C4 alkoxy), 1 to 3 carbon atoms (i.e., -O-C1-C3 alkyl or C1-C3 alkoxy), or 1 to 2 carbon atoms (i.e., -O-C1-C2 alkyl or C1-C2 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), n-propoxy (-CH2-CH2-CH3), isopropoxy (-CH(CH3)2), n-butoxy (-CH2-CH2-CH2-CH3), isobutoxy (-CH2-CH(CH3)2), sec-butoxy (-CH(CH3)CH2-CH3), t-butoxy (-O-C(CH3)3 or -OtBu), and the like.

[0103] The term "haloalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms of the alkyl group have been replaced by halogen atoms. The alkyl portion of a haloalkyl group can, for example, have 1 to 4 carbon atoms (i.e., C1-C4 haloalkyl or C 1-4(Haloalkyl). Suitable non-limiting examples of haloalkyl groups, which may also be referred to as fluoroalkyl groups, include trifluoromethyl (-CF3), difluoromethyl (-CHF2), fluoromethyl (-CFH2), 2-fluoroethyl (-CH2CH2F), 2-fluoropropyl (-CH2CHF2), 2,2,2-trifluoroethyl (-CH2CF3), 1,1-difluoroethyl (-CF2CH3), 2-fluoropropyl (-CH2CHFCH3), 1,1-difluoropropyl (-CF2CH2CH3), 2,2-difluoropropyl (-CH2CF2CH3), 3,3-difluoropropyl (-CH2CH2CHF2), 3,3,3-trifluoropropyl (-CH2CH2CHF3), 1,1-difluorobutyl (-CF2CH2CH2CH3), perfluoroethyl (-CF2CF3), perfluoropropyl (-CF2CF2CF3), 1,1,2,2,3,3-hexafluorobutyl (-CF2-CF2CF2CH3), perfluorobutyl (-CF2CF2CF2CF3), 1,1,1,3,3,3-hexafluoropropan-2-yl (-CH2(CF3)2) groups, etc., but are not limited thereto. Additional groups in which the halogen substitution is by bromine, iodine, or chlorine atoms are also understood to be for use herein.

[0104] The term "cycloalkyl" refers to a saturated or partially unsaturated ring having 3 to 6 carbon atoms as a single ring (C3-C6 cycloalkyl or C 3-6 cycloalkyl), and includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl rings.

[0105] The term "halogen" or "halo" refers to an element or substituent selected from the group of F, Cl, Br, and I.

[0106] As used herein, "heterocyclic ring" or "heterocyclic group" refers to a chemical ring containing carbon atoms and at least one ring heteroatom selected from O, S, and N. Examples of 5- and 6-membered heterocyclic rings include, by way of example and not limitation, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, 4-piperidinyl, pyrrolidinyl, 2-pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, triazinyl, 6-H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiadiazinyl, thienyl, thianthrenyl, pyranyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, morpholinyl, and oxazolidinyl.

[0107] "Multidrug resistance" or "drug resistance" refers to malaria or the parasite that causes malaria that has developed resistance to treatment with at least one therapeutic agent historically administered to treat malaria. For example, there are multidrug-resistant strains of Plasmodium falciparum that have a high degree of resistance to chloroquine, quinine, mefloquine, pyrimethamine, sulfadoxine, and atovaquone.

[0108] All ranges disclosed and / or claimed herein include the recited endpoints and are independently combinable. For example, the ranges "from 2 to 10" and "2 - 10" include the endpoints, 2 and 10, and all intermediate values therebetween in the context of the units contemplated. For example, reference to "claims 2 - 10" or "C2-C 10 alkyl" includes the units 2, 3, 4, 5, 6, 7, 8, 9, and 10, since claims and atoms are counted in serial order without fractions or decimal points unless otherwise stated in the context of an average number. On the other hand, the context of "pH of 5 - 9" or "temperature of 5°C - 9°C" includes the integers 5, 6, 7, 8, and 9, and all fractional or decimal units therebetween, such as 6.5 and 8.24.

[0109] "Subject" refers to an animal, such as a mammal, that is or is intended to be the target of a treatment, observation, or experiment. The methods described herein may be useful in both human therapy and veterinary applications. In some embodiments, the subject is a mammal; in some embodiments, the subject is a human; and in some embodiments, the subject is selected from bovine and equine subjects. "Subject in need thereof" or "human in need thereof" refers to a subject, such as a human, who may have or is suspected of having a disease or condition that would benefit from a particular treatment, such as treatment with a compound of formula (I) described herein, or a pharmaceutically acceptable salt or co-crystal thereof. This includes subjects who may be at risk of or are predisposed to such diseases or conditions and for whom the treatment would prevent the onset of the disease or condition.

[0110] The terms "pharmaceutically acceptable salts" or "pharmacologically acceptable salts" refer to salts prepared by conventional means, including basic salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid, etc. The "pharmaceutically acceptable salts" of the presently disclosed compounds include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, etc., as well as those formed from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts can be prepared by standard procedures, for example, by reacting the free acid with a suitable organic or inorganic base. Any compound recited herein can alternatively be administered as its pharmaceutically acceptable salt. "Pharmaceutically acceptable salts" also include free acids, bases, and zwitterionic forms. A description of suitable pharmaceutically acceptable salts is set forth in Handbook of Pharmaceutical Salts, Properties, Selection and Use, Wiley VCH (2002). When the compounds disclosed herein contain acidic functional groups such as carboxy groups, suitable pharmaceutically acceptable cationic counterparts for the carboxy groups are well known to those skilled in the art and include alkali, alkaline earth, ammonium, quaternary ammonium cations, etc. Such salts are known to those skilled in the art. For additional examples of "pharmacologically acceptable salts", see Berge et al., J. Pharm. Sci. 66:1 (1977).

[0111] The compounds described in this specification include all of their pharmaceutically acceptable salts, co-crystals, esters, solvates, hydrates, isomers (including optical isomers, racemates, or other mixtures thereof), tautomers, isotopes, polymorphs, or pharmaceutically acceptable prodrugs. In many cases, for the sake of brevity, a compound or a formula of a compound may be described as including "or its pharmaceutically acceptable salt". In each case, each form of the compound referred to in the previous sentence is intended and understood to be included in each such description or definition.

[0112] The terms "pharmacologically active amount", "pharmaceutically effective amount", or "effective amount" relate to the amount of a compound that provides a detectable decrease in parasite activity in vitro or in vivo or that reduces the likelihood of the emergence of drug resistance.

[0113] The term "treatment" or "treating" refers to an approach for obtaining a beneficial or desired result, including clinical results. Beneficial or desired clinical results may include one or more of the following: (i) inhibiting a disease or condition, such as a malaria infection (e.g., reducing one or more symptoms resulting from the disease or condition and / or reducing the extent of the disease or condition); (ii) delaying or arresting the occurrence of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or (iii) alleviating the disease, i.e., resulting in the regression of clinical symptoms (e.g., improving the disease state, providing partial or complete remission of the disease or condition, enhancing the effect of another agent, delaying the progression of the disease, improving the quality of life, and / or extending the survival period).

[0114] The term "inhibiting" or "inhibition" indicates a decrease, e.g., a significant decrease, in the baseline activity of a biological activity or process. For example, "inhibition" of malaria, babesiosis, or toxoplasmosis infection means that the symptoms or progression of such an infection, as a direct or indirect response to the presence of a compound of formula (I), or a pharmaceutically acceptable salt or co-crystal thereof, is reduced compared to the symptoms or progression of such an infection in the absence of such a compound or its pharmaceutically acceptable salt or co-crystal.

[0115] "Therapeutically effective amount" or "diagnostically effective amount" refers to an amount of a drug sufficient to achieve a desired effect in a subject being treated with the specified drug. For example, it can be the amount of a compound disclosed herein useful in treating an infection in a subject, such as malaria, babesiosis, or toxoplasmosis infection. Ideally, the therapeutically effective amount or diagnostically effective amount of a drug is an amount sufficient to inhibit or treat a disease without causing a substantial cytotoxic effect on the subject. The therapeutically effective amount or diagnostically effective amount of a drug depends on the subject being treated, the severity of the disease, and the mode of administration of the therapeutic composition.

[0116] The compounds and pharmaceutical compositions herein can be administered in either a single dose or multiple doses by any of the recognized modes of administration of drugs having similar utilities, as described in the patents and patent applications incorporated by reference, including, for example, rectal, buccal, intranasal, and transdermal routes, by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, as an inhalant, or via an impregnated or coated device such as a stent or an arterial insertion cylindrical polymer.

[0117] In some embodiments, the daily human dose can be from about 0.1 mg to about 1,000 mg. In other embodiments, the daily human dose can be from about 0.1 mg to about 500 mg. In other embodiments, the daily human dose can be from about 1 mg to about 250 mg. In still other embodiments, the daily human dose can be from about 1 mg to about 200 mg. In further embodiments, the daily human dose can be from the group consisting of: a) from about 1 mg to about 150 mg; b) from about 1 mg to about 100 mg; c) from about 1 mg to about 75 mg; d) from about 1 mg to about 50 mg; e) from about 5 mg to about 50 mg; f) from about 5 mg to about 40 mg; g) from about 1 mg to about 25 mg; and from about 1 mg to about 20 mg.

[0118] In other embodiments, the aforementioned doses for daily use may be administered as a once-weekly or twice-weekly (semi-weekly) dose. In some embodiments, the compound may be administered once every two weeks (every other week) as a prophylaxis for the disease conditions described herein. Non-limiting examples of once-weekly, twice-weekly, or biweekly doses include doses of 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, and 200 mg.

[0119] Within each dosage range, a pharmaceutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, may consist of a single daily dose, or divided doses two, three, or four times daily.

[0120] Prodrugs of the disclosed compounds are also contemplated herein. Prodrugs are active or inactive compounds that are chemically modified into active compounds through in vivo physiological actions such as hydrolysis, metabolism, etc., after administration of the prodrug to a subject. The suitability and techniques involved in the production and use of prodrugs are well known to those skilled in the art. For a general discussion of prodrugs, including esters, see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985).

[0121] The term "prodrug" is also intended to include any covalent carrier that releases the active parent drug of the present invention in vivo when administered to the prodrug. Prodrugs often have enhanced properties such as solubility and bioavailability compared to the active agent drug, so the compounds disclosed herein can be delivered in prodrug form. Accordingly, also contemplated are prodrugs of the presently disclosed compounds, methods of delivering the prodrugs, and compositions containing such prodrugs. Prodrugs of the disclosed compounds are typically prepared by modifying one or more functional groups present in the compound in such a way that the modification is cleaved either in routine operations or in vivo to afford the parent compound. Prodrugs include compounds having phosphonic acid and / or amino groups functionalized with any group that is cleaved in vivo to afford the corresponding amino and / or phosphonic acid groups, respectively.

[0122] Certain examples of the presently disclosed compounds contain one or more asymmetric centers; thus, these compounds can exist in different stereoisomeric forms. Accordingly, the compounds and compositions can be provided as individual pure enantiomers or as mixtures of stereoisomers including racemic mixtures. In certain embodiments, the compounds disclosed herein are synthesized or purified to be in a substantially enantiopure form, such as an enantiomeric excess of 90%, 95%, 97%, or greater than 99%, e.g., in enantiopure form.

[0123] It is understood that the substituents and substitution patterns of the compounds described herein are chemically stable and can be selected by one of ordinary skill in the art to provide compounds that can be readily synthesized by techniques known in the art and further by the methods shown in this disclosure.

[0124] The compounds and pharmaceutical compositions disclosed herein can be used to inhibit or prevent parasitosis. For example, human or animal (non-human) parasitosis includes malaria, toxoplasmosis, theileriosis, amebiasis, giardiasis, leishmaniasis, trypanosomiasis, neosporosis (Neospora cranium infection), and coccidiosis caused by organisms such as Toxoplasma (e.g., Toxoplasma protozoa), Eimeria (Eimeria disease), Babesia bovis (babesiosis), Theileria (Theileria annulata - tropical theileriosis and Theileria parva - East Coast fever), etc., as well as infections caused by helminths such as roundworms, schistosomes, and threadworms.

[0125] Provided is a method for treating coccidiosis in a non-human subject, the method comprising administering to the non-human subject in need thereof a pharmaceutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the non-human subject is a poultry subject including chickens, ducks, and turkeys. In some embodiments, the chicken in need of such treatment is infected with a pathogen selected from the group consisting of Eimeria tenella, E. maxima, E. mitis, E. acervulina, E. brunetti, E. praecox, and E. necatrix.

[0126] In some embodiments, the non-human subject is a ruminant subject including cows, bison, sheep, and goats. In some embodiments, coccidiosis in ruminants is associated with an infection by a pathogen selected from the group consisting of Eimeria bovis, E. zuernii, E. auburnensis, and E. alabamensis.

[0127] In goats, coccidiosis can be associated with infections by pathogens selected from the group of E. christenseni, E. arloingi, E. caprina, and E. ninakohlyakimovae.

[0128] The compounds and compositions described herein are also effective in inhibiting fungal pathogens including Pneumocystis carinii, Aspergillus fumigatus, and the like.

[0129] In certain embodiments, parasitosis can be caused by parasites that cause malaria. Specific species of parasites included in this group include all species that can cause human or animal infections. Exemplary species include Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, Plasmodium knowlesi, and Plasmodium quartan. The compounds and compositions disclosed herein are particularly useful for inhibiting drug-resistant malaria such as chloroquine-resistant malaria or multi-drug resistant malaria caused by organisms resistant to chloroquine, quinine, mefloquine, pyrimethamine, dapsone, and / or atovaquone.

[0130] Toxoplasmosis is caused by a spore-forming parasite of the phylum Apicomplexa called Toxoplasma gondii. It is a common tissue parasite of humans and animals. Most infections appear to be asymptomatic (90%), but toxoplasmosis poses a serious health risk to immunocompromised individuals such as organ transplant recipients, cancer and AIDS patients, and fetuses of infected mothers. The compounds disclosed herein may be used alone to treat toxoplasmosis or may be co-administered with "antifolate drugs" such as sulfonamides, pyrimethamine, trimethoprim, biguanides and / or atovaquone.

[0131] In a further aspect, the compounds disclosed herein may be co-administered with another pharmaceutically active compound. For example, the compound may be quinidine, chloroquine, atovaquone, proguanil, primaquine, amodiaquine, mefloquine, piperaquine, artemisinin, methylene blue, pyrimethamine, sulfadoxine, artemether-lumefantrine (Coartem®), dapsone-chlorproguanil (LAPDAP®), artesunate, quinidine, clopidol, pyridine / pyridinol analogs, 4(1H)-quinolone analogs, dihydroartemisinin, a mixture of atovaquone and proguanil, endoperoxide, acridone disclosed in WO 2008 / 064011 (incorporated herein by reference in its entirety), pharmachin disclosed in US Provisional Patent Application entitled "Compounds for Treating Parasitic Disease" filed on November 18, 2008 (incorporated herein by reference in its entirety), or any combination thereof.

[0132] The compounds disclosed herein can typically be included in pharmaceutical compositions (including therapeutic and prophylactic formulations) in combination with one or more pharmaceutically acceptable media or carriers and optionally with other therapeutic components (such as drugs used to relieve itching, e.g., antibiotics, anti-inflammatory agents, or antihistamines). The compositions disclosed herein may advantageously be combined with and / or used in combination with the other antimalarial agents described above.

[0133] Such pharmaceutical compositions can be administered to a subject by various mucosal administration modes including oral, rectal, intranasal, intrapulmonary, or transdermal delivery, or topical delivery to other surfaces. Optionally, the composition can be administered by non-mucosal routes including intramuscular, subcutaneous, intravenous, intraarterial, intraarticular, intraperitoneal, intrathecal, intraventricular, or parenteral routes. In other alternative embodiments, the compound can be administered ex vivo by direct exposure to cells, tissues or organs derived from the subject.

[0134] In some embodiments, an antimalarial agent or combination of antimalarial agents comprising a compound described herein, or a pharmaceutically acceptable salt thereof, may be administered to an animal, such as a chicken, as an additive to their prepared feed or grains.

[0135] In some embodiments, a pharmaceutically effective amount of a compound herein (including those of formula (I) and all other formulas and individual compounds described herein), or a pharmaceutically acceptable salt thereof, may be administered by injection to a human in need thereof. In some embodiments, the injection may be subcutaneous. In other embodiments, the injection is intramuscular.

[0136] The compounds of formula I, or pharmaceutically acceptable salts or co-crystals thereof, can be incorporated into a form for administration by injection, including sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and aqueous or oily suspensions or emulsions with similar pharmaceutical media. Aqueous solutions in saline can also be customarily used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0137] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, can be administered using a formulation containing sesame oil, preferably pharmaceutical-grade sesame oil. The components of the injection formulation can include additional polar compounds such as those selected from the group of monoglycerides, diglycerides, free fatty acids, plant sterols, sesamin, and sesamolin. Some injection formulations further contain ethanol. In some embodiments, the injection formulation contains about 5 wt% to about 10 wt% ethanol. In other embodiments, the injection formulation contains about 7 wt% to about 8 wt% ethanol. In other embodiments, the injection formulation contains about 7.25 wt% to about 7.75 wt% ethanol. In other embodiments, the injection formulation contains about 7.5 wt% ethanol.

[0138] Additional components that can be used for intramuscular injection include vegetable oils such as peanut oil, almond oil, olive oil, castor oil, and soybean oil. Similarly, synthetic oils such as polyethylene glycol, triglycerides of higher saturated fatty acids, and mono-esters of higher fatty acids are also suitable.

[0139] The injectable composition may also contain one or more excipients, such as benzyl alcohol or benzoic acid compounds, for example, benzyl benzoate or sodium benzoate. Other useful excipients include cholesteryl fatty acid esters such as methyl cholate, hydrophobic colloidal anhydrous silica, colloidal silicon dioxide, cholesteryl oleate, cholesteryl nonanoate, cholesteryl stearate, polyoxyethylene(5)sorbitan monooleate, polyoxyethylene(6)stearate, polyvalent metal salts of fatty acids, such as aluminum stearate, fatty acid esters of carbohydrates such as leopearl (registered trademark), sorbitan fatty acid esters such as sorbitan monolaurate, sorbitan sesquioleate, and sorbitan monostearate, and glycerol fatty acid esters such as glycerol monostearate.

[0140] The sterile injectable solution is prepared by incorporating the required amount of the compound of the present disclosure into a suitable solvent, optionally together with various other ingredients enumerated above, and then filter sterilizing. Generally, the dispersion is prepared by incorporating various sterile active ingredients into a sterile medium containing a basic dispersion medium and the other required ingredients enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and lyophilization techniques, whereby a powder of the active ingredient and any additional desired ingredients are obtained from its previously sterile filtered solution. In some embodiments, for parenteral administration, a sterile injectable solution is prepared containing a pharmaceutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or co-crystal thereof, for example, 0.1 to 1000 mg. However, it will be understood that the actual amount of the compound to be administered will usually be determined by the physician in light of the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound to be administered and its relative activity, the age, weight, and response of the individual subject, and the severity of the subject's symptoms.

[0141] To formulate a pharmaceutical composition, the compound can be combined with various pharmaceutically acceptable additives, as well as a base or vehicle for dispersion of the compound. Desirable additives include, but are not limited to, pH regulators such as arginine, sodium hydroxide, glycine, hydrochloric acid, and citric acid. In addition, local anesthetics (e.g., benzyl alcohol), tonicity agents (e.g., sodium chloride, mannitol, sorbitol), adsorption inhibitors (e.g., Tween 80 or Miglyol 812), solubilizers (e.g., cyclodextrin and its derivatives), stabilizers (e.g., serum albumin), and reducing agents (e.g., glutathione) can be included. Among many other suitable adjuvants well known in the art, adjuvants such as aluminum hydroxide (e.g., Amphogel, Wyeth Laboratories, Madison, N.J.), Freund's adjuvant, MPL™ (3-O-deacylated monophosphoryl lipid A; Corixa, Hamilton, Ind.) and IL-12 (Genetics Institute, Cambridge, Mass.) can be included in the composition. When the composition is liquid, the tonicity of the formulation is typically adjusted to a value such that substantial, irreversible tissue damage is not induced at the administration site, with the tonicity of a 0.9% (w / v) physiological saline solution being taken as 1. Generally, the tonicity of the solution is adjusted to about 0.3 to about 3.0, such as about 0.5 to about 2.0, or about 0.8 to about 1.7.

[0142] The compound can be dispersed in a base or vehicle, which may contain a hydrophilic compound having the ability to disperse the compound, and any desired additives. The base can be selected from a wide range of suitable compounds including polycarboxylic acids or their salts, copolymers of carboxylic acid anhydrides (e.g., maleic anhydride) and other monomers (e.g., methyl (meth)acrylate, acrylic acid, etc.), hydrophilic vinyl polymers such as polyvinyl acetate, polyvinyl alcohol, polyvinyl pyrrolidone, cellulose derivatives such as hydroxymethyl cellulose, hydroxypropyl cellulose, etc., and natural polymers such as chitosan, collagen, sodium alginate, gelatin, hyaluronic acid, and their non-toxic metal salts. In many cases, biodegradable polymers such as polylactic acid, poly(lactic - glycolic acid) copolymer, polyhydroxybutyric acid, poly(hydroxybutyric - glycolic acid) copolymer and mixtures thereof are selected as the base or vehicle. Alternatively or additionally, synthetic fatty acid esters such as polyglycerol fatty acid esters, sucrose fatty acid esters, etc. can be used as the vehicle. Hydrophilic polymers and other vehicles can be used alone or in combination and can impart enhanced structural integrity to the vehicle by partial crystallization, ionic bonding, cross-linking, etc. The vehicle can be provided in various forms including fluid or viscous solutions, gels, pastes, powders, microspheres and films for direct application to mucosal surfaces.

[0143] The compound can be combined with the base or vehicle according to various methods, and the release of the compound can be due to diffusion, disintegration of the vehicle, or formation of associated water channels. In some situations, the compound is dispersed in microcapsules (microspheres) or nanocapsules (nanospheres) prepared from a suitable polymer such as isobutyl 2 - cyanoacrylate (see, e.g., Michael et al., J. Pharmacy Pharmacol. 43:1 - 5, 1991) and dispersed in a biocompatible dispersion medium to obtain long - term sustained delivery and biological activity.

[0144] The compositions of the present disclosure can alternatively include, as pharmaceutically acceptable vehicle substances necessary to approximate physiological conditions, pH regulators and buffers, tonicity regulators, wetting agents, etc., such as sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, and triethanolamine oleate. For solid compositions, conventional non-toxic pharmaceutically acceptable vehicles can be used, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc.

[0145] The pharmaceutical composition for administering the compound can also be formulated as a solution, microemulsion, or other ordered structure suitable for a high concentration of the active ingredient. The vehicle can be a solvent or a dispersion medium, including, for example, water, ethanol, polyols (such as glycerol, propylene glycol, liquid polyethylene glycol, etc.), and suitable mixtures thereof. The appropriate fluidity of the solution can be maintained, for example, by the use of a coating such as lecithin, in the case of a dispersion formulation by maintaining the desired particle size, and by the use of surfactants. In many cases, it will be desirable to include in the composition an isotonic agent, such as sugars, polyalcohols such as mannitol and sorbitol, or sodium chloride. Prolonged absorption of the compound can be achieved by including in the composition an agent that delays absorption, such as monostearate and gelatin.

[0146] In certain embodiments, the compounds can be administered in a long-term release formulation, e.g., a composition comprising a sustained release polymer. These compositions can be prepared using a controlled release vehicle that protects from rapid release, e.g., a polymer, a microencapsulation delivery system, or a bioadhesive gel. The long-term delivery in the various compositions of the present disclosure is made possible by including in the composition agents that retard absorption, e.g., aluminum monostearate hydrogel and gelatin. When a controlled release formulation is desired, suitable controlled release binders for use in accordance with the present disclosure include any biocompatible controlled release material that is inert to the active agent and capable of incorporating the compound and / or other biological active agents. A number of such materials are known in the art. Useful controlled release binders are materials that are slowly metabolized under physiological conditions after delivery (e.g., at mucosal surfaces, or in the presence of body fluids). Suitable binders include, but are not limited to, biocompatible polymers and copolymers well known in the art for use in sustained release formulations. Such biocompatible compounds are non-toxic and inert to surrounding tissues and do not cause significant adverse side effects such as nasal irritation, immune response, inflammation, etc. These are also metabolized to biocompatible metabolites and are easily excreted from the body.

[0147] Exemplary polymeric materials for use in the present disclosure include, but are not limited to, polymer matrices derived from copolymers and homopolymer polyesters having hydrolyzable ester linkages. Some of these are known in the art to be biodegradable and to have no or low toxicity degradation products. Exemplary polymers include polyglycolic acid and polylactic acid, poly(DL-lactic acid-glycolic acid copolymer), poly(D-lactic acid-glycolic acid copolymer), and poly(L-lactic acid-glycolic acid copolymer). Other useful biodegradable or bioerodible polymers include, but are not limited to, polymers such as poly(ε-caprolactone), poly(ε-propiolactone-CO-lactic acid), poly(ε-propiolactone-CO-glycolic acid), poly(β-hydroxybutyric acid), poly(alkyl-2-cyanoacrylate), hydrogels such as poly(hydroxyethyl methacrylate), polyamides, poly(amino acids) (e.g., L-leucine, glutamic acid, L-aspartic acid, etc.), poly(ester urea), poly(2-hydroxyethyl DL-aspartic acid amide), polyacetal polymers, polyorthoesters, polycarbonates, polymaleamides, polysaccharides, and copolymers thereof. Many methods for preparing such formulations are well known to those skilled in the art (see, e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978). Other useful formulations include controlled release microcapsules (U.S. Pat. Nos. 4,652,441 and 4,917,893), lactic acid-glycolic acid copolymers useful in the preparation of microcapsules and other formulations (U.S. Pat. Nos. 4,677,191 and 4,728,721), and sustained release compositions of water-soluble peptides (U.S. Pat. No. 4,675,189).

[0148] The pharmaceutical compositions of the present disclosure are typically sterile and stable under the conditions of manufacture, storage, and use. Sterile solutions can be prepared by incorporating the required amount of the compound in a suitable solvent, optionally with one or a combination of the ingredients listed herein, followed by filtration sterilization. In general, dispersions are prepared by incorporating the compound and / or other biologically active agents in a sterile medium containing a basic dispersion medium and the other necessary ingredients from those listed herein. In the case of sterile powders, the methods of preparation include vacuum drying and lyophilization to obtain a powder of the compound and any additional desired ingredients from a previously sterile filtered solution. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0149] In some embodiments, a method of delivering a pharmaceutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof may be administered through a medical implant, particularly an implant designed to provide continuous, sustained, or long-term release of the active compound. In some embodiments, the implant contains the desired amount of the compound and an ethylene vinyl acetate (EVA) copolymer, such as the copolymer designs described in U.S. Patent Nos. 7,736,665 (Patel et al.), 8,852,623 (Patel et al.), 9,278,163 (Patel et al.), 10,111,830 (Patel et al.), and 10,123,971 (Patel et al.), each assigned to Titan Pharmaceuticals, Inc.

