Substituted biaryl oxopolyoctylquinolones with enhanced antiparasitic activity

Abstract

Provided herein are oxdoxine-like quinolone (ELQ) compounds of Formula (I): or a pharmaceutically acceptable salt thereof, as well as pharmaceutical compositions comprising the compounds and methods for using the compounds to treat or prevent parasitic diseases, including malaria, toxoplasmosis, and babesiosis. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to novel biaryl endochin-like quinolone (ELQ) compounds that can be used to treat or prevent parasitic diseases, including malaria, toxoplasmosis and babesiosis.

[0002] Government Support Statement

[0003] This invention was made with government support under Grants R01AI100569 and R01 AI141412 from the National Institutes of Health and Grant W81XWH-19-2-0031 from the US Department of Defense. The government has certain rights in this invention. Background Art

[0004] In 2020, an estimated 241 million cases of malaria occurred globally, with approximately 93% of these cases occurring on the African continent. In the same year, an estimated 627,000 deaths were attributed to malaria worldwide, with children accounting for approximately 77% of all malaria deaths worldwide. These figures indicate an increase in cases and deaths compared to previous years due to disruptions in health care delivery caused by the ongoing COVID pandemic. 1 Before the pandemic and over the past two decades, the World Health Organization (WHO) noted a steady decline in cases and deaths around the world, largely due to increased vector control measures and the use of bed nets, as well as the introduction of artemisinin combination therapies (ACTs). Now, the situation has become complicated, not only by the surge in the COVID-19 pandemic, but also by the 2 and Africa 3 Resistance to ACTs has emerged in regions where resistance to first-line antimalarials such as chloroquine, mefloquine, amodiaquine, antifolates, and quinine has become entrenched. Therefore, despite an overall downward trend in malaria deaths, new medicines are urgently needed to address multidrug resistance and contribute to global eradication efforts.

[0005] To meet the challenges of today's evolving antimalarial drug resistance landscape and make progress towards the global goal of malaria eradication, Medicines for Malaria Venture (MMV) has created a list of desired Target Product Profiles (TPPs) and associated Target Candidate Profiles (TCPs) that provide valuable guidance (or "roadmap") needed to achieve the ultimate eradication goal. 4,5 In the present invention, the present invention relates to a kind of medicine that can be used for the treatment of acute but uncomplicated malaria and quick-acting parenteral preparation and is suitable for the new oral medication of serious and complicated disease.There are also TPPs for the medicine that can be used for chemoprevention, in described TPPs, medicine will be given to the object or particularly vulnerable colony (for example, pregnant women and children) that moves to high malaria endemic area or is in epidemic period.And in these TPPs, the drug molecule with TCP is described, to fill the concrete vacancy in the treatment and / or prevention pharmacopoeia of new and available medicine.This type of TCP comprises the medicine of removing asexual blood stage parasite (TCP-1), or the molecule that targets the latent liver stage hypnotic daughter (TCP-3) of malarial parasite (vivax) and foramen ovale (ovale) or replicates the liver schizont (TCP-4) of all malarial species and the medicine of propagation (TCP-5) in the blood or in the insect vector. Recently, MMV described a new TPP for a long-acting injectable (LAI-C) for treatment and chemoprophylaxis over a 2- to 4-month period to protect against seasonal malaria or in the setting of an epidemic. 5 .

[0006]

[0007] Figure 1: Coenzyme Q 10 , Nendoxin, ELQ-300, ELQ-331, ELQ-596 and ELQ-598 structures.

[0008] More than 10 years ago, ELQ-300 (Figure 1) was discovered as part of a research alliance with MMV to optimize the first umami for human use. 6 Like all known cytochrome bc1 inhibitors, ELQ-300 is a coenzyme Q 10 Since its discovery, almost everything we have learned about ELQ-300 suggests that it will be a highly valuable tool to add to the antimalarial toolbox to prevent and treat malaria and interrupt transmission. 6 Distinguishing properties of the drug include: low nM IC relative to multidrug-resistant strains including field isolates of P. falciparum; 50; Pan-malarial activity against various Plasmodium species that infect humans 7 ; For the liver 6 Potent activity against replicating parasites in the blood and vector infection stages 6 ; Q of Plasmodium falciparum cytochrome bc1 complex i Novel and selective targeting of sites 8 Excellent metabolic stability and extended pharmacokinetics in preclinical species (mice, rats, and dogs); and a clean safety profile 6 While this was enough for ELQ-300 to be selected as a preclinical candidate by MMV in 2012, its further development was derailed in 2014 when it was removed from the pipeline due to high crystallinity, which limited absorption and hampered the determination of the in vivo therapeutic index required for regulatory approval. Fortunately, this issue was resolved and interest in ELQ-300 was renewed with the reintroduction of a prodrug with significantly reduced crystallinity (ELQ-331, Figure 1), which improved oral bioavailability and enhanced overall antimalarial properties. 9 ELQ-331 was accepted by MMV as a preclinical candidate in October 2020. Since then, MMV has developed an oral formulation of ELQ-331 and recently described a low-cost and scalable synthetic route for the core molecule ELQ-300, which increases the feasibility of developing this drug for human use. 10 As a result, the prodrug ELQ-331 continues to advance through the MMV clinical development pipeline.

[0009] There remains a need to discover and develop new ELQ compounds with improved intrinsic potency, selectivity, pharmacokinetic properties and / or efficacy. Summary of the Invention

[0010] One embodiment provides a compound of formula (I):

[0011]

[0012] in:

[0013] R 1a 、R 1b and R 1c Each of which is independently selected from the group consisting of: H, halogen, CN, C1-C6 alkyl, and C1-C6 alkoxy;

[0014] R2 is selected from the group consisting of:

[0015] a) Oxo (=O);

[0016] b) -OH;

[0017] c) -O-CH2-OC(=O)-O-R6;

[0018] d) -O-CH2-CH2-OC(=O)-O-R6;

[0019] e)-O-CH2(CH3)-OC(=O)-O-R6;

[0020] f)-OC(=O)-CH2-CH2-C(=O)-O-R6;

[0021] g) -O-CH2-OC(=O)-R6;

[0022] h) -O-(C=O)-R7;

[0023] i) -O-(C=O)-O-R7;

[0024] j)-OC(O)-NR8R9;

[0025] k)-O-CH2-OC(O)-O-(CH2) n1 -NR8R9;

[0026] l)-O-CH2-OC(O)-O-(CH2) n1 -NR8-C(=O)-O-R9; and

[0027] m)-O-(CH2)-O-PO3;

[0028] The dashed line (-----) in each example represents an optional single or double bond;

[0029] Z is selected from the group consisting of H and C; and

[0030] R3, R4 and R5 are each independently selected from the group consisting of H, halogen, C1-C4 alkyl, -O-C1-C4 alkyl, -S-C1-C4 alkyl, -SO2-C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, -S-C1-C4 haloalkyl, SF3, -SF5, CN, NO2, -SO2-NH2, -SO2-NH(C1-C4 alkyl), -S O2-N(C1-C4 alkyl)2, -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, 2-pyrrolidone, -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 -C(O)NH(C The cycloalkyl ring of said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said -O-C3-C6 cycloalkyl and said -S-C3-C6 cycloalkyl 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 -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;

[0031] 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 heterocyclic group, -(CH2) n1 -3-6 membered heterocyclic group, phenyl group, -(CH2) n1 -phenyl and -(CH2) n1 -NR8R9;

[0032] 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 heterocyclic group), phenyl group, -(CH2) n1 -phenyl, -(CH2) n1 -O-(CH2) n2 -C1-C2 alkyl, -(CH2-CH2-O) n1 -C1-C2 alkyl and -(CH2) n1 -NR8R9;

[0033] R8 and R9 are each independently selected from the group consisting of H and C1-C6 alkyl;

[0034] R 10 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;

[0035] R 11 Selected from H, OH and O - the groups formed;

[0036] n1 and n2 are each an integer independently selected from the group consisting of: 1, 2, 3, 4, 5, and 6; and

[0037] n3 is an integer selected from the group consisting of: 0, 1, 2, 3, 4, 5, and 6;

[0038] 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-7-methoxy-2-methyl-4(1H)-quinolinone (CAS Reg. No. 1354745-39-3), 1H-quinolinone (CAS Reg. No. 1374758-04-9);

[0039] 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. DETAILED DESCRIPTION

[0040] One embodiment provides a compound of formula (I), wherein R2 is selected from the group consisting of:

[0041] a) Oxo (=O);

[0042] b) -OH;

[0043] c) -O-CH2-OC(=O)-O-R6;

[0044] d) -O-CH2-CH2-OC(=O)-O-R6;

[0045] e)-O-CH2(CH3)-OC(=O)-O-R6;

[0046] f) -OC(=O)-CH2-CH2-C(=O)-O-R6; and

[0047] g) -O-CH2-OC(=O)-R6; and

[0048] R 1a 、R 1b 、R 1c , R3, R4, R5, R6, R8, R9, R 10 and R 11 As defined above for formula (I); or a pharmaceutically acceptable salt thereof.

[0049] It should be understood that The X variable is marked with a wavy line A crossed floating bond represents a benzene ring, pyridine ring, or pyridine ring that is bound to an adjacent benzene ring through one of its five available carbon atoms, as seen in the following example:

[0050]

[0051] It should also be understood that in each example, the dashed lines between the ring nitrogen and the 2-carbon atom, between the 2-carbon atom and the 3-carbon atom, and between the 3-carbon atom and the 4-carbon atom of the quinoline ring represent an optional single bond or an optional double bond, depending on the valence of the R2 substituent, as represented by the oxo group and hydroxyl group in the non-limiting exemplary structures below.

[0052]

[0053] Another embodiment provides a compound of formula (I), wherein R2 is selected from the group consisting of:

[0054] a) Oxo (=O);

[0055] b) -OH;

[0056] c) -O-CH2-OC(=O)-O-R6;

[0057] d) -O-CH2-CH2-OC(=O)-O-R6; and

[0058] e) -O-CH2(CH3)-OC(=O)-O-R6; and

[0059] R1, R3, R4, R5, R6, R8, R9, R 10 and R 11 As defined above for formula (I); or a pharmaceutically acceptable salt thereof.

[0060] Another embodiment provides a compound of formula (I), wherein:

[0061] R1 is selected from the group consisting of H, F and Cl;

[0062] R2 is selected from the group consisting of oxo (=O) and a moiety of the formula -O-CH2-OC(=O)-O-(C1-C6 alkyl);

[0063] Z is selected from the group consisting of H and C; and

[0064] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl The alkyl group, the -O-C3-C6 cycloalkyl group, and the cycloalkyl ring of the -S-C3-C6 cycloalkyl group 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

[0065] R6, R7, R8, R9, R 10 and R 11 As defined above for formula (I); and

[0066] provided that, when R2 is selected from the group consisting of oxo (=O), then at least one of R3, R4 and R5 is not H;

[0067] or a pharmaceutically acceptable salt thereof.

[0068] Another embodiment provides a compound of formula (I): wherein:

[0069] R1 is selected from the group consisting of H, F and Cl;

[0070] R2 is selected from the group consisting of oxo (=O) and a moiety of the formula -O-CH2-OC(=O)-O-(C1-C4 alkyl);

[0071] Z is selected from the group consisting of H and C;

[0072] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl The alkyl group, the -O-C3-C6 cycloalkyl group, and the cycloalkyl ring of the -S-C3-C6 cycloalkyl group 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

[0073] R6, R7, R8, R9, R 10 and R 11 As defined above for formula (I); and

[0074] provided that, when R2 is selected from the group consisting of oxo (=O), then at least one of R3, R4 and R5 is not H;

[0075] or a pharmaceutically acceptable salt thereof.

[0076] Another embodiment provides a compound of formula (I): wherein:

[0077] R1 is selected from the group consisting of H, F and Cl;

[0078] R2 is selected from the group consisting of oxo (=O) and a moiety of the formula -O-CH2-OC(=O)-O-(C1-C3 alkyl);

[0079] Z is selected from the group consisting of H and C; and

[0080] R3, R4 and R5 are each independently selected from the group consisting of H, halogen, methyl, methoxy (-O-CH3), CH2F, CHF2, CF3, -O-CH2F, -O-CHF2, -O-CF3, -S-CF3, -SF5, CN, 2-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C The cycloalkyl ring of the -C-C6 cycloalkyl, the -O-C-C6 cycloalkyl and the -S-C-C6 cycloalkyl 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

[0081] R6, R7, R8, R9, R 10 and R 11 As defined above for formula (I); and

[0082] provided that, when R2 is selected from the group consisting of oxo (=O), then at least one of R3, R4 and R5 is not H;

[0083] or a pharmaceutically acceptable salt thereof.

[0084] Another embodiment provides a compound of formula (II):

[0085]

[0086] in:

[0087] R1 is selected from the group consisting of H, F and Cl;

[0088] R2 is selected from the group consisting of oxo (=O) and -O-CH2-OC(=O)-O-(C1-C 10 alkyl) moieties;

[0089] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 The cycloalkyl group, the -O-C3-C6 cycloalkyl group, and the -S-C3-C6 cycloalkyl group 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;

[0090] 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

[0091] The dashed line (-----) in each example represents an optional single or double bond;

[0092] provided that, when R2 is selected from the group consisting of oxo (=O), then at least one of R3, R4 and R5 is not H;

[0093] or a pharmaceutically acceptable salt thereof.

[0094] Another embodiment provides a compound of formula (II), wherein:

[0095] R1 is selected from the group consisting of H, F and Cl;

[0096] R2 is selected from the group consisting of oxo (=O) and a moiety of the formula -O-CH2-OC(=O)-O-(C1-C6 alkyl);

[0097] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl The alkyl group, the -O-C3-C6 cycloalkyl group, and the cycloalkyl ring of the -S-C3-C6 cycloalkyl group 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

[0098] The dashed line (-----) in each example represents an optional single or double bond;

[0099] R 10 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;

[0100] provided that, when R2 is selected from the group consisting of oxo (=O), then at least one of R3, R4 and R5 is not H;

[0101] or a pharmaceutically acceptable salt thereof.

[0102] Another embodiment provides a compound of formula (II), wherein:

[0103] R1 is selected from the group consisting of H, F and Cl;

[0104] R2 is selected from the group consisting of oxo (=O) and a moiety of formula -O-CH2-OC(=O)-O-(C1-C4 alkyl); and

[0105] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 The cycloalkyl group, the -O-C3-C6 cycloalkyl group, and the -S-C3-C6 cycloalkyl group 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;

[0106] 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

[0107] The dashed line (-----) in each example represents an optional single or double bond;

[0108] provided that, when R2 is selected from the group consisting of oxo (=O), then at least one of R3, R4 and R5 is not H;

[0109] or a pharmaceutically acceptable salt thereof.

[0110] Another embodiment provides a compound of formula (II), wherein:

[0111] R1 is selected from the group consisting of H, F and Cl;

[0112] R2 is selected from the group consisting of oxo (=O) and a moiety of the formula -O-CH2-OC(=O)-O-(C1-C3 alkyl); and

[0113] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl wherein the cycloalkyl ring of the -O-C3-C6 cycloalkyl, the -O-C3-C6 cycloalkyl and the -S-C3-C6 cycloalkyl 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;

[0114] 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

[0115] The dashed line (-----) in each example represents an optional single or double bond;

[0116] provided that, when R2 is selected from the group consisting of oxo (=O), then at least one of R3, R4 and R5 is not H;

[0117] or a pharmaceutically acceptable salt thereof.

[0118] Various embodiments provide a compound of formula (III):

[0119]

[0120] in:

[0121] R1 is selected from the group consisting of H, F and Cl;

[0122] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 The cycloalkyl group, the -O-C3-C6 cycloalkyl group, and the -S-C3-C6 cycloalkyl group 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;

[0123] 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

[0124] The dashed line (-----) in each example represents an optional single or double bond;

[0125] The condition is that in R 10 When it is H, at least one of R3, R4 and R5 is not H;

[0126] or a pharmaceutically acceptable salt thereof.

[0127] Another embodiment provides a compound of formula (III), wherein:

[0128] R1 is selected from the group consisting of H, F and Cl;

[0129] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl The alkyl group, the -O-C3-C6 cycloalkyl group, and the cycloalkyl ring of the -S-C3-C6 cycloalkyl group 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

[0130] 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

[0131] The dashed line (-----) in each example represents an optional single or double bond;

[0132] The condition is that in R 10 When it is H, at least one of R3, R4 and R5 is not H;

[0133] or a pharmaceutically acceptable salt thereof.

[0134] Another embodiment provides a compound of formula (III), wherein:

[0135] R1 is selected from the group consisting of H, F and Cl; and

[0136] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 The cycloalkyl group, the -O-C3-C6 cycloalkyl group, and the -S-C3-C6 cycloalkyl group 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;

[0137] 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

[0138] The dashed line (-----) in each example represents an optional single or double bond;

[0139] The condition is that in R 10 When it is H, at least one of R3, R4 and R5 is not H;

[0140] or a pharmaceutically acceptable salt thereof.

[0141] Another embodiment provides a compound of formula (III), wherein:

[0142] R1 is selected from the group consisting of H, F and Cl; and

[0143] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl wherein the cycloalkyl ring of the -O-C3-C6 cycloalkyl, the -O-C3-C6 cycloalkyl and the -S-C3-C6 cycloalkyl 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;

[0144] 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

[0145] The dashed line (-----) in each example represents an optional single or double bond;

[0146] The condition is that in R 10 When it is H, at least one of R3, R4 and R5 is not H;

[0147] or a pharmaceutically acceptable salt thereof.

[0148] Two additional separate examples provide compounds of formula (III-A) and (III-B), respectively:

[0149]

[0150] Wherein in each individual embodiment:

[0151] R1 is selected from the group consisting of H, F and Cl;

[0152] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl The cycloalkyl group, the -O-C3-C6 cycloalkyl group and the -S-C3-C6 cycloalkyl group 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;

[0153] R 10 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;

[0154] The condition is that in R 10 When it is H, at least one of R3 and R4 is not H;

[0155] or a pharmaceutically acceptable salt thereof.

[0156] Two additional embodiments provide compounds of formula (III-A) and (III-B), respectively, wherein in each separate embodiment:

[0157] R1 is selected from the group consisting of H, F and Cl;

[0158] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl The alkyl group, the -O-C3-C6 cycloalkyl group, and the cycloalkyl ring of the -S-C3-C6 cycloalkyl group 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;

[0159] R 10 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;

[0160] The condition is that in R 10 When it is H, at least one of R3 and R4 is not H;

[0161] or a pharmaceutically acceptable salt thereof.

[0162] Two additional embodiments provide compounds of formula (III-A) and (III-B), respectively, wherein in each separate embodiment:

[0163] R1 is selected from the group consisting of H, F and Cl; and

[0164] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl The alkyl group, the -O-C3-C6 cycloalkyl group, and the cycloalkyl ring of the -S-C3-C6 cycloalkyl group 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;

[0165] R 10 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;

[0166] The condition is that in R 10 When it is H, at least one of R3 and R4 is not H;

[0167] or a pharmaceutically acceptable salt thereof.

[0168] Two additional embodiments provide compounds of formula (III-A) and (III-B), respectively, wherein in each separate embodiment:

[0169] R1 is selected from the group consisting of H, F and Cl; and

[0170] 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-pyrrolidone, -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;

[0171] R 10 Selected from the group consisting of: H, F, methyl, methoxy, CH2F, CHF2, CF3, -O-CH2F, -O-CHF2, -O-CF3 and -S-CF3;

[0172] The condition is that in R 10 When it is H, at least one of R3 and R4 is not H;

[0173] or a pharmaceutically acceptable salt thereof.

[0174] Two additional embodiments provide compounds of formula (III-A) and (III-B), respectively, wherein in each separate embodiment:

[0175] R1 is selected from the group consisting of H, F and Cl; and

[0176] 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;

[0177] R 10 Selected from the group consisting of: H, F, methyl, methoxy, CH2F, CHF2, CF3, -O-CH2F, -O-CHF2, -O-CF3 and -S-CF3;

[0178] The condition is that in R 10 When it is H, at least one of R3 and R4 is not H;

[0179] or a pharmaceutically acceptable salt thereof.

[0180] Two additional embodiments provide compounds of formula (III-A) and (III-B), respectively, wherein in each separate embodiment:

[0181] R1 is selected from the group consisting of H, F and Cl; and

[0182] 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;

[0183] R 10 Selected from the group consisting of: H, F, methyl, methoxy, CH2F, CHF2, CF3, -O-CH2F, -O-CHF2, -O-CF3 and -S-CF3;

[0184] The condition is that in R 10 When it is H, at least one of R3 and R4 is not H;

[0185] or a pharmaceutically acceptable salt thereof.

[0186] Two separate examples provide compounds of formula (III-A2) and (III-B2), respectively:

[0187]

[0188] Wherein in each individual embodiment:

[0189] R1 is selected from the group consisting of H, F and Cl;

[0190] R2 is selected from the group consisting of:

[0191] a) Oxo (=O);

[0192] b) -OH;

[0193] c) -O-CH2-OC(=O)-O-R6;

[0194] d) -O-CH2-CH2-OC(=O)-O-R6;

[0195] e)-O-CH2(CH3)-OC(=O)-O-R6;

[0196] f)-OC(=O)-CH2-CH2-C(=O)-O-R6;

[0197] g) -O-CH2-OC(=O)-R6;

[0198] h) -O-(C=O)-R7;

[0199] i) -O-(C=O)-O-R7;

[0200] j)-OC(O)-NR8R9;

[0201] k)-O-CH2-OC(O)-O-(CH2)n1 -NR8R9;

[0202] l)-O-CH2-OC(O)-O-(CH2) n1 -NR8-C(=O)-O-R9; and

[0203] m)-O-(CH2)-O-PO3;

[0204] The dashed line (-----) in each example represents an optional single or double bond;

[0205] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl The cycloalkyl group, the -O-C3-C6 cycloalkyl group and the -S-C3-C6 cycloalkyl group 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;

[0206] 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 heterocyclic group, -(CH2) n1 -3-6 membered heterocyclic group, phenyl group, -(CH2) n1 -phenyl and -(CH2) n1 -NR8R9;

[0207] 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 heterocyclic group), phenyl group, -(CH2) n1 -phenyl, -(CH2) n1 -O-(CH2) n2 -C1-C2 alkyl, -(CH2-CH2-O) n1 -C1-C2 alkyl and -(CH2) n1 -NR8R9;

[0208] R8 and R9 are each independently selected from the group consisting of H and C1-C6 alkyl;

[0209] R 10 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;

[0210] R 11 Selected from H, OH and O - the groups formed;

[0211] n1 and n2 are each an integer independently selected from the group consisting of: 1, 2, 3, 4, 5, and 6; and

[0212] n3 is an integer selected from the group consisting of: 0, 1, 2, 3, 4, 5, and 6;

[0213] or a pharmaceutically acceptable salt thereof.

[0214] Two additional embodiments provide compounds of formula (III-A2) and (III-B2), respectively, wherein in each separate embodiment:

[0215] R1, R2, R6, R7, R8, R9, R 10 、R 11 Each of n1, n2, n3 and the dashed line is as defined above for Formulas (III-A2) and (III-B2);

[0216] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl The alkyl group, the -O-C3-C6 cycloalkyl group, and the cycloalkyl ring of the -S-C3-C6 cycloalkyl group 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;

[0217] R 10 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;

[0218] The condition is that in R 10 When it is H, at least one of R3 and R4 is not H;

[0219] or a pharmaceutically acceptable salt thereof.

[0220] Two additional embodiments provide compounds of formula (III-A2) and (III-B2), respectively, wherein in each separate embodiment:

[0221] R1, R2, R6, R7, R8, R9, R 10 、R 11 Each of n1, n2, n3 and the dashed line is as defined above for Formulas (III-A2) and (III-B2);

[0222] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl The alkyl group, the -O-C3-C6 cycloalkyl group, and the cycloalkyl ring of the -S-C3-C6 cycloalkyl group 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;

[0223] R 10 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;

[0224] The condition is that in R 10 When it is H, at least one of R3 and R4 is not H;

[0225] or a pharmaceutically acceptable salt thereof.

[0226] Two additional embodiments provide compounds of formula (III-A2) and (III-B2), respectively, wherein in each separate embodiment:

[0227] R1, R2, R6, R7, R8, R9, R 10 、R 11 Each of n1, n2, n3 and the dashed line is as defined above for Formulas (III-A2) and (III-B2);

[0228] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 The cycloalkyl group, the -O-C3-C6 cycloalkyl group, and the -S-C3-C6 cycloalkyl group 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;

[0229] R 10 Selected from the group consisting of: H, F, methyl, methoxy, CH2F, CHF2, CF3, -O-CH2F, -O-CHF2, -O-CF3 and -S-CF3;

[0230] The condition is that in R 10 When it is H, at least one of R3 and R4 is not H;

[0231] or a pharmaceutically acceptable salt thereof.

[0232] Two additional embodiments provide compounds of formula (III-A2) and (III-B2), respectively, wherein in each separate embodiment:

[0233] R1, R2, R6, R7, R8, R9, R 10 、R 11 Each of n1, n2, n3 and the dashed line is as defined above for Formulas (III-A2) and (III-B2);

[0234] 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;

[0235] R 10 Selected from the group consisting of: H, F, methyl, methoxy, CH2F, CHF2, CF3, -O-CH2F, -O-CHF2, -O-CF3 and -S-CF3;

[0236] The condition is that in R 10 When it is H, at least one of R3 and R4 is not H;

[0237] or a pharmaceutically acceptable salt thereof.

[0238] Two additional embodiments provide compounds of formula (III-A2) and (III-B2), respectively, wherein in each separate embodiment:

[0239] R1, R2, R6, R7, R8, R9, R 10 、R 11 Each of n1, n2, n3 and the dashed line is as defined above for Formulas (III-A2) and (III-B2);

[0240] 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;

[0241] R 10 Selected from the group consisting of: H, F, methyl, methoxy, CH2F, CHF2, CF3, -O-CH2F, -O-CHF2, -O-CF3 and -S-CF3;

[0242] The condition is that in R 10 When it is H, at least one of R3 and R4 is not H;

[0243] or a pharmaceutically acceptable salt thereof.

[0244] Another embodiment provides a compound of formula (IV):

[0245]

[0246] in:

[0247] R1 is selected from the group consisting of H, F and Cl; and

[0248] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said -O-C3-C6 cycloalkyl and the cycloalkyl ring of said -S-C3-C6 cycloalkyl 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;

[0249] R 10 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;

[0250] or a pharmaceutically acceptable salt thereof.

[0251] Another embodiment provides a compound of formula (IV), wherein:

[0252] R1 is selected from the group consisting of H, F and Cl; and

[0253] 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-pyrrolidone, 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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said -O-C3-C6 cycloalkyl and the cycloalkyl ring of said -S-C3-C6 cycloalkyl 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;

[0254] or a pharmaceutically acceptable salt thereof.

[0255] Another embodiment provides a compound of formula (IV), wherein:

[0256] R1 is selected from the group consisting of H, F and Cl; and

[0257] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said -O-C3-C6 cycloalkyl and the cycloalkyl ring of said -S-C3-C6 cycloalkyl 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;

[0258] R 10 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;

[0259] or a pharmaceutically acceptable salt thereof.

[0260] Another further embodiment provides a compound of formula (IV), wherein:

[0261] R1 is Cl; and

[0262] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said -O-C3-C6 cycloalkyl and the cycloalkyl ring of said -S-C3-C6 cycloalkyl 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;

[0263] R 10 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;

[0264] or a pharmaceutically acceptable salt thereof.

[0265] Yet another embodiment provides a compound of formula (IV): wherein:

[0266] R1 is Cl; and

[0267] 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;

[0268] R 10 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;

[0269] or a pharmaceutically acceptable salt thereof.

[0270] Another embodiment provides a compound of formula (IV), wherein:

[0271] R1 is Cl; and

[0272] 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;

[0273] R 10 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;

[0274] or a pharmaceutically acceptable salt thereof.

[0275] Another embodiment provides a compound of formula (V):

[0276]

[0277] in:

[0278] R1 is selected from the group consisting of H, F and Cl; and

[0279] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said -O-C3-C6 cycloalkyl and the cycloalkyl ring of said -S-C3-C6 cycloalkyl 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;

[0280] R 10 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;

[0281] or a pharmaceutically acceptable salt thereof.

[0282] Another embodiment provides a compound of formula (V), wherein:

[0283] R1 is selected from the group consisting of H, F and Cl; and

[0284] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said -O-C3-C6 cycloalkyl and the cycloalkyl ring of said -S-C3-C6 cycloalkyl 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;

[0285] R 10 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;

[0286] or a pharmaceutically acceptable salt thereof.

[0287] Another embodiment provides a compound of formula (V), wherein:

[0288] R1 is selected from the group consisting of H, F and Cl; and

[0289] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said -O-C3-C6 cycloalkyl and the cycloalkyl ring of said -S-C3-C6 cycloalkyl 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;

[0290] R 10 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;

[0291] or a pharmaceutically acceptable salt thereof.

[0292] Another further embodiment provides a compound of formula (V), wherein:

[0293] R1 is Cl; and

[0294] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said -O-C3-C6 cycloalkyl and the cycloalkyl ring of said -S-C3-C6 cycloalkyl 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;

[0295] R 10 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;

[0296] or a pharmaceutically acceptable salt thereof.

[0297] Yet another embodiment provides a compound of formula (V): wherein:

[0298] R1 is Cl; and

[0299] 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;

[0300] R 10 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;

[0301] or a pharmaceutically acceptable salt thereof.

[0302] Another embodiment provides a compound of formula (V), wherein:

[0303] R1 is Cl; and

[0304] 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;

[0305] R 10 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;

[0306] or a pharmaceutically acceptable salt thereof.

[0307] Various embodiments provide a compound of formula (VI):

[0308]

[0309] in:

[0310] R1 is selected from the group consisting of H, F and Cl;

[0311] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl The alkyl group, the -O-C3-C6 cycloalkyl group, and the cycloalkyl ring of the -S-C3-C6 cycloalkyl group 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

[0312] R6 is C1-C 10 alkyl;

[0313] R 10 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;

[0314] or a pharmaceutically acceptable salt thereof.

[0315] Another embodiment provides a compound of formula (VI), wherein:

[0316] R1 is selected from the group consisting of H, F and Cl; and

[0317] 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-pyrrolidone, -C(O)NH2, -C(O)NH(C1-C2 alkyl), -C(O)N(C1-C3 alkyl)3, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 The cycloalkyl group, the -O-C3-C6 cycloalkyl group, and the -S-C3-C6 cycloalkyl group 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;

[0318] R6 is a C1-C6 alkyl group;

[0319] R 10 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;

[0320] or a pharmaceutically acceptable salt thereof.

