Sulfonamides and their uses for the treatment of helminth infections and diseases - Patents.com

Abstract

Formula I: TIFF2024506322000141.tif52154[where, R 1 , R 2 , R, A, m, n and p are as defined herein], as well as pharma- ceutically acceptable salts, tautomers, isotopologues and stereoisomers thereof, compositions comprising an effective amount of the sulfonamide compounds, and methods for treating or preventing animal and human heartworm infections and diseases.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 147,710, filed February 9, 2021, the disclosure of which is incorporated herein by reference in its entirety.

[0002] Disclosed herein are compounds and methods for the prevention and / or treatment of helminth infections and diseases resulting from helminth infections. Disclosed herein are compounds and methods for the prevention and / or treatment of helminthiasis. Also provided herein are such compounds for use in such methods. Also disclosed herein are pharmaceutical compositions comprising such compounds for use in such methods of preventing or treating helminth infections and / or diseases associated with helminth infections. [Background technology]

[0003] Several types of parasitic worms (helminths) exist worldwide, the most common being intestinal nematodes or soil-transmitted helminths (STHs), schistosomes (the parasites responsible for schistosomiasis), and the filarial worms that cause lymphatic filariasis (LF) and onchocerciasis. Filariasis is a parasitic disease caused by thread-like filarial nematodes or roundworms. Filariasis is a vector-borne disease transmitted by insect bites. Infectious nematode larvae can be introduced into humans through the bite of blood-sucking insects such as mosquitoes or flies. Heartworm disease can also affect domestic animals, such as dogs. In dogs, dirofilariasis, also known as heartworm disease, is caused by the nematodes Dirofilaria immitis and Dirofilaria repens. Dirofilariasis is considered endemic in 49 states of the United States. Vectors are also blood-sucking insects such as mosquitoes.

[0004] The primary causes of human filariasis are the filarial nematodes Wuchereria bancrofti, Brugia malayi, Brugia timori, Onchocerca volvulus, and Mansonella species, which have human hosts. The nematodes Wuchereria bancrofti, Brugia malayi, and Onchocerca volvulus are responsible for the majority of debilitating filarial infections in over 80 developing countries in tropical and subtropical regions, where 1.1 billion people are at risk and approximately 150 million people are infected. All three species are responsible for severe disease resulting in high morbidity and mortality. Infection can cause severe morbidity in up to 50% of people infected with the nematode.

[0005] W. bancrofti and B. malayi infections can progress to lymphatic filariasis, often manifested as hydrocele and / or lymphedema in men and, in extreme cases, elephantiasis. O. volvulus infections can progress to severe dermatitis and / or onchocerciasis, the latter disease commonly referred to as river blindness due to vision loss. Community-led mass drug administration programs have been designed to control these infections and eliminate them as a public health problem.

[0006] Current efforts aim to eliminate these parasitic nematodes through the use of drugs such as diethylcarbamazine, ivermectin, and albendazole, which kill larvae but not adult worms. In countries where O. volvulus infection is not co-endemic, i.e., outside of Africa, the antihelminthic diethylcarbamazine is used to treat lymphatic filariasis. Ivermectin is used to treat onchocerciasis. The greatest efficacy of both drugs is against first-stage larvae, which are found in the bloodstream or dermis. Because the worm can live up to 14 years and is reproductive for most of its lifespan, populations in endemic areas must be treated with high coverage (at least 65%) for many years to interrupt disease transmission to uninfected individuals.

[0007] Two major limitations in the treatment of filarial disease are (i) the lack of macrofilaricidal drugs (i.e., those that permanently sterilize the worms in onchocerciasis) and (ii) the risk of the worms developing drug resistance. For example, currently available treatments for onchocerciasis include ivermectin, which kills larvae but has little or no activity against adult Onchocerca volvulus parasites. Therefore, infected patients must be re-treated with ivermectin over several years until the adult worms die naturally. In addition, in some areas, there is a possibility of signs of resistance to ivermectin within the parasite. (Non-Patent Document 1) Additionally, there are risks associated with ivermectin treatment of patients co-infected with (i) Wuchereria bancrofti, Brugia malayi, Brugia timori, and / or Onchocerca volvulus and (ii) Loa loa. In such co-infected patients, ivermectin treatment can result in severe reactions, including encephalopathy, coma, or even death.

[0008] Heartworm infection, caused by the endoparasite Dirofilaria immitis (D. immitis), can be a severe, life-threatening disease in animals such as dogs and cats. Heartworms have a complex life cycle that involves several life stages before maturing into adult worms that ultimately infect the pulmonary arteries of the host animal. Heartworm transmission also requires mosquitoes to serve as intermediate hosts to complete this life cycle. For example, the initiation of the heartworm life cycle and transmission process involves a mosquito biting a previously infected dog and ingesting blood containing heartworm microfilariae (larval stage 1). Within the mosquito, the microfilariae molt over a two-week period and develop into infective larval stage 3 (L3) nymphs. When a mosquito bites another dog, infective L3 larvae enter the host through the puncture wound, migrate into tissues, and typically begin molting within 1–3 days after infection to become larval stage 4 (L4) larvae. L4 larvae then continue to migrate through tissues and molt approximately 50–70 days after infection to become sexually immature or “young” adult worms (larval stage 5, immature adult worms). Sexually mature worms eventually migrate to the dog’s heart and lungs as early as 70 days after infection. Approximately 6–7 months after infection, D. immitis adult worms mature, sexually reproduce in the pulmonary arteries, and produce microfilariae (MF) that circulate in the dog’s blood, thus completing the heartworm life cycle.

[0009] The most commonly used heartworm preventatives are macrocyclic lactones (MLs), such as ivermectin, moxidectin, and selamectin. These drugs are administered monthly to kill D. immitis L3 and L4 larvae that have infected the host within the past 30 days. Their primary action is to disrupt the heartworm life cycle by killing L3 and L4 larvae, thus preventing adult development and subsequent disease. While highly effective in preventing heartworm disease, MLs can kill circulating microfilariae, so owners are advised to test their dogs (i.e., heartworm-positive dogs) for existing heartworm infections before initiating ML treatment. A sudden decrease in the number of microfilariae in the blood can lead to hypersensitivity-type reactions and circulatory shock (e.g., anaphylaxis), likely due to dead or dying microfilariae. These potential adverse effects can be life-threatening to dogs and are therefore presented as warnings on many ML product labels. Therefore, the discovery of novel heartworm preventatives that can selectively target L3 and L4 stage larvae against microfilariae could offer potential safety advantages. By not killing circulating microfilariae in heartworm-positive dogs, targeted treatments could prevent adverse effects known to occur with other heartworm preventatives that lack D. immitis stage selectivity. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Osei-Atweneboana MY, et al., Phenotypic Evidence of Emerging Ivermectin Resistance in Onchocerca volvulus, PLoS Negl Trop Dis 5(3):e998(2011) Summary of the Invention

[0011] Therefore, there is a need for alternative and more effective treatments for heartworm disease.

[0012] Citation or identification of any reference in this application shall not be construed as an admission that such reference is prior art to the present application.

[0013] Formula (I): [ka] Provided herein are sulfonamide compounds of the formula: 1 , R 2 , R, A, m, n and p are as defined herein.

[0014] Formula (Ia): [ka] Provided herein are sulfonamide compounds of the formula: 1 , R 2 and n is as defined herein.

[0015] In one aspect, provided herein are sulfonamide compounds as described in the present disclosure, e.g., sulfonamide compounds of Formula (I), Formula (Ia), or Formula (II), or compounds from Table 1, Table 2, Table 3, or Table 4.

[0016] In one aspect, provided herein are sulfonamide compounds as described in the present disclosure, e.g., sulfonamide compounds of Formula (I), Formula (Ia), or Formula (II), or compounds from Table 1 or Table 2.

[0017] In one aspect, provided herein are pharmaceutical compositions comprising an effective amount of a sulfonamide compound, as described herein, and a pharmaceutically acceptable carrier, excipient, or vehicle. In some embodiments, the pharmaceutical composition is suitable for oral, parenteral, mucosal, transdermal, or topical administration.

[0018] In one aspect, provided herein is a method for treating a subject infected with a helminth. In another aspect, provided herein is the use of a sulfonamide compound for treating or preventing a helminth infection, comprising administering to a subject suffering from a helminth infection an effective amount of a sulfonamide compound as described herein. In one aspect, the helminth infection is a filarial infection.

[0019] In one aspect, provided herein is a method for treating a subject infected with a heartworm. In another aspect, provided herein is the use of a sulfonamide compound for the treatment or prevention of a filarial infection, the use comprising administering to a subject suffering from a filarial infection an effective amount of a sulfonamide compound as described herein.

[0020] In certain embodiments, the methods described herein comprise administering to a subject a therapeutically effective amount of a compound of Formula (I), (Ia), (II), or a compound from Table 1 or Table 2, Table 3, or Table 4, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof.

[0021] In certain embodiments, the methods described herein comprise administering to a subject a therapeutically effective amount of a compound of Formula (I), (Ia), (II), or a compound from Table 1 or Table 2 or Table 3, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof.

[0022] The compounds of the present invention are useful for the treatment of helminth diseases, helminths being classified as cestodes (tapeworms), nematodes (roundworms) and trematodes (flatworms or flukes). Non-limiting examples of filarial nematodes of the family Onchocercidae include Brugia species (i.e., B. malayi, B. pahangi, B. timori, etc.), Wuchereria species (i.e., W. bancrofti, etc.), Dirofilaria species (D. immitis, D. repens, D. ursi, D. tenuis, D. spectans, D. lutrae, etc.), Dipetalonema species (i.e., D. reconditum, etc.), (D. reconditum, D. repens, etc.), Onchocerca species (i.e. O. gibsoni, O. gutturosa, O. volvulus, etc.), Elaeophora species (E. bohmi, E. elaphi, E. poeli, E. sagitta, E. schneideri, etc.), Mansonella species (i.e. M. ozzardi, M. perstans, etc.) and Loa species (i.e. L. loa). In certain embodiments, the heartworm is Onchocerca volvulus. In certain embodiments, the heartworm is Wuchereria bancrofti. In certain embodiments, the heartworm is Brugia malayi. In certain embodiments, the heartworm is Brugia timori. In certain embodiments, the heartworm is Mansonella.In certain embodiments, the heartworm is Dirofilaria immitis.

[0023] In one aspect, provided herein is a use of a sulfonamide compound for treating or preventing a helminth infection, comprising administering to a subject suffering from a helminth infection an effective amount of a sulfonamide compound described herein. In another aspect, provided herein is a use of a sulfonamide compound for treating or preventing a heartworm infection, comprising administering to a subject suffering from a heartworm infection an effective amount of a sulfonamide compound described herein.

[0024] In one aspect, provided herein are sulfonamide compounds for use as pharmaceuticals. In certain embodiments, provided herein are sulfonamide compounds for use in a method for treating or preventing a helminth infection, the method comprising administering an effective amount of the sulfonamide compound to a subject. In certain embodiments, provided herein are sulfonamide compounds for use in a method for treating or preventing a heartworm infection, the method comprising administering an effective amount of the sulfonamide compound to a subject.

[0025] In another aspect, provided herein are methods for preparing the sulfonamide compounds described herein.

[0026] The present embodiments can be more fully understood by reference to the detailed description and examples that are intended to exemplify non-limiting embodiments. [Brief explanation of the drawings]

[0027] [Figure 1] 1 shows the life cycle of L. sigmodontis (a rodent filarial nematode) from microfilaria (L1) to the adult stage. DETAILED DESCRIPTION OF THE INVENTION

[0028] definition As used herein, the terms "comprise" and "comprise" can be used interchangeably. The terms "comprise" and "comprise" specify the presence of specified referenced features or components, but should be interpreted as not excluding the presence or addition of one or more features or components or groups thereof. Furthermore, the terms "comprise" and "comprise" are intended to include examples encompassed by the term "consisting of." Thus, the term "consisting of" can be used in place of the terms "comprise" and "comprise" to provide more specific embodiments of the present invention.

[0029] The term "consisting of" means that the subject matter comprises at least 90%, 95%, 97%, 98%, or 99% of the specified features or components that make it up. In another embodiment, the term "consisting of" excludes from the scope of any succeeding statement any other features or components, except those that are not essential to the technical effect to be achieved.

[0030] As used herein, the term "or" should be interpreted as an inclusive "or" meaning any one or any combination. Thus, "A, B, or C" means any of "A; B; C; A and B; A and C; B and C; A, B, and C." Exceptions to this definition may occur only where combinations of elements, features, steps, or acts are inherently mutually exclusive in some way.

[0031] As used herein and unless otherwise specified, an "alkyl" group is a saturated, partially saturated, or unsaturated, straight-chain or branched, acyclic hydrocarbon having 1 to 10 carbon atoms, typically 1 to 8 carbons, or in some embodiments 1 to 6, 1 to 4, or 2 to 6 carbon atoms. Representative alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl, while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, and the like. An "alkenyl" is an alkyl group containing one or more carbon-carbon double bonds. An "alkynyl" group is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH), -CH=C(CH), -C(CH)=CH, -C(CH)=CH(CH), -C(CHCH)=CH, -C≡CH, -C≡C(CH), -C≡C(CHCH), -CHC≡CH, -CHC≡C(CH), and -CHC≡C(CHCH), among others. Alkyl groups can be substituted or unsubstituted.When alkyl groups described herein are referred to as "substituted," these include one or more optional substituents such as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy; oxo (=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclic, heterocyclic alkyl ... The group may be substituted with cyclocyclylamino, heteroarylamino, heterocycloalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or -B(OH)2.

[0032] As used herein and unless otherwise specified, a "cycloalkyl" group refers to a saturated or partially saturated cyclic alkyl group of 3 to 10 carbon atoms having a single cyclic ring or multiple fused or bridged rings, which may be optionally substituted. In some embodiments, cycloalkyl groups have 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple or bridged ring structures such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like. Examples of unsaturated cycloalkyl groups include, among others, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. The cycloalkyl group can be substituted or unsubstituted. Examples of such substituted cycloalkyl groups include, for example, cyclohexanol.

[0033] As used herein and unless otherwise specified, an "aryl" group is an aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, aryl groups contain 6 to 14 carbons in the ring portion of the group, and in other embodiments, 6 to 12 or even 6 to 10 carbon atoms. Particular aryl groups include phenyl, biphenyl, naphthyl, and the like. Aryl groups can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing condensed rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).

[0034] As used herein and unless otherwise specified, a "heteroaryl" group is an aromatic ring system having 1 to 4 heteroatoms as ring atoms, with the remainder of the atoms being carbon atoms. In some embodiments, heteroaryl groups contain 3 to 6 ring atoms, and in other embodiments, 6 to 9 or even 6 to 10 atoms, in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indol-2-onyl), isoindolin-1-onyl, azaindolyl, pyrrolopyridyl (e.g., 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), azabenzimidazolyl, Heteroaryl groups include, but are not limited to, groups such as aryl, imidazopyridyl (e.g., 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, 3,4-dihydroisoquinolin-1(2H)-onyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be substituted or unsubstituted.

[0035] As used herein and unless otherwise specified, a "heterocyclyl" refers to an aromatic ring system (also referred to as heteroaryl) or a non-aromatic cycloalkyl (also referred to as heterocycloalkyl) in which 1 to 4 of the ring carbon atoms are independently replaced with heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In some embodiments, heterocyclyl groups contain 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. A heterocyclyl can also be attached to another group at any ring atom (i.e., any carbon atom or heteroatom of the heterocyclic ring). A heterocyclyl group can be substituted or unsubstituted. Heterocyclyl groups encompass unsaturated, partially saturated, and saturated ring systems, such as imidazolyl, imidazolinyl, and imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl) groups. The term heterocyclyl includes fused ring species including fused aromatic and non-aromatic groups, such as 1- and 2-aminotetralin, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The term also includes bridged polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyl. Representative examples of heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl (e.g., piperazine-2-oxo- nyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithionyl, dihydrodithionyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, indolyl (e.g., indol-2-onyl), isoindolin-1-onyl, indolinyl, iso indolyl, isoindolinyl, azaindolyl, pyrrolopyridyl (e.g., 1H-pyrrolo[2,3-b]pyridyl), indazolyl, indolizinyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazol-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl benzothiazinyl, benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl (e.g., 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl), azabenzimidazolyl, imidazopyridyl (e.g., 1H-imidazo[4,5-b]pyridyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, 3,Representative non-aromatic heterocyclyl groups include, but are not limited to, 4-dihydroisoquinolin-1(2H)-onyl, quinolidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, tetrahydropyrimidin-2(1H)-one, and tetrahydroquinolinyl groups. Representative non-aromatic heterocyclyl groups do not include fused ring species containing fused aromatic groups. Examples of non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups include, but are not limited to, pyridyl or morpholinyl groups which may be mono- or more than once substituted, for example, di-, tri-, tetra-, penta-, or hexa-substituted or di-substituted with various substituents such as those described below.

[0036] As used herein and unless otherwise specified, a "cycloalkylalkyl" group is a radical of the formula: -alkyl-cycloalkyl, where alkyl and cycloalkyl are defined above. Substituted cycloalkylalkyl groups can be substituted on the alkyl, the cycloalkyl, or both the alkyl and cycloalkyl portions of the group. Representative cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl, and the like.

[0037] As used herein and unless otherwise specified, an "aralkyl" group is a radical of the formula: -alkyl-aryl, where alkyl and aryl are defined above. Substituted aralkyl groups can be substituted at the alkyl, aryl, or both the alkyl and aryl portions of the group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups, and aralkyl groups in which the aryl group is fused to a cycloalkyl group, such as indan-4-ylethyl.

[0038] As used herein and unless otherwise specified, a "heterocyclylalkyl" group is a radical of the formula: -alkyl-heterocyclyl, where alkyl and heterocyclyl are defined above. A "heteroarylalkyl" group is a radical of the formula: -alkyl-heteroaryl, where alkyl and heteroaryl are defined above. A "heterocycloalkylalkyl" group is a radical of the formula: -alkyl-heterocycloalkyl, where alkyl and heterocycloalkyl are defined above. Substituted heterocyclylalkyl groups can be substituted at the alkyl, the heterocyclyl, or both the alkyl and heterocyclyl portions of the group. Representative heterocyclylalkyl groups include, but are not limited to, morpholin-4-ylethyl, morpholin-4-ylpropyl, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[0039] As used herein and unless otherwise specified, "halogen" is fluorine, chlorine, bromine or iodine.

[0040] As used herein and unless otherwise specified, a "hydroxyalkyl" group is an alkyl group, as defined above, substituted with one or more hydroxy groups.

[0041] As used herein and unless otherwise specified, an "alkoxy" group is an -O-(alkyl), where alkyl is defined above. An "alkylthio" group is an -S-(alkyl), where alkyl is defined above.

[0042] As used herein, and unless otherwise specified, an "alkoxyalkyl" group is -(alkyl)-O-(alkyl), where alkyl is defined above.

[0043] As used herein, and unless otherwise specified, a "cycloalkyloxy" group is --O-(cycloalkyl), where cycloalkyl is defined above.

[0044] As used herein, and unless otherwise specified, an "aryloxy" group is --O-(aryl), where aryl is defined above.

[0045] As used herein and unless otherwise specified, a "heterocyclyloxy" group is -O-(heterocyclyl), where heterocyclyl is defined above. A "heteroaryloxy" group is -O-(heteroaryl), where heteroaryl is defined above. A "heterocycloalkyloxy" group is -O-(heterocycloalkyl), where heterocycloalkyl is defined above.

[0046] As used herein and unless otherwise specified, an "amino" group refers to a group of the formula: -NH, -NH(R # ) or -N(R # )2 radical, and each R # are independently alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl (e.g., heteroaryl or heterocycloalkyl), or heterocyclylalkyl (e.g., heteroarylalkyl or heterocycloalkylalkyl) groups as defined above, each of which is independently substituted or unsubstituted.

[0047] In one embodiment, an "amino" group is an "alkylamino" group that is a radical of the formula: -NH-alkyl or -N(alkyl), where each alkyl is independently defined above. The terms "cycloalkylamino," "arylamino," "heterocyclylamino," "heteroarylamino," "heterocycloalkylamino," and the like reflect the above description of "alkylamino" when the term "alkyl" is replaced by "cycloalkyl," "aryl," "heterocyclyl," "heteroaryl," "heterocycloalkyl," and the like, respectively.

[0048] As used herein and unless otherwise specified, a "carboxy" group is a radical of the formula: --C(O)OH.

[0049] As used herein and unless otherwise specified, an "acyl" group refers to a group of the formula: -C(O)(R # ) or a radical of —C(O)H, and R # is defined above. A "formyl" group is a radical of the formula: --C(O)H.

[0050] As used herein and unless otherwise specified, an "amide" group refers to a group of the formula: -C(O)-NH, -C(O)-NH(R # ), -C(O)-N(R # )2, -NH-C(O)H, -NH-C(O)-(R # ), -N(R # )-C(O)H or -N(R # )-C(O)-(R # ) radical, and each R # are independently defined above.

[0051] In one embodiment, an "amide" group has the formula: -C(O)-NH, -C(O)-NH(R # ), -C(O)-N(R # )2 radical, an "aminocarbonyl" group, and each R # are independently defined above.

[0052] In one embodiment, an "amide" group has the formula: -NH-C(O)H, -NH-C(O)-(R # ), -N(R # )-C(O)H or -N(R # )-C(O)-(R # ) is an "acylamino" group, which is a radical of each R # are independently defined above.

[0053] As used herein and unless otherwise specified, a "sulfonylamino" group refers to a group of the formula: -NHSO(R # ) or -N(R # )SO2(R # ) radical, and each R # is defined above.

[0054] As used herein and unless otherwise specified, an “ester” group refers to an ester group of the formula: —C(O)—O—(R # ) or -OC(O)-(R # ) and R # is defined above.

[0055] In one embodiment, an "ester" group is an "alkoxycarbonyl" group that is a radical of the formula: -C(O)-O-(alkyl), where alkyl is defined above. The terms "cycloalkyloxycarbonyl," "aryloxycarbonyl," "heterocyclyloxycarbonyl," "heteroaryloxycarbonyl," "heterocycloalkyloxycarbonyl," and the like reflect the above description of "alkoxycarbonyl" when the term "alkoxy" is replaced by "cycloalkyloxy," "aryloxy," "heterocyclyloxy," "heteroaryloxy," "heterocycloalkyloxy," and the like, respectively.

[0056] As used herein and unless otherwise specified, a "carbamate" group refers to a group of the formula: -OC(O)-NH, -OC(O)-NH(R # ), -OC(O)-N(R #)2, -NH-C(O)-O-(R # ) or -N(R # )-C(O)-O-(R # ) radical, and each R # are independently defined above.

[0057] As used herein and unless otherwise specified, a "urea" group refers to a group of the formula: -NH(CO)NH, -NHC(O)NH(R # ), -NHC(O)N(R # )2, -N(R # )C(O)NH2, -N(R # )C(O)NH(R # ) or -N(R # )C(O)N(R # )2 radical, and each R # are independently defined above.

[0058] As used herein and unless otherwise specified, a "sulfinyl" group refers to a group of the formula: -S(O)R # is the radical of R # is defined above.

[0059] As used herein and unless otherwise specified, a "sulfonyl" group refers to a group of the formula: -S(O)R # is the radical of R # is defined above.

[0060] As used herein and unless otherwise specified, an "aminosulfonyl" group refers to a group of the formula: -SO2NH2, -SO2NH(R # ) or -SO2N(R # )2 radical, and each R # are independently defined above.

[0061] When groups described herein, except for alkyl groups, are referred to as "substituted," they can be substituted with one or more suitable substituents. Illustrative examples of substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogen; alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl, heterocycloalkylalkyl (optionally further substituted); hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy; oxo (=O); oxide (e.g., For example, a nitrogen atom substituted with oxide is called an N-oxide); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or -B(OH)2.

[0062] As used herein, the term "sulfonamide compound" includes compounds of Formula (I), Formula (Ia), Formula (II) provided herein, as well as further embodiments of compounds of Formula (I), Formula (Ia), and Formula (II). For example, the term "sulfonamide compound" includes deuterated compounds of Formula (I), Formula (Ia), Formula (II), Table 1, Table 2, Table 3, or Table 4. In one embodiment, a "sulfonamide compound" is a compound shown in Table 1, Table 2, Table 3, or Table 4. In certain embodiments, the term "sulfonamide compound" includes pharmaceutically acceptable salts, tautomers, isotopologues, and / or stereoisomers of sulfonamide compounds provided herein.

[0063] As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of the compounds of Formula (I), Formula (Ia), Formula (II), Table 1, Table 2, Table 3 or Table 4 include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Accordingly, examples of specific salts include hydrochlorides and mesylates. Other examples are well known in the art, see, for example, Remington's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995).

[0064] As used herein and unless otherwise specified, the term "stereoisomer" or "stereoisomerically pure" refers to one stereoisomer of a sulfonamide compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of that compound, or greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of that compound, or greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of that compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of that compound. The sulfonamide compounds may have chiral centers and may occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms, including mixtures thereof, are included within the scope of the embodiments disclosed herein.

[0065] The use of stereomerically pure forms of such sulfonamide compounds, as well as mixtures of these forms, are encompassed by the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of the enantiomers of a particular sulfonamide compound may be used in the methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques, such as chiral columns or chiral resolving agents. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN, 1972).

[0066] It should also be noted that the sulfonamide compounds may include E and Z isomers or mixtures thereof, as well as cis and trans isomers or mixtures thereof. In certain embodiments, the sulfonamide compounds are isolated as either the E or Z isomer. In other embodiments, the sulfonamide compounds are a mixture of E and Z isomers.

[0067] "Tautomer" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of isomeric forms depend on the environment in which the compound is found, and may vary depending on, for example, whether the compound is a solid or an organic or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomeric forms, called tautomers of each other: [ka]

[0068] As will be readily understood by one skilled in the art, various types of functional groups and other structures can exhibit tautomerism, and all tautomers of the compounds of Formula (I), Formula (Ia) and Formula (II) are included within the scope of the present invention.

[0069] It is also noted that the Sulfonamide Compounds may contain unnatural proportions of atomic isotopes at at least one of the atoms. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I), sulfur-35( 35 S) or carbon-14 ( 14 It can be radiolabeled with a radioisotope such as carbon-13 ( 13 C) or nitrogen-15( 15 N). As used herein, an "isotopologue" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" can also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term "isotopic composition" refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutics, e.g., cancer and inflammation therapeutics, research reagents, e.g., binding assay reagents, and diagnostics, e.g., in vivo imaging agents. All isotopic variations of the sulfonamide compounds described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, isotopologues of sulfonamide compounds are provided, e.g., isotopologues are carbon-13 or nitrogen-15 enriched sulfonamide compounds. As used herein, "deuterated" refers to a compound in which at least one hydrogen (H) is replaced with deuterium (D or 2 H), i.e., the compound is enriched with deuterium at at least one position. Note that if there is a discrepancy between the drawn structure and the name of that structure, the drawn structure takes precedence.

[0070] As used herein, "inhibit" and "inhibition" refer to a relative decrease in a particular response of a specified activity (e.g., worm motility) in the presence of a sulfonamide compound. Inhibition of worm motility, such as the motility of Onchocerca volvulus, Brugia malayi, and / or Brugia timori, can be determined by the assays described herein.

[0071] As used herein, "treating" means alleviating, in whole or in part, a disorder, disease, or condition or one or more symptoms associated with the disorder, disease, or condition, or slowing or halting further progression or worsening of those symptoms, or reducing or eradicating the cause of the disorder, disease, or condition itself. In one embodiment, the disorder, disorder, or condition is a helminth infection.

[0072] As used herein, "preventing" refers to a method of delaying and / or preventing, in whole or in part, the onset, recurrence, or spread of a disorder, disease, or condition; barring a subject from acquiring a disorder, disease, or condition; or reducing the risk that a subject will acquire a disorder, disease, or condition. In one embodiment, the disorder, disorder, or condition is a helminth infection.

[0073] The term "effective amount" with respect to a sulfonamide compound means an amount capable of treating or preventing a disorder, disease, or condition disclosed herein, or a symptom thereof. In one embodiment, the disorder, disease, or condition is a helminth infection.

[0074] The term "subject" or "patient" includes humans and other primates, as well as domesticated and semi-domesticated animals, including, but not limited to, poultry, honeybees, cows, sheep, cattle, goats, pigs, horses, dogs, cats, rabbits, rats, mice, etc. The term "poultry" encompasses all types of domesticated birds, including, but not limited to, chickens, turkeys, ducks, geese, ratites, and game birds. In certain embodiments, the subject is a human. In certain embodiments, the subject is a dog. In certain embodiments, the subject is a cat. In certain embodiments, the subject is a farm animal. In certain embodiments, the subject is a cow. In certain embodiments, the subject is a sheep. In another embodiment, the subject is a goat.

[0075] The terms "combination" or "administration in combination" include administration as a mixture, simultaneous administration in separate formulations, and consecutive administration in any order.

[0076] As used herein, the term "helminthic infection" or "helminth infection" refers to an infection caused by a parasitic worm. An infection caused by helminths, known as "helminthiasis" (plural "helminthiasis"), is any macroparasitic disease of humans and other animals in which parts of the body are infected with parasitic worms known as helminths. There are many species of these parasites, broadly classified as tapeworms, flukes, and roundworms.

[0077] As used herein, the term "filariasis" refers to a helminth infection caused by filarial nematodes. Non-limiting examples of filarial nematodes of the family Onchocercidae include Brugia species (i.e., B. malayi, B. pahangi, B. timori, etc.), Wuchereria species (i.e., W. bancrofti, etc.), Dirofilaria species (D. immitis, D. repens, D. ursi, D. tenuis, D. spectans, D. lutrae, etc.), Dipetalonema species (i.e., D. reconditum, etc.), (D. reconditum, D. repens, etc.), Onchocerca species (i.e., O. gibsoni, O. gutturosa, O. volvulus, etc.), Elaeophora species (e.g., E. bohmi, E. elaphi, E. poeli, E. sagitta, E. schneideri, etc.), Mansonella species (i.e., M. ozzardi, M. perstans, etc.), and Loa species (i.e., L. loa). Infection is the colonization of a host organism by a parasitic species. Infection with human filarial nematodes can cause lymphatic filariasis or onchocerciasis. The term "lymphatic filariasis" refers to infection with the nematodes Wuchereria bancrofti, Brugia malayi, or Brugia timori. The term "onchocerciasis" refers to infection with the nematode Onchocerca volvulus.Lymphatic filariasis can cause hydrocele, lymphedema, and elephantiasis. Onchocerciasis can cause dermatitis and blindness, known as river blindness. In dogs, infection with a nematode species called Dirofilaria immitis or Dirofilaria repens causes dirofilariasis. In sheep and goats, infection with a nematode species called Haemonchus contortus causes haemonchusis.

[0078] The terms "worm" or "nematode" are used interchangeably herein to refer to all life stages of an organism, such as eggs, unfertilized eggs, fertilized eggs, larvae or nymphs, larvae in any one of the four larval stages (L1, L2, L3, L4), sexually immature stage worms (L5 stage), mature stage worms, fully mature stage worms, adults, pre-parasitic stage worms or parasitic stage worms.

[0079] As used herein, the term "microfilariae" or "mf" refers to an early stage in the life cycle of certain parasitic nematodes. Microfilariae are considered to be the first larval stage, also referred to as L1. The terms "microfilariae," "mf," or "L1" are used alternatively and / or interchangeably.

[0080] As used herein, the term "macrofilaria" refers to the adult stage in the life cycle of certain parasitic nematodes.

[0081] Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0082] Surprisingly, compounds disclosed herein have been found to be effective in treating helminth infections, such as filarial infections. In vitro and in vivo results demonstrate that the compounds disclosed herein are effective against filarial nematodes. In some embodiments, the compounds disclosed herein surprisingly exhibit differential activity between adult and juvenile stages of parasitic nematodes. In some such embodiments, the compounds disclosed herein are selectively effective against adult filarial nematodes (also referred to as macrofilaricidal activity). In other embodiments, the compounds disclosed herein are selectively effective against juvenile stages of filarial nematodes (also referred to as microfilaricidal activity). Thus, the compounds disclosed herein may be potent antifilarial agents.

[0083] compound Formula (I): [ka] Provided herein are sulfonamide compounds having the formula: and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof, wherein: --- is a single or double bond; Each A is independently N or CR 1 and; Each R 1are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is a substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R is absent, H, substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl, or CO(substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl); m is 0 to 3; n is 0 to 3; and p is 0 to 3; provided that m and n cannot both be 0; When the above groups are referred to as "substituted", it refers to halogen; alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, cycloalkylalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl, hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; oxo (=O); oxide; amino, alkylamino, cycloalkylamino, arylamino, each of which is optionally further substituted. , heterocyclylamino, heteroarylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxyamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; and -B(OH)2.