[0150] In some embodiments, the implant may include dimensions from 0.5 to about 7 mm in diameter. In some embodiments, the device is from about 0.5 to 10 cm in length. In one embodiment, the device is from about 1 to about 3 cm in length. In one embodiment, the device is from about 2 cm to about 3 cm in length. In another embodiment, the device is about 2.6 cm in length. In one embodiment, the device is from about 1 to about 3 mm in diameter. In another embodiment, the device is from about 2 to about 3 mm in diameter. In one embodiment, the device is about 2.4 mm in diameter. In some embodiments where the device includes dimensions of an overall diameter of about 2.4 mm and an overall length of about 2.6 cm, the device releases 1 mg of a pharmaceutical substance per day, respectively.

[0151] In some embodiments, the implantable device comprises from about 10 wt% to about 85 wt% of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and the remainder of the implant comprises an ethylene vinyl acetate (EVA) copolymer. In some embodiments, the implant comprises about 75% active drug (compound of formula I, or a pharmaceutically acceptable salt thereof) and about 25% EVA. In other separate embodiments, the implants each comprise about 10% active drug / about 90% EVA, about 20% active drug / about 80% EVA, about 30% active drug / about 70% EVA, about 40% active drug / about 60% EVA, about 50% active drug / about 50% EVA, about 60% active drug / about 40% EVA, about 70% active drug / about 30% EVA, and about 80% active drug / about 20% EVA.

[0152] Additional aspects include methods of administering the active drug described herein (a compound of Formula I, or a pharmaceutically acceptable salt thereof) to a subject in need thereof in a sustained release, controlled release, or long - term release gel formulation, such as a hydrogel formulation. Gel carriers useful for delivering a pharmaceutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, include, but are not limited to, injectable block copolymer - based thermoresponsive hydrogels; Carbopol (polyacrylic acid) gels; chitosan gels such as chitosan thermogel; nanoparticle - containing / nanocomposite hydrogels; modified poly(ethylene glycol) gels; carrageenan gels; and sorbitan monostearate aqueous gels, including thermoresponsive hydrogel carriers. Examples of useful gel carriers include those described in Sarah Gordon's chapter Gels as Vaccine Delivery Systems, Subunit Vaccine Delivery, p.203 - 220, Springer New York 2015 (Print ISBN: 1 - 4939 - 1416 - 2), U.S. Patent No. 10,272,140 (Yu et al.), U.S. Patent No. 9,526,787 (Ko et al.), and Bobbala et al., AAPS J. 2016 Jan, 18(1), pp. 261 - 269.

[0153] Oral gel, gel bead, or gel droplet formulations may be used to deliver an effective amount of a compound herein, or a pharmaceutically acceptable salt thereof, to an animal such as a poultry. Examples of gel formulations that may be used with the active drug described herein include those described in U.S. Patent No. 10,155,034 (Lee) and U.S. Patent No. 8,858,959 (Jenkins et al.).

[0154] In accordance with the various treatment methods of the present disclosure, a compound can be delivered to a subject in a manner consistent with the usual methods relevant to the management of a disorder for which treatment or prevention is sought. In accordance with the disclosure herein, a prophylactically or therapeutically effective amount of a compound and / or other biologically active agent is administered to a subject in need of such treatment for a sufficient time and under conditions sufficient to prevent, inhibit, and / or ameliorate a selected disease or condition or one or more symptoms thereof.

[0155] Typical subjects for which treatment by the compositions and methods of the present disclosure is contemplated include humans, as well as non-human primates and other animals. To identify a subject for prevention or treatment by the methods of the present disclosure, established screening methods are used to determine risk factors associated with parasitic infection and to determine the status of existing diseases or conditions in the subject. These screening methods include, for example, the preparation of a blood smear specimen from an individual suspected of having malaria. The blood smear specimen is then fixed in methanol, stained with Giemsa, and examined microscopically for the presence of malaria parasite-infected red blood cells. By these and other routine methods, a clinician can select patients in need of treatment using the methods and pharmaceutical compositions of the present disclosure.

[0156] Administration of the compounds of the present disclosure can be for prophylactic or therapeutic purposes. When provided prophylactically, the compound is provided before any symptoms. Prophylactic administration of the compound serves to prevent or ameliorate any subsequent disease process. When provided therapeutically, the compound is provided at the time of (or immediately following) the onset of symptoms of a disease or infection.

[0157] For prophylactic and therapeutic purposes, the compounds can be administered to a subject by oral route or single bolus delivery, continuous delivery over a long period (e.g., transdermal, mucosal or intravenous continuous delivery), or an iterative dosing protocol (e.g., an iterative dosing protocol of once per hour, once per day or once per week). The therapeutically effective dose of the present compound can be provided as an iterative dose within a long-term prophylactic or treatment plan that results in clinically significant results to alleviate one or more symptoms or detectable conditions associated with the target disease or condition shown herein. The determination of the effective dose in this context is typically based on animal model studies conducted prior to human clinical trials, with the dosing protocol that significantly reduces the incidence or severity of the symptoms or conditions of the target disease in the subject as the indicator. Suitable models in this regard include, for example, mice, rats, chickens, pigs, cats, non-human primates, and other acceptable animal model subjects known in the art. Alternatively, the effective dose can be determined using in vitro models (e.g., whole cell assays that monitor the effects of various drugs on parasite growth rate). Using such models, only normal calculations and adjustments are required to determine the appropriate concentrations and doses for administering a therapeutically effective amount of the compound (e.g., an amount effective to induce a desired immune response or alleviate one or more symptoms of the target disease). In an alternative embodiment, the effective amount or effective dose of the compound may simply inhibit or enhance one or more selected biological activities correlated with the disease or condition shown herein, for either therapeutic or diagnostic purposes.

[0158] The actual dosage of the compound will vary depending on factors such as the symptoms of the disease in the subject and specific circumstances (e.g., the age, size, health, degree of symptoms, sensitivity factors, etc. of the subject), the time and route of administration, other drugs or treatments administered simultaneously, and the specific pharmacology of the compound for inducing the desired activity or biological response in the subject. The dosing schedule can be adjusted to provide an optimal prophylactic or therapeutic response. A therapeutically effective amount is also an amount where the therapeutically beneficial effects clinically outweigh any toxicity or adverse side effects of the compound and / or other biologically active agents. A non-limiting range of the therapeutically effective amount of the compound and / or other biologically active agents in the methods and formulations of the present disclosure is from about 0.01 mg / kg body weight to about 20 mg / kg body weight, such as from about 0.05 mg / kg to about 5 mg / kg body weight, or from about 0.2 mg / kg to about 2 mg / kg body weight.

[0159] The dosage can be varied by the attending clinician to maintain the desired concentration at the target site (e.g., the lung or the systemic circulation). Higher or lower concentrations can be selected based on the mode of delivery, e.g., a comparison of transdermal, rectal, oral, pulmonary, or intranasal delivery versus intravenous or subcutaneous delivery. The dosage can also be adjusted based on the release rate of the dosage form, e.g., an inhalant for the lung versus a powder, a sustained-release oral formulation versus an injection granule or a transdermal delivery formulation.

[0160] The present disclosure also includes kits, packages, and multi-container units that include the pharmaceutical compositions, active ingredients, and / or these means of administration for use in the prevention and treatment of diseases and other conditions in mammalian subjects described herein. Diagnostic kits are also provided. In one aspect, these kits include a container or formulation that includes one or more of the conjugates described herein. In one example, this component is formulated in a pharmaceutical formulation for delivery to a subject. The conjugate is optionally included in a bulk dispensing container or in unit or multiple unit dosage forms. Any dispensing means, e.g., a pulmonary or intranasal spray applicator, can be provided. The packaging material optionally includes a label or instructions indicating for what treatment purposes and / or in what manner the packaged drug can be used.

[0161] Initially, ELQ-596 was prepared using previously reported approaches 12 。4-OEt-quinoline 1 was prepared according to the literature (Scheme 1 below) and reacted with pinacol ester 2 as previously described 12 。Finally, 4(1H)-quinolone ELQ-596 was obtained after hydrolysis of 4-chloroquinoline using potassium acetate (KOAc) in glacial acetic acid (AcOH).

[0162] Scheme 1. Synthesis of ELQ-596 a TIFF2025524371000022.tif59128 Scheme 1: (a) Pd(dppf)Cl2, aqueous K2CO3 solution, DMF, 80 °C, 99%; (b): HBr, AcOH, 90 °C, 59%.

[0163] As exemplified in Scheme 1, provided herein is a process for preparing a compound of formula (I) wherein R1 is selected from the group consisting of H, F, and Cl and R3, R4, and R5 are as defined above: TIFF2025524371000023.tif35128 comprising a) reacting a compound of formula: TIFF2025524371000024.tif18128 wherein R1 is selected from the group consisting of H, F, and Cl with a compound of formula: TIFF2025524371000025.tif31128 of an optionally substituted 2-([1,1'-biphenyl]-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to produce a first step product compound of formula: TIFF2025524371000026.tif31128 in a first step; and b) treating the first step product compound in an acidic medium to produce a compound of formula (I) in a second step.

[0164] Additional aspects include methods of producing the aforementioned first process product compounds. Another aspect provides a compound of formula (XI): TIFF2025524371000027.tif34128wherein R1 is selected from the group consisting of H, F, and Cl, and R3, R4, and R5 are each independently selected from the group consisting 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), and -C(O)NH(-CH2-C3-C6 cycloalkyl).

[0165] Another aspect provides a compound of formula (XI) wherein R1 is selected from the group consisting of H, F, and Cl, and R3, R4, and R5 are each independently selected from the group consisting of H, halogen, C1-C3 alkyl, -O-C1-C3 alkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-CF3, -SF5, CN, -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2, -C(O)NH(C3-C6 cycloalkyl), and -C(O)NH(-CH2-C3-C6 cycloalkyl).

[0166] Another aspect provides a compound of formula (XI) wherein R1 is selected from the group consisting of H, F, and Cl, and R3, R4, and R5 are each independently selected from the group consisting 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).

[0167] Another aspect provides a compound of formula (XI) wherein R1 is selected from the group consisting of H, F, and Cl, and R3, R4, and R5 are each independently selected from the group consisting 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).

[0168] Another aspect provides a compound of formula (XI) wherein R1 is selected from the group consisting of H, F, and Cl, and R3, R4, and R5 are each independently selected from the group consisting 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).

[0169] Another aspect provides a compound of formula (XI) wherein R1 is selected from the group consisting of H, F, and Cl, and R3, R4, and R5 are each independently selected from the group consisting of H, halogen, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 haloalkyl, -SF5, and CN.

[0170] Another aspect provides a compound of formula (XI) wherein R1 is selected from the group consisting of H, F, and Cl, and R3, R4, and R5 are each independently selected from the group consisting of H, F, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 fluoroalkyl, -O-C1-C2 fluoroalkyl, -SF5, and CN.

[0171] Another aspect provides a compound of formula (XI) wherein R1 is selected from the group consisting of H, F, and Cl, and R3, R4, and R5 are each independently selected from the group consisting of H, F, C1-C2 fluoroalkyl, -O-C1-C2 fluoroalkyl, and -SF5.

[0172] Within each aspect regarding the compound of formula (XI), all variables are as defined for a particular aspect, provided that at least one of R3, R4, and R5 is H. There are additional aspects where, within each aspect regarding the compound of formula (XI), all variables are as defined for a particular aspect except that R1 is F. There are also additional aspects where, within each aspect regarding the compound of formula (XI), all variables are as defined for a particular aspect except that R1 is Cl.

[0173] Also provided are two separate aspects, each comprising a compound of formula (X-1) and a compound of formula (X-2): TIFF2025524371000028.tif33132 wherein, in each aspect, R1 is selected from the group consisting of H, F, and Cl, and R3 is selected from the group consisting 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).

[0174] Two further distinct embodiments each include a compound of formula (X-1) and a compound of formula (X-2), wherein R1 is selected from the group consisting of H, F, and Cl, and R3 is selected from the group consisting 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).

[0175] Two further distinct embodiments each include a compound of formula (X-1) and a compound of formula (X-2), wherein R1 is selected from the group consisting of H, F, and Cl, and R3 is selected from the group consisting 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).

[0176] Two further distinct embodiments each include a compound of formula (X-1) and a compound of formula (X-2), wherein R1 is selected from the group consisting of H, F, and Cl, and R3 is selected from the group consisting 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).

[0177] Two further distinct embodiments each include a compound of formula (X-1) and a compound of formula (X-2), wherein R1 is selected from the group consisting of H, F, and Cl, and R3 is selected from the group consisting 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).

[0178] Two further distinct embodiments each include a compound of formula (X-1) and a compound of formula (X-2), wherein R1 is selected from the group consisting of H, F, and Cl, and R3 is selected from the group consisting of H, halogen, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 haloalkyl, -SF5, and CN.

[0179] Two further distinct embodiments each include a compound of formula (X-1) and a compound of formula (X-2), wherein R1 is selected from the group consisting of H, F, and Cl, and R3 is selected from the group consisting of H, F, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 fluoroalkyl, -O-C1-C2 fluoroalkyl, -SF5, and CN.

[0180] Two further distinct embodiments each include a compound of formula (X-1) and a compound of formula (X-2), wherein R1 is selected from the group consisting of H, F, and Cl, and R3 is selected from the group consisting of H, F, C1-C2 fluoroalkyl, -O-C1-C2 fluoroalkyl, and -SF5.

[0181] Within each aspect regarding the compound of formula (X-1) or formula (X-2), there are additional aspects where, except when R1 is F, all variables are as defined for a particular aspect. Within each aspect regarding the compound of formula (X-1) or formula (X-2), there are additional aspects where, except when R1 is Cl, all variables are as defined for a particular aspect.

[0182] In some embodiments, step a) of the above preparation method is completed in the presence of a palladium catalyst. In some embodiments, the palladium catalyst is selected from the group consisting of dichloro-((bis-diphenylphosphino)ferrocenyl)-palladium(II) (Pd(dppf)Cl2), dichloro-tris(diphenylphosphino)-palladium(II) (PdCl2(PPh)3), palladium(II) acetate (PD(OAc)2), palladium(II) chloride (PDCl2), tris(dibenzylideneacetone) dipalladium (PD2(dba)3), and tetrakis(triphenylphosphine)palladium (PD(PhP3)4). In some embodiments, the palladium catalyst is present at a concentration of about 0.01 equivalent to about 0.1 equivalent. In other embodiments, the catalyst is present at a concentration of about 0.03 equivalent to about 0.07 equivalent.

[0183] In some embodiments, the preparation is completed in an organic solvent in the presence of a base. In some embodiments, the organic solvent is selected from the group consisting of DMF, THF, dioxane, acetone, and toluene. In some embodiments, the base is selected from the group consisting of K2CO3, CsF, Cs2CO3, NaOH, Na2CO3, and K2CO3. In some embodiments, the base is present at a concentration of about 0.5 equivalent to about 3 equivalents.

[0184] To vary the benzenoid substituents R1 and X, the inventors decided to employ Approach I, which generates 4(1H)-quinolone in the final reaction step (Scheme 2 below). To vary the biphenyl substituents R3, R4, and R5, Approach II was used, in which the outer ring of the biphenyl side chain is introduced in the latter half of the 4(1H)-quinolone synthesis. TIFF2025524371000029.tif26157

[0185] To prepare the β-ketoester intermediates 8a and 8b, the inventors adapted a recently developed route for the large-scale synthesis of ELQ-300 10 . Ethyl 2-(4-(trifluoromethoxy)phenyl)acetate 6 was obtained in 58% yield by a Suzuki reaction of commercially available ethyl 2-(4-bromophenyl)acetate 5 and (4-(trifluoromethoxy)phenyl)boronic acid in dimethylformamide (DMF) using dichloride [1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) (Pd(dppf)Cl2) and potassium carbonate (K2CO3) (Scheme 3). By acylation of 5 and 6 with freshly prepared lithium hexamethyldisilazane (LiHMDS) and excess acetic anhydride (Ac2O) in tetrahydrofuran (THF), bisacylated enol acetates 7a and 7b were obtained as a mixture of equally reactive E- and Z-isomers in quantitative yield and in purity (>95%) sufficient to be used in the next step without further purification. The two stereoisomers can be isolated by flash chromatography. However, the inventors were unable to clearly assign the two stereoisomers using NOESY 2D NMR. GC-MS analysis showed that the major stereoisomer of 7a is 80% of the mixture, while the major stereoisomer of 7b is 95% of the mixture. Using catalytic p-toluenesulfonic acid (p-TsOH) in AcOH, bisacylated 7a and 7b were converted to β-ketoester intermediates 8a and 8b, which 1 were found to exist as a mixture of keto and enol tautomers as determined by 1H-NMR. After concentration, the crude reaction mixture mainly contained β-ketoester 8a or 8b and the catalyst p-TsOH, which was required for the next reaction and could be used without further purification.

[0186] Provided herein is a novel compound useful in the synthesis of a compound of formula (I) or a pharmaceutically acceptable salt thereof. One embodiment provides a compound of formula (A): TIFF2025524371000030.tif33128Wherein R3, R4, and R5 are each independently selected from the group consisting 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), and -C(O)NH(-CH2-C3-C6 cycloalkyl). In some embodiments, at least one of R3, R4, and R5 is hydrogen. In some embodiments, R3 is selected from the group consisting 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), and -C(O)NH(-CH2-C3-C6 cycloalkyl); and R4 is hydrogen; and R5 is hydrogen.

[0187] One embodiment provides a compound of formula (A) wherein R3, R4, and R5 are each independently selected from the group consisting 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).

[0188] Another aspect provides a compound of formula (A) wherein R3, R4, and R5 are each independently selected from the group consisting 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).

[0189] A further aspect provides a compound of formula (A) wherein R3, R4, and R5 are each independently selected from the group consisting 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).

[0190] Another aspect provides a compound of formula (A) wherein R3, R4, and R5 are each independently selected from the group consisting 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).

[0191] An additional aspect provides a compound of formula (A) wherein R3, R4, and R5 are each independently selected from the group consisting of halogen, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 haloalkyl, -SF5, and CN.

[0192] Two separate aspects each provide a compound of formula (A-1) and a compound of formula (A-2): In TIFF2025524371000031.tif36128, in each aspect, R3 is selected from the group consisting of 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), and -C(O)NH(-CH2-C3-C6 cycloalkyl). In several separate aspects regarding the compound of formula (A-1) and the compound of formula (A-2) respectively, R3 is selected from the group consisting of Cl, F, CH2F, CHF2, CF3, -O-CF3, and SF5. In other separate aspects, R3 is selected from the group consisting of F, CF3, -O-CF3, and SF5.

[0193] Scheme 3. Synthesis of β-ketoesters 8a and 8b a TIFF2025524371000032.tif50132 a Reaction (a): (4-(Trifluoromethoxy)phenyl)boronic acid, Pd(dppf)Cl2, K2CO3, DMF, 80 °C, 58%; (b): LiHMDS, Ac2O, and THF, -20 °C to room temperature for 20 hours to 72 hours; (c) 10% p-TsOH and AcOH, 100 °C for 2 to 16 hours, 89 to 100%.

[0194] Relatively easy modification of the benzenoid substituents X, Y, and Z was achieved by reaction of β-ketoester 8b with various anilines (10a - d). The crude β-ketoester mixture was reacted with anilines 10a - d under Dean - Stark conditions with refluxing benzene to obtain Schiff bases 10a - d, which were used without further purification (Scheme 4). The formation of 4(1H)-quinolones ELQ-596, ELQ-601, ELQ-649, and ELQ-650 was achieved by Conrad - Limpach cyclization of Schiff bases 10a - d at 250 °C in Dowtherm A 15、16 was achieved by 17 . The crude product obtained from this reaction was purified by HPLC and 1It was determined by 1H-NMR to have a purity of >98%. To enable the detection and quantification of ELQ-596 and ELQ-650 positional isomers, the product was converted to their corresponding 4-chloro derivatives using POCl3 and analyzed by GC-MS. From the results, it was found that negligible amounts (<0.5%) of ELQ-596 isomers and ELQ-650 isomers were generated under these conditions.

[0195] Scheme 4. Synthesis from β-ketoester 8b of a series of ELQ compounds having variable substitutions (X, Y, and Z) on the benzenoid ring a TIFF2025524371000033.tif73128 a Reaction (a): 10% p-TsOH, benzene, reflux, 24 - 72 h; (b): Dowsum A, 250 °C, 5 min, 28 - 37%.

[0196] The synthesis of 4(1H)-quinolone 12 was achieved using the same method as described above. The crude β-ketoester 8a mixture was reacted with commercially available 4-chloro-3-methoxyaniline 9b under Dean-Stark conditions with refluxing benzene to obtain Schiff base 11, which was used without further purification (Scheme 5). The formation of 4(1H)-quinolone 12 was achieved by the Conrad-Limpach cyclization of Schiff base 11 at 250 °C in Dowsum A 15、16 as achieved 17 . Subsequently, 4-chloroquinoline 13 was prepared from 4(1H)-quinolone 12 using neat POCl3 13 .

[0197] One embodiment provides a compound of formula (XII): TIFF2025524371000034.tif39128In the formula, R1 is selected from the group consisting of H, F, and Cl; and R3, R4, and R5 are each independently selected from the group consisting 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), and -C(O)NH(-CH2-C3-C6 cycloalkyl). In some embodiments, at least one of R3, R4, and R5 is hydrogen. In some embodiments, R3 is selected from the group consisting 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), and -C(O)NH(-CH2-C3-C6 cycloalkyl); R4 is hydrogen; R5 is hydrogen, and Z is selected from the group consisting of H, F, and OMe.

[0198] One embodiment provides a compound of formula (XII) wherein R1 is selected from the group consisting of H, F, and Cl; and R3, R4, and R5 are each independently selected from the group consisting 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), and Z is selected from the group consisting of H, F, and OMe.

[0199] Another aspect provides a compound of formula (XII) wherein R1 is selected from the group consisting of H, F, and Cl; and R3, R4, and R5 are each independently selected from the group consisting 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), and Z is selected from the group consisting of H, F, and OMe.

[0200] A further aspect provides a compound of formula (XII) wherein R1 is selected from the group consisting of H, F, and Cl; and R3, R4, and R5 are each independently selected from the group consisting 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), and Z is selected from the group consisting of H, F, and OMe.

[0201] Another aspect provides a compound of formula (XII) wherein R1 is selected from the group consisting of H, F, and Cl; and R3, R4, and R5 are each independently selected from the group consisting 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), and Z is selected from the group consisting of H, F, and OMe.

[0202] An additional aspect provides a compound of formula (XII) wherein R1 is selected from the group consisting of H, F, and Cl; and R3, R4, and R5 are each independently selected from the group consisting of halogen, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 haloalkyl, -SF5, 2-pyrrolidinone, and CN, and Z is selected from the group consisting of H, F, and OMe.

[0203] Two separate aspects each provide a compound of formula (XI-1) and a compound of formula (XI-2): TIFF2025524371000035.tif37129 wherein in each aspect, R1 is selected from the group consisting of H, F, and Cl; and R3 is selected from the group consisting of 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), and -C(O)NH(-CH2-C3-C6 cycloalkyl), and Z is selected from the group consisting of H, F, and OMe.

[0204] In several separate aspects, each relating to a compound of formula (A-1) and a compound of formula (A-2), R1 is selected from the group consisting of H, F, and Cl; and R3 is selected from the group consisting of Cl, F, CH2F, CHF2, CF3, -O-CF3, and SF5, and Z is selected from the group consisting of H, F, and OMe.

[0205] In another separate aspect, R1 is selected from the group consisting of H, F, and Cl; and R3 is selected from the group consisting of F, CF3, -O-CF3, and SF5, and Z is selected from the group consisting of H, F, and OMe.

[0206] Additional embodiments are provided corresponding to each embodiment for the compounds of formula (X-1) and the compounds of formula (XI-2) where R3 is as defined and R1 is Cl. Additional embodiments are also provided corresponding to each embodiment for the compounds of formula (X-1) and the compounds of formula (XI-2) where R3 is as defined and R1 is F.

[0207] Scheme 5. Synthesis of 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline 13 from β-ketoester 8a a TIFF2025524371000036.tif46128 a Reaction (a): 10% p-TsOH, benzene, reflux, 21 h; (b): Dowtherm A, 250 °C, 5 min, 50%; POCl3, reflux, 45 min, 100%.

[0208] Next, the modification of the biphenyl substituents R 1 and R 2 was achieved by the selective Suzuki reaction of 4-chloroquinoline 13 with various boronic acids or pinacol esters 14a - k in DMF using Pd(dppf)Cl2 and K2CO3 (Scheme 6). Subsequently, the obtained 4-chloroquinolines 15a - k were converted to their corresponding 4(1H)-quinolones using KOAc in AcOH.

[0209] Scheme 6. Synthesis of a series of ELQ compounds having a structural modification in the terminal benzene ring a TIFF2025524371000037.tif81166 a Reaction (a): Pd(dppf)Cl2, K2CO3, DMF, 80 °C, 11 - 67%; (b): KOAc, AcOH, 16 h, 36 - 87%.

[0210] For the in vivo tests of the inventors, it was necessary to convert ELQ-596 to the corresponding alkoxycarbonate prodrug, ELQ-598. This was achieved using tetra-n-butylammonium iodide (TBAI) and K2CO3 in DMF according to the previously reported method (Scheme 7). 9 。

[0211] Scheme 7. Synthesis of the alkoxycarbonate prodrug ELQ-598 a TIFF2025524371000038.tif23128 a Reaction (a) TBAI, K2CO3 and DMF, 60 °C, 24 h, 73%.