[0321] Another embodiment provides a compound of formula (VI), wherein:

[0322] R1 is selected from the group consisting of H, F and Cl; and

[0323] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl The alkyl group, the -O-C3-C6 cycloalkyl group, and the cycloalkyl ring of the -S-C3-C6 cycloalkyl group 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

[0324] R6 is a C1-C4 alkyl group;

[0325] R 10 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;

[0326] or a pharmaceutically acceptable salt thereof.

[0327] Another embodiment provides a compound of formula (VI), wherein:

[0328] R1 is selected from the group consisting of H, F and Cl;

[0329] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 The cycloalkyl group, the -O-C3-C6 cycloalkyl group, and the -S-C3-C6 cycloalkyl group 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

[0330] R6 is a C1-C3 alkyl group;

[0331] R 10 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;

[0332] or a pharmaceutically acceptable salt thereof.

[0333] Various embodiments provide a compound of formula (VII):

[0334]

[0335] in:

[0336] R1 is selected from the group consisting of H, F and Cl; and

[0337] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 The cycloalkyl group, the -O-C3-C6 cycloalkyl group, and the -S-C3-C6 cycloalkyl group 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;

[0338] R 10 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;

[0339] or a pharmaceutically acceptable salt thereof.

[0340] Another embodiment provides a compound of formula (VII), wherein:

[0341] R1 is Cl; and

[0342] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 The cycloalkyl group, the -O-C3-C6 cycloalkyl group, and the -S-C3-C6 cycloalkyl group 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;

[0343] R 10 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;

[0344] or a pharmaceutically acceptable salt thereof.

[0345] Another embodiment provides a compound of formula (VII), wherein:

[0346] R1 is selected from the group consisting of H, F and Cl; and

[0347] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 The cycloalkyl group, the -O-C3-C6 cycloalkyl group and the -S-C3-C6 cycloalkyl group 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 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;

[0348] or a pharmaceutically acceptable salt thereof.

[0349] Another embodiment provides a compound of formula (VII), wherein:

[0350] R1 is Cl; and

[0351] 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-pyrrolidone, -C(O)NH2, -C(O)NH(C1-C2 alkyl), -C(O)N(C1-C3 alkyl)3, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 The cycloalkyl group, the -O-C3-C6 cycloalkyl group, and the -S-C3-C6 cycloalkyl group 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;

[0352] R 10 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;

[0353] or a pharmaceutically acceptable salt thereof.

[0354] Another embodiment provides a compound of formula (VII), wherein:

[0355] R1 is selected from the group consisting of H, F and Cl; and

[0356] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 The cycloalkyl group, the -O-C3-C6 cycloalkyl group, and the -S-C3-C6 cycloalkyl group 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;

[0357] R 10 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;

[0358] or a pharmaceutically acceptable salt thereof.

[0359] Another embodiment provides a compound of formula (VII), wherein:

[0360] R1 is Cl; and

[0361] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 The cycloalkyl group, the -O-C3-C6 cycloalkyl group, and the -S-C3-C6 cycloalkyl group 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;

[0362] R 10 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;

[0363] or a pharmaceutically acceptable salt thereof.

[0364] Another embodiment provides a compound of formula (VII), wherein:

[0365] R1 is selected from the group consisting of H, F and Cl; and

[0366] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl wherein the cycloalkyl ring of the -O-C3-C6 cycloalkyl, the -O-C3-C6 cycloalkyl and the -S-C3-C6 cycloalkyl 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;

[0367] R 10 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;

[0368] or a pharmaceutically acceptable salt thereof.

[0369] Another embodiment provides a compound of formula (VII), wherein:

[0370] R1 is Cl; and

[0371] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl wherein the cycloalkyl ring of the -O-C3-C6 cycloalkyl, the -O-C3-C6 cycloalkyl and the -S-C3-C6 cycloalkyl 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;

[0372] R 10 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;

[0373] or a pharmaceutically acceptable salt thereof.

[0374] Another embodiment provides a compound of formula (VII), wherein:

[0375] R1 is Cl; and

[0376] 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;

[0377] R 10 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;

[0378] or a pharmaceutically acceptable salt thereof.

[0379] Various embodiments provide a compound of formula (VIII):

[0380]

[0381] in:

[0382] R1 is selected from the group consisting of H, F and Cl;

[0383] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, The cycloalkyl rings of the -O-C3-C6 cycloalkyl and the -S-C3-C6 cycloalkyl 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;

[0384] R6 is C1-C 10 alkyl;

[0385] R 10 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;

[0386] or a pharmaceutically acceptable salt thereof.

[0387] Another embodiment provides a compound of formula (VIII), wherein:

[0388] R1 is selected from the group consisting of H, F and Cl;

[0389] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said - The cycloalkyl ring of the O-C3-C6 cycloalkyl and the -S-C3-C6 cycloalkyl 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

[0390] R6 is a C1-C6 alkyl group;

[0391] R 10 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;

[0392] or a pharmaceutically acceptable salt thereof.

[0393] Another embodiment provides a compound of formula (VIII), wherein:

[0394] R1 is selected from the group consisting of H, F and Cl;

[0395] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said - The cycloalkyl ring of the O-C3-C6 cycloalkyl and the -S-C3-C6 cycloalkyl 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

[0396] R6 is a C1-C6 alkyl group;

[0397] R 10 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;

[0398] or a pharmaceutically acceptable salt thereof.

[0399] Another embodiment provides a compound of formula (VIII), wherein:

[0400] R1 is selected from the group consisting of H, F and Cl; and

[0401] 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;

[0402] R6 is a C1-C6 alkyl group;

[0403] R 10Selected 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;

[0404] or a pharmaceutically acceptable salt thereof.

[0405] Another embodiment provides a compound of formula (VIII), wherein:

[0406] R1 is selected from the group consisting of H, F and Cl; and

[0407] 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;

[0408] R6 is a C1-C6 alkyl group;

[0409] R 10 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;

[0410] or a pharmaceutically acceptable salt thereof.

[0411] Another embodiment provides a compound of formula (VIII), wherein:

[0412] R1 is Cl;

[0413] 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

[0414] R6 is a C1-C6 alkyl group;

[0415] R 10 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;

[0416] or a pharmaceutically acceptable salt thereof.

[0417] Another embodiment provides a compound of formula (VIII), wherein:

[0418] R1 is Cl;

[0419] 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

[0420] R6 is a C1-C4 alkyl group;

[0421] R 10 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;

[0422] or a pharmaceutically acceptable salt thereof.

[0423] Another embodiment provides a compound of formula (VIII), wherein:

[0424] R1 is Cl;

[0425] 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

[0426] R6 is ethyl;

[0427] R 10 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;

[0428] or a pharmaceutically acceptable salt thereof.

[0429] Various embodiments provide a compound of formula (IX):

[0430]

[0431] in:

[0432] R1 is selected from the group consisting of H, F and Cl;

[0433] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, The cycloalkyl rings of the -O-C3-C6 cycloalkyl and the -S-C3-C6 cycloalkyl 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;

[0434] R6 is C1-C 10 alkyl;

[0435] R 10 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;

[0436] or a pharmaceutically acceptable salt thereof.

[0437] Another embodiment provides a compound of formula (IX), wherein:

[0438] R1 is selected from the group consisting of H, F and Cl;

[0439] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said - The cycloalkyl ring of the O-C3-C6 cycloalkyl and the -S-C3-C6 cycloalkyl 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

[0440] R6 is a C1-C6 alkyl group;

[0441] R 10 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;

[0442] or a pharmaceutically acceptable salt thereof.

[0443] Another embodiment provides a compound of formula (IX), wherein:

[0444] R1 is selected from the group consisting of H, F and Cl;

[0445] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said - The cycloalkyl ring of the O-C3-C6 cycloalkyl and the -S-C3-C6 cycloalkyl 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

[0446] R6 is a C1-C6 alkyl group;

[0447] or a pharmaceutically acceptable salt thereof.

[0448] Another embodiment provides a compound of formula (IX), wherein:

[0449] R1 is selected from the group consisting of H, F and Cl; and

[0450] 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;

[0451] R6 is a C1-C6 alkyl group;

[0452] R 10 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;

[0453] or a pharmaceutically acceptable salt thereof.

[0454] Another embodiment provides a compound of formula (IX), wherein:

[0455] R1 is selected from the group consisting of H, F and Cl; and

[0456] 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;

[0457] R6 is a C1-C6 alkyl group;

[0458] R 10 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;

[0459] or a pharmaceutically acceptable salt thereof.

[0460] Another embodiment provides a compound of formula (IX), wherein:

[0461] R1 is Cl;

[0462] 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

[0463] R6 is a C1-C6 alkyl group;

[0464] R 10 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;

[0465] or a pharmaceutically acceptable salt thereof.

[0466] Another embodiment provides a compound of formula (IX), wherein:

[0467] R1 is Cl;

[0468] 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

[0469] R6 is a C1-C4 alkyl group;

[0470] R 10Selected 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;

[0471] or a pharmaceutically acceptable salt thereof.

[0472] Another embodiment provides a compound of formula (IX), wherein:

[0473] R1 is Cl;

[0474] 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

[0475] R6 is ethyl;

[0476] R 10 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;

[0477] or a pharmaceutically acceptable salt thereof.

[0478] Another embodiment provides a compound of formula (X):

[0479]

[0480] in:

[0481] R2 is selected from the group consisting of:

[0482] a) Oxo (=O);

[0483] b) -OH;

[0484] c) -O-CH2-OC(=O)-O-R6;

[0485] d) -O-CH2-CH2-OC(=O)-O-R6;

[0486] e)-O-CH2(CH3)-OC(=O)-O-R6;

[0487] f)-OC(=O)-CH2-CH2-C(=O)-O-R6;

[0488] g) -O-CH2-OC(=O)-R6;

[0489] h) -O-(C=O)-R7;

[0490] i) -O-(C=O)-O-R7;

[0491] j)-OC(O)-NR8R9;

[0492] k)-O-CH2-OC(O)-O-(CH2) n1 -NR8R9;

[0493] l)-O-CH2-OC(O)-O-(CH2) n1 -NR8-C(=O)-O-R9; and

[0494] m)-O-(CH2)-O-PO3;

[0495] The dashed line (-----) in each example represents an optional single or double bond;

[0496] 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 The cycloalkyl group, the -O-C3-C6 cycloalkyl group, and the -S-C3-C6 cycloalkyl group 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;

[0497] 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 heterocyclic group, -(CH2) n1 -3-6 membered heterocyclic group, phenyl group, -(CH2) n1 -phenyl and -(CH2) n1 -NR8R9;

[0498] 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 heterocyclic group), phenyl group, -(CH2) n1 -phenyl, -(CH2) n1 -O-(CH2) n2 -C1-C2 alkyl, -(CH2-CH2-O) n1 -C1-C2 alkyl and -(CH2) n1 -NR8R9;

[0499] R8 and R9 are each independently selected from the group consisting of H and C1-C6 alkyl;

[0500] R 11 Selected from H, OH and O - the groups formed;

[0501] n1 and n2 are each an integer independently selected from the group consisting of: 1, 2, 3, 4, 5, and 6; and

[0502] n3 is an integer selected from the group consisting of: 0, 1, 2, 3, 4, 5, and 6;

[0503] or a pharmaceutically acceptable salt thereof.

[0504] Additional embodiments include a compound of formula (X) wherein:

[0505] R2 is selected from the group consisting of:

[0506] a) Oxo (=O);

[0507] b) -OH; and

[0508] c) -O-CH2-OC(=O)-O-R6;

[0509] 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 and -SF5;

[0510] R6 is selected from the group consisting of: C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C6 cycloalkyl and -(CH2) n1 -C3-C6 cycloalkyl; and

[0511] R 11 Selected from H, OH and O - the groups formed;

[0512] or a pharmaceutically acceptable salt thereof.

[0513] Additional embodiments include a compound of formula (X) wherein:

[0514] R2 is selected from the group consisting of:

[0515] d) Oxo (=O);

[0516] e) -OH; and

[0517] f) -O-CH2-OC(=O)-O-R6;

[0518] 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 and -O-C1-C3 haloalkyl;

[0519] R6 is selected from the group consisting of: C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C6 cycloalkyl and -(CH2) n1 -C3-C6 cycloalkyl; and

[0520] R 11 Selected from H, OH and O - the groups formed;

[0521] or a pharmaceutically acceptable salt thereof.

[0522] Still further embodiments include a compound of formula (X) wherein:

[0523] R2 is selected from the group consisting of:

[0524] g) Oxo (=O);

[0525] g) -OH; and

[0526] i) -O-CH2-OC(=O)-O-R6;

[0527] R3 and R4 are each independently selected from the group consisting of H, halogen, C1-C3 alkyl, -O-C1-C3 alkyl, CF3 and -O-CF3;

[0528] R5 is H;

[0529] R6 is C1-C6 alkyl; and

[0530] R 11 Selected from H, OH and O - the groups formed;

[0531] or a pharmaceutically acceptable salt thereof.

[0532] Yet another embodiment provides a compound of formula (XI):

[0533]

[0534] in:

[0535] R2 is selected from the group consisting of:

[0536] a) Oxo (=O);

[0537] b) -OH;

[0538] c) -O-CH2-OC(=O)-O-R6;

[0539] d) -O-CH2-CH2-OC(=O)-O-R6;

[0540] e)-O-CH2(CH3)-OC(=O)-O-R6;

[0541] f)-OC(=O)-CH2-CH2-C(=O)-O-R6;

[0542] g) -O-CH2-OC(=O)-R6;

[0543] h) -O-(C=O)-R7;

[0544] i) -O-(C=O)-O-R7;

[0545] j)-OC(O)-NR8R9;

[0546] k)-O-CH2-OC(O)-O-(CH2) n1 -NR8R9;

[0547] l)-O-CH2-OC(O)-O-(CH2) n1 -NR8-C(=O)-O-R9; and

[0548] m)-O-(CH2)-O-PO3;

[0549] The dashed line (-----) in each example represents an optional single or double bond;

[0550] 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-pyrrolidone, -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), wherein said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said -O-C3-C6 cycloalkyl and the cycloalkyl ring of the -S-C3-C6 cycloalkyl 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

[0551] 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 heterocyclic group, -(CH2) n1 -3-6 membered heterocyclic group, phenyl group, -(CH2) n1 -phenyl and -(CH2) n1 -NR8R9;

[0552] 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 heterocyclic group), phenyl group, -(CH2) n1 -phenyl, -(CH2) n1 -O-(CH2) n2 -C1-C2 alkyl, -(CH2-CH2-O) n1 -C1-C2 alkyl and -(CH2) n1 -NR8R9;

[0553] R8 and R9 are each independently selected from the group consisting of H and C1-C6 alkyl;

[0554] R 11 Selected from H, OH and O - the groups formed;

[0555] n1 and n2 are each an integer independently selected from the group consisting of: 1, 2, 3, 4, 5, and 6; and

[0556] n3 is an integer selected from the group consisting of: 0, 1, 2, 3, 4, 5, and 6;

[0557] or a pharmaceutically acceptable salt thereof.

[0558] Further embodiments include a compound of formula (XI) wherein:

[0559] R2 is selected from the group consisting of:

[0560] a) Oxo (=O);

[0561] b) -OH; and

[0562] c) -O-CH2-OC(=O)-O-R6;

[0563] 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 and -SF5;

[0564] R6 is selected from the group consisting of: C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C6 cycloalkyl and -(CH2) n1 -C3-C6 cycloalkyl; and

[0565] R 11 Selected from H, OH and O - the groups formed;

[0566] or a pharmaceutically acceptable salt thereof.

[0567] Further embodiments include a compound of formula (XI) wherein:

[0568] R2 is selected from the group consisting of:

[0569] a) Oxo (=O);

[0570] b) -OH; and

[0571] c) -O-CH2-OC(=O)-O-R6;

[0572] 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 and -O-C1-C3 haloalkyl;

[0573] R6 is selected from the group consisting of: C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C6 cycloalkyl and -(CH2) n1 -C3-C6 cycloalkyl; and

[0574] R 11 Selected from H, OH and O - the groups formed;

[0575] or a pharmaceutically acceptable salt thereof.

[0576] Still further embodiments include a compound of formula (XI) wherein:

[0577] R2 is selected from the group consisting of:

[0578] a) Oxo (=O);

[0579] b) -OH; and

[0580] c) -O-CH2-OC(=O)-O-R6;

[0581] R3 and R4 are each independently selected from the group consisting of H, halogen, C1-C3 alkyl, -O-C1-C3 alkyl, CF3 and -O-CF3;

[0582] R5 is H;

[0583] R6 is C1-C6 alkyl; and

[0584] R 11 Selected from H, OH and O - the groups formed;

[0585] or a pharmaceutically acceptable salt thereof.

[0586] Another embodiment provides a compound of formula (XII):

[0587]

[0588] in:

[0589] R2 is selected from the group consisting of:

[0590] a) Oxo (=O);

[0591] b) -OH;

[0592] c) -O-CH2-OC(=O)-O-R6;

[0593] d) -O-CH2-CH2-OC(=O)-O-R6;

[0594] e)-O-CH2(CH3)-OC(=O)-O-R6;

[0595] f)-OC(=O)-CH2-CH2-C(=O)-O-R6;

[0596] g) -O-CH2-OC(=O)-R6;

[0597] h) -O-(C=O)-R7;

[0598] i) -O-(C=O)-O-R7;

[0599] j)-OC(O)-NR8R9;

[0600] k)-O-CH2-OC(O)-O-(CH2) n1 -NR8R9;

[0601] l)-O-CH2-OC(O)-O-(CH2) n1 -NR8-C(=O)-O-R9; and

[0602] m)-O-(CH2)-O-PO3;

[0603] The dashed line (-----) in each example represents an optional single or double bond;

[0604] 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-pyrrolidone, -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), wherein said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said -O-C3-C6 cycloalkyl and the cycloalkyl ring of the -S-C3-C6 cycloalkyl 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

[0605] 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 heterocyclic group, -(CH2) n1 -3-6 membered heterocyclic group, phenyl group, -(CH2) n1 -phenyl and -(CH2) n1 -NR8R9;

[0606] 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 heterocyclic group), phenyl group, -(CH2) n1 -phenyl, -(CH2) n1 -O-(CH2) n2 -C1-C2 alkyl, -(CH2-CH2-O) n1-C1-C2 alkyl and -(CH2) n1 -NR8R9;

[0607] R8 and R9 are each independently selected from the group consisting of H and C1-C6 alkyl;

[0608] R 11 Selected from H, OH and O - the groups formed;

[0609] n1 and n2 are each an integer independently selected from the group consisting of: 1, 2, 3, 4, 5, and 6; and

[0610] n3 is an integer selected from the group consisting of: 0, 1, 2, 3, 4, 5, and 6;

[0611] or a pharmaceutically acceptable salt thereof.

[0612] Additional embodiments include a compound of formula (XII) wherein:

[0613] R2 is selected from the group consisting of:

[0614] a) Oxo (=O);

[0615] b) -OH; and

[0616] c) -O-CH2-OC(=O)-O-R6;

[0617] 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 and -SF5;

[0618] R6 is selected from the group consisting of: C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C6 cycloalkyl and -(CH2) n1 -C3-C6 cycloalkyl; and

[0619] R 11 Selected from H, OH and O - the groups formed;

[0620] or a pharmaceutically acceptable salt thereof.

[0621] Additional embodiments include a compound of formula (XII) wherein:

[0622] R2 is selected from the group consisting of:

[0623] a) Oxo (=O);

[0624] b) -OH; and

[0625] c) -O-CH2-OC(=O)-O-R6;

[0626] 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 and -O-C1-C3 haloalkyl;

[0627] R6 is selected from the group consisting of: C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C6 cycloalkyl and -(CH2) n1 -C3-C6 cycloalkyl; and

[0628] R 11 Selected from H, OH and O - the groups formed;

[0629] or a pharmaceutically acceptable salt thereof.

[0630] Still further embodiments include a compound of formula (XII) wherein:

[0631] R2 is selected from the group consisting of:

[0632] a) Oxo (=O);

[0633] b) -OH; and

[0634] c) -O-CH2-OC(=O)-O-R6;

[0635] R3 and R4 are each independently selected from the group consisting of H, halogen, C1-C3 alkyl, -O-C1-C3 alkyl, CF3 and -O-CF3;

[0636] R5 is H;

[0637] R6 is C1-C6 alkyl; and

[0638] R 11 Selected from H, OH and O - the groups formed;

[0639] or a pharmaceutically acceptable salt thereof.

[0640] Three additional examples provide compounds of formula (XIII), formula (XIV), and formula (XV), respectively:

[0641]

[0642] In each embodiment:

[0643] R1 is selected from the group consisting of H, F and Cl;

[0644] R2 is selected from the group consisting of:

[0645] a) Oxo (=O);

[0646] b) -OH;

[0647] c) -O-CH2-OC(=O)-O-R6;

[0648] d) -O-CH2-CH2-OC(=O)-O-R6;

[0649] e)-O-CH2(CH3)-OC(=O)-O-R6;

[0650] f)-OC(=O)-CH2-CH2-C(=O)-O-R6;

[0651] g) -O-CH2-OC(=O)-R6;

[0652] h) -O-(C=O)-R7;

[0653] i) -O-(C=O)-O-R7;

[0654] j)-OC(O)-NR8R9;

[0655] k)-O-CH2-OC(O)-O-(CH2) n1 -NR8R9;

[0656] l)-O-CH2-OC(O)-O-(CH2) n1 -NR8-C(=O)-O-R9; and

[0657] m)-O-(CH2)-O-PO3;

[0658] The dashed line (-----) in each example represents an optional single or double bond;

[0659] 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-pyrrolidone, -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), wherein said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said -O-C3-C6 cycloalkyl and the cycloalkyl ring of the -S-C3-C6 cycloalkyl 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

[0660] 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 heterocyclic group, -(CH2) n1 -3-6 membered heterocyclic group, phenyl group, -(CH2) n1 -phenyl and -(CH2) n1 -NR8R9;

[0661] 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 heterocyclic group), phenyl group, -(CH2) n1 -phenyl, -(CH2) n1 -O-(CH2) n2 -C1-C2 alkyl, -(CH2-CH2-O) n1-C1-C2 alkyl and -(CH2) n1 -NR8R9;

[0662] R8 and R9 are each independently selected from the group consisting of H and C1-C6 alkyl;

[0663] R 10 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;

[0664] R 11 Selected from H, OH and O - the groups formed;

[0665] n1 and n2 are each an integer independently selected from the group consisting of: 1, 2, 3, 4, 5, and 6; and

[0666] n3 is an integer selected from the group consisting of: 0, 1, 2, 3, 4, 5, and 6;

[0667] or a pharmaceutically acceptable salt thereof.

[0668] Another embodiment 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 embodiments include different pharmaceutical compositions comprising pharmaceutically effective amounts of a compound of formula (II), a compound of formula (III), a compound of formula (IV), a compound of formula (V), a compound of formula (VI), a compound of formula (VII), a compound of formula (VIII), and a compound of formula (IX), a compound of formula (X), a compound of formula (XI), a compound of formula (XII), a compound of formula (XIII), a compound of formula (XIV), and a compound of formula (XV), as well as each subgeneric group describing a subset of those formulae and the individual ELQ compounds described herein.

[0669] Also provided herein is a method for treating malaria in a human subject, comprising administering to a human in need thereof a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0670] Also provided herein is a method for inhibiting malaria in a human subject, comprising administering to a human in need thereof a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0671] Methods for treating or inhibiting malaria in a human subject include treating or inhibiting infection caused by Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae.

[0672] Also provided herein is a method for 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 malarial infections that can be treated using the compounds and methods herein include malaria that is resistant to treatment with one or more agents selected from the group consisting of chloroquine, sulphadoxine-pyrimethamine, quinine, piperaquine, mefloquine, artemisinin-based combination therapy (ACT, including artemether-lumefantrine and artesunate-mefloquine), pyrimethamine, dapsone, atovaquone, and Plasmodium falciparum dihydroorotate dehydrogenase (DHOD inhibitors or PfDHOD inhibitors). DHOD inhibitors include, but are not limited to, DSM265 (Coteron JM et al., J Med Chem 54, 5540-5561 (2011)).

[0673] Also provided herein is a method for treating chloroquine-resistant malaria in a human subject, comprising administering to a human in need thereof a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0674] Also provided herein is a method for treating latent malarial infection in a human subject, comprising administering to a human in need thereof a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0675] The methods for treating malarial infection described herein may further comprise co-administering to a human in need thereof a therapeutically effective amount of 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, phenylsulfone-chlorproguanil, artesunate, quinidine, clopidol, and dihydroartemisinin, or a pharmaceutically acceptable salt thereof, together with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0676] Also provided herein is a method for treating toxoplasmosis (Toxoplasma gondii infection) in a human subject, comprising administering to a human in need thereof a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0677] Also provided herein is a method for treating babesiosis in a human subject, comprising administering to a person in need thereof a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Methods for treating babesiosis in a human subject include treating an infection caused by Babesia microti.

[0678] Also provided herein is a method for treating babesiosis in a non-human subject, the method comprising administering a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a non-human subject in need thereof. Such methods include bovine babesiosis and equine babesiosis, wherein the bovine babesiosis includes infections caused by Babesia bovis and Babesia bigemina, and the equine babesiosis includes infections caused by Babesia caballi and Theileria equi.

[0679] definition

[0680] The term "alkyl" refers to a straight or branched chain hydrocarbon. For example, an alkyl group may include a group having 1 to 4 carbon atoms (i.e., a C1-C4 alkyl group or a C 1-4Examples 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, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(CH3)CH2CH3), and 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3). Similarly, "alkenyl" refers to a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond, such as prop-1-enyl or pent-1,3-dienyl. The term "alkynyl" refers to a straight or branched chain hydrocarbon containing at least one carbon-carbon triple bond, such as pent-3-ynyl.

[0681] The term "alkoxy" refers to a group having the formula -O-alkyl in which an alkyl group, as defined above, is attached to the parent molecular group through an oxygen atom, as seen in the variables R3, R4, and R5. Examples of the alkyl portion of the 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-butyl (-CH2-CH2-CH2-CH3), isobutoxy (-CH2-CH(CH3)2), sec-butoxy (-CH(CH3)CH2-CH3), tert-butoxy (-OC(CH3)3 or -OtBu), and the like.

[0682] The term "haloalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms of the alkyl group are replaced by a halogen atom. The alkyl portion of the haloalkyl group may have, for example, 1 to 4 carbon atoms (i.e., C1-C4 haloalkyl or C 1-4Halogenated alkyl). Non-limiting examples of suitable haloalkyl groups, which may also be referred to as fluoroalkyl groups, include, but are not limited to, 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 (-CH2CF2C H3), 3,3-difluoropropyl (-CH2CH2CHF2), 3,3,3-trifluoropropyl (-CH2CH2CHF3), 1,1-difluorobutyl (-CF2CH2CH2CH3), perfluoroethyl (-CF2CF3), perfluoropropyl (-CF2CF2CF3), 1,1,2,2,3,3-hexylfluorobutyl (-CF2-CF2CF2CH3), perfluorobutyl (-CF2CF2CF2CF3), 1,1,1,3,3,3-hexylfluoroprop-2-yl (-CH2(CF3)2), etc. Other groups in which halogen substitution is carried out with bromine atoms, iodine atoms or chlorine atoms can also be understood for use herein.

[0683] The term "cycloalkyl" refers to a saturated or partially unsaturated ring having 3 to 6 carbon atoms (C3-C6 cycloalkyl or C 3-6 Cycloalkyl), such as a monocyclic ring, includes a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring and a cyclohexyl ring.

[0684] The term "halogen" or "halo" refers to an element or substituent selected from the group consisting of F, Cl, Br and I.

[0685] As used herein, "heterocycle" 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 heterocycles include, by way of example and without limitation, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidinyl), thiazolyl, tetrahydrothiophenyl, thiooxytetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, 4-piperidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, triazinyl, 6H-1,2,5-thiadiazolyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, morpholinyl, and oxazolidinyl.

[0686] "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 used to treat malaria. For example, there are multidrug-resistant strains of Plasmodium falciparum that have high levels of resistance to chloroquine, quinine, mefloquine, pyrimethamine, sulfadoxine, and atovaquone.

[0687] All ranges disclosed and / or claimed herein are inclusive of the recited endpoints and are independently combinable. For example, a range of "2 to 10" and "2-10" includes the endpoints 2 and 10, and all intermediate values ​​between the context of the units being considered. For example, unless described in the context of an average, a reference to "claims 2-10" or "C2-C 10 References to "alkyl" include units 2, 3, 4, 5, 6, 7, 8, 9, and 10 because the claims and atoms are numbered as consecutive numbers without fractions or decimal points. On the other hand, the context of "a pH of 5-9" or "a temperature of 5°C to 9°C" includes the integers 5, 6, 7, 8, and 9 and all fractional and decimal units therebetween, such as 6.5 and 8.24.

[0688] A "subject" refers to an animal, such as a mammal, that has been or will be the subject of treatment, observation, or experiment. The methods described herein can be used for 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. A "subject in need" or "human in need" refers to a subject, such as a human, that may have or is suspected of having a disease or condition that would benefit from certain treatment; for example, treatment with a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt or cocrystal thereof. This includes subjects who may be determined to be at risk for or susceptible to such a disease or condition, such that treatment will prevent the development of the disease or condition.

[0689] The term "pharmaceutically acceptable salt" or "pharmacologically acceptable salt" refers to salts prepared by conventional means, including alkaline 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, and the like. "Pharmaceutically acceptable salts" of the presently disclosed compounds also include salts formed with cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and 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 a free acid with a suitable organic or inorganic base. Any chemical compound listed in this specification can be administered alternatively in the form of its pharmaceutically acceptable salt. "Pharmaceutically acceptable salts" also include free acid, base and zwitterionic forms. A description of suitable pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts, Properties, Selection and Use, Wiley VCH (2002). When the compounds disclosed herein include acidic functional groups such as carboxyl groups, pharmaceutically acceptable cations suitable for the carboxyl groups are well known to those skilled in the art and include alkali cations, alkaline earth cations, ammonium cations, quaternary ammonium cations, and the like. Such salts are known to those skilled in the art. For further examples of "pharmacologically acceptable salts", see Berge et al., J. Pharm. Sci. 66:1 (1977).

[0690] The compounds described herein include all pharmaceutically acceptable salts, cocrystals, esters, solvates, hydrates, isomers (including optical isomers, racemates or other mixtures thereof), tautomers, isotopes, polymorphs or pharmaceutically acceptable prodrugs thereof. In many instances, for the sake of brevity, a compound or a formula of a compound may be described as including "or a pharmaceutically acceptable salt thereof." In each instance, it is understood that each form of the compound mentioned in the preceding sentence is contemplated and is included in each description or definition discussed.