[0084] Furthermore, the following formula (I): [ka] Provided herein are sulfonamide compounds having the formula: and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof, wherein: --- is a single or double bond; Each A is independently N or CR 1 and; Each R 1are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; alkylsulfonyl, aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is a substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R is absent, H, substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl, or CO(substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl); m is 0 to 3; n is 0 to 3; and p is 0 to 3; provided that m and n cannot both be 0; When the above groups are referred to as "substituted", it refers to halogen; alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, cycloalkylalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl, hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; oxo (=O); oxide; amino, alkylamino, cycloalkylamino, arylamino, each of which is optionally further substituted. , heterocyclylamino, heteroarylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxyamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; and -B(OH)2.

[0085] Formula (Ia): [ka] Provided herein are sulfonamide compounds having the formula: and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof, wherein: Each R 1 are independently halogen, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~7 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, or -OR; R 2 teeth, a. Halogen, CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~62-pyridyl or 3-pyridyl substituted with one or more substituents independently selected from cycloalkyl, -OR and -NR2; b. Substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 Cycloalkyl and (C 1~3 alkyl) (substituted or unsubstituted C 3~6 2-imidazolyl or 5-imidazolyl substituted by one or more substituents independently selected from: (cycloalkyl); c. Substituted or unsubstituted C 1~4 pyrazyl substituted with one or more substituents independently selected from alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, -OR and NR2; d. unsubstituted or one or more substituted or unsubstituted C 1~4 Alkyl-substituted pyrazolyl; e. Unsubstituted or containing one or more C 1~4 Alkyl-substituted 2-furanyl and; Each R is independently selected from H and substituted, unsubstituted C 1~4 Alkyl or (C 1~3 Alkyl) (substituted or unsubstituted C 3~6 cycloalkyl); n is 1 to 3; provided that the compound is 5-cyano-N-[5-(trifluoromethyl)-8-quinolinyl]-2-pyridinesulfonamide: [ka] isn't it.

[0086] Furthermore, the following formula (Ia): [ka] Provided herein are sulfonamide compounds having the formula: and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof, wherein: Each R 1 are independently halogen, —CN, substituted or unsubstituted C1~4 Alkyl, substituted or unsubstituted C 3~7 Cycloalkyl, substituted or unsubstituted acyl, substituted or unsubstituted C 1~4 sulfonyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, or -OR; R 2 teeth, a. Halogen, CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 2-pyridyl or 3-pyridyl substituted with one or more substituents independently selected from cycloalkyl, -OR and -NR2; b. Substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 Cycloalkyl, (C 1~3 alkyl) (substituted or unsubstituted C 3~6 2-imidazolyl substituted by one or more substituents independently selected from cycloalkyl) and substituted or unsubstituted aryl; c. Substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 Cycloalkyl and (C 1~3 alkyl) (substituted or unsubstituted C 3~6 5-imidazolyl substituted by one or more substituents independently selected from (cycloalkyl); d. Substituted or unsubstituted C 1~4 pyrazyl substituted with one or more substituents independently selected from alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, -OR and NR2; e. Unsubstituted or one or more substituted or unsubstituted C 1~4 Alkyl-substituted pyrazolyl; f. Unsubstituted or containing one or more C 1~4 Alkyl-substituted 2-furanyl and; Each R is independently selected from H and substituted or unsubstituted C 1~4 Alkyl, (C 1~3 alkyl), (substituted or unsubstituted C 3~6cycloalkyl) or substituted or unsubstituted aryloxy; n is 1 to 3; provided that the compound is 5-cyano-N-[5-(trifluoromethyl)-8-quinolinyl]-2-pyridinesulfonamide: [ka] isn't it.

[0087] In one embodiment of the compound of Formula (I), m is 2, n is 1, and A is CR 1 is.

[0088] In one embodiment of the compound of Formula (I), m is 1, n is 1, and A is CR 1 is.

[0089] In one embodiment of the compound of Formula (I), m is 3, n is 0, and A is CR 1 is.

[0090] In one embodiment of the compound of Formula (I), m is 2, n is 1, and A is CR1.

[0091] In one embodiment of the compound of Formula (I), m is 2, n is 0, and A is CR1.

[0092] In one embodiment of the compound of Formula (I), m is 2, n is 1, and A is CR 1 In one such embodiment, - is a single bond. In one embodiment of the compound of formula (I), each R 1are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is halogen, CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 and 2-pyridyl substituted with one or more substituents independently selected from cycloalkyl, -OR and -NR2.

[0093] In one embodiment of the compound of Formula (I), m is 2, n is 1, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is independently H or substituted or unsubstituted C 1~4 Alkyl or substituted or unsubstituted C 3~6 In one embodiment of the compound of Formula (I), each R 1are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is halogen, CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 and 2-pyridyl substituted with one or more substituents independently selected from cycloalkyl, -OR and -NR2.

[0094] In one embodiment of the compound of Formula (I), m is 2, n is 1, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is independently H or substituted or unsubstituted C 1~4 Alkyl or substituted or unsubstituted C 3~6 In one embodiment of the compound of Formula (I), each R 1 are independently H, F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, phenyl, pyrrolidyl, piperidyl, piperazinyl, or morpholinyl; R 2is 2-pyridyl substituted with one or more substituents independently selected from F, Cl, -CN, -CH, -CHCH, -CHCHCH, -CH(CH), cyclopropyl, cyclobutyl, cyclopentyl, -OCH, -OCHCHCH, and -N(CH).

[0095] In one embodiment of the compound of Formula (I), m is 2, n is 1, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is independently -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, cyclobutyl, or cyclopentyl. In one embodiment of a compound of Formula (I), each R 1 are independently H, Cl, -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH3, -phenyl, pyrrolidyl, piperidyl, piperazinyl, or morpholinyl; R 2 is 2-pyridyl substituted with one or more substituents independently selected from -CH3, -CH2CH3, -CH2CH2CH3, -cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH2CH3 and -N(CH3)2.

[0096] In one embodiment of the compound of Formula (I), m is 2, n is 1, and A is CR 1 If R 1 are independently H or Cl; R 2 is 2-pyridyl substituted with one or more substituents independently selected from -CH or -cyclopropyl. In one such embodiment, - is a single bond; p is 0; and R is -CH or cyclopropyl.

[0097] In one embodiment of the compound of Formula (I), m is 2, n is 1, and A is CR 1In one such embodiment, - is a single bond. In one embodiment of the compound of Formula (I), each R 1 are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is one or more substituted or unsubstituted C 1~4 It is an alkyl-substituted 2-imidazolyl.

[0098] In one embodiment of the compound of Formula (I), m is 2, n is 1, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is H or substituted or unsubstituted C 1~4 In one embodiment of the compound of Formula (I), each R 1are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is one or more substituted or unsubstituted C 1~4 It is an alkyl-substituted 2-imidazolyl.

[0099] In one embodiment of the compound of Formula (I), m is 2, n is 1, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is independently -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, cyclobutyl, or cyclopentyl. In one embodiment of a compound of Formula (I), each R 1 are independently H, F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, phenyl, pyrrolidyl, piperidyl, piperazinyl, or morpholinyl; R 2 is 2-imidazolyl substituted with one or more substituents independently selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, and -CF3.

[0100] In one embodiment of the compound of Formula (I), m is 2, n is 1, and A is CR 1 If R 1 are independently H; R 2 is 2-imidazolyl substituted with -CH(CH3)2; --- is a single bond; p is 0; and R is -CH3.

[0101] In one embodiment of the compound of Formula (I), m is 2, n is 1, and A is CR 1 In one such embodiment, - is a single bond. In one embodiment of the compound of Formula (I), each R 1 are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is a substituted or unsubstituted C 1~4 and pyrazolyl substituted with one or more substituents independently selected from alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, and -OR.

[0102] In one embodiment of the compound of Formula (I), m is 2, n is 1, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is H or substituted or unsubstituted C 1~4In one embodiment of the compound of Formula (I), each R 1 are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is a substituted or unsubstituted C 1~4 and pyrazolyl substituted with one or more substituents independently selected from alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, and -OR.

[0103] In one embodiment of the compound of Formula (I), m is 2, n is 1, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is independently -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, cyclobutyl, or cyclopentyl. In one embodiment of a compound of Formula (I), each R 1 are independently H, F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, phenyl, pyrrolidyl, piperidyl, piperazinyl, or morpholinyl; R 2is pyrazolyl substituted with one or more substituents independently selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, and -CF3.

[0104] In one embodiment of the compound of Formula (I), m is 2, n is 1, and A is CR 1 If R 1 are independently H; R 2 is pyrazolyl substituted with -CH(CH3)2; --- is a single bond; p is 0; and R is -CH3.

[0105] In one embodiment of the compound of Formula (I), m is 1, n is 1, and A is CR 1 In one such embodiment, - is a single bond. In one embodiment of the compound of Formula (I), each R 1 are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is halogen, CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 and 2-pyridyl substituted with one or more substituents independently selected from cycloalkyl, -OR and -NR2.

[0106] In one embodiment of the compound of Formula (I), m is 1, n is 1, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, R is independently H or substituted or unsubstituted C 1~4 Alkyl or substituted or unsubstituted C 3~6 In one embodiment of the compound of Formula (I), each R 1 are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is halogen, CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 and 2-pyridyl substituted with one or more substituents independently selected from cycloalkyl, -OR and -NR2.

[0107] In one embodiment of the compound of Formula (I), m is 1, n is 1, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is independently H or substituted or unsubstituted C 1~4 Alkyl or substituted or unsubstituted C 3~6 In one embodiment of the compound of Formula (I), each R 1are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is halogen, CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 and 2-pyridyl substituted with one or more substituents independently selected from cycloalkyl, -OR and -NR2.

[0108] In one embodiment of the compound of Formula (I), m is 1, n is 1, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is independently H or substituted or unsubstituted C 1~4 Alkyl or substituted or unsubstituted C 3~6 In one embodiment of the compound of Formula (I), each R 1 are independently H, F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, phenyl, pyrrolidyl, piperidyl, piperazinyl, or morpholinyl; R 2is 2-pyridyl substituted with one or more substituents independently selected from F, Cl, -CN, -CH, -CHCH, -CHCHCH, -CH(CH), cyclopropyl, cyclobutyl, cyclopentyl, -OCH, -OCHCHCH, and -N(CH).

[0109] In one embodiment of the compound of Formula (I), m is 1, n is 1, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is independently -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, cyclobutyl, or cyclopentyl. In one embodiment of a compound of Formula (I), each R 1 are independently H, Cl, -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH3, -phenyl, pyrrolidyl, piperidyl, piperazinyl, or morpholinyl; R 2 is 2-pyridyl substituted with one or more substituents independently selected from -CH3, -CH2CH3, -CH2CH2CH3, -cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH2CH3 and -N(CH3)2.

[0110] In one embodiment of the compound of Formula (I), m is 1, n is 1, and A is CR 1 If R 1 are independently H; R 2 is 2-pyridyl substituted with one or more substituents independently selected from -CH or -N(CH). In one such embodiment, - is a single bond; p is 0; and R is cyclopropyl.

[0111] In one embodiment of the compound of Formula (I), m is 1, n is 1, and A is CR 1In one such embodiment, - is a single bond. In one embodiment of the compound of Formula (I), each R 1 are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is one or more substituted or unsubstituted C 1~4 It is an alkyl-substituted 2-imidazolyl.

[0112] In one embodiment of the compound of Formula (I), m is 1, n is 1, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is H, substituted or unsubstituted C 1~4 Alkyl or substituted or unsubstituted C 3~6 In one embodiment of the compound of Formula (I), each R 1are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is one or more substituted or unsubstituted C 1~4 It is an alkyl-substituted 2-imidazolyl.

[0113] In one embodiment of the compound of Formula (I), m is 1, n is 1, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is H, substituted or unsubstituted C 1~4 Alkyl or substituted or unsubstituted C 3~6 In one embodiment of the compound of Formula (I), each R 1 are independently H, F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, phenyl, pyrrolidyl, piperidyl, piperazinyl, or morpholinyl; R 2 is 2-imidazolyl substituted with one or more substituents independently selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, and -CF3.

[0114] In one embodiment of the compound of Formula (I), m is 1, n is 1, and A is CR 1 If R 1 are independently H; R 2 is 2-imidazolyl substituted with -CH(CH3)2; --- is a single bond; p is 0; and R is -CH3.

[0115] In one embodiment of the compound of Formula (I), m is 1, n is 1, and A is CR 1 In one such embodiment, - is a single bond. In one embodiment of the compound of Formula (I), each R 1 are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is a substituted or unsubstituted C 1~4 and pyrazolyl substituted with one or more substituents independently selected from alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, and -OR.

[0116] In one embodiment of the compound of Formula (I), m is 1, n is 1, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is H, substituted or unsubstituted C 1~4Alkyl or substituted or unsubstituted C 3~6 In one embodiment of the compound of Formula (I), each R 1 are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is a substituted or unsubstituted C 1~4 and pyrazolyl substituted with one or more substituents independently selected from alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, and -OR.

[0117] In one embodiment of the compound of Formula (I), m is 1, n is 1, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is independently -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, cyclobutyl, or cyclopentyl. In one embodiment of a compound of Formula (I), each R 1 are independently H, F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, phenyl, pyrrolidyl, piperidyl, piperazinyl, or morpholinyl; R 2is pyrazolyl substituted with one or more substituents independently selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, and -CF3.

[0118] In one embodiment of the compound of Formula (I), m is 1, n is 1, and A is CR 1 If R 1 are independently H; R 2 is pyrazolyl substituted with -CH(CH3)2; --- is a single bond; p is 0; and R is cyclopropyl.

[0119] In one embodiment of the compound of Formula (I), m is 3, n is 0, and A is CR 1 In one such embodiment, - is a single bond. In one embodiment of the compound of Formula (I), each R 1 are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is halogen, CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 and 2-pyridyl substituted with one or more substituents independently selected from cycloalkyl, -OR and -NR2.

[0120] In one embodiment of the compound of Formula (I), m is 3, n is 0, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, R is independently H or substituted or unsubstituted C 1~4 Alkyl or substituted or unsubstituted C 3~6 In one embodiment of the compound of Formula (I), each R 1 are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is halogen, CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 and 2-pyridyl substituted with one or more substituents independently selected from cycloalkyl, -OR and -NR2.

[0121] In one embodiment of the compound of Formula (I), m is 3, n is 0, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is independently H or substituted or unsubstituted C 1~4 Alkyl or substituted or unsubstituted C 3~6 In one embodiment of the compound of Formula (I), each R 1are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is halogen, CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 and 2-pyridyl substituted with one or more substituents independently selected from cycloalkyl, -OR and -NR2.

[0122] In one embodiment of the compound of Formula (I), m is 3, n is 0, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is independently H or substituted or unsubstituted C 1~4 Alkyl or substituted or unsubstituted C 3~6 In one embodiment of the compound of Formula (I), each R 1 are independently H, F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, phenyl, pyrrolidyl, piperidyl, piperazinyl, or morpholinyl; R 2is 2-pyridyl substituted with one or more substituents independently selected from F, Cl, -CN, -CH, -CHCH, -CHCHCH, -CH(CH), cyclopropyl, cyclobutyl, cyclopentyl, -OCH, -OCHCHCH, and -N(CH).

[0123] In one embodiment of the compound of Formula (I), m is 3, n is 0, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is independently H, -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, cyclobutyl, or cyclopentyl. In one embodiment of a compound of Formula (I), each R 1 are independently H, Cl, -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH3, -phenyl, pyrrolidyl, piperidyl, piperazinyl, or morpholinyl; R 2 is 2-pyridyl substituted with one or more substituents independently selected from F, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , -cyclopropyl, cyclobutyl, cyclopentyl, —OCH 3 , —OCH 2 CH 2 CH 3 and —N(CH 3 ) 2 .

[0124] In one embodiment of the compound of Formula (I), m is 3, n is 0, and A is CR 1 If R 1 are independently H; R 2 is 2-pyridyl substituted with one or more substituents independently selected from F, -CH, or -N(CH). In one such embodiment, - is a single bond; p is 0; and R is H, -CH, or cyclopropyl.

[0125] In one embodiment of the compound of Formula (I), m is 3, n is 0, and A is CR 1In one such embodiment, - is a single bond. In one embodiment of the compound of Formula (I), each R 1 are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; alkylsulfonyl, aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is one or more substituted or unsubstituted C 1~4 It is a 2-imidazolyl substituted with alkyl or substituted or unsubstituted aryl.

[0126] In one embodiment of the compound of Formula (I), m is 3, n is 0, and A is CR 1 In one such embodiment, - is a single bond. In one embodiment of the compound of Formula (I), each R 1are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is one or more substituted or unsubstituted C 1~4 It is an alkyl-substituted 2-imidazolyl.

[0127] In one embodiment of the compound of Formula (I), m is 3, n is 0, and A is CR 1 In one such embodiment, - is a single bond. In one embodiment of the compound of Formula (I), each R 1 are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R2 is a substituted or unsubstituted C 1~4 and pyrazolyl substituted with one or more substituents independently selected from alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, and -OR.

[0128] In one embodiment of the compound of Formula (I), m is 2, n is 0, and A is CR 1 In one such embodiment, - is a single bond. In one embodiment of the compound of Formula (I), each R 1 are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is halogen, CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 and 2-pyridyl substituted with one or more substituents independently selected from cycloalkyl, -OR and -NR2.

[0129] In one embodiment of the compound of Formula (I), m is 2, n is 0, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, R is independently H or substituted or unsubstituted C 1~4 Alkyl or substituted or unsubstituted C 3~6 In one embodiment of the compound of Formula (I), each R1 are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is halogen, CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 and 2-pyridyl substituted with one or more substituents independently selected from cycloalkyl, -OR and -NR2.

[0130] In one embodiment of the compound of Formula (I), m is 2, n is 0, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is independently H or substituted or unsubstituted C 1~4 Alkyl or substituted or unsubstituted C 3~6 In one embodiment of the compound of Formula (I), each R 1are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is halogen, CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 and 2-pyridyl substituted with one or more substituents independently selected from cycloalkyl, -OR and -NR2.

[0131] In one embodiment of the compound of Formula (I), m is 2, n is 0, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is independently H or substituted or unsubstituted C 1~4 Alkyl or substituted or unsubstituted C 3~6 In one embodiment of the compound of Formula (I), each R 1 are independently H, F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, phenyl, pyrrolidyl, piperidyl, piperazinyl, or morpholinyl; R 2is 2-pyridyl substituted with one or more substituents independently selected from F, Cl, -CN, -CH, -CHCH, -CHCHCH, -CH(CH), cyclopropyl, cyclobutyl, cyclopentyl, -OCH, -OCHCHCH, and -N(CH).

[0132] In one embodiment of the compound of Formula (I), m is 2, n is 0, and A is CR 1 In one such embodiment, --- is a single bond. In one such embodiment, p is 0. In one such embodiment, R is independently H, -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, cyclobutyl, or cyclopentyl. In one embodiment of a compound of Formula (I), each R 1 are independently H, Cl, -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH3, -phenyl, pyrrolidyl, piperidyl, piperazinyl, or morpholinyl; R 2 is 2-pyridyl substituted with one or more substituents independently selected from F, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , -cyclopropyl, cyclobutyl, cyclopentyl, —OCH 3 , —OCH 2 CH 2 CH 3 and —N(CH 3 ) 2 .

[0133] In one embodiment of the compound of Formula (I), m is 2, n is 0, and A is CR 1 If R 1 are independently H; R 2 is 2-pyridyl substituted with -CH3. In one such embodiment, --- is a single bond; p is 0; and R is -CH3.

[0134] In one embodiment of the compound of Formula (I), m is 2, n is 0, and A is CR 1 In one such embodiment, - is a single bond. In one embodiment of the compound of Formula (I), each R 1are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is one or more substituted or unsubstituted C 1~4 It is an alkyl-substituted 2-imidazolyl.

[0135] In one embodiment of the compound of Formula (I), m is 2, n is 0, and A is CR 1 In one such embodiment, - is a single bond. In one embodiment of the compound of Formula (I), each R 1 are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R2 is a substituted or unsubstituted C 1~4 and pyrazolyl substituted with one or more substituents independently selected from alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, and -OR.

[0136] In one embodiment of the compound of Formula (Ia), each R 1 are independently halogen, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~7 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, or -OR; R 2 is halogen, CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 and 2-pyridyl substituted with one or more substituents independently selected from cycloalkyl, -OR and -NR2.

[0137] In one embodiment of the compound of Formula (Ia), each R 1 are independently halogen, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~7 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, or -OR; R 2 is halogen, -CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 and 3-pyridyl substituted with one or more substituents independently selected from cycloalkyl, -OR and -NR2.

[0138] In one embodiment of the compound of Formula (Ia), each R 1 are independently halogen, —CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted acyl; substituted or unsubstituted C 1~4 Alkylamino, substituted or unsubstituted C 1~4 Alkylsulfonyl, substituted or unsubstituted C 3~7 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, or -OR; R2 is a substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 Cycloalkyl, (C 1~3 alkyl) (substituted or unsubstituted C 3~6 and 2-imidazolyl or 5-imidazolyl substituted with one or more substituents independently selected from aryl, cycloalkyl, and substituted or unsubstituted aryl.

[0139] In one embodiment of the compound of Formula (Ia), each R 1 are independently halogen, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~7 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, or -OR; R 2 is a substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 Cycloalkyl and (C 1~3 alkyl) (substituted or unsubstituted C 3~6 and 2-imidazolyl or 5-imidazolyl substituted with one or more substituents independently selected from:

[0140] In one embodiment of the compound of Formula (Ia), each R 1 are independently halogen, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~7 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, or -OR; R 2 is a substituted or unsubstituted C 1~4 and pyrazyl substituted with one or more substituents independently selected from alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, and -OR and NR. In one embodiment of a compound of Formula (Ia), each R is independently -CH, -CHCH, -CHCHCH, -CH(CH), -CHCH(CH), or -CH(cyclopropyl). In some embodiments of a compound of Formula (Ia), n is 1 or 2.

[0141] In one embodiment of the compound of Formula (Ia), each R 1 are independently halogen, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~7 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, or -OR; R 2 is unsubstituted or contains one or more substituted or unsubstituted C 1~4 In some embodiments of the compound of Formula (Ia), n is 1 or 2.

[0142] In one embodiment of the compound of Formula (Ia), each R 1 are independently halogen, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~7 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, or -OR; R 2 is unsubstituted or contains one or more C 1~4 In some embodiments of the compound of Formula (Ia), n is 1 or 2.

[0143] In some embodiments of the compound of Formula (Ia), each R 1 are independently F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2(cyclopropyl), azetidinyl, phenyl, pyrrolidyl, piperidyl, piperazinyl, or morpholinyl.

[0144] In some embodiments of the compound of Formula (Ia), each R 1 are independently F, Cl, -CH3, -CH2CH3, CF3, cyclopropyl, cyclohexyl, -OCH3-OCH(CH3)2, -OCH2(cyclopropyl), azetidinyl, phenyl, or morpholinyl.

[0145] In some embodiments of the compounds of Formula (Ia), R 2 is 2-pyridyl substituted with one or more substituents independently selected from F, Cl, -CN, -CH, -CHCH, --CHCHCH, -CH(CH)-CHCH(CH), cyclopropyl, cyclobutyl, cyclopentyl, -OCH, -OCHCHCH, -OCHCH(CH), -NH, -NHCH, and -N(CH). In certain embodiments of compounds of Formula (Ia), R 2 is 2-pyridyl substituted with one or more substituents independently selected from F, Cl, -CN, -CH, -CH(CH), -CHCH(CH), cyclopropyl, -OCH, -OCHCH(CH), and -N(CH).

[0146] In some embodiments of the compounds of Formula (Ia), R 2 is 3-pyridyl substituted with one or more substituents independently selected from F, Cl, —CN, —CH 3 , —CH 2 CH 3 , and —CF 3 . In certain embodiments of compounds of Formula (Ia), R 2 is 3-pyridyl substituted with -CF3.

[0147] In certain embodiments of compounds of Formula (Ia), R 2 is 2-imidazolyl substituted with one or more substituents independently selected from -CH3, -CH2CH3, -CH2CF3, cyclopropyl, -CH2CH(CH3)2, phenyl, and p-trifluoromethylphenyl.

[0148] In certain embodiments of compounds of Formula (Ia), R 2 is 2-imidazolyl substituted with one or more substituents independently selected from -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, and -CH2CH(CH3)2.

[0149] In certain embodiments of compounds of Formula (I), R 2is 2-imidazolyl substituted with one or more substituents independently selected from -CH3, -CH2CH3, -CH2CF3, cyclopropyl, -CH2CH(CH3)2, phenyl, and p-trifluoromethylphenyl.

[0150] In certain embodiments of compounds of Formula (I), R 2 is 2-imidazolyl substituted with one or more substituents independently selected from -CH3, -CH2CH3, cyclopropyl, and -CH2CH(CH3)2.

[0151] In certain embodiments of compounds of Formula (Ia), R 2 is 5-imidazolyl substituted with one or more substituents independently selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, and CH2-cyclopropyl.

[0152] In certain embodiments of compounds of Formula (Ia), R 2 is 5-imidazolyl substituted with one or more substituents independently selected from -CH(CH3)2 and -CH2-cyclopropyl.

[0153] In some embodiments of the compounds of Formula (Ia), R 2 is 2-pyrazyl substituted with one or more substituents independently selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3), -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH(CH3)2, -N(CH3)2, pyrrolidyl, piperidyl, piperazinyl, and morpholinyl.

[0154] In some embodiments of the compounds of Formula (Ia), R 2 is 2-pyrazyl substituted with one or more substituents independently selected from -CH3, -OCH3, -N(CH3)2 and pyrrolidyl.

[0155] In one embodiment of the compound of Formula (Ia), R2 is pyrazolyl that is unsubstituted or substituted with one or more substituents independently selected from -CH3, -CH2CH3, -CH2CH2CH3 and -CH(CH3)2.

[0156] In one embodiment of the compound of Formula (Ia), R 2 is 2-furanyl that is unsubstituted or substituted with one or more substituents independently selected from -CH, -CHCH, -CHCHCH, and -CH(CH). In some embodiments of the compound of Formula (Ia), n is 1 or 2.

[0157] In certain embodiments of compounds of Formula (Ia), each R 1 are independently F, Cl, -CH3, -CH2CH2CH3, -CF3, cyclopropyl, cyclohexyl, -OCH3, -OCH(CH3)2, -OCH2(cyclopropyl), azetidinyl, phenyl, or morpholinyl; R 2 is 2-pyridyl substituted with one or more substituents independently selected from F, Cl, CN, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCH(CH), cyclopropyl, cyclobutyl, cyclopentyl, -OCH, -OCHCH, -OCHCHCH, -OCHCH(CH), -NH, -NHCH, and -N(CH). In some such embodiments, R 2 is 2-pyridyl substituted with one or more substituents independently selected from F, Cl, CN, —CH, —CH(CH), —CHCH(CH), cyclopropyl, —OCH, —OCHCH(CH), or —N(CH). In some such embodiments, each R 1 are independently F, Cl, —CH 3 , —CF 3 , cyclopropyl, cyclohexyl, —OCH 3 , —OCH(CH 3 ) 2 , —OCH 2 (cyclopropyl), azetidinyl, phenyl, or morpholinyl.

[0158] In certain embodiments of compounds of Formula (Ia), each R1 are independently F, Cl, -CH3, -CH2CH3, CF3, cyclohexyl, -OCH3, or morpholinyl; R 2 is 3-pyridyl substituted with one or more substituents independently selected from F, Cl, —CN, —CH 3 , —CH 2 CH 3 , and —CF 3 . In certain embodiments of compounds of Formula (Ia), R 2 is 3-pyridyl substituted with —CF. In some such embodiments, each R 1 are independently F, —CH3, or —OCH3.

[0159] In certain embodiments of compounds of Formula (Ia), each R 1 are independently F, Br, Cl, -CN, -CH3, -CH2CH3, CF3, cyclohexyl, -OCH3, -N(CH3)2, -C(O)CH3, benzoyl, methylsulfonyl, morpholinyl, phenyl, -O-(m-trifluoromethyl)phenyl, or p-fluorophenyl; R 2 is 2-imidazolyl substituted with one or more substituents independently selected from -CH, -CHCH, -CHCHCH, cyclopropyl, CHCH(CH). In some such embodiments, R 2 is 2-imidazolyl substituted with one or more substituents independently selected from -CH, -CHCH, -CHCF, cyclopropyl, -CHCH(CH), phenyl, and p-trifluoromethylphenyl. In some such embodiments, each R 1 are independently F, Br, Cl, —CN, —CH, —CHCH, CF, —N(CH), —C(O)CH, benzoyl, methylsulfonyl, morpholinyl, —OCH, phenyl, —O-(m-trifluoromethyl)phenyl, or p-fluorophenyl.

[0160] In certain embodiments of compounds of Formula (Ia), each R 1 are independently F, Cl, -CH3, -CH2CH3, CF3, cyclohexyl, -OCH3, or morpholinyl; R 2is 2-imidazolyl substituted with one or more substituents independently selected from -CH, -CHCH, -CHCHCH, cyclopropyl, and -CHCH(CH). In some such embodiments, R 2 is 2-imidazolyl substituted with one or more substituents independently selected from -CH, -CHCH, cyclopropyl, and -CHCH(CH). In some such embodiments, each R 1 are independently F, Cl, —CH 3 , —CH 2 CH 3 , CF 3 , morpholinyl, or —OCH 3 .

[0161] In certain embodiments of compounds of Formula (Ia), each R 1 are independently F, Cl, -CH3, -CH2CH3, CF3, cyclohexyl, -OCH3, or morpholinyl; R 2 is 5-imidazolyl substituted with one or more substituents independently selected from -CH, -CHCH, -CHCHCH, -CH(CH), -CHCH(CH), cyclopropyl, and -CH-cyclopropyl. 2 is 5-imidazolyl substituted with one or more substituents independently selected from -CH, -CHCH, -CHCHCH, -CH(CH), cyclopropyl, and -CH-cyclopropyl. 2 is 5-imidazolyl substituted with one or more substituents independently selected from —CH(CH) and —CH-cyclopropyl. In some such embodiments, each R 1 is independently Cl or morpholinyl.

[0162] In certain embodiments of compounds of Formula (Ia), each R 1 are independently F, Cl, -CH3, -CH2CH3, -CF3, cyclohexyl, -OCH3, or morpholinyl; R 2is 2-pyrazyl substituted with one or more substituents independently selected from -CH, -CHCH, -CHCHCH, -CHCH(CH), -OCH, -OCHCH, -OCHCHCH, -OCHCH(CH), pyrrolidyl, piperidyl, piperazinyl, and morpholinyl. In some such embodiments, R 2 is 2-pyrazyl substituted with one or more substituents independently selected from -CH, -OCH, -N(CH), and pyrrolidyl. In some such embodiments, each R 1 is independently Cl or morpholinyl.

[0163] In certain embodiments of compounds of Formula (Ia), each R 1 are independently F, Cl, -CH3, -CH2CH3, -CF3, cyclohexyl, -OCH3, or morpholinyl; R 2 is pyrazolyl that is unsubstituted or substituted with one or more substituents independently selected from -CH, -CHCH, -CHCHCH, and -CH(CH). In some such embodiments, R 2 is pyrazolyl that is unsubstituted or substituted with —CH and —CH(CH). In some such embodiments, each R 1 is independently F or morpholinyl.

[0164] In certain embodiments of compounds of Formula (Ia), each R 1 are independently F, Cl, -CH3, -CH2CH3, -CF3, cyclohexyl, -OCH3, or morpholinyl; R 2 is 2-furanyl that is unsubstituted or substituted with one or more substituents independently selected from -CH, -CHCH, -CHCHCH, and -CH(CH). In some such embodiments, R 2 is unsubstituted 2-furanyl. In some such embodiments, each R 1 is independently F, —CH 3 , —OCH 3 , or morpholinyl.

[0165] Formula (II): [ka] Provided herein are sulfonamide compounds having the formula: and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof, wherein: Each R 1 are independently H, halogen, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~7 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, or -OR; R 2 teeth, a. Unsubstituted or halogen, CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted C 6~10 pyridyl substituted with one or more substituents independently selected from aryl, substituted or unsubstituted monocyclic heteroaryl, -OR and -NR2; b. Unsubstituted or substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 Cycloalkyl and (C 1~3 Alkyl) (substituted or unsubstituted C 3~6 2-imidazolyl substituted by one or more substituents independently selected from (cycloalkyl); c. Unsubstituted or substituted or unsubstituted C 1~4 pyrazyl substituted by one or more substituents independently selected from alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, -OR and NR2; d. Unsubstituted or substituted or unsubstituted C 1~4 Alkyl and substituted or unsubstituted C 3~6 pyrazolyl substituted by one or more substituents independently selected from cycloalkyl; e. Unsubstituted or substituted or unsubstituted C 1~4pyrimidyl substituted with one or more substituents independently selected from alkyl and -OR; and; Each R is independently H, substituted or unsubstituted C 1~4 Alkyl or (C 1~3 alkyl) (substituted or unsubstituted C 3~6 cycloalkyl); n is 1 to 3; However, R 1 and R 2 are never both non-substituted.