[0212] Results and Discussion Principle of the synthesis of the 3-biaryl version of ELQ-300. The inventors maintain a large chemical library of over 600 ELQ derivatives and have, over the years, evaluated the anti-parasitic activity of these drugs against a series of parasites, including Plasmodium falciparum, Toxoplasma gondii, Babesia microti, B. duncani, and relevant parasites particularly important for veterinary medicine. All this information is stored in a database along with information on chemical structure, physicochemical properties, cross-resistance patterns, cytotoxicity in mammalian cells, enzyme inhibitor profiles, and synthesis details. Pharmacological data and in vivo efficacy data are also stored in a database of promising molecules of interest. Recently, the inventors performed a retrospective analysis of compounds made over the years and found that no one had synthesized the biphenyl analog of ELQ-300, namely ELQ-596 (Figure 1). As described above, the inventors synthesized the compounds in batch sizes of approximately 800 mg. ELQ-596 was then tested for anti-malarial activity against four laboratory strains of Plasmodium falciparum, including the drug-sensitive D6 strain, the multi-drug resistant Dd2 strain, the atovaquone (ATV)-resistant clinical isolate Tm90-C2B, and the ELQ-300-resistant D1 clone previously isolated from Dd2. In vitro assays were performed in quadruplicate in 96-well plates in an initial range of 250 nM to 2.5 nM and retested in a 1 / 10 range if the drug potency was below this initial range. After incubating the plates for 72 hours using the SyBr Green assay, the 18、19 . Fluorescence measurements were obtained using a fluorescence plate reader and processed using Graphpad Prism software to obtain the IC 50 values along with the 95% confidence intervals for each measurement. The stock solution was freshly prepared in DMSO.

[0213] (Table 1) Structure-activity profile of 3-biaryl-ELQ against the drug-sensitive (D6) and drug-resistant (Dd2, C2B, and D1) strains of Plasmodium falciparum. The IC 50 values represent the concentration of the drug that inhibits parasite growth by 50% compared to a control without the drug added. TIFF2025524371000039.tif228161Note: Values are the mean of assays performed in quadruplicate (95% confidence interval).

[0214] (Table 2) Structure-activity profile of 3-biaryl-ELQs against drug-sensitive (D6) and drug-resistant (Dd2, C2B, and D1) strains of Plasmodium falciparum. IC 50 Values represent the concentration of drug that inhibits parasite growth by 50% compared to a drug-free control. TIFF2025524371000040.tif232161TIFF2025524371000041.tif70161Note: Values are the mean of assays performed in quadruplicate (95% confidence interval).

[0215] In vitro activity of selected 3-biaryl-ELQs against Plasmodium falciparum strains. IC 50 Values are shown in Tables 1 and 2 with the 95% confidence interval of one experiment performed in quadruplicate. (Assays were repeated at least twice.) Also, the alkoxycarbonate ester prodrug of ELQ-596, ELQ-598, was prepared and included in the assays along with historical control artemisinin (ATV), ELQ-300, and ELQ-400. The latter, like ATV, is a drug that targets the Q o site of the Pf cyt bc1 complex. The IC 50 values of ELQ-596 were 8- to 10-fold improved over ELQ-300 against D6 and Dd2 strains as well as ATV r and C2B (Table 1), but note that it was higher against the D1 clone than ELQ-300 r These results are interpreted as suggesting a higher inhibitory effect of ELQ-596 against wild-type Pf cyt bc1 as well as the mutant cyt bc1 complex of the clinical isolate Tm90-C2B.

[0216] ELQ-596 Metabolic Stability. ELQ-596 was then evaluated for its metabolic stability in the presence of pooled mouse liver microsomes. Since it is very structurally similar to ELQ-300, the new analog was expected to be stable under the assay conditions. The drug was incubated in the presence of pooled mouse liver microsomes (0.5 mg / ml) at 37 °C in the presence of NADPH and tested for P450 drug-dependent metabolism. Samples were taken at 45-minute intervals and analyzed for the presence of the test compound by LC-MS / MS. Ketanserin was used as an internal standard for the metabolic rate of a known drug with known moderate stability. As shown in Table 3, the test demonstrated extreme stability of ELQ-596 against microsomal attack, with degradation during the 45-minute incubation being negligible, and the T 1 / 2 in this in vitro assay was estimated to be >4,000 minutes.

[0217] (Table 3) Metabolic Stability of ELQ-596 in the Presence of Mouse Microsomes TIFF2025524371000042.tif29128

[0218] In vivo efficacy of ELQ-596 and alkoxycarbonate ester prodrug ELQ-598 against murine malaria. Next, the inventors were interested in testing ELQ-596 in vivo. Since it is a highly crystalline compound like ELQ-300, an alkoxycarbonate ester prodrug, ELQ-598 was prepared. Also, similar to ELQ-331, ELQ-598 shows a significant decrease in crystal lattice energy as demonstrated by a 229 °C decrease in melting point (Table 3). All test animals were first inoculated (day 0) by tail vein injection with 35,000 infected erythrocytes from donor mice infected with Plasmodium yoelii, and ELQ-598 was tested in a 4-day study using a modified Peters protocol. Then, animals were orally gavaged with ELQ-598 dissolved in PEG400 (100 μl) on days 1, 2, 3, and 4. On day 5, a drop of blood was taken from the tail, a blood smear specimen was prepared, fixed with methanol, and stained with Giemsa. Then, a technician examined the stained smear specimens by microscope to determine the percent parasitemia. Doses of 0.0025, 0.005, 0.01, 0.03, 0.1, 0.3, 1.0, and 10 mg / kg / day were used in the experiment. From two separate studies (4 mice / group), ED 50 and ED 90The average estimated values were 0.006 and 0.01 mg / kg / day, respectively, and the non-relapse dose (NRD) was 0.1 mg / kg / day (Table 4). These values are approximately one-third lower than those of ELQ-300 and ELQ-331. Fortunately, the superiority of ELQ-596 was carried over to the single-dose treatment (SDC) of the prodrug ELQ-598. In this model, animals were inoculated on day 0 in exactly the same way as in the 4-day test, but the drug was administered only on day 1, and the technician prepared smear specimens on day 5 and then weekly for animals remaining free of parasitemia. Animals that remained free of parasitemia until day 30 were considered cured. In this latter experiment, the lowest fully prophylactic single-dose treatment was 0.5 mg / kg (prodrug 0.6 mg / kg), the lowest dose tested so far. Therefore, the prodrug ELQ-598 is at least 6-fold more effective as a single-dose treatment against blood-stage malaria infection in mice compared directly with ELQ-331.

[0219] (Table 4) Comparison of ELQ-300, prodrug ELQ-331, and ELQ-596 and prodrug ELQ-598 TIFF2025524371000043.tif110128MP = melting point; ED 50 - Dose required to suppress parasitemia by 50% relative to untreated control (4-day Peters test), ED 90 - Dose required to suppress parasitemia by 90% relative to untreated control (4-day Peters test, Plasmodium yoelii Kenya strain), NRD - non-relapse dose (4-day Peters test), and SDC - single-dose treatment (lowest single dose at which all 4 mice in the group are completely cured). NT = not tested. ND = not determined. Note: Prodrugs were administered based on the molar equivalent to the parent drug.

[0220] Selective inhibition of the parasite cytochrome bc1 complex by ELQ-596. The ability of ELQ-596 to inhibit cytochrome bc1 activity from Plasmodium falciparum mitochondria was evaluated. As shown in Table , ELQ-596 showed a potent inhibitory effect on the Plasmodium falciparum cytochrome bc1 complex, IC50 The value was 0.1 nM. This value is much lower than the previously cited IC 50 values for either atovaquone or ELQ-300. It should be noted that the prodrug ELQ-598 shows only weak inhibitory activity against the parasite enzyme. Also, for the inhibition of the human host cytochrome bc1 complex isolated from human liver tissue, ELQ-596 was evaluated and no detectable inhibition was observed at a concentration of 10,000 nM. Taken together, the inventors' data show that ELQ-596 is a highly selective inhibitor of the malaria parasite cytochrome bc1 complex, and the selectivity index based on enzyme inhibitory activity is ≧18,000-fold. Such a high level of selectivity suggests a low likelihood of side effects in humans due to inhibition of host enzyme complexes.

[0221] (Table 5) Comparison of the inhibition of Plasmodium falciparum (parasite) and human (host) cytochrome bc1 complexes TIFF2025524371000044.tif59159 a The data were obtained from Nilsen et al., 2013. b The data were obtained from Frueh et al., 2017. The assay conditions are shown in the Methods section.

[0222] Safety and mitochondrial toxicity of ELQ-596 and prodrug ELQ-598. Of course, enhanced efficacy is only desirable if it is not accompanied by enhanced toxicity. Although our in vivo efficacy test model was not intended as a formal toxicity assessment, no changes in appearance, behavior, or body weight were seen after administration of ELQ-598 at any dose level. Similarly, the cytotoxicity of ELQ-596 was evaluated using the TiterGlo luminescence assay kit, which determines cell viability by measuring cellular ATP. In this assay, ATP is consumed as a co-substrate of luciferase when luciferase reacts with its substrate, luciferin, to emit light. Using the human HepG2 cell line in a medium where glucose was replaced with galactose to promote dependence on the oxidative phosphorylation process and reverse the so-called "crabtree effect", an EC 50 of >10 μM for ELQ-596 was observed, whereas the control drug, rotenone, showed significant cytotoxicity under these conditions (EC 50 =?) (Table 6). The incubation period for these experiments was 48 hours.

[0223] (Table 6) Comparison of the inhibition of the cytochrome bc1 complex of Plasmodium falciparum (parasite) and human (host) The 59128 cytotoxicity experiment was performed in a medium where glucose was replaced with galactose to reverse the crabtree effect. The assay conditions for Cyt bc1 are shown in the methods section. NT = not tested.

[0224] Based on previous pharmacokinetic experiments conducted in mice, rats, and dogs, pharmacology experts predict that a single oral dose of 30 mg of formulated ELQ-331 will protect adults from malaria infection if taken once a week. Our "backup plan" is that a more potent drug, perhaps the prodrug ELQ-598 or a variant thereof, could be delivered and provide a similar long-term protection at a significantly lower dose, perhaps 5 - 10 mg, on a once-weekly or alternate-week schedule.

[0225] Materials and Methods Chemical Synthesis Procedures Unless otherwise specified, all chemicals and reagents were obtained from Sigma-Aldrich Chemical Company, St. Louis, MO (USA), Combi-Blocks, San Diego (CA), or TCI America, Portland (OR) and used as received. Quinolone 1 and 4,4,5,5-tetramethyl-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)-1,3,2-dioxaborolane (14k) were obtained as previously reported 12 . Melting points were determined using an Optimelt Automated Melting point system from Stanford Research Systems, Sunnyvale, CA (USA). Analytical TLC was performed using Merck 60F-254 250 micron precoated silica gel plates, and spots were visualized with UV light at 254 nm. GC-MS was performed using an Agilent Technologies 7890B gas chromatograph (30 m, DBS column was programmed to hold at 100 °C or 200 °C for 2 min and then ramp to 300 °C at 30 °C / min, injector temperature was set at 250 °C) and an Agilent Technologies 5977A mass selective detector, and recorded at 70 eV. Flash chromatography on silica gel columns was performed using an Isolera One flash chromatography system from Biotage, Uppsala, Sweden 1 1H-NMR spectra were recorded at 400.14 MHz using a Bruker 400 MHz Avance NEO NanoBay NMR spectrometer. NMR raw data were analyzed using iNMR Spectrum Analyst software 1 1H chemical shifts are reported in parts per million (ppm) relative to the tetramethylsilane (TMS) internal standard or the residual solvent peak. Coupling constant values (J) are reported in Hertz (Hz). For fluorine-containing compounds, decoupling was performed at 376 MHz 19F was also recorded (data not shown). HPLC analysis was performed using an Agilent 1260 Infinity instrument, detection = 254 nm and a Phenomenex, Luna® 5 μm C8(2) 100 Å reverse-phase LC column 150 × 4.6 mm, at 40 °C, eluting with a gradient of 25% / 75% A / B to 25% - 90% A / B (A: 0.05% formic acid in milliQ water, B: 0.05% formic acid in methanol). GC-MS, 1 Determined by 1H-NMR, 13C-NMR and HPLC, the purity of all compounds was >95% in in vitro tests and >98% in in vivo tests.

[0226] 4,6-Dichloro-3-iodo-7-methoxy-2-methylquinoline (2). A stirred solution of 4(1H)-quinolone 1 (10.0 g, 28.6 mmol, 1 equiv) and POCl3 (14 ml, 146 mmol, 5.1 equiv) in DCM (100 ml) was refluxed for 72 h. After cooling to room temperature, the mixture was filtered, the precipitate was washed with DCM (3 × 5 ml) and air-dried to give pure 2 (9.8 g, 93% yield) as a white powder. GC-MS showed one peak at M + = 366.9 (100%). TIFF2025524371000046.tif11130

[0227] 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'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-596). Ethyl 2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)acetate (6). A stirred mixture of ethyl 2-(4-bromophenyl)acetate 5 (24.3 g, 100.0 mmol, 1.0 equiv), (4-(trifluoromethoxy)phenyl)boronic acid (24.72 g, 120.0 mmol, 1.2 equiv), K2CO3 (27.6 g, 200.0 mmol, 1.2 equiv) and (Pd(dppf)Cl2) (3.65 g, 5.0 mmol, 0.05 equiv) in DMF (250 ml) was deoxygenated by bubbling argon through the reaction mixture for 15 minutes. The stirred reaction mixture was then heated at 80 °C under an argon atmosphere for 18 hours, as determined by GC-MS, until no starting material 5 remained. The reaction mixture was cooled to room temperature, filtered through celite, and the DMF was removed under reduced pressure. The resulting black oily solid was resuspended in DCM (500 ml), stirred vigorously at room temperature for 30 minutes, filtered through celite, concentrated to dryness, and purified by flash chromatography on silica gel using a gradient of ethyl acetate / hexane (1 / 9) as the elution solvent mixture to give 6 (18.7 g, 58% yield) as a white solid. GC-MS showed one peak M + = 324.1 (42%); 251.2 (100%). TIFF2025524371000047.tif11146

[0228] Ethyl 3-acetoxy-2-(4-bromophenyl)but-2-enoate (7a). The temperature described was recorded by an internal thermometer. Under an Ar atmosphere, a stirred solution of anhydrous THF (50 ml) and HMDS (41.5 g, 257.0 mmol, 2.5 equiv) was cooled to -20 °C in a 75% ethylene glycol, 25% ethanol and dry ice bath. While monitoring to ensure that the temperature did not exceed -10 °C, n-butyllithium (2.5 M) in hexanes (n-BuLi) (98.8 mL, 247.0 mol, 2.4 equiv) was added. The temperature of the mixture was then lowered to -30 °C, and a solution of 5 (25.0 g, 103.0 mol, 1.0 equiv) in THF (50 ml) was slowly added. The mixture was warmed to -10 °C and stirred for 35 minutes while maintaining this temperature. Next, acetic anhydride (31.5 g, 309.0 mmol, 3.0 equiv) was added dropwise, and then the mixture was slowly warmed to room temperature. The mixture became turbid as it warmed, but did not gel. The progress of the reaction was monitored by GC-MS, and after 1 hour at 25 °C, 25% of the starting material was still present. Additional acetic anhydride (3.15 g, 30.0 mmol, 0.3 equiv) was added. After stirring for 72 hours at room temperature, 19% of the starting material was still present as determined by GC-MS. The reaction was stopped, the mixture was added to saturated ammonium chloride solution (100 ml), extracted with ethyl acetate (3 x 100 ml), and then the organic layers were combined and concentrated to give 35.0 g of a brown oil. GC-MS analysis showed one major peak (100%) at M + = 326 (2%), 238 (100%), one minor peak (27%) at M + = 326 (2%), 238 (100%) and another minor peak (19%, corresponding to 5) at M + = 242 (25%), 168.9 (100%). The peak at M + = 326 corresponds to the E and Z stereoisomers of the desired product 7a. 2D NOESY NMR was unable to clearly assign the two stereoisomers. The percentage of the major stereoisomer with respect to the minor stereoisomers was estimated to be 80% by GC-MS. The product can be used in the next step without further purification.

[0229] For analysis and characterization, two stereoisomers were purified by flash chromatography using hexane and ethyl acetate (5 - 15% gradient).

[0230] NMR of the major stereoisomer of 7a: TIFF2025524371000048.tif11128

[0231] NMR of the minor stereoisomer of 7a: TIFF2025524371000049.tif11128

[0232] Ethyl 3 - acetoxy - 2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)but - 2 - enoate (7b). The temperatures stated were recorded with an internal thermometer. Under an Ar atmosphere, a stirred solution of anhydrous THF (50 ml) and HMDS (16.6 g, 102.9 mmol, 2.3 equiv) was cooled to -20 °C in a bath of 75% ethylene glycol, 25% ethanol and dry ice. While monitoring to ensure the temperature did not exceed -10 °C, n - butyllithium in hexane (2.5 M) (n - BuLi) (39.4 mL, 98.5 mmol, 2.2 equiv) was added dropwise, followed by 6 (14.5 g, 44.75 mmol, 1.0 equiv) in THF (50 ml). After stirring at -15 °C to -10 °C for 35 min, acetic anhydride (10.05 g, 11.3 ml, 98.5 mmol, 2.2 equiv) was added dropwise while monitoring to ensure the temperature did not exceed -10 °C. The solution was then slowly warmed to room temperature, where it turned into a pale yellow gel. After stirring at room temperature for 20 h, the mixture was added to saturated ammonium chloride solution (200 ml) and extracted with ethyl acetate (3 × 100 ml). The organic layers were then combined and concentrated to give 17.3 g of a brown oil. GC - MS analysis showed one major peak (100%) at M + = 408 (3%), 320 (100%), one minor peak (5%) at M + = 408 (3%), 320 (100%), and another minor peak (5%) at M + = 324 (42%), 251 (100%) (corresponding to starting material 6). M +The peak at =408 corresponds to a mixture of the E and Z stereoisomers of the desired product 7b. The two stereoisomers could not be clearly assigned by 2D NOESY NMR. The percentage of the major stereoisomer with respect to the minor stereoisomers was estimated to be 95% by GC-MS. The product could be used in the next step without further purification.

[0233] For analysis and characterization, the two stereoisomers were purified by flash chromatography using hexane and ethyl acetate (5 - 50% gradient).

[0234] NMR of the major stereoisomer of 7b: TIFF2025524371000050.tif18161

[0235] NMR of the minor stereoisomer of 7b: TIFF2025524371000051.tif11137

[0236] Ethyl 2-(4-bromophenyl)-3-oxobutanoate (8a). A stirred solution of 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 heated at 100 °C. After 2 h, the starting material 7a was no longer detected by TLC and GC-MS. The dark brown solution was cooled to room temperature and concentrated under reduced pressure. After most of the acetic acid was removed, cyclohexane (2×100 ml) was added to the brown oil and concentrated again to give 30.5 g of 8a as a dark brown oil. Since this material still contained 1.9 g of p-TsOH, the yield of 8a was 28.6 g (yield 100%). The product could be used in the subsequent Conrad-Limpach reaction without further purification. Both the keto and enol forms can 1 be detected by 1H-NMR.

[0237] Ethyl 3-hydroxy-2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)but-2-enoate (8b). A stirred solution of bis-acylated 7b (11.8 g, 0.29 mol, 1 eq) in glacial acetic acid (25 ml) and 98% p-TsOH monohydrate (549 mg, 0.29 mol, 0.1 eq) was heated at 100 °C. After 16 h, starting material 7b was no longer detected by TLC and GC-MS. Notably, β-ketoester 8b decomposed at the mass spectrometer inlet, showing major peaks at M + = 294 (32%), 251 (100%). The dark brown solution was cooled to room temperature and concentrated under reduced pressure. After most of the acetic acid had been removed, cyclohexane (2 × 50 ml) was added to the brown oil and concentrated again to give 10.0 g of 10b as a dark brown oil. Since this material still contained 549 mg of p-TsOH, the yield of 5 was 9.45 g (89% yield). The product could be used in the subsequent Conrad–Limpach reaction without further purification. Both keto and enol forms could be 1 detected by 1H-NMR.

[0238] General procedure for the preparation of Schiff bases (10a–d and 11). A stock solution of β-ketoester 8a or 8b containing 0.1 eq of p-TsOH (0.25 mM) in benzene was prepared (0.92 g / 10 ml = 2.5 mM) and stored. A stirred solution of the substituted aniline (9a–d) and a fixed amount of β-ketoester 8a or 8b in benzene was heated to reflux for 24–72 h using a Dean–Stark trap, continuously removing water by azeotropy, and monitoring the disappearance of β-ketoester 8a or 8b by GC-MS. The solution was then concentrated under reduced pressure to give the product Schiff bases (10a–d and 11) as yellow–brown highly viscous oils.

[0239] General procedure for the Conrad-Limpach reaction (ELQ). The intermediate Schiff bases (10a-d and 11) were diluted with 5 ml of warm Dowtherm A and added dropwise over about 5 minutes to 65 ml of boiling Dowtherm A (250 °C) with vigorous stirring to maintain boiling. The mixture was boiled for an additional 5 minutes, then cooled to room temperature, diluted with hexane (250 ml) to form a precipitate, which was filtered and washed with ethyl acetate and acetone until a colorless filtrate was obtained.

[0240] 2-Methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-649). TIFF2025524371000052.tif37128 A mixture of aniline 9a (0.47 g, 5.0 mol, 1 equiv), benzene (125 ml), and β-ketoester 8b (5.0 mmol, 1 equiv) containing p-TsOH (0.5 mmol, 0.1 equiv) was heated to reflux for 24 h according to the general procedure for the preparation of Schiff bases. Then, following the general procedure for the Conrad-Limpach reaction, ELQ-649 (0.64 g, 32% yield) was obtained as a white powder after crystallization using DMF. TIFF2025524371000053.tif25161 The purity of the product was >98% by HPLC and 1 1H-NMR.

[0241] 6-Chloro-7-methoxy-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-596). TIFF2025524371000054.tif40128 A mixture of aniline 9b (0.78 g, 5.0 mmol, 1 equiv), benzene (125 ml), and β-ketoester 8b (5.0 mmol, 1 equiv) containing p-TsOH (in mmol, 0.1 equiv) was heated to reflux for 72 h according to the general procedure for the preparation of Schiff bases. Then, following the general procedure for the Conrad-Limpach reaction, ELQ-596 (0.77 g, 34% yield) was obtained as a white powder. TIFF2025524371000055.tif18161 The purity of the product is >98% as determined by HPLC and 1 1H-NMR.

[0242] 6-Fluoro-7-methoxy-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-650). TIFF2025524371000056.tif37128 According to the general procedure for the preparation of Schiff bases, a mixture of aniline 9c (0.71 g, 5.0 mmol, 1 equiv), benzene (125 ml), and β-ketoester 8b (5.0 mmol, 1 equiv) containing p-TsOH (0.5 mmol, 0.1 equiv) was heated to reflux for 46 h. Then, ELQ-650 (0.61 g, yield 28%) was obtained as a white powder according to the general procedure for the Conrad–Limpach reaction. TIFF2025524371000057.tif18161 The purity of the product is >98% as determined by HPLC and 1 1H-NMR.

[0243] 5,7-Difluoro-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-601). TIFF2025524371000058.tif36128 According to the general procedure for the preparation of Schiff bases, a mixture of aniline 9d (0.71 g, 5.0 mmol, 1 equiv), benzene (125 ml), and β-ketoester 8b (5.0 mmol, 1 equiv) containing p-TsOH (0.5 mmol, 0.1 equiv) was heated to reflux for 72 h. Then, ELQ-601 (0.80 g, yield 37%) was obtained as a white powder according to the general procedure for the Conrad–Limpach reaction. TIFF2025524371000059.tif18161 The purity of the product is >98% as determined by HPLC and 1 1H-NMR.

[0244] General procedure for the preparation of Schiff base of 3-(4-bromophenyl)-6-chloro-7-methoxy-2-methylquinolin-4(1H)-one (12). A mixture of aniline 9b (13.0 g, 83.0 mmol, 1 eq), benzene (150 ml), and β-ketoester 8a (23.7 g, 83.0 mmol, 1 eq) containing p-TsOH (8.3 mmol, 0.1 eq) was heated to reflux for 21 h. Then, according to the general procedure of the Conrad-Limpach reaction, Dowtherm A (30 ml) was used to dilute the Schiff base and added to boiling Dowtherm A (200 ml). Precipitation occurred upon cooling with stirring. Hexane (800 ml) was added to form a sticky solid, which was filtered, stirred with acetone (150 ml) for 15 min, filtered, washed with acetone (3 × 25 ml), and air-dried to obtain pure 12 (14.7 g, yield 49.5%) as a white solid. TIFF2025524371000060.tif11140

[0245] 3-(4-Bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline (13). 4(1H)-Quinolone 12 (14.7 g, 39.0 mmol) was refluxed with POCl3 (70 ml) for 45 min. After cooling to room temperature, the solution was slowly added dropwise to vigorously stirred water (800 ml) over 10 min and stirred for an additional 5 min. The resulting precipitate was washed with water (50 ml) and acetone (2 × 25 ml) and air-dried to obtain pure 13 (15.7 g, yield 100%). GC-MS showed one peak at M + = 395 (63%), 397 (100%), 399 (47%), 401 (10%). TIFF2025524371000061.tif11161

[0246] General procedure for the preparation of biphenylquinolines (15a~k). A stirred mixture of quinoline 13, substituted phenylboronic acids 14a~g, 14i and 14j or pinacol esters 14h and 14k, K2CO3 and Pd(dppf)Cl2 in DMF was deoxygenated by bubbling argon through the solution for 15 minutes. The stirred reaction mixture was then heated at 80 °C under an argon atmosphere until the starting material 13 had almost disappeared as determined by GC-MS. The reaction mixture was cooled to room temperature, filtered through celite, and the DMF was removed under reduced pressure. The resulting black oily solid was resuspended in DCM, stirred vigorously at room temperature for 30 minutes, filtered through celite, and concentrated to dryness. The residue was dissolved in 3 - 5 ml of DCM and, if all the solids had dissolved, the product was purified by flash chromatography. If the product was insoluble in methylene chloride, these were filtered off, washed with DCM, and the filtrate was further purified by flash chromatography to obtain additional product.

[0247] General procedure for the hydrolysis of 4-chloroquinoline. A stirred mixture of 4-chloroquinoline, potassium acetate (KOAc) and glacial acetic acid was heated at 120 °C for 16 - 26 hours in a reaction vial with a loose stopper.