[0691] The terms "pharmacologically active amount", "pharmaceutically effective amount" or "effective amount" relate to an amount of a compound that provides a detectable reduction in parasitic activity in vitro or in vivo, or reduces the likelihood of drug resistance emerging.

[0692] The terms "treat" or "treatment" refer to methods for obtaining beneficial or desired results (including clinical results). Beneficial or desired clinical results can include one or more of the following: (i) inhibiting a disease or condition, such as malarial infection (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the extent of the disease or condition); (ii) slowing or inhibiting the development 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 of the disease or condition (e.g., metastasis)); and / or (iii) relieving the disease, i.e., causing a 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 drug treatment, delaying the progression of the disease, improving quality of life, and / or prolonging survival).

[0693] The term "inhibiting" or "inhibition" refers to a decrease, such as a significant decrease, in the baseline activity of a biological activity or process. For example, "inhibition" of a malaria, babesiosis, or toxoplasmosis infection refers to a decrease in the symptoms or progression of the 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, relative to the symptoms or progression of the infection in the absence of the compound, or a pharmaceutically acceptable salt or co-crystal thereof.

[0694] A "therapeutically effective amount" or "diagnostically effective amount" refers to an amount of a given agent sufficient to achieve the desired effect in a subject being treated with the agent. For example, this can be an amount of a compound disclosed herein that can be used to treat an infection in a subject, such as malaria, babesiosis, or toxoplasmosis. Ideally, a therapeutically effective amount or diagnostically effective amount of a drug is an amount sufficient to inhibit or treat the disease without causing a substantial cytotoxic effect in the subject. The therapeutically effective amount or diagnostically effective amount of an agent will depend on the subject being treated, the severity of the affliction, and the manner in which the therapeutic composition is administered.

[0695] The compounds and pharmaceutical compositions herein can be administered in single or multiple doses by any accepted mode of administration for pharmaceutical agents with similar utilities (e.g., those described in the patents and patent applications incorporated by reference), including rectal, buccal, intranasal, and transdermal routes, intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, as an inhalant, or, for example, by impregnated or coated devices such as stents or cylindrical polymers inserted into arteries.

[0696] In some embodiments, the human daily dose may be from about 0.1 mg to about 1,000 mg. In other embodiments, the human daily dose may be from about 0.1 mg to about 500 mg. In other embodiments, the human daily dose may be from about 1 mg to about 250 mg. In still other embodiments, the human daily dose may be from about 1 mg to about 200 mg. In further embodiments, the human daily dose may be from the following range groups: a) about 1 mg to about 150 mg; b) about 1 mg to about 100 mg; c) about 1 mg to about 75 mg; d) about 1 mg to about 50 mg; e) about 5 mg to about 50 mg; f) about 5 mg to about 40 mg; g) about 1 mg to about 25 mg; and about 1 mg to about 20 mg.

[0697] In other embodiments, the dosages listed above for daily use can be administered as weekly or twice weekly (semi-weekly) doses. In some embodiments, the compound can be delivered every two weeks (every other week) as a prevention of disease states as described herein. Non-limiting examples of weekly, twice weekly, or biweekly dosages include 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 doses.

[0698] Within each dosage range, the pharmaceutically effective amount of the compound or pharmaceutically acceptable salt thereof can comprise a single daily administration or can be divided into two, three, or four administrations per day.

[0699] Also contemplated herein are prodrugs of the disclosed compounds. A prodrug is an active compound or an inactive compound that is chemically modified to an active compound by physiological actions in the body, such as hydrolysis or metabolism, after the prodrug is administered to a subject. The applicability and techniques involved in preparing and using prodrugs are well known to those skilled in the art. For a general discussion of prodrugs involving esters, see Svensson and Tunek, Drug Metabolism Reviews 165 (1988) and Bundgaard, Design of Prodrugs, Elsevier (1985).

[0700] The term "prodrug" is also intended to include any covalently bonded carrier that releases the active parent drug of the present invention in vivo when the prodrug is administered to a subject. Since prodrugs generally have enhanced properties relative to the properties of the active pharmaceutical agent, such as solubility and bioavailability, the compounds disclosed herein can be delivered in prodrug form. Therefore, it is also envisioned that the prodrugs of the currently disclosed compounds, the method for delivering the prodrugs, and the compositions containing such prodrugs are prepared. The prodrugs of the disclosed compounds are typically prepared by modifying one or more functional groups present in the compound in a certain manner so that the modification is cut in conventional manipulations or in vivo to produce the parent compound. Prodrugs include compounds with phosphonate groups and / or amino groups that are functionalized with any group that is cut in vivo to produce corresponding amino and / or phosphonate groups.

[0701] Specific examples of the presently disclosed compounds include one or more asymmetric centers; thus, these compounds can exist in different stereoisomeric forms. Thus, 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 in substantially enantiomerically pure form or purified to substantially enantiomerically pure form, such as 90% enantiomeric excess, 95% enantiomeric excess, 97% enantiomeric excess, or even greater than 99% enantiomeric excess, such as enantiomerically pure form.

[0702] It is understood that substituents and substitution patterns of the compounds described herein can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and can be readily synthesized by techniques known in the art and further by the methods described in this disclosure.

[0703] The compounds and pharmaceutical compositions disclosed herein can be used to inhibit or prevent parasitic diseases. For example, parasitic diseases of humans or animals (non-human) include malaria, toxoplasmosis, theileriosis, amebiasis, giardiasis, leishmaniasis, trypanosomiasis, neosporosis (Neospora cranium infection), and coccidiosis caused by organisms such as Toxoplasma (e.g., Toxoplasma gondii), Eimeria (Eimeriosis), Babesia bovis (babesiosis), Theileria (Theileria annulata - tropical theileriosis and Theileria parva - East Coast fever), and also include parasitic diseases caused by organisms such as ascaris, schistosomes, and filarial worms. Infection caused by worms such as worm.

[0704] Provided is a method for treating coccidiosis in a non-human subject, the method comprising administering a pharmaceutically effective amount of Formula (I) or a pharmaceutically acceptable salt thereof to a non-human subject in need 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.

[0705] In some embodiments, the non-human subject is a ruminant subject, including cattle, bison, sheep, and goats. In some embodiments, coccidiosis in ruminants involves a pathogen selected from the group consisting of: Eimeria bovis, E. zuernii, E. auburnensis, E. alabamensis.

[0706] In goats, coccidiosis may be associated with infection with a pathogen selected from the group consisting of: E. christenseni, E. arloingi, E. caprina, and E. ninakohlyakimovae.

[0707] The compounds and compositions described herein are also effective in inhibiting fungal pathogens, including Pneumocystis carinii, Aspergillus fumigatus, and others.

[0708] In a specific embodiment, the parasitic disease may be caused by a parasite that causes malaria. Specific parasitic species included in this group include all species that can cause infection in humans or animals. Illustrative species include Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium knowlesi, and Plasmodium malariae. The compounds and compositions disclosed herein can be particularly useful for inhibiting drug-resistant malaria, such as chloroquine-resistant malaria or multidrug-resistant malaria caused by organisms resistant to chloroquine, quinine, mefloquine, pyrimethamine, dapsone, and / or atovaquone.

[0709] Toxoplasmosis is caused by a sporozoan parasite of the apicomplexa subphylum called Toxoplasma gondii. It is a common tissue parasite of humans and animals. Most infections appear to be asymptomatic (90%), however, toxoplasmosis poses a serious health risk to immunocompromised individuals such as organ transplant recipients, cancer and AIDS patients, and unborn children of infected mothers. The compounds disclosed herein can be used alone to treat toxoplasmosis, or they can be co-administered with "antifolates" such as sulfonamides, pyrimethamine, trimethoprim, biguanides, and / or atovaquone.

[0710] In other embodiments, the compounds disclosed herein can be co-administered with another pharmaceutically active compound. For example, the compounds can be co-administered with quinine, chloroquine, atovaquone, proguanil, primaquine, amodiaquine, mefloquine, piperaquine, artemisinin, methylene blue, pyrimethamine, sulfadoxine, artemether-lumefantrine, Dapsone-chlorproguanil Artesunate, quinidine, clopidol, pyridine / pyridinol analogs, 4(1H)-quinolone analogs, dihydroartemisinin, a mixture of atovaquone and proguanil, an endoperoxide, an acridonoid as disclosed in WO 2008 / 064011 (which is incorporated herein by reference in its entirety), a pharmachin as disclosed in U.S. provisional patent application filed on November 18, 2008, entitled "Compounds for Treating Parasitic Disease" (which is incorporated herein by reference in its entirety), or any combination of these drugs.

[0711] The compounds disclosed herein can typically be included in pharmaceutical compositions (including therapeutic and prophylactic formulations) in combination with one or more pharmaceutically acceptable vehicles or carriers and optionally other therapeutic ingredients (e.g., antibiotics, anti-inflammatory drugs, or drugs for alleviating itching, such as antihistamines). The compositions disclosed herein can advantageously be combined and / or used in combination with other antimalarial agents as described above.

[0712] Such pharmaceutical compositions can be administered to a subject by a variety of mucosal administration modes, including oral, rectal, intranasal, intrapulmonary or transdermal delivery, or by topical delivery to other surfaces. Optionally, the composition can be administered by a non-mucosal route, including intramuscular, subcutaneous, intravenous, intraarterial, intraarticular, intraperitoneal, intrathecal, intracerebroventricular 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.

[0713] In some embodiments, an antimalarial agent or combination of antimalarial agents, including a compound described herein or a pharmaceutically acceptable salt thereof, can be administered to an animal, such as chicken, as an additive to the animal's prepared feed or grain.

[0714] In some embodiments, a pharmaceutically effective amount of a compound of the present invention (including compounds of formula (I) and all other compounds of formulae as well as individual compounds described herein) or a pharmaceutically acceptable salt thereof can be administered to a person in need thereof by injection. In some embodiments, the injection can be subcutaneous. In other embodiments, the injection is intramuscular.

[0715] The compound of formula I or its pharmaceutically acceptable salt or cocrystal can be incorporated into the form of administration by injection including aqueous or oil suspension or emulsion with sesame oil, corn oil, cottonseed oil or peanut oil and elixir, mannitol, dextrose or sterile aqueous solution and similar pharmaceutical vehicles. The saline of aqueous solution can also be routinely used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol (and its applicable mixture), cyclodextrin derivatives and vegetable oils can also be used. Suitable fluidity can be maintained, for example, by using coatings such as lecithin, in the case of dispersants, by maintaining the required particle size and by using a surfactant. Prevention of the effect of microorganisms can be achieved by a variety of antibacterial and antifungal agents (such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.).

[0716] In some embodiments, the compound or its pharmaceutically acceptable salt can be administered using a formulation comprising sesame oil (preferably, pharmaceutical grade sesame oil). The components of the injectable formulation may include additional polar compounds, such as polar compounds selected from the group consisting of monoglycerides, diglycerides, free fatty acids, phytosterols, sesamin, and sesamolin. Some injectable formulations further comprise ethanol. In some embodiments, the injectable formulation comprises about 5% by weight to about 10% by weight of ethanol. In other embodiments, the injectable formulation comprises about 7% by weight to about 8% by weight of ethanol. In other embodiments, the injectable formulation comprises about 7.25% by weight to about 7.75% by weight of ethanol. In other embodiments, the injectable formulation comprises about 7.5% by weight of ethanol.

[0717] Other components that can be used for intramuscular injection include vegetable oils, such as peanut oil, almond oil, olive oil, castor oil and soybean oil. Synthetic oils are also suitable, such as polyethylene glycol, triglycerides of high saturated fatty acids, monoesters of higher fatty acids, etc.

[0718] The injectable composition may also contain one or more excipients, such as benzoic acid alcohol or benzoic acid compounds, including benzyl benzoate or sodium benzoate. Other useful excipients include methyl bile ester, hydrophobic colloidal anhydrous silica, colloidal silicon dioxide, cholesterol-based fatty acid esters (such as cholesteryl oleate, cholesteryl nonanoate, cholesteryl stearate), polyoxyethylene (5) sorbitan monooleate, polyoxyethylene (6) stearate, multivalent metal salts of fatty acids (e.g., aluminum stearate), fatty acid esters of carbohydrates (such as ), sorbitan fatty acid esters (such as sorbitan monolaurate, sorbitan hemioleate and sorbitan monostearate) and glycerol fatty acid esters such as glyceryl monostearate.

[0719] By the desired amount of compound according to the present disclosure is incorporated in a suitable solvent together with the various other ingredients listed above as needed, followed by filtration sterilization to prepare a sterile injectable solution. Typically, a dispersant is prepared by incorporating various sterilized active ingredients into a sterile vehicle, the sterile vehicle containing a basic dispersion medium and other ingredients required for the ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred preparation methods are vacuum drying technology and freeze drying technology, which are prepared by their previously aseptically filtered solution to produce active ingredients plus any other desired powder of the desired ingredients. In certain embodiments, for parenteral administration, a sterile injectable solution containing a therapeutically effective amount (e.g., 0.1 mg to 1000 mg) of a compound of formula I or its pharmaceutically acceptable salt or co-crystal is prepared. However, it should be understood that the amount of the compound actually administered will generally be determined by a physician according to relevant circumstances, and the circumstances include the condition to be treated, the selected route of administration, the compound actually administered and its relative activity, the age, weight and response of individual subjects, the severity of the subject's symptoms, etc.

[0720] In order to formulate the pharmaceutical composition, the compound can be combined with various pharmaceutically acceptable additives and alkali or vehicles for dispersing the compound. Desirable additives include, but are not limited to, pH control agents such as arginine, sodium hydroxide, glycine, hydrochloric acid, citric acid, etc. In addition, local anesthetics (e.g., benzyl alcohol), isotonic agents (e.g., sodium chloride, mannitol, sorbitol), adsorption inhibitors (e.g., Tween 80 or Miglyol 812), solubility enhancers (e.g., cyclodextrin and its derivatives), stabilizers (e.g., serum albumin), and reducing agents (e.g., glutathione) can be included. Adjuvants such as aluminum hydroxide (e.g., Amphogel, Wyeth Laboratories, Madison, NJ), Freund's adjuvant, MPL™ (3-O-deacylated monophosphoryl lipid A; Corixa, Hamilton, Ind.), and IL-12 (Genetics Institute, Cambridge, Mass.), as well as many other suitable adjuvants well known in the art, can be included in the composition. When the composition is a liquid, the tonicity of the formulation (as measured with reference to the tonicity of a 0.9% (w / v) saline solution as a whole) is typically adjusted to a value that will not induce significant irreversible tissue damage at the site of administration. Typically, the tonicity of the solution is adjusted to a value of about 0.3 to about 3.0 (e.g., about 0.5 to about 2.0 or about 0.8 to about 1.7).

[0721] Described compound can be dispersed in alkali or vehicle, and described alkali or described vehicle can comprise the hydrophilic compound and the additive of any expectation that described compound is dispersed.Described alkali can be selected from the suitable compound of various scopes, and described suitable compound includes but not limited to: polycarboxylic acid or its salt, carboxylic anhydride (for example, maleic anhydride) and other monomer (for example, (methyl) methyl acrylate, acrylic acid etc.) copolymer, hydrophilic vinyl polymer (as polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidone), cellulose derivative (as hydroxymethyl cellulose, hydroxypropyl cellulose etc.) and natural polymer, as chitosan, collagen, sodium alginate, gelatin, hyaluronic acid and its nontoxic metal salt.Usually, biodegradable polymer is selected as alkali or vehicle, for example polylactic acid, poly (lactic acid-glycolic acid) copolymer, polyhydroxybutyric acid, poly (hydroxybutyric acid-glycolic acid) copolymer and its mixture.Alternately or in addition, can adopt as synthetic fatty acid esters such as polyglycerol fatty acid ester, sucrose fatty acid ester as vehicle. Hydrophilic polymers and other vehicles can be used alone or in combination, and can impart enhanced structural integrity to the vehicle through partial crystallization, ionic bonding, cross-linking, etc. Vehicles can be provided in a variety of forms, including fluid or viscous solutions, gels, pastes, powders, microspheres, and films for direct application to mucosal surfaces.

[0722] The compound can be combined with alkali or vehicle according to various methods, and the release of the compound can be achieved by the disintegration of diffusion, vehicle or the relevant formation of water channels. In some cases, the compound is dispersed in microcapsules (microspheres) or nanocapsules (nanospheres) prepared by suitable polymers (e.g., isobutyl 2-cyanoacrylate) (see, e.g., Michael et al., Pharmacy and Pharmacology magazine (J.Pharmacy Pharmacol.) 43: 1-5, 1991), and is dispersed in a biocompatible dispersion medium that produces sustained delivery and biological activity over a long period of time.

[0723] The compositions of the present disclosure may alternatively contain pharmaceutically acceptable vehicle substances required to approximate physiological conditions, such as pH regulators and buffers, tonicity regulators, wetting agents, and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate. For solid compositions, conventional non-toxic pharmaceutically acceptable vehicles may be used, including, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.

[0724] The pharmaceutical composition for applying the compound can also be formulated as a solution, microemulsion or other ordered structures of the active ingredient suitable for high concentration. Vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol etc.) and its suitable mixture. For example, by using coatings such as lecithin, by keeping desired granularity and by using a surfactant in the case of dispersible formulations, the appropriate fluidity of the solution can be kept. In many cases, it will be desirable to include isotonic agents in the composition, for example sugar, polyols such as mannitol and sorbitol or sodium chloride. By including in the composition the medicament (for example monostearate and gelatin) that delays absorption, the extended absorption of the compound can be achieved.

[0725] In certain embodiments, the compound can be applied in the form of a time-release formulation, for example, in the form of a composition comprising a slow-release polymer. These compositions can be prepared with a medium (for example, a controlled-release medium, such as a polymer, a microencapsulated delivery system or a bioadhesive gel) that will prevent immediate release. The extended delivery in the various compositions of the present disclosure can be achieved by including a medicament (for example, aluminum monostearate hydrogel and gelatin) that delays absorption in the composition. When a controlled-release formulation is desired, the controlled-release adhesive suitable for use according to the present disclosure includes any biocompatible controlled-release material that is inert to the active agent and can be incorporated into the compound and / or other bioactive agents. Many such materials are known in the art. Available controlled-release adhesives are materials that are slowly metabolized under physiological conditions (for example, at the mucosal surface or in the presence of body fluids) after delivery. Suitable adhesives include, but are not limited to, biocompatible polymers and copolymers well known in the art for slow-release formulations. This biocompatible compound is nontoxic and inert to surrounding tissues and does not trigger significant adverse side effects, such as nasal irritation, immune response, inflammation, etc. It is metabolized into metabolites which are also biocompatible and easily eliminated from the body.

[0726] Exemplary polymeric materials for use in the present disclosure include, but are not limited to, polymer matrices derived from co- and homopolyesters having hydrolyzable ester bonds. Many of these polymer matrices are known in the art to be biodegradable and to produce non-toxic or low-toxic degradation products. Exemplary polymers include polyglycolic acid and polylactic acid, poly(DL-lactic-co-glycolic acid), poly(D-lactic-co-glycolic acid), and poly(L-lactic-co-glycolic acid). Other useful biodegradable or bioerodible polymers include, but are not limited to, poly(ε-caprolactone), poly(ε-caprolactone-co-lactic acid), poly(ε-caprolactone-co-glycolic acid), poly(β-hydroxybutyric acid), poly(alkyl-2-cyanoacrylates), hydrogels (such as poly(hydroxyethyl methacrylate)), polyamides, poly(amino acids) (e.g., L-leucine, glutamic acid, L-aspartic acid, etc.), poly(ester ureas), poly(2-hydroxyethyl DL-asparagine), 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, edited by JR Robinson, 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 for preparing 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).

[0727] Pharmaceutical composition of the present disclosure is normally sterile and stable under manufacture, storage and use conditions.As required, can be by the compound of required amount and a kind of composition in the composition enumerated above or its combination be incorporated in suitable solvent, carry out subsequently filtration sterilization to prepare sterile solution.Usually, by compound and / or other bioactivator be incorporated in sterile vehicle to prepare dispersant, described sterile vehicle contains basic dispersion medium and other required components from the composition enumerated above.In the case of sterile powder, preparation method comprises vacuum drying and lyophilization, and described vacuum drying and described lyophilization are produced compound by previously aseptically filtered solution and add the powder of any other desired composition.Can realize the prevention of the effect of microorganism by various antibacterial and antifungal (for example, parahydroxybenzoate, chlorobutanol, phenol, sorbic acid, thimerosal etc.).

[0728] In some embodiments, the method of delivering a pharmaceutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, can be administered to a subject in need thereof via a medical implant (specifically an implant designed to provide sustained, extended, or timed release of the active compound). In some embodiments, the implant comprises an amount of the desired compound and an ethylene vinyl acetate (EVA) copolymer, such as the copolymer designs described in U.S. Pat. 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 to Titan Pharmaceuticals, Inc.

[0729] In some embodiments, the implant may comprise a size of 0.5 mm to about 7 mm in diameter. In some embodiments, the length of the device is about 0.5 cm to 10 cm. In one embodiment, the length of the device is about 1 cm to about 3 cm. In one embodiment, the length of the device is about 2 cm to about 3 cm. In another embodiment, the length of the device is about 2.6 cm. In one embodiment, the diameter of the device is about 1 mm to about 3 mm. In another embodiment, the diameter of the device is about 2 mm to about 3 mm. In one embodiment, the diameter of the device is about 2.4 mm. In some embodiments in which the device comprises a size of an overall diameter of about 2.4 mm and an overall length of about 2.6 cm, each of the devices releases 1 mg of drug substance per day.

[0730] In some embodiments, the implantable device comprises about 10% to about 85% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the remainder of the implant comprises ethylene vinyl acetate (EVA) copolymer. In some embodiments, the implant comprises about 75% active drug (a compound of formula I or a pharmaceutically acceptable salt thereof) and about 25% EVA. In other separate embodiments, the implant comprises 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, respectively.

[0731] Additional embodiments include methods in which the active drug described herein (a compound of Formula I or a pharmaceutically acceptable salt thereof) is administered to a subject in need thereof in the form of a sustained-release, extended-release, or time-release gel formulation (e.g., a hydrogel formulation). Gel carriers that can be used to deliver a pharmaceutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof include thermoresponsive hydrogel carriers, including but not limited to injectable thermoresponsive hydrogels based on block copolymers; carbapol (polyacrylic acid) gels; chitosan gels, such as chitosan thermogels; nanoparticle-containing / nanocomposite hydrogels; modified poly(ethylene glycol) gels; carrageenan gels; and sorbitan monostearate-encapsulated hydrogels. Examples of useful gel carriers include the gel carriers described in Sarah Gordon's chapter: Gels as Vaccine Delivery Systems, Subunit Vaccine Delivery, Springer New York, 2015, pp. 203-220 (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., January 2016, 18(1), pp. 261-269.

[0732] Oral gel, gel beads or gel drop formulations can also be used to deliver effective amounts of the compounds herein or pharmaceutically acceptable salts thereof to animals, such as poultry. Examples of gel formulations that can be used with the active drugs described herein include those described in U.S. Pat. No. 10,155,034 (Lee) and U.S. Pat. No. 8,858,959 (Jenkins et al.).

[0733] According to the various treatment methods disclosed herein, the compounds can be delivered to the subject in a manner consistent with conventional methods associated with the management of the condition for which treatment or prevention is sought. According to the disclosure herein, a prophylactically effective amount or a therapeutically effective amount of a compound and / or other biologically active agent is administered to a subject in need of such treatment for a period of time and under conditions sufficient to prevent, inhibit and / or ameliorate the selected disease or condition, or one or more symptoms thereof.

[0734] The typical object that is intended to be used for the treatment of compositions and methods of the present invention comprises mankind and non-human primates and other animals.In order to identify the object that is used for preventing or treating according to the method for the present invention, generally recognized screening methods are adopted to determine the risk factors relevant to parasitic infection, to determine the state of the existing disease or symptom of the object.These screening methods include, for example, preparing blood smears by the individuality of suspected malaria.Then the blood smears are fixed in methanol, and dyed with Giemsa (Giemsa), and the existence of the red blood cells infected by Plasmodium is examined microscopically.These and other conventional methods allow clinicians to select patients who need to use the therapy of method and pharmaceutical composition of the present invention.

[0735] The administration of the compounds of the present disclosure can be for preventive or therapeutic purposes. When provided prophylactically, the compound is provided before any symptoms. The prophylactic administration of the compound is used to prevent or improve any subsequent disease process. When provided therapeutically, the compound is provided at the onset of disease or infection symptoms (or shortly after onset).

[0736] For prevention and treatment purposes, the compound can be administered to the subject by oral route or single bolus delivery, by continuous delivery (e.g., continuous transdermal, mucosal or intravenous delivery) over an extended period of time, or with a repeated administration regimen (e.g., by hourly, daily or weekly repeated administration regimens). The compound can be provided in a therapeutically effective dose in a repeated dose within an extended prevention or treatment regimen that will produce clinically significant results to alleviate one or more symptoms or detectable conditions associated with the target disease or condition as described herein. In this context, the determination of an effective dose is typically based on animal model studies followed by human clinical trials, and is guided by an administration regimen that significantly reduces the occurrence or severity of the target disease symptoms or symptoms of the subject. Suitable models in this regard include, for example, mice, rats, birds, pigs, cats, non-human primates, and other accepted animal model subjects known in the art. Alternatively, an effective dose can be determined using an in vitro model (e.g., whole cell assays monitoring the effects of various drugs on parasite growth rate). Using such models, only ordinary calculations and adjustments are required to determine the appropriate concentration and dosage for administering a therapeutically effective amount of a compound (e.g., an amount effective to elicit a desired immune response or alleviate one or more symptoms of a target disease). In alternative embodiments, an effective amount or effective dose of a compound may be to inhibit or enhance only one or more selected biological activities associated with a disease or condition described herein for therapeutic or diagnostic purposes.

[0737] The actual dosage of the compound will vary depending on factors such as the disease indication and the specific state of the subject (e.g., the subject's age, size, health, degree of symptoms, predisposing factors, etc.), the time and route of administration, other drugs or treatments administered concurrently, and the specific pharmacology of the compound for eliciting the desired activity or biological response of the subject. The dosage regimen can be adjusted to provide the optimal prophylactic or therapeutic response. A therapeutically effective amount is also an amount in which any toxic or deleterious side effects of the compound and / or other bioactive agents are clinically outweighed by the beneficial effects of the treatment. A non-limiting range for a therapeutically effective amount of the compound and / or other bioactive agents within 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.

[0738] Dosage can be changed by the attending clinician to maintain the target site (e.g., lung or macrocirculation) desired concentration. Higher or lower concentrations can be selected based on the mode of delivery, for example, delivery via the epidermis, rectum, oral, lung or intranasal relative to intravenous or subcutaneous delivery. Dosage can also be adjusted based on the release rate of the formulation administered (e.g., intrapulmonary spray relative to powders, sustained-release oral granules relative to injected granules or transdermal delivery formulations, etc.).

[0739] The present disclosure also includes kits, packages, and multi-container units containing the pharmaceutical compositions described herein, active ingredients, and / or devices for administering the compositions for the prevention and treatment of diseases and other conditions in mammalian subjects. Kits for diagnostic use are also provided. In one embodiment, these kits include containers or formulations containing one or more conjugates described herein. In one example, these components are formulated in a pharmaceutical formulation for delivery to a subject. The conjugates are optionally contained in bulk dispensing containers or in unit or multi-unit dosage forms. Optional dispensing means, such as pulmonary or intranasal spray applicators, may be provided. The packaging material optionally includes a label or instructions indicating which therapeutic purposes and / or modes of use the packaged agent may be used for.

[0740] Initially, ELQ-596 was prepared using a previously reported method. 12 4-OEt-quinolone 1 was prepared according to the literature (Scheme 1, below) and reacted with pinacol ester 2 as previously described 12 Finally, 4-chloro-quinoline was hydrolyzed in glacial acetic acid (AcOH) using potassium acetate (KOAc) to obtain 4(1H)quinolone ELQ-596.

[0741] Scheme 1: Synthesis of ELQ-596. a

[0742]

[0743] Scheme 1: (a) Pd(dppf)Cl2, K2CO3 aqueous solution, DMF, 80℃, 99%; (b): HBr, AcOH, 90℃, 59%.

[0744] As illustrated 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, the method comprising:

[0745] a) causative form:

[0746] Compounds and formulas The first step is to react an optionally substituted 2-([1,1′-biphenyl]-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane compound to form a first step product compound of the formula: wherein R1 is selected from the group consisting of H, F and Cl; and

[0747] b) a second step of treating the product compound of the first step with an acidic medium to form a compound of formula (I).

[0748] Another embodiment comprises a method of producing a first step product compound as described above. Another embodiment provides a compound of formula (XI):

[0749]

[0750] 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-pyrrolidone, -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).

[0751] Another embodiment 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), -C(O)NH(-CH2-C3-C6 cycloalkyl).

[0752] Another embodiment 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-pyrrolidone, -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).

[0753] Another embodiment 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-pyrrolidone, -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).

[0754] Another embodiment 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-pyrrolidone, -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).

[0755] Another embodiment 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.

[0756] Another embodiment 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.

[0757] Another embodiment 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.

[0758] In each of the embodiments involving compounds of formula (XI), there are additional embodiments in which all variables are as defined for the specific embodiment, with the proviso that at least one of R3, R4, and R5 is H. In each of the embodiments involving compounds of formula (XI), except that R1 is F, there are additional embodiments in which all variables are as defined for the specific embodiment. In each of the embodiments involving compounds of formula (XI), except that R1 is Cl, there are additional embodiments in which all variables are as defined for the specific embodiment.

[0759] Two separate examples are also provided, comprising a compound of formula (X-1) and a compound of formula (X-2), respectively:

[0760]

[0761] In each embodiment, 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-pyrrolidone, -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).

[0762] Two additional separate embodiments comprise a compound of formula (X-1) and a compound of formula (X-2), respectively, 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-pyrrolidone, -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).

[0763] Two additional separate embodiments comprise a compound of formula (X-1) and a compound of formula (X-2), respectively, 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-pyrrolidone, -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).

[0764] Two additional separate embodiments comprise a compound of formula (X-1) and a compound of formula (X-2), respectively, 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-pyrrolidone, -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).

[0765] Two additional separate embodiments comprise a compound of formula (X-1) and a compound of formula (X-2), respectively, 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-pyrrolidone, -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).

[0766] Two additional separate embodiments comprise a compound of formula (X-1) and a compound of formula (X-2), respectively, 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.

[0767] Two additional separate embodiments comprise compounds of formula (X-1) and (X-2), respectively, 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.