[0166] Furthermore, the following formula (II): [ka] Provided herein are sulfonamide compounds having the formula: and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof, wherein: Each R 1 are independently halogen, —CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~7 Cycloalkyl, substituted or unsubstituted acyl, substituted or unsubstituted C 1~4 sulfonyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, or -OR; R 2 teeth, a. Unsubstituted or halogen, CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted C 6~10 pyridyl substituted with one or more substituents independently selected from aryl, substituted or unsubstituted monocyclic heteroaryl, -OR and -NR2; b. Unsubstituted or substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 Cycloalkyl, (C 1~3 Alkyl) (substituted or unsubstituted C 3~62-imidazolyl substituted by one or more substituents independently selected from cycloalkyl) and substituted or unsubstituted aryl; c. Unsubstituted or substituted or unsubstituted C 1~4 pyrazyl substituted by one or more substituents independently selected from alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, -OR and NR2; d. Unsubstituted or substituted or unsubstituted C 1~4 Alkyl and substituted or unsubstituted C 3~6 pyrazolyl substituted by one or more substituents independently selected from cycloalkyl; e. Unsubstituted or substituted or unsubstituted C 1~4 pyrimidyl substituted with one or more substituents independently selected from alkyl and -OR; and; Each R is independently selected from H and substituted or unsubstituted C 1~4 Alkyl, (C 1~3 alkyl), (substituted or unsubstituted C 3~6 cycloalkyl) or substituted or unsubstituted aryloxy; n is 1 to 3; However, R 1 and R 2 are never both non-substituted.

[0167] In one embodiment of the compound of Formula (II), each R 1 are independently H, halogen, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~7 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, or -OR; R 2 is unsubstituted or is selected from halogen, CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted C 6~10and pyridyl substituted with one or more substituents independently selected from aryl, substituted or unsubstituted monocyclic heteroaryl, -OR and -NR2.

[0168] In one embodiment of the compound of Formula (II), each R 1 are independently H, halogen, —CN, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~7 Cycloalkyl, substituted or unsubstituted acyl, substituted or unsubstituted C 1~4 sulfonyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, or -OR; R 2 is unsubstituted or is a substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 Cycloalkyl, (C 1~3 Alkyl) (substituted or unsubstituted C 3~6 and 2-imidazolyl substituted with one or more substituents independently selected from substituted or unsubstituted aryl, cycloalkyl, and substituted or unsubstituted aryl.

[0169] In one embodiment of the compound of Formula (II), each R 1 are independently H, halogen, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~7 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, or -OR; R 2 is unsubstituted or is a substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~6 Cycloalkyl and (C 1~3 Alkyl) (substituted or unsubstituted C 3~6 and 2-imidazolyl substituted by one or more substituents independently selected from:

[0170] In one embodiment of the compound of Formula (II), each R 1 are independently H, halogen, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C3~7 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, or -OR; R 2 is unsubstituted or is a substituted or unsubstituted C 1~4 and pyrazyl substituted with one or more substituents independently selected from alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, and -OR and NR. In one embodiment of a compound of Formula (II), each R is independently H, -CH, -CHCH, -CHCHCH, or -CHCH(CH). In some embodiments of a compound of Formula (II), n is 1 or 2.

[0171] In one embodiment of the compound of Formula (II), each R 1 are independently H, halogen, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~7 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, or -OR; R 2 is unsubstituted or is a substituted or unsubstituted C 1~4 Alkyl and substituted or unsubstituted C 3~6 and pyrazolyl substituted with one or more substituents independently selected from cycloalkyl.

[0172] In one embodiment of the compound of Formula (II), each R 1 are independently H, halogen, substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 3~7 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, or -OR; R 2 is unsubstituted or is a substituted or unsubstituted C 1~4 and pyrimidyl substituted with one or more substituents independently selected from alkyl and -OR.

[0173] In some embodiments of the compound of Formula (II), each R 1is independently H, F, Cl, -CH, -CHCH, -CHCHCH, -CHCH(CH), -CF, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH, -OCHCH, pyrrolidyl, piperidyl, piperazinyl, or morpholinyl. 1 are independently H, F, Cl, —CH 3 , —CH 2 CH 3 , CF 3 , cyclohexyl, —OCH 3 , or morpholinyl.

[0174] In some embodiments of the compound of Formula (II), R 2 is pyridyl unsubstituted or substituted with one or more substituents independently selected from F, Cl, CN, -CH, -CHCH, -CHCHCH, -CHCH(CH), -C(CH), -(CH)CN, -CHF, -CF, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, phenyl substituted with CN, phenyl substituted with F, oxadiazolyl, -OCH, -OCHCHCH, -OCHCH(CH), -NH, -NHCH, and -N(CH). In certain embodiments of a compound of Formula (II), R 2 is pyridyl unsubstituted or substituted with one or more substituents independently selected from F, Cl, CN, CH, -CHCH(CH), -C(CH), -(CH)CN, -CHF, -CF, cyclopropyl, phenyl, phenyl substituted with CN, phenyl substituted with F, oxadiazolyl, -OCH, -OCHCH(CH) and -N(CH).

[0175] In certain embodiments of compounds of Formula (II), R 2 is 2-imidazolyl that is unsubstituted or substituted with one or more substituents independently selected from -CH, -CHCH, -CHCF, -CHCHCH, -CHCH(CH), substituted cyclopropyl, -CH-cyclopropyl, phenyl, and p-trifluoromethylphenyl.

[0176] In certain embodiments of compounds of Formula (II), R 2 is 2-imidazolyl that is unsubstituted or substituted with one or more substituents independently selected from -CH, -CHCH, -CHCHCH, -CHCH(CH), substituted cyclopropyl, and -CH-cyclopropyl. In certain embodiments of compounds of Formula (II), R 2 is 2-imidazolyl that is unsubstituted or substituted with one or more substituents independently selected from -CH, -CHCH, -CHCH(CH), cyclopropyl substituted with one or more F, and -CH-cyclopropyl.

[0177] In some embodiments of the compound of Formula (II), R 2 is 2-pyrazyl unsubstituted or substituted with one or more substituents independently selected from -CH, -CHCH, -CHCHCH, -CHCH(CH), -OCH, -OCHCH, -OCHCHCH, -OCHCH(CH), pyrrolidyl, piperidyl, piperazinyl, and morpholinyl.

[0178] In some embodiments of the compound of Formula (II), R 2 is 2-pyrazyl that is unsubstituted or substituted with one or more substituents independently selected from -CH3, -OCH3, and pyrrolidyl.

[0179] In some embodiments of the compound of Formula (II), R 2 is pyrazolyl that is unsubstituted or substituted with one or more substituents independently selected from -CH, -CHCH, -CHCHCH, -CHCH(CH), -OCH, -OCHCH, -OCHCHCH, -OCHCH(CH), pyrrolidyl, piperidyl, piperazinyl, and morpholinyl.

[0180] In some embodiments of the compound of Formula (II), R 2is pyrazolyl that is unsubstituted or substituted with one or more substituents independently selected from -CH2CH3 and morpholinyl.

[0181] In some embodiments of the compound of Formula (II), R 2 is pyrimidyl unsubstituted or substituted with one or more substituents independently selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3), -OCH3, -OCH2CH3, -OCH2CH2CH3 and -OCH2CH(CH3)2.

[0182] In some embodiments of the compound of Formula (II), R 2 is pyrimidyl that is unsubstituted or substituted with one or more substituents independently selected from -CH3 and -OCH3.

[0183] In certain embodiments of compounds of Formula (II), each R 1 are independently H, F, Cl, -CH, -CHCHCH, -CF, cyclohexyl, -OCH, or morpholinyl; R 2 is 2-pyridyl that is unsubstituted or substituted with one or more substituents independently selected from F, Cl, CN, -CH, -CHCH, -CHCHCH, -CHCH(CH), cyclopropyl, cyclobutyl, cyclopentyl, -OCH, -OCHCH, -OCHCHCH, -OCHCH(CH), -CF, phenyl substituted with CN, -NH, -NHCH, and -N(CH). In some such embodiments, R 2 is 2-pyridyl that is unsubstituted or substituted with one or more substituents independently selected from F, Cl, CN, —CH, —CHCH(CH), cyclopropyl, —OCH, —OCHCH(CH), —CF, phenyl substituted with CN, or —N(CH). In some such embodiments, each R 1 are independently H, F, Cl, —CH3, cyclohexyl, and —OCH3.

[0184] In certain embodiments of compounds of Formula (II), each R 1 are independently H, F, Cl, -CH, -CHCHCH, -CF, cyclohexyl, -OCH, or morpholinyl; R 2 is 3-pyridyl that is unsubstituted or substituted with one or more substituents independently selected from F, Cl, CN, -CH, -CHCH, -CHCHCH, -CHCH(CH), -C(CH), -CHF, -CF, cyclopropyl, cyclobutyl, cyclopentyl, -OCH, -OCHCH, -OCHCHCH, -OCHCH(CH), phenyl, phenyl substituted with F, oxadiazolyl, -NH, -NHCH, and -N(CH).

[0185] In certain embodiments of compounds of Formula (II), each R 1 are independently H, F, Cl, -CH, -CHCHCH, -CF, cyclohexyl, -OCH, or morpholinyl; R 2 is 3-pyridyl that is unsubstituted or substituted with one or more substituents independently selected from F, Cl, CN, —CH, —C(CH), —CHF, —CF, —OCH, cyclopropyl, phenyl, phenyl substituted with F, oxadiazolyl, and —NH.

[0186] In certain embodiments of compounds of Formula (II), each R 1 are independently H, F, Cl, -CH, -CHCHCH, -CF, cyclohexyl, -OCH, or morpholinyl; R 2 is 4-pyridyl unsubstituted or substituted with one or more substituents independently selected from F, Cl, CN, -CH, -CHCH, -CHCHCH, -CHCH(CH), -CF, cyclopropyl, cyclobutyl, cyclopentyl, -OCH, -OCHCH, -OCHCHCH, -OCHCH(CH), phenyl, -NH, -NHCH, and -N(CH).

[0187] In certain embodiments of compounds of Formula (II), each R 1 are independently H, F, Cl, -CH, -CHCHCH, -CF, cyclohexyl, -OCH, or morpholinyl; R 2 is 4-pyridyl that is unsubstituted or substituted with one or more substituents independently selected from -CH3, cyclopropyl, and -CF3.

[0188] In certain embodiments of compounds of Formula (II), each R 1 are independently F, Cl, Br, -CN, -CH3, -CH2CH3, -CF3, cyclohexyl, -OCH3, -N(CH3)2, -C(O)CH3, phenyl, -O-(m-trifluoromethyl)phenyl, p-fluorophenyl, benzoyl, methylsulfonyl, or morpholinyl; R 2 is 2-imidazolyl substituted with one or more substituents independently selected from -CH, -CHCH, -CHCF, -CHCHCH, -CHCH(CH), substituted cyclopropyl, -CH-cyclopropyl, phenyl, and p-trifluoromethylphenyl. In some such embodiments, R 2 is 2-imidazolyl that is unsubstituted or substituted with one or more substituents independently selected from -CH, -CHCH, -CHCF, -CHCH(CH), cyclopropyl substituted with one or more F, -CH-cyclopropyl, phenyl, and p-trifluoromethylphenyl. In some such embodiments, each R 1 are independently selected from H, F, Br, Cl, —CN, —CH, —CHCH, CF, —OCH, —N(CH), —C(O)CH, phenyl, —O-(m-trifluoromethyl)phenyl, p-fluorophenyl, benzoyl, and methylsulfonyl.

[0189] In certain embodiments of compounds of Formula (II), each R 1are independently F, Cl, -CH3, -CH2CH3, -CF3, cyclohexyl, -OCH3, or morpholinyl; R 2 is 2-imidazolyl substituted with one or more substituents independently selected from -CH, -CHCH, -CHCHCH, -CHCH(CH), substituted cyclopropyl, and -CH-cyclopropyl. In some such embodiments, R 2 is 2-imidazolyl that is unsubstituted or substituted with one or more substituents independently selected from -CH, -CHCH, -CHCH(CH), cyclopropyl substituted with one or more F, and -CH-cyclopropyl. In some such embodiments, each R 1 are independently H, F, Cl, —CH3, —CH2CH3, CF3, and —OCH3.

[0190] In certain embodiments of compounds of Formula (II), each R 1 are independently H, F, Cl, -CH, -CHCH, CF, cyclohexyl, -OCH, or morpholinyl; R 2 is 2-pyrazyl that is unsubstituted or substituted with one or more substituents independently selected from -CH, -CHCH, -CHCHCH, -CHCH(CH), -OCH, -OCHCH, -OCHCHCH, -OCHCH(CH), pyrrolidyl, piperidyl, piperazinyl, and morpholinyl. In some such embodiments, R 2 is 2-pyrazyl that is unsubstituted or substituted with one or more substituents independently selected from —CH, —OCH, and pyrrolidyl. In some such embodiments, each R 1 is independently H, Cl, —CH 3 , —CH 2 CH 3 , —OCH 3 , or morpholinyl.

[0191] In certain embodiments of compounds of Formula (II), each R 1are independently H, F, Cl, -CH, -CHCH, CF, cyclohexyl, -OCH, or morpholinyl; R 2 is pyrazolyl that is unsubstituted or substituted with one or more substituents independently selected from -CH, -CHCH, -CHCHCH, -CHCH(CH), -OCH, -OCHCH, -OCHCHCH, -OCHCH(CH), pyrrolidyl, piperidyl, piperazinyl, and morpholinyl. In some such embodiments, R 2 is pyrazolyl that is unsubstituted or substituted with one or more substituents independently selected from -CH2CH3 and morpholinyl.

[0192] In certain embodiments of compounds of Formula (II), each R 1 are independently H, F, Cl, -CH, -CHCH, CF, cyclohexyl, -OCH, or morpholinyl; R 2 is pyrimidyl unsubstituted or substituted with one or more substituents independently selected from -CH, -CHCH, -CHCHCH, -CHCH(CH), -OCH, -OCHCH, -OCHCHCH, -OCHCH(CH), pyrrolidyl, piperidyl, piperazinyl, and morpholinyl. In some such embodiments, R 2 is pyrimidyl that is unsubstituted or substituted with one or more substituents independently selected from -CH3 and -OCH3.

[0193] Further embodiments provided herein include a combination of at least one of the specific embodiments set forth above.

[0194] Representative compounds of formula (I), formula (Ia) and formula (II) are shown in Tables 1 and 2.

[0195] Further representative compounds of formula (I), formula (Ia) and formula (II) are shown in Tables 1, 2, 3 and 4.

[0196] Each of the compounds in Tables 1, 2 and 3 was tested in one or more of the in vitro parasite motility assays and found to be active.

[0197] In further embodiments, each of the compounds in Table 1, Table 2, Table 3 and Table 4 was tested in one or more in vitro parasite motility assays and found to have activity.

[0198] Compound preparation method The sulfonamide compounds of Formula (I), Formula (Ia), and Formula (II), Tables 1, 2, and 3, can be prepared using conventional organic synthesis and commercially available starting materials. Furthermore, the sulfonamide compounds of Formula (I), Formula (Ia), and Formula (II), Tables 1, 2, and 3, and Table 4, can be prepared using conventional organic synthesis and commercially available starting materials. By way of example, and not limitation, the sulfonamide compounds of Formula (I), Formula (Ia), and Formula (II), Tables 1, 2, 3, and 4 can be prepared as outlined in Scheme 1, shown below, and in the Examples set forth herein. It should be noted that one of ordinary skill in the art would know how to modify the procedures set forth in the exemplary Schemes and Examples to arrive at the desired products.

[0199] [ka] As shown in Scheme 1, the compounds of formula (I), formula (Ia), formula (II), Table 1, Table 2, Table 3 and Table 4 (wherein R 1 , R 2, R, A, m, n, and p are as defined herein) can be prepared starting from an appropriately derivatized heterocyclic amine (B) and sulfonyl (D) (where LG (leaving group) is Cl or Bt (1H-benzo[d][1,2,3]triazolyl)). Compound (B) of formula I (where (B) is quinolone-8-amine) is commercially available or can be prepared according to known methods (see, for example, J. Heterocyclic Chem., 39, 631 (2002)). Compounds where (B) is either hexahydroquinoline-amine or tetrahydro-indoleamine are commercially available or can be prepared according to known methods (see, for example, Org. Biomol. Chem., 2020, 18, 1214-1220). An appropriately substituted 8-nitroquinoline derivative (A) is reduced, for example, using SnCl or H in the presence of a catalyst such as Pd / C in a solvent such as MeOH or EtOH and heated at a temperature ranging from 25 to 70°C to provide a derivatized quinolone-8-amine (B). Sulfonyl chlorides (D) (where LG is Cl) are commercially available or can be prepared according to known methods (see, for example, Bull. Korean Chem. Soc., 33, 383 (2012)). The appropriately derivatized R 2 Thio-alkylation of the containing moiety (C) (where X is Cl) with (4-methoxyphenyl)methanethiol or phenylmethanethiol in a solvent such as THF or DMSO in the presence of a base such as NaH or CsF at temperatures ranging from 0 to 80° C. provides the intermediate benzyl thiol. Subsequent oxidative chlorination of the benzyl thiol with 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (DCH) or NaOCl in a solvent such as DCM and water in the presence of an acid such as HOAc at temperatures ranging from −10 to 25° C. provides the sulfonyl (D) (where LG is Cl). Alternatively, the appropriately derivatized R 2Treatment of the containing moiety (C) (where X is Br) with a base such as nBuLi in the presence of SO2Cl2 in a solvent such as THF at temperatures ranging from -78 to 25°C or in the presence of SO2 gas in a solvent such as Et2O at temperatures ranging from -70 to 25°C, followed by reaction with NCS in a solvent such as CHCl3 and water at temperatures ranging from 0 to 25°C provides the sulfonyl (D) (where LG is Cl). Alternatively, the appropriately derivatized R 2 Treatment of moiety (C) (where X is SH) with Cl gas in the presence of an acid such as HOAc in a solvent such as DCM and water at temperatures ranging from 0 to 25°C provides sulfonyl (D) (where LG is Cl). Sulfonyl (D) (where LG is Bt) is prepared according to known methods. The appropriately derivatized R 2 Treatment of moiety (C) (where X is H) with a base such as nBuLi in the presence of SO gas in a solvent such as THF at a temperature ranging from -78 to 0°C, followed by addition of N-chlorobenzotriazole in the presence of a base such as TEA at a temperature ranging from 0 to 25°C, provides sulfonyl (D) (where LG is benzotriazole). Compounds of Formula (I), Formula (Ia), Formula (II), Table 1, Table 2, Table 3, and Table 4 can be obtained by treating quinolone-8-amine (B) and sulfonyl (D) with a base such as NaHMDS or pyridine in a solvent such as THF or DCM at a temperature ranging from -78 to 130°C.

[0200] In one embodiment, a compound of formula (I): [ka] Provided herein is a method for preparing a sulfonamide compound of formula (B): [ka] in the presence of a base, in a solvent under conditions suitable to provide a sulfonamide compound of formula (D): [ka] wherein: --- is a single or double bond; Each A is independently N or CR 1 and; Each R 1 are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R 2 is a substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R is absent, H, substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl, or CO(substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl); m is 0 to 3; n is 0 to 3; and p is 0 to 3; However, m and n cannot both be 0.

[0201] In some embodiments, the base is NaHMDS or pyridine. In some embodiments, the solvent is THF or DCM. In some embodiments, the contacting is performed at a temperature ranging from room temperature to −78 to 130° C. In some embodiments, LG is Cl or 1H-benzo[d][1,2,3]triazolyl.

[0202] In some embodiments, the method comprises reacting a compound of formula (B): [ka] The method further comprises preparing a compound of formula (A): [ka] with a reducing agent in a solvent under conditions suitable to provide a compound of formula (A).

[0203] In some embodiments, the reducing agent is SnCl or H gas in the presence of a catalyst. In one embodiment, the catalyst is Pd / C. In one embodiment, the solvent is MeOH or EtOH. In some embodiments, the contacting is performed at a temperature ranging from 25 to 70°C.

[0204] In some embodiments, the method comprises reacting a compound of formula (D): [ka] The method further comprises preparing a compound of formula: a)R 2 contacting —X, where X is Cl, with (4-methoxyphenyl)methanethiol or phenylmethanethiol in a first solvent; b) contacting the product of step a) with 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione or NaOCl in a second solvent under conditions suitable to provide a compound of formula (D) (where LG is Cl).

[0205] In some embodiments, the contacting in step (a) comprises the presence of a base. In one embodiment, the base in step (a) is NaH. In some embodiments, the first solvent is THF. In some embodiments, the contacting in step (a) occurs at a temperature ranging from 0 to 80° C. In some embodiments, the base in step (a) is CsF and the first solvent is DMSO.

[0206] In some embodiments, the method of step b) further comprises the presence of an acid. In one embodiment, the acid is HOAc. In some embodiments, the second solvent is DCM and water. In some embodiments, the contacting of step (b) occurs at a temperature ranging from -10 to 25°C.

[0207] In some embodiments, the method comprises reacting a compound of formula (D): [ka] The method further comprises preparing a compound of formula: a)R 2 reacting —X, where X is Br, with a base in a first solvent in the presence of SO gas; b) contacting the product of step a) with NCS in a second solvent under conditions suitable to provide a compound of formula (D), wherein LG is Cl.

[0208] In one embodiment, the base in step (a) is nBuLi. In one embodiment, the first solvent is EtO. In some embodiments, the contacting in step (a) occurs at a temperature ranging from -70 to 25°C.

[0209] In some embodiments, the second solvent is CHCl3 and water. In some embodiments, the contacting in step (b) is carried out at a temperature ranging from 0 to 25°C.

[0210] In some embodiments, the base in step (a) is nBuLi. In one embodiment, the first solvent is THF. In some embodiments, the contacting in step (a) occurs at a temperature ranging from -78 to 25°C. In some embodiments, the contacting of the product of step a) with SO2Cl2 occurs at a temperature ranging from -78 to 25°C.

[0211] In some embodiments, the method comprises reacting a compound of formula (D): [ka] The method further comprises preparing a compound of formula R 2 -X, where X is SH, with an acid in the presence of Cl gas, in a solvent under conditions suitable to provide a compound of formula (D), to provide a compound of formula (D), where LG is Cl.

[0212] In one embodiment, the acid is HOAc. In one embodiment, the solvent is DCM and water. In some embodiments, the contacting is performed at a temperature ranging from 0 to 25°C.

[0213] In some embodiments, the method comprises reacting a compound of formula (D): [ka] The method further comprises preparing a compound of formula: a)R 2 reacting —X, where X is H, with a base in the presence of SO gas in a first solvent; b) contacting the product of step a) with N-chlorobenzotriazole in a second solvent under conditions suitable to provide a compound of Formula (D), wherein LG is 1H-benzo[d][1,2,3]triazonyl.

[0214] In one embodiment, the base in step (a) is nBuLi. In one embodiment, the first solvent is EtO. In some embodiments, the contacting in step (a) occurs at a temperature ranging from -78 to 0°C.

[0215] In some embodiments, the method further comprises the presence of a base in step (b). In some embodiments, the base is TEA. In some embodiments, the second solvent is THF. In some embodiments, the contacting in step (b) is performed at a temperature ranging from 0 to 25°C.

[0216] How to use Sulfonamide compounds, including compounds of Formula (I), Formula (Ia), Formula (II), Table 1, Table 2, and Table 3, have utility as pharmaceuticals for treating, preventing, or ameliorating conditions in animals and humans. Additionally, sulfonamide compounds, including compounds of Formula (I), Formula (Ia), Formula (II), Table 1, Table 2, Table 3, and Table 4, have utility as pharmaceuticals for treating, preventing, or ameliorating conditions in animals and humans. The sulfonamide compounds provided herein have utility for use in the treatment or prevention of any disease, disorder, or condition disclosed herein.

[0217] In one aspect, provided herein is a method for treating a disease caused by helminth infection. In certain embodiments, the compounds described herein are used in human medical therapy, particularly in the treatment of helminth infection. In certain embodiments, the compounds provided herein are used in animal medical therapy, particularly in the treatment of helminth infection. In certain embodiments, the method comprises administering a therapeutically effective amount of the compound described to a subject suffering from a disease caused by helminth infection.

[0218] In one aspect, provided herein is a method for treating a disease caused by heartworm infection. In certain embodiments, the compounds described herein are used in human medical therapy, particularly in the treatment of heartworm infection. In certain embodiments, the compounds provided herein are used in animal medical therapy, particularly in the treatment of heartworm infection. In certain embodiments, the method comprises administering a therapeutically effective amount of the compound described to a subject suffering from a disease caused by heartworm infection.

[0219] In one embodiment, provided herein are methods for treating or preventing helminth infections and diseases, the methods comprising administering to a subject an effective amount of a sulfonamide compound, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof. In some such embodiments, the helminth infection is a heartworm infection.

[0220] In one aspect, provided herein are methods for treating diseases caused by helminth infection. In certain embodiments, sulfonamide compounds or pharmaceutically acceptable salts, tautomers, isotopologues, or stereoisomers thereof are used in human medical therapy, particularly in the treatment of helminth infections. In certain embodiments, sulfonamide compounds or pharmaceutically acceptable salts, tautomers, isotopologues, or stereoisomers thereof are used in animal medical therapy, particularly in the treatment of helminth infections. In certain embodiments, the method comprises administering a therapeutically effective amount of a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof to a subject having a disease caused by helminth infection.

[0221] In one aspect, provided herein are methods for treating diseases caused by heartworm infection. In certain embodiments, sulfonamide compounds or pharmaceutically acceptable salts, tautomers, isotopologues, or stereoisomers thereof are used in human medical therapy, particularly in the treatment of heartworm infection. In certain embodiments, sulfonamide compounds or pharmaceutically acceptable salts, tautomers, isotopologues, or stereoisomers thereof are used in animal medical therapy, particularly in the treatment of heartworm infection. In certain embodiments, the method comprises administering a therapeutically effective amount of a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof to a subject having a disease caused by heartworm infection.

[0222] In another aspect, methods for preventing diseases caused by helminth infections are also provided. In certain embodiments, the sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof is used in human medical therapy, particularly for the prevention of helminth infections. In certain embodiments, the sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof is used in animal medical therapy, particularly for the prevention of helminth infections. In certain embodiments, the method comprises administering a therapeutically effective amount of the sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof to a subject to prevent diseases caused by helminth infections.

[0223] In another aspect, methods for preventing disease caused by heartworm infection are also provided. In certain embodiments, the sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof is used in human medical therapy, particularly for the prevention of heartworm infection. In certain embodiments, the sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof is used in animal medical therapy, particularly for the prevention of heartworm infection. In certain embodiments, the method comprises administering a therapeutically effective amount of the sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof to a subject to prevent disease caused by heartworm infection.

[0224] In another aspect, provided herein are methods of treating or preventing a parasitic disease. In certain embodiments, the parasitic disease is associated with a worm. In certain embodiments, the parasitic disease is caused by a worm. In certain embodiments, the parasites are classified as cestodes (tapeworms), nematodes (roundworms), and trematodes (flatworms or flukes). In certain embodiments, the parasitic disease is associated with a helminth. In certain embodiments, the parasitic disease is associated with a nematode. In certain embodiments, the nematode is Wuchereria bancrofti. In certain embodiments, the nematode is Brugia malayi. In certain embodiments, the nematode is Brugia timori. In certain embodiments, the nematode is Onchocerca volvulus. In certain embodiments, the nematode is Dirofilaria immitis. In some embodiments, the nematode is Haemonchus contortus. In particular embodiments, the nematode is Ascaris lumbricoides. In particular embodiments, the nematode is Necator americanus. In yet another embodiment, the nematode is Ancylostoma duodenale. In yet other embodiments, the nematode is Trichuris trichiura. In particular embodiments, the parasitic disease is associated with a trematode. In particular embodiments, the parasitic disease is associated with Schistosoma. In particular embodiments, the parasitic disease is associated with Schistosoma mansoni. In certain embodiments, the parasitic disease is enterobiasis, pinworm disease, ascariasis, hookworm disease, American hookworm disease, dracunculiasis, filariasis, onchocerciasis, schistosomiasis, or trichuriasis. In certain embodiments, the parasitic disease is schistosomiasis. In certain embodiments, the parasitic disease is urinary schistosomiasis. In certain embodiments, the parasitic disease is intestinal schistosomiasis. In certain embodiments, the parasitic disease is Asian intestinal schistosomiasis. In certain embodiments, the parasitic disease is visceral schistosomiasis.In certain embodiments, the parasitic disease is acute schistosomiasis. In certain embodiments, the parasitic disease is lymphatic filariasis. In certain embodiments, the parasitic disease is bancroftian filariasis. In certain embodiments, the parasitic disease is subcutaneous filariasis. In certain embodiments, the parasitic disease is serosal filariasis. In certain embodiments, the parasitic disease is elephantiasis. In certain embodiments, the parasitic disease is tropical elephantiasis. In certain embodiments, the parasitic disease is onchocerciasis. In certain embodiments, the dirofilariasis is canine dirofilariasis. In some embodiments, the dirofilariasis is caused by Dirofilaria immitis or Dirofilaria repens. In certain embodiments, the parasitic disease is haemonchosis. In certain embodiments, the haemonchosis is haemonchosis in sheep and goats, hi some embodiments, the haemonchosis is caused by Haemonchus contortus.

[0225] In certain aspects, the methods of the present invention comprise administering a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof to a subject. In certain embodiments, the methods comprise administering a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof to a subject for 14 days or less. In certain embodiments, the methods comprise administering a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof to a subject for 7 days or less. In certain embodiments, the subject is in need of treatment for a helminth infection. In certain embodiments, the subject is in need of treatment for a filarial infection. In certain embodiments, the subject has a helminth infection. In certain embodiments, the subject is at risk of having a helminth infection. In certain embodiments, the subject has a filarial infection. In certain embodiments, the subject is at risk of having a filarial infection. In certain embodiments, the subject is a pediatric subject. In certain embodiments, the subject is under the age of 9. In certain embodiments, the subject is under 8 years of age. In certain embodiments, the subject is a pregnant woman. In certain embodiments, the subject is a postpartum woman. In certain embodiments, the subject is a woman of childbearing potential. In certain embodiments, the subject is an individual who is about to conceive. In certain embodiments, the subject is a domestic animal. In certain embodiments, the subject is a dog.

[0226] The compounds disclosed herein exhibit efficacy against helminths, and thus have the potential to kill such helminths and / or inhibit the growth, molting, or motility of such helminths. The compounds disclosed herein exhibit efficacy against heartworms, and thus have the potential to kill such heartworms and / or inhibit the growth, molting, or motility of such heartworms. Thus, in one aspect, there is provided a method for killing heartworms, comprising contacting a heartworm with a sulfonamide compound, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, in an amount effective to kill the heartworm. In another aspect, there is provided a method for inhibiting heartworm growth or molting, comprising contacting a heartworm with a sulfonamide compound, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, in an amount effective to inhibit the heartworm growth or molting. In another aspect, provided herein is a method of inhibiting the motility of heartworms, comprising contacting the heartworms with a sulfonamide compound, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, in an amount effective to inhibit the motility of the heartworms. In certain embodiments, the heartworms are eggs. In certain embodiments, the eggs are unfertilized eggs. In certain embodiments, the eggs are fertilized eggs. In certain embodiments, the heartworms are larvae. In certain embodiments, the heartworms are in a larval or juvenile stage. In certain embodiments, the heartworms are larvae at any one of the four larval stages (L1, L2, L3, L4). In certain embodiments, the heartworms are L1-stage larvae or microfilariae. In certain embodiments, the microfilariae are L1-stage larvae. In certain embodiments, the heartworms are L2-stage larvae. In certain embodiments, the heartworms are L3-stage larvae. In certain embodiments, the heartworms are L4-stage larvae. In certain embodiments, the worms are in a sexually immature stage (L5 stage). In certain embodiments, the worms are mature. In certain embodiments, the worms are fully mature. In certain embodiments, the worms are in an adult stage. In certain embodiments, the worms are in a pre-parasitic stage. In certain embodiments, the worms are in a parasitic stage.In certain embodiments, the insects are contacted with the sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof inside the subject, hi certain embodiments, the insects are contacted with the sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof outside the subject.

[0227] As discussed herein, compounds useful for the treatment or prevention of certain diseases and disorders in humans and animals are provided herein. In certain embodiments, sulfonamide compounds or pharmaceutically acceptable salts, tautomers, isotopologues, or stereoisomers thereof are used to treat diseases caused by helminth infection. In certain embodiments, sulfonamide compounds or pharmaceutically acceptable salts, tautomers, isotopologues, or stereoisomers thereof are used to treat diseases caused by filarial worm infection, including, but not limited to, heartworm disease, ascariasis, trichuriasis, schistosomiasis, haemonchosis, onchocerciasis, and lymphatic filariasis. In certain embodiments, treatment or prevention of such diseases and disorders can be achieved by administering sulfonamide compounds or pharmaceutically acceptable salts, tautomers, isotopologues, or stereoisomers thereof alone or in combination with another active agent as part of a combination therapy. "Combination," as in phrases such as "in combination with another active agent," includes, for example, simultaneous administration of a first agent and a second agent, which may be dissolved or mixed in the same pharmaceutically acceptable carrier, or administration of the first agent followed by administration of the second agent, or administration of the second agent followed by administration of the first agent. Thus, the methods and compositions of the present invention include combination therapeutic treatment methods and combination pharmaceutical compositions. The term "combination therapy" refers to the administration of two or more therapeutic substances, e.g., a compound described herein and another drug (e.g., an antihelminthic drug such as ivermectin, albendazole, flubendazole, diethylcarbamazine, or emodepside). Other drugs may be administered simultaneously with, before, or after administration of the macrolide antibiotic.