[0248] 4,6-Dichloro-3-(4'-chloro-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (15a). According to the general procedure for the preparation of biphenylquinolines, a mixture of 13 (740 mg, 1.86 mmol, 1 equiv), 14a (435 mg, 2.79 mmol, 1.5 equiv), K2CO3 (513 mg, 3.72 mmol, 2 equiv) and Pd(dppf)Cl2 (68 mg, 0.093 mmol, 0.05 equiv) and DMF (75 ml) was heated for 16 hours to obtain crude 25 (911 mg) as a black solid. DCM (5 ml) was added, the precipitate was filtered off, and washed with methylene chloride (2 × 5 ml) to obtain pure 15a (158 mg) as a white solid. The filtrate was further purified by flash chromatography using a gradient of ethyl acetate / hexane (3 / 7) as the elution solvent to obtain additional 15a (99 mg), giving a combined yield of 15a (257 mg, 32% yield). GC-MS showed one peak at M+ =427 (100%). TIFF2025524371000062.tif11152

[0249] 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 biphenylquinolines, a mixture of 13 (794 mg, 2.0 mmol, 1 equiv.), 14b (326 mg, 2.4 mmol, 1.2 equiv.), K2CO3 (552 mg, 4.0 mmol, 2 equiv.), and Pd(dppf)Cl2 (73 mg, 0.10 mmol, 0.05 equiv.) in DMF (75 mL) was heated for 16 h to give crude 15b (898 mg) as a black solid. The product was soluble in DCM and purified by flash chromatography using a gradient of ethyl acetate / hexane (3 / 7) as the eluent to give pure 15b (328 mg, 40% yield) as a white solid. GC-MS detects one peak M + =407 (100%). TIFF2025524371000063.tif11148

[0250] 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 biphenylquinolines, a mixture of 13 (794 mg, 2.0 mmol, 1 equiv.), 14c (427 mg, 2.4 mmol, 1.2 equiv.), K2CO3 (552 mg, 4.0 mmol, 2 equiv.), and Pd(dppf)Cl2 (73 mg, 0.10 mmol, 0.05 equiv.) in 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 purified by flash chromatography using a gradient of ethyl acetate / hexane (3 / 7) as the eluent to give pure 15c (331 mg, 37% yield) as a white solid. GC-MS detects one peak M + =450 (63%), 434 (100%). TIFF2025524371000064.tif11131

[0251] 4,6-Dichloro-7-methoxy-2-methyl-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)quinoline (15d). According to the general procedure for the preparation of biphenylquinoline, a mixture of 13 (794 mg, 2.0 mmol, 1 equiv), 14d (456 mg, 2.4 mmol, 1.2 equiv), K2CO3 (552 mg, 4.0 mmol, 2 equiv) and Pd(dppf)Cl2 (73 mg, 0.10 mmol, 0.05 equiv) and DMF (75 ml) was heated for 36 h to give crude 15d (1.12 g) as a reddish black solid. DCM (5 ml) was added, the precipitate was filtered and washed with methylene chloride (2 x 5 ml) to give pure 15d (320 mg, 35% yield) as a white solid. GC-MS showed one peak M+ = 461 (100%). TIFF2025524371000065.tif18161

[0252] 4'-(4,6-Dichloro-7-methoxy-2-methylquinolin-3-yl)-[1,1'-biphenyl]-4-carbonitrile (15e). According to the general procedure for the preparation of biphenylquinoline, a mixture of 13 (794 mg, 2.0 mmol, 1 equiv), 14e (353 mg, 2.4 mmol, 1.2 equiv), K2CO3 (552 mg, 4.0 mmol, 2 equiv) and Pd(dppf)Cl2 (73 mg, 0.10 mmol, 0.05 equiv) and DMF (75 ml) was heated for 36 h to give crude 15e (769 mg) as a black solid. DCM (5 ml) was added, the precipitate was filtered and 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 gradient of ethyl acetate / hexane (3 / 7) as the eluting solvent to give an additional 29 (90 mg), giving a combined yield of 15e (380 mg, 45% yield). GC-MS showed one peak M + = 418 (100%). TIFF2025524371000066.tif11128

[0253] 4,6-Dichloro-3-(4'-(difluoromethyl)-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (15f). According to the general procedure for the preparation of biphenylquinoline, a mixture of 13 (397 mg, 1.0 mmol, 1 equiv), 14f (206 mg, 1.2 mmol, 1.2 equiv), K2CO3 (276 mg, 2.0 mmol, 2 equiv) and Pd(dppf)Cl2 (73 mg, 0.10 mmol, 0.1 equiv) and DMF (3 ml) was heated for 36 h to give crude 15f as a brown solid. DCM (5 ml) was added, the precipitate was filtered and washed with DCM (2 × 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-MS showed one peak M + = 443.1 (100%). TIFF2025524371000067.tif11134

[0254] 4,6-Dichloro-7-methoxy-3-(4'-methoxy-[1,1'-biphenyl]-4-yl)-2-methylquinoline (15g). According to the general procedure for the preparation of biphenylquinoline, a mixture of 13 (794 mg, 2.0 mmol, 1 equiv), 14g (365 mg, 2.4 mmol, 1.2 equiv), K2CO3 (552 mg, 4.0 mmol, 2 equiv) and Pd(dppf)Cl2 (73 mg, 0.10 mmol, 0.05 equiv) and DMF (75 ml) was heated for 16 h to give crude 15g (1.29 g) as a black solid. DCM (5 ml) was added, the precipitate was filtered and washed with DCM (2 × 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 give an additional 15g (143 mg), giving a combined yield of 15g (398 mg, 47% yield). GC-MS showed one peak M + = 423 (100%). TIFF2025524371000068.tif11154

[0255] 4,6-Dichloro-3-(4'-(difluoromethoxy)-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (15h). Following the general procedure for the preparation of biphenylquinoline, a mixture of 13 (794 mg, 2.0 mmol, 1 equiv), 14h (648 mg, 2.4 mmol, 1.2 equiv), K2CO3 (552 mg, 4.0 mmol, 2 equiv) and Pd(dppf)Cl2 (73 mg, 0.10 mmol, 0.05 equiv) and DMF (75 ml) was heated for 16 h to give crude 15h (1.073 g) as a black solid. DCM (5 ml) was added, the precipitate was filtered, washed with DCM (2 × 5 ml), and then crystallized from DCM to give pure 15h (412 mg) as a white solid. The filtrate was further purified by flash chromatography using a gradient of ethyl acetate / hexane (3 / 7) as the elution solvent to give an additional 15h (140 mg), giving a combined yield of 15h (552 mg, 60%). GC-MS showed one peak M + = 459 (100%). TIFF2025524371000069.tif18161

[0256] 4,6-Dichloro-7-methoxy-2-methyl-3-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)quinoline (15i). Following the general procedure for the preparation of biphenylquinoline, a mixture of 13 (794 mg, 2.0 mmol, 1 equiv), 14i (456 mg, 2.4 mmol, 1.2 equiv), K2CO3 (552 mg, 4.0 mmol, 2 equiv) and Pd(dppf)Cl2 (73 mg, 0.10 mmol, 0.05 equiv) and DMF (75 ml) was heated at 120 °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 chromatography using a gradient of ethyl acetate / hexane (6 / 4) as the elution solvent to give 15i (100 mg, 11% yield) with a purity of about 95% as a white solid. GC-MS showed one major peak M + = 461 (100%). TIFF2025524371000070.tif11128

[0257] 4,6-Dichloro-7-methoxy-2-methyl-3-(3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinoline (15j). According to the general procedure for the preparation of biphenylquinoline, a mixture of 13 (794 mg, 2.0 mmol, 1 equiv), 14j (494 mg, 2.4 mmol, 1.2 equiv), K2CO3 (552 mg, 4.0 mmol, 2 equiv) and Pd(dppf)Cl2 (73 mg, 0.10 mmol, 0.05 equiv) 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 purified by flash chromatography 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 showed one peak M + = 477 (100%) and one minor peak M + = 397 (100%) corresponding to starting material 13. GC-MS and NMR indicated that 15j was of sufficient purity (ca. 95%) for use in the next step.

[0258] 4,6-Dichloro-7-methoxy-2-methyl-3-(4'-(4-(trifluoromethoxy)phenoxy)-[1,1'-biphenyl]-4-yl)quinoline (15k). According to the general procedure for the preparation of biphenylquinoline, a mixture of 13 (794 mg, 2.0 mmol, 1 equiv), 14k (1.18 g, 3 mmol, 1.5 equiv), K2CO3 (552 mg, 4.0 mmol, 2 equiv) and Pd(dppf)Cl2 (73 mg, 0.10 mmol, 0.05 equiv) and DMF (75 ml) was heated for 48 h to give crude 15k (1.42 g) as a black solid. DCM (5 ml) was added, the precipitate was filtered off and washed with DCM (2 × 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 give an additional 15k (489 mg), giving a combined yield of 15k (599 mg, 53% yield). GC-MS showed one peak M + = 569 (100%). TIFF2025524371000071.tif18161

[0259] 6-Chloro-3-(4'-chloro-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-637). TIFF2025524371000072.tif431284-Chloroquinoline was hydrolyzed according to the general procedure. A mixture of 15a (157 mg, 0.3 mmol, 1 equiv), KOAc (360 mg, 3.7 mmol, 10 equiv) and glacial acetic acid (10 ml) was heated for 26 h. After cooling to room temperature, the reaction mixture was further cooled to 4 °C. The resulting solid was collected by filtration under reduced pressure, washed with excess water and subsequently with acetone (3×5 ml), and air-dried to give ELQ-637 as a light grayish brown powder (0.104 g, 69% yield). TIFF2025524371000073.tif18161

[0260] 6-Chloro-7-methoxy-2-methyl-3-(4'-methyl-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-603). TIFF2025524371000074.tif361284-Chloroquinoline was hydrolyzed according to the general procedure. A mixture of 15b (204 mg, 0.5 mmol, 1 equiv), KOAc (490 mg, 5.0 mmol, 10 equiv) and glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was added to ice water (20 ml). The resulting precipitate was filtered, washed with water (3×10 ml), acetone (2×10 ml), DCM (2×10 ml), hexane (10 ml), and air-dried to give pure ELQ-603 (170 mg, 87% yield) as a white solid. TIFF2025524371000075.tif18161

[0261] 3-(4'-(tert-Butyl)-[1,1'-biphenyl]-4-yl)-6-chloro-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-651). Following the general procedure for the hydrolysis of 4-chloroquinoline, a mixture of 15c (225 mg, 0.5 mmol, 1 equiv), KOAc (490 mg, 5.0 mmol, 10 equiv) and glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was added to ice water (20 ml). The resulting precipitate was filtered, washed with water (3×10 ml), acetone (2×10 ml), DCM (2×10 ml), hexane (10 ml), and air-dried to obtain pure ELQ-651 (184 mg, 85% yield) as a white solid. TIFF2025524371000077.tif18161

[0262] 6-Chloro-7-methoxy-2-methyl-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-647). Following the general procedure for the hydrolysis of 4-chloroquinoline, a mixture of 15d (231 mg, 0.5 mmol, 1 equiv), KOAc (490 mg, 5.0 mmol, 10 equiv) and glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was added to ice water (20 ml). The resulting precipitate was filtered, washed with water (3×10 ml), acetone (2×10 ml), DCM (2×10 ml), hexane (10 ml), and air-dried to obtain pure ELQ-647 (180 mg, 81% yield) as a white solid. TIFF2025524371000079.tif18161

[0263] 4'-(6-Chloro-7-methoxy-2-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-[1,1'-biphenyl]-4-carbonitrile (ELQ-602). Following the general procedure for the hydrolysis of 4-chloroquinoline, a mixture of 15e (231 mg, 0.5 mmol, 1 equiv), KOAc (490 mg, 5.0 mmol, 10 equiv) and glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was added to ice water (20 ml). The resulting precipitate was filtered, washed with water (3×10 ml), acetone (2×10 ml), DCM (2×10 ml), hexane (10 ml), and air-dried to give pure ELQ-602 (172 mg, 86% yield) as a white solid. TIFF2025524371000081.tif18161

[0264] 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 4-chloroquinoline, a mixture of 15f (210 mg, 0.5 mmol, 1 equiv), KOAc (490 mg, 5.0 mmol, 10 equiv) and glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was added to ice water (10 ml). The resulting precipitate was filtered, washed with water (3×3 ml), acetone (2×3 ml), methylene chloride (2×3 ml), hexane (20 ml), and air-dried to give pure ELQ-659 (105 mg, 52% yield) as a white solid. TIFF2025524371000083.tif18161

[0265] 6-Chloro-7-methoxy-3-(4'-methoxy-[1,1'-biphenyl]-4-yl)-2-methylquinolin-4(1H)-one (ELQ-645). Following the general procedure for the hydrolysis of 361284-chloroquinoline, a mixture of 15 g (212 mg, 0.5 mmol, 1 equiv), KOAc (490 mg, 5.0 mmol, 10 equiv) and glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was added to ice water (20 ml). The resulting precipitate was filtered, washed with water (3×10 ml), acetone (2×10 ml), DCM (2×10 ml), hexane (10 ml), and air-dried to obtain pure ELQ-645 (160 mg, 79% yield) as a white solid. TIFF2025524371000085.tif18156

[0266] 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 351284-chloroquinoline, a mixture of 15 h (230 mg, 0.5 mmol, 1 equiv), KOAc (490 mg, 5.0 mmol, 10 equiv) and glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was added to ice water (20 ml). The resulting precipitate was filtered, washed with water (3×10 ml), acetone (2×10 ml), DCM (2×10 ml), hexane (10 ml), and air-dried to obtain pure ELQ-600 (165 mg, 75% yield) as a white solid. TIFF2025524371000087.tif18161

[0267] 6-Chloro-7-methoxy-2-methyl-3-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-646). Following the general procedure for the hydrolysis of 3-chloroquinoline, a mixture of 15i (87 mg, 0.188 mmol, 1 equiv), KOAc (184 mg, 1.82 mmol, 10 equiv) and glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was added to ice water (20 ml). The resulting precipitate was filtered, washed with water (3 × 10 ml), acetone (2 × 10 ml), DCM (2 × 10 ml), hexane (10 ml) and air-dried to give ELQ-646 (30 mg, 36% yield) as a white solid. The product was 95 - 98% by NMR and HPLC. TIFF2025524371000089.tif11161

[0268] 6-Chloro-7-methoxy-2-methyl-3-(3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-604). Following the general procedure for the hydrolysis of 3-chloroquinoline, a mixture of 15j (476 mg, 1.0 mmol, 1 equiv), KOAc (980 mg, 10.0 mmol, 10 equiv) and glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was added to ice water (20 ml). The resulting precipitate was filtered, washed with water (3 × 10 ml), acetone (2 × 10 ml), DCM (2 × 10 ml), hexane (10 ml) and air-dried to give crude ELQ-604 (350 mg). The product was crystallized from DMF to give ELQ-604 (200 mg, 43% yield). By NMR and HPLC, the purity of the product was shown to be about 95 - 98%. TIFF2025524371000091.tif18161

[0269] ((6-Chloro-7-methoxy-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4-yl)oxy)methyl ethyl carbonate (ELQ-598). TIFF2025524371000092.tif A stirred mixture of 31128 DMF (25 ml), ELQ-596 (460 mg, 1.0 mmol, 1 equiv), tetrabutylammonium iodide (742 mg, 2.0 mmol, 2 equiv), chloroethyl methyl carbonate (278 mg, 2.0 mmol, 2 equiv) and anhydrous K2CO3 (278 mg, 2.0 mmol, 2 equiv) was heated at 60 °C for 24 h, where TLC indicated that no starting material was present anymore. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness to afford 700 mg of a brown oil. The resulting residue was stirred with ethyl acetate (50 ml) for 30 min, the insoluble tetrabutylammonium iodide was filtered off and washed with ethyl acetate (3 x 10 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 showed one peak with purity >98%. GC-MS showed one peak M + =561 (53%), 459 (100%). TIFF2025524371000093.tif 18161

[0270] 6-dichloro-7-methoxy-2-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinoline: TIFF2025524371000094.tifA mixture of 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline (7.08 g, 0.18 mol), bis(pinacolato)diboron (1.4 equiv, 6.34 g, 0.025 mol), and potassium acetate (3.0 equiv, 5.24 g, 0.0534 mol) in 250 mL of N,N-dimethylformamide was degassed by bubbling argon through it at room temperature for 20 minutes through a glass tube inserted below the liquid surface. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.65 g, 0.00089 mol) was added, and then the mixture was heated at 80 °C under an argon atmosphere. After 72 hours, TLC and GC / MS indicated that unreacted quinoline starting material was still present. The reaction mixture was cooled to room temperature, degassed again, and then additional [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (2.4 mol%, 0.32 g, 0.00044 mol) was added. The reaction mixture was heated again at 80 °C for 72 hours under an argon atmosphere. TLC and GC / MS indicated that a small amount of unreacted 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline still remained, but heating of the reaction mixture was stopped, and it was filtered through celite and concentrated under reduced pressure with heating. The resulting black residue was dissolved in dichloromethane (250 mL) and filtered through celite. The dark filtrate was concentrated under reduced pressure with heating to give a black sludge. This material was dissolved again in dichloromethane (300 mL) and washed with 5% brine (2 × 100 mL) and then 10% brine (100 mL). The combined organic layers were dried (MgSO4) and evaporated under reduced pressure with warming to give a black solid (11.44 g). This material was dissolved in 15 mL of dichloromethane and filtered through a plug of silica gel (100 g, pre-moistened with dichloromethane) and washed with dichloromethane / ethyl acetate (98 / 2 v / v) until no more product eluted by TLC. The filtrate was evaporated to give a pale greenish-gray solid (7.22 g).Eluted with a gradient of dichloromethane / ethyl acetate from 100% dichloromethane to 98 / 2 by volume ratio, the desired product (R. f = 0.21, dichloromethane / ethyl acetate 98 / 2 by volume ratio) was obtained as an off-white solid. TIFF2025524371000095.tif18158

[0271] 4,6-Dichloro-7-methoxy-2-methyl-3-(3'-(pentafluorosulfanyl)-[1,1'-biphenyl]-4-yl)quinoline: In N,N-dimethylformamide (55 mL), 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), potassium carbonate anhydrous (2.0 equivalents, 0.0021 mol, 0.29 g), and meta-bromophenylsulfur pentafluoride (1.3 equivalents, 0.0013 mol, 0.38 g) was degassed by bubbling argon through a glass tube under the liquid surface at room temperature for 20 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.038 g, 0.000052 mol) was added, and then the mixture was heated at 80 °C for 22 hours under an argon atmosphere. The cooled reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was dissolved in dichloromethane (125 mL) and filtered again through Celite. The filtrate was adsorbed onto silica and purified by flash chromatography, eluting with a gradient of hexane / ethyl acetate from 95 / 5 to 77 / 23 by volume ratio. The desired product (R f = 0.41 (hexane / ethyl acetate 3 / 2 by volume ratio, silica) was obtained as a white solid TIFF2025524371000097.tif18160.

[0272] 6-Chloro-7-methoxy-2-methyl-3-(3'-(pentafluorosulfanyl)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-662): TIFF2025524371000098.tif281604, 6-Dichloro-7-methoxy-2-methyl-3-(3'-(pentafluorosulfanyl)-[1,1'-biphenyl]-4-yl)quinoline (0.45 g, 0.00086 mol) and potassium acetate (10 equivalents, 0.0086 mol, 0.85 g) were heated in glacial acetic acid (9 mL) at 120 °C for 6 hours. After cooling, the reaction mixture was cooled at 5 °C for 30 minutes. Filtered under reduced pressure and washed with excess water and subsequently with acetone (5 × 1.5 mL) to obtain the desired product as fine white crystals TIFF2025524371000099.tif18157。

[0273] ((6-Chloro-7-methoxy-2-methyl-3-(3'-(pentafluoro-λ 6 -sulfanyl)-[1,1'-biphenyl]-4-yl)quinolin-4-yl)oxy)methylethyl carbonate (ELQ-674) TIFF2025524371000100.tif3215915 mL of DMF, 6-Chloro-7-methoxy-2-methyl-3-(3'-(pentafluoro-λ 6-(sulfanyl)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (0.173 g, 0.00034 mol) was mixed with tetrabutylammonium iodide (2.0 equiv, 0.00069 mol, 0.25 g) and anhydrous potassium carbonate (2.0 equiv, 0.00069 mol, 0.095 g). After stirring briefly at room temperature, chloromethyl ethyl carbonate (2.0 equiv, 0.00069 mol, 0.095 g) was added as a solution in 1 mL of DMF. The reaction mixture was sealed with a stopper pierced with a needle and stirred at 60 °C for 24 h, at which point TLC indicated completion of the reaction. The cooled reaction mixture was filtered under reduced pressure to remove solids, and the solvent was removed from the filtrate by heating under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate and stirred to cause precipitation of tetrabutylammonium iodide; this was removed by filtration under reduced pressure, and the solvent was removed from the filtrate by warming under reduced pressure. The residue was subjected to automated flash chromatography on silica eluting with a gradient of hexane / ethyl acetate from 90:10 to 65:35 by volume to give the desired product (R F = 0.40, hexane:ethyl acetate 1:1 by volume) as a white solid TIFF2025524371000101.tif25157.

[0274] 4,6-Dichloro-7-methoxy-2-methyl-3-(4'-(pentafluorosulfanyl)-[1,1'-biphenyl]-4-yl)quinoline: TIFF2025524371000102.tif27160In N,N-dimethylformamide (75 mL), 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), potassium carbonate anhydrous (2.0 equiv, 0.0021 mol, 0.29 g), and para-bromophenylsulfur pentafluoride (1.3 equiv, 0.0013 mol, 0.38 g) was degassed by bubbling argon through a glass tube under the liquid surface at room temperature for 20 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.038 g, 0.000052 mol) was added, and then the mixture was heated at 80 °C for 22 hours under an argon atmosphere. The cooled reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was dissolved in dichloromethane (125 mL) and filtered again through Celite. The filtrate was adsorbed onto silica and purified by flash chromatography eluting with a gradient of hexane / ethyl acetate from 95 / 5 to 75 / 25 by volume. Thereby, the desired product (R f = 0.43 (hexane / ethyl acetate 3 / 2 by volume, silica) was obtained as an off-white solid TIFF2025524371000103.tif18157.

[0275] 6-Chloro-7-methoxy-2-methyl-3-(4'-(pentafluorosulfanyl)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-663): TIFF2025524371000104.tif291604,6-Dichloro-7-methoxy-2-methyl-3-(4'-(pentafluorosulfanyl)-[1,1'-biphenyl]-4-yl)quinoline (0.38 g, 0.00073 mol) and potassium acetate (10 equiv, 0.0073 mol, 0.72 g) were heated in glacial acetic acid (12 mL) at 120 °C for 6 hours. After cooling, the reaction mixture was cooled at 5 °C for 30 minutes. It was filtered under reduced pressure and washed with excess water and then acetone (5 × 1.5 mL) to obtain the desired product as silver crystals TIFF2025524371000105.tif11150。

[0276] ((6-Chloro-7-methoxy-2-methyl-3-(4'-(pentafluoro-λ 6 -sulfanyl)-[1,1'-biphenyl]-4-yl)quinolin-4-yl)oxy)methylethyl carbonate (ELQ-674) TIFF2025524371000106.tif3315915 mL of DMF, 6-chloro-7-methoxy-2-methyl-3-(4'-(pentafluoro-λ 6 -sulfanyl)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (0.166 g, 0.00033 mol) was mixed with tetrabutylammonium iodide (2.0 equivalents, 0.00066 mol, 0.24 g) and anhydrous potassium carbonate (1.0 equivalent, 0.00033 mol, 0.046 g). After stirring briefly at room temperature, chloromethylethyl carbonate (1.0 equivalent, 0.00033 mol, 0.046 g) was added as a solution in 1 mL of DMF. The reaction mixture was sealed with a stopper pierced with a needle and stirred at 60 °C for 24 h. TLC indicated that a small amount of unreacted starting material was still present, but the reaction mixture was cooled, filtered under reduced pressure to remove the solid, and the solvent was removed from the filtrate by heating under reduced pressure. The residue was dissolved in 40 mL of ethyl acetate and stirred to cause precipitation of tetrabutylammonium iodide; this was removed by filtration under reduced pressure and the solvent was removed from the filtrate by warming under reduced pressure. The residue was subjected to silica automated flash chromatography eluting with a gradient of hexane / ethyl acetate in a volume ratio of 9:1 to 7:3 to give the desired product as a white solid TIFF2025524371000107.tif18159。

[0277] 4,6-Dichloro-7-methoxy-2-methyl-3-(4'-(trifluoroethoxy)-[1,1'-biphenyl]-4-yl)quinoline: TIFF2025524371000108.tif23157In N,N-dimethylformamide (80 mL), 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), potassium carbonate anhydrous (2.0 equiv, 0.0022 mol, 0.30 g), and 1-bromo-4-(2,2,2-trifluoroethoxy)benzene (1.3 equiv, 0.0014 mol, 0.36 g) was degassed by bubbling argon through a glass tube under the liquid surface at room temperature for 20 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.040 g, 0.000055 mol) was added, and then the mixture was heated at 80 °C for 16 hours under an argon atmosphere. The cooled reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was dissolved in dichloromethane (125 mL) and filtered again through Celite. The filtrate was adsorbed onto silica and purified by flash chromatography, eluting with a gradient of hexane / ethyl acetate from 100 / 0 to 75 / 25 by volume. The concentrated fractions were combined, dissolved 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 again by flash chromatography, eluting with a gradient of hexane / ethyl acetate from 100 / 0 to 80 / 20 by volume. Thereby, the desired product (R f = 0.39 (hexane / ethyl acetate 3 / 2 by volume, silica) was obtained as an off-white solid TIFF2025524371000109.tif11150.

[0278] 6-Chloro-7-methoxy-2-methyl-3-(4'-(trifluoroethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-670): TIFF2025524371000110.tif 28160 4,6-Dichloro-7-methoxy-2-methyl-3-(4'-(trifluoroethoxy)-[1,1'-biphenyl]-4-yl)quinoline (0.39 g, 0.00079 mol) and potassium acetate (10 equivalents, 0.0079 mol, 0.78 g) were heated in glacial acetic acid (18 mL) at 120 °C for 20 h. After cooling, the reaction mixture was cooled at 5 °C for 1 h. It was filtered under reduced pressure and washed with excess water and subsequently with acetone (3 × 1.5 mL) to give the desired product as an off-white solid. TIFF2025524371000111.tif 18161.