[0768] Two additional separate embodiments comprise compounds of formula (X-1) and (X-2), respectively, 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.

[0769] In each of the embodiments involving compounds of formula (X-1) or (X-2), except that R1 is F, there are additional embodiments in which all variables are as defined for that specific embodiment. In each of the embodiments involving compounds of formula (X-1) or (X-2), except that R1 is Cl, there are additional embodiments in which all variables are as defined for that specific embodiment.

[0770] In some embodiments, step a) of the preparation method above is performed 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-triphenylphosphino-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 equivalents to about 0.1 equivalents. In some embodiments, the catalyst is present at a concentration of about 0.03 equivalents to about 0.07 equivalents.

[0771] In some embodiments, the preparation is performed 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 KCO, CsF, CsCO, NaOH, NaCO, and KCO. In some embodiments, the base is present at a concentration of about 0.5 equivalents to about 3 equivalents.

[0772] To modify the benzene substituents R1 and X, it was decided to adopt Method I (Scheme 2, below), in which the 4(1H)-quinolone is formed in the final reaction step. To modify the biphenyl substituents R3, R4 and R5, Method II was used, in which the exocyclic ring of the biphenyl side chain is introduced late in the 4(1H)-quinolone synthesis.

[0773]

[0774] To prepare the β-ketoester intermediates 8a and 8b, a route recently developed for the large-scale synthesis of ELQ-300 was employed. 10 . The Suzuki reaction of commercially available ethyl 2-(4-bromophenyl)acetate 5 and (4-(trifluoromethoxy)phenyl)boronic acid with [1,1′-bis(diphenylphosphino)-ferrocene]palladium(II) dichloride (Pd(dppf)Cl2) and potassium carbonate (K2CO3) in dimethylformamide (DMF) provided ethyl 2-(4′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)acetate 6 in 58% yield (Scheme 3). Acylation of 5 and 6 using freshly prepared lithium hexamethyldisilazide (LiHMDS) and excess acetic anhydride (Ac2O) in tetrahydrofuran (THF) gave the bis-acylated enol acetates 7a and 7b as a mixture of equally reactive E and Z isomers in quantitative yields and sufficient purity (>95%) to be used in the next step without further purification. The two stereoisomers can be separated by flash chromatography. However, NOESY 2D NMR could not be used to unambiguously assign the two stereoisomers. GC-MS analysis showed that the major stereoisomer of 7a accounted for 80% of the mixture, while the major stereoisomer of 7b accounted for 95% of the mixture. Using catalytic p-toluenesulfonic acid (p-TsOH) in AcOH, the bis-acylated 7a and 7b were converted to the β-ketoester intermediates 8a and 8b, which existed as a mixture of keto and enol tautomers, as described by 1 After concentration, the crude reaction mixture contained mainly β-ketoester 8a or 8b and catalytic p-TsOH, which was required for the next reaction and was used without further purification.

[0775] Provided herein are novel compounds that can be used to synthesize compounds of formula (I) or pharmaceutically acceptable salts thereof. One embodiment provides a compound of formula (A):

[0776]

[0777] wherein 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-pyrrolidone, -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-pyrrolidone, -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.

[0778] 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-pyrrolidone, -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).

[0779] Another embodiment 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-pyrrolidone, -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).

[0780] Another embodiment 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-pyrrolidone, -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);

[0781] Another embodiment 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-pyrrolidone, -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).

[0782] Another embodiment 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.

[0783] Two separate examples provide compounds of formula (A-1) and (A-2), respectively:

[0784]

[0785] In each embodiment, 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-pyrrolidone, -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 separate embodiments, each of the compounds of formula (A-1) and formula (A-2), R3 is selected from the group consisting of Cl, F, CH2F, CHF2, CF3, -O-CF3, and SF5. In other separate embodiments, R3 is selected from the group consisting of F, CF3, -O-CF3, and SF5.

[0786] Scheme 3: Synthesis of β-ketoesters 8a and 8b. a

[0787]

[0788] a Reaction (a): (4-(trifluoromethoxy)phenyl)boronic acid, Pd(dppf)Cl2, K2CO3, DMF, 80°C, 58%; (b): LiHMDS, Ac2O and THF, over 20 hours to 72 hours, -20°C to room temperature; (c) 10% p-TsOH and AcOH, over 2-16 hours, 100°C, 89-100%.

[0789] Relatively flexible variations in the phenyl-type substituents X, Y, and Z were achieved by reacting the β-ketoester 8b with various anilines (10a-d). The crude β-ketoester mixture was reacted with the anilines 10a-d under Dean-Stark conditions using refluxing benzene to provide the Schiff bases 10a-d, which were used without further purification (Scheme 4). Conrad-Limpach cyclization of the Schiff bases 10a-d in Dowtherm A at 250°C was performed. 15,16 Complete formation of 4(1H)-quinolones ELQ-596, ELQ-601, ELQ-649, and ELQ-650 17 The purity of the crude product obtained from this reaction was >98%, as determined by HPLC and 1 The results were confirmed by H-NMR. To allow for the detection and quantification of the ELQ-596 and ELQ-650 positional isomers, the products were converted to their corresponding 4-chloro derivatives using POCl3 and analyzed by GC-MS. The results showed that negligible amounts (<0.5%) of the ELQ-596 and ELQ-650 isomers were formed under these conditions.

[0790] Scheme 4: Synthesis of a series of ELQ compounds with variable substitution of benzene-type rings (X, Y and Z) from β-ketoester 8b. a

[0791]

[0792] a Reaction (a): 10% p-TsOH, benzene, reflux, 24-72 hours; (b): Dowtherm A, 250°C, 5 minutes, 28-37%.

[0793] The synthesis of 4(1H)-quinolone 12 was accomplished using the same method described above. The crude β-ketoester 8a mixture was reacted with commercially available 4-chloro-3-methoxyaniline 9b under Dean-Stark conditions using refluxing benzene to provide the Schiff base 11, which was used without further purification (Scheme 5). The Schiff base 11 was synthesized by Konrad-Limpach cyclization in Dowtherm A at 250°C. 15,16 Complete the formation of 4(1H)-quinolone 12 17 Then use pure POCl3 13 Preparation of 4-chloroquinoline 13 from 4(1H)-quinolone 12.

[0794] One embodiment provides a compound of formula (XII):

[0795]

[0796] 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-pyrrolidone, -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-pyrrolidone, -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 OM.

[0797] 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-pyrrolidone, -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 OM.

[0798] Another 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-C2 alkyl, -O-C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 haloalkyl, -S-CF3, -SF5, CN, 2-pyrrolidone, -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 OM.

[0799] Another 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, methyl, methoxy, CH2F, CHF2, CF3, -O-CH2F, -O-CHF2, -O-CF3, -S-CF3, -SF5, CN, 2-pyrrolidone, -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 OM.

[0800] Another 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, methyl, methoxy, CH2F, CHF2, CF3, -O-CH2F, -O-CHF2, -O-CF3, -S-CF3, -SF5, CN, 2-pyrrolidone, -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 OM.

[0801] Another 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: halogen, C1-C2 alkyl, -O-C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 haloalkyl, -SF5, 2-pyrrolidone and CN, and Z is selected from the group consisting of H, F and OM.

[0802] Two separate examples provide compounds of formula (XI-1) and (XI-2), respectively:

[0803]

[0804] wherein in each embodiment, 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-pyrrolidone, -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 OM.

[0805] In some separate embodiments relating to compounds of formula (A-1) and (A-2), respectively, 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 OM.

[0806] In other separate embodiments, 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 OM.

[0807] Provided are additional embodiments corresponding to each embodiment of the compound of formula (X-1) and formula (XI-2) as just described, wherein R3 is as defined, and R1 is Cl. Provided are additional embodiments corresponding to each embodiment of the compound of formula (X-1) and formula (XI-2) as just described, wherein R3 is as defined, and R1 is F.

[0808] Scheme 5: Synthesis of 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline 13 from β-ketoester 8a. a

[0809]

[0810] a Reaction (a): 10% p-TsOH, benzene, reflux, 21 hours; (b): Dowtherm A, 250°C, 5 minutes, 50%; POCl3, reflux, 45 minutes, 100%.

[0811] The biphenyl substituent R was then completed by selective Suzuki reaction of various boronic acids or pinacol esters 14a–k with 4-chloro-quinoline 13 using DMF containing Pd(dppf)Cl2 and K2CO3. 1 and R 2 The resulting 4-chloro-quinolines 15a-k are then converted to their corresponding 4(1H)-quinolones using EtOAc in AcOH.

[0812] Scheme 6: Synthesis of a series of ELQ compounds with structural variations at the terminal benzene ring. a

[0813]

[0814] a Reaction (a): Pd(dppf)Cl2, K2CO3, DMF, 80°C, 11-67%; (b): KOAc, AcOH, 16 hours, 36-87%.

[0815] For in vivo processing, ELQ-596 needs to be converted to the corresponding alkoxy carbonate prodrug ELQ-598. This was done using tetra-n-butylammonium iodide (TBAI) and K2CO3 in DMF according to previously published methods (Scheme 7). 9 Completed.

[0816] Scheme 7: Synthesis of alkoxy carbonate prodrug ELQ-598. a

[0817]

[0818] a Reaction (a): TBAI, K2CO3 and DMF, 60°C, 24 hours, 73%.

[0819] Results and discussion

[0820] Synthesis principles for 3-biaryl versions of ELQ-300. We maintain a large chemical library of >600 ELQ derivatives, and over the years, we (and others) have evaluated these drugs for their antiparasitic activity against a range of parasites, including Plasmodium falciparum, Toxoplasma gondii, Babesia microti, Babesia duncani, and related parasites of particular importance for veterinary medicine. All of this information is stored in a database containing information on chemical structure, physicochemical properties, cross-resistance patterns, mammalian cell toxicity, enzyme inhibitor profiles, and synthesis details. Pharmacological data and in vivo efficacy data are also stored in a database for promising molecules of interest. Recently, a retrospective analysis of the compounds prepared over the years was performed, and it was realized that neither we nor anyone else had yet synthesized a biphenyl analog of ELQ-300, namely ELQ-596 ( FIG. 1 ). As described above, batch sizes of approximately 800 mg of the compound were synthesized. ELQ-596 was then tested for its anti-plasmodial activity against four laboratory strains of Plasmodium falciparum, including the drug-sensitive D6 strain, the multidrug-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 with an initial range of 250 nM to 2.5 nM, and retested at a range of 1 / 10 of the initial range if drug potency expanded below this initial range. SyBr Green assays were used, and plates were incubated for 72 hours before harvesting. 18,19 Fluorescence readings were captured in a fluorescence plate reader and processed using Graphpad Prism software to generate IC 50 Values ​​and 95% confidence intervals for each determination. Stock solutions were freshly prepared in DMSO.

[0821] Table 1: Structure-activity profile of 3-biaryl-ELQ against drug-sensitive (D6) and drug-resistant (Dd2, C2B, and D1) strains of Plasmodium falciparum IC 50 The values ​​represent the drug concentration that inhibited parasite growth by 50% relative to the control without drug addition.

[0822]

[0823]

[0824] Table 2: Structure-activity profiles of 3-biaryl-ELQs against drug-sensitive (D6) and drug-resistant (Dd2, C2B, and D1) strains of Plasmodium falciparum. 50 The values ​​represent the drug concentration that inhibited parasite growth by 50% relative to the control without drug addition.

[0825]

[0826]

[0827] The in vitro activities of selected 3-biaryl-ELQs against P. falciparum strains are shown in Tables 1 and 2. 50 The values ​​are presented with 95% confidence intervals for individual experiments performed in quadruplicate. (Assays were repeated at least twice.) ELQ-598, an alkoxy-carbonate prodrug of ELQ-596, was also prepared and included in the assay using the historical controls atovaquone (ATV), ELQ-300, and ELQ-400. The latter is a Q-like drug that targets the cytochrome bcl complex of Plasmodium falciparum. o Note that ELQ-596 is effective against D6 and Dd2 strains and ATV. r IC of C2B (Table 1) 50 The IC values ​​of ELQ-300 against these insect strains were 50 Improved by 8 to 10 times, and its r The values ​​for the D1 clone were higher. These results are interpreted to indicate a higher inhibitory effect of ELQ-596 relative to wild-type P. falciparum cytochrome bcl and the mutant cytochrome bcl complex of clinical isolate Tm90-C2B.

[0828] ELQ-596 Metabolic Stability. The metabolic stability of ELQ-596 in the presence of pooled rat liver-derived microsomes was then evaluated. Due to its close structural similarity to ELQ-300, the new analog was expected to be stable under the assay conditions. The drug was incubated in the presence of pooled rat liver microsomes (0.5 mg / ml) at 37°C in the presence of NADPH to test P450 drug-dependent metabolism. Samples were extracted at 45 minute intervals and analyzed by LC-MS / MS for the presence of test compounds. Ketanserin served as an internal standard for the metabolic rate of known drugs with known intermediate stability. As shown in Table 3, the tests showed that ELQ-596 was extremely stable to microsomal attack, with negligible decomposition over the 45 minute incubation period, which resulted in a T of >4,000 minutes in this in vitro assay. 1 / 2 .

[0829] Table 3: Metabolic stability of ELQ-596 in the presence of mouse microsomes.

[0830]

[0831] In vivo efficacy of ELQ-596 and alkoxy carbonate prodrug ELQ-598 against murine malaria Next, we focused on testing ELQ-596 in vivo. Since it is a highly crystalline compound like ELQ-300, the alkoxy carbonate prodrug ELQ-598 was prepared. And, like ELQ-331, ELQ-598 exhibited a significant reduction in lattice energy, as evidenced by a 229°C drop in melting point (Table 3). ELQ-598 was tested in a 4-day test using a modified Peters protocol, in which all test animals were first inoculated with 35,000 infected red blood cells from donor mice infected with P. yoelii by tail vein injection (day 0). On days 1, 2, 3, and 4, animals were administered ELQ-598 dissolved in PEG400 (100 μl) by oral gavage. On day 5, a drop of blood was drawn from the tail and a blood smear was prepared, fixed with methanol, and stained with Giemsa. The operator then examined the stained smear microscopically to determine the percent parasitemia. Doses of 0.0025 mg / kg / day, 0.005 mg / kg / day, 0.01 mg / kg / day, 0.03 mg / kg / day, 0.1 mg / kg / day, 0.3 mg / kg / day, 1.0 mg / kg / day, and 10 mg / kg / day were used for the experiment. Based on two separate studies (4 mice / group), ED 50 and ED 90The mean estimated values ​​for ELQ-596 were 0.006 mg / kg / day and 0.01 mg / kg / day, respectively, with a non-relapse dose (NRD) of 0.1 mg / kg / day (Table 4). These values ​​are approximately 1 / 3 of the values ​​for ELQ-300 and ELQ-331. Reassuringly, the superiority of ELQ-596 transferred to the single curative dose (SDC) of the prodrug ELQ-598. In this model, animals were vaccinated precisely on day 0 in a 4-day test, but drug was only administered on day 1, with operators preparing smears on day 5 and again weekly thereafter to identify animals that were still non-parasitaemic. Animals that were still non-parasitaemic by day 30 were scored as cured. In this latter experiment, the lowest fully protective single curative dose was 0.5 mg / kg (0.6 mg / kg for the prodrug), the lowest dose tested to date. Thus, the prodrug ELQ-598 was at least 6 times more effective as a single curative dose against blood-stage malaria infection in mice than ELQ-331 used directly.

[0832] Table 4: Comparison of ELQ-300, prodrugs ELQ-331 and ELQ-596, and prodrug ELQ-598.

[0833]

[0834] MP = melting point; ED 50 -Dose required to suppress parasitemia by 50% relative to untreated controls (4-day Petri dish test), ED 90 =Dose required to suppress parasitemia by 90% relative to untreated controls (4-day Petri dish test, P. yoelii Kenya strain), NRD - non-relapse dose (4-day Petri dish test), and SDC - single curative dose (lowest single dose that provides complete cure of all 4 mice in the group). NT = not tested. ND = not determined. Note: Prodrugs are dosed based on molar equivalence to the parent drug.

[0835] Selective Inhibition of Parasite Cytochrome bcl Complex by ELQ-596 The ability of ELQ-596 to inhibit the activity of cytochrome bcl from Plasmodium falciparum was evaluated. As shown in Table 5, ELQ-596 had an IC of 0.1 nM. 50 The IC values ​​of atovaquone and ELQ-300 were significantly lower than those of atovaquone and ELQ-300. 50values. Note that the prodrug ELQ-598 exhibited only weak inhibitory activity against the parasite enzyme. ELQ-596 was also evaluated for inhibition of the human host cytochrome bc1 complex isolated from human liver tissue and found to have no detectable inhibition at a concentration of 10,000 nM. Overall, the data demonstrate that ELQ-596 is a highly selective inhibitor of the Plasmodium cytochrome bc1 complex, with a selectivity index of ≥18,000-fold based on enzyme inhibition activity. This high level of selectivity suggests a low potential for side effects in humans due to inhibition of the host enzyme complex.

[0836] Table 5: Comparative inhibition of P. falciparum (parasite) and human (host) cytochrome bcl complexes.

[0837]

[0838]

[0839] a Data taken from Nilsen et al., 2013. b Data taken from Frueh et al., 2017.

[0840] Assay conditions are presented in the Methods section.

[0841] Safety and mitochondrial toxicity of ELQ-596 and the prodrug ELQ-598. Of course, enhanced efficacy is only desirable if it is not accompanied by enhanced toxicity. Although the in vivo efficacy test model is not intended as a formal toxicity assessment, no changes in appearance, behavior, or weight were observed following administration of ELQ-598 at any dosing level. The cytotoxicity of ELQ-596 was also evaluated using the TiterGlo luminescence assay kit, which determines cell viability by measuring cellular ATP. In the assay, ATP is consumed as a co-substrate of luciferase in reaction with its substrate luciferin with the release of light. Using the human HepG2 cell line in a cell culture medium in which galactose was substituted for glucose to promote reliance on the oxidative phosphorylation process and reverse the so-called "Crabtree effect", an EC of ELQ-596 was observed. 50 >10 μM, while the control drug rotenone demonstrated considerable cytotoxicity under these conditions (EC 50 =? ) (Table 6) The incubation period for these experiments was 48 hours.

[0842] Table 6: Comparative inhibition of P. falciparum (parasite) and human (host) cytochrome bcl complexes.

[0843]

[0844] The Klebsiella pneumoniae effect was reversed by replacing glucose with galactose.

[0845] Cytotoxicity assay. Cytochrome bc1 assay conditions are presented in the Methods section. NT = not tested.

[0846] Based on previous pharmacokinetic experiments in mice, rats, and dogs, pharmacologists predict that a single 30 mg oral dose of formulated ELQ-331 will protect adults against malaria infection if taken weekly. A "backup plan" is believed to be delivering a more potent drug, perhaps the prodrug ELQ-598 or a variant thereof, which could provide the same degree of long-term protection but at a significantly lower dose, perhaps 5 mg to 10 mg on a weekly or biweekly schedule.

[0847] Materials and Methods

[0848] Chemical synthesis procedures.

[0849] Unless otherwise noted, all chemicals and reagents were obtained from Sigma-Aldrich Chemical Company in 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. 12The HPLC-MS / MS data are shown in Table 1. Melting points were obtained on an Optimelt automatic melting point system from Stanford Research Systems, Sunnyvale, CA (USA). Analytical TLC utilized Merck 60F-254 250 microns of pre-coated silica gel plates, and the spots were visualized under 254nm UV light. GC-MS was obtained using an Agilent Technologies 7890B gas chromatograph (30m, DBS column was set to 100°C or 200°C for 2 minutes, then 300°C / min was reached, with the inlet temperature being set to 250°C) and an Agilent Technologies 5977A mass selective detector operated at 70eV. Flash chromatography was performed on a silica gel column using an Isolera One flash chromatography system from Biotage, Uppsala, Sweden. The data were acquired using a Bruker 400 MHz Avance NEO NanoBay NMR spectrometer operating at 400.14 MHz. 1 H-NMR spectrum: The raw NMR data were analyzed using iNMR spectrum analysis software. 1 H chemical shifts are reported in parts per million (ppm) relative to an internal tetramethylsilane (TMS) standard or the residual solvent peak. Coupling constant values ​​(J) are reported in Hertz (Hz). Decoupled spectroscopy (TEM) operating at 376 MHz was also obtained for fluorinated compounds. 19 F (data not shown). Using Agilent 1260 Infinity instrument and Phenomenex 1260 Infinity instrument for detection at 254 nm 5μm C8(2) HPLC analysis was performed on a reverse phase LC column 150 x 4.6 mm at 40°C and eluted with a gradient of 25% / 75% A / B to 25% to 90% A / B (A: milliQ water containing 0.05% formic acid, B: methanol containing 0.05% formic acid). All compounds were >95% pure for in vitro testing and >98% pure for in vivo testing, as determined by GC-MS, 1 confirmed by H-NMR and HPLC.

[0850] 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 eq) and POCl3 (14 ml, 146 mmol, 5.1 eq) in DCM (100 ml) was refluxed for 72 hours. After cooling to room temperature, the mixture was filtered and the precipitate was washed with DCM (3 x 5 ml) and air dried to give pure 2 (9.8 g, 93% yield) as a white powder. At M + =366.9 (100%), GC-MS showed one peak. 1 H-NMR (400MHz; DMSO-d6): δ8.23(s,1H),7.70(s,H),7.08(s,1H),4.07(s,3H),2.42(s,3H).

[0851] 4,4,5,5-Tetramethyl-2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-1,3,2-dioxaborolane (4).

[0852] 6-Chloro-7-methoxy-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-596).

[0853] 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), KCO (27.6 g, 200.0 mmol, 1.2 equiv) and (Pd(dppf)Cl) (3.65 g, 5.0 mmol, 0.05 equiv) in DMF (250 ml) was deoxygenated by blowing argon through the reaction mixture for 15 minutes. The stirred reaction mixture was then heated at 80° C. under argon for 18 hours until no more starting material 5 remained as determined by GC-MS. The reaction was cooled to room temperature and filtered through celite, and the DMF was removed in vacuo. The resulting black oily solid was resuspended in DCM (500 ml) and stirred vigorously at room temperature for 30 minutes, filtered through celite, concentrated to dryness, and purified by flash chromatography on silica gel using a gradient of ethyl acetate / hexane (1 / 9) as the eluting solvent mixture to give 6 (18.7 g, 58% yield) as a white solid. + =324.1 (42%); 251.2 (100%), GC-MS showed one peak.1 H-NMR (400MHz; CDCl3): δ7.63-7.59(m,2H),7.56-7.53(m,2H),7.41-7.38(m,2H), 7.32-7.29(m,2H),4.21(q,J=7.1Hz,2H),3.69(s,2H),1.32-1.29(t,J=7.1Hz,3H).

[0854] 3-acetoxy-2-(4-bromophenyl) but-2-enoic acid ethyl ester (7a). The temperature produced is recorded by an internal thermometer. A stirred solution of dry THF (50ml) and HMDS (41.5g, 257.0mmol, 2.5 equivalents) is cooled to -20°C in 75% ethylene glycol, 25% ethanol and a dry ice bath under Ar. When monitoring the temperature to ensure that it does not exceed -10°C, hexane (n-BuLi) (98.8mL, 247.0mol, 2.4 equivalents) containing n-butyllithium (2.5M) is added. The temperature of the mixture is then reduced to -30°C, and a solution of 5 (25.0g, 103.0mol, 1.0 equivalents) in THF (50ml) is slowly added. The mixture is allowed to heat to -10°C, and stirred for 35 minutes while maintaining this temperature. Next, acetic anhydride (31.5 g, 309.0 mmol, 3.0 equivalents) was added dropwise and the mixture was then allowed to slowly warm to room temperature. The mixture became cloudy upon heating, but did not become jelly-like. The reaction progress 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 equivalents) was added. After stirring at room temperature for 72 hours, 19% of the starting material was still present, as determined by GC-MS. The reaction was stopped and the mixture was poured into a saturated ammonium chloride solution (100 ml), extracted with ethyl acetate (3 x 100 ml), and the organic layers were combined and concentrated to produce 35.0 g of a brown oil. GC-MS analysis was performed at M + =326 (2%), 238 (100%) showed a main peak (100%), in the case of M + =326 (2%), 238 (100%) showed a secondary peak (27%), and in M + =242 (25%), 168.9 (100%), another minor peak (19%, corresponding to 5) was shown. + =326 corresponds to the stereoisomers E and Z of the desired product 7a. Two D NOESY NMRs did not provide a clear assignment of the two stereoisomers. By GC-MS, the percentage of the major stereoisomer relative to the minor stereoisomer was estimated to be 80%. The product was used in the next step without further purification.

[0855] For analytical and characterization purposes, both stereoisomers were purified by flash chromatography using hexanes and ethyl acetate (5% to 15% gradient).

[0856] NMR of the main stereoisomer of 7a: 1 H-NMR (400MHz; CDCl3): δ7.51-7.48(m,2H),7.18-7.15(m,2H),4.14(q,J=7.1Hz,2H),2.23(s,3H),1.88(s,3H),1.19(t,J=7.1Hz,3H).

[0857] NMR of the minor stereoisomer of 7a: 1 H-NMR (400MHz; CDCl3): δ7.47-7.44(m,2H),7.08-7.05(m,2H),4.20(q,J=7.1Hz,2H),2.40(s,3H),1.88(s,3H),1.23(t,J=7.1Hz,3H).

[0858] 3-Acetoxy-2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)but-2-enoic acid ethyl ester (7b). The resulting temperature was recorded by an internal thermometer. A stirred solution of dry THF (50 ml) and HMDS (16.6 g, 102.9 mmol, 2.3 equiv) was cooled to -20 ° C in 75% ethylene glycol, 25% ethanol and a dry ice bath under Ar. While monitoring the temperature to ensure it did not exceed -10 ° C, n-BuLi (2.5 M) in hexanes (n-BuLi) (39.4 mL, 98.5 mmol, 2.2 equiv) was added dropwise, followed by a solution of 6 (14.5 g, 44.75 mmol, 1.0 equiv) in THF (50 ml). After stirring at -15°C to -10°C for 35 minutes, acetic anhydride (10.05 g, 11.3 ml, 98.5 mmol, 2.2 equivalents) was added dropwise while monitoring the temperature not to exceed -10°C. The solution was then allowed to gradually warm to room temperature, at which point it became a pale yellow gel. After stirring at room temperature for 20 hours, the mixture was poured into a saturated ammonium chloride solution (200 ml) and extracted with ethyl acetate (3 x 100 ml). The organic layers were then combined and concentrated to produce 17.3 g of a brown oil. GC-MS analysis was performed at M + =408 (3%), 320 (100%) showed a main peak (100%), in the case of M + =408 (3%), 320 (100%) showed a secondary peak (5%), and in M +=324 (42%), 251 (100%) showed another minor peak (5%, corresponding to the starting material 6). + =408 corresponds to a mixture of stereoisomers E and Z of the desired product 7b. Two D NOESY NMRs did not provide a clear assignment of the two stereoisomers. By GC-MS, the percentage of the major stereoisomer relative to the minor stereoisomer was estimated to be 95%. The product was used in the next step without further purification.

[0859] For analytical and characterization purposes, both stereoisomers were purified by flash chromatography using hexanes and ethyl acetate (5% to 50% gradient).

[0860] NMR of the main stereoisomer of 7b: 1 H-NMR (400MHz; CDCl3): δ7.66-7.62(m,2H),7.60-7.57(m,2H),7.41-7.38(m,2H),7.3 2-7.30(m,2H),4.20(q,J=7.1Hz,2H),2.27(s,3H),1.98(s,3H),1.25(t,J=7.1Hz,3H).

[0861] NMR of the minor stereoisomer of 7b: 1 H-NMR (400MHz; CDCl3): δ7.66-7.62(m,2H),7.57-7.54(m,2H),7.32-7.29(m ,4H),4.25(q,J=7.1Hz,2H),2.44(s,3H),1.90(s,3H),1.27(t,J=7.1Hz,3H).

[0862] 2-(4-bromophenyl)-3-oxobutanoic acid ethyl ester (8a). A stirred solution of bis-acylated 7a (32.6 g, 0.10 mol, 1 equivalent) in glacial acetic acid (100 ml) and p-TsOH monohydrate 98% (1.9 g, 0.1 mol, 0.1 equivalent) was heated at 100 ° C. After no more than 2 hours, the starting material 7a was detected by TLC and GC-MS. The dark brown solution was cooled to room temperature and concentrated under vacuum. After eliminating most of the acetic acid, cyclohexane (2x100 ml) was added to the brown oil and concentrated again to produce 30.5 g of 8a as a dark brown oil. Since this material still contains 1.9 g of p-TsOH, the output of 8a is 28.6 g (100% yield). The product can be used for the following Conrad-Limpach reaction without purification. Both the keto form and the enol form can be obtained by 1 H-NMR detected.

[0863] Ethyl 3-hydroxy-2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)but-2-enoate (8b). A stirred solution of the bisacylated 7b (11.8 g, 0.29 mol, 1 eq) in glacial acetic acid (25 ml) and p-TsOH monohydrate 98% (549 mg, 0.29 mol, 0.1 eq) was heated at 100°C. After no more than 16 hours, the starting material 7b was detected by TLC and GC-MS. It should be noted that the β-ketoester 8b decomposed in the injection port of the mass spectrometer to give a 100% yield at M 2 . + =294 (32%), 251 (100%) produce main peak. The dark brown solution is cooled to room temperature and concentrated under vacuum. After eliminating most of the acetic acid, cyclohexane (2x50ml) is added to the brown oil and concentrated again to produce 10.0g of 10b as a dark brown oil. Since this material still contains 549mg p-TsOH, the output of 5 is 9.45g (89% yield). The product can be used for the following Conrad-Limpach reaction without purification. Both the keto form and the enol form can be 1 H-NMR detected.

[0864] General procedure for the preparation of Schiff bases (10a-d and 11). A stock solution of β-ketoester 8a or 8b in benzene (0.92 g / 10 ml = 2.5 mM) containing 0.1 equivalents of p-TsOH (0.25 mM) was prepared and maintained. A stirred solution of aliquots of substituted anilines (9a-d) in benzene and β-ketoester 8a or 8b was heated at reflux for 24-72 hours using a Dean-Stark trap to continuously remove water through the azeotropic point and monitored by GC-MS for the disappearance of β-ketoester 8a or 8b. The solution was then concentrated in vacuo to yield the product Schiff base (10a-d and 11) as a yellow-brown, highly viscous oil.

[0865] 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 portionwise over approximately 5 minutes to 65 ml of boiling Dowtherm A (250° C.) with vigorous stirring to maintain the boiling of Dowtherm A. The mixture was kept boiling for an additional 5 minutes, then allowed to cool to room temperature and diluted with hexane (250 ml), resulting in a precipitate that was filtered and washed with ethyl acetate and acetone until a colorless filtrate was obtained.