[0228] In one embodiment, a method for treating or preventing helminth infections and diseases is provided, the method comprising administering to a subject an effective amount of a sulfonamide compound, or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof, in combination with one or more anti-helminthic agents. In some such embodiments, the helminth infection is a heartworm infection. In one embodiment, treating the helminth infection comprises administering an anti-helminthic agent such as a benzimidazole, e.g., flubendazole, albendazole, mebendazole, thiabendazole, fenbendazole, or triclabendazole. In one embodiment, treatment of helminth infections involves administration of one or more antihelminthic agents, such as ivermectin, abamectin, diethylcarbamazine (DEC), suramin, pyrantel pamoate, levamisole, niclosamide, nitazoxanide, oxyclozanide, praziquantel, emodepside, monepantel, delquantel, or peletierin sulfate. In certain embodiments, a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof is used in combination with one or more antihelminthic agents to treat helminth infections. In some embodiments, the antihelminthic agent is a benzimidazole, such as flubendazole, albendazole, mebendazole, thiabendazole, fenbendazole, or triclabendazole. In some embodiments, the antihelminthic agent is one or more of ivermectin, abamectin, diethylcarbamazine (DEC), suramin, pyrantel pamoate, levamisole, niclosamide, nitazoxanide, oxyclozanide, praziquantel, emodepside, monepantel, delquantel, or pelletierin sulfate. In one embodiment, the antihelminthic agent is ivermectin, moxidectin, or selamectin. In certain embodiments, a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof is used in a method for treating or preventing heartworm infections and diseases, the method comprising administering to a subject an effective amount of a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof in combination with one or more antihelminthic agents.In some such embodiments, the antihelminthic agent is selected from flubendazole, albendazole, mebendazole, thiabendazole, fenbendazole, triclabendazole, ivermectin, abamectin, diethylcarbamazine (DEC), suramin, pyrantel pamoate, levamisole, niclosamide, nitazoxanide, oxyclozanide, praziquantel, emodepside, monepantel, delquantel, or pelletierin sulfate. In one embodiment, the antihelminthic agent is a Wolbachia targeted agent. In one embodiment, the Wolbachia targeted agent is doxycycline.

[0229] Pharmaceutical Compositions and Routes of Administration Provided herein are pharmaceutical compositions comprising an effective amount of a sulfonamide compound described herein and a pharmaceutically acceptable carrier, excipient, or vehicle. The sulfonamide compound can be administered to a subject enterally (e.g., orally, rectally), topically, or parenterally (e.g., intravenously, intramuscularly, subcutaneously) in conventional dosage forms such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable formulations may contain excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), lubricants (e.g., magnesium stearate, light anhydrous silicic acid, talc, or sodium lauryl sulfate), flavoring agents (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben ... The pharmaceutical compositions can be prepared by commonly used methods using conventional organic or inorganic additives such as benzophenone-4, benzotriazole, ...

[0230] The dosage of the sulfonamide compound administered to a subject can vary considerably and be at the discretion of a medical professional. Generally, the sulfonamide compound can be administered to a subject at a dosage of about 0.5 mg / kg to about 20 mg / kg of subject's body weight, 1 to 4 times daily; however, the dosage may be appropriately modified depending on the subject's age, body weight, and medical condition, as well as the type of administration. In one embodiment, the dosage is about 0.1 mg / kg to about 3 mg / kg of subject's body weight, about 0.5 mg / kg to about 2 mg / kg of subject's body weight, about 1 mg / kg to about 2 mg / kg of subject's body weight, or about 1.5 mg / kg to about 2 mg / kg of subject's body weight. In one embodiment, the dosage is about 1 mg / kg to about 3 mg / kg of subject's body weight. In one embodiment, the dosage is about 0.5 mg / kg to about 1 mg / kg of subject's body weight. In one embodiment, the dosage is about 1 mg / kg to about 2 mg / kg of subject's body weight. In one embodiment, the dose is about 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mg / kg of subject body weight. In one embodiment, one dose is given per day. The amount of sulfonamide compound administered in any given case may depend on factors such as the solubility of the active ingredient, the formulation used, and the route of administration. In one embodiment, application of a local concentration provides an intracellular exposure or concentration of about 0.01-10 μM.

[0231] In another embodiment, provided herein is a method for treating or preventing a disease or disorder, comprising administering to a subject suffering from a helminth infection from about 1 mg / day to about 1200 mg / day of a sulfonamide compound. In another embodiment, provided herein is a method for treating or preventing a disease or disorder, comprising administering to a subject suffering from a helminth infection from about 0.375 mg / day to about 750 mg / day, about 0.75 mg / day to about 375 mg / day, about 3.75 mg / day to about 75 mg / day, about 7.5 mg / day to about 55 mg / day, or about 18 mg / day to about 37 mg / day of a sulfonamide compound. In one embodiment, the method for treating a disease or disorder comprises administering to a subject suffering from a helminth infection from about 0.375 mg / day to about 750 mg / day of a sulfonamide compound. In one embodiment, a method for treating a disease or disorder comprises administering to a subject suffering from a helminth infection about 0.75 mg / day to about 375 mg / day of a sulfonamide compound. In one embodiment, a method for treating a disease or disorder comprises administering to a subject suffering from a helminth infection about 3.75 mg / day to about 75 mg / day of a sulfonamide compound. In one embodiment, a method for treating a disease or disorder comprises administering to a subject suffering from a helminth infection about 7.5 mg / day to about 55 mg / day of a sulfonamide compound. In one embodiment, a method for treating a disease or disorder comprises administering to a subject suffering from a helminth infection about 18 mg / day to about 37 mg / day of a sulfonamide compound.

[0232] In another embodiment, provided herein is a unit dosage form comprising about 1 mg to 200 mg, about 35 mg to about 1400 mg, about 125 mg to about 1000 mg, about 250 mg to about 1000 mg, or about 500 mg to about 1000 mg of a sulfonamide compound. In one embodiment, the unit dosage form comprises about 1 mg to 200 mg of a sulfonamide compound. In one embodiment, the unit dosage form comprises about 35 mg to about 1400 mg of a sulfonamide compound. In one embodiment, the unit dosage form comprises about 125 mg to about 1000 mg of a sulfonamide compound. In one embodiment, the unit dosage form comprises about 250 mg to about 1000 mg of a sulfonamide compound. In one embodiment, the unit dosage form comprises about 500 mg to about 1000 mg of a sulfonamide compound.

[0233] In certain embodiments, provided herein are unit dosage forms comprising about 100 mg or 400 mg of a sulfonamide compound.

[0234] In another embodiment, provided herein is a unit dosage form comprising 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 40 mg, 50 mg, 70 mg, 100 mg, 125 mg, 130 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg, or 1400 mg of a sulfonamide compound. In one embodiment, the unit dosage form comprises 1 mg of a sulfonamide compound. In one embodiment, the unit dosage form comprises 5 mg of a sulfonamide compound. In one embodiment, the unit dosage form comprises 10 mg of a sulfonamide compound. In one embodiment, the unit dosage form comprises 15 mg of a sulfonamide compound. In one embodiment, the unit dosage form comprises 20 mg of a sulfonamide compound. In one embodiment, the unit dosage form comprises 25 mg of a sulfonamide compound. In one embodiment, the unit dosage form contains 30 mg of the sulfonamide compound. In one embodiment, the unit dosage form contains 35 mg of the sulfonamide compound. In one embodiment, the unit dosage form contains 40 mg of the sulfonamide compound. In one embodiment, the unit dosage form contains 50 mg of the sulfonamide compound. In one embodiment, the unit dosage form contains 70 mg of the sulfonamide compound. In one embodiment, the unit dosage form contains 100 mg of the sulfonamide compound. In one embodiment, the unit dosage form contains 125 mg of the sulfonamide compound. In one embodiment, the unit dosage form contains 130 mg of the sulfonamide compound. In one embodiment, the unit dosage form contains 140 mg of the sulfonamide compound. In one embodiment, the unit dosage form contains 175 mg of the sulfonamide compound. In one embodiment, the unit dosage form contains 200 mg of the sulfonamide compound. In one embodiment, the unit dosage form contains 250 mg of the sulfonamide compound. In one embodiment, the unit dosage form contains 280 mg of the sulfonamide compound. In one embodiment, the unit dosage form contains 350 mg of the sulfonamide compound. In one embodiment, the unit dosage form contains 500 mg of the sulfonamide compound. In one embodiment, the unit dosage form contains 560 mg of the sulfonamide compound. In one embodiment, the unit dosage form contains 700 mg of the sulfonamide compound. In one embodiment, the unit dosage form contains 750 mg of the sulfonamide compound.In one embodiment, the unit dosage form comprises 1000 mg of the sulfonamide compound. In one embodiment, the unit dosage form comprises 1400 mg of the sulfonamide compound.

[0235] The sulfonamide compounds can be administered once, twice, three times, four times, or more times per day, hi certain embodiments, doses of 600 mg or less are administered as a single daily dose, and doses of more than 600 mg are administered twice daily in an amount equal to half of the total daily dose.

[0236] The sulfonamide compound can be administered orally for convenience. In one embodiment, when administered orally, the sulfonamide compound is administered with food and water. In another embodiment, the sulfonamide compound is dispersed in water or juice (e.g., apple juice or orange juice) and orally administered as a suspension.

[0237] The sulfonamide compounds may also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, topically to the ear, nose, eye or skin, or topically ocularly (i.e., subconjunctivally, intravitreal, retrobulbar, intracameral). The mode of administration is left to the discretion of the healthcare professional and may depend in part on the site of the medical condition.

[0238] In one embodiment, provided herein is a capsule containing the sulfonamide compound without additional carriers, excipients, or vehicles.

[0239] In another embodiment, provided herein is a composition comprising an effective amount of a sulfonamide compound and a pharmaceutically acceptable carrier or vehicle, which may comprise an excipient, diluent, or mixtures thereof. In one embodiment, the composition is a pharmaceutical composition.

[0240] The compositions may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories, suspensions, gels, intraruminal devices (e.g., for long-term prophylaxis or controlled release), implants, topical pour-ons, transdermal delivery gels, spot-ons, implants (including devices), gels, liquids (e.g., PLGA), and the like. The compositions may be formulated to contain a daily dose or a convenient fraction of a daily dose in a dosage unit, which may be a single tablet or capsule or a convenient volume of liquid. In one embodiment, solutions are prepared from water-soluble salts, such as hydrochlorides. Generally, compositions are prepared according to methods known in pharmaceutical chemistry. Capsules may be prepared by mixing the sulfonamide compound with suitable carriers or diluents and filling the appropriate amount of the mixture into capsules. Typical carriers and diluents include, but are not limited to, inert powdered substances, such as many different types of starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol, and sucrose, grain flours, and similar edible powders.

[0241] Tablets can be prepared by direct compression, wet granulation, or dry granulation. The formulation typically includes a diluent, binder, lubricant, and disintegrant, as well as a compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are starch, gelatin, and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginates, methylcellulose, and polyvinylpyrrolidine, are also convenient. Polyethylene glycol, ethylcellulose, and waxes can also serve as binders.

[0242] Lubricants may be necessary in tablet formulations to prevent the tablet and punch from adhering to the dye. Lubricants can be selected from slippery solids such as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell when wet, breaking up the tablet and releasing the compound. Disintegrants include starch, clay, cellulose, algin, and gums. More specifically, for example, corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resins, alginic acid, guar gum, citrus pulp, and carboxymethylcellulose can be used, as well as sodium lauryl sulfate. Tablets can be coated with sugar as a flavor and sealant, or with a film-forming protective agent to modify the dissolution properties of the tablet. The composition can also be formulated as a chewable tablet, for example, by using substances such as mannitol in the formulation.

[0243] When it is desired to administer the sulfonamide compound as a suppository, a typical base can be used. Cocoa butter is a conventional suppository base, and can be modified by adding wax to slightly raise its melting point. In particular, water-miscible suppository bases, including polyethylene glycols of various molecular weights, are widely used.

[0244] The effect of sulfonamide compounds can be delayed or prolonged by appropriate formulation. For example, slowly dissolving pellets of sulfonamide compounds can be prepared and incorporated into tablets or capsules or as sustained-release implantable devices. This technique also involves producing pellets with several different dissolution rates and filling capsules with a mixture of pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Parenteral formulations can also be made long-acting by dissolving or suspending the sulfonamide compounds in an oily or emulsified medium or adding an amount of PLGA that allows them to disperse slowly in serum. [Example]

[0245] The following examples are presented by way of example, not limitation. Compounds are named using the automatic name generation tool provided in Chemdraw Ultra 17.0 (Cambridgesoft). This tool generates systematic names for chemical structures with adherence to the Cahn-Ingold-Prelog rules of stereochemistry. Those skilled in the art can modify the procedures described in the illustrative examples to arrive at the desired products.

[0246] Abbreviations used:

[0247] [Table 1]

[0248] [Table 2]

[0249] [Table 3]

[0250] Example 1. N-(7-chloroquinolin-8-yl)-3-cyclopropylpyridine-2-sulfonamide [ka] 2-Chloro-3-cyclopropylpyridine. To a mixture of 2-chloro-3-iodopyridine (10.0 g, 41.8 mmol) and potassium cyclopropyltrifluoroborate (9.27 g, 62.7 mmol) in water (10 mL) and dioxane (100 mL) was added (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (3.06 g, 4.18 mmol) and potassium carbonate (20.2 g, 146 mmol) under nitrogen. The mixture was stirred at 100 °C for 24 hours. The mixture was concentrated in vacuo. The residue was filtered, and the filter cake was washed with ethyl acetate. The filtrate was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give 2-chloro-3-cyclopropylpyridine (3.2 g, 20.83 mmol, 49.89% yield).

[0251] 3-Cyclopropyl-2-((4-methoxybenzyl)thio)pyridine. To a mixture of (4-methoxyphenyl)methanethiol (4.82 g, 31.3 mmol) in DMSO (30 mL) was added cesium fluoride (6.33 g, 41.7 mmol) and 2-chloro-3-cyclopropylpyridine (3.20 g, 20.8 mmol). The mixture was stirred at 80 °C for 16 h. The mixture was poured into brine (40 mL). The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine and concentrated in vacuo. The residue was purified by preparative HPLC to give 3-cyclopropyl-2-((4-methoxybenzyl)thio)pyridine (5.6 g, crude).

[0252] 3-Cyclopropylpyridine-2-sulfonyl chloride. To a solution of 3-cyclopropyl-2-((4-methoxybenzyl)thio)pyridine (700 mg, 2.58 mmol) in DCM (9.8 mL), acetic acid (1.4 mL), and water (2.8 mL) was added a solution of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (DCH) (1.52 g, 7.74 mmol) in DCM (5.6 mL) dropwise over 0.5 h at 0°C. The mixture was stirred at 0-5°C for 3 h. The mixture was poured into water. The aqueous phase was extracted with DCM. The combined organic phase was washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3-cyclopropylpyridine-2-sulfonyl chloride (562 mg, crude).

[0253] N-(7-chloroquinolin-8-yl)-3-cyclopropylpyridine-2-sulfonamide. To a mixture of 7-chloroquinolin-8-amine (138 mg, 0.774 mmol) in pyridine (5.6 mL) was added dropwise a solution of 3-cyclopropylpyridine-2-sulfonyl chloride (561 mg, 2.58 mmol) in DCM (5.6 mL) under nitrogen at 0° C. The mixture was stirred at 25° C. for 16 hours. The product was isolated and purified by standard methods to give N-(7-chloroquinolin-8-yl)-3-cyclopropylpyridine-2-sulfonamide (89.23 mg, 0.245 mmol, 10% yield, 98.9% purity). MS (ESI) m / z 360.1 [M+1] + .

[0254] Example 2. N-(7-chloroquinolin-8-yl)-6-(pyrrolidin-1-yl)pyrazine-2-sulfonamide [ka] 2-((4-Methoxybenzyl)thio)-6-(pyrrolidin-1-yl)pyrazine. To a mixture of 2-chloro-6-[(4-methoxyphenyl)methylsulfanyl]pyrazine (2.50 g, 9.37 mmol) and pyrrolidine (1.33 g, 18.74 mmol) in ACN (30.00 mL) was added potassium carbonate (2.59 g, 18.74 mmol). The mixture was stirred at 80° C. for 12 hours. The mixture was diluted with ethyl acetate, and the resulting mixture was filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography to give 2-[(4-methoxyphenyl)methylsulfanyl]-6-pyrrolidin-1-yl-pyrazine (2.70 g, 8.96 mmol, 96% yield).

[0255] 6-(Pyrrolidin-1-yl)pyrazine-2-sulfonyl chloride. To a mixture of 2-[(4-methoxyphenyl)methylsulfanyl]-6-pyrrolidin-1-yl-pyrazine (2.00 g, 6.64 mmol) in DCM (21 mL), water (6 mL), and acetic acid (3 mL) was added a solution of 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (3.92 g, 19.9 mmol) in DCM (12 mL) dropwise over 1 hour at 0° C. The mixture was stirred at 0° C. for 1.5 hours. The mixture was poured into water. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 6-pyrrolidin-1-ylpyrazine-2-sulfonyl chloride (1.62 g, crude).

[0256] N-(7-chloroquinolin-8-yl)-6-(pyrrolidin-1-yl)pyrazine-2-sulfonamide. To a mixture of 7-chloroquinolin-8-amine (350.00 mg, 1.96 mmol) in THF (10 mL) was added sodium bis(trimethylsilyl)amide (1 M, 6.53 mL) at −65° C. under N2 protection. The mixture was stirred at 25° C. for 0.5 hours. To this mixture was added 6-pyrrolidin-1-ylpyrazine-2-sulfonyl chloride (1.62 g, 6.53 mmol) in THF (5 mL) at −65° C. The mixture was stirred at 25° C. for 1 hour. The mixture was quenched with water. The product was isolated and purified by standard methods to give N-(7-chloro-8-quinolyl)-6-pyrrolidin-1-yl-pyrazine-2-sulfonamide (229.10 mg, 0.580 mmol, 9% yield, 98.1% purity). MS(ESI) m / z 390.1 [M+1] + .

[0257] Example 3. N-(7-chloroquinolin-8-yl)-3-(dimethylamino)pyrazine-2-sulfonamide [ka] 3-((4-Methoxybenzyl)thio)-N,N-dimethylpyrazin-2-amine. A mixture of 2-chloro-3-[(4-methoxyphenyl)methylsulfanyl]pyrazine (3.00 g, 11.3 mmol), N-methylmethanamine (1.38 g, 16.9 mmol, HCl salt), and potassium carbonate (4.66 g, 33.8 mmol) in ACN (20 mL) was stirred at 70° C. for 12 h. The resulting mixture was filtered, and the filtrate was concentrated to give 3-[(4-methoxyphenyl)methylsulfanyl]-N,N-dimethyl-pyrazin-2-amine (3.30 g, crude).

[0258] 3-(Dimethylamino)pyrazine-2-sulfonyl chloride. To a mixture of 3-[(4-methoxyphenyl)methylsulfanyl]-N,N-dimethyl-pyrazin-2-amine (3.10 g, 11.3 mmol) in DCM (21 mL), water (6 mL), and acetic acid (3 mL) was added a DCM solution of 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (6.65 g, 33.8 mmol) dropwise over 0.5 h at 0 °C. The mixture was stirred at 5 °C for 1 h. The mixture was poured into water. The aqueous phase was extracted with DCM. The combined organic layers were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated to remove most of the solvent. The suspension was filtered, and the filtrate was concentrated to give 3-(dimethylamino)pyrazine-2-sulfonyl chloride (3.10 g, crude).

[0259] N-(7-chloroquinolin-8-yl)-3-(dimethylamino)pyrazine-2-sulfonamide. To a mixture of 7-chloroquinolin-8-amine (550.00 mg, 3.08 mmol) in THF (20 mL) was added sodium hexamethyldisilazane (1 M, 10.3 mL) under N protection at −65° C. The mixture was stirred at 25° C. for 0.5 hours. Then, to the mixture was added a solution of 3-(dimethylamino)pyrazine-2-sulfonyl chloride (2.28 g, 10.3 mmol) in THF (10 mL) at −65° C. The mixture was stirred at 25° C. for 1 hour. The mixture was quenched with water. The product was isolated and purified by standard methods to give N-(7-chloro-8-quinolyl)-3-(dimethylamino)pyrazine-2-sulfonamide (303.00 mg, 0.816 mmol, 27% yield, 98% purity). MS(ESI) m / z 364 [M+1] + .

[0260] Example 4. N-(7-chloroquinolin-8-yl)-1-isopropyl-1H-pyrazole-5-sulfonamide [ka] Lithium 1-isopropyl-1H-pyrazole-5-sulfinate. To a solution of 1-isopropyl-1H-pyrazole (1.50 g, 13.6 mmol) in diethyl ether (50 mL) in the presence of SO was added n-BuLi (2.5 M, 6.54 mL) at -70°C. The mixture was stirred at -70°C for 0.5 h and at 0°C for 2 h. Excess SO was purged, and the mixture was stirred at -70°C for 1 h. The mixture was then warmed to 20°C. The mixture was filtered, and the filter cake was collected and dried under vacuum to give lithium 1-isopropyl-1H-pyrazole-5-sulfinate (2.40 g, crude).

[0261] 1-Isopropyl-1H-pyrazole-5-sulfonyl chloride. Lithium 1-isopropyl-1H-pyrazole-5-sulfinate (2.40 g, 13.3 mmol) was added to chloroform (40 mL) and water (50 mL) at 0° C., followed by the addition of N-chlorosuccinimide (2.67 g, 19.9 mmol) in portions. The mixture was stirred at 0° C. for 1 hour. The mixture was diluted with cold water (20 mL). The aqueous phase was extracted with chloroform. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 1-isopropyl-1H-pyrazole-5-sulfonyl chloride (1.20 g, 5.64 mmol, 42% yield, 98% purity). 1 H NMR(400MHz,CDCl3)δ 7.62(d,J=1.9Hz,1H),6.98(d,J=2.0Hz,1H),5.28-5.18(m,1H),1.60(s,6H).

[0262] N-(7-chloroquinolin-8-yl)-1-isopropyl-1H-pyrazole-5-sulfonamide. To a solution of 7-chloroquinolin-8-amine (205 mg, 1.15 mmol) in pyridine (4.55 g, 57.5 mmol) was added a mixture of 1-isopropyl-1H-pyrazole-5-sulfonyl chloride (400 mg, 1.92 mmol) in DCM (5 mL) at 0° C. The mixture was stirred at 25° C. for 8 hours. The product was isolated and purified by standard methods to give N-(7-chloroquinolin-8-yl)-1-isopropyl-1H-pyrazole-5-sulfonamide (89.25 mg, 0.251 mmol, 22% yield, 98.5% purity). MS (ESI) m / z 351.1 [M+1] + .

[0263] Example 5. N-(7-chloroquinolin-8-yl)-5-methoxypyrazine-2-sulfonamide [ka] N-(7-chloroquinolin-8-yl)-5-methoxypyrazine-2-sulfonamide. To a solution of 5-chloro-N-(7-chloroquinolin-8-yl)pyrazine-2-sulfonamide (150 mg, 0.422 mmol) in MeOH (3 mL) was added sodium methanolate (66 mg, 1.69 mmol) under nitrogen. The mixture was stirred at 60° C. for 2 hours. The product was isolated and purified by standard methods to give N-(7-chloroquinolin-8-yl)-5-methoxypyrazine-2-sulfonamide (127.59 mg, 0.354 mmol, 84% yield, 97.3% purity). MS (ESI) m / z 351 [M+1] + .

[0264] Example 6. N-(7-chloroquinolin-8-yl)-6-methoxypyrazine-2-sulfonamide [ka] 2-Chloro-6-((4-methoxybenzyl)thio)pyrazine. To a mixture of (4-methoxyphenyl)methanethiol (5.18 g, 33.6 mmol, 5 mL) in THF (25 mL) was added sodium hydride (2.01 g, 50.3 mmol, 60% purity). The mixture was stirred at 25° C. for 10 minutes. Then, to the mixture was added a solution of 2,6-dichloropyrazine (5.00 g, 33.6 mmol) in THF (15 mL) dropwise with stirring at 25° C. The resulting mixture was stirred at 25° C. for 3 hours. The resulting mixture was quenched with water (50 mL) at 0° C. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give 2-chloro-6-((4-methoxybenzyl)thio)pyrazine (6.33 g, 23.3 mmol, 69% yield, 98% purity).

[0265] 2-Methoxy-6-((4-methoxybenzyl)thio)pyrazine. To a solution of 2-chloro-6-((4-methoxybenzyl)thio)pyrazine (3.00 g, 11.25 mmol) in MeOH (20 mL) was added sodium methanolate (911 mg, 16.9 mmol). The mixture was stirred at 60° C. for 16 hours. The mixture was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 2-methoxy-6-((4-methoxybenzyl)thio)pyrazine (2.90 g, 11.1 mmol, 98% yield).

[0266] 6-Methoxypyrazine-2-sulfonyl chloride. To a mixture of 2-methoxy-6-((4-methoxybenzyl)thio)pyrazine (1.50 g, 5.7 mmol) in DCM (21 mL), HO (6 mL), and acetic acid (3 mL) was added 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (3.38 g, 17.2 mmol) in DCM (12 mL) dropwise over 1 h at −5° C. The mixture was then stirred at 0° C. for 1 h. The mixture was poured into water. The aqueous phase was extracted with DCM. The combined organic layers were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated to remove most of the solvent. The suspension was filtered, and the filtrate was concentrated to give 6-methoxypyrazine-2-sulfonyl chloride (1.50 g, crude).

[0267] N-(7-chloroquinolin-8-yl)-6-methoxypyrazine-2-sulfonamide. To a mixture of 7-chloroquinolin-8-amine (300 mg, 1.68 mmol) in THF (10 mL) was added sodium hexamethyldisilazane (1 M, 5.6 mL) under N protection at −65° C. The mixture was stirred at 25° C. for 0.5 h. Then, a solution of 6-methoxypyrazine-2-sulfonyl chloride (1.17 g, 5.60 mmol) in THF (5 mL) was added to the mixture at −65° C. The mixture was then stirred at 25° C. for 1 h. The product was isolated and purified by standard methods to give N-(7-chloroquinolin-8-yl)-6-methoxypyrazine-2-sulfonamide (97.8 mg, 0.265 mmol, 5% yield, 95.1% purity). MS(ESI)m / z 351[M+1] + .

[0268] Example 7. 1-Ethyl-N-(7-methoxyquinolin-8-yl)-1H-imidazole-2-sulfonamide [ka] 1-((1-Ethyl-1H-imidazol-2-yl)sulfonyl)-1H-benzo[d][1,2,3]triazole. To a mixture of 1-ethyl-1H-imidazole (15.0 g, 156 mmol) in THF (450 mL) was added dropwise a solution of n-butyllithium in hexane (2.5 N, 66 mL, 164 mmol) under nitrogen at −78°C. The resulting reaction mixture was stirred at −78°C for 1 hour. Sulfur dioxide was bubbled through a THF solution of the above organometallic reagent at −78°C until a sample of the solution gave an acidic pH test. The mixture was stirred at that temperature for 15 minutes and then at room temperature for 1 hour. N-Chlorobenzotriazole (23.0 g, 156 mmol) was added in one portion, and the mixture was stirred at room temperature for 2 hours. TEA (39.4 g, 390 mmol) was added, followed by stirring at room temperature for 16 hours. Water (300 mL) was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate, and filtered. The residue was recrystallized from ethyl acetate to give the title compound (23.0 g, 83.0 mmol, 53% yield).

[0269] 7-Methoxyquinoline. To a slurry of sodium hydride (3.50 g, 86.2 mmol) in dry DMF (100 mL) at 0 °C, quinolin-7-ol (5.0 g, 34.5 mmol) in dry DMF (200 mL) was added. The mixture was stirred for 1 hour and then allowed to warm to room temperature. Iodomethane (9.80 g, 69.0 mmol) was added, and the mixture was stirred for 16 hours. The reaction mixture was then poured into ice water and extracted with ethyl acetate. The combined extracts were washed with brine, dried, and concentrated to give the crude product, which was purified by silica gel column chromatography to give the title compound (2.75 g, 17.3 mmol, 50% yield).

[0270] 7-Methoxy-8-nitroquinoline. Chilled concentrated sulfuric acid (7.5 mL) was added to 7-methoxyquinoline (2.75 g, 17.29 mmol) at 0 °C. Concentrated nitric acid (5.8 mL) was added dropwise while maintaining the temperature below 0 °C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured onto ice and neutralized with ammonium hydroxide. The yellow precipitate was filtered to give the desired product (2.80 g, 13.7 mmol, 79% yield).

[0271] 7-Methoxyquinolin-8-amine. To a solution of 7-methoxy-8-nitroquinoline (1.00 g, 4.88 mmol) in MeOH (20 mL) and THF (20 mL) was added palladium on charcoal (200 mg, 10%). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours and filtered through Celite. The filtrate was concentrated in vacuo to give the desired product (790 mg, 0.25 mmol, 92% yield).

[0272] 1-Ethyl-N-(5-methoxyquinolin-8-yl)-1H-imidazole-2-sulfonamide. To a solution of 7-methoxyquinolin-8-amine (200 mg, 1.15 mmol) in THF (5 mL) was slowly added a solution of sodium bis(trimethylsilyl)amide in THF (2 M, 1.15 mL, 2.30 mmol) at −78° C. under nitrogen. The resulting reaction mixture was stirred at that temperature for 1 hour, and then a solution of 1-((1-ethyl-1H-imidazol-2-yl)sulfonyl)-1H-benzo[d][1,2,3]triazole (400 mg, 1.44 mmol) in THF (8 mL) was added at −78° C. The resulting solution was then stirred at room temperature for 1 hour. The reaction mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative HPLC to give the title compound (102.2 mg, 0.308 mmol, 27% yield). MS (ESI) m / z 332.8 [M+1] + .

[0273] Example 8. 1-Ethyl-N-(3-methylquinolin-8-yl)-1H-imidazole-2-sulfonamide [ka] 1-((1-Ethyl-1H-imidazol-2-yl)sulfonyl)-1H-benzo[d][1,2,3]triazole. To a solution of 1-ethyl-1H-imidazole (15.0 g, 156 mmol) in THF (450 mL) was added dropwise a solution of n-BuLi in hexane (2.5 N, 66 mL, 164 mmol) under nitrogen at −78°C. The resulting reaction mixture was stirred at −78°C for 1 hour. Sulfur dioxide was bubbled through the THF solution of the organometallic reagent at −78°C until a sample of the solution gave a pH acidity test. The mixture was stirred at that temperature for 15 minutes and then at room temperature for 1 hour. N-Chlorobenzotriazole (23.0 g, 156 mmol) was added in one portion, and the mixture was stirred at room temperature for 2 hours. Triethylamine (39.4 g, 390 mmol) was added, followed by stirring at room temperature for 16 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was recrystallized from ethyl acetate to give the title compound (23.0 g, 83.0 mmol, 53% yield). MS (ESI) m / z 278.1 [M+H] + .

[0274] 1-Ethyl-N-(3-methylquinolin-8-yl)-1H-imidazole-2-sulfonamide. To a solution of 3-methylquinolin-8-amine (200 mg, 1.26 mmol) in THF (5 mL) was slowly added a solution of sodium bis(trimethylsilyl)amide in THF (2 M, 1.25 mL, 2.50 mmol) at −78° C. under nitrogen. The resulting reaction mixture was then stirred at that temperature for 1 hour, and a solution of 1-ethyl-N-(4-methoxyquinolin-8-yl)-1H-imidazole-2-sulfonamide (400 mg, 1.44 mmol) in THF (8 mL) was added at −78° C. The resulting solution was stirred at room temperature for 1 hour. The product was isolated and purified by standard methods to give the title compound (59.6 mg, 0.189 mmol, 14% yield). 1H NMR(400MHz,DMSO-d6)δ 8.36(s,1H),8.18(s,1H),7.67-7.56(m,2H),7.38-7.32(m,2H),6.62(s,1H)4.42-4.39(m,2H),2.24(s,3H),1.42(t,J=6.8Hz,3H).MS(ESI)m / z 316.8[M+H] + .Purity = 98.6% at 214nm, Purity = 96.6% at 254nm.