[0279] 4,6-Dichloro-7-methoxy-2-methyl-3-(4'-((trifluoromethyl)thio)-[1,1'-biphenyl]-4-yl)quinoline TIFF2025524371000112.tif 27160 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 potassium carbonate (2.0 equivalents, 0.0024 mol, 0.33 g), and 4-bromo-(trifluoromethylthio)benzene (1.3 equivalents, 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 at room temperature for 30 min. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.044 g, 0.000060 mol) was added and the mixture was then heated at 80 °C for 24 h under an argon atmosphere. The cooled reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure with heating and the resulting dark solid was dissolved in dichloromethane (300 mL) and filtered through Celite again. The filtrate was adsorbed onto silica and purified by flash chromatography eluting with a gradient of 100% dichloromethane to hexane / ethyl acetate 98 / 2 by volume. This gave the desired product (R f = 0.47 (dichloromethane / ethyl acetate 98 / 2 by volume, silica) as a white solid. TIFF2025524371000113.tif 11160。

[0280] 6-Chloro-7-methoxy-2-methyl-3-(4'-((trifluoromethyl)thio)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one TIFF2025524371000114.tif 28160 4,6-Dichloro-7-methoxy-2-methyl-4-(4'-(trifluoromethylthio)-[1,1'-biphenyl]-4-yl)quinoline (0.47 g, 0.00095 mol) and potassium acetate (10 equivalents, 0.0095 mol, 0.93 g) were heated in glacial acetic acid (10 mL) at 120 °C for 2 hours. After cooling, the reaction mixture was cooled at 5 °C for 20 minutes. It was filtered under reduced pressure and washed with excess water and subsequently with acetone (3 × 2 mL) to obtain the desired product as cream-colored crystals TIFF2025524371000115.tif 18154。

[0281] 4,6-Dichloro-7-methoxy-2-methyl-3-(3'((trifluoromethyl)thio)-[1,1'-biphenyl]-4-yl)quinoline: TIFF2025524371000116.tif27160In N,N-dimethylformamide (80 mL), 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 (0.57 g, 0.0013 mol), potassium carbonate anhydrous (2.0 equiv, 0.0026 mol, 0.36 g), and 3-bromophenyltrifluoromethyl sulfide (1.3 equiv, 0.0017 mol, 0.43 g) was degassed by bubbling argon through a glass tube under the liquid surface at room temperature for 20 min. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.047 g, 0.00006 mol) was added, and then the mixture was heated at 80 °C for 23 h under an argon atmosphere. The cooled reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was dissolved in dichloromethane (125 mL) and filtered again through Celite. The filtrate was adsorbed onto silica and purified by flash chromatography eluting with a gradient of dichloromethane / ethyl acetate from 100 / 0 to 92 / 8 by volume ratio. Thereby, the desired product (R f = 0.61 (dichloromethane / ethyl acetate 98 / 2 by volume ratio, silica) was obtained as an off-white solid (1.0 g, including residual solvent), which was used in the subsequent step without drying.

[0282] 6-Dichloro-7-methoxy-2-methyl-3-(3'((trifluoromethyl)thio)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-678): TIFF2025524371000117.tif271604,6-Dichloro-7-methoxy-2-methyl-3-(3'((trifluoromethyl)thio)-[1,1'-biphenyl]-4-yl)quinoline (1.0 g, including residual solvent) and potassium acetate (0.02 mol, 1.99 g) were heated in glacial acetic acid (15 mL) at 120 °C for 28 h. After cooling, the reaction mixture was cooled at 5 °C for 1.5 h. It was filtered under reduced pressure and washed with excess water and then acetone (4 × 1.5 mL) to obtain the desired product as gray crystals. TIFF2025524371000118.tif18154。

[0283] 4,6-Dichloro-7-methoxy-2-methyl-3-(4'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)quinoline TIFF2025524371000119.tif26160 In N,N-dimethylformamide (130 mL), 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 equiv), and potassium carbonate anhydrous (2.0 equiv, 0.0050 mol, 0.69 g) was degassed by bubbling argon through a glass tube under the liquid surface at room temperature for 25 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.091 g, 0.000125 mol) was added, and then the mixture was heated at 80 °C for 4 days under an argon atmosphere. The cooled reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was dissolved in dichloromethane (150 mL) and filtered through Celite again. The filtrate was adsorbed onto silica and purified by flash chromatography eluting with a gradient of hexane / ethyl acetate from 85 / 15 to 30 / 70 by volume. Thereby, the desired product (R f = 0.25 (hexane / ethyl acetate 3 / 2 by volume, silica) was obtained as a white solid TIFF2025524371000120.tif11141。

[0284] 6-Chloro-7-methoxy-2-methyl-3-(4'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-658) TIFF2025524371000121.tif 28160 4,6-dichloro-7-methoxy-2-methyl-3-(4'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)quinoline (0.42 g, 0.00090 mol) and potassium acetate (10 equivalents, 0.0090 mol, 0.88 g) were heated in glacial acetic acid (10 mL) at 120 °C for 3 hours. After cooling, the reaction mixture was cooled at 5 °C for 1 hour. It was filtered under reduced pressure and washed with excess water and subsequently with acetone (3 × 2 mL) to obtain the desired product as fine white crystals TIFF2025524371000122.tif 11141

[0285] 4,6-dichloro-7-methoxy-2-methyl-3-(3'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4-yl)quinoline: TIFF2025524371000123.tif 25160 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 potassium carbonate (2.0 equivalents, 0.0022 mol, 0.30 g), and 1-bromo-4-(2,2,2-trifluoroethoxy)benzene (1.3 equivalents, 0.0014 mol, 0.36 g) in N,N-dimethylformamide (50 mL) was degassed by passing argon through a glass tube under the liquid surface at room temperature for 20 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.040 g, 0.000055 mol) was added and the mixture was then heated at 80 °C for 23 hours under an argon atmosphere. The cooled reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was dissolved in dichloromethane (125 mL) and filtered through celite again. The filtrate was adsorbed onto silica and purified by flash chromatography eluting with a gradient of hexane / ethyl acetate from 95 / 5 to 72 / 28 by volume. The desired product was obtained as a white solid TIFF2025524371000124.tif 18159

[0286] 6-Chloro-7-methoxy-2-methyl-3-(3'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-673): TIFF2025524371000125.tif271604, 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 equivalents, 0.0061 mol, 0.59 g) were heated in glacial acetic acid (10 mL) at 120 °C for 22 h. After cooling, the reaction mixture was added to 60 mL of water. After stirring for 3 min, the resulting solid was collected by filtration under reduced pressure and washed with excess water and subsequently with acetone (2 × 2 mL). The desired product was thus obtained as a white solid TIFF2025524371000126.tif18159。

[0287] 4'-(4,6-Dichloro-7-methoxy-2-methylquinolin-3-yl)-[1,1'-biphenyl]-4-sulfonamide TIFF2025524371000127.tif25160In N,N-dimethylformamide (130 mL), 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 equiv), and potassium carbonate anhydrous (2.0 equiv, 0.0050 mol, 0.69 g) was degassed by bubbling argon through a glass tube under the liquid surface at room temperature for 20 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.091 g, 0.000125 mol) was added, and then the mixture was heated at 80 °C for 24 hours under an argon atmosphere. The cooled reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was triturated in dichloromethane (125 mL) and filtered under reduced pressure. Since a precipitate was observed in the filtrate, this was concentrated to 90 mL and filtered under reduced pressure again. The resulting pale tan solid was the desired product of sufficient purity for the next reaction TIFF2025524371000128.tif18154.

[0288] 4'-(6-Chloro-7-methoxy-2-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-[1,1'-biphenyl]-4-sulfonamide (ELQ-680) TIFF2025524371000129.tif281604'-(4,6-Dichloro-7-methoxy-2-methylquinolin-3-yl)-[1,1'-biphenyl]-4-sulfonamide (0.30 g, 0.00064 mol) and potassium acetate (10 equiv, 0.0064 mol, 0.63 g) were heated in glacial acetic acid (10 mL) at 120 °C for 20 hours. After cooling, the reaction mixture was cooled at 5 °C for 20 minutes. It was filtered under reduced pressure and washed with excess water and then acetone (3 × 1.5 mL) to give the desired product as a grayish-beige powder TIFF2025524371000130.tif11132.

[0289] 4,6-Dichloro-7-methoxy-2-methyl-3-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)quinoline TIFF2025524371000131.tif26160A mixture of 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline (0.85 g, 0.0021 mol), 2-(trifluoromethyl)pyridin-5-boronic acid (1.3 eq, 0.0028 mol, 0.53 g), and potassium carbonate anhydrous (2.0 eq, 0.0042 mol, 0.58 g) in N,N-dimethylformamide (100 mL) was degassed by bubbling argon through a glass tube under the liquid surface and stirred at room temperature for 20 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.077 g, 0.00011 mol) was added and the reaction mixture was heated at 80 °C for 19 hours under an argon atmosphere. The cooled reaction mixture was filtered through celite and subsequently the filtrate was concentrated under reduced pressure with heating. The resulting solid was dissolved in 110 mL of DCM and subsequently filtered under reduced pressure. The evaporated filtrate was subjected to silica automated flash chromatography eluting with a gradient of hexane:ethyl acetate from 9:1 to 72:28 by volume to give the desired product (R f = 0.35, hexane:ethyl acetate 6:4 by volume, silica) as a white solid TIFF2025524371000132.tif18160.

[0290] 6-Chloro-7-methoxy-2-methyl-3-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)quinolin-4(1H)-one (ELQ-683) TIFF2025524371000133.tif 29160 4,6-dichloro-7-methoxy-2-methyl-3-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)quinoline (0.37 g, 0.00080 mol) and potassium acetate (10 equivalents, 0.0080 mol, 0.79 g) were stirred in glacial acetic acid (15 mL) at 120 °C for 20 h. After cooling, the reaction mixture was further cooled at 5 °C for 20 min, followed by filtration under reduced pressure and washed with excess water and then acetone (3 × 1.5 mL). The desired product was obtained as a cream-colored powder. TIFF2025524371000134.tif 18160.

[0291] 4,6-dichloro-7-methoxy-2-methyl-3-(4-(5-(trifluoromethoxy)pyridin-2-yl)phenyl)quinoline TIFF2025524371000135.tif 27160 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), potassium carbonate anhydrous (2.0 equivalents, 0.0022 mol, 0.30 g), and 2-bromo-5-(trifluoromethoxy)benzene (1.3 equivalents, 0.0015 mol, 0.35 g) in N,N-dimethylformamide (80 mL) was degassed by bubbling argon through a glass tube inserted below the liquid surface for 20 min at room temperature. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.040 g, 0.000055 mol) was added and then heated at 80 °C for 4 days under an argon atmosphere. The cooled reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was dissolved in dichloromethane (100 mL) and filtered again through Celite. After evaporation of the filtrate, the residue was purified by automated flash chromatography on silica eluting with a gradient of hexane:ethyl acetate from 1:0 to 6:4 by volume and then with a gradient of hexane:ethyl acetate from 1:0 to 75:25 by volume on the same silica gel column in a second flash chromatography. The desired product (Rf = 15. Obtained as a white powder using hexane:ethyl acetate (volume ratio 8:2), silica TIFF2025524371000136.tif18158。

[0292] 6-Chloro-7-methoxy-2-methyl-3-(4-(5-(trifluoromethoxy)pyridin-2-yl)phenyl)quinolin-4(1H)-one (ELQ-681) TIFF2025524371000137.tif281604,6-Dichloro-7-methoxy-2-methyl-3-(4-(5-(trifluoromethoxy)pyridin-2-yl)phenyl)quinoline (0.29 g, 0.00061 mol) and potassium acetate (10 equivalents, 0.0061 mol, 0.60 g) were heated in 10 mL of glacial acetic acid at 120 °C for 20 h. After cooling, the reaction mixture was cooled at 5 °C for 14 h. Filtered under reduced pressure and washed with excess water and subsequently with acetone (3 × 1.5 mL) to obtain the desired product as a white powder TIFF2025524371000138.tif18159。

[0293] 4,6-Dichloro-3-(3'-ethoxy-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline TIFF2025524371000139.tif24160In N,N-dimethylformamide (100 mL), a mixture of 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline (0.70 g, 0.0018 mol), 3-ethoxyphenylboronic acid (1.2 equiv, 0.0022 mol, 0.37 g), and an aqueous potassium carbonate solution (2.0 equiv, 0.0036 mol, 0.50 g of anhydrous potassium carbonate dissolved in 1.8 mL of water) was degassed by bubbling argon through a glass tube under the liquid surface at room temperature for 20 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.066 g, 0.000090 mol) was added, and then the mixture was heated at 80 °C for 20 hours under an argon atmosphere. The cooled reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was dissolved in dichloromethane (100 mL), filtered under reduced pressure, and purified by flash chromatography eluting with a gradient of hexane:ethyl acetate from 1:0 to 75:25 by volume. Thereby, the desired product (R f = 0.35, hexane:ethyl acetate 7:3 by volume, silica) was obtained as a white solid TIFF2025524371000140.tif25160.

[0294] 6-Chloro-3-(3'-ethoxy-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-691) TIFF2025524371000141.tif271604,6-Dichloro-3-(3'-ethoxy-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (0.34 g, 0.00078 mol) and potassium acetate anhydrous (10 equiv, 0.77 g, 0.0078 mol) were heated in glacial acetic acid (10 mL) at 120 °C for 23 hours. The cooled reaction mixture was further cooled at 5 °C overnight and then filtered under reduced pressure, washed with excess water and subsequently with acetone (3 × 1 mL) to give a white solid TIFF2025524371000142.tif19166[[ID=…]] [[ID=…]]

[0295] [[ID=…]] 4,6-Dichloro-7-methoxy-2-methyl-3-(4-(pyridin-4-yl)phenyl)quinoline TIFF2025524371000143.tif27160A mixture of 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline (0.71 g, 0.0018 mol), pyridine-4-boronic acid (1.3 equivalents, 0.0024 mol, 0.29 g), and an aqueous potassium carbonate solution (2.0 equivalents, 0.0036 mol, 0.50 g of anhydrous potassium carbonate dissolved in 1.3 mL of water) in N,N-dimethylformamide (80 mL) was degassed by passing argon through a glass tube under the liquid surface at room temperature for 20 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.066 g, 0.000090 mol) was added, and then the mixture was heated at 80 °C for 20 hours under an argon atmosphere. The cooled reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was dissolved in dichloromethane (100 mL) and filtered under reduced pressure. The evaporated filtrate was purified by flash chromatography eluting with a gradient of hexane:ethyl acetate from 85:15 to 0:100 by volume. This gave the desired product (R f = 0.3, 100% ethyl acetate, silica) as a white solid TIFF2025524371000144.tif11143.

[0296] 6-Chloro-7-methoxy-2-methyl-3-(4-(pyridin-4-yl)phenyl)quinolin-4(1H)-one (ELQ-714) TIFF2025524371000145.tif30158 4,6-Dichloro-7-methoxy-2-methyl-3-(4-(pyridin-4-yl)phenyl)quinoline (0.17 g, 0.00043 mol) and potassium acetate (10 equivalents, 0.0043 mol, 0.42 g) were heated in glacial acetic acid (10 mL) at 120 °C for 24 h. After cooling to room temperature, the reaction mixture was cooled at 5 °C overnight and then filtered under reduced pressure and washed with excess water and subsequently with acetone (3 × 0.75 mL). The desired product was obtained as a pale yellow solid (50 mg). Additional pure product was recovered from the filtrate (27 mg), giving a total of 77 mg of the desired product. TIFF2025524371000146.tif18159.

[0297] 4,6-Dichloro-3-(2'-chloro-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline TIFF2025524371000147.tif33160 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 equivalents, 0.0023 mol, 0.55 g), and aqueous potassium carbonate (2.0 equivalents, 0.0032 mol, 0.44 g of anhydrous potassium carbonate dissolved in 1.6 mL of water) in N,N-dimethylformamide (80 mL) was degassed by passing argon through a glass tube under the liquid surface at room temperature for 20 min. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.066 g, 0.000090 mol) was added and the mixture was then heated at 80 °C for 24 h under an argon atmosphere. The cooled reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure with heating and the resulting dark solid was dissolved in dichloromethane (150 mL) and filtered under reduced pressure. The residue obtained by evaporating the filtrate was subjected to automated flash chromatography eluting with a gradient of hexane:ethyl acetate from 95:5 to 82:18 by volume, but the desired product (R F= 0.24, hexane:ethyl acetate volume ratio 8:2) was not effectively separated from the significant byproduct (R) resulting from the double addition of the boronic ester to quinoline (substituting chlorine). F = 0.21, hexane:ethyl acetate volume ratio 8:2) and was not effectively separated; this byproduct was observed by GC-MS at m / z = 503, t R = 21 min (temperature program: 2 min at 250 °C, then heating to 300 °C at 30 °C / min, DBS column). The mixture containing impurities (0.45 g) was used in the subsequent reaction without further purification.

[0298] 6-Chloro-3-(2'-chloro-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-713) TIFF2025524371000148.tif301584, 6-Dichloro-3-(2'-chloro-[1, biphenyl]-4-yl)-7-methoxy-2-methylquinoline (material containing 0.15 g of impurities, see above) was heated in 10 mL of glacial acetic acid with potassium acetate anhydrous (0.34 g, 0.0035 mol) at 110 °C for 24 h. After cooling, the reaction mixture was cooled to 5 °C and then filtered under reduced pressure and washed with excess water and subsequently with acetone (2 × 1.5 mL). The desired product was obtained as a white solid (0.0668 g). Separately, another portion of 4,6-dichloro-3-(2'-chloro-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (material containing 0.30 g of the same impurities from the above reaction) was treated in the same manner with potassium acetate anhydrous (0.69 g) and glacial acetic acid (10 mL) to give 0.116 g of a cream-colored solid, which was also the desired product (total yield 0.18 g, 23% in two steps from 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline, TIFF2025524371000149.tif18157).

[0299] 4,6-Dichloro-7-methoxy-2-methyl-3-(4'-nitro-[1,1'-biphenyl]-yl)quinoline TIFF2025524371000150.tif32160In N,N-dimethylformamide (80 mL), 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 equiv, 0.0023 mol, 0.57 g), and aqueous potassium carbonate solution (2.0 equiv, 0.0036 mol, 0.50 g of anhydrous potassium carbonate dissolved in 1.8 mL of water) was degassed by bubbling argon through a glass tube under the liquid surface at room temperature for 20 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.066 g, 0.000090 mol) was added, and then the mixture was heated at 80 °C for 21 hours under an argon atmosphere. The cooled reaction mixture was filtered under reduced pressure, and the filtrate was concentrated with heating under reduced pressure. The residue was dissolved in dichloromethane (125 mL) and filtered under reduced pressure. The evaporated filtrate was subjected to silica automated flash chromatography eluting with a gradient of hexane:ethyl acetate from 9:1 to 1:1 by volume to obtain the desired product as an off-white solid TIFF2025524371000151.tif11160。

[0300] 6-Chloro-7-methoxy-2-methyl-3-(4'-nitro-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-715) TIFF2025524371000152.tif301604,6-Dichloro-7-methoxy-2-methyl-3-(4'-nitro-[1,1'-biphenyl]-4-yl)quinoline (0.07 g, 0.00016 mol) and anhydrous potassium acetate (10 equiv, 0.00016 mol, 0.016 g) were heated in glacial acetic acid (10 mL) at 120 °C for 21 hours. The cooled reaction mixture was cooled at 5 °C overnight and then filtered under reduced pressure, washed with excess water and then with acetone (3 × 3 mL) to obtain the desired product as a beige powder TIFF2025524371000153.tif18158。

[0301] 4,6-Dichloro-3-(2',6'-dimethyl-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline In N,N-dimethylformamide (80 mL), 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 equiv, 0.0036 mol, 0.54 g), and an aqueous potassium carbonate solution (2.0 equiv, 0.0036 mol, 0.50 g of anhydrous potassium carbonate dissolved in 1.8 mL of water) was degassed by passing argon through a glass tube under the liquid surface at room temperature for 20 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.066 g, 0.000090 mol) was added, and then the mixture was heated at 80 °C for 12 days under an argon atmosphere. The reaction was not complete, but the heating was stopped. The cooled reaction mixture was filtered under reduced pressure, and the obtained solid was washed with DMF, followed by excess water and finally acetone (5 mL). The obtained off-white solid (0.33 g) was boiled in 35 mL of DMF and slowly cooled to obtain white crystals and a small amount of dark precipitate that settled. By filtration under reduced pressure, white crystals contaminated with a small amount of dark precipitate were obtained. By GC / MS, t R = 12.659 minutes, held at 200 °C for 2 minutes and then heated from 30 °C / min to 300 °C, only m / z (421.1) of the desired product was observed on a DB5 column. This material (0.19 g) was used in the next reaction without further analysis or purification.

[0302] 6-Chloro-3-(2',6'-dimethyl-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-729) TIFF2025524371000155.tif301584,6-Dichloro-3-(2',6'-dimethyl-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (0.19 g of crude crystallization material from the previous reaction, 0.19 g) and potassium acetate anhydrous (0.44 g, 0.0045 mol) were heated in glacial acetic acid (15 mL) at 110 °C for 5 days. The hot reaction mixture was filtered under reduced pressure to remove a small amount of gray solid, and the cooled filtrate was cooled to 5 °C and then filtered under reduced pressure and washed with excess water and subsequently with acetone (3 × 1 mL). The resulting solid (79 mg) was recrystallized from 1.5 mL of DMF to give the desired product as shiny off-white crystals (63 mg, 9% in two steps from 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline, TIFF2025524371000156.tif18157).

[0303] 4,6-Dichloro-7-methoxy-2-methyl-3-(2'-methyl-[1,1'-biphenyl]-4-yl)quinoline TIFF2025524371000157.tif32160In N,N-dimethylformamide (80 mL), 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 equiv, 0.0035 mol, 0.77 g), and an aqueous potassium carbonate solution (2.0 equiv, 0.0050 mol, 0.69 g of anhydrous potassium carbonate dissolved in 2.5 mL of water) was degassed by bubbling argon through a glass tube under the liquid surface at room temperature for 20 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.091 g, 0.000125 mol) was added, and then the mixture was heated at 80 °C for 1 day under an argon atmosphere. The cooled reaction mixture was filtered through Celite under reduced pressure, and the filtrate was concentrated under reduced pressure with heating. The residue was dissolved in 125 mL of dichloromethane and filtered under reduced pressure, and the evaporated filtrate was purified by automated flash chromatography on silica gel eluting with a gradient of hexane:ethyl acetate from 95:5 to 81:19 to give the desired product as a solid (R f = 0.31, hexane:ethyl acetate 7:3, silica, 0.08 g, 80%, TIFF2025524371000158.tif11156).

[0304] 6-Chloro-7-methoxy-2-methyl-3-(2'-methyl-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-718) TIFF2025524371000159.tif30158 4,6-Dichloro-7-methoxy-2-methyl-3-(2'-methyl-[1,1'-biphenyl]-4-yl)quinoline (0.08 g, 0.00020 mol) and potassium acetate (10 equivalents, 0.0020 mol, 0.19 g) were heated in glacial acetic acid (10 mL) at 120 °C for 21 h. After cooling to room temperature, the reaction mixture was cooled at 5 °C for 30 min. Filtration was carried out under reduced pressure and the excess water and subsequently 2 × 3 mL of acetone were used for washing to recover the desired product. The obtained solid (34 mg) was recrystallized from N,N-dimethylformamide (2 mL). The desired product was obtained as a gray powder TIFF2025524371000160.tif11131.

[0305] 4,6-Dichloro-7-methoxy-2-methyl-3-(2',3',4'-trifluoro-[1,1'-biphenyl]-4-yl)quinoline TIFF2025524371000161.tif30160 In N,N-dimethylformamide (80 mL), 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 equivalents, 0.0022 mol, 0.39 g), and aqueous potassium carbonate solution (2.0 equivalents, 0.0036 mol, 0.50 g of anhydrous potassium carbonate dissolved in 1.8 mL of water) was degassed by bubbling argon through a glass tube under the liquid surface at room temperature for 20 min. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.065 g, 0.000090 mol) was added and subsequently heated at 80 °C for 20 h under an argon atmosphere. The cooled reaction mixture was filtered under reduced pressure and the obtained solid was washed with additional DMF and subsequently with water. After air drying, the white solid thus obtained was dissolved in boiling DMF (50 mL), filtered while hot under reduced pressure, then the filtrate was concentrated to 30 mL by boiling and subsequently cooled slowly. Filtration under reduced pressure gave the desired product as tawny crystals TIFF2025524371000162.tif27157.

[0306] 6-Chloro-7-methoxy-2-methyl-3-(2',3',4'-trifluoro-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-747) TIFF2025524371000163.tif301604, 6-Dichloro-7-methoxy-2-methyl-3-(2',3',4'-trifluoro-[1,1'-biphenyl]-4-yl)quinoline (0.39 g, 0.00087 mol) and potassium acetate (10 equivalents, 0.0087 mol, 0.86 g) were heated in glacial acetic acid (10 mL) at 120 °C for 2 days. After cooling to room temperature, the reaction mixture was cooled at 5 °C for 2 hours. Filtered under reduced pressure and washed with excess water and subsequently with acetone (3 × 1.5 mL) to obtain the desired product as a beige powder TIFF2025524371000164.tif21149。

[0307] 4-Chloro-6-fluoro-7-methoxy-2-methyl-3-(2',3',4'-trifluoro-[1,1'-biphenyl]-4-yl)quinoline TIFF2025524371000165.tif29160In N,N-dimethylformamide (80 mL), a mixture of 3-(4-bromophenyl)-4-chloro-6-fluoro-7-methoxy-2-methylquinoline (0.70 g, 0.0018 mol), 2,3,4-trifluorophenylboronic acid (1.2 equiv, 0.0022 mol, 0.39 g), and an aqueous potassium carbonate solution (2.0 equiv, 0.0036 mol, 0.50 g of anhydrous potassium carbonate dissolved in 1.8 mL of water) was degassed by bubbling argon through a glass tube under the liquid surface at room temperature for 20 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.065 g, 0.000090 mol) was added, and then the mixture was heated at 80 °C for 20 hours under an argon atmosphere. The cooled reaction mixture was filtered under reduced pressure, and the resulting solid was washed with additional DMF and then with water. After air drying, the cream-colored crystals (0.89 g) thus obtained were dissolved in boiling DMF (60 mL), filtered hot under reduced pressure, and then the filtrate was concentrated to 40 mL by boiling and subsequently cooled slowly. Filtration was carried out under reduced pressure, and the product was washed with DMF (10 mL) and then with acetone (15 mL) to give the desired product as white crystals (0.41 g). On the other hand, the filtrate from the initial filtration of the reaction mixture was concentrated while heating under reduced pressure. The residue was dissolved in 125 mL of dichloromethane and filtered under reduced pressure, and then the evaporated filtrate was subjected to silica gel automated flash chromatography eluting with a gradient of hexane:ethyl acetate from 93:7 to 70:30 by volume; similarly, the desired product (R f = 0.24, hexane:ethyl acetate 7:3 by volume, silica) was obtained as a white solid (0.23 g, total yield from crystallization and chromatography 0.64 g, 82%, TIFF2025524371000166.tif25157).

[0308] 6-Fluoro-7-methoxy-2-methyl-3-(2',3',4'-trifluoro-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-748) TIFF2025524371000167.tif301604-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 potassium acetate (10 equivalents, 0.0095 mol, 0.93 g) were heated in glacial acetic acid (10 mL) at 120 °C for 2 days. After cooling to room temperature, the reaction mixture was cooled at 5 °C for 2 hours. It was filtered under reduced pressure and washed with excess water and subsequently with acetone (3 × 1.5 mL) to obtain the desired product as an off-white powder TIFF2025524371000168.tif18160.