[0866] 2-Methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-649).

[0867]

[0868] Following the general procedure for the preparation of Schiff bases, a mixture of aniline 9a (0.47 g, 5.0 mol, 1 eq), benzene (125 ml), β-ketoester 8b (5.0 mmol, 1 eq) containing p-TsOH (0.5 mmol, 0.1 eq) was heated at reflux for 24 h and then followed the general procedure of the Conrad-Limpach reaction to give ELQ-649 (0.64 g, 32% yield) after crystallization using DMF as a white powder. 1 H-NMR (400 MHz; DMSO-d6): δ 11.68 (s, 1H), 8.10 (dd, J = 8.1, 1.5 Hz, 1H), 7.87-7.83 (m, 2H), 7.73-7.70 (m, 2H), 7.65 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.56-7.54 (m, 1H), 7.49-7.46 (m, 2H), 7.39-7.36 (m, 2H), 7.30 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 2.29 (s, 3H). By HPLC and 1 H-NMR showed that the purity of the product was >98%.

[0869] 6-Chloro-7-methoxy-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-596).

[0870]

[0871] Following the general procedure for the preparation of Schiff bases, a mixture of aniline 9b (0.78 g, 5.0 mmol, 1 eq), benzene (125 ml), β-ketoester 8b (5.0 mmol, 1 eq) containing p-TsOH (0.5 mmol, 0.1 eq) was heated at reflux for 72 h, and then followed the general procedure of the Conrad-Limpach reaction to give ELQ-596 (0.77 g, 34% yield) as a white powder. 1 H-NMR (400 MHz; DMSO-d6): δ 11.69 (s, 1H), 8.01 (s, 1H), 7.87-7.83 (m, 2H), 7.72-7.69 (m, 2H), 7.50-7.44 (m, 2H), 7.38-7.35 (m, 2H), 7.09 (s, 1H), 3.97 (s, 3H), 2.26 (s, 3H). By HPLC and 1 H-NMR showed that the purity of the product was >98%.

[0872] 6-Fluoro-7-methoxy-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-650).

[0873]

[0874] Following the general procedure for the preparation of Schiff bases, a mixture of aniline 9c (0.71 g, 5.0 mmol, 1 eq), benzene (125 ml), β-ketoester 8b (5.0 mmol, 1 eq) containing p-TsOH (0.5 mmol, 0.1 eq) was heated at reflux for 46 h, and then followed the general procedure of the Conrad-Limpach reaction to give ELQ-650 (0.61 g, 28% yield) as a white powder. 1 H-NMR (400 MHz; DMSO-d6): δ11.66 (s, 1H), 7.86-7.83 (m, 2H), 7.73-7.69 (m, 3H), 7.50-7.44 (m, 2H), 7.37-7.35 (m, 2H), 7.11 (d, J=7.4 Hz, 1H), 3.96 (s, 3H), 2.26 (s, 3H). 1 H-NMR showed that the purity of the product was >98%.

[0875] 5,7-Difluoro-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-601).

[0876]

[0877] Following the general procedure for the preparation of Schiff bases, a mixture of aniline 9d (0.71 g, 5.0 mmol, 1 eq), benzene (125 ml), β-ketoester 8b (5.0 mmol, 1 eq) containing p-TsOH (0.5 mmol, 0.1 eq) was heated at reflux for 72 h, and then followed the general procedure of the Conrad-Limpach reaction to give ELQ-601 (0.80 g, 37% yield) as a white powder. 1 H-NMR (400 MHz; DMSO-d6): δ 11.76 (s, 1H), 7.87-7.83 (m, 2H), 7.73-7.69 (m, 2H), 7.48-7.46 (m, 2H), 7.36-7.32 (m, 2H), 7.11-7.08 (m, 1H), 7.04 (ddd, J = 11.9, 9.6, 2.4 Hz, 1H), 2.22 (s, 3H). By HPLC and 1 H-NMR showed that the purity of the product was >98%.

[0878] 3-(4-Bromophenyl)-6-chloro-7-methoxy-2-methylquinolin-4(1H)-one (12). Following the general procedure for the preparation of Schiff bases, a mixture of aniline 9b (13.0 g, 83.0 mmol, 1 eq), benzene (150 ml), β-ketoester 8a (23.7 g, 83.0 mmol, 1 eq) containing p-TsOH (8.3 mmol, 0.1 eq) was heated under reflux for 21 h. The Schiff base was then diluted with Dowtherm A (30 ml) and added to boiling Dowtherm A (200 ml) following the general procedure for the Conrad-Limpach reaction. After cooling, a precipitate formed while stirring. Hexanes (800 ml) were added to form a sticky solid which was filtered and stirred with acetone (150 ml) for 15 min, filtered, washed with acetone (3 x 25 ml) and air dried to give pure 12 (14.7 g, 49.5% yield) as a white solid. 1 H-NMR (400MHz; DMSO-d6): δ11.70(s,1H),7.99(s,1H),7.58-7.56(m,2H),7.24-7.18(m,2H),7.07(s,1H),3.96(s,3H),2.21(s,3H).

[0879] 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 minutes. After cooling to room temperature, the solution was slowly poured into vigorously stirred water (800 ml) over 10 minutes and stirred for another 5 minutes. The formed precipitate was washed with water (50 ml), acetone (2 x 25 ml) and air dried to give pure 13 (15.7 g, 100% yield). At M + In the case of =395 (63%), 397 (100%), 399 (47%), and 401 (10%), GC-MS showed one peak. 1 H-NMR (400 MHz; DMSO-d6): 1 H-NMR (400MHz; DMSO-d6): δ8.18(s,1H),7.76-7.73(m,2H),7.64(s,1H),7.37-7.34(m,2H),4.05(s,3H),2.38(s,3H).

[0880] 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, KCO and Pd(dppf)Cl in DMF was deoxygenated by blowing argon through the solution for 15 minutes. The stirred reaction mixture was then heated at 80°C under argon until almost no more starting material 13 remained as determined by GC-MS. The reaction was cooled to room temperature and filtered through celite, and the DMF was removed in vacuo. The resulting black oily solid was resuspended in DCM and vigorously stirred at room temperature for 30 minutes, filtered through celite, and concentrated to dryness. The residue was extracted with 3-5 ml of DCM, and if all the solids dissolved, the product was purified by flash chromatography. In some instances where the product was insoluble in methylene chloride, the product was filtered, washed with DCM, and the filtrate was further purified by chromatography to obtain additional product.

[0881] 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 in a loosely capped reaction vial for 16-26 hours.

[0882] 4,6-dichloro-3-(4'-chloro-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (15a). Following the general procedure for the preparation of biphenylquinoline, a mixture of 13 (740 mg, 1.86 mmol, 1 eq), 14a (435 mg, 2.79 mmol, 1.5 eq), KCO (513 mg, 3.72 mmol, 2 eq) and Pd(dppf)Cl (68 mg, 0.093 mmol, 0.05 eq) and DMF (75 ml) was heated for 16 h to produce crude 25 (911 mg) as a black solid. DCM (5 ml) was added and the precipitate was filtered and washed with methylene chloride (2 x 5 ml) to produce 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 eluting solvent to give a combined yield of 15a (257 mg, 32% yield) in additional 15a (99 mg). + =427 (100%), GC-MS showed one peak. 1 H-NMR (400MHz; CDCl3): δ8.27(s,1H),7.74-7.71(m,2H),7.65-7.62(m,2H),7.49-7.46(m,3H),7.39-7.36(m,2H),4.10(s,3H),2.52(s,3H).

[0883] 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 biphenylquinoline, a mixture of 13 (794 mg, 2.0 mmol, 1 eq), 14b (326 mg, 2.4 mmol, 1.2 eq), K2CO3 (552 mg, 4.0 mmol, 2 eq) and Pd(dppf)Cl2 (73 mg, 0.10 mmol, 0.05 eq) and DMF (75 ml) was heated for 16 h to produce 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 eluting solvent to produce pure 15b (328 mg, 40% yield) as a white solid. + = 407 (100%), GC-MS showed one peak. 1 H-NMR (400MHz; CDCl3): δ8.27(s,1H),7.76-7.73(m,2H),7.62-7.59(m,2H) ),7.49(s,1H),7.37-7.30(m,4H),4.09(s,3H),2.53(s,3H),2.45(s,3H).

[0884] 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 biphenylquinoline, a mixture of 13 (794 mg, 2.0 mmol, 1 eq), 14c (427 mg, 2.4 mmol, 1.2 eq), K2CO3 (552 mg, 4.0 mmol, 2 eq) and Pd(dppf)Cl2 (73 mg, 0.10 mmol, 0.05 eq) and DMF (75 ml) was heated for 16 h to produce 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 elution solvent to give pure 15c (331 mg, 37% yield) as a white solid. + =450 (63%) and 434 (100%), GC-MS showed one peak. 1H-NMR (400MHz; CDCl3): δ8.28(s,1H),7.77-7.74(m,2H),7.66-7.64(m,2H),7.55-7 .52(m,2H),7.50(s,1H),7.37-7.33(m,2H),4.10(s,3H),2.53(s,3H),1.41(s,9H).

[0885] 4,6-Dichloro-7-methoxy-2-methyl-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)quinoline (15d). Following the general procedure for the preparation of biphenylquinoline, a mixture of 13 (794 mg, 2.0 mmol, 1 eq), 14d (456 mg, 2.4 mmol, 1.2 eq), KCO (552 mg, 4.0 mmol, 2 eq), and Pd(dppf)Cl (73 mg, 0.10 mmol, 0.05 eq) and DMF (75 ml) was heated for 36 h to produce crude 15d (1.12 g) as a reddish-black solid. DCM (5 ml) was added, and the precipitate was filtered and washed with methylene chloride (2 x 5 ml) to produce pure 15d (320 mg, 35% yield) as a white solid. In the case of M+ = 461 (100%), GC-MS showed one peak. 1 H-NMR (400MHz; CDCl3): δ8.28(s,1H),7.83-7.80(m,2H),7.78-7.76(m,4H),7.50(s,1H),7.42-7.40(m,2H),4.10(s,3H),2.53(s,3H).

[0886] 4'-(4,6-dichloro-7-methoxy-2-methylquinolin-3-yl)-[1,1'-biphenyl]-4-carbonitrile (15e). Following the general procedure for the preparation of biphenylquinoline, a mixture of 13 (794 mg, 2.0 mmol, 1 eq), 14e (353 mg, 2.4 mmol, 1.2 eq), KCO (552 mg, 4.0 mmol, 2 eq) and Pd(dppf)Cl (73 mg, 0.10 mmol, 0.05 eq) and DMF (75 ml) was heated for 36 hours to produce crude 15e (769 mg) as a black solid. DCM (5 ml) was added, and the precipitate was filtered and washed with DCM (2x5 ml) to produce 15e (384 mg) as a white solid. The product was further recrystallized by DMF to produce 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 additional 29 (90 mg) in a combined yield of 15e (380 mg, 45% yield). + =418 (100%), GC-MS showed one peak. 1 H-NMR (400MHz; CDCl3): δ8.26(s,1H),7.82-7.79(m,4H),7.77-7.75(m,2H),7.49(s,1H),7.44-7.41(m,2H),4.09(s,3H),2.51(s,3H).

[0887] 4,6-Dichloro-3-(4'-(difluoromethyl)-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (15f). Following the general procedure for the preparation of biphenylquinoline, a mixture of 13 (397 mg, 1.0 mmol, 1 eq), 14f (206 mg, 1.2 mmol, 1.2 eq), K2CO3 (276 mg, 2.0 mmol, 2 eq) and Pd(dppf)Cl2 (73 mg, 0.10 mmol, 0.1 eq) and DMF (3 ml) was heated for 36 h to produce crude 15f as a brown solid. DCM (5 ml) was added and the precipitate was filtered and washed with DCM (2x5 ml) to produce 15f as a white solid. The product was further recrystallized from DMF to produce pure 15f (220 mg, 50% yield) as a white solid. At M + =443.1 (100%), GC-MS showed one peak. 1H-NMR (400MHz; CDCl3): δ8.26(s,1H),7.79-7.73(m,4H),7.66-7.61(m,2H),7 .48(s,1H),7.40-7.35(m,2H),6.73(t,1H,J=57Hz),4.08(s,3H),2.51(s,3H).

[0888] 4,6-dichloro-7-methoxy-3-(4'-methoxy-[1,1'-biphenyl]-4-yl)-2-methylquinoline (15 g). Following the general procedure for the preparation of biphenylquinoline, a mixture of 13 (794 mg, 2.0 mmol, 1 eq), 14 g (365 mg, 2.4 mmol, 1.2 eq), KCO (552 mg, 4.0 mmol, 2 eq), and Pd(dppf)Cl (73 mg, 0.10 mmol, 0.05 eq) and DMF (75 ml) was heated for 16 h to yield crude 15 g (1.29 g) as a black solid. DCM (5 ml) was added, and the precipitate was filtered and washed with DCM (2 x 5 ml) to yield pure 15 g (255 mg) as a white solid. The filtrate was further purified by flash chromatography using a gradient of DCM / ethyl acetate (95 / 5) as eluting solvent to give a combined yield of 15 g (398 mg, 47% yield) of an additional 15 g (143 mg). + =423 (100%), GC-MS showed one peak. 1 H-NMR (400MHz; CDCl3): δ8.27(s,1H),7.73-7.71(m,2H),7.66-7.64(m,2H),7.49(s ,1H),7.35-7.33(m,2H),7.05-7.03(m,2H),4.09(s,3H),3.90(s,3H),2.53(s,3H).

[0889] 4,6-Dichloro-3-(4'-(difluoromethoxy)-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (15h). Following the general procedure for the preparation of biphenylquinolines, a mixture of 13 (794 mg, 2.0 mmol, 1 eq), 14h (648 mg, 2.4 mmol, 1.2 eq), KCO (552 mg, 4.0 mmol, 2 eq), and Pd(dppf)Cl (73 mg, 0.10 mmol, 0.05 eq) in DMF (75 ml) was heated for 16 h to yield crude 15h (1.073 g) as a black solid. DCM (5 ml) was added, and the precipitate was filtered, washed with DCM (2 x 5 ml), and then crystallized from DCM to yield 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 eluting solvent to give a combined yield of 15h (552 mg, 60% yield) of additional 15h (140 mg). + =459 (100%), GC-MS showed one peak. 1 H-NMR (400MHz; CDCl3): δ8.27(s,1H),7.74-7.68(m,4H),7.49(s,1H),7.39-7.36(m ,2H),7.28-7.24(m,2H),6.60(t,J=73.8Hz,1H),4.10(s,3H),2.52(d,J=2.9Hz,3H).

[0890] 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 biphenylquinolines, a mixture of 13 (794 mg, 2.0 mmol, 1 eq), 14i (456 mg, 2.4 mmol, 1.2 eq), KCO (552 mg, 4.0 mmol, 2 eq), and Pd(dppf)Cl (73 mg, 0.10 mmol, 0.05 eq) in DMF (75 ml) was heated at 120 °C for 36 h to produce crude 15i (932 mg) as a black solid. The product was soluble in DCM and purified by flash chromatography using a gradient of ethyl acetate / hexane (6 / 4) as the elution solvent to produce approximately 95% pure 15i (100 mg, 11% yield) as a white solid. In M + =461 (100%), GC-MS showed one main peak. 1H-NMR (400MHz; CDCl3): δ8.28(s,1H),7.96-7.88(m,2H),7.79-7.76(m,2H), 7.69-7.63(m,2H),7.50(s,1H),7.43-7.40(m,2H),4.10(s,3H),2.53(s,3H).

[0891] 4,6-Dichloro-7-methoxy-2-methyl-3-(3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinoline (15j). Following the general procedure for the preparation of biphenylquinoline, a mixture of 13 (794 mg, 2.0 mmol, 1 eq), 14j (494 mg, 2.4 mmol, 1.2 eq), K2CO3 (552 mg, 4.0 mmol, 2 eq) and Pd(dppf)Cl2 (73 mg, 0.10 mmol, 0.05 eq) and DMF (75 ml) was heated for 16 h to produce 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 elution solvent to give 15j (639 mg, 67% yield) as a white solid. + = 477 (100%), GC-MS showed a peak corresponding to the starting material 13 and + = 397 (100%), a minor peak was shown. GC-MS and NMR indicated that 15j was pure enough (about 95%) to be used in the next step.

[0892] 4,6-Dichloro-7-methoxy-2-methyl-3-(4'-(4-(trifluoromethoxy)phenoxy)-[1,1'-biphenyl]-4-yl)quinoline (15k). Following the general procedure for the preparation of biphenylquinolines, a mixture of 13 (794 mg, 2.0 mmol, 1 eq), 14k (1.18 g, 3 mmol, 1.5 eq), KCO (552 mg, 4.0 mmol, 2 eq) and Pd(dppf)Cl (73 mg, 0.10 mmol, 0.05 eq) and DMF (75 ml) was heated for 48 h to give crude 15k (1.42 g) as a black solid. DCM (5 ml) was added and the precipitate was filtered and washed with DCM (2 x 5 ml) to give pure 15k (110 mg) as a white solid. The filtrate was further purified by flash chromatography using a gradient of ethyl acetate / hexane (3 / 7) as the eluting solvent to give additional 15k (489 mg) in a combined yield of 15k (599 mg, 53% yield). + =569 (100%), GC-MS showed one peak.1 H-NMR (400MHz; CDCl3): δ8.28(s,1H),7.75-7.72(m,2H),7.71-7.69(m,2H),7.50(s,1H),7.39- 7.35(m,2H),7.26-7.23(m,2H),7.17-7.13(m,2H),7.12-7.08(m,2H),4.10(s,3H),2.53(s,3H).

[0893] 6-Chloro-3-(4'-chloro-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-637).

[0894]

[0895] Following the general procedure for the hydrolysis of 4-chloroquinoline, a mixture of 15a (157 mg, 0.3 mmol, 1 eq), KOAc (360 mg, 3.7 mmol, 10 eq) 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 recovered by vacuum filtration, rinsed with excess water, followed by acetone (3×5 ml), and air-dried to yield ELQ-637 (0.104 g, 69% yield) as a light gray-brown powder. 1 H-NMR (400MHz; DMSO-d6): δ11.70(s,1H),8.01(s,1H),7.78-7.73(m,2H),7.72-7.66 (m,2H),7.57-7.51(m,2H),7.38-7.32(m,2H),7.08(s,1H),3.97(s,3H),2.26(s,3H).

[0896] 6-Chloro-7-methoxy-2-methyl-3-(4'-methyl-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-603).

[0897]

[0898] Following the general procedure for the hydrolysis of 4-chloroquinoline, a mixture of 15b (204 mg, 0.5 mmol, 1 eq), KOAc (490 mg, 5.0 mmol, 10 eq) and glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was poured into ice water (20 ml). The resulting precipitate was filtered, washed with water (3 x 10 ml), acetone (2 x 10 ml), DCM (2 x 10 ml), hexane (10 ml), and air-dried to yield pure ELQ-603 (170 mg, 87% yield) as a white solid. 1 H-NMR (400MHz; DMSO-d6): δ11.69-11.67(s,1H),8.02(s,1H),7.66-7.60(m,4H ),7.32-7.28(m,4H),7.08(s,1H),3.97(s,3H),2.36-2.33(s,3H),2.25(s,3H).

[0899] 3-(4'-(tert-Butyl)-[1,1'-biphenyl]-4-yl)-6-chloro-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-651).

[0900]

[0901] Following the general procedure for the hydrolysis of 4-chloroquinoline, a mixture of 15c (225 mg, 0.5 mmol, 1 eq), KOAc (490 mg, 5.0 mmol, 10 eq) and glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was poured into ice water (20 ml). The resulting precipitate was filtered, washed with water (3 x 10 ml), acetone (2 x 10 ml), DCM (2 x 10 ml), hexane (10 ml), and air-dried to yield pure ELQ-651 (184 mg, 85% yield) as a white solid. 1 H-NMR (400MHz; DMSO-d6): δ11.68(s,1H),8.02(s,1H),7.67-7.64(m,4H),7.51 (m,2H),7.34-7.32(m,2H),7.09(s,1H),3.98(s,3H),2.27(s,3H),1.34(s,9H).

[0902] 6-Chloro-7-methoxy-2-methyl-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-647).

[0903]

[0904] Following the general procedure for the hydrolysis of 4-chloroquinoline, a mixture of 15d (231 mg, 0.5 mmol, 1 eq), KOAc (490 mg, 5.0 mmol, 10 eq) and glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was poured into ice water (20 ml). The resulting precipitate was filtered, washed with water (3 x 10 ml), acetone (2 x 10 ml), DCM (2 x 10 ml), hexane (10 ml), and air-dried to yield pure ELQ-647 (180 mg, 81% yield) as a white solid. 1 H-NMR (400MHz; DMSO-d6): δ11.71(s,J=0.2Hz,1H),8.02(s,J=1.7Hz,1H),7.98-7.95(m,2H),7 .85-7.83(m,2H),7.79-7.77(m,2H),7.41-7.39(m,2H),7.10(s,1H),3.98(s,3H),2.27(s,3H).

[0905] 4'-(6-Chloro-7-methoxy-2-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-[1,1'-biphenyl]-4-carbonitrile (ELQ-602).

[0906]

[0907] Following the general procedure for the hydrolysis of 4-chloroquinoline, a mixture of 15e (231 mg, 0.5 mmol, 1 eq), KOAc (490 mg, 5.0 mmol, 10 eq) and glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was poured into ice water (20 ml). The resulting precipitate was filtered, washed with water (3 x 10 ml), acetone (2 x 10 ml), DCM (2 x 10 ml), hexane (10 ml), and air-dried to yield pure ELQ-602 (172 mg, 86% yield) as a white solid. 1 H-NMR (400 MHz; DMSO-d6): δ11.70 (s, 1H), 7.96 (broad d, J = 32.4 Hz, 4H), 7.77 (broad d, J = 7.9 Hz, 2H), 7.39 (broad d, J = 7.8 Hz, 2H), 7.07 (s, 1H), 3.97 (s, 3H), 2.26 (s, 3H).

[0908] 6-Chloro-3-(4'-(difluoromethyl)-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-659).

[0909]

[0910] Following the general procedure for the hydrolysis of 4-chloroquinoline, a mixture of 15f (210 mg, 0.5 mmol, 1 eq), KOAc (490 mg, 5.0 mmol, 10 eq) and glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was poured into ice water (10 ml). The resulting precipitate was filtered, washed with water (3 x 3 ml), acetone (2 x 3 ml), methylene chloride (2 x 3 ml), hexane (20 ml), and air-dried to yield pure ELQ-659 (105 mg, 52% yield) as a white solid. 1 H-NMR (400MHz; DMSO-d6): δ11.70(s,1H),8.02(s,1H),7.87(d,J=7.9Hz,2H),7.74(d,J=7.9Hz,2H),7.6 8(d,J=7.9Hz,2H),7.37(d,J=7.9Hz,2H),7.10(t,J=56.3Hz,1H),7.09(s,1H),3.98(s,3H),2.27(s,3H).

[0911] 6-Chloro-7-methoxy-3-(4'-methoxy-[1,1'-biphenyl]-4-yl)-2-methylquinolin-4(1H)-one (ELQ-645).

[0912]

[0913] Following the general procedure for hydrolysis of 4-chloroquinoline, a mixture of 15 g (212 mg, 0.5 mmol, 1 eq), KOAc (490 mg, 5.0 mmol, 10 eq) and glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was poured into ice water (20 ml). The resulting precipitate was filtered, washed with water (3 x 10 ml), acetone (2 x 10 ml), DCM (2 x 10 ml), hexane (10 ml), and air-dried to yield pure ELQ-645 (160 mg, 79% yield) as a white solid. 1 H-NMR (400MHz; DMSO-d6): δ11.67(s,1H),8.02(s,1H),7.68-7.62(m,3H),7 .32-7.29(m,2H),7.09-7.04(m,2H),3.98(s,3H),3.82(s,3H),2.26(s,2H).

[0914] 6-Chloro-3-(4'-(difluoromethoxy)-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-600).

[0915]

[0916] Following the general procedure for the hydrolysis of 4-chloroquinoline, a mixture of 15h (230 mg, 0.5 mmol, 1 eq), KOAc (490 mg, 5.0 mmol, 10 eq) and glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was poured into ice water (20 ml). The resulting precipitate was filtered, washed with water (3 x 10 ml), acetone (2 x 10 ml), DCM (2 x 10 ml), hexane (10 ml), and air-dried to yield pure ELQ-600 (165 mg, 75% yield) as a white solid. 1 H-NMR (400 MHz; DMSO-d6): δ11.74 (s, 1H), 8.02 (s, 1H), 7.77 (broad d, J = 8.7 Hz, 2H), 7.67 (broad d, J = 8.3 Hz, 2H), 7.31 (t, J = 73.8 Hz, 1H)), 7.34 (broad d, J = 8.3 Hz, 2H), 7.29 (broad d, J = 8.6 Hz, 2H), 7.07 (s, 1H), 3.96 (s, 3H), 2.25 (s, 3H).

[0917] 6-Chloro-7-methoxy-2-methyl-3-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-646).

[0918]

[0919] Following the general procedure for hydrolyzing 4-chloroquinoline, a mixture of 15i (87 mg, 0.188 mmol, 1 eq), KOAc (184 mg, 1.82 mmol, 10 eq) and glacial acetic acid (5 ml) was heated for 16 hours. After cooling to room temperature, the reaction mixture was poured into ice water (20 ml). The resulting precipitate was filtered, washed with water (3x10 ml), acetone (2x10 ml), DCM (2x10 ml), hexane (10 ml), and air-dried to produce ELQ-646 (30 mg, 36% yield) as a white solid. The purity of the product was 95-98% by NMR and HPLC. 1H-NMR (400MHz; DMSO-d6): δ11.70(s,1H),8.07-8.04(m,1H),8.02(s,2H),7 .80-7.73(m,4H),7.41-7.37(m,2H),7.10(s,1H),3.98(s,3H),2.28(s,3H).

[0920] 6-Chloro-7-methoxy-2-methyl-3-(3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-604).

[0921]

[0922] Following the general procedure for hydrolysis of 4-chloroquinoline, a mixture of 15j (476 mg, 1.0 mmol, 1 eq), KOAc (980 mg, 10.0 mmol, 10 eq) and glacial acetic acid (5 ml) was heated for 16 h. After cooling to room temperature, the reaction mixture was poured into ice water (20 ml). The resulting precipitate was filtered, washed with water (3 x 10 ml), acetone (2 x 10 ml), DCM (2 x 10 ml), hexane (10 ml), and air-dried to yield crude ELQ-604 (350 mg). The product was crystallized from DMF to yield ELQ-604 (200 mg, 43% yield). NMR and HPLC indicated the purity of the product to be approximately 95-98%. 1 H-NMR (400MHz; DMSO-d6): δ11.70(s,1H),8.02(s,1H),7.79(ddd,J=7.9,1.7,0.9Hz,1H),7.76-7.73( m,2H),7.69(s,1H),7.63(t,J=8.0Hz,1H),7.40-7.36(m,3H),7.09(s,1H),3.98(s,3H),2.27(s,3H).

[0923] Ethyl ((6-chloro-7-methoxy-2-methyl-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4-yl)oxy)methyl carbonate (ELQ-598).

[0924]

[0925] A stirred mixture of ELQ-596 (460 mg, 1.0 mmol, 1 eq), tetrabutylammonium iodide (742 mg, 2.0 mmol, 2 eq), chloromethylethyl carbonate (278 mg, 2.0 mmol, 2 eq) and dried KCO (278 mg, 2.0 mmol, 2 eq) in DMF (25 ml) was heated at 60° C. for 24 h, at which time TLC showed no more starting material remaining. The mixture was allowed to cool to room temperature, filtered, and the filtrate was concentrated to dryness to yield 700 mg of a brown oil. The resulting residue was stirred with ethyl acetate (50 ml) for 30 min, and the soluble tetrabutylammonium iodide was filtered and washed with ethyl acetate (3×10 ml). The filtrate was concentrated to dryness and purified by flash chromatography using a gradient of ethyl acetate / hexane (1 / 1) as eluent to yield pure ELQ-598 (412 mg, 73% yield) as a white solid. HPLC showed 1 peak and greater than 98% purity. + =561 (53%) and 459 (100%), GC-MS showed one peak. 1 H-NMR (400MHz; CDCl3): δ8.08(s,1H),7.74-7.70(m,4H),7.51-7.48(m,2H),7.46(s,1H),7.37-7 .34(m,2H),5.31(s,2H),4.13(q,J=7.1Hz,2H),4.07(s,3H),2.56(s,3H),1.22(t,J=7.1Hz,3H).

[0926] 6-Dichloro-7-methoxy-2-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinoline:

[0927]

[0928] A mixture of 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline (7.08 g, 0.18 mol), bis(pinacolato)diboron (1.4 eq., 6.34 g, 0.025 mol), and potassium acetate (3.0 eq., 5.24 g, 0.0534 mol) in 250 mL of N,N-dimethylformamide was degassed by bubbling argon through a glass tube inserted below the liquid surface at room temperature for 20 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.65 g, 0.00089 mol) was added, followed by heating at 80°C under an argon atmosphere. After 72 hours, TLC and GC / MS indicated that unreacted quinoline starting material was still present. The reaction was cooled to room temperature and degassed again, followed by the addition of additional [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (2.4 mol%, 0.32 g, 0.00044 mol). The reaction was again heated at 80°C under argon for 72 hours. Although TLC and GC / MS indicated that a small amount of unreacted 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline remained, the reaction was removed from the heat, filtered through celite, and concentrated under reduced pressure by heating. The resulting black residue was dissolved in dichloromethane (250 mL) and filtered through celite. The dark filtrate was concentrated under reduced pressure by heating to give a black residue. This material was redissolved in dichloromethane (300 mL) and washed with 5% brine (2 x 100 mL) and then with 10% brine (100 mL). The organic layer drying (MgSO 4 ) that is collected is made, and under reduced pressure, by heating evaporation, thereby produces black solid (11.44g).This material is dissolved in 15mL dichloromethane, and by silica gel plug filtration (100g, with dichloromethane pre-wetting), with 98 / 2v / v dichloromethane / ethyl acetate washing, until by TLC, no more product wash-out.The evaporation of filtrate has produced light green grey solid (7.22g).On silica, the automation flash chromatography that carries out wash-out with the gradient of 100% dichloromethane and 98 / 2v / v dichloromethane / ethyl acetate has produced the desired product (R f =0.21,98 / 2v / v dichloromethane / ethyl acetate) (3.66 g, 46%, 1 H-NMR (400MHz; CDCl3): δ8.23(s,1H),7.97-7.94(m,2H),7.46(s,1H),7.30-7.27(m,2H),4.06(s,3H),2.43(s,3H),1.38(s,12H)).