[0275] Example 9. N-(6-fluoroquinolin-8-yl)-5-methylpyridine-2-sulfonamide [ka] 2-(Benzylthio)-5-methylpyridine. To a solution of phenylmethanethiol (23.3 g, 188 mmol) in anhydrous THF (200 mL) was added sodium hydride (60% in mineral oil, 8.28 g, 207 mmol) in portions at 0 °C. The resulting mixture was then stirred at room temperature for 1 hour, and 2-chloro-5-methylpyridine (20.0 g, 157 mmol) was added in portions at 0 °C. The resulting mixture was stirred at 70 °C for 30 hours. The reaction was treated with water, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (1% ethyl acetate in petroleum ether) to give the desired compound (10.5 g, 50% purity, 24.4 mmol, 16% yield).

[0276] 5-Methylpyridine-2-sulfonyl chloride. Chlorine was bubbled through a solution of 2-(benzylthio)-5-methylpyridine (3.0 g, 50% pure crude material, 6.98 mmol) in acetic acid (20 mL), DCM (20 mL), and water (7 mL) at 0 °C for 0.5 h. The resulting mixture was then stirred at that temperature for 1 h. The reaction mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated to give the crude product (3.2 g), which was used in the next step without further purification.

[0277] 6-Fluoroquinolin-8-amine. Palladium on charcoal (10 mg, 10%) was added to a solution of 6-fluoro-8-nitroquinoline (100 mg, 0.52 mmol) in MeOH (5 mL). The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give the crude product (110 mg, 80% purity), which was used in the next step without further purification.

[0278] N-(6-Fluoroquinolin-8-yl)-5-methylpyridine-2-sulfonamide. To a solution of 6-fluoroquinolin-8-amine (100 mg, crude) in THF (3 mL) was slowly added a solution of sodium bis(trimethylsilyl)amide in THF (2 M, 0.50 mL, 1.0 mmol) at −78° C. under nitrogen. The resulting solution was stirred at −78° C. for 1 hour. Crude 5-methylpyridine-2-sulfonyl chloride (300 mg crude material) was then added to the above solution. The resulting solution was stirred at −78° C. and then at room temperature for 1 hour. The reaction mixture was quenched with aqueous ammonium chloride and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative HPLC to give the desired compound (26.1 mg, 0.0822 mmol, 16% yield for two steps). MS(ESI)m / z 317.8[M+1] + .

[0279] Example 10. N-(7-chloroquinolin-8-yl)-3-(dimethylamino)pyridine-2-sulfonamide [ka] Lithium 3-fluoropyridine-2-sulfinate. To a solution of 2-bromo-3-fluoropyridine (2.00 g, 11.4 mmol) in diethyl ether (30 mL) was added butyllithium (2.5 M, 5.5 mL) at -70°C. The mixture was stirred at -70°C for 1 hour. Excess sulfur dioxide was purged, and the mixture was stirred at -70°C for 1 hour. A yellow solid formed. The mixture was filtered, and the filter cake was dried under vacuum to give lithium 3-fluoropyridine-2-sulfinate (1.90 g, crude).

[0280] 3-Fluoropyridine-2-sulfonyl chloride. Lithium 3-fluoropyridine-2-sulfinate (1.90 g, 11.4 mmol) was added in portions to chloroform (40 mL) and water (50 mL) at 0 °C. NCS (3.04 g, 22.7 mmol) was then added in portions to the above mixture. This mixture was stirred at 0 °C for 1 hour. The resulting mixture was extracted with chloroform. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 3-fluoropyridine-2-sulfonyl chloride (2.00 g, 6.13 mmol, 54% yield, 60% purity).

[0281] N-(7-chloroquinolin-8-yl)-3-methylpyrazine-2-sulfonamide. To a mixture of 7-chloroquinolin-8-amine (328 mg, 1.84 mmol) in THF (20 mL) was added sodium bis(trimethylsilyl)amide (1 M, 12.3 mL) dropwise under nitrogen at −65° C. The mixture was stirred at 25° C. for 0.5 hours. Then, 3-fluoropyridine-2-sulfonyl chloride (2.00 g, 6.13 mmol) in THF (10 mL) was added dropwise to the above mixture under nitrogen at −65° C. The mixture was stirred at 25° C. for 1 hour. The resulting mixture was added to saturated ammonium chloride. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography to give N-(7-chloroquinolin-8-yl)-3-fluoropyridine-2-sulfonamide (500 mg, 1.32 mmol, 22% yield, 89% purity).

[0282] N-(7-chloroquinolin-8-yl)-3-(dimethylamino)pyridine-2-sulfonamide. To a mixture of N-(7-chloroquinolin-8-yl)-3-fluoropyridine-2-sulfonamide (423 mg, 1.11 mmol) and N-methylmethanamine hydrochloride (545 mg, 6.69 mmol) in DMSO (5 mL) was added N-ethyl-N-isopropyl-propan-2-amine (1.44 g, 11.2 mmol). The mixture was stirred at 80° C. for 54 hours. The product was isolated and purified by standard methods to give N-(7-chloroquinolin-8-yl)-3-(dimethylamino)pyridine-2-sulfonamide (137.92 mg, 0.371 mmol, 33% yield, 97.5% purity). MS (ESI): m / z 363.0 [M+1] + .

[0283] Example 11. N-(6-hydroxyquinolin-8-yl)pyridine-2-sulfonamide [ka] N-(6-Methoxyquinolin-8-yl)pyridine-2-sulfonamide. To a solution of 6-methoxyquinolin-8-amine (200 mg, 1.14 mmol) in pyridine (6 mL) was added pyridine-2-sulfonyl chloride (305 mg, 1.17 mmol). The reaction mixture was heated in a microwave at 130° C. for 5 minutes. The reaction was cooled to room temperature and quenched with water. The solid product was filtered and washed with water and diethyl ether to give the desired product (330 mg, 1.04 mmol, 91% yield).

[0284] N-(6-hydroxyquinolin-8-yl)pyridine-2-sulfonamide. To a solution of N-(6-methoxyquinolin-8-yl)pyridine-2-sulfonamide (150 mg, 0.47 mmol) in dry DCM (2 mL) was added tribromoborane (297 mg, 1.19 mmol). The resulting reaction mixture was heated at reflux for 16 h. The product was isolated and purified by standard methods to give the desired product (50 mg, 0.16 mmol, 35% yield) as a pink powder. MS (ESI) m / z 302 [M+1] + .

[0285] Example 12. N-(6-fluoroquinolin-8-yl)-3,5-dimethylbenzenesulfonamide [ka] 6-Fluoro-8-nitroquinoline. Propane-1,2,3-triol (14 mL) was preheated to 160°C for 1 hour and then cooled to 80°C. 4-Fluoro-2-nitroaniline (10.0 g, 64 mmol) and sodium iodide (200 mg, 1.28 mmol) were added, and the mixture was heated to 150°C. Concentrated sulfuric acid (8.4 mL) was then added dropwise. The reaction was stirred at 150°C for 45 minutes. After the reaction was complete, the mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate, dried over sodium sulfate, and concentrated. The residue was washed with MeOH / hexane (1:10) to give the desired product (4.0 g, 20.8 mmol, 33% yield).

[0286] 6-Fluoroquinolin-8-amine. To a suspension of 6-fluoro-8-nitroquinoline (4.0 g, 20.8 mmol) in EtOH (100 mL) was added tin dichloride (9.40 g, 41.7 mmol). The resulting mixture was heated to reflux for 2 hours. After the reaction was complete, sodium hydroxide (3.5 g, 83.4 mmol) in water (100 mL) was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the desired product as a yellow solid (1.2 g, 7.4 mmol, yield: 35%).

[0287] N-(6-Fluoroquinolin-8-yl)-3,5-dimethylbenzenesulfonamide. To a solution of 3,5-dimethylbenzene-1-sulfonyl chloride (180 mg, 1.0 mmol) in pyridine (5 mL) was added 6-fluoroquinolin-8-ylamine (163 mg, 1.0 mmol). The mixture was stirred at room temperature overnight. The product was isolated and purified by standard methods to give the desired product (28.4 mg, 0.86 mmol, yield: 8.6%). MS (ESI) m / z 331 [M+1] + .

[0288] Example 13. 3-(N-(5-morpholinoquinolin-8-yl)sulfamoyl)benzamide [ka] 4-(8-Nitroquinolin-5-yl)morpholine. 5-Chloro-8-nitroquinoline (600 mg, 2.88 mmol) was suspended in morpholine (3 mL), and the mixture was irradiated in a microwave oven at 100 °C for 10 min. After cooling to room temperature, the residue was concentrated and washed with hexane to give the desired product, which was used in the next step without further purification (480 mg, 64% yield, 1.84 mmol).

[0289] 5-Morpholinoquinolin-8-amine. Palladium on carbon (100 mg, 10%) was added to a solution of 4-(8-nitroquinolin-5-yl)morpholine (480 mg, 1.84 mmol) in MeOH (10 mL). The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated to give the desired product, which was used in the next step without further purification. (405 mg, yield: 95%, 1.76 mmol).

[0290] 3-Cyano-N-(5-morpholinoquinolin-8-yl)benzenesulfonamide. To a solution of 5-morpholinoquinolin-8-amine (92 mg, 0.40 mmol) in pyridine (2 mL) was added 3-cyanobenzene-1-sulfonyl chloride (81 mg, 0.40 mmol), and the reaction mixture was stirred at room temperature overnight. Concentration in vacuo gave the crude product, which was purified by silica gel column chromatography to give the desired product (118.7 mg, 0.30 mmol, 75% yield).

[0291] 3-(N-(5-morpholinoquinolin-8-yl)sulfamoyl)benzamide. To a solution of 3-cyano-N-(5-morpholinoquinolin-8-yl)benzenesulfonamide (118.7 mg, 0.30 mmol) in dimethyl sulfoxide (2 mL) was added potassium carbonate (83 mg, 0.60 mmol) and hydrogen peroxide (31 mg, 0.90 mmol). The reaction mixture was stirred at room temperature for 2 hours. The product was isolated and purified by standard methods to give the title compound (71.7 mg, 0.17 mmol, 57% yield). MS (ESI) m / z 413.2 [M+1] + .

[0292] Example 14. 4-Methyl-N-(6-methylquinolin-8-yl)benzenesulfonamide [ka] 6-Methyl-8-nitroquinoline. Glycerol (3.25 mL, 44.5 mmol) was preheated to 165°C for 1 hour and cooled to 150°C. 4-Methyl-2-nitroaniline (2.5 g, 16.5 mmol) and sodium iodide (100 mg, 0.7 mmol) were added, followed by sulfuric acid (2.1 mL, 39 mmol) at 150°C over 10 minutes. The reaction mixture was stirred at 150°C for 2 hours. The resulting reaction mixture was carefully poured into ice-cold water, and the precipitate was collected by filtration. The resulting solid was recrystallized in 10% ethyl acetate and petroleum ether to give the desired product (1 g, 90% pure by LC-MS, 5.31 mmol, 32% yield).

[0293] 6-Methylquinolin-8-amine. To a solution of 6-methyl-8-nitroquinoline (1 g, 5.31 mmol) in EtOH (20 mL) was added tin(II) chloride (4.01 g, 21.27 mmol). The resulting reaction mixture was heated to reflux for 35 minutes and then cooled to room temperature. The reaction mixture was poured into 10% aqueous sodium hydroxide solution (15 mL) and extracted with ethyl acetate. The combined organic layers were washed with 10% sodium hydroxide solution, water, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the desired product (800 mg, 5.06 mmol, 94% yield, 90% pure by LC-MS).

[0294] 4-Methyl-N-(6-methylquinolin-8-yl)benzenesulfonamide. To a solution of 6-methylquinolin-8-amine (200 mg, 1.26 mmol) in pyridine (6 mL) was added 4-methylbenzene-1-sulfonyl chloride (359 mg, 1.89 mmol). The resulting reaction mixture was heated in a microwave at 130° C. for 3 minutes, cooled to room temperature, and quenched with water (18 mL). The product was isolated and purified by standard methods to give the desired product (43 mg, 0.13 mmol, 11% yield). MS (ESI) m / z 312.9 [M+1] + .

[0295] Example 15. N-(5-(4-hydroxy-4-phenylpiperidin-1-yl)quinolin-8-yl)-4-methylbenzenesulfonamide [ka] N-(5-(4-hydroxy-4-phenylpiperidin-1-yl)quinolin-8-yl)-4-methylbenzenesulfonamide. A mixture of N-(5-bromoquinolin-8-yl)-4-methylbenzenesulfonamide (500 mg, 1.33 mmol), 4-phenylpiperidin-4-ol (1.14 g, 6.65 mmol), tris(dibenzylideneacetone)dipalladium (61 mg, 0.066 mmol), racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (43.7 mg, 0.066 mmol), and cesium carbonate (0.66 g, 2 mmol) in DMF (2 mL) was heated at 110 °C overnight under a nitrogen atmosphere. The product was isolated and purified by standard methods to give the desired product (16.0 mg, 0.032 mmol, 2.4% yield). MS(ESI)m / z 474.2[M+1] + .

[0296] Example 16. 4-Methyl-N-(3-methylquinolin-8-yl)benzenesulfonamide [ka] 3-Methyl-8-nitroquinoline. To a solution of 3-methylquinoline (1 g, 6.99 mmol) in sulfuric acid (2 mL) was slowly added nitric acid (1 mL) at -5 °C. The resulting solution was stirred at room temperature overnight. The reaction mixture was poured into ice water and adjusted to pH 9 with ammonia. The mixture was filtered, and the cake was dissolved in MeOH (5 mL), heated to reflux for 0.5 h, and slowly cooled to room temperature. The mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography to give the title compound (309 mg, 1.6 mmol, 23% yield).

[0297] 3-Methyl-quinolin-8-amine. A mixture of 3-methyl-8-nitro(nitr)quinoline (300 mg, 1.60 mmol) and palladium on carbon (10%, 30 mg) in MeOH (10 mL) was stirred under a hydrogen atmosphere at 25 °C for 3 hours. The reaction mixture was then filtered over Celite, and the residue was washed with MeOH. The reaction mixture was filtered over Celite and evaporated in vacuo to give the crude product (250 mg, 1.58 mmol, 99% yield), which was used in the next step without further purification.

[0298] 4-Methyl-N-(3-methylquinolin-8-yl)benzenesulfonamide. 3-Methyl-quinolin-8-amine. To a solution of (172 mg, 1.09 mmol) in pyridine (10 mL) was added 4-methyl-benzenesulfonyl chloride (420 mg, 2.2 mmol). The resulting mixture was heated at 100° C. overnight. The product was isolated and purified by standard methods to give the title product (155.5 mg, 0.50 mmol, 46% yield). MS (ESI) m / z 313.1 [M+1] + .

[0299] Example 17. N-(6-fluoroquinolin-8-yl)-3,5-dimethoxybenzenesulfonamide [ka] 3,5-Dimethoxybenzenesulfonyl chloride. To a solution of 1-bromo-3,5-dimethoxy-benzene (1 g, 4.61 mmol) in THF, a 2.5 N solution of n-butyllithium (2 mL, 5 mmol) was added dropwise at 78 °C and stirred at the same temperature for 1 hour. Sulfuryl chloride (0.42 mL, 5.0 mmol) was then added, and the mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water, extracted with DCM, and dried over sodium sulfate. Concentration in vacuo gave the crude product (1.0 g, 50% pure by LC-MS), which was used in the next step without further purification.

[0300] N-(6-Fluoroquinolin-8-yl)-3,5-dimethoxybenzenesulfonamide. 6-Fluoroquinolin-8-amine (684 mg, 4.23 mmol) was added to a solution of 3,5-dimethoxybenzenesulfonyl chloride (1.0 g, 4.23 mmol) in pyridine (2 mL) and stirred overnight at room temperature. The product was isolated and purified by standard methods to give the title product (167 mg, 0.461 mmol, 11% yield). MS (ESI) m / z 363.3 [M+H] + .

[0301] Example 18. N-(6-phenylquinolin-8-yl)pyridine-2-sulfonamide [ka] Pyridine-2-sulfonyl chloride. Pyridine-2-thiol (5.0 g, 45 mmol) was dissolved in 6N aqueous hydrochloric acid (20 mL), and chlorine was bubbled into the mixture at 0 °C for 30 minutes. The mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate and evaporated at low temperature. The resulting residue was used directly in the next step (4.6 g, crude).

[0302] N-(6-phenylquinolin-8-yl)pyridine-2-sulfonamide. Pyridine-2-sulfonyl chloride (180 mg, crude) was added to a solution of 6-phenylquinolin-8-amine (120 mg, 0.545 mmol) in pyridine (3 mL). The mixture was stirred at room temperature overnight. The product was isolated and purified by standard methods to give the title product (36 mg, 0.1 mmol, 18% yield). MS (ESI) m / z 362.1 [M+H] + .

[0303] Example 19. 6-Cyano-pyridine-2-sulfonic acid quinolin-8-ylamide [ka] 2-Bromo-6-(4-methoxybenzylsulfanyl)-pyridine. To a suspension of sodium hydride (60% in oil, 1.01 g, 25.32 mmol) in THF (20 mL) was added (4-methoxyphenyl)methanethiol (1.56 g, 10.13 mmol) at -15 °C. A solution of 2,6-dibromopyridine (3.0 g, 12.66 mmol) in THF (15 mL) was added to the reaction mixture and stirred at 25 °C for 2 hours. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give 2-bromo-6-(4-methoxybenzylsulfanyl)-pyridine (1.2 g, 30%). MS (ESI): m / z 309.9 [M+1] + .

[0304] 6-Bromo-pyridine-2-sulfonic acid quinolin-8-ylamide. 2-Bromo-6-(4-methoxy-benzylsulfanyl)-pyridine (1.2 g, 3.87 mmol) was added dropwise to concentrated sulfuric acid (12 mL) at -30°C, and stirring was continued at 25°C until a clear solution was obtained. This was again cooled to -30°C, and NaOCl solution (10% aq, 36 mL) was added dropwise to the reaction mixture via a dropping funnel. The reaction mixture was slowly warmed to 25°C and stirred for 2 hours. The reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. A crude solution of the sulfonyl chloride in DCM (10 mL) was added to a solution of quinolin-8-amine (279 mg, 1.93 mmol) in DCM (15 mL) and pyridine (3 mL, 38.71 mmol) at 0° C. and stirred for 12 hours. Upon completion, the reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography to give the product 6-bromo-pyridine-2-sulfonic acid quinolin-8-ylamide (930 mg, 66%). MS (ESI): m / z 363.8 [M+1] + .

[0305] 6-Cyano-pyridine-2-sulfonic acid quinolin-8-ylamide. To a degassed solution of 6-bromo-pyridine-2-sulfonic acid quinolin-8-ylamide (400 mg, 1.10 mmol) in DMA (5 mL) in a stirred sealed tube, zinc cyanide (141.8 mg, 117.41 mmol) was added, followed by TMEDA (0.052 mL, 0.329 mmol), Pd(dba) (100 mg, 0.11 mmol), and Xantphos (63.54 mg, 0.11 mmol). The resulting mixture was heated at 80°C for 5 h. The reaction mass was then cooled to 25°C, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 6-cyano-pyridine-2-sulfonic acid quinolin-8-ylamide (25 mg, 8%). MS (ESI): m / z 311.1 [M+1] + .

[0306] Example 20. 6-Phenyl-N-(quinolin-8-yl)pyridine-2-sulfonamide [ka] 2-Bromo-3-phenylpyridine. To a stirring solution of 2-bromo-3-iodopyridine (1.5 gm, 5.28 mmol) in toluene (10 mL) was added EtOH (5 mL), water (2 mL), and potassium carbonate (802 mg, 5.81 mmol), followed by phenylboronic acid (773 mg, 6.34 mmol). The resulting mixture was degassed with argon for 15 minutes, and Pd(PPh3)4 (305 mg, 0.26 mmol) was added under an inert atmosphere. The resulting mixture was heated to 70°C under an argon atmosphere for 4 hours. The reaction mixture was cooled to 25°C and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mass was purified by silica gel column chromatography to give 2-bromo-3-phenylpyridine (250 mg, 20%). MS (ESI): m / z 233.8 [M+1] + .

[0307] 2-{[(4-Methoxyphenyl)methyl]sulfanyl}-3-phenylpyridine. To a stirred solution of 4-methoxybenzylamine (790 mg, 2.56 mmol) in DMSO (10 mL) was added CsF (779 mg, 5.13 mmol) followed by 2-bromo-3-phenylpyridine (600 mg, 2.56 mmol) at 25 °C. The resulting mixture was heated at 80 °C for 3 h. Upon completion, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude mass was purified by flash column chromatography to give 2-{[(4-methoxyphenyl)methyl]sulfanyl}-3-phenylpyridine (600 mg, 76%). MS (ESI): m / z 308.2 [M+1] + .

[0308] 3-Phenylpyridine-2-sulfonyl chloride. A solution of 2-{[(4-methoxyphenyl)methyl]sulfanyl}-3-phenylpyridine (100 mg, 0.32 mmol) in H2SO4 (4 mL) was cooled to -10 °C, and sodium hypochlorite (10% aqueous solution, 10 mL) was added and stirred under cooled conditions for 0.5 h. The reaction mixture was quenched with ice-cold water and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-phenylpyridine-2-sulfonyl chloride (70 mg, crude, 84%).

[0309] 6-Phenyl-N-(quinolin-8-yl)pyridine-2-sulfonamide. To a stirred solution of quinolin-8-amine (22 mg, 0.154 mmol) in pyridine (0.3 mL) was added dropwise a solution of 3-phenylpyridine-2-sulfonyl chloride (65 mg, 0.26 mmol) in DCM (2.5 mL) at 0 °C under an argon atmosphere. The reaction mixture was warmed to 25 °C and stirred for 16 h. Upon completion, the reaction mixture was diluted with DCM. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mass was purified by preparative HPLC to give 6-phenyl-N-(quinolin-8-yl)pyridine-2-sulfonamide (30 mg, 32%). MS (ESI): m / z 362.1 [M+1]+.

[0310] Example 21. 4-Cyclopropyl-N-(1,5-naphthyridin-4-yl)pyridine-2-sulfonamide [ka] 2-Chloro-4-cyclopropylpyridine. To a stirred solution of 4-bromo-2-chloropyridine (1 g, 5.19 mmol) in dioxane (25 mL) and water (2.5 mL) was added potassium carbonate (2.51 g, 18.19 mmol), followed by cyclopropylboronic acid (669 mg, 7.79 mmol). The resulting mixture was degassed with argon and Pd(dppf)Cl. DCM (381 mg, 0.52 mmol) was added under an inert atmosphere. The resulting mixture was heated at 110 °C for 16 h. Upon completion, the reaction mixture was cooled to 25 °C and filtered through a short pad of Celite. The filtrate was concentrated under reduced pressure and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography to give 2-chloro-4-cyclopropylpyridine (700 mg, 88%). MS(ESI):m / z 154.2[M+1] + .

[0311] 4-Cyclopropyl-2-{[(4-methoxyphenyl)methyl]sulfanyl}pyridine. To a stirred solution of (4-methoxyphenyl)methanethiol (2.62 g, 16.99 mmol) in DMSO (20 mL) was added CsF (3.2 g, 21.24 mmol) followed by 2-chloro-4-cyclopropylpyridine (1.3 g, 8.50 mmol) at 25 °C. The resulting mixture was heated at 80 °C for 16 h. Upon completion, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude mass was purified by column chromatography to give 4-cyclopropyl-2-{[(4-methoxyphenyl)methyl]sulfanyl}pyridine (2.1 g, 91%). MS (ESI): m / z 271.9 [M+1] + .

[0312] 4-Cyclopropylpyridine-2-sulfonyl chloride. A solution of 4-cyclopropyl-2-{[(4-methoxyphenyl)methyl]sulfanyl}pyridine (100 mg, 0.37 mmol) in H2SO4 (4 mL) was cooled to -10 °C, and sodium hypochlorite (10% aqueous solution, 10 mL) was added and stirred under cooled conditions for 0.5 h. The reaction mixture was quenched with ice-cold water and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-cyclopropylpyridine-2-sulfonyl chloride (80 mg, crude, 99%).

[0313] 4-Cyclopropyl-N-(1,5-naphthyridin-4-yl)pyridine-2-sulfonamide. To a solution of 1,5-naphthyridin-4-amine (60 mg, 0.41 mmol) in pyridine (3 mL) was added dropwise a solution of 4-cyclopropylpyridine-2-sulfonyl chloride (300 mg, 1.38 mmol) in DCM (3 mL) at 0° C. under an argon atmosphere. The reaction mixture was warmed to 25° C. and stirred for 16 hours. Upon completion, the reaction mixture was diluted with DCM. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mass was purified by preparative HPLC to give 4-cyclopropyl-N-(1,5-naphthyridin-4-yl)pyridine-2-sulfonamide (15 mg, 3%). MS (ESI): m / z 327.0 [M+1] + .

[0314] Example 22. N-(3-cyclopropylquinolin-8-yl)-3-methylpyridine-2-sulfonamide [ka] 3-Cyclopropylquinolin-8-amine. To a stirred solution of 3-bromoquinolin-8-amine (100 mg, 0.45 mmol) in toluene-water (10.5 mL, 20:1) in a sealed tube was added cyclopropylboronic acid (116 mg, 1.34 mmol) and K3PO4 (333 mg, 1.57 mmol). After degassing the solution with argon for 10 minutes, tricyclohexylphosphine (19 mg, 0.07 mmol) and Pd(OAc)2 (10 mg, 0.05 mmol) were added under an inert atmosphere. The resulting mixture was heated at 110 °C for 16 hours. Upon completion, the reaction mixture was cooled to 25 °C, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by column chromatography to give 3-cyclopropylquinolin-8-amine (70 mg, 84%). MS(ESI):m / z 185.1[M+1] + .

[0315] 3-Methylpyridine-2-sulfonyl chloride. Concentrated H2SO4 (6.4 mL) was added dropwise to 2-{[(4-methoxyphenyl)methyl]sulfanyl}-3-methylpyridine (400 mg, 1.63 mmol) in a round-bottom flask at -20 °C, and stirring was continued for 15 min. NaOCl (24.11 mL, 359.18 mmol) was added using an addition funnel at -20 °C over 30 min, then slowly warmed to 0 °C over 30 min. Upon completion, the reaction mixture was quenched with cold water and extracted with dry DCM. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to a minimum volume and used directly in the next step.

[0316] N-(3-cyclopropylquinolin-8-yl)-3-methylpyridine-2-sulfonamide. To a stirred solution of 3-cyclopropylquinolin-8-amine (50 mg, 0.27 mmol) in pyridine (2 mL) at 0 °C was slowly added a solution of 3-methylpyridine-2-sulfonyl chloride (104 mg, 0.54 mmol) in DCM (4 mL). The resulting mixture was warmed to 25 °C and stirred for 16 h. Upon completion, the reaction mixture was diluted with DCM, washed with water and brine, dried over Na SO , filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give N-(3-cyclopropylquinolin-8-yl)-3-methylpyridine-2-sulfonamide (24 mg, 26%). MS (ESI): m / z 340.3 [M+1] + .

[0317] Example 23. N-(5-methylquinolin-8-yl)furan-2-sulfonamide [ka] 5-Methyl-8-nitroquinoline. Glycerol (6.5 mL, 89 mmol) was preheated at 165°C for 1 hour and cooled to 150°C. 5-Methyl-2-nitroaniline (5 g, 33 mmol) and sodium iodide (100 mg, 0.7 mmol) were added. Sulfuric acid (4.2 mL, 78 mmol) was then added dropwise over 10 minutes at the same temperature, and the reaction mixture was stirred at 150°C for 5 hours. After cooling to 25°C, the resulting reaction mixture was carefully poured into ice-cold water, and the resulting solid product was filtered off. The collected solid was recrystallized from 10% ethyl acetate in petroleum ether to give 5-methyl-8-nitroquinoline (4 g, 90% purity, 21.27 mmol, 64.7% yield). MS (ESI) m / z 189.0 [M+H] + .

[0318] 5-Methylquinolin-8-amine. To a solution of 5-methyl-8-nitroquinoline (2 g, 10.63 mmol) in EtOH (50 mL) was added tin(II) chloride (8.02 g, 42.55 mmol). The resulting reaction mixture was heated to reflux for 2 hours and cooled to 25 °C. Sodium hydroxide solution (10%, 50 mL) was added, and the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with 10% sodium hydroxide solution, water, and brine. The organic phase was dried over anhydrous sodium sulfate and filtered. Concentration under vacuum gave the crude product (1.5 g, 9.49 mmol, 89.3% yield), which was used in the next step without further purification. MS (ESI) m / z 159.1 [M+H] + .

[0319] N-(5-methylquinolin-8-yl)furan-2-sulfonamide. To a solution of 5-methylquinolin-8-amine (200 mg, 1.26 mmol) in pyridine (6 mL) was added furan-2-sulfonyl chloride (316 mg, 1.89 mmol). After irradiating in a microwave at 130 °C for 3 minutes, the reaction mixture was cooled to 25 °C and then quenched with water. The resulting product was filtered and washed with water and diethyl ether to give the title compound (51 mg, 0.17 mmol, 13% yield). 1H NMR(400MHz,DMSO-d6)δ 10.10(br MS(ESI)m / z 289.0[M+H] + ;Purity: 97.4% at 214nm, 90.2% at 254nm.

[0320] Example 24. N-(5-fluoroquinolin-8-yl)furan-2-sulfonamide [ka] 5-Fluoroquinoline. To a suspension of quinolin-5-amine (1.5 g, 10.4 mmol) in fluoroboric acid (10 mL wt % = 48%) was added sodium nitrite (934 mg, 13.5 mmol) in portions at -5 °C. The mixture was stirred for 1 hour and then poured into a 50% solution of ethyl acetate in petroleum ether. The resulting suspension was filtered, and the filter cake was air-dried. The collected solid was added to refluxing xylene and stirred under reflux for 2 hours, then cooled to 25 °C. The xylene was decanted, and the residue was dissolved in hydrochloric acid (20 mL, 1N). After neutralization with sodium carbonate, the mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give the desired compound (1.1 g, 7.43 mmol, 71% yield). MS (ESI) m / z 148.0. [M+H] + .

[0321] 5-Fluoro-8-nitroquinoline. 5-Fluoroquinoline (300 mg, 2.02 mmol) was dissolved in concentrated sulfuric acid (2 mL) at 0° C., and then nitric acid (1 mL, 65%) was slowly added at −5° C. The mixture was stirred at −5° C. for 1 hour and then at 25° C. overnight. The reaction mixture was poured onto ice, and the resulting mixture was basified to pH 10 with aqueous ammonium hydroxide (10 mL, 11 M) and extracted with ethyl acetate. After removing all volatiles under vacuum, the residue was purified by silica gel column chromatography to provide the title product (168 mg, 0.87 mmol, 43% yield). 1 H NMR (400 MHz, chloroform-d3) δ 8.17-8.15 (m, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.34-7.30 (m, 1H), 6.88-6.84 (m, 1H).

[0322] 5-Fluoroquinolin-8-amine. To a suspension of 5-fluoro-8-nitroquinoline (192 mg, 1.0 mmol) and iron dust (366 mg, 6.0 mmol) in water (8 mL) was added acetic acid (0.5 mL). The resulting mixture was heated at 100° C. for 1.5 hours and then cooled to 25° C. The reaction mixture was basified with solid sodium hydroxide and then treated with ethyl acetate with continued stirring. The collected solid was rinsed with ethyl acetate, and the combined filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to provide the desired product (130 mg, 0.80 mmol, 80% yield). MS (ESI) m / z 163.1 [M+H] + .

[0323] N-(5-fluoroquinolin-8-yl)furan-2-sulfonamide. To a solution of 5-fluoroquinolin-8-amine (100 mg, 0.62 mmol) in pyridine (3 mL) was added furan-2-sulfonyl chloride (113 mg, 0.68 mmol), and the reaction mixture was irradiated in a microwave at 110° C. for 15 minutes. After removing all volatiles in vacuo, the residue was purified by silica gel column chromatography to give the desired product (54.3 mg, 0.19 mmol, 31% yield). 1H NMR (400 MHz, chloroform-d) δ 9.10 (s, 1H), 8.84 (dd, J = 4.4, 1.6 Hz, 1H), 8.40 (dd, J = 8.8, 1.6 Hz, 1H), 7.80-7.77 (m, 1H), 7.54-7.51 (m, 1H), 7.39 (s, 1H), 7.17 (t, J = 8.8 Hz, 1H), 7.07 (d, J = 3.6 Hz, 1H), 6.35 (m, 1H); MS (ESI) m / z 293.0 [M+H] + ; Purity = 99.2% at 254nm.

[0324] Example 25. N-(5-morpholinoquinolin-8-yl)-1H-pyrazole-4-sulfonamide [ka] 4-(8-Nitroquinolin-5-yl)morpholine. 5-Chloro-8-nitroquinoline (600 mg, 2.88 mmol) was suspended in morpholine (3 mL), and the mixture was irradiated in a microwave oven at 100 °C for 10 min. After cooling to 25 °C, the residue was concentrated and washed with hexane (20 mL) to give the desired product, which was used in the next step without further purification (480 mg, 64% yield, 1.84 mmol). MS (ESI) m / z 260.1 [M+H] + .