[0309] 4-chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)quinoline TIFF2025524371000169.tif26160In N,N-dimethylformamide (60 mL), a mixture of 3-(4-bromophenyl)-4-chloro-6-fluoro-7-methoxy-2-methylquinoline (0.57 g, 0.0015 mol), 2-(trifluoromethyl)pyridine-5-boronic acid (1.2 equivalents, 0.0018 mol, 0.34 g), and an aqueous potassium carbonate solution (2.0 equivalents, 0.0030 mol, 0.41 g of anhydrous potassium carbonate dissolved in 1.5 mL of water) was degassed by bubbling argon through a glass tube under the liquid surface at room temperature for 20 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.055 g, 0.000075 mol) was added and then heated at 80 °C for 4 days under an argon atmosphere. The cooled reaction mixture was filtered under reduced pressure and the filtrate was evaporated under reduced pressure with heating. The residue was dissolved in dichloromethane (125 mL) and filtered under reduced pressure. Automatic flash chromatography on silica gel eluting with a gradient of hexane:ethyl acetate from 85:15 to 63:37 by volume. The desired product was obtained as a white crystalline solid TIFF2025524371000170.tif18160.

[0310] 6-Fluoro-7-methoxy-2-methyl-3-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)quinolin-4(1H)-one (ELQ-758) TIFF2025524371000171.tif 29160 4-Chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)quinoline (0.43 g, 0.00096 mol) and potassium acetate (10 equivalents, 0.0096 mol, 0.94 g) were heated in glacial acetic acid (10 mL) at 120 °C for 1 day. After cooling, the reaction mixture was cooled at 5 °C overnight. Filtered under reduced pressure and washed with excess water and subsequently with acetone (3 × 1.5 mL) to obtain the desired product as beige crystals TIFF2025524371000172.tif 18160

[0311] Synthesis of ELQ Biphenyl The compound of formula (I) may be prepared as illustrated in Scheme 8 below TIFF2025524371000173.tif 25150

[0312] Scheme 8: Synthesis of a series of 6-chloro 7-methoxy 3-biaryl-ELQ and ELQ-687 with structural modifications on the terminal benzene ring TIFF2025524371000174.tif 28160 a Reaction (a): Pd(dppf)Cl2, K2CO3, DMF, 80 °C, 19 - 98%; (b): KOAc, AcOH, 16 - 24 hours, 57 - 91%.

[0313] Scheme 9: Synthesis of a series of 6-chloro 7-methoxy 3-biaryl-ELQ with structural modifications on the internal benzene ring TIFF2025524371000175.tif 29160 a Reaction (a): Pd(dppf)Cl2, K2CO3, DMF, 80 °C, 60%; (b): KOAc, AcOH, 16 - 24 hours, 99%.

[0314] Scheme 10 TIFF2025524371000176.tif27160

[0315] Scheme 11: Synthesis of a Series of 7-Fluoro-7-methoxy-3-biaryl-ELQ and ELQ-688 with Structural Modifications on the External Benzene Ring TIFF2025524371000177.tif27160 a Reaction (a): Pd(dppf)Cl2, K2CO3, DMF, 80 °C, 15 - 51%; (b): KOAc, AcOH, 16 - 24 h, 88 - 93%.

[0316] Scheme 12: Synthesis of a Series of 6-Chloro-7-methoxy-3-biaryl-ELQ Alkoxycarbonate Prodrugs a Reaction (a): TBAI, K2CO3 and DMF, 60 °C, 24 h, 54 - 70%. TIFF2025524371000178.tif33142

[0317] Scheme 13: Synthesis of the Pivaloyl Prodrug of ELQ-596 a Reaction (a): NaH and THF, 60 °C, 2 h 55%.

[0318] Scheme 14: Synthesis of a Series of 7-Fluoro-7-methoxy-3-biaryl-ELQ Alkoxycarbonate Prodrugs a Reaction (a): TBAI, K2CO3 and DMF, 60 °C, 24 h, 74 - 77%. TIFF2025524371000179.tif37128

[0319] Scheme 15: Synthesis of the ELQ-601 Alkoxycarbonate Prodrug a Reaction (a): TBAI, K2CO3 and DMF, 60 °C, 24 h. 72%. TIFF2025524371000180.tif206156

[0320] Scheme 16: Synthesis of a Series of ELQ N-Oxides and ELQ-N-Hydroxys a Reaction (a) MCPBA and CHCl3, 80 °C, 24 h, 48 - 70%. (b) EtOH / 10% aqueous NaOH (4 / 1), 2 h, 48 - 87%.

[0321] Chemical Synthesis Procedure Unless otherwise specified, all chemicals and reagents were obtained from Sigma-Aldrich Chemical Company, St. Louis, MO (USA), Combi-Blocks, San Diego (CA), or TCI America, Portland (OR) and used as received. 3-(4-Bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline (1), 3-bromo-4,6-dichloro-7-methoxy-2-methylquinoline (4), 3-(4-bromophenyl)-4-chloro-6-fluoro-7-methoxy-2-methylquinoline (5), 3-(4-bromophenyl)-4-chloro-6-fluoro-7-methoxy-2-methylquinoline (7), ELQ-596, ELQ-598, ELQ-650, and ELQ-601 were obtained as previously reported. Melting points were determined on an Optimelt Automated Melting point system from Stanford Research Systems, Sunnyvale, CA (USA). Analytical TLC was performed using Merck 60F-254 250 micron precoated silica gel plates and spots were visualized with UV light at 254 nm. GC-MS was performed using an Agilent Technologies 7890B gas chromatograph (30 m, DBS column was programmed to hold at 100 °C or 200 °C for 2 min and then ramp at 30 °C / min to 300 °C, injector temperature was set at 250 °C) and an Agilent Technologies 5977A mass selective detector and recorded at 70 eV. Flash chromatography on silica gel columns was performed using an Isolera One flash chromatography system from Biotage, Uppsala, Sweden. 1The 1H-NMR spectra were recorded at 400.14 MHz using a Bruker 400 MHz Avance NEO NanoBay NMR spectrometer. The raw NMR data were analyzed using iNMR Spectrum Analyst software. 1 1H chemical shifts are reported in parts per million (ppm) relative to the internal standard of tetramethylsilane (TMS) or the residual solvent peak. Coupling constant values (J) are reported in Hertz (Hz). For fluorine-containing compounds, 19F was also recorded at 376 MHz (data not shown). HPLC analysis was performed using an Agilent 1260 Infinity instrument, detection = 254 nm and a Phenomenex, Luna® 5 μm C8(2) 100 Å reverse-phase LC column 150 × 4.6 mm, at 40 °C, eluting with a gradient from 25%:75% A / B to 10%:90% A / B (A: 0.05% formic acid in milliQ water, B: 0.05% formic acid in methanol). GC-MS 19 By determination with 1H-NMR and HPLC, the purity of all compounds was at least >95% in in vitro tests and >98% in in vivo tests. 1

[0322] ​General Procedure A for the Synthesis of Biphenylquinolines (3a - p). A stirred mixture of quinoline 1 (1 equiv), substituted phenylboronic acid (1.1 - 1.2 equiv) 2a, 2c, 2e - 2g, 2j - 2m, 15g, or pinacol ester 2b, 2d, 2h, 2i, 2n and 2o, 2 M aqueous K2CO3 solution (2 equiv), and Pd(dppf)Cl2 (0.05 equiv) in DMF was deoxygenated by bubbling argon through the solution for 15 minutes. The stirred reaction mixture was then heated at 80 °C under an argon atmosphere until starting material 1 was no longer detected by GC - MS. The reaction mixture was cooled to room temperature, filtered through celite, and the DMF was removed under reduced pressure. The resulting black oily solid was resuspended in DCM, stirred vigorously at room temperature for 30 minutes, filtered through celite, and concentrated to dryness. The residue was dissolved in 3 - 5 ml of DCM, and if all the solids dissolved, the product was purified by flash chromatography. If the product was insoluble in methylene chloride, these were filtered, washed with DCM, and the filtrate was further purified by flash chromatography to obtain additional material.

[0323] General Procedure B for the Hydrolysis of 4 - Chloroquinolines. A stirred mixture of 4 - chloroquinoline (3a - o, 1 equiv), potassium acetate (KOAc, 10 equiv), and glacial acetic acid was heated at 120 °C for 16 - 24 hours in a reaction vial with a loose stopper. After cooling to room temperature, the reaction mixture was added to ice water (20 - 30 ml). The resulting precipitate was filtered, washed with water (3×15 ml), acetone (3×10 ml), DCM (3×10 ml), hexane (3×10 ml), and air - dried to obtain the desired product. If the purity of the product was less than 98% by NMR and HPLC, it could be obtained in pure form by crystallization from DMF.

[0324] General Procedure C for the Synthesis of Alkoxycarbonate Prodrug: A stirred mixture of 4-(1H)-quinolone ELQ (1 equiv), tetrabutylammonium iodide (TBAI) (2 equiv), anhydrous K2CO3 (2 equiv), and chloroethyl methyl carbonate (2 equiv) in DMF was heated at 60 °C for 24 h. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness to give an oil. The resulting residue was stirred with ethyl acetate for 30 min, the insoluble TBAI was filtered off and washed with ethyl acetate. The filtrate was concentrated to dryness and purified by flash chromatography using a gradient of ethyl acetate / hexane as the eluent to give the desired product. If the purity of the resulting prodrug was less than 98% as determined by GC-MS and NMR, it could be obtained in pure form by crystallization from hexane / ethyl acetate.

[0325] General Procedure D for the Synthesis of N-Oxide Prodrug: MCPBA (1.5 equiv) was added to a stirred solution of ELQ alkoxycarbonate (1 equiv) in chloroform and the solution was heated at 90 °C for 24 h. After cooling to room temperature, the yellow solution was concentrated to dryness under reduced pressure and purified by flash chromatography on silica gel.

[0326] General Procedure E for the Hydrolysis of N-Oxide Prodrug: A solution of alkoxycarbonate nitrone in ethanol / 10% aqueous NaOH (4 / 1) was heated at 60 °C for 2 h, and some white precipitate formed. The solution was concentrated to dryness. The resulting solid was then washed with water (3 × 10 ml), DCM (3 × 10 ml), and air-dried to give the desired N-hydroxy ELQ.

[0327] 3-(3',5'-Bis(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-4,6-dichloro-7-methoxy-2-methylquinoline (3a): According to the general procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 equiv), 2a (568 mg, 2.2 mmol, 1.1 equiv), aqueous K2CO3 (2 ml, 2 equiv), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.05 equiv) and DMF (75 ml) was heated for 16 h to give crude 3a (1.09 g) as a black solid. DCM (15 ml) was added, the precipitate was filtered and washed with methylene chloride (2 × 5 ml) to give pure 3a (305 mg) as a white solid, and a further pure 3a (126 mg) was obtained by a second recovery from DCM. The mother liquor was further purified by flash chromatography using a gradient of ethyl acetate / hexane (3 / 7) as the eluting solvent to give additional 3a (48 mg), giving a combined yield of 3a (479 mg, 45%). GC-MS showed one peak M + = 529 (100%). TIFF2025524371000181.tif18160

[0328] 4,6-Dichloro-3-(4'-cyclohexyl-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (3b): According to the general procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 equiv), 2b (630 mg, 2.2 mmol, 1.1 equiv), aqueous K2CO3 (2 ml, 2 equiv), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.05 equiv) and DMF (75 ml) was heated for 48 h to give crude 3a (1.03 g) 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 from ethyl acetate / hexane to give pure 3b (400 mg, 42%) as a pale yellow solid. GC-MS showed one peak M + = 475 (42%). TIFF2025524371000182.tif18161

[0329] 4,6-Dichloro-3-(2'-chloro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (3c): According to the general procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 equiv), 2c (528 mg, 2.2 mmol, 1.1 equiv), aqueous K2CO3 (2 ml, 2 equiv), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.05 equiv) and DMF (75 ml) was heated for 48 h to give crude 3c (1.0 g) as a black solid. The product was purified by flash chromatography using a gradient of ethyl acetate / hexane (2 / 8) as the eluting solvent and was determined by GC-MS to give 3c (190 mg, 19% yield) of about 98% purity as a white solid. GC-MS showed one peak M + = 511 (100%). TIFF2025524371000183.tif18161

[0330] 4,6-Dichloro-7-methoxy-2-methyl-3-(2'-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinoline (3d): According to the general procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 equiv), 2d (664 mg, 2.2 mmol, 1.1 equiv), aqueous K2CO3 (2 ml, 2 equiv), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.05 equiv) and DMF (75 ml) was heated for 16 h to give crude 3d (1.26 g) 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 3d (654 mg) as a white solid. The product was crystallized from ethyl acetate to give pure 3d (431 mg, 44% yield). GC-MS showed one peak M + = 491 (100%). TIFF2025524371000184.tif11139

[0331] 4,6-Dichloro-7-methoxy-2-methyl-3-(2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinoline (3e): According to General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 equiv), 2e (494 mg, 2.4 mmol, 1.2 equiv), aqueous K2CO3 (2 ml, 2 equiv), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.05 equiv) and DMF (75 ml) was heated for 24 h to give crude [3e (2.65 g) as a black solid. The product was purified by flash chromatography using a gradient of ethyl acetate / hexane (2 / 8) as the elution solvent to give 3e (638 mg, 67% yield) as a white solid. GC-MS showed one peak at M + = 477 (100%). TIFF2025524371000185.tif11128

[0332] 4,6-Dichloro-3-(2'-fluoro-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (3f): According to General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 equiv), 2f (494 mg, 2.4 mmol, 1.2 equiv), aqueous K2CO3 (2 ml, 2 equiv), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.05 equiv) 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 elution solvent to give 3f (369 mg, 45% yield) as a white solid. GC-MS showed one peak at M + = 411 (100%). TIFF2025524371000186.tif11157

[0333] 4,6-Dichloro-7-methoxy-2-methyl-3-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)quinoline (3g): According to General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 equiv), 2g (456 mg, 2.4 mmol, 1.2 equiv), aqueous K2CO3 (2 ml, 2 equiv), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.05 equiv) and DMF (75 ml) was heated for 10 days to obtain crude 3g (1.65 g) 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 obtain 3g (41 mg) as a white solid. The overlapping fractions were concentrated under reduced pressure and the solid was crystallized in ethyl acetate and hexane to obtain an additional 3g (200 mg), giving a combined 3g (241 mg, 22% yield). GC-MS showed one peak at M + = 461 (100%). TIFF2025524371000187.tif18161

[0334] 4,6-Dichloro-3-(3',5'-difluoro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (3h): According to General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 equiv), 2h (778 mg, 2.4 mmol, 1.2 equiv), aqueous K2CO3 (2 ml, 2 equiv), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.05 equiv) and DMF (75 ml) was heated for 24 hours to obtain crude 3h (1.55 g) as a black solid. The product was purified by flash chromatography using a gradient of ethyl acetate / hexane (2 / 8) as the eluting solvent and was determined by GC-MS and NMR to be approximately 95% pure 3h (677 mg, 66% yield) as a white solid. GC-MS showed one peak at M + = 513 (100%). TIFF2025524371000188.tif11165

[0335] 4,6-Dichloro-3-(3',5'-difluoro-4'-methoxy-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (3i): According to General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 equiv), 2i (648 mg, 2.4 mmol, 1.2 equiv), aqueous K2CO3 (2 ml, 2 equiv), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.05 equiv) and DMF (75 ml) was heated for 24 h to give crude 3i (1.48 g) as a black solid. The product was purified by flash chromatography using a gradient of ethyl acetate / hexane (2 / 8) as the eluting solvent and was determined by GC-MS and NMR to give 3i (903 mg, 98% yield) with a purity of about 95% as a white solid. GC-MS showed one peak M + = 459 (100%). TIFF2025524371000189.tif18161

[0336] 4,6-Dichloro-7-methoxy-3-(2'-methoxy-5'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-methylquinoline (3j): According to General Procedure A, a mixture of 1 (1.19 g, 3.0 mmol, 1 equiv), 2j (850 mg, 3.6 mmol, 1.2 equiv), aqueous K2CO3 (3 ml, 6.0 mmol, 2 equiv), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.05 equiv) and DMF (150 ml) was heated for 18 h to give crude 3j (2.1 g) 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 3j (976 mg, 64% yield) as a white solid. GC-MS showed one peak M + = 507 (100%). TIFF2025524371000190.tif18161

[0337] 4,6-Dichloro-7-methoxy-3-(2'-methoxy-[1,1'-biphenyl]-4-yl)-2-methylquinoline (3k): According to General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 equiv), 2k (365 mg, 2.4 mmol, 1.2 equiv), aqueous K2CO3 (2 ml, 2 equiv), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.05 equiv) and DMF (100 ml) was heated for 48 h to give crude 3k (1.2 g) 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 3k (540 mg, 64% yield) as a white solid. GC-MS showed one peak M + = 423 (100%). TIFF2025524371000191.tif18161

[0338] 4,6-Dichloro-7-methoxy-3-(2'-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-2-methylquinoline (3l): According to General A, a mixture of 1 (794 mg, 2.0 mmol, 1 equiv), 2l (528 mg, 2.4 mmol, 1.2 equiv), aqueous K2CO3 (2 ml, 2 equiv), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.05 equiv) and DMF (75 ml) was heated for 18 h to give crude 3l (1.0 g) as a yellow solid. The product was 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. GC-MS showed one peak M + = 491 (100%). TIFF2025524371000192.tif11128

[0339] 4,6-Dichloro-3-(4'-fluoro-2'-methoxy-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (3m): According to General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 equiv), 2m (408 mg, 2.4 mmol, 1.2 equiv), aqueous K2CO3 (2 ml, 2 equiv), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.05 equiv) and DMF (75 ml) was heated for 18 h. The mixture was filtered through celite, and the white insoluble solid seen on the celite was separated and air-dried to give pure 3m (503 mg, 57% yield) as a white solid. GC-MS showed one peak M + = 441 (100%). TIFF2025524371000193.tif11155

[0340] 4,6-Dichloro-7-methoxy-3-(2'-methoxy-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-methylquinoline (3n): According to General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 equiv), 2n (763 mg, 2.4 mmol, 1.2 equiv), aqueous K2CO3 (2 ml, 2 equiv), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.05 equiv) and DMF (75 ml) was heated for 36 h to give crude 3n (1.40 g) as a black solid. The product was purified by flash chromatography using a gradient of ethyl acetate / hexane (2 / 8) as the elution solvent to give 3n (597 mg) as a white solid. The product was crystallized in DCM / hexane to give pure 3n (360 mg), and a second recovery from the mother liquor gave an additional 3n (120 mg), for a total of pure 3n (480 mg, 47% yield) as a white solid. GC-MS showed one peak M + = 445 (100%). TIFF2025524371000194.tif18161

[0341] 4'-(4,6-Dichloro-7-methoxy-2-methylquinolin-3-yl)-2-methoxy-[1,1'-biphenyl]-4-carbonitrile (3o): According to the general procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 equiv), 3o (622 mg, 2.4 mmol, 1.2 equiv), aqueous K2CO3 (2 ml, 2 equiv), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.05 equiv) and DMF (75 ml) was heated for 110 h to obtain crude 3o (1.0 g) 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 3o (581 mg) as a white solid. The product was crystallized from ethyl acetate / DCM to give pure 3o (485 mg, 54% yield) as a white solid. GC-MS showed one peak at M + = 448 (100%). TIFF2025524371000195.tif18161

[0342] 4,6-Dichloro-3-(4-cyclohexylphenyl)-7-methoxy-2-methylquinoline (3p): According to the general procedure A, a mixture of 4 (321 mg, 1.0 mmol, 1 equiv), 2p (300 mg, 1.05 mmol, 1.05 equiv), aqueous K2CO3 (1 ml, 2 equiv), Pd(dppf)Cl2 (37 mg, 0.1 mmol, 0.05 equiv) and DMF (25 ml) was heated for 16 h and maintained at room temperature for 72 h. The mixture was filtered through celite and the white solid on the celite was separated to give pure 3p (90 mg) as a white solid. The filtrate was concentrated to dryness under reduced pressure and purified by flash chromatography using a gradient of ethyl acetate / hexane (1 / 9) as the eluting solvent to give 3p (89 mg). The product was further crystallized from DMF to give pure 3p (26 mg), giving a total combined 3p (116 mg, 29% yield). GC-MS showed one peak at M + = 399 (100%). TIFF2025524371000196.tif18161

[0343] 3-(3',5'-Bis(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-4-chloro-6-fluoro-7-methoxy-2-methylquinoline (6a): According to General Procedure A, a mixture of 5 (3.81 g, 10.0 mmol, 1 equiv), 2a (2.84 g, 11.0 mmol, 1.1 equiv), aqueous K2CO3 (20 ml, 2 equiv), Pd(dppf)Cl2 (366 mg, 0.5 mmol, 0.05 equiv) and DMF (200 ml) was heated for 16 h to give crude 6a (5.82 g) as a black solid. The product was purified by flash chromatography using a gradient of ethyl acetate / hexane (3 / 7) as the eluting solvent. A white precipitate formed while evaporating the solvent of the combined fractions under reduced pressure. The product was filtered and washed with cold hexane to give pure 6a (2.46 g, 48% yield) as a white solid. GC-MS showed one peak M + = 513 (100%). TIFF2025524371000197.tif11129

[0344] 4-Chloro-3-(4'-cyclohexyl-[1,1'-biphenyl]-4-yl)-6-fluoro-7-methoxy-2-methylquinoline (6b): According to General Procedure A, a mixture of 5 (3.81 g, 10 mmol, 1 equiv), 2b (3.43 g, 12.0 mmol, 1.2 equiv), aqueous K2CO3 (2 ml, 2 equiv), Pd(dppf)Cl2 (366 mg, 0.5 mmol, 0.05 equiv) 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 from ethyl acetate / hexane to give pure 6b (698 mg, 15% yield) as a white solid. GC-MS showed one peak M + = 459 (100%). TIFF2025524371000198.tif18161

[0345] 4,6-Dichloro-3-(4'-fluoro-2-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (9): According to General Procedure A, a mixture of 4 (386 mg, 1.05 mmol, 1 equiv), 8 (440 mg, 1.15 mmol, 1.1 equiv), aqueous K2CO3 (1.1 ml, 2 equiv), Pd(dppf)Cl2 (38 mg, 0.5 mmol, 0.05 equiv) 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 using a gradient of ethyl acetate / hexane (2 / 8) as the eluting solvent to give 9 (401 mg), which was further crystallized from ethyl acetate / hexane to give pure 9 (310 mg, 60% yield) as a white solid. GC-MS showed one peak M + = 495 (100%). TIFF2025524371000199.tif11141

[0346] 4-Chloro-3-(4-cyclohexylphenyl)-6-fluoro-7-methoxy-2-methylquinoline (6p): According to General Procedure A, a mixture of 5 (305 mg, 1.0 mmol, 1 equiv), 2p (300 mg, 1.05 mmol, 1.05 equiv), aqueous K2CO3 (1 ml, 2 equiv), Pd(dppf)Cl2 (37 mg, 0.05 mmol, 0.05 equiv) and DMF (25 ml) was heated for 16 h and maintained at room temperature for 72 h. The mixture was filtered through Celite, and the white solid on the Celite was separated to give pure 6p (97 mg) as a white solid. The filtrate was concentrated to dryness under reduced pressure and purified by flash chromatography using a gradient of ethyl acetate / hexane (1 / 9) as the eluting solvent to give 6p (228 mg). The product was further crystallized from DMF to give pure 6p (97 mg), and a total of 3p (194 mg, 51% yield) was obtained. GC-MS showed one peak M + = 383 (100%). TIFF2025524371000200.tif18161

[0347] TIFF2025524371000201.tif361283-(3',5'-Bis(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-6-chloro-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-689): According to General Procedure B, a mixture of 3a (690 mg, 1.30 mmol, 1 equiv), KOAc (1.28 g, 13 mmol, 10 equiv), and glacial acetic acid (5 ml) was heated for 16 h to give pure ELQ-689 (532 mg, 80% yield) as a white solid. TIFF2025524371000202.tif11142

[0348] TIFF2025524371000203.tif361286-Chloro-3-(4'-cyclohexyl-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-690): According to General Procedure B, a mixture of 3b (238 mg, 0.5 mmol, 1 equiv), KOAc (490 mg, 5 mmol, 10 equiv), and glacial acetic acid (2 ml) was heated for 18 h to give pure ELQ-690 (207 mg, 90% yield) as a white solid. TIFF2025524371000204.tif18161

[0349] TIFF2025524371000205.tif301286-Chloro-3-(2'-chloro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-692): According to General Procedure B, a mixture of 3c (190 mg, 0.37 mmol, 1 equiv), KOAc (363 mg, 3.7 mmol, 10 equiv), and glacial acetic acid (5 ml) was heated for 24 h to give pure ELQ-692 (161 mg, 88% yield) as a white solid. TIFF2025524371000206.tif11142Melting point 337.8 - 338.9 °C (decomp).

[0350] TIFF2025524371000207.tif 311286-Chloro-7-methoxy-2-methyl-3-(2'-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-693): According to General Procedure B, a mixture of 3d (430 mg, 0.87 mmol, 1 equiv), KOAc (853 mg, 8.7 mmol, 10 equiv), and glacial acetic acid (4 ml) was heated for 24 h to give pure ELQ-693 (334 mg, 81% yield) as a white solid. TIFF2025524371000208.tif 11135 Melting point 325.9 - 327.1 °C (decomp.).

[0351] TIFF2025524371000209.tif 351286-Chloro-7-methoxy-2-methyl-3-(2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-702): According to General Procedure B, a mixture of 3e (638 mg, 1.33 mmol, 1 equiv), KOAc (1.30 g, 13.3 mmol, 10 equiv), and glacial acetic acid (5 ml) was heated for 24 h to give pure ELQ-702 (334 mg, 76% yield) as a white solid. TIFF2025524371000210.tif 11142 Melting point 293.1 - 294.3 °C (decomp.).

[0352] TIFF2025524371000211.tif 351286-Chloro-3-(2'-fluoro-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-703): According to General Procedure B, a mixture of 3f (369 mg, 0.90 mmol, 1 equiv), KOAc (882 mg, 9.0 mmol, 10 equiv), and glacial acetic acid (5 ml) was heated for 24 h to give pure ELQ-703 (262 mg, 74% yield) as a white solid. TIFF2025524371000212.tif 18161 Melting point 370.4 - 371 °C (decomp.).