[0929] 4,6-Dichloro-7-methoxy-2-methyl-3-(3'-(pentafluorosulfanyl)-[1,1'-biphenyl]-4-yl)quinoline:

[0930]

[0931] A mixture of 4,6-dichloro-7-methoxy-2-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinoline (0.46 g, 0.0010 mol), anhydrous potassium carbonate (2.0 eq, 0.0021 mol, 0.29 g), and m-bromophenylsulfur pentafluoride (1.3 eq, 0.0013 mol, 0.38 g) in N,N-dimethylformamide (55 mL) was degassed by blowing argon through a glass tube below 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, followed by heating at 80°C under an argon atmosphere for 22 hours. The cooled reaction mixture was filtered through celite. The filtrate is under reduced pressure concentrated by heating, and the dark solid produced is dissolved in dichloromethane (125mL), and again filtered through diatomite.The filtrate is adsorbed on silica, and the flash chromatography that carries out wash-out by the gradient of 95 / 5 to 77 / 23v / v hexane / ethyl acetate is purified.The desired product (R) obtained is a white solid. f =0.41 (3 / 2 v / v hexane / ethyl acetate, silica) (0.45 g, 70%, 1 H-NMR (400MHz; CDCl3): δ8.26(s,1H),8.06-8.04(m,1H),7.83-7.81(m,1H),7.78(ddd,J=8.3,2.2,1.0H z,1H),7.74-7.71(m,2H),7.61-7.57(m,1H),7.48(s,1H),7.42-7.38(m,2H),4.08(s,3H),2.50(s,3H)).

[0932] 6-Chloro-7-methoxy-2-methyl-3-(3'-(pentafluorosulfanyl)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-662):

[0933]

[0934] 4,6-Dichloro-7-methoxy-2-methyl-3-(3'-(pentafluorosulfanyl)-[1,1'-biphenyl]-4-yl)quinoline (0.45 g, 0.00086 mol) and potassium acetate (10 equiv, 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 iced at 5°C for 30 minutes. Vacuum filtration, rinsing with excess water, followed by rinsing with acetone (5 x 1.5 mL) gave the desired product (0.21 g, 48%, 1 H-NMR (400MHz; DMSO-d6): δ11.75(s,1H),8.14-8.11(m,1H),8.05-8.02(m,2H),7.92(ddd,J=8.3 ,2.3,0.8Hz,1H),7.77-7.72(m,3H),7.41-7.38(m,2H),7.09(s,1H),3.97(s,3H),2.26(s,3H)).

[0935] Carbonic acid ((6-chloro-7-methoxy-2-methyl-3-(3'-(pentafluoro-λ 6 -sulfanyl)-[1,1'-biphenyl]-4-yl)quinolin-4-yl)oxy)methyl ethyl ester (ELQ-674)

[0936]

[0937] 6-chloro-7-methoxy-2-methyl-3-(3'-(pentafluoro-λ 6 -sulfanyl)-[1,1'-biphenyl]-4-yl)quinoline-4(1H)-one (0.173g, 0.00034mol) was combined with tetrabutylammonium iodide (2.0 equivalents, 0.00069mol, 0.25g) and anhydrous potassium carbonate (2.0 equivalents, 0.00069mol, 0.095g) in 15mL DMF. After brief stirring at room temperature, chloromethyl ethyl carbonate (2.0 equivalents, 0.00069mol, 0.095g) was added as a solution in 1mL DMF. The reaction solution was allowed to stir at 60°C and sealed with a needle vent septum for 24 hours, whereupon TLC indicated that the reaction was complete. The cooled reaction mixture was vacuum filtered 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 precipitate tetrabutylammonium iodide; this tetrabutylammonium iodide was removed by vacuum filtration, and the solvent was removed from the filtrate by heating under reduced pressure. Automated flash chromatography of the residue on silica eluted with a gradient of 90:10 to 65:35 v:v hexane:ethyl acetate gave the desired product (R) as a white solid. F=0.40, 1:1 v:v hexane:ethyl acetate) (90 mg, 44%, 1 H-NMR (400MHz; CDCl3): δ8.06(s,1H),8.06-8.04(m,1H),7.82-7.77(m,2H),7.74-7.71(m,2H),7.62-7.56(m,1H),7 .53-7.50(m,2H),7.45(s,1H),5.30(s,2H),4.11(q,J=7.1Hz,2H),4.06(s,3H),2.54(s,3H),1.21(t,J=7.1Hz,3H)).

[0938] 4,6-Dichloro-7-methoxy-2-methyl-3-(4'-(pentafluorosulfanyl)-[1,1'-biphenyl]-4-yl)quinoline:

[0939]

[0940] A mixture of 4,6-dichloro-7-methoxy-2-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinoline (0.46 g, 0.0010 mol), anhydrous potassium carbonate (2.0 eq, 0.0021 mol, 0.29 g), and p-bromophenylsulfur pentafluoride (1.3 eq, 0.0013 mol, 0.38 g) in N,N-dimethylformamide (75 mL) was degassed by blowing argon through a glass tube below 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, followed by heating at 80°C under an argon atmosphere for 22 hours. The cooled reaction mixture was filtered through celite. The filtrate is under reduced pressure concentrated by heating, and the dark solid produced is dissolved in dichloromethane (125mL), and again filtered through diatomite.The filtrate is adsorbed on silica, and the flash chromatography that carries out wash-out by the gradient of 95 / 5 to 75 / 25v / v hexane / ethyl acetate is carried out purifying.This has produced the desired product (R f =0.43 (3 / 2 v / v hexane / ethyl acetate, silica) (0.38 g, 83%, 1 H-NMR (400MHz; CDCl3): δ8.25(s,1H),7.89-7.86(m,2H),7.77-7.72(m,4H),7.48(s,1H),7.41-7.38(m,2H),4.08(s,3H),2.50(s,3H)).

[0941] 6-Chloro-7-methoxy-2-methyl-3-(4'-(pentafluorosulfanyl)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-663):

[0942]

[0943] 4,6-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 iced at 5°C for 30 minutes. Vacuum filtration, rinsing with excess water, followed by rinsing with acetone (5 x 1.5 mL) gave the desired product (0.26 g, 72%, 1 H-NMR (400MHz; DMSO-d6): δ11.71(s,1H),8.02(s,1H),8.01-7.98(m,2H),7.97-7.93( m,2H),7.78-7.75(m,2H),7.42-7.39(m,2H),7.09(s,1H),3.97(s,3H),2.27(s,3H)).

[0944] Carbonic acid ((6-chloro-7-methoxy-2-methyl-3-(4'-(pentafluoro-λ 6 -sulfanyl)-[1,1'-biphenyl]-4-yl)quinolin-4-yl)oxy)methyl ethyl ester (ELQ-674)

[0945]

[0946] 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 combined with tetrabutylammonium iodide (2.0 equiv., 0.00066 mol, 0.24 g) and anhydrous potassium carbonate (1.0 equiv., 0.00033 mol, 0.046 g) in 15 mL of DMF. After brief stirring at room temperature, ethyl chloromethyl carbonate (1.0 equiv., 0.00033 mol, 0.046 g) was added as a solution in 1 mL of DMF. The reaction mixture was allowed to stir at 60°C and sealed with a needle-vented septum for 24 hours. Although a small amount of unreacted starting material was present by TLC, the reaction mixture was cooled, vacuum filtered 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 precipitate tetrabutylammonium iodide, which was removed by vacuum filtration and the solvent removed from the filtrate by heating under reduced pressure. Automated flash chromatography of the residue on silica eluted with a gradient of 9:1 to 7:3 v:v hexane:ethyl acetate gave the desired product (0.17 g, 86%, 1 H-NMR (400MHz; CDCl3): δ8.06(s,1H),7.90-7.86(m,2H),7.76-7.72(m,4H),7.52-7.49(m,2H),7 .45(s,1H),5.30(s,2H),4.10(q,J=7.1Hz,2H),4.06(s,3H),2.54(s,3H),1.21(t,J=7.1Hz,3H)).

[0947] 4,6-Dichloro-7-methoxy-2-methyl-3-(4'-(trifluoroethoxy)-[1,1'-biphenyl]-4-yl)quinoline:

[0948]

[0949] 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 eq, 0.0022 mol, 0.30 g), and 1-bromo-4-(2,2,2-trifluoroethoxy)benzene (1.3 eq, 0.0014 mol, 0.36 g) in N,N-dimethylformamide (80 mL) was degassed by blowing argon through a glass tube below 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, followed by heating at 80°C under an argon atmosphere for 16 hours. The cooled reaction mixture was filtered through celite. At 40 DEG C, 80 DEG C of 48 DEG C and 20 DEG C of 85 DEG C.Filtrate is under reduced pressure through heating and concentrated, and the dark solid that is produced is dissolved among the methylene dichloride (125mL), and once more passes through diatomite filtration.Filtrate is adsorbed on the silicon-dioxide, and the flash chromatography that carries out wash-out by the gradient with 100 / 0 to 75 / 25v / v hexane / ethyl acetate is carried out purifying.The fraction through concentration is merged, and is dissolved among ethyl acetate (50mL) and the methylene dichloride (50mL).Filtrate is under reduced pressure through heating and concentrated, and the dark solid that is produced is adsorbed on the silicon-dioxide, and once more passes through diatomite filtration.Filtrate is adsorbed on the silicon-dioxide, and the flash chromatography that carries out wash-out by the gradient with 100 / 0 to 80 / 20v / v hexane / ethyl acetate is carried out purifying.This has produced the expectation product (R f =0.39 (3 / 2 v / v hexane / ethyl acetate, silica) (0.39 g, 72%, 1 H-NMR (400MHz; CDCl3): δ8.25(s,1H),7.71-7.68(m,2H),7.67-7.64(m,2H),7.47(s,1H) ,7.35-7.32(m,2H),7.08-7.05(m,2H),4.43(q,J=8.1Hz,2H),4.07(s,3H),2.50(s,3H)).

[0950] 6-Chloro-7-methoxy-2-methyl-3-(4'(trifluoroethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-670):

[0951]

[0952] 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 equiv, 0.0079 mol, 0.78 g) were heated in glacial acetic acid (18 mL) at 120°C for 20 hours. After cooling, the reaction mixture was iced at 5°C for one hour. Vacuum filtration, rinsing with excess water, followed by rinsing with acetone (3 x 1.5 mL) gave the desired product (0.06 g, 11.5%, 1 H-NMR (400MHz; DMSO-d6): δ11.67(s,1H),8.01(s,1H),7.71-7.69(m,2H),7.66-7.64(m,J=8.3Hz,2H),7.3 3-7.30(m,J=8.2Hz,2H),7.18-7.16(m,2H),7.08(s,1H),4.83(q,J=8.9Hz,2H),3.97(s,3H),2.26(s,3H)).

[0953] 4,6-Dichloro-7-methoxy-2-methyl-3-(4'-((trifluoromethyl)thio)-[1,1'-biphenyl]-4-yl)quinoline

[0954]

[0955] 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 eq, 0.0024 mol, 0.33 g), and 4-bromo-(trifluoromethylthio)benzene (1.3 eq, 0.0013 mol, 0.38 g) in N,N-dimethylformamide (80 mL) was degassed by blowing argon through a glass tube below the liquid surface at room temperature for 30 minutes. [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.044 g, 0.000060 mol) was added, followed by heating at 80°C under an argon atmosphere for 24 hours. The cooled reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure by heating, and the dark solid produced was dissolved in dichloromethane (300 mL) and filtered through diatomaceous earth again. The filtrate was adsorbed onto silica and purified by flash chromatography using a gradient of 100% dichloromethane to 98 / 2 v / v dichloromethane / ethyl acetate. This produced the desired product (R f =0.47,98 / 2v / v dichloromethane / ethyl acetate, silica) (0.47 g, 79%,1 H-NMR (400MHz; CDCl3): δ8.25(s,1H),7.78-7.72(m,6H),7.47(s,1H),7.40-7.37(m,2H),4.07(s,3H),2.50(s,3H), 19 F NMR (376MHz; CDCl3): δ-42.7).

[0956] 6-Chloro-7-methoxy-2-methyl-3-(4'-((trifluoromethyl)thio)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one

[0957]

[0958] 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 equiv, 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 iced at 5° C. for 20 minutes. Vacuum filtration, rinsing with excess water, followed by rinsing with acetone (3×2 mL) gave the desired product (0.31 g, 69%, 1 H-NMR (400MHz; DMSO-d6): δ11.71(s,1H),8.02(s,1H),7.91-7.89(m,2H),7.85-7.80 (m,2H),7.77-7.75(m,2H),7.40-7.38(m,2H),7.09(s,1H),3.98(s,3H),2.27(s,3H). 19 F NMR (376MHz; DMSO): δ-42.0).

[0959] 4,6-Dichloro-7-methoxy-2-methyl-3-(3'((trifluoromethyl)thio)-[1,1'-biphenyl]-4-yl)quinoline:

[0960]

[0961] 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), anhydrous potassium carbonate (2.0 eq., 0.0026 mol, 0.36 g), and 3-trifluoromethylbromothiobenzene (1.3 eq., 0.0017 mol, 0.43 g) in N,N-dimethylformamide (80 mL) was degassed by blowing argon through a glass tube below the liquid surface at room temperature for 20 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (5 mol%, 0.047 g, 0.00006 mol) was added, followed by heating at 80°C under an argon atmosphere for 23 hours. The cooled reaction mixture was filtered through celite. The filtrate is under reduced pressure concentrated by heating, and the dark solid produced is dissolved in dichloromethane (125mL), and again filtered through diatomite.The filtrate is adsorbed on silica, and the flash chromatography that carries out wash-out by the gradient of 100 / 0 to 92 / 8v / v dichloromethane / ethyl acetate is carried out purifying.This has produced the desired product (R f = 0.61, 98 / 2 v / v dichloromethane / ethyl acetate, silica) (1.0 g, containing residual solvent), the desired product was used in the next step without drying.

[0962] 6-Dichloro-7-methoxy-2-methyl-3-(3'((trifluoromethyl)thio)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-678):

[0963]

[0964] 4,6-Dichloro-7-methoxy-2-methyl-3-(3'((trifluoromethyl)thio)-[1,1'-biphenyl]-4-yl)quinoline (1.0 g, containing residual solvent) and potassium acetate (0.02 mol, 1.99 g) were heated in glacial acetic acid (15 mL) at 120°C for 28 hours. After cooling, the reaction mixture was iced at 5°C for 1.5 hours. Vacuum filtration, rinsing with excess water, followed by rinsing with acetone (4 x 1.5 mL) gave the desired product as gray crystals (0.40 g, 65% over two steps; 1H-NMR(400MHz; DMSO-d6): δ11.70(s,1H),8.04 -8.02(m,1H),8.02(s,1H),7.99-7.96(m,1H),7.76-7.72(m,3H),7.69-7 .64(m,1H),7.40-7.37(m,2H),7.09(s,1H),3.98(s,3H),2.27(s,3H).;19 F NMR (376MHz; DMSO): δ-41.9).

[0965] 4,6-Dichloro-7-methoxy-2-methyl-3-(4'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)quinoline

[0966]

[0967] A mixture of 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline (1.00 g, 0.0025 mol), 4-(methylsulfonyl)boric acid (0.60 g, 0.0030 mol, 1.2 equivalents) and anhydrous potassium carbonate (2.0 equivalents, 0.0050 mol, 0.69 g) in N,N-dimethylformamide (130 mL) was degassed by blowing 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, followed by heating at 80 ° C under an argon atmosphere for 4 days. The cooled reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated by heating under reduced pressure, and the resulting dark solid was dissolved in dichloromethane (150 mL) and filtered through diatomaceous earth again. The filtrate was adsorbed onto silica and purified by flash chromatography eluting with a gradient of 85 / 15 to 30 / 70 v / v hexane / ethyl acetate. This gave the desired product (R f =0.25 (3 / 2 v / v hexane / ethyl acetate, silica) (0.42 g, 36%, 1 H-NMR (400MHz; DMSO-d6): δ8.20(s,1H),8.08-8.03(m,4H),7.96-7.93(m,2 H),7.66(s,1H),7.56-7.53(m,2H),4.07(s,3H),3.29(s,3H),2.43(s,3H)).

[0968] 6-Chloro-7-methoxy-2-methyl-3-(4'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-658)

[0969]

[0970] 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 equiv, 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 iced at 5° C. for 1 hour. Vacuum filtration, rinsing with excess water, followed by rinsing with acetone (3×2 mL) gave the desired product (0.24 g, 59%, 1 H-NMR (400MHz; DMSO-d6): δ11.71(s,1H),8.04-7.99(m,5H),7.80-7.78(m,2 H),7.42-7.40(m,2H),7.09(s,1H),3.97(s,3H),3.27(s,3H),2.27(s,3H)).

[0971] 4,6-Dichloro-7-methoxy-2-methyl-3-(3'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4-yl)quinoline:

[0972]

[0973] 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 eq, 0.0022 mol, 0.30 g), and 1-bromo-4-(2,2,2-trifluoroethoxy)benzene (1.3 eq, 0.0014 mol, 0.36 g) in N,N-dimethylformamide (50 mL) was degassed by blowing argon through a glass tube below 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, followed by heating at 80°C under an argon atmosphere for 23 hours. The cooled reaction mixture was filtered through celite. The filtrate is under reduced pressure concentrated by heating, and the dark solid produced is dissolved in dichloromethane (125mL), and again filtered through diatomite.The filtrate is adsorbed on silica, and is purified by the flash chromatography that the gradient of 95 / 5 to 72 / 28v / v hexane / ethyl acetate is eluted.The desired product (R) obtained is a white solid. f =0.38 (7 / 3 v / v hexane / ethyl acetate, silica), 0.30 g, 55%,1 H-NMR (400MHz; CDCl3): δ8.25(s,1H),7.71-7.68(m,2H),7.67-7.64(m,2H),7.47(s,1H) ,7.35-7.32(m,2H),7.08-7.05(m,2H),4.43(q,J=8.1Hz,2H),4.07(s,3H),2.50(s,3H)).

[0974] 6-Chloro-7-methoxy-2-methyl-3-(3'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-673):

[0975]

[0976] 4,6-dichloro-7-methoxy-2-methyl-3-(3'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4-yl)quinoline (0.30 g, 0.00061 mol) and potassium acetate (10 equivalents, 0.0061 mol, 0.59 g) were heated in glacial acetic acid (10 mL) at 120 ° C for 22 hours. After cooling, the reaction mixture was poured into 60 mL of water. After stirring for 3 minutes, the resulting solid was recovered by vacuum filtration and rinsed with excess water followed by acetone (2 x 2 mL). This produced the desired product (0.14 g, 47%, 1 H-NMR (400MHz; DMSO-d6): δ11.67(s,1H),8.01(s,1H),7.71-7.69(m,2H),7.66-7.64(m,J=8.3Hz,2H),7.3 3-7.30(m,J=8.2Hz,2H),7.18-7.16(m,2H),7.08(s,1H),4.83(q,J=8.9Hz,2H),3.97(s,3H),2.26(s,3H)).

[0977] 4'-(4,6-dichloro-7-methoxy-2-methylquinolin-3-yl)-[1,1'-biphenyl]-4-sulfonamide

[0978]

[0979] By blowing argon through a glass tube under the liquid surface at room temperature for 20 minutes, 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 equivalents) and anhydrous potassium carbonate (2.0 equivalents, 0.0050 mol, 0.69 g) in N, N- dimethylformamide (130 mL) degassed. [1,1'- bis (diphenylphosphino) ferrocene] - dichloropalladium (II) (5 mol%, 0.091 g, 0.000125 mol) was added, followed by heating at 80 ° C under an argon atmosphere for 24 hours. The cooled reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated by heating under reduced pressure, and the resulting dark solid was rotated in dichloromethane (125 mL) and vacuum filtered. Since precipitation was observed in the filtrate, the filtrate was concentrated to 90 mL and vacuum filtered again. The resulting light tan solid was the desired product (0.30 g, 26%, 1 H-NMR (400MHz; DMSO-d6): δ8.20(s,1H),8.00-7.90(m,6H),7.65(s,1H),7.54-7.51(m,2H),7.44(br s,2H),4.07(s,3H),2.43(s,3H)).

[0980] 4'-(6-chloro-7-methoxy-2-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-[1,1'-biphenyl]-4-sulfonamide (ELQ-680)

[0981]

[0982] 4'-(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 iced at 5°C for 20 minutes. Vacuum filtration, rinsing with excess water, followed by rinsing with acetone (3 x 1.5 mL) gave the desired product (0.21 g, 71%, 1 H-NMR (400MHz; DMSO-d6): δ11.70(s,1H),8.02(s,1H),7.94-7.92(m,4H),7. 77-7.75(m,2H),7.40-7.38(m,4H),7.09(s,1H),3.97(s,3H),2.27(s,3H)).

[0983] 4,6-Dichloro-7-methoxy-2-methyl-3-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)quinoline

[0984]

[0985] While degassing by blowing argon through a glass tube under the liquid surface, a mixture of 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline (0.85 g, 0.0021 mol), 2-(trifluoromethyl)pyridinyl-5-boric acid (1.3 equivalents, 0.0028 mol, 0.53 g) and anhydrous potassium carbonate (2.0 equivalents, 0.0042 mol, 0.58 g) in N,N-dimethylformamide (100 mL) was 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 was allowed to heat at 80 ° C under argon for 19 hours. The cooled reaction mixture was filtered through diatomaceous earth, followed by the filtrate being concentrated by heating under reduced pressure. The resulting solid was dissolved in 110 mL of DCM and then vacuum filtered. Automated flash chromatography of the evaporated filtrate on silica eluting with a gradient of 9:1 to 72:28 v:v hexanes:ethyl acetate gave the desired product as a white powder (R f = 0.35, 6:4 v:v hexane:ethyl acetate on silica) (0.37 g, 38%, 1 H-NMR (400MHz; CDCl3): δ9.07-9.03(m,1H),8.26(s,1H),8.16-8.13(m,1H),7.83-7.8 0(m,1H),7.78-7.75(m,2H),7.48(s,1H),7.46-7.43(m,2H),4.08(s,3H),2.50(s,3H). 19 F NMR (376MHz; CDCl3): δ-67.7).

[0986] 6-Chloro-7-methoxy-2-methyl-3-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)quinolin-4(1H)-one (ELQ-683)

[0987]

[0988] 4,6-Dichloro-7-methoxy-2-methyl-3-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)quinoline (0.37 g, 0.00080 mol) and anhydrous potassium acetate (10 equiv., 0.0080 mol, 0.79 g) were stirred in glacial acetic acid (15 mL) at 120° C. for 20 hours. After cooling, the reaction mixture was iced at 5° C. for another 20 minutes, followed by vacuum filtration, rinsing with excess water, followed by rinsing with acetone (3×1.5 mL). The desired product (0.23 g, 65%, 1 H-NMR (400MHz; DMSO-d6): δ11.72(s,1H),9.18-9.14(m,1H),8.44-8.41(m,1H),8.02(s,1H),8.0 2-7.99(m,1H),7.87-7.85(m,2H),7.45-7.43(m,2H),7.09(s,1H),3.98(s,3H),2.28(s,3H).19-F NMR (376MHz; DMSO): δ-66.2).

[0989] 4,6-Dichloro-7-methoxy-2-methyl-3-(4-(5-(trifluoromethoxy)pyridin-2-yl)phenyl)quinoline

[0990]

[0991] A mixture of 4,6-dichloro-7-methoxy-2-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinoline (0.50 g, 0.0011 mol), anhydrous potassium carbonate (2.0 eq., 0.0022 mol, 0.30 g), and 2-bromo-5-(trifluoromethoxy)benzene (1.3 eq., 0.0015 mol, 0.35 g) in N,N-dimethylformamide (80 mL) was degassed by bubbling argon through a glass tube inserted below 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, followed by heating at 80°C under an argon atmosphere for 4 days. The cooled reaction mixture was filtered through celite. Filtrate is under reduced pressure by heating concentration, and the dark solid produced is dissolved in dichloromethane (100mL), and again by diatomite filtration.After filtrate evaporation, residue is passed through on silicon-dioxide with 1:0 to 6:4v:v hexane: the automation flash chromatography that the gradient of ethyl acetate carries out wash-out is carried out purifying, is afterwards on same silica gel column with 1:0 to 75:25v:v hexane: the gradient of ethyl acetate carries out wash-out and carries out flash chromatography for the second time.The desired product (R) that is white powder has been obtained.f = 15, 8:2 v:v hexane:ethyl acetate on silica) (0.29 g, 55%, 1 H-NMR (400MHz; CDCl3): δ8.67-8.66(m,1H),8.25(s,1H),8.14-8.11(m,2H),7.88-7.86(m ,1H),7.70-7.67(m,1H),7.48(s,1H),7.42-7.39(m,2H),4.07(s,3H),2.49(s,3H).); 19-F NMR (376MHz; CDCl3): δ-58.1).

[0992] 6-Chloro-7-methoxy-2-methyl-3-(4-(5-(trifluoromethoxy)pyridin-2-yl)phenyl)quinolin-4(1H)-one (ELQ-681)

[0993]

[0994] 4,6-Dichloro-7-methoxy-2-methyl-3-(4-(5-(trifluoromethoxy)pyridin-2-yl)phenyl)quinoline (0.29 g, 0.00061 mol) and anhydrous potassium acetate (10 equiv., 0.0061 mol, 0.60 g) were heated in 10 mL of glacial acetic acid at 120° C. for 20 hours. The cooled reaction mixture was iced at 5° C. for 14 hours. Vacuum filtration, rinsing with excess water, followed by rinsing with acetone (3×1.5 mL) gave the desired product (0.17 g, 60% yield) as a white powder. 1 H-NMR (400MHz; DMSO-d6): δ11.72(s,1H),8.77-8.77(m,1H),8.18-8.16(m,1H),8.13-8.10(m, 2H),8.02(s,1H),8.02-7.99(m,1H),7.42-7.39(m,2H),7.10(s,1H),3.98(s,3H),2.27(s,3H). 19-F NMR (376MHz; DMSO): δ-57.1).

[0995] 4,6-Dichloro-3-(3'-ethoxy-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline

[0996]

[0997] A mixture of 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline (0.70 g, 0.0018 mol), 3-ethoxyphenylboronic acid (1.2 eq, 0.0022 mol, 0.37 g), and aqueous potassium carbonate (2.0 eq, 0.0036 mol, 0.50 g anhydrous potassium carbonate dissolved in 1.8 mL water) in N,N-dimethylformamide (100 mL) was degassed by bubbling argon through a glass tube below 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, followed by heating at 80°C under an argon atmosphere for 20 hours. The cooled reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure with heating, and the resulting dark solid was dissolved in dichloromethane (100 mL), vacuum filtered, and purified by flash chromatography eluting with a gradient of 1:0 to 75:25 v:v hexane:ethyl acetate. This gave the desired product (R) as a white solid. f =0.35, 7:3 v:v hexane:ethyl acetate, silica) (0.34 g, 43%, 1 H-NMR (400MHz; CDCl3): δ8.28(s,1H),7.77-7.74(m,2H),7.50(s,1H),7.41(t,J=7.9Hz,1H),7.37-7.34(m,2H),7.28(ddd,J=7.6,1.7,1.0 Hz,3H),7.24(t,J=2.0Hz,1H),6.95(ddd,J=8.2,2.5,0.9Hz,1H),4.17(t,J=7.0Hz,3H),4.10(s,3H),2.53(s,3H),1.49(t,J=7.0Hz,3H)).

[0998] 6-Chloro-3-(3'-ethoxy-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-691)

[0999]

[1000] 4,6-Dichloro-3-(3'-ethoxy-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (0.34 g, 0.00078 mol) and anhydrous potassium acetate (10 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 iced at 5°C overnight and then vacuum filtered, rinsed with excess water, followed by acetone (3 x 1 mL) to yield a white solid (desired product; 0.20 g, 61%, 1 H-NMR (400MHz; DMSO-d6): δ11.68(s,1H),8.01(s,1H),7.70-7.67(m,2H),7.41-7.35(m,1H),7.34-7.31(m,2H),7.26(ddd,J=7.7,1.6,1.0Hz,1 H),7.23-7.20(m,1H),7.08(s,1H),6.93(ddd,J=8.2,2.5,0.9Hz,1H),4.12(q,J=7.0Hz,2H),3.97(s,3H),2.26(s,3H),1.37(t,J=7.0Hz,3H)).

[1001] 4,6-Dichloro-7-methoxy-2-methyl-3-(4-(pyridin-4-yl)phenyl)quinoline

[1002]

[1003] A mixture of 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline (0.71 g, 0.0018 mol), pyridine-4-boronic acid (1.3 eq, 0.0024 mol, 0.29 g) and aqueous potassium carbonate (2.0 eq, 0.0036 mol, 0.50 g anhydrous potassium carbonate dissolved in 1.3 mL of water) in N,N-dimethylformamide (80 mL) was degassed by blowing argon through a glass tube below 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, followed by heating at 80°C under an argon atmosphere for 20 hours. The cooled reaction mixture was filtered through celite. The filtrate is under reduced pressure concentrated by heating, and the dark solid produced is dissolved in dichloromethane (100mL), and vacuum filtered. The filtrate of evaporation is purified by flash chromatography using 85:15 to 0:100v / v hexane: the gradient of ethyl acetate is eluted. This will produce the desired product (R f =0.3, 100% ethyl acetate, silica) (0.17 g, 24%,1 H-NMR (400MHz; CDCl3): δ8.73-8.71(m,2H),8.25(s,1H),7.81-7.78(m,2H),7 .61-7.59(m,2H),7.47(s,1H),7.43-7.40(m,2H),4.08(s,3H),2.50(s,3H)).

[1004] 6-Chloro-7-methoxy-2-methyl-3-(4-(pyridin-4-yl)phenyl)quinolin-4(1H)-one (ELQ-714)

[1005]

[1006] 4,6-Dichloro-7-methoxy-2-methyl-3-(4-(pyridin-4-yl)phenyl)quinoline (0.17 g, 0.00043 mol) and anhydrous potassium acetate (10 equiv, 0.0043 mol, 0.42 g) were heated in glacial acetic acid (10 mL) at 120° C. for 24 hours. After cooling to room temperature, the reaction mixture was iced at 5° C. overnight, followed by vacuum filtration, rinsing with excess water, followed by rinsing with acetone (3×0.75 mL). The desired product (50 mg) was obtained as a light yellow solid. Additional clean product was recovered from the filtrate (27 mg), for a total of 77 mg of the desired product (48%, 1 H-NMR (400MHz; DMSO-d6): δ11.79(s,1H),8.76-8.74(m,2H),8.02(s,1H),8.00-7.98( m,2H),7.92-7.90(m,2H),7.46-7.44(m,2H),7.11(s,1H),3.98(s,3H),2.27(s,3H)).