[0325] 5-Morpholinoquinolin-8-amine. Palladium on carbon (100 mg, 10%) was added to a solution of 4-(8-nitroquinolin-5-yl)morpholine (480 mg, 1.84 mmol) in MeOH (10 mL). The mixture was stirred overnight at 25° C. under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated to give the desired product, which was used in the next step without further purification (405 mg, yield: 95%, 1.76 mmol). MS (ESI) m / z 230.1 [M+H] + .

[0326] N-(5-morpholinoquinolin-8-yl)-1H-pyrazole-4-sulfonamide. To a solution of 5-morpholinoquinolin-8-amine (80 mg, 0.35 mmol) in pyridine (2 mL) was added 1H-pyrazole-4-sulfonyl chloride (58 mg, 0.35 mmol), and the reaction mixture was stirred at 25° C. for 16 hours. The solution was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography to give the desired product (25.7 mg, 0.072 mmol, 21% yield). 1 H NMR(400MHz, methanol-d)δ 8.93-8.88(m,2H),7.85(s,2H),7.75-7.71(m,1H),7.59(d,J=8.8Hz,1H) ,7.26(d,J=8.8Hz,1H),3.95-3.93(m,4H),3.09-3.07(m,4H);MS(ESI)m / z 360.1[M+H] + ;Purity: 96.5% at 214nm.

[0327] Example 26. N-(quinazolin-8-yl)pyridine-2-sulfonamide [ka] N-(quinazolin-8-yl)pyridine-2-sulfonamide. Quinazolin-8-amine (175 mg, 1.206 mmol), pyridine-2-sulfonyl chloride (257 mg, 1.447 mmol), and pyridine (5 mL, 61.8 mmol) were combined and stirred at 25° C. for 48 hours. The reaction was heated at 70° C. for 3 hours. The crude material was purified by column chromatography. This crude material was dissolved in MeOH, filtered through a frit to remove insoluble material, and then purified directly on a semi-preparative HPLC. The product fractions were combined and concentrated under reduced pressure. The product was dissolved in MeOH, washed through a resin column, eluted with MeOH, and condensed to give N-(quinazolin-8-yl)pyridine-2-sulfonamide (27.4 mg, 0.096 mmol, 7.94% yield). 1H NMR(400MHz,DMSO-d6)δ ppm 10.34(s,1H),9.60(s,1H),9.23(s,1H),8.59(dt,J=4.69,1.17Hz,1H),7.98-8.09(m, 3H),7.89(dd,J=8.20,1.17Hz,1H),7.68-7.74(m,1H),7.59-7.65(m,1H);MS(ESI)m / z 287.0[M+1] +

[0328] Example 27. N-(quinolin-8-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-sulfonamide [ka] [1,2,4]Triazolo[4,3-a]pyridine-3-sulfonyl chloride. To a solution of 3-bromo-[1,2,4]triazolo[4,3-a]pyridine (530 mg, 2.68 mmol), a solution of n-butyllithium in hexane (1.1 mL, 2.75 mmol, 2.5 N) was added dropwise at −78° C. under nitrogen. After stirring the mixture at −78° C. for 1 hour, sulfuryl chloride (359 mg, 2.68 mmol) was slowly added. The resulting mixture was stirred at 25° C. for 1 hour. The reaction was quenched with water, and the aqueous layer was extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to give the desired crude product (430 mg, crude), which was carried on to the next step without further purification. MS (ESI) m / z 218.0 [M+H] + .

[0329] N-(quinolin-8-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-sulfonamide. To a solution of quinolin-8-amine (70 mg, 0.48 mmol) in pyridine (1.5 mL) was added N-(quinolin-8-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-sulfonamide (430 mg, crude) at 0° C. The reaction was stirred at 25° C. for 16 hours. The reaction was concentrated, and the residue was purified by high-performance liquid chromatography to give the desired product (5.6 mg, 0.017 mmol, 3.5%). 1H NMR(400MHz,DMSO-d6)δ 9.00(d,J=4.4Hz,1H),8.59(d,J=8.4Hz,1H),8.32(d,J=6.4Hz,1H),7.97(d,J=7.2H z,1H),7.73-7.52(m,4H),7.38(t,J=8.0Hz,1H),6.70(t,J=7.2Hz,1H).MS(ESI)m / z 325.8[M+H] + .Purity=98.7% at 214nm, Purity=97.3% at 254nm.

[0330] Example 28. N-(quinolin-8-yl)pyrimidine-4-sulfonamide [ka] Pyrimidine-4-thiol. A mixture of pyrimidin-4-ol (7.00 g, 72.9 mmol) and phosphorus pentasulfide (16.24 g, 73.15 mmol) in pyridine (105 mL) was stirred under reflux for 3 hours. The reaction mixture was concentrated, and the residue was treated with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the desired product (7.00 g, 62.5 mmol, 85% yield). 1 H NMR(400MHz,DMSO-d6)δ 14.11(br,1H),8.29(s,1H),7.86(d,J=6.4Hz,1H),7.18(d,J=6.4Hz,1H).MS(ESI)m / z 113.0[M+H] + .

[0331] N-(quinolin-8-yl)pyrimidine-4-sulfonamide. To a stirred mixture of aqueous hydrochloric acid (2N, 89 mL) and DCM (118 mL) cooled to −5°C (internal temperature), precooled (−5°C) sodium hypochlorite (10% solution, 1.55 M, 78 mL, 122.7 mmol) was added at a rate to maintain the temperature below 0°C. Pyrimidine-2-thiol (4.00 g, 35.7 mmol) was added portionwise while maintaining the internal temperature between −10°C and −5°C. After the addition was complete, the mixture was stirred at 10°C to −5°C for 20 min. Excess chlorine was quenched by the addition of cold (0°C) aqueous sodium sulfite (1 M) until the mixture's yellowish-green color disappeared and iodide paper (potassium iodide / starch) no longer rapidly developed color. The reaction mixture was then transferred to a separatory funnel (pre-cooled in a freezer or with ice water), and the organic layer was quickly separated and collected in a clean flask. The aqueous phase was quickly extracted with cold (-10 °C) DCM. The combined organic extracts were dried over magnesium sulfate under a nitrogen atmosphere and cooled in a dry ice-acetone bath. A solution of sodium bis(trimethylsilyl)amide in THF (2 M, 2.1 mL, 4.20 mmol) was slowly added to a solution of quinolin-8-ylamine (400 mg, 2.78 mmol) in THF (1 mL) at -78 °C under nitrogen and stirred for an additional 1 h. The solution of pyrimidine-4-sulfonyl chloride in DCM obtained above was then quickly filtered and added to the above solution. After 1 h, the reaction mixture was quenched with aqueous ammonium chloride and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by high performance liquid chromatography to give the desired product (11.0 mg, 0.038 mmol, 1% yield). 1 H NMR(400MHz,MeOH-d4)δ 9.13,(s,1H),8.99(d,J=4.8Hz,1H),8.79(dd,J=4.4Hz,1.2Hz,1H),8.26(d,J=8.0Hz,1H),8.0 5(d,J=4.8Hz,1H),7.89(d,J=7.6Hz,1H),7.63(d,J=8.4Hz,1H),7.52-7.46(m,2H).MS(ESI)m / z 287.0[M+H] +.Purity = 97.4% at 214nm, Purity = 98.0% at 254nm.

[0332] Example 29. 1-Ethyl-N-(5-methoxyquinolin-8-yl)-1H-imidazole-2-sulfonamide [ka] 1-((1-Ethyl-1H-imidazol-2-yl)sulfonyl)-1H-benzo[d][1,2,3]triazole. To a solution of 1-ethyl-1H-imidazole (15.0 g, 156 mmol) in THF (450 mL) was added dropwise a solution of n-butyllithium in hexane (2.5 N, 66 mL, 164 mmol) under nitrogen at −78°C. The resulting reaction mixture was stirred at −78°C for 1 hour. Sulfur dioxide was bubbled through the THF solution of the above organometallic reagent at −78°C until a sample of the solution gave a pH acidity test. The mixture was stirred at that temperature for 15 minutes and then at 25°C for 1 hour. N-Chlorobenzotriazole (23.0 g, 156 mmol) was added in one portion, and the mixture was stirred at 25°C for 2 hours. Triethylamine (39.4 g, 390 mmol) was added, followed by stirring at 25°C for 16 hours. Water was added, and the solution was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate, and filtered. After concentration, the residue was recrystallized from ethyl acetate to give the title compound (23.0 g, 83.0 mmol, 53% yield). MS (ESI) m / z 278.1 [M+H] + .

[0333] 1-Ethyl-N-(5-methoxyquinolin-8-yl)-1H-imidazole-2-sulfonamide. To a solution of 5-methoxyquinolin-8-amine (200 mg, 1.15 mmol) in THF (5 mL) was slowly added a solution of sodium bis(trimethylsilyl)amide in THF (2 M, 1.15 mL, 2.30 mmol) at −78° C. under nitrogen. The resulting reaction mixture was then stirred at that temperature for 1 hour, and a solution of 1-((1-ethyl-1H-imidazol-2-yl)sulfonyl)-1H-benzo[d][1,2,3]triazole (400 mg, 1.44 mmol) in THF (8 mL) was added at −78° C. The resulting solution was then stirred at 25° C. for 1 hour. The reaction mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative high performance liquid chromatography to give the title compound (15.6 mg, 0.047 mmol, 4% yield). 1 H NMR(400MHz,DMSO-d6)δ 10.09(brs,1H),8.79(dd,J1=4.4Hz,J2=1.6Hz,1H),8.49(dd,J1=8.0Hz,J2=1.2Hz,1H),7.65(d,J=8.4Hz,1H),7.52(dd,J1=8.4Hz,J2=4.0Hz, 1H),7.39(d,J=0.8Hz,1H),7.03(d,J=8.4Hz,1H),6.85(d,J=1.2Hz,1H),4.30(q,J=7.2Hz,2H),3.96(s,3H),1.31(t,J=7.2Hz,3H).MS(ESI)m / z 332.8[M+H] + .Purity=98.6% at 214nm, Purity=98.6% at 254nm.

[0334] Example 30. 5-Methyl-N-(quinoxalin-5-yl)pyridine-2-sulfonamide [ka] 2-(Benzylthio)-5-methylpyridine. To a solution of phenylmethanethiol (23.3 g, 188 mmol) in anhydrous THF (200 mL) was added sodium hydride (60% in mineral oil, 8.28 g, 207 mmol) in portions at 0 °C. The resulting mixture was stirred at 25 °C for 1 hour, and 2-chloro-5-methylpyridine (20.0 g, 157 mmol) was added in portions at 0 °C. The resulting mixture was stirred at 70 °C for 30 hours. The reaction was treated with water, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the desired compound (10.5 g, 50% purity, 24.4 mmol, 16% yield). MS (ESI) m / z 216.1 [M+H] + .

[0335] 5-Methylpyridine-2-sulfonyl chloride. Chlorine was bubbled through a solution of 2-(benzylthio)-5-methylpyridine (3.0 g, 50% pure crude material, 6.98 mmol) in acetic acid (20 mL), DCM (20 mL), and water (7 mL) at 0° C. for 30 minutes. The resulting mixture was then stirred at that temperature for 1 hour. The reaction was diluted with DCM, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated to give the crude product (3.2 g), which was used in the next step without further purification. MS (ESI) m / z 191.9 [M+H] + .

[0336] 5-Methyl-N-(quinoxalin-5-yl)pyridine-2-sulfonamide. To a solution of quinoxalin-5-amine (200 mg, 1.38 mmol) in anhydrous THF (3 mL) was slowly added a solution of sodium bis(trimethylsilyl)amide in THF (2 M, 1.38 mL, 2.76 mmol) under nitrogen at −78°C. After stirring the mixture at −78°C for 1 hour, crude 5-methylpyridine-2-sulfonyl chloride (500 mg, crude) was added. The mixture was stirred at 25°C for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to give the desired product, which was purified by preparative high-performance liquid chromatography to give the desired product (14.8 mg, 0.049 mmol, 4% yield). 1 H NMR(400MHz,DMSO-d6)δ 10.20(brs,1H),8.98(d,J=1.6Hz,1H),8.87(d,J=2.0Hz,1H),8.43(s,1H),7.95(d,J=8.4Hz,1H),7.85-7.77(m,4H),2.32(s,3H).MS(ESI)m / z 300.8[M+H] + .Purity = 98.3% at 214nm, Purity = 98.1% at 254nm.

[0337] Example 31. 3-Ethyl-N-(5-morpholino-8-quinolyl)imidazole-4-sulfonamide [ka] (3-Ethylimidazol-4-yl)sulfinyloxylithium. To a solution of 1-ethylimidazole (10 g, 104.03 mmol) in diethyl ether (100 mL) was slowly added n-butyllithium (54.27 mL, 124.83 mmol) under nitrogen at −70° C. This mixture was stirred at −70° C. for 30 minutes and at 0° C. for 30 minutes. Excess sulfur dioxide was then bubbled in, and the mixture was stirred at −70° C. for 1 hour. The mixture was then warmed to 25° C., filtered, and the filter cake was dried under vacuum to give crude (3-ethylimidazol-4-yl)sulfinyloxylithium (17 g, crude).

[0338] 3-Ethylimidazole-4-sulfonyl chloride. To a solution of (3-ethylimidazol-4-yl)sulfinyloxylithium (17 g, crude) in chloroform (100 mL) and water (100 mL) was added NCS (13.66 g, 102.33 mmol) at 0 °C, and the mixture was stirred at 0 °C for 1 hour. The mixture was diluted with cold water, and the aqueous phase was extracted with chloroform. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 3-ethylimidazole-4-sulfonyl chloride (3.5 g, 17.982 mmol, 17.573% yield). LCMS (ESI): m / z 195.0 [M+1] + .

[0339] 3-Ethyl-N-(5-morpholino-8-quinolyl)imidazole-4-sulfonamide. To a solution of 5-morpholinoquinolin-8-amine (294.49 mg, 1.28 mmol) in pyridine (8 mL) was added a solution of 3-ethylimidazole-4-sulfonyl chloride (250 mg, 1.28 mmol) in DCM (2 mL). The mixture was stirred at 25° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by flash silica gel chromatography to give the crude product, which was further purified by preparative HPLC followed by lyophilization to give 3-ethyl-N-(5-morpholino-8-quinolyl)imidazole-4-sulfonamide (63.21 mg, 0.1625 mmol, 12.651% yield, 99.6% purity). 1 H NMR(400MHz,DMSO-d6)δ 8.82(dd,J1=4.2,J2=1.6Hz,1H),8.50(dd,J1=8.4,J2=1.5Hz,1H),7.84(s,1H),7.58-7.50(m,2H),7.24(d,J=1.0Hz,1H), 7.17(d,J=8.2Hz,1H),4.31(q,J=7.1Hz,2H),3.85-3.81(m,4H),3.02-2.89(m,4H),1.35(t,J=7.2Hz,3H);LCMS(ESI):m / z 388.1[M+1] - .

[0340] Example 32. N-(5-chloro-8-quinolyl)-3-isopropyl-imidazole-4-sulfonamide [ka] (3-Isopropylimidazol-4-yl)sulfinyloxylithium. To a solution of 1-isopropylimidazole (10 g, 90.78 mmol) in diethyl ether (150 mL) was slowly added n-butyllithium (47.36 mL, 108.93 mmol, 2.5 M in THF) under nitrogen at −70° C. The mixture was stirred at −70° C. for 30 minutes and at 0° C. for 30 minutes. Excess sulfur dioxide was then bubbled in, and the mixture was stirred at −70° C. for 1 hour. The mixture was then warmed to 25° C., filtered, and the filter cake was dried under vacuum to give crude (3-isopropylimidazol-4-yl)sulfinyloxylithium (16 g, crude).

[0341] 3-Isopropylimidazole-4-sulfonyl chloride. To a solution of (3-isopropylimidazol-4-yl)sulfinyloxylithium (16 g, 88.81 mmol) in chloroform (100 mL) and water (100 mL) was added NCS (11.86 g, 88.81 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was diluted with cold water, and the aqueous phase was extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 3-isopropylimidazole-4-sulfonyl chloride (1.4 g, 6.7092 mmol, 7.5541% yield). 1 H NMR(400MHz,DMSO-d6)δ 9.30(d,J=1.5Hz,1H),7.66(d,J=1.5Hz,1H),5.22-5.11(m,1H),1.50(d,J=6.8Hz,6H).

[0342] N-(5-chloro-8-quinolyl)-3-isopropyl-imidazole-4-sulfonamide. To a solution of 5-chloroquinolin-8-amine (200 mg, 1.12 mmol) in pyridine (4 mL) was added a solution of 3-isopropylimidazole-4-sulfonyl chloride (233.65 mg, 1.12 mmol) in DCM (1 mL). The mixture was stirred at 25° C. for 16 hours. The mixture was diluted with 10% citric acid (50 mL), and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue which was purified by preparative HPLC followed by lyophilization to give N-(5-chloro-8-quinolyl)-3-isopropyl-imidazole-4-sulfonamide (166.84 mg, 0.4670 mmol, 41.709% yield, 98.2% purity). 1 H NMR(400MHz,DMSO-d6)δ 10.65(s,1H),8.96(dd,J1=4.2,J2=1.6Hz,1H),8.55(dd,J1=8.5,J2=1.4Hz,1H),8.07(s,1H),7.79-7 .73(m,2H),7.72-7.66(m,1H),7.37(s,1H),5.04-4.92(m,1H),1.34(d,J=6.7Hz,6H);LCMS(ESI):m / z 351.1[M+1] + .

[0343] Example 33. 3-(Cyclopropylmethyl)-N-(5-morpholino-8-quinolyl)imidazole-4-sulfonamide [ka] 1-(Cyclopropylmethyl)imidazole. To a solution of 1H-imidazole (20 g, 293.77 mmol) in ACN (250 mL) was added potassium carbonate (109.44 mL, 587.54 mmol), followed by bromomethylcyclopropane (51.56 g, 381.9 mmol). The mixture was stirred at 80 °C for 48 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue that was purified by silica gel chromatography to give 1-(cyclopropylmethyl)imidazole (13 g, 106.41 mmol, 36.222% yield). 1 H NMR(400MHz,CDCl3)δ 7.32(s,1H),6.84(s,1H),6.78(s,1H),3.57(d,J=7.0Hz,2H),1.06-0.91(m,1H),0.52-0.39(m,2H),0.19-0.07(m,2H).

[0344] [3-(Cyclopropylmethyl)imidazol-4-yl]sulfinyloxylithium. To a solution of 1-(cyclopropylmethyl)imidazole (13 g, 106.41 mmol) in diethyl ether (200 mL) was slowly added n-butyllithium (55.52 mL, 127.69 mmol) under nitrogen at −70° C. The mixture was stirred at −70° C. for 30 minutes and at 0° C. for 30 minutes. Excess sulfur dioxide was bubbled through, and the mixture was stirred at −70° C. for 1 hour. The mixture was then warmed to 25° C., filtered, and the filter cake was dried under vacuum to give crude [3-(cyclopropylmethyl)imidazol-4-yl]sulfinyloxylithium (20 g, crude), which contained [1-(cyclopropylmethyl)imidazol-4-yl]sulfinyloxylithium. This was used directly without further purification.

[0345] 3-(Cyclopropylmethyl)imidazole-4-sulfonyl chloride. To a solution of [3-(cyclopropylmethyl)imidazol-4-yl]sulfinyloxylithium (20 g, crude) (containing [1-(cyclopropylmethyl)imidazol-4-yl]sulfinyloxylithium) in chloroform (100 mL) and water (100 mL) was added NCS (13.89 g, 104.08 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was diluted with cold water, and the aqueous phase was extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give crude 3-(cyclopropylmethyl)imidazole-4-sulfonyl chloride (1 g, crude), which contained 1-(cyclopropylmethyl)imidazole-4-sulfonyl chloride. 1 H NMR(400MHz,DMSO-d6)δ 9.18(d,J=1.5Hz,1H),7.69(d,J=1.6Hz,1H),4.20(d,J=7.5Hz,2H),1.58-1.45(m,1H),0.59-0.45(m,4H).

[0346] 3-(Cyclopropylmethyl)-N-(5-morpholino-8-quinolyl)imidazole-4-sulfonamide. To a solution of 5-morpholinoquinolin-8-amine (220 mg, 0.9600 mmol) in pyridine (4 mL) was added a solution of 3-(cyclopropylmethyl)imidazole-4-sulfonyl chloride (211.75 mg, 0.9600 mmol) (which contained 1-(cyclopropylmethyl)imidazole-4-sulfonyl chloride) in DCM (1 mL). The mixture was stirred at 25° C. for 16 hours. The mixture was diluted with 10% citric acid (50 mL), and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue which was purified by preparative HPLC followed by lyophilization to give 3-(cyclopropylmethyl)-N-(5-morpholino-8-quinolyl)imidazole-4-sulfonamide (42.14 mg, 0.0971 mmol, 10.122% yield, 95.3% purity). 1H NMR(400MHz,DMSO-d6)δ 10.42-10.02(m,1H),8.80(dd,J1=4.1,J2=1.5Hz,1H),8.49(dd,J1=8.5,J2=1.5,Hz, 1H),7.89(s,1H),7.62(d,J=8.1Hz,1H),7.54(dd,J1=8.6,J2=4.2,Hz,1H),7.23(d,J =0.9Hz,1H),7.18(d,J=8.3Hz,1H),4.12(d,J=7.3Hz,2H),3.88-3.80(m,4H),3.03-2 .92(m,4H),1.42-1.29(m,1H),0.57-0.48(m,2H),0.38-0.34(m,2H);LCMS(ESI):m / z 414.2[M+1] +

[0347] Example 34. 1-(cyclopropylmethyl)-N-(5-morpholino-8-quinolyl)imidazole-4-sulfonamide [ka] [1-(Cyclopropylmethyl)imidazol-4-yl]sulfinyloxylithium. To a solution of 1-(cyclopropylmethyl)imidazole (13 g, 106.41 mmol) in diethyl ether (200 mL) was slowly added n-butyllithium (55.52 mL, 127.69 mmol) under nitrogen at −70° C. The mixture was stirred at −70° C. for 30 minutes and at 0° C. for 30 minutes. Excess sulfur dioxide was bubbled through, and the mixture was stirred at −70° C. for 1 hour. The mixture was then warmed to 25° C., filtered, and the filter cake was dried under vacuum to give crude [1-(cyclopropylmethyl)imidazol-4-yl]sulfinyloxylithium (also containing [3-(cyclopropylmethyl)imidazol-4-yl]sulfinyloxylithium). This was used directly without further purification.

[0348] 1-(Cyclopropylmethyl)imidazole-4-sulfonyl chloride. To a solution of [1-(cyclopropylmethyl)imidazol-4-yl]sulfinyloxylithium (20 g, crude) (containing [3-(cyclopropylmethyl)imidazol-4-yl]sulfinyloxylithium) in chloroform (100 mL) and water (100 mL) was added NCS (13.89 g, 104.08 mmol) at 0°C. The mixture was stirred at 0°C for 1 hour. The mixture was diluted with cold water, and the aqueous phase was extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give crude 1-(cyclopropylmethyl)imidazole-4-sulfonyl chloride (1 g, crude). (3-(cyclopropylmethyl)imidazole-4-sulfonyl chloride was also contained.) 1 H NMR(400MHz,DMSO-d6)δ 9.18(d,J=1.5Hz,1H),7.69(d,J=1.6Hz,1H),4.20(d,J=7.5Hz,2H),1.58-1.45(m,1H),0.59-0.45(m,4H).

[0349] 1-(Cyclopropylmethyl)-N-(5-morpholino-8-quinolyl)imidazole-4-sulfonamide. To a solution of 5-morpholinoquinolin-8-amine (220 mg, 0.9600 mmol) in pyridine (4 mL) was added a solution of 1-(cyclopropylmethyl)imidazole-4-sulfonyl chloride (211.75 mg, 0.9600 mmol) (which contained 3-(cyclopropylmethyl)imidazole-4-sulfonyl chloride) in DCM (1 mL). The mixture was stirred at 25° C. for 16 hours. The mixture was diluted with 10% citric acid (50 mL), and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue which was purified by preparative HPLC followed by lyophilization to give 1-(cyclopropylmethyl)-N-(5-morpholino-8-quinolyl)imidazole-4-sulfonamide (6.19 mg, 0.0143 mmol, 72.242% yield, 95.7% purity). 1H NMR (400 MHz, MeOH-d4) δ 8.80(dd,J1=4.1,J2=1.6Hz,1H),8.57(dd,J1=8.5,J2=1.5Hz,1H),7.80(d,J=1.3 Hz,1H),7.76(d,J=8.3Hz,1H),7.63(d,J=1.1Hz,1H),7.51(dd,J1=8.5,J2=4.2Hz ,1H),7.15(d,J=8.3Hz,1H),3.98-3.87(m,4H),3.79(d,J=7.3Hz,2H),3.05-2.95 (m,4H),1.14-1.01(m,1H),0.56-0.47(m,2H),0.28-0.24(m,2H);LCMS(ESI):m / z 414.2[M+1] + .

[0350] Example 35. 1-Cyclopropyl-N-(5-morpholino-8-quinolyl)imidazole-2-sulfonamide [ka] (1-Cyclopropylimidazol-2-yl)sulfinyloxylithium. To a solution of 1-cyclopropylimidazole (10 g, 92.47 mmol) in diethyl ether (150 mL) was slowly added n-butyllithium (48.25 mL, 110.97 mmol) under nitrogen at -70°C. The mixture was stirred at -70°C for 30 minutes and at 0°C for 30 minutes. Excess sulfur dioxide was bubbled in, and the mixture was stirred at -70°C for 1 hour. The mixture was then warmed to 25°C, filtered, and the filter cake was dried under vacuum to give crude (1-cyclopropylimidazol-2-yl)sulfinyloxylithium (16 g, crude). ((3-cyclopropylimidazol-4-yl)sulfinyloxylithium is also present.)

[0351] 1-Cyclopropylimidazole-2-sulfonyl chloride. To a solution of (1-cyclopropylimidazol-2-yl)sulfinyloxylithium (16 g, crude) (containing (3-cyclopropylimidazol-4-yl)sulfinyloxylithium) in chloroform (100 mL) and water (100 mL) was added NCS (11.99 g, 89.82 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was diluted with cold water, and the aqueous phase was extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give crude 1-cyclopropylimidazole-2-sulfonyl chloride (1 g, crude) (containing 3-cyclopropylimidazole-4-sulfonyl chloride).

[0352] 1-Cyclopropyl-N-(5-morpholino-8-quinolyl)imidazole-2-sulfonamide. To a solution of 5-morpholinoquinolin-8-amine (256.72 mg, 1.12 mmol) in pyridine (4 mL) was added a solution of 1-cyclopropylimidazole-2-sulfonyl chloride (277.66 mg, 1.34 mmol) (containing 3-cyclopropylimidazole-4-sulfonyl chloride) in DCM (1 mL). The mixture was stirred at 25° C. for 16 hours. The mixture was diluted with 10% citric acid (50 mL), and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography to give the crude product. This was further purified by preparative HPLC followed by lyophilization to give 1-cyclopropyl-N-(5-morpholino-8-quinolyl)imidazole-2-sulfonamide (23.42 mg, 0.0586 mmol, 5.2308% yield, 99.9% purity). 1H NMR(400MHz, methanol-d4)δ 8.86(dd,J1=4.4,J2=1.5Hz,1H),8.76(dd,J1=8.5,J2=1.5Hz,1H),7.79(d,J=8.3Hz,1H),7.64(dd,J1=8.5,J2=4.4Hz,1H),7.28(s, 1H),7.23(d,J=8.3Hz,1H),6.98(s,1H),3.99-3.89(m,4H),3.87-3.80(m,1H),3.11-3.01(m,4H),1.19-1.04(m,4H);LCMS(ESI):m / z 400.2[M+1] + .

[0353] Example 36. 3-Methyl-N-(2-methylisoindolin-4-yl)pyridine-2-sulfonamide [ka] 2-Methyl-4-nitroisoindoline. To a solution of 1,2-bis(bromomethyl)-3-nitro-benzene (2.00 g, 6.47 mmol) and methylamine (2 M, 3.6 mL) was added TEA (1.44 g, 14.24 mmol). The mixture was stirred at 25 °C under N for 0.5 h. Methylamine (2 M, 15.0 mL) was added to the above mixture. The mixture was stirred at 25 °C under N for an additional 1 h. The resulting mixture was concentrated in vacuo. The residue was poured into water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give 2-methyl-4-nitro-isoindoline (200 mg, 1.05 mmol, 16% yield, 93.3% purity). MS (ESI): m / z 179.2 [M+1]+.

[0354] 2-Methylisoindoline-4-amine. To a solution of 2-methyl-4-nitroisoindoline (200 mg, 1.12 mmol) in 2,2,2-trifluoroethanol (10 mL) was added Pd / C (40 mg). The mixture was stirred at 45 °C under H (15 psi) for 3 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give 2-methylisoindoline-4-amine (150 mg, crude). MS (ESI): m / z 149.0 [M+1] + .

[0355] 3-Methyl-N-(2-methylisoindolin-4-yl)pyridine-2-sulfonamide. To a solution of 2-methylisoindolin-4-amine (143 mg, 0.966 mmol) in pyridine (3.83 g, 48.40 mmol) was added a mixture of 3-methylpyridine-2-sulfonyl chloride (400 mg, 1.61 mmol) in DCM (5 mL) at 0° C. under N. The mixture was stirred at 25° C. under N for 3 hours. The resulting mixture was concentrated. The residue was diluted with brine, and the aqueous phase was extracted with DCM. The combined organic phase was washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give 3-methyl-N-(2-methylisoindolin-4-yl)pyridine-2-sulfonamide (120.74 mg, 0.330 mmol, 34% yield, 95.5% purity, FA). 1 H NMR(400MHz,CD3OD-d4)δ 8.50-8.39(m,2H),7.82(dd,J1=7.8,J2=0.7Hz,1H),7.48(dd,J1=7.7,J2=4.6Hz,1H),7.29-7.20 (m,2H),7.16(d,J=6.6Hz,1H),4.65(s,2H),4.46(s,2H),2.97(s,3H),2.59(s,3H);MS(ESI):m / z 304.1[M+1] + .

[0356] Example 37. 3-Fluoro-N-(1,2,3,4-tetrahydroquinolin-8-yl)pyridine-2-sulfonamide [ka] Lithium 3-fluoropyridine-2-sulfinate. To a solution of 2-bromo-3-fluoropyridine (4.8 g, 27.27 mmol) in diethyl ether (100 mL) was added n-BuLi (2.5 M, 13.09 mL) at -70°C. The mixture was stirred at -70°C for 0.5 h. Excess sulfur dioxide was bubbled in, and the mixture was stirred at -70°C for 1 h. The mixture was then warmed to 25°C. The mixture was filtered, and the filter cake was collected and dried under vacuum to give lithium 3-fluoropyridine-2-sulfinate (4 g, crude).

[0357] 3-Fluoropyridine-2-sulfonyl chloride. To a solution of lithium 3-fluoropyridine-2-sulfinate (4 g) in chloroform (50 mL) and water (50 mL) was added NCS (4.79 g, 35.87 mmol) in portions at 0 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was diluted with cold water, and the aqueous phase was extracted with chloroform. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3-fluoropyridine-2-sulfonyl chloride (3 g, 13.19 mmol, 86% purity).

[0358] 1,2,3,4-Tetrahydroquinolin-8-amine. To a solution of quinolin-8-amine (10 g, 69.36 mmol) in acetic acid (50 mL) was added platinum dioxide (0.4 g, 1.76 mmol) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (20 psi) at 30° C. for 40 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give 1,2,3,4-tetrahydroquinolin-8-amine (9.4 g, 63.43 mmol, 91.44% yield). 1H NMR(400MHz,DMSO-d6)δ 6.34(dd,J1=6.0,J2=1.2Hz,1H),6.80(t,J=7.6Hz,1H),6.21(d,J=7.2Hz,1H), 4.60(brs,2H),3.20(t,J=5.6Hz,2H),2.62(t,J=6.0Hz,2H),1.79-1.73(m,2H).

[0359] 3-Fluoro-N-(1,2,3,4-tetrahydroquinolin-8-yl)pyridine-2-sulfonamide. To a solution of 1,2,3,4-tetrahydroquinolin-8-amine (1.30 g, 8.79 mmol) in pyridine (10 mL) was slowly added 3-fluoropyridine-2-sulfonyl chloride (2 g, 8.79 mmol) dissolved in DCM (5 mL) at 0 °C under nitrogen. The mixture was stirred at 25 °C for 16 hours. The resulting mixture was concentrated under reduced pressure to give a residue, which was then diluted with water. The resulting mixture was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give 3-fluoro-N-(1,2,3,4-tetrahydroquinolin-8-yl)pyridine-2-sulfonamide (1.6 g, crude). The crude product was triturated with MeOH for 30 min, then the mixture was filtered, and the filter cake was triturated with 20% ACN in water for 10 min. The resulting mixture was lyophilized to give 3-fluoro-N-(1,2,3,4-tetrahydroquinolin-8-yl)pyridine-2-sulfonamide (150.21 mg, 482.87 μmol, 14.84% yield, 98.8% purity). 1 H NMR(400MHz,DMSO-d6)δ 9.77(s,1H),8.57(d,J=4.8,1H),8.03-7.98(m,1H),7.82-7.79(m,1H),6.74(d,J=7.6Hz,1H),6.67(d,J=7.6Hz,1H ),6.31(t,J=7.6Hz,1H),5.49(s,1H),3.19(t,J=5.6Hz,2H),2.62(t,J=6.0Hz,2H),1.74-1.68(m,2H);MS(ESI):m / z 308.1[M+1] + .