[0353] TIFF2025524371000213.tif351286-Chloro-7-methoxy-2-methyl-3-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-704): According to General Procedure B, a mixture of 3g (200mg, 0.43 mmol, 1 equiv), KOAc (421mg, 4.3 mmol, 10 equiv), and glacial acetic acid (5ml) was heated for 24 hours to obtain pure ELQ-704 (152mg, 80% yield) as a white solid. TIFF2025524371000214.tif11151Melting point 350.7~351.3 °C (decomposition).

[0354] TIFF2025524371000215.tif421286-Chloro-3-(3',5'-difluoro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-717): According to General Procedure B, a mixture of 3h (677mg, 1.3 mmol, 1 equiv), KOAc (1.27g, 13 mmol, 10 equiv), and glacial acetic acid (10ml) was heated for 24 hours to obtain pure ELQ-717 (507mg, 79% yield) as a white solid. TIFF2025524371000216.tif11128

[0355] TIFF2025524371000217.tif381286-Chloro-3-(3',5'-difluoro-4'-methoxy-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-716): According to General Procedure B, a mixture of 3i (917mg, 1.98 mmol, 1 equiv), KOAc (1.95g, 19.8 mmol, 10 equiv), and glacial acetic acid (15ml) was heated for 18 hours to obtain pure ELQ-716 (500mg, 57% yield) as a white solid. TIFF2025524371000218.tif11140

[0356] TIFF2025524371000219.tif321286-Chloro-7-methoxy-3-(2'-methoxy-5'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-methylquinolin-4(1H)-one (ELQ-727): According to General Procedure B, a mixture of 3j (976 mg, 1.92 mmol, 1 equiv), KOAc (1.88 g, 19.2 mmol, 10 equiv), and glacial acetic acid (10 mL) was heated for 18 h to afford pure ELQ-727 (697 mg, 74% yield) as a white solid. TIFF2025524371000220.tif11142Melting point: 297.3 - 298.1 °C (decomp).

[0357] TIFF2025524371000221.tif311286-Chloro-7-methoxy-3-(2'-methoxy-[1,1'-biphenyl]-4-yl)-2-methylquinolin-4(1H)-one (ELQ-728): According to General Procedure B, a mixture of 3k (540 mg, 1.27 mmol, 1 equiv), KOAc (1.24 g, 12.7 mmol, 10 equiv), and glacial acetic acid (5 mL) was heated for 18 h to afford pure ELQ-728 (467 mg, 91% yield) as a white solid. TIFF2025524371000222.tif18161Melting point: 327.3 - 327.9 °C (decomp).

[0358] TIFF2025524371000223.tif321286-Chloro-7-methoxy-3-(2'-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-2-methylquinolin-4(1H)-one (ELQ-742): According to General Procedure B, a mixture of 3l (600 mg, 1.22 mmol, 1 equiv), KOAc (1.20 g, 12.2 mmol, 10 equiv), and glacial acetic acid (10 mL) was heated for 18 h to afford pure ELQ-742 (455 mg, 79% yield) as a white solid. TIFF2025524371000224.tif11129Melting point: 350.7 - 351.2 °C (decomp).

[0359] TIFF2025524371000225.tif 32128 6-Chloro-3-(4'-fluoro-2'-methoxy-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-743): According to General Procedure B, a mixture of 3m (500 mg, 1.13 mmol, 1 equiv), KOAc (1.11 g, 11.3 mmol, 10 equiv), and glacial acetic acid (10 mL) was heated for 18 h to give ELQ-743 (455 mg). The product was further crystallized from DMF to afford pure ELQ-743 (290 mg, 50% yield) as a white solid. TIFF2025524371000226.tif 25161 Melting point: 360.7 - 361.1 °C (decomp.).

[0360] TIFF2025524371000227.tif 32128 6-Chloro-7-methoxy-3-(2'-methoxy-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-methylquinolin-4(1H)-one (ELQ-744): According to General Procedure B, a mixture of 3n (380 mg, 0.75 mmol, 1 equiv), KOAc (735 mg, 7.5 mmol, 10 equiv), and glacial acetic acid (10 mL) was heated for 18 h to give ELQ-744 (314 mg, 85% yield) as a white solid. TIFF2025524371000228.tif 18158 Melting point: 344.5 - 345.1 °C (decomp.).

[0361] TIFF2025524371000229.tif 32128 4'-(6-Chloro-7-methoxy-2-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-2-methoxy-[1,1'-biphenyl]-4-carbonitrile (ELQ-745): According to General Procedure B, a mixture of 3o (449 mg, 1.0 mmol, 1 equiv), KOAc (980 mg, 10.0 mmol, 10 equiv), and glacial acetic acid (10 mL) was heated for 18 h to give ELQ-745 (384 mg, 89% yield) as a white solid. TIFF2025524371000230.tif 11133 Melting point: 352.7 - 353.2 °C (decomp.).

[0362] TIFF2025524371000231.tif391283-(4'-Cyclohexyl-[1,1'-biphenyl]-4-yl)-6-fluoro-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-694): According to General Procedure B, a mixture of 6a (2.05 g, 4.0 mmol, 1 equiv), KOAc (3.90 g, 40.0 mmol, 10 equiv), and glacial acetic acid (10 mL) was heated for 24 h to give ELQ-694 (1.76 g, 89% yield) as a white solid. TIFF2025524371000232.tif11155

[0363] TIFF2025524371000233.tif381283-(3',5'-Bis(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-6-fluoro-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-697): According to General Procedure B, a mixture of 6b (698 mg, 1.52 mmol, 1 equiv), KOAc (1.49 g, 15.2 mmol, 10 equiv), and glacial acetic acid (10 mL) was heated for 24 h to give ELQ-697 (623 mg, 93% yield) as a white solid. TIFF2025524371000234.tif18159

[0364] TIFF2025524371000235.tif321286-Chloro-3-(4'-fluoro-2-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-762): According to General Procedure B, a mixture of 9 (310 mg, 0.63 mmol, 1 equiv), KOAc (517 mg, 6.3 mmol, 10 equiv), and glacial acetic acid (5 mL) was heated for 24 h to give ELQ-762 (300 mg, 99% yield) as a white solid. TIFF2025524371000236.tif11139Melting point 300 - 301 °C.

[0365] TIFF2025524371000237.tif35128((6-Chloro-7-methoxy-2-methyl-3-(3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4-yl)oxy)methyl ethyl carbonate (ELQ-652): Following General Procedure C, crude ELQ-652 (193 mg) was obtained using a mixture of ELQ-604 (150 mg, 0.33 mmol, 1 equiv), TBAI (244 mg, 0.66 mmol, 2 equiv), anhydrous K2CO3 (92 mg, 0.66 mmol, 2 equiv) and chloromethyl ethyl carbonate (91.7 mg, 0.66 mmol, 2 equiv) in DMF (15 ml). The product was purified by flash chromatography using ethyl acetate / hexane (3 / 7), followed by crystallization in ethyl acetate / hexane to give pure ELQ-652 (100 mg, 54% yield) as a white solid. GC-MS showed one peak M + = 561 (45%), M + = 459 (100%). TIFF2025524371000238.tif18157

[0366] TIFF2025524371000239.tif35128((6-Chloro-7-methoxy-2-methyl-3-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)quinolin-4-yl)oxy)methyl ethyl carbonate (ELQ-671): Following General Procedure C, crude ELQ-671 (188 mg) was obtained using a mixture of ELQ-646 (150 mg, 0.34 mmol, 1 equiv), TBAI (251 mg, 0.68 mmol, 2 equiv), anhydrous K2CO3 (95 mg, 0.68 mmol, 2 equiv) and chloromethyl ethyl carbonate (95 mg, 0.68 mmol, 2 equiv) in DMF (30 ml). The product was purified by flash chromatography using ethyl acetate / hexane (3 / 7), followed by crystallization in ethyl acetate / hexane to give pure ELQ-671 (91 mg) and a second yield (23 mg), for a total of ELQ-671 (114 mg, 61% yield) as a white solid. GC-MS showed one peak M + = 545 (37%), M += 443 (100%) is shown. TIFF2025524371000240.tif25157

[0367] ((3-(3',5'-Bis(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-6-chloro-7-methoxy-2-methylquinolin-4-yl)oxy)methyl ethyl carbonate (ELQ-699): According to General Procedure C, using a mixture of ELQ-689 (511 mg, 1.0 mmol, 1 equivalent), TBAI (738 mg, 2.0 mmol, 2 equivalents), anhydrous K2CO3 (278 mg, 2.0 mmol, 2 equivalents) and chloromethyl ethyl carbonate (278 mg, 2.0 mmol, 2 equivalents) in DMF (50 ml), crude ELQ-699 (707 mg) was obtained. The product was purified by flash chromatography using ethyl acetate / hexane (2 / 8), followed by crystallization in ethyl acetate / hexane to obtain pure ELQ-699 (400 mg, yield 65%) as a white solid. GC-MS shows one peak M + = 613 (30%), M + = 511 (100%) is shown. TIFF2025524371000241.tif18157TIFF2025524371000242.tif36128

[0368] ((6-Chloro-7-methoxy-2-methyl-3-(2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4-yl)oxy)methyl ethyl carbonate (ELQ-711): According to General Procedure C, using a mixture of ELQ-702 (230 mg, 0.5 mmol, 1 equivalent), TBAI (369 mg, 1.0 mmol, 2 equivalents), anhydrous K2CO3 (139 mg, 1.0 mmol, 2 equivalents) and chloromethyl ethyl carbonate (139 mg, 2.0 mmol, 2 equivalents) in DMF (25 ml), crude ELQ-711 (737 mg) was obtained. The product was purified by flash chromatography using ethyl acetate / hexane (2 / 8), followed by crystallization in ethyl acetate / hexane to obtain pure ELQ-711 (160 mg, yield 57%) as a white solid. GC-MS shows one peak M+ = 561 (33%), M + shows = 459 (100%). TIFF2025524371000243.tif18156

[0369] TIFF2025524371000244.tif30128 ((6-Chloro-7-methoxy-3-(2'-methoxy-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-methylquinolin-4-yl)oxy)methyl ethyl carbonate (ELQ-749): According to General Procedure C, a mixture of ELQ-744 (980 mg, 2.0 mmol, 1 equiv), TBAI (1.48 g, 4.0 mmol, 2 equiv), anhydrous K2CO3 (556 mg, 4.0 mmol, 2 equiv) and chloromethyl ethyl carbonate (556 mg, 4.0 mmol, 2 equiv) in DMF (100 ml) was used to obtain crude ELQ-749 (737 mg). The product was purified by flash chromatography using ethyl acetate / hexane (4 / 6), followed by crystallization in ethyl acetate / hexane to give pure ELQ-749 (830 mg, 70% yield) as pale yellow crystals. GC-MS shows one peak M + = 591 (48%), M + shows = 489 (100%). TIFF2025524371000245.tif18156

[0370] TIFF2025524371000246.tif 321286-Chloro-7-methoxy-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4-yl pivalate (ELQ-753): A mixture of ELQ-596 (1.84 g, 4.0 mmol, 1 equiv) and sodium hydride 60% oil suspension (320 mg, 8.0 mmol, 2 equiv) in anhydrous THF (75 ml) was heated at 60 °C for 30 min. Then, pivaloyl chloride (968 mg, 8.0 mmol, 2 equiv) was added and the turbid solution was heated for an additional 2 h. After cooling to room temperature, water (2 ml) was added, and a yellow sticky solid formed. This was filtered and the sticky solid was washed with ethyl acetate (3 × 10 ml). The combined filtrates were concentrated under reduced pressure 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) and subsequently crystallized from ethyl acetate to give pure ELQ-753 (1.20 g, 55% yield) as white crystals. GC-MS showed one peak M + = 543 (5%), M + = 57 (100%). TIFF2025524371000247.tif 18160

[0371] TIFF2025524371000248.tif 30128 Ethyl (((6-fluoro-7-methoxy-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4-yl)oxy)methyl) carbonate (ELQ-672): Following General Procedure C, using a mixture of ELQ-650 (1.77 g, 4.0 mmol, 1 equiv), TBAI (2.95 g, 8.0 mmol, 2 equiv), anhydrous K2CO3 (1.11 g, 8.0 mmol, 2 equiv) and chloromethyl ethyl carbonate (1.11 g, 8.0 mmol, 2 equiv) in DMF (150 ml), crude ELQ-672 (2.75 g) was obtained. The product was purified by flash chromatography using ethyl acetate / hexane (2 / 8) and subsequently crystallized from ethyl acetate / hexane to give pure ELQ-650 (1.62 g, 74% yield) as white crystals. GC-MS showed one peak M +=545(40%), M + =443(100%) is shown. TIFF2025524371000249.tif18158

[0372] TIFF2025524371000250.tif35128 ((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 General Procedure C, using a mixture of ELQ-694 (495 mg, 1.0 mmol, 1 equivalent), TBAI (738 g, 2.0 mmol, 2 equivalents), anhydrous K2CO3 (278 mg, 2.0 mmol, 2 equivalents) and chloromethyl ethyl carbonate (278 mg, 2.0 mmol, 2 equivalents) in DMF (50 ml), crude ELQ-696 (816 mg) was obtained. The product was purified by flash chromatography using ethyl acetate / hexane (2 / 8), followed by trituration with hexane and cooling at 4 °C for 12 h to give pure ELQ-696 (459 mg, 77% yield) as a white solid. GC-MS showed one peak M + =597(25%), M + =495(100%) is shown. TIFF2025524371000251.tif18155

[0373] TIFF2025524371000252.tif38128 ((3-(4'-Cyclohexyl-[1,1'-biphenyl]-4-yl)-6-fluoro-7-methoxy-2-methylquinolin-4-yl)oxy)methyl ethyl carbonate (ELQ-698): According to General Procedure C, using a mixture of ELQ-697 (442 mg, 1.0 mmol, 1 equivalent), TBAI (738 g, 2.0 mmol, 2 equivalents), anhydrous K2CO3 (278 mg, 2.0 mmol, 2 equivalents), and chloromethyl ethyl carbonate (278 mg, 2.0 mmol, 2 equivalents) in DMF (50 ml), crude ELQ-698 (816 mg) was obtained. The product was purified by flash chromatography using ethyl acetate / hexane (2 / 8) to give pure ELQ-698 (420 mg, 77% yield) as a white solid. GC-MS showed one peak at M + = 543 (50%), M + = 207 (100%). TIFF2025524371000253.tif25160

[0374] TIFF2025524371000254.tif35128 ((5,7-Difluoro-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4-yl)oxy)methyl ethyl carbonate (ELQ-761): According to General Procedure C, using a mixture of ELQ-601 (431 mg, 1.0 mmol, 1 equivalent), TBAI (738 g, 2.0 mmol, 2 equivalents), anhydrous K2CO3 (278 mg, 2.0 mmol, 2 equivalents), and chloromethyl ethyl carbonate (278 mg, 2.0 mmol, 2 equivalents) in DMF (50 ml), crude ELQ-761 (521 mg) was obtained. The product was purified by flash chromatography using ethyl acetate / hexane (2 / 8) to give pure ELQ-761 (382 mg, 72% yield) as a white solid. GC-MS showed one peak at M + = 533 (25%), M + = 431 (100%). TIFF2025524371000255.tif25160

[0375] TIFF2025524371000256.tif 351286-Chloro-4-(((ethoxycarbonyl)oxy)methoxy)-7-methoxy-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinoline 1-oxide (ELQ-707): According to General Procedure D, using a solution of ELQ-598 (562 mg, 1.0 mmol, 1 equivalent) and MCPBA (260 mg, 1.5 mmol, 1.5 equivalents) in chloroform (25 ml), crude ELQ-707 (1.0 g) was obtained. The crude ELQ-707 was dissolved in DCM (5 ml), cooled at 4 °C for 12 hours, filtered, and the filtrate was purified by flash chromatography using ethyl acetate / DCM (6 / 4), followed by crystallization in ethyl acetate / hexane to obtain pure ELQ-707 (397 mg, 69% yield) as yellow crystals. TIFF2025524371000257.tif 18158

[0376] TIFF2025524371000258.tif 41128 3-(3',5'-Bis(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-6-chloro-4-(((ethoxycarbonyl)oxy)methoxy)-7-methoxy-2-methylquinoline 1-oxide (ELQ-736): According to General Procedure D, using a solution of ELQ-699 (250 mg, 0.41 mmol, 1 equivalent) and MCPBA (106 mg, 1.5 mmol, 1.5 equivalents) in chloroform (25 ml), crude ELQ-736 (1.0 g) was obtained. The product was purified by flash chromatography using ethyl acetate / DCM (6 / 4), followed by crystallization in ethyl acetate / hexane to obtain pure ELQ-736 (180 mg, 70% yield) as a white solid. TIFF2025524371000259.tif 11156

[0377] TIFF2025524371000260.tif351284 - (((Ethoxycarbonyl)oxy)methoxy)-6-fluoro-7-methoxy-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinoline 1-oxide (ELQ-709): According to General Procedure D, using a solution of ELQ-672 (545 mg, 1.0 mmol, 1 equivalent) and MCPBA (260 mg, 1.5 mmol, 1.5 equivalents) in chloroform (25 ml), crude ELQ-709 (898 mg) was obtained. The product was purified by flash chromatography using ethyl acetate / DCM (6 / 4), followed by crystallization in ethyl acetate / hexane to give pure ELQ-709 (352 mg, 63% yield) as a white solid. TIFF2025524371000261.tif11148

[0378] 3-(3',5'-Bis(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-4-(((ethoxycarbonyl)oxy)methoxy)-6-fluoro-7-methoxy-2-methylquinoline 1-oxide (ELQ-737): According to General Procedure D, using a solution of ELQ-696 (245 mg, 0.41 mmol, 1 equivalent) and MCPBA (105 mg, 1.5 mmol, 1.5 equivalents) in chloroform (25 ml), crude ELQ-737 (376 mg) was obtained. The product was purified by flash chromatography using ethyl acetate / DCM (6 / 4), followed by crystallization in ethyl acetate / hexane to give pure ELQ-737 (121 mg, 48% yield) as white crystals. TIFF2025524371000262.tif11156

[0379] TIFF2025524371000263.tif401284 - (((Ethoxycarbonyl)oxy)methoxy)-5,7-difluoro-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinoline 1-oxide (ELQ-735): According to General Procedure D, crude ELQ-735 (581 mg) was obtained using a solution of ELQ-761 (382 mg, 0.72 mmol, 1 equivalent) and MCPBA (187 mg, 1.5 mmol, 1.5 equivalents) in chloroform (25 ml). The product was purified by flash chromatography using ethyl acetate / DCM (6 / 4), followed by crystallization in ethyl acetate / hexane to give pure ELQ-735 (235 mg, 59% yield) as white crystals.

[0380] TIFF2025524371000264.tif351286 - Chloro-1-hydroxy-7-methoxy-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-708): According to General Procedure E, pure ELQ-708 (92 mg, 77% yield) was obtained as a brown solid using a solution of ELQ-707 (145 mg, 0.25 mmol, 1 equivalent) in ethanol / 10% aqueous NaOH (10 ml). TIFF2025524371000265.tif18159

[0381] TIFF2025524371000266.tif411283-(3',5'-Bis(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-6-chloro-1-hydroxy-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-739): According to General Procedure E, pure ELQ-739 (72 mg, 86% yield) was obtained as a red solid using a solution of ELQ-736 (100 mg, 0.16 mmol, 1 equivalent) in ethanol / 10% aqueous NaOH (10 ml). TIFF2025524371000267.tif11157

[0382] 6-Fluoro-1-hydroxy-7-methoxy-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-710): Following general procedure E, using a solution of ELQ-709 (140 mg, 0.25 mmol, 1 equiv) in ethanol / 10% aqueous NaOH (10 mL), pure ELQ-710 (100 mg, 87% yield) was obtained as a white solid. TIFF2025524371000268.tif18154

[0383] TIFF2025524371000269.tif411283-(3',5'-Bis(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-6-fluoro-1-hydroxy-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-740): Following general procedure E, using a solution of ELQ-737 (100 mg, 0.16 mmol, 1 equiv) in ethanol / 10% aqueous NaOH (10 mL), pure ELQ-740 (68 mg, 8�% yield) was obtained as a white solid. TIFF2025524371000270.tif11163

[0384] TIFF2025524371000271.tif351285,7-Difluoro-1-hydroxy-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-738): Following general procedure E, using a solution of ELQ-735 (100 mg, 0.16 mmol, 1 equiv) in ethanol / 10% aqueous NaOH (10 mL), pure ELQ-738 (54 mg, 48% yield) was obtained as a yellow solid. TIFF2025524371000272.tif18160

[0385] Ethyl (Z)-3-((3-methoxyphenyl)imino)-2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)butanoate TIFF2025524371000273.tif25158Meta-anisidine (1.10 g, 0.0089 mol) was mixed with ethyl 3-oxo-2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)butanoate (a mixture of 3.44 g in a molar ratio of 10:1 with para-toluenesulfonic acid monohydrate, thus 3.27 g, 0.0089 mol of ethyl 3-oxo-2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)butanoate and 0.17 g, 0.00089 mol of para-toluenesulfonic acid monohydrate). The mixture was refluxed in benzene (75 mL) under Dean-Stark conditions for 3 days. The solvent was removed while heating under reduced pressure, and the residue (a hard, brown oil) was used in the next reaction without purification or analysis.

[0386] 7-Methoxy-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-685) TIFF2025524371000274.tif26153Ethyl (Z)-3-((3-methoxyphenyl)imino)-2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)butanoate (the crude product from the previous reaction) was dissolved in hot Dowtherm A (8 mL, with an additional 7 mL used to wash the flask) and added gradually over 8 minutes to boiling Dowtherm A (100 mL, 255 °C). After heating for a total of 11 minutes, the mixture was cooled to room temperature with stirring. Hexane (300 mL) was added with stirring, and the resulting solid was collected by filtration under reduced pressure and washed with excess hexane followed by acetone (50 mL). The crude product (a cream-colored solid, 1.76 g) was recrystallized from N,N-dimethylformamide (15 mL) to give 1.25 g of the desired product; a second yield was also recovered from the mother liquor (0.23 g, a total of 1.48 g of fine, almost white crystals; 39% yield in two steps from meta-anisidine, melting point: 389.8 - 392.1 °C (decomposition), TIFF2025524371000275.tif25160.

[0387] Ethyl(((7-methoxy-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4-yl)oxy)methyl)carbonate (ELQ-695) TIFF2025524371000276.tif28143In N,N-dimethylformamide (17 mL), a stirred mixture of 7-methoxy-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-685; 0.45 g, 0.0011 mol), tetrabutylammonium iodide (2.0 equiv, 0.0022 mol, 0.81 g), and potassium carbonate anhydrous (2.0 equiv, 0.0022 mol, 0.30 g) was treated with chloromethyl ethyl carbonate (2.0 equiv, 0.0022 mol, 0.30 g). The mixture was heated at 60 °C for 21 h. The cooled reaction mixture was filtered under reduced pressure to remove solids, and the filtrate was concentrated while heating...

Claims

1. Compound of formula (I): And in the formula: R 1a These are independently selected from the group consisting of C1-C6 alkoxy, H, halogen, CN, and C1-C6 alkyl; R 1b, and R 1c Each of these independently represents H, halogen, CN, and C. 1 -C 6 Alkyl, and C 1 -C 6 Selected from the group of alkoxys; R 2 but, a) Oxo (=O), b) -OH, c)-O-CH 2 -O-C(=O)-O-R 6 、 d)-O-CH 2 -CH 2 -O-C(=O)-O-R 6 、 e)-O-CH 2 (CH 3 )-O-C(=O)-O-R 6 、 f)-O-C(=O)-CH 2 -CH 2 -C(=O)-O-R 6 、 g)-O-CH 2 -O-C(=O)-R 6 、 h)-O-(C=O)-R 7 、 i)-O-(C=O)-O-R 7 、 j)-O-C(O)-NR 8 R 9 、 k)-O-CH 2 -O-C(O)-O-(CH 2 ) n1 -NR 8 R 9 、 l O-O-CH 2 -OC(O)-O-(CH 2 ) n1 -NR 8 -C(=O)-OR 9 , and m)-O-(CH 2 )-O-PO 3 Selected from the group; The dashed lines (-----) in each example represent any single or double bond; Z is selected from the groups C and N; and R 3 These independently include -OC1-C4 haloalkyl, H, halogen, C1-C4 alkyl, -OC1-C4 alkyl, -SC1-C4 alkyl, -SO2-C1-C4 alkyl, C1-C4 haloalkyl, -SC1-C4 haloalkyl, SF3, -SF5, CN, 2-pyrrolizinone, 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-C Selected from the group -C(O)NH(C3-C6 cycloalkyl), -C(O)NH(-CH2-C3-C6 cycloalkyl), -C3-C6 cycloalkyl, -OC3-C6 cycloalkyl, and -SC3-C6 cycloalkyl, where the cycloalkyl rings of -C(O)NH(C3-C6 cycloalkyl), -C(O)NH(-CH2-C3-C6 cycloalkyl), -C3-C6 cycloalkyl, -OC3-C6 cycloalkyl, and -SC3-C6 cycloalkyl are H, OH, oxo (=O), halogen, C1-C4 alkyl, -OC1-C4 alkyl, -SC1-C4 alkyl, -SO2-C1-C4 alkyl, C1-C4 haloalkyl, -OC1-C4 haloalkyl, -SC1-C4 haloalkyl, SF3, -SF5, CN, NO It is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting of -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; R 4, and R 5 Each of these is independent of H, halogen, and C. 1 -C 4 Alkyl, -OC 1 -C 4 Alkyl, -SC 1 -C 4 Alkyl, -SO 2 -C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Haloalkyl, -SC 1 -C 4 Haloalkyl, SF 3 ,-SCIENCE FICTION 5 , CN, 2-pyrrolidinone, NO 2 , -SO 2 -NH 2 , -SO 2 -NH(C 1 -C 4 Alkyl), -SO 2 -N(C 1 -C 4 Alkyl) 2 -C(O)NH 2 -C(O)NH(C 1 -C 4 Alkyl), -C(O)N(C 1 -C 4 Alkyl) 2 -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -OC 3 -C 6 Cycloalkyl, and -SC 3 -C 6 Selected from the cycloalkyl group, where -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -O-C 3 -C 6 Cycloalkyl, and -S-C 3 -C 6 The cycloalkyl ring of the cycloalkyl group is further substituted with 0, 1, 2, or 3 substituents selected from the group consisting of H, OH, oxo (=O), halogen, C 1 -C 4 Alkyl, -O-C 1 -C 4 Alkyl, -S-C 1 -C 4 Alkyl, -SO 2 -C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, -O-C 1 -C 4 Haloalkyl, -S-C 1 -C 4 Haloalkyl, SF 3 , -SF 5 , CN, NO 2 , -SO 2 -NH 2 , -SO 2 -NH(C 1 -C 4 Alkyl), -SO 2 -N(C 1 -C 4 Alkyl) 2 , -C(O)NH 2 , -C(O)NH(C 1 -C 4 Alkyl), and -C(O)N(C 1 -C 4 Alkyl) 2 and is further substituted with 0, 1, 2, or 3 substituents selected from the group; R 6 However, C 1 -C 10 Alkyl, C 2 -C 10 Alkenil, C 2 -C 10 Alkinyl, C 3 -C 6 Cycloalkyl, -(CH 2 ) n1 -C 3 -C 6 Cycloalkyl, 3-6 membered heterocyclyl, -(CH 2 ) n1 -3- to 6-membered heterocyclyl, phenyl, -(CH 2 ) n1 -phenyl and -(CH 2 ) n1 -NR 8 R 9 Selected from the group; R 7 However, C 1 -C 10 Alkyl, C 2 -C 10 Alkenil, C 2 -C 10 Alkinyl, C 3 -C 6 Cycloalkyl, -(CH 2 ) n3 -(C 3 -C 6 Cycloalkyl), -(CH 2 ) n3 -(3-6 member heterocyclyl), phenyl, -(CH 2 ) n1 -phenyl, -(CH 2 ) n1 -O-(CH 2 ) n2 -C 1 -C 2 Alkyl, -(CH 2 -CH 2 -O) n1 -C 1 -C 2 Alkyl and -(CH 2 ) n1 -NR 8 R 9 Selected from the group; R 8 and R 9 Each of them independently, H and C 1 -C 6 Selected from the alkyl group; R 10 However, H, halogen, C 1 -C 6 Alkyl, -OC 1 -C 6 Alkyl, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Haloalkyl and -SC 1 -C 4 Selected from the haloalkyl group; R 11 However, H, OH, and O - Selected from the group; n1 and n2 are integers independently selected from the group 1, 2, 3, 4, 5, and 6; and n3 is an integer selected from the group 0, 1, 2, 3, 4, 5, and 6; However, the above compounds include 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), and 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)quinoline-4(1H)-one (CAS Reg. No. 1354745-28-0), 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)quinoline-4(1H)-one (CAS Not a compound selected from the group Reg. No. 1374758-04-9) Compounds, or pharmaceutically acceptable salts thereof, cocrystals, esters, solvates, hydrates, isomers (including optical isomers, racemates, or other mixtures thereof), tautomers, isotopes, polymorphs, or pharmaceutically acceptable prodrugs.