[1007] 4,6-Dichloro-3-(2'-chloro-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline

[1008]

[1009] A mixture of 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline (0.70 g, 0.0018 mol), 2-chlorophenylboronic acid pinacol ester (1.3 eq, 0.0023 mol, 0.55 g), and aqueous potassium carbonate (2.0 eq, 0.0032 mol, 0.44 g anhydrous potassium carbonate dissolved in 1.6 mL water) in N,N-dimethylformamide (80 mL) was degassed by bubbling argon through a glass tube below 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, followed by heating at 80°C under an argon atmosphere for 24 hours. The cooled reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure by heating and the resulting dark solid was dissolved in dichloromethane (150 mL) and vacuum filtered. Automated flash chromatography of the residue obtained from evaporation of the filtrate using a gradient of 95:5 to 82:18 v:v hexane:ethyl acetate was not effective in removing the significant by-product (R F =0.21, 8:2 v:v hexane:ethyl acetate) to isolate the desired product (R F = 0.24, 8:2 v:v hexane:ethyl acetate), which results in the bisaddition of the boronate ester to the quinoline (instead of the chloride); this byproduct is identified by GC / MS at m / z = 503, t R = 21 min (temperature program: 250°C for 2 min, followed by 30°C / min temperature increase to 300°C, DB5 column). The impure mixture (0.45 g) was used in the next reaction without further purification.

[1010] 6-Chloro-3-(2'-chloro-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-713)

[1011]

[1012] 4,6-dichloro-3-(2'-chloro-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (0.15 g impure material, see above) was heated in 10 mL of glacial acetic acid at 110° C. with anhydrous potassium acetate (0.34 g, 0.0035 mol) for 24 hours. After cooling, the reaction mixture was iced at 5° C. and then vacuum filtered, rinsed with excess water, followed by acetone (2×1.5 mL). The desired product (0.0668 g) was obtained as a white solid. Separately, another portion of 4,6-dichloro-3-(2'-chloro-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (0.30 g of impure material from the same reaction, above) was treated in the same manner with anhydrous potassium acetate (0.69 g) and glacial acetic acid (10 mL) to give 0.116 g of a cream solid, which was also the desired product (total yield 0.18 g, 23% over two steps starting from 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline). 1 H-NMR (400MHz; DMSO-d6): δ11.70(s,1H),8.02(s,1H),7.60-7.58(m,1H),7. 50-7.39(m,5H),7.36-7.33(m,2H),7.09(s,1H),3.97(s,3H),2.27(s,3H)).

[1013] 4,6-Dichloro-7-methoxy-2-methyl-3-(4'-nitro-[1,1'-biphenyl]-4-yl)quinoline

[1014]

[1015] A mixture of 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline (0.70 g, 0.0018 mol), 4-nitrophenylboronic acid pinacol ester (1.3 eq, 0.0023 mol, 0.57 g) and aqueous potassium carbonate (2.0 eq, 0.0036 mol, 0.50 g anhydrous potassium carbonate dissolved in 1.8 mL water) in N,N-dimethylformamide (80 mL) was degassed by blowing argon through a glass tube below 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, followed by heating at 80°C under an argon atmosphere for 21 hours. The cooled reaction mixture was vacuum filtered, and the filtrate was concentrated by heating under reduced pressure. The residue was dissolved in dichloromethane (125 mL) and vacuum filtered. Automated flash chromatography of the evaporated filtrate on silica eluting with a gradient of 9:1 to 1:1 v:v hexane:ethyl acetate gave the desired product as an off-white solid (0.07 g, 9%, 1 H-NMR (400MHz; CDCl3): δ8.37-8.34(m,2H),8.26(s,1H),7.86-7.83(m,2H),7 .80-7.77(m,2H),7.48(s,1H),7.44-7.41(m,2H),4.08(s,3H),2.50(s,3H)).

[1016] 6-Chloro-7-methoxy-2-methyl-3-(4'-nitro-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-715)

[1017]

[1018] 4,6-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 was iced at 5° C. overnight and then vacuum filtered, rinsed with excess water, followed by acetone (3×3 mL) to afford the desired product (14 mg, 21%, 1H-NMR (400MHz; DMSO-d6): δ11.72(s,1H),8.35-8.32(m,2H),8.05-8.02(m,3H) ,7.85-7.81(m,2H),7.44-7.41(m,2H),7.09(s,1H),3.98(s,3H),2.28(s,3H)).

[1019] 4,6-Dichloro-3-(2',6'-dimethyl-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline

[1020]

[1021] 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 aqueous potassium carbonate (2.0 equiv., 0.0036 mol, 0.50 g of anhydrous potassium carbonate dissolved in 1.8 mL of water) in N,N-dimethylformamide (80 mL) was degassed by blowing argon through a glass tube below 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, followed by heating at 80°C under an argon atmosphere for 12 days. Although the reaction was incomplete, it was removed from the heat. The reaction mixture of cooling is carried out vacuum filtration, and the solid obtained is rinsed with DMF, then rinsed with excessive water, and finally rinsed with acetone (5mL).The smoky grey solid (0.33g) that is produced is boiled in 35mL DMF, and allows its slow cooling, thereby forms white crystals and a small amount of sinking dark precipitate.Vacuum filtration has produced the white crystals that mix with a small amount of black precipitate.GC / MS only demonstrates desired product (421.1) at t R = 12.659 min, 200°C for 2 min, then 30°C / min to 300°C, m / z on DB5 column. This material (0.19 g) was used in the next reaction without further analysis or purification.

[1022] 6-Chloro-3-(2',6'-dimethyl-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-729)

[1023]

[1024] 4,6-dichloro-3-(2',6'-dimethyl-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (0.19 g crude crystalline material from the previous reaction, 0.19 g) and anhydrous potassium acetate (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 vacuum filtered to remove a small amount of gray solid, and the cooled filtrate was iced at 5° C. and then vacuum filtered, rinsed with excess water, followed by 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% over two steps starting from 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline, 1 H-NMR (400MHz; DMSO-d6): δ11.68(s,1H),8.02(s,1H),7.34-7.31(m,2H),7.19-7.12(m,5H),7.09(s,1H),3.97(s,3H),2.27(s,3H),2.04(s,6H)).

[1025] 4,6-Dichloro-7-methoxy-2-methyl-3-(2'-methyl-[1,1'-biphenyl]-4-yl)quinoline

[1026]

[1027] 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 equivalents, 0.0035 mol, 0.77 g) and aqueous potassium carbonate (2.0 equivalents, 0.0050 mol, 0.69 g of anhydrous potassium carbonate dissolved in 2.5 mL of water) in N,N-dimethylformamide (80 mL) was degassed by blowing argon through a glass tube below 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, followed by heating at 80°C under an argon atmosphere for 1 day. The cooled reaction mixture was vacuum filtered through celite, and the filtrate was concentrated by heating under reduced pressure. The residue was dissolved in 125 mL of dichloromethane and vacuum filtered, and the evaporated filtrate was purified by automated flash chromatography on silica gel eluting with a gradient of 95:5 to 81:19 v:v hexanes:ethyl acetate to give the desired product (R f =0.31, 7:3 v:v hexane:ethyl acetate, silica, 0.08 g, 80%, 1H-NMR (400MHz; CDCl3): δ8.26(s,1H),7.48-7.45(m,3H),7.35-7.28(m,6H),4.07(s,3H),2.52(s,3H),2.36(s,3H)).

[1028] 6-Chloro-7-methoxy-2-methyl-3-(2'-methyl-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-718)

[1029]

[1030] 4,6-dichloro-7-methoxy-2-methyl-3-(2'-methyl-[1,1'-biphenyl]-4-yl)quinoline (0.08 g, 0.00020 mol) and anhydrous potassium acetate (10 equivalents, 0.0020 mol, 0.19 g) were heated in glacial acetic acid (10 mL) at 120 ° C for 21 hours. After cooling to room temperature, the reaction mixture was iced at 5 ° C for 30 minutes. The desired product was recovered by vacuum filtration, rinsed with excess water, and then rinsed with 2x3 mL of acetone, and the resulting solid (34 mg) was recrystallized by N, N-dimethylformamide (2 mL). The desired product (17 mg, 22%, 1 H-NMR (400MHz; DMSO-d6): δ11.68(s,1H),8.02(s,1H),7.38-7.26(m,8H),7.09(s,1H),3.97(s,3H),2.31(s,3H),2.27(s,3H)).

[1031] 4,6-Dichloro-7-methoxy-2-methyl-3-(2',3',4'-trifluoro-[1,1'-biphenyl]-4-yl)quinoline

[1032]

[1033] A mixture of 3-(4-bromophenyl)-4,6-dichloro-7-methoxy-2-methylquinoline (0.70 g, 0.0018 mol), 2,3,4-trifluorophenylboronic acid (1.2 eq, 0.0022 mol, 0.39 g) and aqueous potassium carbonate (2.0 eq, 0.0036 mol, 0.50 g anhydrous potassium carbonate dissolved in 1.8 mL water) in N,N-dimethylformamide (80 mL) was degassed by bubbling argon through a glass tube below 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, followed by heating at 80°C under argon for 20 hours. The cooled reaction mixture was vacuum filtered, and the resulting solid was rinsed with additional DMF, followed by water. After air drying, the white solid thus obtained was dissolved in boiling DMF (50 mL) and vacuum filtered while hot, and the filtrate was then concentrated by boiling to 30 mL, followed by slow cooling. Vacuum filtration yielded the desired product as tan crystals (0.39 g, 48%, 1 H-NMR (400 MHz; CDCl3): δ8.25 (s, 1H), 7.66-7.64 (m, 2H), 7.47 (s, 1H), 7.38-7.36 (m, 2H), 7.27-7.23 (m, ~1H, overlapping with the residual peak of CDCl3 solvent), 7.12-7.06 (m, 1H), 4.07 (s, 3H), 2.50 (s, 3H).

[1034] 19-F NMR (376MHz; CDCl3): δ-135.1, -138.4, -159.7).

[1035] 6-Chloro-7-methoxy-2-methyl-3-(2',3',4'-trifluoro-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-747)

[1036]

[1037] 4,6-Dichloro-7-methoxy-2-methyl-3-(2',3',4'-trifluoro-[1,1'-biphenyl]-4-yl)quinoline (0.39 g, 0.00087 mol) and anhydrous potassium acetate (10 equiv., 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 iced at 5° C. for 2 hours. Vacuum filtration, rinsing with excess water, followed by rinsing with acetone (3×1.5 mL) gave the desired product (0.28 g, 76%, 1H-NMR (400MHz; DMSO-d6): δ11.71(s,1H),8.01(s,1H),7.59-7.56(m,2H),7 .50-7.42(m,2H),7.40-7.37(m,2H),7.09(s,1H),3.97(s,3H),2.27(s,3H).

[1038] 19 F NMR (376MHz; DMSO): δ-136.4, -139.6, -161.0).

[1039] 4-Chloro-6-fluoro-7-methoxy-2-methyl-3-(2',3',4'-trifluoro-[1,1'-biphenyl]-4-yl)quinoline

[1040]

[1041] 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 eq, 0.0022 mol, 0.39 g) and aqueous potassium carbonate (2.0 eq, 0.0036 mol, 0.50 g anhydrous potassium carbonate dissolved in 1.8 mL water) in N,N-dimethylformamide (80 mL) was degassed by bubbling argon through a glass tube below 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, followed by heating at 80°C under argon for 20 hours. The cooled reaction mixture was vacuum filtered, and the resulting solid was rinsed with additional DMF, followed by water. At 4 DEG C, 3-dextrose 4-nitropropene (0.41g) is dissolved in 40mL of boiling water.After the air drying, the paste crystals (0.89g) obtained thus is dissolved in the DMF (60mL) of boiling, and carries out vacuum filtration when hot, and then filtrate is concentrated by boiling to 40mL, is to slowly cool down afterwards.Vacuum filtration, with DMF (10mL) flushing, be to flush with acetone (15mL) afterwards and produced the expectation product (0.41g) for white crystals.Simultaneously, the filtrate that will be obtained by the initial filtration of reaction mixture is under reduced pressure through heating and concentrates.Make residue be dissolved in the 125mL methylene dichloride, and carry out vacuum filtration, be on silica gel with 93:7 to 70:30v:v hexane: the gradient of ethyl acetate carries out wash-out and the filtrate of evaporation is carried out automation flash chromatography, this has also produced the expectation product (R) that is white solid. f = 0.24, 7:3 v:v hexanes:ethyl acetate, silica) (0.23 g, total yield by crystallization and chromatography 0.64 g, 82%, 1H-NMR(400MHz; CDCl3): δ7.86(d,J F =11.8Hz,1H),7.66-7.63(m,2H),7.50(d,J F =8.1Hz,1H),7.39-7.36(m,2H),7.29-7.23(m,~1H,overlapping with residual peak of CDCl3 solvent),7.12-7.06(m,1H),4.06(s,3H),2.50(s,3H), 19 F NMR (376MHz; CDCl3): δ-131.3, -135.1, -138.4, -159.8).

[1042] 6-Fluoro-7-methoxy-2-methyl-3-(2',3',4'-trifluoro-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-748)

[1043]

[1044] 4-Chloro-6-fluoro-7-methoxy-2-methyl-3-(2',3',4'-trifluoro-[1,1'-biphenyl]-4-yl)quinoline (0.41 g, 0.00095 mol) and anhydrous potassium acetate (10 equiv., 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 iced at 5° C. for 2 hours. Vacuum filtration, rinsing with excess water, followed by rinsing with acetone (3×1.5 mL) gave the desired product (0.34 g, 82%, 1 H-NMR (400MHz; DMSO-d6): δ11.69(s,1H),7.72(d,J F =11.7Hz,1H),7.59-7.56(m,2H),7.51-7.42(m,2H),7.40-7.37(m,2H),7.12(d,J F =7.3Hz,1H),3.96(s,3H),2.26(s,3H), 19 F NMR (376MHz; DMSO): δ-136.4,-139.4,-139.6,-161.0).

[1045] 4-Chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)quinoline

[1046]

[1047] 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 eq, 0.0018 mol, 0.34 g) and aqueous potassium carbonate (2.0 eq, 0.0030 mol, 0.41 g anhydrous potassium carbonate dissolved in 1.5 mL water) in N,N-dimethylformamide (60 mL) was degassed by blowing argon through a glass tube below 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, followed by heating at 80°C under an argon atmosphere for 4 days. The cooled reaction mixture was vacuum filtered, and the filtrate was evaporated by heating under reduced pressure. The residue was dissolved in dichloromethane (125 mL) and vacuum filtered. The evaporated filtrate was subjected to automated flash chromatography on silica gel, eluting with a gradient of 85:15 to 63:37 v:v hexane:ethyl acetate. The desired product (0.43 g, 64%, 1 H-NMR (400MHz; CDCl3): δ9.07-9.04(m,1H),8.16-8.13(m,1H),7.86(d,J F =11.8Hz,1H),7.82-7.80(m,1H),7.78-7.75(m,2H),7.51(d,J F =8.1Hz,1H),7.46-7.43(m,2H),4.07(s,3H),2.50(s,3H), 19 F NMR (376MHz; CDCl3): δ-67.7,-131.1).

[1048] 6-Fluoro-7-methoxy-2-methyl-3-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)quinolin-4(1H)-one (ELQ-758)

[1049]

[1050] 4-Chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)quinoline (0.43 g, 0.00096 mol) and anhydrous potassium acetate (10 equiv., 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 iced at 5° C. overnight. Vacuum filtration, rinsing with excess water, followed by rinsing with acetone (3×1.5 mL) gave the desired product as beige crystals (0.32 g, 78%, 1H-NMR (400MHz; DMSO-d6): δ11.69(s,1H),9.17-9.15(m,1H),8.44-8.41(m,1H),8.03-7.98(m,1H),7.87-7.84(m,2H),7.72(d,J F =11.7Hz,1H),7.45-7.42(m,2H),7.12(d,J F =7.3Hz,1H),3.97(s,3H),2.27(s,3H), 19 F NMR (376MHz; DMSO): δ-66.2,-139.4).

[1051] Synthesis of ELQ biphenyl

[1052] Compounds of formula (I) can be prepared as shown in Scheme 8 below.

[1053]

[1054] Scheme 8: Synthesis of a series of 6-chloro-7-methoxy-3-biaryl-ELQ and ELQ-687 with structural variations at the terminal phenyl ring.

[1055]

[1056] a Reaction (a): Pd(dppf)Cl2, K2CO3, DMF, 80°C, 19-98%; (b): KOAc, AcOH, 16-24 hours, 57-91%.

[1057] Scheme 9: Synthesis of a series of 6-chloro-7-methoxy-3-biaryl-ELQs with structural variations at the internal phenyl ring.

[1058]

[1059] a Reaction (a): Pd(dppf)Cl2, K2CO3, DMF, 80°C, 60%; (b): KOAc, AcOH, 16-24 hours, 99%.

[1060] Plan 10

[1061]

[1062] Scheme 11: Synthesis of a series of 7-fluoro-7-methoxy-3-biaryl-ELQ and ELQ-688 with structural variations at the exophenyl ring.

[1063]

[1064] a Reaction (a): Pd(dppf)Cl2, K2CO3, DMF, 80°C, 15-51%; (b): KOAc, AcOH, 16-24 hours, 88-93%.

[1065] Scheme 12: Synthesis of a series of 6-chloro-7-methoxy-3-biaryl-ELQ carbonate alkoxy ester prodrugs.

[1066] a Reaction (a): TBAI, K2CO3 and DMF, 60°C, 24 hours, 54-70%.

[1067]

[1068] Scheme 13: Synthesis of the pivaloyl prodrug of ELQ-596.

[1069] a Reaction (a): NaH and THF, 60°C, 2 hours, 55%.

[1070] Scheme 14: Synthesis of a series of 7-fluoro-7-methoxy-3-biaryl-ELQ carbonate alkoxy ester prodrugs.

[1071] a Reaction (a): TBAI, K2CO3 and DMF, 60°C, 24 hours, 74-77%.

[1072]

[1073] Scheme 15: Synthesis of ELQ-601 alkoxy carbonate prodrug.

[1074] a Reaction (a): TBAI, K2CO3 and DMF, 60°C, 24 hours, 72%.

[1075]

[1076]

[1077] Scheme 16: Synthesis of a series of ELQ N-oxides and ELQ-N-hydroxyls

[1078] a Reaction (a): MCPBA and CHCl3, 80°C, 24 hours, 48-70% (b) EtOH / 10% NaOH aqueous solution (4 / 1), 2 hours, 48-87%.

[1079] Chemical synthesis procedures.

[1080] Unless otherwise noted, all chemicals and reagents were obtained from Sigma-Aldrich Chemical Company, St. Louis, MO (USA), Combi-Blocks, San Diego, CA, or TCI USA, Portland, OR, and were 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 obtained on an Optimelt automated melting point system from Stanford Research Systems, Sunnyvale, CA (USA). Analytical TLC utilizes Merck 60F-254 250 micron through pre-coated silica gel plate, and spot is visualized under 254nm UV light.Use Agilent Technologies 7890B gas chromatograph (30m, DBS column is set at 100 ℃ or 200 ℃ for 2 minutes, then reaches 300 ℃ with 30 ℃ / minute, wherein inlet temperature is set to 250 ℃) and Agilent Technologies 5977A mass selective detector operated with 70eV to obtain GC-MS.Use the Isolera One flash chromatography system from Baitazi, Uppsala, Sweden to carry out flash chromatography on silica gel column.Use the Bruker 400MHz Avance NEO NanoBay NMR spectrometer that is operated with 400.14MHz to obtain 1 H-NMR spectrum: The raw NMR data were analyzed using iNMR spectrum analysis software. 1 H chemical shifts are reported in parts per million (ppm) relative to an internal tetramethylsilane (TMS) standard or the residual solvent peak. Coupling constant values ​​(J) are reported in Hertz (Hz). Decoupled spectroscopy (TEM) operating at 376 MHz was also obtained for fluorinated compounds. 19 F (data not shown). Agilent 1260 Infinity instrument with detection at 254 nm and Fenome 5μm C8(2) HPLC analysis was performed on a reverse phase LC column 150 x 4.6 mm at 40°C and eluted with a gradient of 25%:75% A / B to 10%:90% A / B (A: milliQ water containing 0.05% formic acid, B: methanol containing 0.05% formic acid). For in vitro testing, the purity of all compounds was at least >95%, and for in vivo testing, the purity was >98%, as determined by GC-MS, 1 confirmed by H-NMR and HPLC.

[1081] General procedure for the synthesis of biphenylquinolines (3a-p): A stirred mixture of quinoline 1 (1 equivalent), substituted phenylboronic acid (1.1-1.2 equivalents) 2a, 2c, 2e-2g, 2j-2m, 15g or pinacol esters 2b, 2d, 2h, 2i, 2n and 2o, 2M KCO aqueous solution (2 equivalents) and Pd(dppf)Cl (0.05 equivalents) in DMF was deoxygenated by bubbling argon through the solution for 15 minutes. The stirred reaction mixture was then heated at 80° C. under argon until no more starting material 1 remained as determined by GC-MS. The reaction was cooled to room temperature and filtered through celite, and the DMF was removed in vacuo. The resulting black oily solid was resuspended in DCM and vigorously stirred at room temperature for 30 minutes, filtered through celite, and concentrated to dryness. The residue was extracted with 3-5 ml of DCM and if all solids dissolved, the product was purified by flash chromatography. In instances where the product was not soluble in methylene chloride, the product was filtered, washed with DCM, and the filtrate was further purified by flash chromatography to give additional material.

[1082] General Procedure B for the hydrolysis of 4-chloroquinoline. A stirred mixture of 4-chloroquinoline (3a-o, 1 equivalent), potassium acetate (KOAc, 10 equivalents) and glacial acetic acid was heated at 120° C. in a loosely capped reaction vial for 16-24 hours. After cooling to room temperature, the reaction mixture was poured into ice water (20-30 ml). The resulting precipitate was filtered, washed with water (3x15 ml), acetone (3x10 ml), DCM (3x10 ml), hexane (3x10 ml), and air-dried to produce the desired product. If the purity of the product was less than 98% by NMR and HPLC, the product could be obtained in pure form by crystallization from DMF.

[1083] General Procedure C for the Synthesis of Alkyl Carbonate Prodrugs: A stirred mixture of 4-(1H)-quinolone ELQ (1 equivalent), tetrabutylammonium iodide (TBAI) (2 equivalents), dry K2CO3 (2 equivalents) and chloromethyl ethyl carbonate (2 equivalents) in DMF was heated at 60°C for 24 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness to produce an oil. The resulting residue was stirred with ethyl acetate for 30 minutes, and the soluble TBAI was filtered and washed with ethyl acetate. The filtrate was concentrated to dryness and purified by flash chromatography using a gradient of ethyl acetate / hexane as eluent to obtain the desired prodrug. If the prodrug produced is less than 98% by GM-MS and NMR, the product can be obtained in pure form by crystallization from hexane / ethyl acetate.

[1084] General Procedure D for the Synthesis of N-Oxide Prodrugs:

[1085] To a stirred solution of ELQ alkoxy carbonate (1 eq) in chloroform was added MCPBA (1.5 eq) and the solution was heated to 90° C. over 24 h. After cooling to room temperature, the yellow solution was concentrated to dryness under vacuum and purified by flash chromatography on silica gel.

[1086] General Procedure E for the Hydrolysis of N-oxide Prodrugs:

[1087] A solution of the carbonate alkoxy nitrone in ethanol / 10% aqueous NaOH (4 / 1) was heated at 60°C for 2 hours, forming a white precipitate. The solution was concentrated to dryness. The resulting solid was then washed with water (3 x 10 ml), DCM (3 x 10 ml), and air-dried to yield the desired N-hydroxy ELQ.

[1088] 3-(3',5'-Bis(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-4,6-dichloro-7-methoxy-2-methylquinoline (3a): Following General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 eq), 2a (568 mg, 2.2 mmol, 1.1 eq), aqueous KCO (2 ml, 2 eq), Pd(dppf)Cl (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 16 h to give crude 3a (1.09 gm) as a black solid. DCM (15 ml) was added and the precipitate was filtered and washed with methylene chloride (2 x 5 ml) to give pure 3a (305 mg) as a white solid. A second crop from DCM gave another pure 3a (126 mg). The mother liquor was further purified by flash chromatography using a gradient of ethyl acetate / hexane (3 / 7) as the eluting solvent to give a combined yield of 3a (479 mg, 45% yield) in additional 3a (48 mg). + =529 (100%), GC-MS showed one peak. 1 H-NMR (400MHz; CDCl3): δ8.25(s,1H),8.12-8.11(m,2H),7.91-7.90(m,1H), 7.78-7.75(m,2H),7.48(s,1H),7.45-7.42(m,2H),4.08(s,3H),2.50(s,3H).

[1089] 4,6-Dichloro-3-(4'-cyclohexyl-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (3b): Following General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 eq), 2b (630 mg, 2.2 mmol, 1.1 eq), aqueous K2CO3 (2 ml, 2 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 48 hours to give crude 3a (1.03 gm) as a black solid. The product was purified twice by flash chromatography using a gradient of ethyl acetate / hexane (1 / 9) as the elution solvent to give 3b (529 mg). The product was crystallized in ethyl acetate / hexane to give pure 3b (400 mg, 42% yield) as a light yellow solid. At M + =475 (42%), GC-MS showed one peak. 1 H-NMR (400MHz; CDCl3): δ8.24(s,1H),7.72(d,J=8.1Hz,2H),7.61(d,J=8.1Hz,2H),7.46(s,1H),7.33-7.31(m,4H),4. 07(s,3H),2.60-2.53(m,1H),2.50(s,3H),1.95-1.86(m,4H),1.79-1.76(m,1H),1.53-1.36(m,4H),1.35-1.24(m,1H).

[1090] 4,6-Dichloro-3-(2'-chloro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (3c): Following General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 eq), 2c (528 mg, 2.2 mmol, 1.1 eq), aqueous KCO (2 ml, 2 eq), Pd(dppf)Cl (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 48 hours to give crude 3c (1.0 gm) 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 about 98% pure 3c (190 mg, 19% yield) as a white solid as determined by GC-MS and NMR. At M + =511 (100%), GC-MS showed one peak. 1H-NMR (400MHz; CDCl3): δ8.26(s,1H),7.57-7.55(m,2H),7.50-7.46(m,2H), 7.41(s,1H),7.36-7.34(m,2H),7.26-7.23(m,2H),4.08(s,3H),2.51(s,3H).

[1091] 4,6-Dichloro-7-methoxy-2-methyl-3-(2'-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinoline (3d): Following General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 eq), 2d (664 mg, 2.2 mmol, 1.1 eq), aqueous K2CO3 (2 ml, 2 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 16 h to give crude 3d (1.26 gm) as a black solid. The product was purified by flash chromatography 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 in ethyl acetate to give pure 3d (431 mg, 44% yield). At M + =491 (100%), GC-MS showed one peak. 1 H-NMR (400MHz; CDCl3): δ8.26(s,1H),7.48(s,1H),7.45-7.44(m,1H),7.43-7.42(t ,1H),7.34-7.31(m,3H),7.17-7.12(m,2H),4.08(s,3H),2.51(s,3H),2.36(s,3H).

[1092] 4,6-Dichloro-7-methoxy-2-methyl-3-(2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinoline (3e): Following General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 eq), 2e (494 mg, 2.4 mmol, 1.2 eq), aqueous KCO (2 ml, 2 eq), Pd(dppf)Cl (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 24 h to give crude 3e (2.65 gm) as a black solid. The product 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. + =477 (100%), GC-MS showed one peak. 1H-NMR (400MHz; CDCl3): δ8.25(s,1H),7.62-7.59(m,2H),7.57-7.54(m,1H), 7.48(s,1H),7.46-7.39(m,3H),7.36-7.33(m,2H),4.08(s,3H),2.50(s,3H).

[1093] 4,6-Dichloro-3-(2'-fluoro-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (3f): Following General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 eq), 2f (494 mg, 2.4 mmol, 1.2 eq), aqueous KCO (2 ml, 2 eq), Pd(dppf)Cl (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 24 h to give crude 3f (738 mg) as a black solid. The product was purified by flash chromatography using a gradient of ethyl acetate / hexane (2 / 8) as the eluting solvent to give 3f (369 mg, 45% yield) as a white solid. At M + =411 (100%), GC-MS showed one peak. 1 H-NMR (400 MHz; CDCl3): δ8.25 (s, 1H), 7.72-7.69 (m, 2H), 7.55 (td, J=7.8, 1.8 Hz, 1H), 7.47 (s, 1H), 7.37-7.34 (m, including 3H of CDCl3), 7.28-7.18 (m, 3H), 4.07 (s, 3H), 2.51 (s, 3H).

[1094] 4,6-Dichloro-7-methoxy-2-methyl-3-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)quinoline (3 g): Following General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 eq), 2 g (456 mg, 2.4 mmol, 1.2 eq), aqueous KCO (2 ml, 2 eq), Pd(dppf)Cl (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 10 days to give crude 3 g (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 give 3 g (41 mg) as a white solid. Overlapping fractions were concentrated in vacuo and the solid was crystallized from ethyl acetate and hexanes to give a combined 3 g (241 mg, 22% yield) of an additional 3 g (200 mg). + =461 (100%), GC-MS showed one peak.1 H-NMR (400MHz; CDCl3): δ8.26 (s, 1H), 7.79 (dd, J = 7.8, 0.5Hz, 1H), 7.64-7.60 (m, 1H) ,7.53-7.50(m,1H),7.48-7.46(m,4H),7.32-7.29(m,2H),4.07(s,3H),2.50(s,3H).

[1095]

[00145] 4,6-Dichloro-3-(3',5'-difluoro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (3h): Following General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 eq), 2h (778 mg, 2.4 mmol, 1.2 eq), aqueous KCO (2 ml, 2 eq), Pd(dppf)Cl (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 24 h to give crude 3h (1.55 gm) as a black solid. The product was purified by flash chromatography using a gradient of ethyl acetate / hexanes (2 / 8) as the eluting solvent to give 3h (677 mg, 66% yield) as a white solid that was approximately 95% pure as determined by GC-MS and NMR. At M + =513 (100%), GC-MS showed one peak. 1 H-NMR (400MHz; CDCl3): δ8.25(s,1H),7.69-7.66(m,2H),7.47(s,1H),7.41-7.38(m,2H),7.34-7.31(m,2H),4.07(s,3H),2.48(s,3H).