[0360] Example 38. 3-Methyl-N-(1-methylindolin-7-yl)pyridine-2-sulfonamide [ka] Lithium 3-methylpyridine-2-sulfinate. To a solution of 2-bromo-3-methylpyridine (10 g, 58.13 mmol) in THF (100 mL) was added n-BuLi (2.5 M, 27.90 mL) slowly under nitrogen at −70° C. The mixture was stirred at −70° C. for 1 h. Excess sulfur dioxide was then purged, and the mixture was stirred at −70° C. for 0.5 h. The mixture was then warmed to 20° C. The mixture was filtered, and the filter cake was collected and dried under vacuum to give lithium 3-methylpyridine-2-sulfinate (12 g, crude).

[0361] 3-Methylpyridine-2-sulfonyl chloride. To a mixture of lithium 3-methylpyridine-2-sulfinate (12 g, 1 eq) in chloroform (50 mL) and water (50 mL) was added NCS (14.73 g, 110.31 mmol) in portions at 0 °C. The mixture was stirred at 0 °C for 1 h. The resulting mixture was separated, and the organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 3-methylpyridine-2-sulfonyl chloride (6 g, crude).

[0362] 1-Methyl-7-nitroindoline. To a solution of 1-methyl-7-nitro-1H-indole (5 g, 28.38 mmol) in acetic acid (50 mL) was added sodium cyanoborohydride (7.13 g, 113.53 mmol) in portions at 25 °C. The mixture was stirred at 70 °C for 48 hours. The mixture was concentrated, and the residue was diluted with water. The aqueous phase was adjusted to pH 8 with sodium hydroxide (2 M) and extracted with DCM. The combined organic layers were concentrated under reduced pressure to give 1-methyl-7-nitroindoline (7.07 g, crude).

[0363] 1-Methylindolin-7-amine. To a solution of 1-methyl-7-nitroindoline (6.5 g, 1 eq) in MeOH (100 mL) under nitrogen, Pd / C (600 mg, 10% purity) and Pd(OH) / C (600 mg, 4.27 mmol) were added. The mixture was then stirred at 25 °C for 4 h under hydrogen (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. This residue was purified by preparative HPLC to give 1-methylindole-7-amine (2.16 g, 14.34 mmol, 97% purity). 1 H NMR (400 MHz, DMSO-d6) δ 6.54-6.50 (m, 1H), 6.44-6.42 (m, 2H), 4.39 (brs, 2H), 3.17 (t, J = 8.4 Hz, 1H), 2.81 (t, J = 8.0 Hz, 2H), 2.74 (s, 3H); compound 1-methylindoline-7-amine (0.72 g, 4.62 mmol, purity 95%) was obtained as a red oil. 1 H NMR(400MHz,DMSO-d6)δ 7.05(d,J=3.2Hz,1H),6.82(dd,J1=7.6,J2=0.4Hz,1H),6.80(d,J=7.6Hz,1 H),6.37(d,J=7.2Hz,1H),6.21(d,J=3.2Hz,1H),4.82(s,2H),4.05(s,3H).

[0364] N-(1-methylindolin-7-yl)acetamide. To a solution of 1-methylindole-7-amine (1.86 g, 12.31 mmol) in acetic acid (30 mL) was added sodium cyanoborohydride (3.87 g, 61.56 mmol) in portions. The mixture was stirred at 60 °C for 48 hours. The mixture was concentrated, and the residue was poured into water. The aqueous phase was adjusted to pH 9, and the mixture was extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give N-(1-methylindolin-7-yl)acetamide (1.1 g, 5.78 mmol, 46.96% yield).

[0365] 1-Methylindoline-7-amine. To a mixture of N-(1-methylindolin-7-yl)acetamide (0.9 g, 4.73 mmol) in MeOH (15 mL) under nitrogen, thionyl chloride (450.26 mg, 3.78 mmol, 274.55 μL) was added. The mixture was stirred at 75° C. for 3 hours. The resulting mixture was concentrated to give a residue, and saturated sodium carbonate was added to the residue, followed by extraction with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1-methylindoline-7-amine (0.7 g). 1 H NMR(400MHz,CDCl3)δ 6.72-6.68(m,2H),6.53-6.51(m,1H),3.34(t,J=8.4Hz,2H),2.98(t,J=8.0Hz,2H),2.86(s,3H).

[0366] 3-Methyl-N-(1-methylindolin-7-yl)pyridine-2-sulfonamide. To a mixture of 1-methylindolin-7-amine (0.65 g, 4.39 mmol) in pyridine (10 mL) was slowly added 3-methylpyridine-2-sulfonyl chloride (840.48 mg) in DCM (10 mL) at 0° C. under nitrogen. The mixture was stirred at 25° C. for 16 hours. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give 3-methyl-N-(1-methylindolin-7-yl)pyridine-2-sulfonamide (430.07 mg, 1.36 mmol, 31.03% yield, 96% purity). 1 H NMR(400MHz,DMSO-d6)δ 8.57(d,J=3.2Hz,1H),7.86(d,J=6.8Hz,1H),7.57(dd,J1=7.6,J2=4.6Hz,1H),6.88(dd,J1=7.0,J2=0.8Hz,1H),6.49(d, MS(ESI):m / z 304.1[M+1] + .

[0367] Example 39. 3-Methyl-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)pyridine-2-sulfonamide [ka] tert-Butyl 8-(3-methylpyridine-2-sulfonamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate. To a solution of tert-butyl 8-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.2 g, 4.83 mmol) in pyridine (20 mL) was added 3-methylpyridine-2-sulfonyl chloride (926 mg) dissolved in DCM (10 mL). The mixture was stirred at 25 °C for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give tert-butyl 8-[(3-methyl-2-pyridyl)sulfonylamino]-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.7 g).

[0368] 3-Methyl-N-(1,2,3,4-tetrahydroisoquinolin-8-yl)pyridine-2-sulfonamide. To a solution of tert-butyl 8-[(3-methyl-2-pyridyl)sulfonylamino]-3,4-dihydro-1H-isoquinoline-2-carboxylate (0.9 g, 2.23 mmol) in DCM (15 mL) was slowly added trifluoromethanesulfonic acid (4.62 g, 40.52 mmol, 3 mL) under nitrogen at 0° C. The mixture was stirred at 0° C. for 1 hour. The resulting mixture was concentrated under reduced pressure to give 3-methyl-N-(1,2,3,4-tetrahydroisoquinolin-8-yl)pyridine-2-sulfonamide (1 g, crude, trifluoromethanesulfonate salt).

[0369] 3-Methyl-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)pyridine-2-sulfonamide. To a mixture of 3-methyl-N-(1,2,3,4-tetrahydroisoquinolin-8-yl)pyridine-2-sulfonamide (1 g, crude, trifluoromethanesulfonate salt) in MeOH (10 mL) was added triethylamine (400 mg, 3.96 mmol, 550.55 μL). Acetic acid (59 mg, 0.989 mmol) and formaldehyde (2.67 g, 32.96 mmol, 37% purity) were then added. The mixture was stirred at 20° C. for 2 hours. The mixture was then cooled to 0° C., and sodium cyanoborohydride (621.40 mg, 9.89 mmol) was added in portions. The mixture was stirred at 25° C. for 14 hours. The resulting mixture was concentrated under reduced pressure to give a residue, and saturated sodium carbonate was added. The resulting mixture was extracted with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give 3-methyl-N-(2-methyl-3,4-dihydro-1H-isoquinolin-8-yl)pyridine-2-sulfonamide (556.67 mg, 1.70 mmol, 97% purity). 1 H NMR(400MHz,DMSO-d6)δ 8.52(d,J=4.0Hz,1H),7.87(d,J=7.2Hz,1H),7.56(dd,J1=7.8,J2=4.4Hz,1H),7.00-6.94(m,1H),6.92(d,J=7.2Hz,1H), 6.85(d,J=7.6Hz,1H),3.49(s,3H),2.79(t,J=5.6Hz,2H),2.53(t,J=5.6Hz,2H),2.48(s,2H),2.33(s,3H);MS(ESI):m / z 318.1[M+1] + .

[0370] Example 40. N-(1-cyclopropyl-1,2,3,4-tetrahydroquinolin-8-yl)-3-(dimethylamino)pyridine-2-sulfonamide [ka] N-(1-cyclopropyl-1,2,3,4-tetrahydroquinolin-8-yl)-3-(dimethylamino)pyridine-2-sulfonamide. To a solution of 3-(dimethylamino)-N-(1,2,3,4-tetrahydroquinolin-8-yl)pyridine-2-sulfonamide (0.7 g, 2.11 mmol) and (1-ethoxycyclopropoxy)trimethylsilane (1.84 g, 10.53 mmol) in MeOH (20 mL) and acetic acid (20 mL) was added sodium cyanoborohydride (662 mg, 10.53 mmol). The mixture was stirred at 25° C. for 32 hours. The resulting mixture was concentrated. The residue was poured into sodium bicarbonate, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated with MeOH. The filter cake and filtrate were combined and concentrated to give the crude product. The crude product was purified by preparative HPLC and then lyophilized to give N-(1-cyclopropyl-1,2,3,4-tetrahydroquinolin-8-yl)-3-(dimethylamino)pyridine-2-sulfonamide (414.09 mg, 1.06 mmol, 50.42% yield, 95.5% purity). 1 H NMR (400 MHz, DMSO-d6) 8.78 (br s,1H),8.21(dd,J1=4.3,J2=1.1Hz,1H),7.77(dd,J1=8.3,J2=1.1Hz,1H),7 .51(dd,J1=8.3,J2=4.3Hz,1H),6.83(d,J=7.0Hz,1H),6.70-6.65(m,1H),6 .62-6.55(m,1H),3.10(t,J=6.1Hz,2H),2.76(s,6H),2.72-2.65(m,1H),2. 59(t,J=6.7Hz,2H),1.83(q,J=6.4Hz,2H),0.69-0.53(m,4H);MS(ESI):m / z 373.2[M+1] + .

[0371] Example 41. 1-Isopropyl-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-1H-pyrazole-5-sulfonamide [ka] 1,2,3,4-Tetrahydroisoquinolin-8-amine. To a solution of isoquinolin-8-amine (5 g, 34.68 mmol) in acetic acid (30 mL) was added platinum dioxide (0.2 g, 0.881 mmol) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (50 psi) at 25° C. for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 1,2,3,4-tetrahydroisoquinolin-8-amine (10 g, crude, acetic acid). 1 H NMR(400MHz,DMSO-d6)δ 6.91(t,J=7.7Hz,1H),6.52(d,J=7.9Hz,1H),6.37(d,J=7.4Hz,1H),3.86(s,2H),3.17(t,J=5.4Hz,2H),2.82(t,J=5.5Hz,2H),1.82(s,3H).

[0372] tert-Butyl 8-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate. To a mixture of 1,2,3,4-tetrahydroisoquinolin-8-amine (9.3 g, crude, acetic acid) and sodium bicarbonate (15.01 g, 178.67 mmol) in water (50 mL) and THF (50 mL) was added di-tert-butyl dicarbonate (9.75 g, 44.67 mmol, 10.26 mL) slowly at 0 °C under nitrogen. The mixture was stirred at 15 °C for 2 hours. The resulting mixture was extracted with ethyl acetate, and the combined organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give tert-butyl 8-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (5.9 g, 23.76 mmol). 1 H NMR(400MHz,CDCl3)δ 7.01(t,J=7.7Hz,1H),6.66-6.51(m,2H),4.36(s,2H),3.71-3.47(m,4H),2.81(s,2H),1.52(s,9H).

[0373] tert-Butyl 8-(1-isopropyl-1H-pyrazole-5-sulfonamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate. To a solution of tert-butyl 8-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (700 mg, 2.82 mmol) in pyridine (8 mL) was slowly added 1-isopropyl-1H-pyrazole-5-sulfonyl chloride (588 mg, 2.82 mmol) dissolved in DCM (2 mL) at 0 °C under nitrogen. The mixture was stirred at 15 °C for 16 hours. This mixture was diluted with 10% citric acid, and the resulting mixture was extracted with ethyl acetate. The combined organic phase was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give tert-butyl 8-(1-isopropyl-1H-pyrazole-5-sulfonamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.2 g, crude).

[0374] tert-Butyl 8-(1-isopropyl-1H-pyrazole-5-sulfonamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate. To a solution of 8-(1-isopropyl-1H-pyrazole-5-sulfonamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.2 g, crude) in DCM (10 mL) was added trifluoroacetic acid (3.08 g, 27.01 mmol, 2.00 mL) slowly at 0° C. under nitrogen. The mixture was stirred at 0° C. for 0.5 hours. The resulting mixture was concentrated under reduced pressure to give tert-butyl 8-(1-isopropyl-1H-pyrazole-5-sulfonamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.2 g, crude, trifluoroacetic acid).

[0375] 1-Isopropyl-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-1H-pyrazole-5-sulfonamide. To a mixture of tert-butyl 8-(1-isopropyl-1H-pyrazole-5-sulfonamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.2 g, crude, trifluoroacetic acid) and formaldehyde (2.24 g, 27.60 mmol, 12.32 mL, 37% purity) in MeOH (20 mL) was added TEA (307.46 mg, 3.04 mmol) and acetic acid (24.88 mg, 0.414 mmol). The mixture was stirred at 15 °C for 30 min, then sodium cyanoborohydride (520.75 mg, 8.29 mmol) was added in portions, and the mixture was stirred at 15 °C for 2 h. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was diluted with saturated sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give 1-isopropyl-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-1H-pyrazole-5-sulfonamide (177.35 mg, 0.509 mmol, 96% purity). 1 H NMR(400MHz,DMSO-d6)δ 8.14(s,1H),7.47(d,J=1.8Hz,1H),7.02-6.98(m,1H),6.78(t,J=8.2Hz,2H),6.47(d,J=1.8Hz,1H),5.15-5.0 5(m,1H),3.80(s,2H),3.03-3.00(m,2H),2.91-2.88(m,2H),2.67(s,3H),1.31(d,J=6.6Hz,6H);MS(ESI):m / z 335.3[M+1] + .

[0376] Example 42. N-(1-cyclopropyl-1,2,3,4-tetrahydroquinolin-8-yl)-3-methylpyridine-2-sulfonamide [ka] 3-Methyl-N-(1,2,3,4-tetrahydroquinolin-8-yl)pyridine-2-sulfonamide. To a solution of 1,2,3,4-tetrahydroquinolin-8-amine (773.37 mg, 5.22 mmol) in pyridine (8 mL) was slowly added 3-methylpyridine-2-sulfonyl chloride (1 g, 5.22 mmol) dissolved in DCM (5 mL) at 0 °C under nitrogen. The mixture was stirred at 15 °C for 16 hours. The mixture was diluted with 10% citric acid, and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give 3-methyl-N-(1,2,3,4-tetrahydroquinolin-8-yl)pyridine-2-sulfonamide (1 g, 3.30 mmol, 63.17% yield).

[0377] N-(1-cyclopropyl-1,2,3,4-tetrahydroquinolin-8-yl)-3-methylpyridine-2-sulfonamide. To a mixture of 3-methyl-N-(1,2,3,4-tetrahydroquinolin-8-yl)pyridine-2-sulfonamide (1 g, 3.30 mmol) and (1-ethoxycyclopropoxy)trimethylsilane (1.72 g, 9.89 mmol) in MeOH (20 mL), DCM (5 mL), and acetic acid (20 mL) was added sodium cyanoborohydride (621.40 mg, 9.89 mmol) in portions at 0° C. under nitrogen. The mixture was stirred at 40° C. for 16 hours. The resulting mixture was concentrated under reduced pressure to give a residue, which was diluted with ethyl acetate. The resulting mixture was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography followed by preparative HPLC to give N-(1-cyclopropyl-1,2,3,4-tetrahydroquinolin-8-yl)-3-methylpyridine-2-sulfonamide (203.15 mg, 0.562 mmol, 17.05% yield, 95% purity). 1H NMR(400MHz,DMSO-d6)δ 9.03(s,1H),8.52(dd,J1=4.5,J2=0.9Hz,1H),7.83(d,J=7.7Hz,1H),7.54(dd,J1=7.7,J2=4.5Hz,1H),6.75(dd,J1=7.6,J2=2.8Hz,2H),6.5 5-6.51(m,1H),3.04(t,J=6.4Hz,2H),2.85-2.80(m,1H),2.38(s,3H),1.77-1.70(m,2H),0.71-0.66(m,2H),0.48-0.45(m,2H);MS(ESI):m / z 344.1[M+1] + .

[0378] Example 43. N-(2-cyclopropylisoindolin-4-yl)-1-isopropyl-1H-imidazole-2-sulfonamide [ka] 1,2-Bis(bromomethyl)-3-nitrobenzene. To a solution of 1,2-dimethyl-3-nitrobenzene (9.5 g, 62.85 mmol) in tetrachloromethane (50 mL) was added benzoyl peroxide (456.69 mg, 1.89 mmol) and 1-bromopyrrolidine-2,5-dione (22.37 g, 125.69 mmol) at 10° C. The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to give 1,2-bis(bromomethyl)-3-nitrobenzene (18 g, crude).

[0379] 2-Cyclopropyl-4-nitroisoindoline. To a solution of 1,2-bis(bromomethyl)-3-nitro-benzene (18 g, 58.26 mmol) and TEA (11.79 g, 116.52 mmol, 16.22 mL) in THF (80 mL) was added a mixture of cyclopropanamine (3.33 g, 58.26 mmol, 4.04 mL) in THF (20 mL). The reaction mixture was stirred at 10 °C for 2 hours. The reaction mixture was concentrated to give the crude product. The crude material was purified twice by silica gel chromatography to give 2-cyclopropyl-4-nitroisoindoline (1.5 g, crude). 1H NMR(400MHz,DMSO-d6)8.04(d,J=7.9Hz,1H),7.69(d,J=7.4Hz,1H),7.51(t,J=7.8Hz,1H),4. 40(s,2H),4.09(s,2H),2.15-2.07(m,1H),0.52-0.46(m,2H),0.46-0.41(m,2H);MS(ESI):m / z 205.0[M+1] + .

[0380] 2-Cyclopropylisoindoline-4-amine. To a solution of 2-cyclopropyl-4-nitroisoindoline (1.4 g, crude) in MeOH (20 mL) was added palladium on carbon (500 mg, 10% purity). The suspension was degassed under vacuum, purged with hydrogen three times, and stirred under hydrogen (15 psi) at 45° C. for 1 h. The reaction mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by silica gel chromatography to give 2-cyclopropylisoindoline-4-amine (0.7 g, 3.62 mmol, 52.74% yield, 90% purity). 1 H NMR(400MHz,CDCl3)7.03(t,J=7.7Hz,1H),6.65(d,J=7.4Hz,1H),6.53(d,J=7.9Hz,1H),4 .07(s,2H),3.97(s,2H),3.52(s,2H),2.10-2.03(m,1H),0.55-0.50(m,4H);MS(ESI):m / z 175.1[M+1] + .

[0381] N-(2-Cyclopropylisoindolin-4-yl)-1-isopropyl-1H-imidazole-2-sulfonamide. To a mixture of 2-cyclopropylisoindolin-4-amine (0.35 g, 1.81 mmol) in pyridine (5 mL) was added dropwise a solution of 1-isopropyl-1H-imidazole-2-sulfonyl chloride (452.68 mg, 2.17 mmol) in DCM (3 mL) at 0° C. The mixture was stirred at 20° C. for 16 hours. The reaction mixture was concentrated, and the residue was diluted with DCM, washed with 10% citric acid, saturated sodium bicarbonate, and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was triturated with MeOH and then lyophilized to give N-(2-cyclopropylisoindolin-4-yl)-1-isopropyl-1H-imidazole-2-sulfonamide (150.66 mg, 0.426 mmol, 23.57% yield, 98% purity). 1 H NMR(400MHz,DMSO-d6)10.26(br s,1H),7.62(s,1H),7.15-7.08(m,2H),7.07-6.97(m,2H),4.80-4.87(m,1H),3.90(s,2H),3.77(s ,2H),1.93-1.97(m,1H),1.25(d,J=6.6Hz,6H),0.47-0.41(m,2H),0.37-0.31(m,2H);MS(ESI):m / z 347.1[M+1] + .

[0382] Example 44. N-(7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-3-methylpyridine-2-sulfonamide [ka] tert-Butyl 8-amino-5-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate. To a solution of tert-butyl 8-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (1 g, 4.03 mmol) in DMF (10 mL) was slowly added N-bromosuccinimide (716.75 mg, 4.03 mmol) dissolved in DMF (3 mL) at 0 °C under nitrogen. The mixture was stirred at 15 °C for 2 hours. The mixture was diluted with water, and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give tert-butyl 8-amino-5-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.2 g, 3.67 mmol, 91.07% yield). 1 H NMR(400MHz,CDCl3)δ 7.24(d,J=8.4Hz,1H),6.48(d,J=8.4Hz,1H),4.33(s,2H),3.64(t,J=5.7Hz,2H),3.57(s,2H),2.81(t,J=5.6Hz,2H),1.51(s,9H).

[0383] tert-Butyl 8-amino-5-bromo-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate. A mixture of tert-butyl 8-amino-5-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.2 g, 3.67 mmol) and N-chlorosuccinimide (538.68 mg, 4.03 mmol) in DMF (15 mL) was stirred at 85 °C for 3 hours. The mixture was diluted with water, and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give tert-butyl 8-amino-5-bromo-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (1 g, 2.77 mmol, 75.40% yield). 1H NMR(400MHz,CDCl3)δ 7.40(s,1H),4.34(s,2H),3.98(s,2H),3.63(t,J=5.6Hz,2H),2.78(t,J=5.7Hz,2H),1.50(s,9H).

[0384] tert-Butyl 8-amino-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate. A mixture of tert-butyl 8-amino-5-bromo-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.42 g, 1.16 mmol) and lithium aluminum hydride (66.11 mg, 1.74 mmol) in THF (8 mL) was stirred at 25 °C for 16 hours. Sodium sulfate decahydrate (0.1 g, 0.31 mmol) was slowly added to the reaction mixture, and the resulting mixture was stirred at 15 °C for 30 minutes. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl 8-amino-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.3 g, 1.06 mmol, 91.36% yield). MS(ESI): m / z 227.0[M-55] + .

[0385] tert-Butyl 7-chloro-8-(3-methylpyridine-2-sulfonamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate. To a solution of tert-butyl 8-amino-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.15 g, 0.53 mmol, crude) in THF (10 mL) was slowly added sodium bis(trimethylsilyl)amide (1 M, 0.8 mL) under nitrogen at -70°C. The mixture was stirred at 15°C for 30 minutes, and then 3-methylpyridine-2-sulfonyl chloride (101.66 mg, 0.53 mmol) dissolved in THF (2 mL) was slowly added at -70°C. The resulting mixture was stirred at 15°C for 2 hours. The resulting mixture was slowly quenched with saturated ammonium chloride (5 mL) at -20°C, and the mixture was diluted with water. The resulting mixture was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography to give tert-butyl 7-chloro-8-(3-methylpyridine-2-sulfonamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.1 g, crude). MS (ESI): m / z 438.0 [M+1] + .

[0386] N-(7-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)-3-methylpyridine-2-sulfonamide (trifluoroacetate). To a solution of tert-butyl 7-chloro-8-(3-methylpyridine-2-sulfonamide)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.18 g, 0.41 mmol, crude) in DCM (4 mL) was slowly added trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL) at 0°C. The mixture was stirred at 15°C for 2 hours. The resulting mixture was concentrated under reduced pressure to give N-(7-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)-3-methylpyridine-2-sulfonamide (trifluoroacetate). MS (ESI): m / z 338.0 [M+1] + .

[0387] N-(7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-3-methylpyridine-2-sulfonamide. To a solution of N-(7-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)-3-methylpyridine-2-sulfonamide (0.2 g, crude) (trifluoroacetate salt) in MeOH (10 mL) was slowly added TEA (71.89 mg, 0.71 mmol) at 0 °C. Formaldehyde (480.43 mg, 5.92 mmol, 0.44 mL, 37% purity), acetic acid (7.11 mg, 0.12 mmol), and sodium cyanoborohydride (111.61 mg, 1.78 mmol) were then added, and the mixture was stirred at 15 °C for 16 hours. The resulting mixture was concentrated under reduced pressure to give a residue, which was diluted with saturated sodium carbonate, and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by preparative HPLC to give N-(7-chloro-2-methyl-3,4-dihydro-1H-isoquinolin-8-yl)-3-methyl-pyridine-2-sulfonamide (14.01 mg, 0.04 mmol, 6.46% yield, 96% purity). 1 H NMR(400MHz,CDCl3)δ 8.53(d,J=3.9Hz,1H),7.64(d,J=7.8Hz,1H),7.40(dd,J1=7.7,J2=4.5Hz,1H),6.99(d,J=8.4Hz,1H),6.92(d,J =8.4Hz,1H),3.80(s,2H),2.94(t,J=6.1Hz,2H),2.73(t,J=6.2Hz,2H),2.54(s,3H),2.51(s,3H);MS(ESI):m / z 352.1[M+1] + .

[0388] Example 45. 1-(2,2,2-trifluoroethyl)-N-[5-[3-(trifluoromethyl)phenoxy]-8-quinolyl]imidazole-2-sulfonamide [ka] 5-Bromo-8-nitro-quinoline. A solution of 5-bromoquinoline (10 g, 48.1 mmol) in concentrated H2SO4 (40 mL) was cooled to 0 °C, and potassium nitrate (7.77 g, 77 mmol) was added slowly in portions under an inert atmosphere. The resulting reaction mixture was allowed to warm to room temperature, and stirring was continued for 16 h. The reaction mixture was poured onto crushed ice. The precipitate thus formed was filtered, washed with water, and dried to give 5-bromo-8-nitro-quinoline (9 g, 74%) as a pale yellow solid. MS (ESI): m / z 253.0 [M+1]+.

[0389] 8-Nitro-5-[3-(trifluoromethyl)phenoxy]quinoline. To a stirred solution of 5-bromo-8-nitroquinoline (5 g, 19.84 mmol) in dry DMF (50 mL) was added K2CO3 (6.85 g, 49.5 mmol), followed by 3-trifluoromethylphenol (6.4 g, 39.68 mmol) at room temperature under an argon atmosphere. The resulting mixture was heated at 100 °C for 16 h. It was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (10–20% EtOAc in hexanes) to give 8-nitro-5-[3-(trifluoromethyl)phenoxy]quinoline (3.5 g, 53%) as a yellowish solid. MS (ESI): m / z 335.37 [M+1]+.

[0390] 5-[3-(trifluoromethyl)phenoxy]quinolin-8-amine. To a stirred solution of 8-nitro-5-[3-(trifluoromethyl)phenoxy]quinoline (1 g, 2.99 mmol) in THF-EtOH-HO (24 mL, 3:2:1 ratio) was added NHCl (238 mg, 4.49 mmol) and Fe powder (838 mg, 14.97 mmol). The resulting mixture was heated at 80 °C for 4 h. Upon completion, the reaction mixture was filtered through a short pad of Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude product was purified by Combiflash chromatography (20-25% EtOAc in hexanes) to give 5-[3-(trifluoromethyl)phenoxy]quinolin-8-amine (700 mg, 77%) as a yellow solid. MS (ESI): m / z 305.4 [M+1]+.

[0391] 1-(2,2,2-Trifluoroethyl)-1H-imidazole-2-thiol. To a stirred solution of 2,2,2-trifluoroethan-1-amine (5 g, 50.5 mmol) in DCM (50 mL) was added 1-[(2-oxo-1,2-dihydropyridin-1-yl)carbothioyl]-1,2-dihydropyridin-2-one (12.8 g, 55.6 mmol) in portions at 0 °C. The resulting mixture was warmed to 10 °C and stirred for 3 h. 2,2-Diethoxyethoxyethan-1-amine (10 g, 75.2 mmol) was added under cooled conditions and stirred at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure, diluted with toluene (50 mL), and concentrated HCl (5 mL) was added. The resulting mixture was heated at 110 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure, diluted with water, adjusted to pH ∼8 with 1(N) aqueous NaOH, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mass was purified by column chromatography (25–30% EtOAc-Hex) to afford 1-(2,2,2-trifluoroethyl)-1H-imidazole-2-thiol (3 g, 33% over two steps) as a white solid. MS (ESI): m / z 183.3 [M+1]+.

[0392] 1-(2,2,2-Trifluoroethyl)-1H-imidazole-2-sulfonyl chloride. 1-(2,2,2-Trifluoroethyl)-1H-imidazole-2-thiol (1.5 g, 8.2 mmol) was placed in a two-neck round-bottom flask and cooled to -10 °C. Concentrated H2SO4 (40 mL) was added slowly under cooled conditions. NaOCl (70 mL) was added over 30 min at -15 °C, and stirring was continued for an additional 0.5 h. Upon completion, the reaction mixture was quenched with ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and partially concentrated under reduced pressure to give 1-(2,2,2-trifluoroethyl)-1H-imidazole-2-sulfonyl chloride as a DCM solution, which was used immediately in the next step without further purification. MS (ESI): m / z 249.3 [M+1]+.

[0393] 1-(2,2,2-Trifluoroethyl)-N-[5-[3-(trifluoromethyl)phenoxy]-8-quinolyl]imidazole-2-sulfonamide. To a stirred solution of 5-[3-(trifluoromethyl)phenoxy]quinolin-8-amine (700 mg, 2.31 mmol) in pyridine (4 mL, 49.6 mmol) and DCM (10 mL) at 0° C., 1-(2,2,2-trifluoroethyl)-1H-imidazole-2-sulfonyl chloride (DCM solution) was added dropwise under an argon atmosphere. The reaction mixture was allowed to warm slowly to room temperature and stirred for 2 hours. Upon completion, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography (25-30% ethyl acetate in hexanes) to give 1-(2,2,2-trifluoroethyl)-N-[5-[3-(trifluoromethyl)phenoxy]-8-quinolyl]imidazole-2-sulfonamide (680 mg, 62%). 1H NMR(400MHz,DMSO-d6)δ 5.44(q,J=8.9Hz,2H),7.00(d,J=1.2Hz,1H),7.19(d,J=8.4Hz,1H),7.31(dd,J=2.4,8.3Hz,1H),7.42(s,1H),7.47(s,1H),7.54(d,J=7.8 Hz,1H),7.57-7.68(m,2H),7.79(d,J=8.4Hz,1H),8.44(dd,J=1.6,8.5Hz,1H),8.91(dd,J=1.7,4.2Hz,1H),10.72(brs,1H).MS(ESI):m / z 517.2[M+1]+.

[0394] Example 46. N-(5-cyano-8-quinolyl)-1-ethyl-imidazole-2-sulfonamide [ka] 8-Nitroquinoline-5-carbonitrile. To a stirring degassed solution of 5-bromo-8-nitroquinoline (200 mg, 0.791 mmol) in DMF (4 mL) was added zinc cyanide (371 mg, 3.16 mmol), followed by DIPEA (0.2 mL, 1.18 mmol), Pd(dba) (136 mg, 0.24 mmol), and Xphos (113 mg, 0.24 mmol). The resulting mixture was heated at 100 °C under MW irradiation for 0.5 h. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography (20–25% EtOAc in hexanes) to give 8-nitroquinoline-5-carbonitrile (75 mg, 47%) as an off-white solid. MS(ESI):m / z 200.3[M+1] + .

[0395] 8-Aminoquinoline-5-carbonitrile. To a stirring solution of 8-nitroquinoline-5-carbonitrile (85 mg, 0.43 mmol) in MeOH (5 mL) was added 10% Pd-C (33 mg). The resulting mixture was hydrogenated under balloon pressure at room temperature for 16 h. Upon completion, the reaction mixture was filtered through a short pad of Celite, and the filtrate was concentrated under reduced pressure. The crude mass was purified by Combiflash chromatography (20-25% EtOAc in hexanes) to give 8-aminoquinoline-5-carbonitrile (40 mg, 55%) as a colorless gum. MS (ESI): m / z 170.18 [M+1]+.

[0396] Isothiocyanatoethane. To a stirring solution of ethylamine (5 g, 55.5 mL, 110.92 mmol, 2 M in THF) in DCM (300 mL) was added 1-[(2-oxo-1,2-dihydropyridin-1-yl)carbothioyl]-1,2-dihydropyridin-2-one (28.4 g, 122 mmol) in portions and stirred at room temperature for 3 h. Upon completion, the reaction mixture was evaporated to dryness to afford isothiocyanatoethane (7.7 g, crude) as a brownish solid, which was used directly in the next step without further purification.