2. R 2 but, a) Oxo (=O), b) -OH, c)-O-CH 2 -O-C(=O)-O-R 6 、 d)-O-CH 2 -CH 2 -OC(=O)-OR 6 , and e)-O-CH 2 (CH 3 )-O-C(=O)-O-R 6 Selected from the group, The compound according to claim 1, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

3. R 2 However, oxo (=O), and formula -O-CH 2 -OC(=O)-O-(C 1 -C 6 Selected from the group of alkyl(alkyl) parts; R 3 These are independently selected from the group -OC1-C3 haloalkyl, H, halogen, C1-C3 alkyl, -OC1-C3 alkyl, C1-C3 haloalkyl, -S-CF3, -SF5, CN, 2-pyrrolizinone, -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, -OC3-C6 cycloalkyl, and -SC3-C6 cycloalkyl, where -C(O)NH(C3-C6 cycloalkyl), -C(O)NH(-CH2-C3-C The cycloalkyl rings of -C3-C6 cycloalkyl, -OC3-C6 cycloalkyl, and -SC3-C6 cycloalkyl groups include H, OH, oxo (=O), halogen, C1-C4 alkyl, -OC1-C4 alkyl, -SC1-C4 alkyl, -SO2-C1-C4 alkyl, C1-C4 haloalkyl, -OC1-C4 haloalkyl, -SC1-C4 haloalkyl, SF3, -SF5, CN, NO2, -SO2-NH2, -SO2-NH(C1-C4 alkyl), -SO2-N(C1-C4 alkyl)2, -C(O)NH2, and -C(O)NH(C1-C4 It is further substituted with 0, 1, 2, or 3 substituents selected from the group of alkyl and -C(O)N(C1-C4 alkyl)2; R 4, and R 5 Each of these is independent of H, halogen, and C. 1 -C 3 Alkyl, -OC 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, -OC 1 -C 3 Haloalkyl, -S-CF 3 ,-SCIENCE FICTION 5 CN, 2-pyrrolidinone, -C(O)NH 2 -C(O)NH(C 1 -C 3 Alkyl), -C(O)N(C 1 -C 3 Alkyl) 2 -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -OC 3 -C 6 Cycloalkyl, and -SC 3 -C 6 Selected from the cycloalkyl group, where -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -OC 3 -C 6 Cycloalkyl, and -SC 3 -C 6 The cycloalkyl ring of a cycloalkyl group can be H, OH, oxo (=O), halogen, or C. 1 -C 4 Alkyl, -OC 1 -C 4 Alkyl, -SC 1 -C 4 Alkyl, -SO 2 -C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Haloalkyl, -SC 1 -C 4 Haloalkyl, SF 3 ,-SCIENCE FICTION 5 , CN, NO 2 , -SO 2 -NH 2 , -SO 2 -NH(C 1 -C 4 Alkyl), -SO 2 -N(C 1 -C 4 Alkyl) 2 -C(O)NH 2 -C(O)NH(C 1 -C 4 alkyl), and -C(O)N(C 1 -C 4 Alkyl) 2 It is further substituted with 0, 1, 2, or 3 substituents selected from the group; However, R 2 If selected from the oxo (=O) group, R 3 , R 4 , and R 5 At least one of them is not H, The compound according to claim 1, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

4. R 2 However, oxo (=O), and formula -O-CH 2 -OC(=O)-O-(C 1 -C 3 Selected from the group of alkyl groups, The compound according to claim 1, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

5. The compound according to claim 1 of formula (II): And in the formula: R 1 However, it is selected from the group of H, F, and Cl; R 2 However, oxo (=O), and formula -O-CH 2 -OC(=O)-O-(C 1 -C 10 Selected from the group of alkyl(alkyl) parts; R 3 These are independently selected from the group -OC1-C4 haloalkyl, H, halogen, C1-C4 alkyl, -OC1-C4 alkyl, C1-C4 haloalkyl, -S-CF3, -SF5, CN, 2-pyrrolizinone, -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, -OC3-C6 cycloalkyl, and -SC3-C6 cycloalkyl, where -C(O)NH(C3-C6 cycloalkyl), -C(O)NH(-CH2-C3-C The cycloalkyl rings of -C3-C6 cycloalkyl, -OC3-C6 cycloalkyl, and -SC3-C6 cycloalkyl groups include H, OH, oxo (=O), halogen, C1-C4 alkyl, -OC1-C4 alkyl, -SC1-C4 alkyl, -SO2-C1-C4 alkyl, C1-C4 haloalkyl, -OC1-C4 haloalkyl, -SC1-C4 haloalkyl, SF3, -SF5, CN, NO2, -SO2-NH2, -SO2-NH(C1-C4 alkyl), -SO2-N(C1-C4 alkyl)2, -C(O)NH2, and -C(O)NH(C1-C4 It is further substituted with 0, 1, 2, or 3 substituents selected from the group of alkyl and -C(O)N(C1-C4 alkyl)2; R 4, and R 5 Each of these is independent of H, halogen, and C. 1 -C 4 Alkyl, -OC 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Haloalkyl, -S-CF 3 ,-SCIENCE FICTION 5 CN, 2-pyrrolidinone, -C(O)NH 2 -C(O)NH(C 1 -C 4 Alkyl), -C(O)N(C 1 -C 4 Alkyl) 2 -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -OC 3 -C 6 Cycloalkyl, and -SC 3 -C 6 Selected from the cycloalkyl group, where -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -OC 3 -C 6 Cycloalkyl, and -SC 3 -C 6 The cycloalkyl ring of a cycloalkyl group can be H, OH, oxo (=O), halogen, or C. 1 -C 4 Alkyl, -OC 1 -C 4 Alkyl, -SC 1 -C 4 Alkyl, -SO 2 -C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Haloalkyl, -SC 1 -C 4 Haloalkyl, SF 3 ,-SCIENCE FICTION 5 , CN, NO 2 , -SO 2 -NH 2 , -SO 2 -NH(C 1 -C 4 Alkyl), -SO 2 -N(C 1 -C 4 Alkyl) 2 -C(O)NH 2 -C(O)NH(C 1 -C 4 alkyl), and -C(O)N(C 1 -C 4 Alkyl) 2 It is further substituted with 0, 1, 2, or 3 substituents selected from the group; R 10 However, H, C 1 -C 6 Alkyl, -OC 1 -C 6 Alkyl, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Haloalkyl and -SC 1 -C 4 Selected from the group of haloalkyls; and The dashed lines (-----) in each example represent any single or double bond; However, R 2 If selected from the oxo (=O) group, R 3 , R 4 , and R 5 At least one of them is not H; for example, R 2 However, oxo (=O), and formula -O-CH 2 -OC(=O)-O-(C 1 -C 6 Selected from the group of alkyl(alkyl) parts; R 3 These are independently selected from the group -OC1-C3 haloalkyl, H, halogen, C1-C3 alkyl, -OC1-C3 alkyl, C1-C3 haloalkyl, -S-CF3, -SF5, CN, 2-pyrrolizinone, -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, -OC3-C6 cycloalkyl, and -SC3-C6 cycloalkyl, where -C(O)NH(C3-C6 cycloalkyl), -C(O)NH(-CH2-C3-C The cycloalkyl rings of -C3-C6 cycloalkyl, -OC3-C6 cycloalkyl, and -SC3-C6 cycloalkyl groups include H, OH, oxo (=O), halogen, C1-C4 alkyl, -OC1-C4 alkyl, -SC1-C4 alkyl, -SO2-C1-C4 alkyl, C1-C4 haloalkyl, -OC1-C4 haloalkyl, -SC1-C4 haloalkyl, SF3, -SF5, CN, NO2, -SO2-NH2, -SO2-NH(C1-C4 alkyl), -SO2-N(C1-C4 alkyl)2, -C(O)NH2, and -C(O)NH(C1-C4 It is further substituted with 0, 1, 2, or 3 substituents selected from the group of alkyl and -C(O)N(C1-C4 alkyl)2; R 4, and R 5 Each of these is independent of H, halogen, and C. 1 -C 3 Alkyl, -OC 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, -OC 1 -C 3 Haloalkyl, -S-CF 3 ,-SCIENCE FICTION 5 CN, 2-pyrrolidinone, -C(O)NH 2 -C(O)NH(C 1 -C 3 Alkyl), -C(O)N(C 1 -C 3 Alkyl) 2 -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -OC 3 -C 6 Cycloalkyl, and -SC 3 -C 6 Selected from the cycloalkyl group, where -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -OC 3 -C 6 Cycloalkyl, and -SC 3 -C 6 The cycloalkyl ring of a cycloalkyl group can be H, OH, oxo (=O), halogen, or C. 1 -C 4 Alkyl, -OC 1 -C 4 Alkyl, -SC 1 -C 4 Alkyl, -SO 2 -C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Haloalkyl, -SC 1 -C 4 Haloalkyl, SF 3 ,-SCIENCE FICTION 5 , CN, NO 2 , -SO 2 -NH 2 , -SO 2 -NH(C 1 -C 4 Alkyl), -SO 2 -N(C 1 -C 4 Alkyl) 2 -C(O)NH 2 -C(O)NH(C 1 -C 4 alkyl), and -C(O)N(C 1 -C 4 Alkyl) 2 It is further substituted with 0, 1, 2, or 3 substituents selected from the group; However, R 2 If selected from the oxo (=O) group, R 3 , R 4 , and R 5 At least one of them is not H, Compounds of formula (II), or pharmaceutically acceptable salts, cocrystals, esters, solvates, hydrates, isomers (including optical isomers, racemates, or other mixtures thereof), tautomers, isotopes, polymorphs, or pharmaceutically acceptable prodrugs thereof.

6. R2 is oxo (=O), and formula -O-CH 2 -OC(=O)-O-(C 1 -C 4 Selected from the group of alkyl(alkyl) parts; and R 3 These are independently selected from the group -OC1-C2 haloalkyl, H, halogen, C1-C2 alkyl, -OC1-C2 alkyl, C1-C2 haloalkyl, -S-CF3, -SF5, CN, 2-pyrrolizinone, -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, -OC3-C6 cycloalkyl, and -SC3-C6 cycloalkyl, where -C(O)NH(C3-C6 cycloalkyl), -C(O)NH(-CH2-C3-C The cycloalkyl rings of -C3-C6 cycloalkyl, -OC3-C6 cycloalkyl, and -SC3-C6 cycloalkyl groups include H, OH, oxo (=O), halogen, C1-C4 alkyl, -OC1-C4 alkyl, -SC1-C4 alkyl, -SO2-C1-C4 alkyl, C1-C4 haloalkyl, -OC1-C4 haloalkyl, -SC1-C4 haloalkyl, SF3, -SF5, CN, NO2, -SO2-NH2, -SO2-NH(C1-C4 alkyl), -SO2-N(C1-C4 alkyl)2, -C(O)NH2, and -C(O)NH(C1-C4 It is further substituted with 0, 1, 2, or 3 substituents selected from the group of alkyl and -C(O)N(C1-C4 alkyl)2; R 4, and R 5 Each of these is independent of H, halogen, and C. 1 -C 2 Alkyl, -OC 1 -C 2 Alkyl, C 1 -C 2 Haloalkyl, -OC 1 -C 2 Haloalkyl, -S-CF 3 ,-SCIENCE FICTION 5 CN, 2-pyrrolidinone, -C(O)NH 2 -C(O)NH(C 1 -C 2 Alkyl), -C(O)N(C 1 -C 2 Alkyl) 2 -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -OC 3 -C 6 Cycloalkyl, and -SC 3 -C 6 Selected from the cycloalkyl group, where -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -OC 3 -C 6 Cycloalkyl, and -SC 3 -C 6 The cycloalkyl ring of a cycloalkyl group can be H, OH, oxo (=O), halogen, or C. 1 -C 4 Alkyl, -OC 1 -C 4 Alkyl, -SC 1 -C 4 Alkyl, -SO 2 -C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Haloalkyl, -SC 1 -C 4 Haloalkyl, SF 3 ,-SCIENCE FICTION 5 , CN, NO 2 , -SO 2 -NH 2 , -SO 2 -NH(C 1 -C 4 Alkyl), -SO 2 -N(C 1 -C 4 Alkyl) 2 -C(O)NH 2 -C(O)NH(C 1 -C 4 alkyl), and -C(O)N(C 1 -C 4 Alkyl) 2 Further substituted with 0, 1, 2, or 3 substituents selected from the group, The compound according to claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

7. R2 is oxo (=O), and formula -O-CH 2 -OC(=O)-O-(C 1 -C 3 Selected from the group of alkyl(alkyl) parts; and R 3 , R 4 , and R 5 Each of these independently represents H, halogen, methyl, methoxy, and CH. 2 F, CHF 2 , CF 3 ,-O-CH 2 F, -O-CHF 2 , -O-CF 3 -S-CF 3 ,-SCIENCE FICTION 5 CN, 2-pyrrolidinone, -C(O)NH 2 -C(O)NH(C 1 -C 2 Alkyl), -C(O)N(C 1 -C 2 Alkyl) 2 -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -OC 3 -C 6 Cycloalkyl, and -SC 3 -C 6 Selected from the cycloalkyl group, where -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -OC 3 -C 6 Cycloalkyl, and -SC 3 -C 6 The cycloalkyl ring of a cycloalkyl group can be H, OH, oxo (=O), halogen, or C. 1 -C 4 Alkyl, -OC 1 -C 4 Alkyl, -SC 1 -C 4 Alkyl, -SO 2 -C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Haloalkyl, -SC 1 -C 4 Haloalkyl, SF 3 ,-SCIENCE FICTION 5 , CN, NO 2 , -SO 2 -NH 2 , -SO 2 -NH(C 1 -C 4 Alkyl), -SO 2 -N(C 1 -C 4 Alkyl) 2 -C(O)NH 2 -C(O)NH(C 1 -C 4 alkyl), and -C(O)N(C 1 -C 4 Alkyl) 2 It is further substituted with 0, 1, 2, or 3 substituents selected from the group; R 10 However, H, halogen, C 1 -C 6 Alkyl, -OC 1 -C 6 Alkyl, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Haloalkyl and -SC 1 -C 4 Selected from the group of haloalkyls, The compound according to claim 5, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

8. The compound according to claim 1 of formula (III): And in the formula: R 1 However, it is selected from the group of H, F, and Cl; R 3 , R 4 , and R 5 Each of these is independent of H, halogen, and C. 1 -C 4 Alkyl, -OC 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Haloalkyl, -S-CF 3 ,-SCIENCE FICTION 5 CN, 2-pyrrolidinone, -C(O)NH 2 -C(O)NH(C 1 -C 4 Alkyl), -C(O)N(C 1 -C 4 Alkyl) 2 -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -OC 3 -C 6 Cycloalkyl, and -SC 3 -C 6 Selected from the cycloalkyl group, where -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -OC 3 -C 6 Cycloalkyl, and -SC 3 -C 6 The cycloalkyl ring of a cycloalkyl group can be H, OH, oxo (=O), halogen, or C. 1 -C 4 Alkyl, -OC 1 -C 4 Alkyl, -SC 1 -C 4 Alkyl, -SO 2 -C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Haloalkyl, -SC 1 -C 4 Haloalkyl, SF 3 ,-SCIENCE FICTION 5 , CN, NO 2 , -SO 2 -NH 2 , -SO 2 -NH(C 1 -C 4 Alkyl), -SO 2 -N(C 1 -C 4 Alkyl) 2 -C(O)NH 2 -C(O)NH(C 1 -C 4 alkyl), and -C(O)N(C 1 -C 4 Alkyl) 2 It is further substituted with 0, 1, 2, or 3 substituents selected from the group; However, R 10 If H, then R 3 , R 4 , and R 5 At least one of them is not H, Compounds, or their pharmaceutically acceptable salts, cocrystals, esters, solvates, hydrates, isomers (including optical isomers, racemates, or other mixtures thereof), tautomers, isotopes, polymorphs, or pharmaceutically acceptable prodrugs.

9. R3 is independently selected from the group consisting of C1-C3 haloalkyl, H, halogen, C1-C3 alkyl, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -S-CF3, -SF5, CN, 2-pyrrolizinone, -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, -OC3-C6 cycloalkyl, and -SC3-C6 cycloalkyl, where -C(O)NH(C3-C6 cycloalkyl), -C(O)NH(-CH2 The cycloalkyl rings of -C3-C6 cycloalkyl, -OC3-C6 cycloalkyl, and -SC3-C6 cycloalkyl groups include H, OH, oxo (=O), halogen, C1-C4 alkyl, -OC1-C4 alkyl, -SC1-C4 alkyl, -SO2-C1-C4 alkyl, C1-C4 haloalkyl, -OC1-C4 haloalkyl, -SC1-C4 haloalkyl, SF3, -SF5, CN, NO2, -SO2-NH2, -SO2-NH(C1-C4 alkyl), -SO2-N(C1-C4 alkyl)2, -C(O)NH2, and -C(O)NH(C1-C4 It is further substituted with 0, 1, 2, or 3 substituents selected from the group of alkyl and -C(O)N(C1-C4 alkyl)2; and R 4, and R 5 Each of these is independent of H, halogen, and C. 1 -C 3 Alkyl, -OC 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, -OC 1 -C 3 Haloalkyl, -S-CF 3 ,-SCIENCE FICTION 5 CN, 2-pyrrolidinone, -C(O)NH 2 -C(O)NH(C 1 -C 3 Alkyl), -C(O)N(C 1 -C 3 Alkyl) 2 -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -OC 3 -C 6 Cycloalkyl, and -SC 3 -C 6 Selected from the cycloalkyl group, where -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -OC 3 -C 6 Cycloalkyl, and -SC 3 -C 6 The cycloalkyl ring of a cycloalkyl group can be H, OH, oxo (=O), halogen, or C. 1 -C 4 Alkyl, -OC 1 -C 4 Alkyl, -SC 1 -C 4 Alkyl, -SO 2 -C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Haloalkyl, -SC 1 -C 4 Haloalkyl, SF 3 ,-SCIENCE FICTION 5 , CN, NO 2 , -SO 2 -NH 2 , -SO 2 -NH(C 1 -C 4 Alkyl), -SO 2 -N(C 1 -C 4 Alkyl) 2 -C(O)NH 2 -C(O)NH(C 1 -C 4 alkyl), and -C(O)N(C 1 -C 4 Alkyl) 2 Further substituted with 0, 1, 2, or 3 substituents selected from the group, The compound according to claim 8, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

10. R3 is independently selected from the group consisting of C1-C2 haloalkyl, H, halogen, C1-C2 alkyl, -OC1-C2 alkyl, -OC1-C2 haloalkyl, -S-CF3, -SF5, CN, 2-pyrrolizinone, -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, -OC3-C6 cycloalkyl, and -SC3-C6 cycloalkyl, where -C(O)NH(C3-C6 cycloalkyl), -C(O)NH(-CH2 The cycloalkyl rings of -C3-C6 cycloalkyl, -OC3-C6 cycloalkyl, and -SC3-C6 cycloalkyl groups include H, OH, oxo (=O), halogen, C1-C4 alkyl, -OC1-C4 alkyl, -SC1-C4 alkyl, -SO2-C1-C4 alkyl, C1-C4 haloalkyl, -OC1-C4 haloalkyl, -SC1-C4 haloalkyl, SF3, -SF5, CN, NO2, -SO2-NH2, -SO2-NH(C1-C4 alkyl), -SO2-N(C1-C4 alkyl)2, -C(O)NH2, and -C(O)NH(C1-C4 It is further substituted with 0, 1, 2, or 3 substituents selected from the group of alkyl and -C(O)N(C1-C4 alkyl)2; R 4, and R 5 Each of these is independent of H, halogen, and C. 1 -C 2 Alkyl, -OC 1 -C 2 Alkyl, C 1 -C 2 Haloalkyl, -OC 1 -C 2 Haloalkyl, -S-CF 3 ,-SCIENCE FICTION 5 CN, 2-pyrrolidinone, -C(O)NH 2 -C(O)NH(C 1 -C 2 Alkyl), -C(O)N(C 1 -C 2 Alkyl) 2 -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -OC 3 -C 6 Cycloalkyl, and -SC 3 -C 6 Selected from the cycloalkyl group, where -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -OC 3 -C 6 Cycloalkyl, and -SC 3 -C 6 The cycloalkyl ring of a cycloalkyl group can be H, OH, oxo (=O), halogen, or C. 1 -C 4 Alkyl, -OC 1 -C 4 Alkyl, -SC 1 -C 4 Alkyl, -SO 2 -C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, -OC 1 -C 4 Haloalkyl, -SC 1 -C 4 Haloalkyl, SF 3 ,-SCIENCE FICTION 5 , CN, NO 2 , -SO 2 -NH 2 , -SO 2 -NH(C 1 -C 4 Alkyl), -SO 2 -N(C 1 -C 4 Alkyl) 2 -C(O)NH 2 -C(O)NH(C 1 -C 4 alkyl), and -C(O)N(C 1 -C 4 Alkyl) 2 Further substituted with 0, 1, 2, or 3 substituents selected from the group, The compound according to claim 8, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

11. R3 is independently selected from the group -O-CH2F, -O-CHF2, -O-CF3, H, halogen, methyl, methoxy, CH2F, CHF2, 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, -OC3-C6 cycloalkyl, and -SC3-C6 cycloalkyl, where -C(O)NH(C3-C6 The cycloalkyl rings of -C(O)NH(-CH2-C3-C6 cycloalkyl), C3-C6 cycloalkyl, -OC3-C6 cycloalkyl, and -SC3-C6 cycloalkyl are H, OH, oxo (=O), halogen, C1-C4 alkyl, -OC1-C4 alkyl, -SC1-C4 alkyl, -SO2-C1-C4 alkyl, C1-C4 haloalkyl, -OC1-C4 haloalkyl, -SC1-C4 haloalkyl, SF3, -SF5, CN, NO2, -SO2-NH2, -SO2-NH(C1-C4 alkyl), -SO2-N(C1-C4 alkyl)2, -C(O)NH2 It is further substituted with 0, 1, 2, or 3 substituents selected from the group -C(O)NH(C1-C4 alkyl) and -C(O)N(C1-C4 alkyl)2; R 4, and R 5 Each of these independently represents H, halogen, methyl, methoxy, and CH. 2 F, CHF 2 , CF 3 ,-O-CH 2 F, -O-CHF 2 , -O-CF 3 -S-CF 3 ,-SCIENCE FICTION 5 CN, 2-pyrrolidinone, -C(O)NH 2 -C(O)NH(C 1 -C 2 Alkyl), -C(O)N(C 1 -C 2 Alkyl) 2 -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -OC 3 -C 6 Cycloalkyl, and -SC 3 -C 6 Selected from the cycloalkyl group, where -C(O)NH(C 3 -C 6 Cycloalkyl), -C(O)NH(-CH 2 -C 3 -C 6 Cycloalkyl), C 3 -C 6 Cycloalkyl, -OC 3 -C 6 Cycloalkyl, and -SC 3 -C 6 The cycloalkyl ring of a cycloalkyl group can be H, OH, oxo (=O), halogen, or C. 1 -C 4 Alkyl, -OC 1 -C 4 Alkyl, -SC 1 -C 4 Alkyl, -SO 2 -C 1 -C 4 Alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 haloalkyl, -S-C 1 -C 4 haloalkyl, SF 3 、-SF 5 、CN, NO 2 、-SO 2 -NH 2 、-SO 2 -NH(C 1 -C 4 alkyl), -SO 2 -N(C 1 -C 4 alkyl) 2 、-C(O)NH 2 、-C(O)NH(C 1 -C 4 alkyl), and -C(O)N(C 1 -C 4 alkyl) 2 further substituted with 0, 1, 2, or 3 substituents selected from the group of The compound according to claim 8, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

12. A compound according to claim 1, selected from the following group: or its pharmaceutically acceptable salts, cocrystals, esters, solvates, hydrates, isomers (including optical isomers, racemates, or other mixtures thereof), tautomers, isotopes, polymorphs, or pharmaceutically acceptable prodrugs.

13. A pharmaceutical composition comprising a pharmaceutically or therapeutically effective amount of a compound selected from any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug.

15. A pharmaceutical composition for the treatment of parasitic diseases (e.g., malaria, toxoplasmosis, or babesiosis) comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates, or other mixtures thereof), tautomer, isotope, polymorph, or pharmaceutically acceptable prodrug thereof.

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