[1096] 4,6-Dichloro-3-(3',5'-difluoro-4'-methoxy-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (3i): Following General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 eq), 2i (648 mg, 2.4 mmol, 1.2 eq), aqueous KCO (2 ml, 2 eq), Pd(dppf)Cl (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 24 h to give crude 3i (1.48 gm) as a black solid. The product was purified by flash chromatography using a gradient of ethyl acetate / hexane (2 / 8) as the eluting solvent to give about 95% pure 3i (903 mg, 98% yield) as a white solid as determined by GC-MS and NMR. At M + =459 (100%), GC-MS showed one peak.1 H-NMR (400MHz; CDCl3): δ8.25(s,1H),7.67-7.63(m,2H),7.47(s,1H),7.37-7.33(m,2H),7.24-7.22(m,2H),4.07-4.06(m,6H),2.49(s,3H).

[1097] 4,6-Dichloro-7-methoxy-3-(2'-methoxy-5'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-methylquinoline (3j): Following General Procedure A, a mixture of 1 (1.19 gm, 3.0 mmol, 1 eq), 2j (850 mg, 3.6 mmol, 1.2 eq), aqueous KCO (3 ml, 6.0 mmol, 2 eq), Pd(dppf)Cl (73 mg, 0.1 mmol, 0.05 eq) and DMF (150 ml) was heated for 18 hours to give crude 3j (2.1 gm) 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 3j (976 mg, 64% yield) as a white solid. + =507 (100%), GC-MS showed one peak. 1 H-NMR (400MHz; CDCl3): δ8.26(s,1H),7.68-7.65(m,2H),7.47(s,1H),7.34-7.31(m, 3H), 7.23-7.20 (m, 1H), 7.00 (d, J = 9.0Hz, 1H), 4.07 (s, 3H), 3.88 (s, 3H), 2.52 (s, 3H).

[1098] 4,6-Dichloro-7-methoxy-3-(2'-methoxy-[1,1'-biphenyl]-4-yl)-2-methylquinoline (3k): Following General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 eq), 2k (365 mg, 2.4 mmol, 1.2 eq), aqueous KCO (2 ml, 2 eq), Pd(dppf)Cl (73 mg, 0.1 mmol, 0.05 eq) and DMF (100 ml) was heated for 48 hours to give crude 3k (1.2 gm) 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 3k (540 mg, 64% yield) as a white solid. At M +=423 (100%), GC-MS showed one peak. (400 MHz; CDCl3): δ 8.26 (s, 1H), 7.70-7.67 (m, 2H), 7.47 (s, 1H), 7.43 (dd, J = 7.5, 1.7 Hz, 1H), 7.36 (ddd, J = 8.2, 7.4, 1.8 Hz, 1H), 7.31-7.28 (m, 2H), 7.09-7.02 (m, 2H), 4.07 (s, 3H), 3.87 (s, 3H), 2.53 (s, 3H).

[1099] 4,6-Dichloro-7-methoxy-3-(2'-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-2-methylquinoline (3l): Following General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 eq), 2l (528 mg, 2.4 mmol, 1.2 eq), aqueous K2CO3 (2 ml, 2 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 18 hours to give crude 3l (1.0 gm) as a yellow solid. The product was purified by flash chromatography using a gradient of ethyl acetate / hexane (2 / 8) as the elution solvent to give 3l (618 mg, 63% yield) as a white solid. At M + =491 (100%), GC-MS showed one peak. 1 H-NMR (400MHz; CDCl3): δ8.26(s,1H),7.69-7.66(m,2H),7.54-7.52(m,1H) ),7.47(s,1H),7.35-7.32(m,3H),7.23(s,1H),4.07(s,3H),2.51(s,3H).

[1100] 4,6-Dichloro-3-(4'-fluoro-2'-methoxy-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (3m): Following General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 eq), 21 (408 mg, 2.4 mmol, 1.2 eq), aqueous KCO (2 ml, 2 eq), Pd(dppf)Cl (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 18 h. Upon filtering the mixture through celite, a white soluble solid present on top of the celite separated and was air dried to yield pure 3m (503 mg, 57% yield) as a white solid. + =441 (100%), GC-MS showed one peak. 1H-NMR (400MHz; CDCl3): δ8.25(s,1H),7.65-7.62(m,2H),7.47(s,1H),7.39-7.35(m ,1H),7.31-7.28(m,2H),6.80-6.74(m,2H),4.07(s,3H),3.86(s,3H),2.52(s,3H).

[1101] 4,6-Dichloro-7-methoxy-3-(2'-methoxy-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-methylquinoline (3n): Following General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 eq), 2n (763 mg, 2.4 mmol, 1.2 eq), aqueous KCO (2 ml, 2 eq), Pd(dppf)Cl (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 36 h to give crude 3n (1.40 gm) as a black solid. The product was purified by flash chromatography using a gradient of ethyl acetate / hexane (2 / 8) as the eluting solvent to give 3n (597 mg) as a white solid. The product was crystallized in DCM / hexanes to give pure 3n (360 mg), and a second crop from the mother liquor gave additional 3n (120 mg) for a total of pure 3n (480 mg, 47% yield) as a white solid. + =445 (100%), GC-MS showed one peak. 1 H-NMR (400MHz; CDCl3): δ8.26 (s, 1H), 7.66-7.63 (m, 2H), 7.47 (s, 1H), 7.42 (d, J = 8.4Hz, 1H), 7.3 3-7.29(m,2H),6.96-6.93(m,1H),6.86(d,J=1.7Hz,1H),4.07(s,3H),3.88(s,3H),2.52(s,3H).

[1102] 4'-(4,6-Dichloro-7-methoxy-2-methylquinolin-3-yl)-2-methoxy-[1,1'-biphenyl]-4-carbonitrile (3o): Following General Procedure A, a mixture of 1 (794 mg, 2.0 mmol, 1 eq), 3o (622 mg, 2.4 mmol, 1.2 eq), aqueous K2CO3 (2 ml, 2 eq), Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.05 eq) and DMF (75 ml) was heated for 110 h to give crude 3o (1.0 g) as a black solid. The product was purified by flash chromatography 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 in ethyl acetate / DCM to give pure 3o (485 mg, 54% yield) as a white solid. At M + =448 (100%), GC-MS showed one peak. 1 H-NMR (400MHz; CDCl3): δ8.25(s,1H),7.68-7.65(m,2H),7.51(d,J=7.8Hz,1H),7.47(s,1H),7.39(dd ,J=7.8,1.5Hz,1H),7.36-7.32(m,2H),7.25(d,J=1.5Hz,1H),4.07(s,3H),3.91(s,3H),2.51(s,3H).

[1103] 4,6-Dichloro-3-(4-cyclohexylphenyl)-7-methoxy-2-methylquinoline (3p): Following General Procedure A, a mixture of 4 (321 mg, 1.0 mmol, 1 eq), 2p (300 mg, 1.05 mmol, 1.05 eq), aqueous KCO (1 ml, 2 eq), Pd(dppf)Cl (37 mg, 0.1 mmol, 0.05 eq) and DMF (25 ml) was heated for 16 h and kept at room temperature for 72 h. After the mixture was filtered through celite, a white solid located on top of the celite separated to yield pure 3p (90 mg) as a white solid. The filtrate was concentrated to dryness in vacuo and purified by flash chromatography using a gradient of ethyl acetate / hexane (1 / 9) as the eluting solvent to yield 3p (89 mg). The product was further crystallized in DMF to give pure 3p (26 mg) of the combined total 3p (116 mg, 29% yield). + =399 (100%), GC-MS showed one peak. 1H-NMR (400MHz; CDCl3): δ8.23(s,1H),7.45(s,1H),7.34-7.31(m,2H),7.18-7.16(m,2H),4.06(s,3H),2. 62-2.55(m,1H),2.45(s,3H),1.99-1.96(m,2H),1.90-1.87(m,2H),1.81-1.76(m,1H),1.51-1.25(m,6H).

[1104] 3-(3',5'-Bis(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-4-chloro-6-fluoro-7-methoxy-2-methylquinoline (6a): Following General Procedure A, a mixture of 5 (3.81 g, 10.0 mmol, 1 eq), 2a (2.84 g, 11.0 mmol, 1.1 eq), aqueous KCO (20 ml, 2 eq), Pd(dppf)Cl (366 mg, 0.5 mmol, 0.05 eq) and DMF (200 ml) was heated for 16 h to give crude 6a (5.82 g) as a black solid. The product was purified by flash chromatography using a gradient of ethyl acetate / hexane (3 / 7) as the elution solvent. During evaporation of the solvent of the combined fractions under vacuum, a white precipitate formed. The product was filtered and washed with cold hexane to give pure 6a as a white solid (2.46 g, 48% yield). + =513 (100%), GC-MS showed one peak. 1 H-NMR (400MHz; CDCl3): δ8.14(s,2H),7.93(s,1H),7.87(d,J=11.8Hz,1H),7.80- 7.78(m,2H),7.52(d,J=8.1Hz,1H),7.47-7.45(m,2H),4.08(s,3H),2.52(s,3H).

[1105] 4-Chloro-3-(4'-cyclohexyl-[1,1'-biphenyl]-4-yl)-6-fluoro-7-methoxy-2-methylquinoline (6b): Following General Procedure A, a mixture of 5 (3.81 g, 10 mmol, 1 eq), 2b (3.43 g, 12.0 mmol, 1.2 eq), aqueous K2CO3 (20 ml, 2 eq), Pd(dppf)Cl2 (366 mg, 0.5 mmol, 0.05 eq) and DMF (200 ml) was heated for 16 h to give crude 6b as a black solid. The product was purified by flash chromatography using a gradient of ethyl acetate / hexane (3 / 7) as the eluting solvent to give 6b (1.28 g). The product was further crystallized in ethyl acetate / hexane to give pure 6b (698 mg, 15% yield) as white crystals. At M + =459 (100%), GC-MS showed one peak. 1 H-NMR (400MHz; CDCl3): δ7.88(d,J=11.9Hz,1H),7.74(d,J=8.2Hz,2H),7.64(d,J=8.2Hz,2H),7.52(d,J=8.1Hz,1H ),7.35(dd,J=8.3,2.1Hz,4H),4.08(s,3H),2.62-2.55(m,1H),2.52(s,3H),1.98-1.79(m,5H),1.56-1.26(m,5H).

[1106] 4,6-Dichloro-3-(4'-fluoro-2-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinoline (9): Following General Procedure A, a mixture of 4 (386 mg, 1.05 mmol, 1 eq), 8 (440 mg, 1.15 mmol, 1.1 eq), aqueous K2CO3 (1.1 ml, 2 eq), Pd(dppf)Cl2 (38 mg, 0.5 mmol, 0.05 eq) and DMF (25 ml) was heated for 48 h to give crude 9 (671 mg) as a black solid. The product was purified by flash chromatography using a gradient of ethyl acetate / hexane (2 / 8) as the elution solvent to give 9 (401 mg) and further crystallized in ethyl acetate / hexane to give pure 9 (310 mg, 60% yield) as a white solid. + =495 (100%), GC-MS showed one peak. 1H-NMR (400MHz; CDCl3): δ8.27(s,1H),7.59-7.54(m,3H),7.50(s,1H),7.32-7.30(m,2H),7.23-7.18(m,2H),4.10(s,3H),2.54(s,3H).

[1107] 4-Chloro-3-(4-cyclohexylphenyl)-6-fluoro-7-methoxy-2-methylquinoline (6p):

[1108] Following General Procedure A, a mixture of 5 (305 mg, 1.0 mmol, 1 eq), 2p (300 mg, 1.05 mmol, 1.05 eq), aqueous KCO (1 ml, 2 eq), Pd(dppf)Cl (37 mg, 0.05 mmol, 0.05 eq) and DMF (25 ml) was heated for 16 h and kept at room temperature for 72 h. After the mixture was filtered through celite, a white solid on top of the celite separated to produce pure 6p (97 mg) as a white solid. The filtrate was concentrated to dryness in vacuo and purified by flash chromatography using a gradient of ethyl acetate / hexane (1 / 9) as eluting solvent to produce 6p (228 mg). The product was further crystallized in DMF to produce pure 6p (97 mg) of the combined total 3p (194 mg, 51% yield). At M + =383 (100%), GC-MS showed one peak. 1 H-NMR (400MHz; CDCl3): δ7.84(d,J=12.0Hz,1H),7.48(d,J=8.1Hz,1H),7.34-7.31(m,2H) ,7.18-7.15(m,2H),4.05(s,3H),2.62-2.55(m,1H),1.99-1.76(m,5H),1.54-1.26(m,5H).

[1109]

[1110] 3-(3',5'-Bis(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-6-chloro-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-689): Following General Procedure B, a mixture of 3a (690 mg, 1.30 mmol, 1 eq), KOAc (1.28 g, 13 mmol, 10 eq), and glacial acetic acid (5 ml) was heated for 16 h to give pure ELQ-689 (532 mg, 80% yield) as a white solid. 1H-NMR (400MHz; DMSO-d6): δ11.73(s,1H),8.39(s,2H),8.10(s,1H),8.03(s,1H ),7.92-7.90(m,2H),7.44-7.42(m,2H),7.10(s,1H),3.98(s,3H),2.28(s,3H).

[1111]

[1112] 6-Chloro-3-(4′-cyclohexyl-[1,1′-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-690): Following General Procedure B, a mixture of 3b (238 mg, 0.5 mmol, 1 eq), KOAc (490 mg, 5 mmol, 10 eq), and glacial acetic acid (2 ml) was heated for 18 h to give pure ELQ-690 (207 mg, 90% yield) as a white solid. 1 H-NMR (400MHz; DMSO-d6): δ11.72-11.67(m,1H),8.02(s,1H),7.67-7.62(m,4H),7.35-7.31(m,4H),7.09(s,1H),3.98(s,3H),2 .69-2.67(m,0.5),2.35-2.33(m,0.5),2.25(s,3H),1.86-1.81(m,4H),1.75-1.70(m,1H),1.48-1.34(m,5H),1.32-1.23(m,1H).

[1113]

[1114] 6-Chloro-3-(2'-chloro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-692): Following General Procedure B, a mixture of 3c (190 mg, 0.37 mmol, 1 eq), KOAc (363 mg, 3.7 mmol, 10 eq), and glacial acetic acid (5 ml) was heated for 24 h to give pure ELQ-692 (161 mg, 88% yield) as a white solid. 1H-NMR (400 MHz; DMSO-d6): δ 11.72 (s, 1H), 8.02 (s, 1H), 7.72-7.72 (m, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.50-7.48 (m, 3H), 7.37 (d, J = 8.2 Hz, 2H), 7.09 (s, 1H), 3.98 (s, 3H), 2.28 (s, 3H). In the case of decomposition, MP 337.8-338.9°C.

[1115]

[1116]

[0149] 6-Chloro-7-methoxy-2-methyl-3-(2'-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-693): Following General Procedure B, a mixture of 3d (430 mg, 0.87 mmol, 1 eq), KOAc (853 mg, 8.7 mmol, 10 eq), and glacial acetic acid (4 ml) was heated for 24 h to give pure ELQ-693 (334 mg, 81% yield) as a white solid. 1 H-NMR (400 MHz; DMSO-d6): δ 11.69 (s, 1H), 8.02 (s, 1H), 7.40-7.33 (m, 6H), 7.28-7.26 (m, 1H), 7.08 (s, 1H), 3.97 (s, 3H), 2.34 (s, 3H), 2.27 (s, 3H). In the case of decomposition, MP 325.9-327.1°C.

[1117]

[1118]

[0149] 6-Chloro-7-methoxy-2-methyl-3-(2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-702): Following General Procedure B, a mixture of 3e (638 mg, 1.33 mmol, 1 eq), KOAc (1.30 g, 13.3 mmol, 10 eq), and glacial acetic acid (5 ml) was heated for 24 h to give pure ELQ-702 (334 mg, 76% yield) as a white solid. 1 H-NMR (400 MHz; DMSO-d6): δ 11.71 (s, 1H), 8.02 (s, 1H), 7.62-7.60 (m, 1H), 7.55-7.48 (m, J = 2.3 Hz, 5H), 7.38-7.35 (m, 2H), 7.09 (s, 1H), 3.98 (s, 3H), 2.26 (s, 3H). In the case of decomposition, MP was 293.1-294.3°C.

[1119]

[1120]

[0266] 6-Chloro-3-(2'-fluoro-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-703): Following General Procedure B, a mixture of 3f (369 mg, 0.90 mmol, 1 eq), KOAc (882 mg, 9.0 mmol, 10 eq), and glacial acetic acid (5 ml) were reacted for 24 h to give pure ELQ-703 (262 mg, 74% yield) as a white solid. 1 H-NMR (400 MHz; DMSO-d6): δ 11.72 (s, 1H), 8.02 (s, 1H), 7.62-7.57 (m, 3H), 7.45-7.32 (m, 5H), 7.08 (s, 1H), 3.97 (s, 3H), 2.27 (s, 3H). In the case of decomposition, MP was 370.4-371°C.

[1121]

[1122]

[0147] 6-Chloro-7-methoxy-2-methyl-3-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)quinolin-4(1H)-one (ELQ-704): Following General Procedure B, a mixture of 3 g (200 mg, 0.43 mmol, 1 eq), KOAc (421 mg, 4.3 mmol, 10 eq), and glacial acetic acid (5 ml) was heated for 24 h to give pure ELQ-704 (152 mg, 80% yield) as a white solid. 1 H-NMR (400 MHz; DMSO-d6): δ 11.74 (s, 1H), 8.02 (s, 1H), 7.87-7.85 (m, 1H), 7.77-7.74 (m, 1H), 7.65-7.62 (m, 1H), 7.49-7.47 (m, 1H), 7.33 (s, 4H), 7.09 (s, 1H), 3.98 (s, 3H), 2.26 (s, 3H). In the case of decomposition, MP 350.7-351.3 ° C.

[1123]

[1124]

[0147] 6-Chloro-3-(3',5'-difluoro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-717): Following General Procedure B, a mixture of 3h (677 mg, 1.3 mmol, 1 eq), KOAc (1.27 g, 13 mmol, 10 eq), and glacial acetic acid (10 ml) was heated for 24 h to give pure ELQ-717 (507 mg, 79% yield) as a white solid. 1 H-NMR (400MHz; DMSO-d6): δ11.72(s,1H),8.02(s,1H),7.85-7.80(m,J=11. 6, 9.0Hz, 4H), 7.39 (d, J = 8.4Hz, 2H), 7.09 (s, 1H), 3.98 (s, 3H), 2.26 (s, 3H).

[1125]

[1126]

[0147] 6-Chloro-3-(3',5'-difluoro-4'-methoxy-[1,1'-biphenyl]-4-yl)-7-methoxy-2-methylquinolin-4(1H)-one (ELQ-716): Following general procedure B, a mixture of 3i (917 mg, 1.98 mmol, 1 eq), KOAc (1.95 g, 19.8 mmol, 10 eq), and glacial acetic acid (15 ml) was heated for 18 h to give pure ELQ-716 (500 mg, 57% yield) as a white solid. 1 H-NMR (400MHz; DMSO-d6): δ8.01(s,1H),7.72(d,J=8.2Hz,2H),7.56(d,J=9.8 Hz, 2H), 7.34 (d, J = 8.2Hz, 2H), 7.08 (s, 1H), 3.98-3.97 (2s, 6H), 2.25 (s, 3H).

[1127]

[1128]

[0147] 6-Chloro-7-methoxy-3-(2'-methoxy-5'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-methylquinolin-4(1H)-one (ELQ-727): Following General Procedure B, a mixture of 3j (976 mg, 1.92 mmol, 1 eq), KOAc (1.88 g, 19.2 mmol, 10 eq), and glacial acetic acid (10 ml) was heated for 18 h to give pure ELQ-727 (697 mg, 74% yield) as a white solid. 1H-NMR (400 MHz; DMSO-d6): δ 11.69 (s, 1H), 8.02 (s, 1H), 7.54-7.52 (m, 2H), 7.38-7.30 (m, 4H), 7.24-7.22 (m, 1H), 7.09 (s, 1H), 3.96-3.95 (m, 3H), 3.88-3.82 (m, 3H), 2.31-2.24 (m, 3H). In the case of decomposition, MP was 297.3-298.1°C.

[1129]

[1130] 6-Chloro-7-methoxy-3-(2'-methoxy-[1,1'-biphenyl]-4-yl)-2-methylquinolin-4(1H)-one (ELQ-728): Following General Procedure B, a mixture of 3k (540 mg, 1.27 mmol, 1 eq), KOAc (1.24 g, 12.7 mmol, 10 eq), and glacial acetic acid (5 ml) was heated for 18 h to give pure ELQ-728 (467 mg, 91% yield) as a white solid. 1 H-NMR (400 MHz; DMSO-d6): δ 11.67 (s, 1H), 8.02 (s, 1H), 7.51-7.49 (m, 2H), 7.38-7.34 (m, 2H), 7.29-7.26 (m, 2H), 7.15-7.13 (m, 1H), 7.09 (s, 1H), 7.06 (td, J = 7.4, 1.0 Hz, 1H), 3.98 (s, 3H), 3.81 (s, 3H), 2.27 (s, 3H). In the case of decomposition, MP 327.3-327.9°C.

[1131]

[1132]

[0147] 6-Chloro-7-methoxy-3-(2'-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-2-methylquinolin-4(1H)-one (ELQ-742): Following General Procedure B, a mixture of 31 (600 mg, 1.22 mmol, 1 eq), KOAc (1.20 g, 12.2 mmol, 10 eq), and glacial acetic acid (10 ml) was heated for 18 h to give pure ELQ-742 (455 mg, 79% yield) as a white solid. 1H-NMR (400 MHz; DMSO-d6): δ 11.70 (s, 1H), 8.02 (s, 1H), 7....

Claims

1. A compound of formula (I), in: R 1a , R 1b and R 1c Each of which is independently selected from the group consisting of: H, halogen, CN, C1-C6 alkyl, and C1-C6 alkoxy; R2 is selected from the group consisting of: n) Oxo (=O); o)-OH; p) -O-CH2-OC(=O)-O-R6; q) -O-CH2-CH2-OC(=O)-O-R6; r)-O-CH2(CH3)-OC(=O)-O-R6; s)-OC(=O)-CH2-CH2-C(=O)-O-R6; t) -O-CH2-OC(=O)-R6; u) -O-(C=O)-R7; v) -O-(C=O)-O-R7; w)-OC(O)-NR8R9; x)-O-CH2-OC(O)-O-(CH2) n1 -NR8R9; y)-O-CH2-OC(O)-O-(CH2) n1 -NR8-C(=O)-O-R9; and z)-O-(CH2)-O-PO3; The dashed line (-----) in each example represents an optional single or double bond; Z is selected from the group consisting of H and C; and R3, R4 and R5 are each independently selected from the group consisting of: H, halogen, C1-C4 alkyl, -O-C1-C4 alkyl, -S-C1-C4 alkyl, -SO2-C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, -S-C1-C4 haloalkyl, SF3, -SF5, CN, 2-pyrrolidone, NO2, -SO2-NH2, -SO2-NH(C1-C -4 alkyl), -SO2-N(C1-C4 alkyl)2, -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -C(O)NH(C3-C6 cycloalkyl), -C(O)NH(-CH2-C3-C6 cycloalkyl), C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl and -S-C3-C6 cycloalkyl, wherein the -C(O)NH(C1-C4 alkyl)2 The cycloalkyl ring of the -C(O)NH(-CH2-C3-C6 cycloalkyl), the C3-C6 cycloalkyl, the -O-C3-C6 cycloalkyl and the -S-C3-C6 cycloalkyl 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 -C1-C4 alkyl, -C1-C4 haloalkyl, -O-C1-C4 haloalkyl, -S-C1-C4 haloalkyl, SF3, -SF5, CN, NO2, -SO2-NH2, -SO2-NH(C1-C4 alkyl), -SO2-N(C1-C4 alkyl)2, -C(O)NH2, -C(O)NH(C1-C4 alkyl) and -C(O)N(C1-C4 alkyl)2; R6 is selected from the group 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 heterocyclic group, -(CH2) n1 -3-6 membered heterocyclic group, phenyl group, -(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 heterocyclic group), phenyl, -(CH2) n1 -phenyl, -(CH2) n1 -O-(CH2) n2 -C1-C2 alkyl, -(CH2-CH2-O) n1 -C1-C2 alkyl and -(CH2) n1 -NR8R9; R8 and R9 are each independently selected from the group consisting of H and C1-C6 alkyl; R 10 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; R 11 Selected from H, OH and O - Groups formed; n1 and n2 are each an integer independently selected from the group consisting of: 1, 2, 3, 4, 5, and 6; and n3 is an integer selected from the group consisting 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-7-methoxy-2-methyl-4(1H)-quinolinone (CAS Reg. No. 1354745-39-3), 1H)-quinolinone (CAS Reg. No. 1374758-04-9); or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

2. The compound according to claim 1, wherein R2 is selected from the group consisting of: f) Oxo (=O); g) -OH; h) -O-CH2-OC(=O)-O-R6; i) -O-CH2-CH2-OC(=O)-O-R6; and j)-O-CH2(CH3)-OC(=O)-O-R6; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

3. The compound according to claim 1, wherein: R2 is selected from the group consisting of oxo (=O) and a moiety of the formula -O-CH2-OC(=O)-O-(C1-C6 alkyl); 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said -O-C3-C6 cycloalkyl and said -S-C3-C6 cycloalkyl 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 As defined above for formula (I); and Provided that, where R2 is selected from the group consisting of oxo (=O), then at least one of R3, R4 and R5 is not H; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

4. The compound of claim 4, wherein R2 is selected from the group consisting of oxo (=O) and a moiety of the formula -O-CH2-OC(=O)-O-(C1-C3 alkyl); or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

5. The compound according to claim 1, which has formula (II): in: R1 is selected from the group consisting of H, F and Cl; R2 is selected from the group consisting of oxo (=O) and -O-CH2-OC(=O)-O-(C1-C 10 alkyl) moieties; 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-pyrrolidone, -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-C6cycloalkyl), C3-C6cycloalkyl, -O-C3-C6cycloalkyl and -S-C3-C6cycloalkyl, wherein the cycloalkyl rings of the -C(O)NH(C3-C6 cycloalkyl), the -C(O)NH(-CH2-C3-C6 cycloalkyl), the C3-C6 cycloalkyl, the -O-C3-C6 cycloalkyl and the -S-C3-C6 cycloalkyl are further substituted by 0, substituted with 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 example represents an optional single or double bond; Provided that, where R2 is selected from the group consisting of oxo (=O), then at least one of R3, R4 and R5 is not H; or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of formula (II), wherein: R1 is selected from the group consisting of H, F and Cl; R2 is selected from the group consisting of oxo (=O) and a moiety of the formula -O-CH2-OC(=O)-O-(C1-C6 alkyl); 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-pyrrolidone, -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-C6cycloalkyl), C3-C6cycloalkyl, -O-C3-C6cycloalkyl and -S-C3-C6cycloalkyl, wherein the cycloalkyl rings of the -C(O)NH(C3-C6 cycloalkyl), the -C(O)NH(-CH2-C3-C6 cycloalkyl), the C3-C6 cycloalkyl, the -O-C3-C6 cycloalkyl and the -S-C3-C6 cycloalkyl are further substituted by 0, substituted with 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 The dashed line (-----) in each example represents an optional single or double bond; R 10 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; Provided that, where R2 is selected from the group consisting of oxo (=O), then at least one of R3, R4 and R5 is not H; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

6. The compound according to claim 5, wherein: R1 is selected from the group consisting of H, F and Cl; R2 is selected from the group consisting of oxo (=O) and a moiety of the formula -O-CH2-OC(=O)-O-(C1-C4 alkyl); 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said -O-C3-C6 cycloalkyl and said -S-C3-C6 cycloalkyl is further substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: H, OH, oxo (= R , -C(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; 10 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 example represents an optional single or double bond; Provided that, where R2 is selected from the group consisting of oxo (=O), then at least one of R3, R4 and R5 is not H; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

7. The compound according to claim 5, wherein: R1 is selected from the group consisting of H, F and Cl; R2 is selected from the group consisting of oxo (=O) and a moiety of the formula -O-CH2-OC(=O)-O-(C1-C3 alkyl); 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said -O-C3-C6 cycloalkyl and said -S-C3-C6 cycloalkyl is further substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: H, OH, oxo (= R , -C(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; 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 The dashed line (-----) in each example represents an optional single or double bond; Provided that, where R2 is selected from the group consisting of oxo (=O), then at least one of R3, R4 and R5 is not H; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

8. The compound according to claim 1, which has formula (III): in: 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-pyrrolidone, -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-C6cycloalkyl), C3-C6cycloalkyl, -O-C3-C6cycloalkyl and -S-C3-C6cycloalkyl, wherein the cycloalkyl rings of the -C(O)NH(C3-C6 cycloalkyl), the -C(O)NH(-CH2-C3-C6 cycloalkyl), the C3-C6 cycloalkyl, the -O-C3-C6 cycloalkyl and the -S-C3-C6 cycloalkyl are further substituted by 0, substituted with 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; and The dashed line (-----) in each example represents an optional single or double bond; The condition is that in R 10 When it is H, at least one of R3, R4 and R5 is not H; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

9. The compound according to claim 8, 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-C3 alkyl, -O-C1-C3 alkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-CF3, -SF5, CN, 2-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said -O-C3-C6 cycloalkyl and said -S-C3-C6 cycloalkyl 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-C6 alkyl, -O-C1-C6 alkyl, C1-C4 haloalkyl, -O-C1-C4 haloalkyl, and -S-C1-C4 haloalkyl; and The dashed line (-----) in each example represents an optional single or double bond; The condition is that in R 10 When it is H, at least one of R3, R4 and R5 is not H; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

10. The compound according to claim 8, 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said -O-C3-C6 cycloalkyl and said -S-C3-C6 cycloalkyl is further substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: H, OH, oxo (= R , -C(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; 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 The dashed line (-----) in each example represents an optional single or double bond; The condition is that in R 10 When it is H, at least one of R3, R4 and R5 is not H; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

11. The compound according to claim 8, 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-pyrrolidone, -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 said -C(O)NH(C3-C6 cycloalkyl), said -C(O)NH(-CH2-C3-C6 cycloalkyl), said C3-C6 cycloalkyl, said -O-C3-C6 cycloalkyl and said -S-C3-C6 cycloalkyl is further substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: H, OH, oxo (= R , -C(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; 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 The dashed line (-----) in each example represents an optional single or double bond; The condition is that in R 10 When it is H, at least one of R3, R4 and R5 is not H; or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

12. The compound according to claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

13. A pharmaceutical composition comprising a pharmaceutically effective amount or a 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. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof for preparing a medicament.

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