[0397] 1-Ethylimidazole-2-thiol. To a stirred solution of isothiocyanatoethane (7.7 g, 88.70 mmol, crude) in toluene (40 mL), 2,2-diethoxyethan-1-amine (19.3 mL, 133.06 mmol) was added dropwise at room temperature and stirred for 2 h. Concentrated HCl (7.5 mL) was then added to the reaction mixture, which was stirred at 110 °C for 3 h. Upon completion, the reaction mixture was evaporated to dryness, and the residue was diluted with water (40 mL). The aqueous portion was basified to pH 8 with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography (eluting with 30-50% ethyl acetate in hexane) to give 1-ethylimidazole-2-thiol (10 g, 70% 2 steps) as a brown solid. MS(ESI):m / z 129.2[M+1]- .

[0398] 1-Ethylimidazole-2-sulfonyl chloride. 1-Ethylimidazole-2-thiol (150 mg, 1.72 mmol) was placed in a two-neck round-bottom flask and cooled to -10 °C. Concentrated H2SO4 (3 mL) was added dropwise slowly with constant stirring and stirred at -10 °C for an additional 10 min. The reaction mixture was cooled to -15 °C, and NaOCl (9 mL) was added dropwise over 30 min. This was stirred at -10 °C for an additional 30 min. Upon completion, the reaction mixture was quenched with ice water and extracted with DCM. The combined organic layers were washed with cold brine, dried over MgSO4 (pre-cooled flask), filtered on a sintered funnel, and partially concentrated at low temperature to give 1-ethylimidazole-2-sulfonyl chloride as a DCM solution, which was used directly in the next step without further purification.

[0399] N-(5-cyano-8-quinolyl)-1-ethyl-imidazole-2-sulfonamide. To a stirring solution of 8-aminoquinoline-5-carbonitrile (50 mg, 0.296 mmol) in pyridine (1 mL, 0.6 mmol) and DCM (4 mL) at 0 °C, 1-ethylimidazole-2-sulfonyl chloride (crude, DCM solution) was added dropwise under an argon atmosphere. This was then stirred from 0 °C to room temperature for 2 h. Upon completion, this was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give N-(5-cyano-8-quinolyl)-1-ethyl-imidazole-2-sulfonamide (20 mg, 21%). 1 H NMR (400 MHz, DMSO-d₆) δ 1.32 (t, J = 7.2 Hz, 3H), 4.40 (q, J = 7.2 Hz, 2H), 7.01 (s, 1H), 7.50 (s, 1H), 7.84 (dd, J = 4.6, 8.4 Hz, 2H), 8.15 (d, J = 7.9 Hz, 1H), 8.46 (d, J = 8.4 Hz, 1H), 9.03 (d, J = 3.4 Hz, 1H) [NH protons not observed]. MS (ESI): m / z 328.0 [M+1]+.

[0400] Example 47. 1-Phenyl-N-[5-(trifluoromethyl)-8-quinolyl]imidazole-2-sulfonamide [ka] 8-Bromo-5-(trifluoromethyl)quinoline. Glycerol (1.5 g, 16.3 mmol) was heated to 160 °C for 1 hour. This was cooled to 110 °C, and 2-bromo-5-(trifluoromethyl)aniline (2.0 g, 8.33 mmol) and sodium iodide (25 mg, 0.16 mmol) were added. The resulting mixture was vigorously stirred and heated to 150 °C. Sulfuric acid (95-98%, 1.8 g, 18.4 mmol) was added dropwise, and heating was continued at 150 °C for 45 minutes. The reaction mixture was allowed to cool to ambient temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography (20-25% EtOAc in hexanes) to give 8-bromo-5-(trifluoromethyl)quinoline (600 mg, 26%) as a colorless gum. MS (ESI): m / z 276.0 [M+1] + .

[0401] 5-(Trifluoromethyl)quinolin-8-amine. To a stirring degassed solution of 8-bromo-5-(trifluoromethyl)quinoline (500 mg, 1.82 mmol) in toluene (8 mL) was added benzophenone imine (395 mg, 2.18 mmol), followed by CsCO (289 mg, 2.72 mmol), Pd(OAc) (41 mg, 0.18 mmol), and Xantphos (210 mg, 0.36 mmol). The resulting mixture was heated at 100 °C for 16 h. The reaction mixture was cooled to ambient temperature, filtered through a short pad of Celite, and washed with DCM. The solvent was removed under reduced pressure, and the residue was dissolved in EtOH-THF (10 mL, 1:1) and acidified to pH 1 with 1 M aqueous HCl. The resulting mixture was stirred at room temperature for 3 h. It was then basified with saturated aqueous NaHCO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography (20-25% EtOAc in hexanes) to give 5-(trifluoromethyl)quinolin-8-amine (310 mg, 80%) as an orange solid. MS (ESI): m / z 200.3 [M+1] + .

[0402] Isothiocyanatobenzene. To a stirred solution of aniline (1 g, 10.73 mmol) in DCM (30 mL), 1-[(2-oxo-1,2-dihydropyridin-1-yl)carbothioyl]-1,2-dihydropyridin-2-one (2.9 g, 12.90 mmol) was added portionwise and stirred at room temperature for 3 h. Upon completion, the reaction mixture was concentrated under reduced pressure to afford isothiocyanatobenzene (1.5 g, crude) as a brownish solid, which was used directly in the next step without further purification.

[0403] 1-Phenylimidazole-2-thiol. To a stirred solution of isothiocyanatobenzene (1.5 g, 11.12 mmol, crude) in toluene (15 mL) was added dropwise 2,2-diethoxyethan-1-amine (2.2 g, 16.66 mmol) at room temperature and stirred for 2 h. Concentrated HCl (1 mL) was then added to the reaction mixture, which was stirred at 110 °C for 3 h. Upon completion, the reaction mixture was evaporated to dryness, and the residue was diluted with water (40 mL). The aqueous portion was basified to pH 8 with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography (eluting with 30-50% ethyl acetate in hexane) to give 1-phenylimidazole-2-thiol (1.2 g, 63% 2 steps) as a colorless gum. MS(ESI):m / z 177.0[M+1] + .

[0404] 1-Phenylimidazole-2-sulfonyl chloride. 1-Phenylimidazole-2-thiol (300 mg, 1.70 mmol) was placed in a two-neck round-bottom flask and cooled to -10 °C. Concentrated H2SO4 (5 mL) was added dropwise slowly with constant stirring and stirred at -10 °C for an additional 10 min. The reaction mixture was cooled to -15 °C, and NaOCl (15 mL) was added dropwise over 30 min. This was stirred at -10 °C for an additional 30 min. Upon completion, the reaction mixture was quenched with ice-water and extracted with DCM. The combined organic layers were washed with cold brine, dried over MgSO4 (pre-cooled flask), filtered on a sintered funnel, and partially concentrated at low temperature to give 1-phenylimidazole-2-sulfonyl chloride as a DCM solution, which was used directly in the next step without further purification.

[0405] 1-Phenyl-N-[5-(trifluoromethyl)-8-quinolyl]imidazole-2-sulfonamide. To a stirred solution of 5-(trifluoromethyl)quinolin-8-amine (200 mg, 0.943 mmol) in pyridine (1 mL, 12.6 mmol) and DCM (5 mL) at 0 °C, 1-phenylimidazole-2-sulfonyl chloride (crude, DCM solution) was added dropwise under an argon atmosphere. This was then stirred from 0 °C to room temperature for 2 h. After completion, this was diluted with water (25 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by Combiflash chromatography (20-25% EtOAc in hexanes) to give 1-phenyl-N-[5-(trifluoromethyl)-8-quinolyl]imidazole-2-sulfonamide (75 mg, 19%) as an off-white solid. MS (ESI): m / z 418.8 [M+1] + .

[0406] Example 48. 1-Ethyl-N-(4-phenyl-8-quinolyl)imidazole-2-sulfonamide [ka] 8-Nitro-4-phenyl-quinoline. To a stirring degassed solution of 4-bromo-8-nitro-quinoline (200 mg, 0.791 mmol) in dioxane-HO (5.5 mL, 10:1) was added KCO (82 mg, 0.59 mmol), followed by phenylboronic acid (58 mg, 0.48 mmol) and Pd(dppf)Cl (15 mg, 0.02 mmol) under an argon atmosphere. The resulting mixture was heated at 100 °C for 16 h. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography (80–100% EtOAc in hexanes) to afford 8-nitro-4-phenyl-quinoline (75 mg, 76%) as an off-white solid. MS(ESI):m / z 251.0[M+1] +

[0407] 4-Phenylquinolin-8-amine. To a stirring solution of 8-nitro-4-phenyl-quinoline (140 mg, 0.56 mmol) in THF-EtOH (24 mL, 1:1 ratio), NHCl (297 mg, 5.6 mmol) and zinc dust (182 mg, 2.8 mmol) were added and stirred at room temperature for 2 h. Upon completion, the reaction mixture was filtered through a short pad of Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude product was purified by Combiflash chromatography (8-10% EtOAc in hexanes) to give 4-phenylquinolin-8-amine (100 mg, 81%) as a gray solid. MS (ESI): m / z 221.3 [M+1]+.

[0408] 1-Ethyl-N-(4-phenyl-8-quinolyl)imidazole-2-sulfonamide. To a stirred solution of 4-phenylquinolin-8-amine (80 mg, 0.363 mmol) in pyridine (1 mL, 12.6 mmol) and DCM (4 mL) at 0°C, 1-ethylimidazole-2-sulfonyl chloride (crude, DCM solution) was added dropwise under an argon atmosphere. This mixture was then stirred at 0°C to room temperature for 2 hours. Upon completion, this mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 1-ethyl-N-(4-phenyl-8-quinolyl)imidazole-2-sulfonamide (70 mg, 51%) as an off-white solid. MS (ESI): m / z 379.2 [M+1] + .

[0409] Example 49. 1-Ethyl-N-(5-methylsulfonyl-8-quinolyl)imidazole-2-sulfonamide [ka] 5-Methylsulfonyl-8-nitroquinoline. To a stirring degassed solution of 5-bromo-8-nitroquinoline (150 mg, 0.595 mmol) in DMSO (8 mL) was added sodium methanesulfinate (73 mg, 0.71 mmol), followed by copper iodide (11 mg, 0.06 mmol) and L-proline (14 mg, 0.12 mmol) under an inert atmosphere. The resulting mixture was heated in a sealed tube at 100 °C for 16 h. The reaction mass was cooled to ambient temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography (5-10% EtOAc in hexanes) to give 5-methylsulfonyl-8-nitroquinoline (45 mg, 30%) as an off-white solid. MS (ESI): m / z 253.2 [M+1] + .

[0410] 5-Methylsulfonylquinolin-8-amine. To a stirred solution of 5-methylsulfonyl-8-nitroquinoline (90 mg, 0.35 mmol) in THF-EtOH (10 mL, 1:1 ratio), NHCl (95 mg, 1.78 mmol) and zinc dust (117 mg, 1.78 mmol) were added and stirred at 10 °C for 0.5 h. Upon completion, the reaction mixture was filtered through a short pad of Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude product was purified by Combiflash chromatography (30-35% EtOAc in hexanes) to give 5-methylsulfonylquinolin-8-amine (75 mg, 94%) as a gray solid. MS (ESI): m / z 223.2 [M+1] + .

[0411] 1-Ethyl-N-(5-methylsulfonyl-8-quinolyl)imidazole-2-sulfonamide. To a stirred solution of 5-methylsulfonylquinolin-8-amine (75 mg, 0.34 mmol) in THF (5 mL) at 0°C, NaH (27.0 mg, 0.676 mmol) was added and stirred at the same temperature for 15 min. The resulting mixture was heated at 80°C for 30 min and cooled to 0°C. 1-Ethylimidazole-2-sulfonyl chloride (crude, DCM solution) was added dropwise under an argon atmosphere. The reaction mixture was stirred from 0°C to room temperature for 2 h. Upon completion, it was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 1-ethyl-N-(5-methylsulfonyl-8-quinolyl)imidazole-2-sulfonamide (10 mg, 8%). 1 H NMR(400MHz,DMSO-d6)δ 1.33(t,J=7.0Hz,3H),4.37(q,J=7.0Hz,2H),6.93(s,1H),7.46(s,1H),7.63-7.83(m,2H),7 .92(d,J=8.0Hz,1H),8.49(d,J=8.8Hz,1H),8.90-8.97(m,1H),10.63(brs,1H).MS(ESI):m / z 381.1[M+1]+.

[0412] Example 50. N-(6-fluoro-8-quinolyl)-1-[4-(trifluoromethyl)phenyl]imidazole-2-sulfonamide [ka] 6-Fluoro-8-nitro-quinoline. 4-Fluoro-2-nitro-aniline (10.0 g, 64.06 mmol) and arsenic pentoxide (10.0 g, 12.82 mmol) were dissolved in a mixture of sulfuric acid (32.0 mL, approximately 70%) and water (20.0 mL). The resulting mixture was heated to 80° C., and ADEA (15.0 mL, 96.086 mmol) was added dropwise over 1 hour. The reaction mixture was then heated to 120° C. for 90 minutes. It was cooled to ambient temperature, poured into an ice / water mixture (200 mL), and filtered. Aqueous ammonia was added dropwise to adjust the pH to approximately 6, and the mixture was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography (10% EtOAc in hexanes) to give 6-fluoro-8-nitro-quinoline (6.5 g, 53%) as a yellow solid. MS (ESI): m / z 193.2 [M+1]+.

[0413] 6-Fluoroquinolin-8-amine. To a stirred solution of 6-fluoro-8-nitroquinoline (3.43 g, 17.86 mmol) in THF-EtOH-HO (42 mL, 3:2:1 ratio), NHCl (1.43 g, 26.8 mmol) and Fe powder (4.98 g, 89.3 mmol) were added and stirred at 90 °C for 2 h. Upon completion, the reaction mixture was filtered through a short pad of Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude product was purified by Combiflash chromatography (10-20% EtOAc in hexanes) to give 6-fluoroquinolin-8-amine (1.5 g, 52%) as a brown solid. MS (ESI): m / z 163.3 [M+1]+.

[0414] 1-Isothiocyanato-4-(trifluoromethyl)benzene. To a stirred solution of 4-(trifluoromethyl)aniline (1 g, 6.21 mmol) in DCM (20 mL), 1-[(2-oxo-1,2-dihydropyridin-1-yl)carbothioyl]-1,2-dihydropyridin-2-one (1.58 g, 6.83 mmol) was added portionwise and stirred at room temperature for 3 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to afford 1-isothiocyanato-4-(trifluoromethyl)benzene (1.2 g, crude) as a brownish solid, which was used directly in the next step without further purification.

[0415] 1-[4-(Trifluoromethyl)phenyl]imidazole-2-thiol. To a stirred solution of 1-isothiocyanato-4-(trifluoromethyl)benzene (1.2 g, 5.91 mmol, crude) in toluene (10 mL) was added dropwise 2,2-diethoxyethan-1-amine (1.28 g, 8.87 mmol) at room temperature and stirred for 2 hours. Concentrated HCl (2 mL) was added to the reaction mixture, which was stirred at 100° C. for 16 hours. Upon completion, the reaction mixture was evaporated to dryness, and the residue was diluted with water. The aqueous portion was basified to pH 8 with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography (30-40% ethyl acetate in hexane) to give 1-[4-(trifluoromethyl)phenyl]imidazole-2-thiol (1.2 g, 83% yield, 2 steps) as an off-white solid. MS(ESI): m / z 245.3 [M+1] + .

[0416] 1-[4-(Trifluoromethyl)phenyl]imidazole-2-sulfonyl chloride. 1-[4-(Trifluoromethyl)phenyl]imidazole-2-thiol (300.0 mg, 1.23 mmol) was cooled to -10 °C, and 1(N)HCl (10 mL) was added dropwise with constant stirring and stirred for 10 min. NaOCl (18 mL) was added dropwise over 30 min, and stirring was continued for an additional 0.5 h. This was quenched with ice water and extracted with DCM. The combined organic layers were washed with cold brine, dried over MgSO (cooled flask), filtered on a sintered funnel, and partially concentrated at low temperature. The DCM solution of 1-[4-(trifluoromethyl)phenyl]imidazole-2-sulfonyl chloride was used directly in the next step without further purification.

[0417] N-(6-Fluoro-8-quinolyl)-1-[4-(trifluoromethyl)phenyl]imidazole-2-sulfonamide. To a stirred 0°C solution of 6-fluoroquinolin-8-amine (100 mg, 0.617 mmol) in pyridine (2 mL, 25.2 mmol) and DCM (10 mL) was added 1-[4-(trifluoromethyl)phenyl]imidazole-2-sulfonyl chloride (crude, DCM solution) dropwise under an argon atmosphere. This was stirred from 0°C to room temperature for 2 hours. Upon completion, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give N-(6-fluoro-8-quinolyl)-1-[4-(trifluoromethyl)phenyl]imidazole-2-sulfonamide (12 mg, 5%). 1 H NMR(400MHz,DMSO-d6)δ 7.19(s,1H),7.43-7.55(m,2H),7.65-7.67(m,4H),7.82(d,J=8.3Hz,2H),8.4 0(d,J=8.1Hz,1H),8.80(dd,J=1.6,4.2Hz,1H),10.60(brs,1H).MS(ESI):m / z 437.2[M+1]+.

[0418] Example 51. N-[5-(4-fluorophenyl)quinolin-8-yl]-1-(2,2,2-trifluoroethyl)-1H-imidazole-2-sulfonamide [ka] 5-(4-Fluorophenyl)-8-nitroquinoline. To a stirred solution of 5-bromo-8-nitroquinoline (1 g, 3.97 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was added K2CO3 (1.37 g, 9.92 mmol) and (4-fluorophenyl)boronic acid (667 mg, 4.76 mmol). The resulting mixture was purged with argon for 5 minutes. X-phos (296 mg, 0.4 mmol) and Pd(dppf)Cl2.DCM (162 mg, 0.2 mmol) were added under an inert atmosphere. The resulting mixture was heated at 100 °C for 16 hours. Upon completion, the reaction mixture was cooled to room temperature, filtered through a short pad of Celite, and washed with ethyl acetate. The filtrate portion was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Combiflash column chromatography (35-40% EtOAc in hexanes) to give 5-(4-fluorophenyl)-8-nitroquinoline (700 mg, 66%) as a yellow solid. MS (ESI): m / z 268.9 [M+1] + .

[0419] 5-(4-Fluorophenyl)quinolin-8-amine. To a stirring degassed solution of 5-(4-fluorophenyl)-8-nitroquinoline (700 mg, 2.61 mmol) in THF (20 mL) was added 10% Pd-C (700 mg) and hydrogenated under a balloon atmosphere at room temperature for 3 h. Upon completion, the reaction mixture was filtered through a short pad of Celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure, and the crude product was purified by CombiFlash column chromatography (25-30% EtOAc in hexanes) to give 5-(4-fluorophenyl)quinolin-8-amine (350 mg, 56%) as a yellow solid. MS (ESI): m / z 238.6 [M+1] + .

[0420] N-[5-(4-fluorophenyl)quinolin-8-yl]-1-(2,2,2-trifluoroethyl)-1H-imidazole-2-sulfonamide. To a stirred solution of 5-(4-fluorophenyl)quinolin-8-amine (100 mg, 0.42 mmol) in pyridine (2 mL) and DCM (4 mL) at 0° C., 1-(2,2,2-trifluoroethyl)-1H-imidazole-2-sulfonyl chloride (230 mg, 0.92 mmol) dissolved in DCM (8 mL) was added dropwise under an inert atmosphere. The resulting mixture was warmed to room temperature and stirred for 3 hours. Upon completion, it was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Combiflash column chromatography (65-70% EtOAc in hexanes) to give N-[5-(4-fluorophenyl)quinolin-8-yl]-1-(2,2,2-trifluoroethyl)-1H-imidazole-2-sulfonamide (55 mg, 29%). 1 H NMR(400MHz,DMSO-d6)δ 5.48(q,J=8.8Hz,2H),7.08(d,J=0.8Hz,1H),7.31-7.42(m,2H),7.46-7.56(m,4H),7.59(dd,J=4.2,8.6Hz,1H) ,7.89(d,J=7.9Hz,1H),8.18(dd,J=1.6,8.6Hz,1H),8.90(dd,J=1.6,4.2Hz,1H),10.83(brs,1H).MS(ESI):m / z 451.2[M+1] + .

[0421] Example 52. N-(5-bromoquinolin-8-yl)-1-ethyl-1H-imidazole-2-sulfonamide [ka] 1-Ethylimidazole-2-sulfonyl chloride. 1-Ethylimidazole-2-thiol (300 mg, 3.44 mmol) was placed in a two-neck round-bottom flask and cooled to -10 °C. Concentrated H2SO4 (5 mL) was added dropwise slowly with constant stirring and stirred at -10 °C for an additional 10 min. The reaction mixture was cooled to -15 °C, and NaOCl (15 mL) was added dropwise over 30 min and stirred at -10 °C for an additional 30 min. Upon completion, the reaction mixture was quenched with ice water and extracted with cold DCM. The combined organic layers were washed with cold brine, dried over MgSO4 (pre-cooled flask), filtered on a sintered funnel, and partially concentrated at low temperature to give 1-ethylimidazole-2-sulfonyl chloride as a DCM solution, which was used directly in the next step without further purification.

[0422] N-(5-bromoquinolin-8-yl)-1-ethyl-1H-imidazole-2-sulfonamide. To a stirred solution of 5-bromoquinolin-8-amine (100 mg, 0.45 mmol) in DCM (3 mL) at 0° C., pyridine (2 mL) was added and stirred at 0° C. for 10 minutes. 1-Ethyl-1H-imidazole-2-sulfonyl chloride (193 mg, 0.99 mmol in DCM) was added under cooled conditions, and the resulting mixture was stirred at room temperature for 2 hours. Upon completion, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give N-(5-bromoquinolin-8-yl)-1-ethyl-1H-imidazole-2-sulfonamide (30 mg, 17%). 1 H NMR(400MHz,DMSO-d6)δ 1.33(t,J=7.0Hz,3H),4.37(q,J=7.0Hz,2H),6.93(s,1H),7.46(s,1H),7.63-7.83(m,2H),7 .92(d,J=8.0Hz,1H),8.49(d,J=8.8Hz,1H),8.90-8.97(m,1H),10.63(brs,1H).MS(ESI):m / z 381.1[M+1] + .

[0423] Example 53. N-(3-acetylquinolin-8-yl)-1-ethyl-1H-imidazole-2-sulfonamide [ka] 1-(8-Nitroquinolin-3-yl)ethan-1-one. To a stirred solution of 3-bromo-8-nitroquinoline (252 mg, 1 mmol) in toluene (3 mL) was added triphenylphosphine (21 mg, 0.08 mmol) under an argon atmosphere, followed by Pd(dba)2 (23 mg, 0.04 mmol) and stirring at room temperature for 15 minutes. A solution of tributyl(1-ethoxyvinyl)stannane (0.34 mL, 1 mmol) in toluene (2 mL) was added, and the resulting mixture was heated at 110 °C for 1 hour. It was cooled to room temperature, and 1(N) HCl (10 mL) was added. The resulting mixture was kept at room temperature for 24 hours. After completion, it was neutralized with 1(N) NaOH and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Combiflash column chromatography (30-35% EtOAc in hexanes) to give 1-(8-nitroquinolin-3-yl)ethan-1-one (160 mg, 74%) as a yellowish solid. MS (ESI): m / z 217.08 [M+1] + .

[0424] 1-(8-Aminoquinolin-3-yl)ethan-1-one. To a stirred solution of 1-(8-nitroquinolin-3-yl)ethan-1-one (110 mg, 0.51 mmol) in a 3:3:1 mixture of THF-EtOH-water (10 mL) was added ammonium chloride (41 mg, 0.76 mmol), followed by iron powder (143 mg, 2.55 mmol). The resulting mixture was stirred at 90 °C for 2 h. Upon completion, the reaction mixture was filtered through a short pad of Celite and washed with dichloromethane. The filtrate portion was evaporated under reduced pressure, diluted with dichloromethane and water, and the layers were separated. The aqueous layer was back-extracted with dichloromethane. The combined organic layers were washed with aqueous NaHCO3, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Combiflash column chromatography (15-20% EtOAc in hexanes) to give 1-(8-aminoquinolin-3-yl)ethan-1-one (80 mg, 84%) as an off-white solid. MS (ESI): m / z 187.23 [M+1] + .

[0425] N-(3-acetylquinolin-8-yl)-1-ethyl-1H-imidazole-2-sulfonamide. To a stirred solution of 1-(8-aminoquinolin-3-yl)ethan-1-one (70 mg, 0.38 mmol) in DCM (3 mL) at 0° C., pyridine (2 mL) was added and stirred at 0° C. for 10 minutes. 1-Ethyl-1H-imidazole-2-sulfonyl chloride (110 mg, 0.56 mmol in DCM) was added under cooling conditions, and the resulting reaction mixture was stirred at room temperature for 2 hours. Upon completion, the reaction mixture was diluted with water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Combiflash column chromatography (25-30% EtOAc in hexanes) to give N-(3-acetylquinolin-8-yl)-1-ethyl-1H-imidazole-2-sulfonamide (46 mg, 35%). 1H NMR(400MHz,DMSO-d6)δ 1.32(t,J=7.1Hz,3H),2.72(s,3H),4.37(q,J=6.8Hz,2H),6.92(s,1H),7.41(s,1H),7.64(t, J=8.0Hz,1H),7.88(d,J=7.2Hz,2H),9.03(s,1H),9.22(s,1H),10.60(brs,1H).MS(ESI):m / z 345.2[M+1] + .

[0426] Example 54. N-[3-(dimethylamino)quinolin-8-yl]-1-ethyl-1H-imidazole-2-sulfonamide [ka] N,N-Dimethyl-8-nitroquinolin-3-amine. To a stirred, degassed solution of 3-bromo-8-nitroquinoline (300 mg, 1.19 mmol) in toluene (8 mL) in a sealed tube, cesium carbonate (773 mg, 2.37 mmol), rac-BINAP (111 mg, 0.18 mmol), and then Pd2(dba)3 (109 mg, 0.12 mmol) were added and purged with argon for an additional 5 minutes. N,N-Dimethylamine (2 M in THF, 6 mL, 12 mmol) was added and stirred at 100 °C for 16 hours. Upon completion, the reactio...

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, --- is a single bond or a double bond; Each A is independently N or CR １ and Each R １ are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, heteroarylalkyl; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino; imino; imido; amidino; enamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkoxyamino; thio(-SH)sulfonyl; alkylsulfonyl, aminosulfonyl; acyl; formyl; carboxy; ester; carbamate; amido; or cyano, each of which is optionally further substituted; R ２ is a substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R is absent, H, substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl, or CO(substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl); m is 0 to 3; n is 0 to 3; and p is 0 to 3; provided that m and n are not both 0; When any of the above-described groups are described as "substituted", each of these groups is optionally further substituted with halogen; alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, cycloalkylalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl, hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy; oxo (=O); oxide; amino, alkylamino, cycloalkylamino, arylamino, heptagon ... and -B(OH)2, optionally substituted with one or more substituents selected from: tetracyclylamino, heteroarylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxyamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amide; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; and -B(OH)2. or a pharma- ceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

2. m is 2, n is 1, and A is CR １ 2. The compound of claim 1,

3. m is 1, n is 1, and A is CR １ 2. The compound of claim 1,

4. m is 3, n is 0, and A is CR １ 2. The compound of claim 1,

5. m is 2, n is 0, and A is CR １ 2. The compound of claim 1,

6. The compound according to any one of claims 1 to 5, wherein -- is a single bond.

7. R １ The compound according to any one of claims 1 to 6, wherein is H and p is 0.

8. R ２ but, a. Halogen, CN, substituted or unsubstituted C １～４ Alkyl, substituted or unsubstituted C ３～６ Cycloalkyl, -OR and -NR ２ 2-pyridyl substituted by one or more substituents independently selected from: b. Substituted or unsubstituted C １～４ Alkyl, substituted or unsubstituted C ３～６ Cycloalkyl, (C １～３ Alkyl) (substituted or unsubstituted C ３～６ 2-imidazolyl substituted with one or more substituents independently selected from aryl, cycloalkyl, and substituted or unsubstituted aryl; c. Substituted or unsubstituted C １～４ pyrazyl substituted by one or more substituents independently selected from alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, and -OR; d. pyrazolyl, unsubstituted or substituted with substituted or unsubstituted C1-4 alkyl; e. 2-furanyl unsubstituted or substituted with one or more C1-4 alkyl groups The compound according to any one of claims 1 to 7,

9. R is H or substituted or unsubstituted C １～４ Alkyl or substituted or unsubstituted C ３～６ The compound of any one of claims 1 to 8, which is cycloalkyl.

10. Formula (Ia) 【Chemistry 2】 [In the formula, Each R １ are independently halogen, —CN, substituted or unsubstituted C １～４ Alkyl, substituted or unsubstituted C ３～７ Cycloalkyl, substituted or unsubstituted acyl, substituted or unsubstituted C １～４ sulfonyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, or -OR; R ２ teeth, a. Halogen, CN, substituted or unsubstituted C １～４ Alkyl, substituted or unsubstituted C ３～６ Cycloalkyl, -OR and -NR ２ 2-pyridyl or 3-pyridyl substituted by one or more substituents independently selected from: b. Substituted or unsubstituted C １～４ Alkyl, substituted or unsubstituted C ３～６ Cycloalkyl, (C １～３ Alkyl) (substituted or unsubstituted C ３～６ 2-imidazolyl substituted with one or more substituents independently selected from aryl, cycloalkyl, and substituted or unsubstituted aryl; c. Substituted or unsubstituted C １～４ Alkyl, substituted or unsubstituted C ３～６ Cycloalkyl and (C １～３ Alkyl) (substituted or unsubstituted C ３～６ 5-imidazolyl substituted by one or more substituents independently selected from: d. Substituted or unsubstituted C １～４ Alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, -OR and NR ２ PyraZyl substituted by one or more substituents independently selected from: e. unsubstituted or one or more substituted or unsubstituted C １～４ Alkyl-substituted pyrazolyl; f. Unsubstituted or one or more C １～４ Alkyl-substituted 2-furanyl and Each R is independently selected from H and substituted or unsubstituted C １～４ Alkyl, (C １～３ Alkyl), (substituted or unsubstituted C ３～６ cycloalkyl) or substituted or unsubstituted aryloxy; n is 1 to 3. or a pharma- ceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof, with the proviso that the compound is not 5-cyano-N-[5-(trifluoromethyl)-8-quinolinyl]-2-pyridinesulfonamide.

11. Each R is independently -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH ２ CH (CH ３ ) ２ , -CH(CH ３ ) ２ or -CH ２ 11. The compound of claim 10, wherein the compound is (cyclopropyl).

12. 12. The compound according to claim 10 or 11, wherein n is 1 or 2.

13. Each R １ are independently F, Cl, Br, CN, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH ２ CH (CH ３ ) ２ , -CF ３ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ ) ２ , -OCH ２ (cyclopropyl), azetidinyl, -N(CH ３ ) ２ , -C(O)CH ３ , benzoyl, methylsulfonyl, phenyl, -O-(m-trifluoromethyl)phenyl or p-fluorophenyl, pyrrolidyl, piperidyl, piperazinyl or morpholinyl.

14. R ２ is F, Cl, -CN, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , cyclopropyl, cyclobutyl, cyclopentyl, -OCH ３ , -OCH ２ CH ２ CH ３ , -OCH ２ CH (CH ３ ) ２ , -NH ２ , -NHCH ３ and -N(CH ３ ) ２ The compound of any one of claims 10 to 13, which is 2-pyridyl substituted with one or more substituents independently selected from:

15. R ２ is F, Cl, -CN, -CH ３ , -CH ２ CH ３ and -CF ３ The compound of any one of claims 10 to 14, which is 3-pyridyl substituted with one or more substituents independently selected from:

16. R ２ But -CH ３ , -CH ２ CH ３ , -CH ２ CF ３ , cyclopropyl, -CH ２ CH (CH ３ ) ２ 16. The compound of any one of claims 10 to 15, which is 2-imidazolyl substituted with one or more substituents independently selected from: phenyl and p-trifluoromethylphenyl.

17. R ２ But -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , cyclopropyl and CH ２ 17. The compound of any one of claims 10 to 16, which is 5-imidazolyl substituted with one or more substituents independently selected from: -cyclopropyl.

18. R ２ is unsubstituted or -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH ２ CH (CH ３ ), -OCH ３ , -OCH ２ CH ３ , -OCH ２ CH ２ CH ３ , -OCH ２ CH (CH ３ ) ２ , -N(CH ３ ) ２ 18. The compound according to any one of claims 10 to 17, which is 2-pyrazyl substituted with one or more substituents independently selected from pyrrolidyl, piperidyl, piperazinyl and morpholinyl.

19. R ２ is unsubstituted or -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ and -CH(CH ３ ) ２ 19. The compound of any one of claims 10 to 18, which is 2-pyrazolyl substituted with one or more substituents independently selected from:

20. Each R １ are independently F, Cl, -CH ３ , -CH ２ CH ２ CH ３ , C.F. ３ , cyclohexyl, -OCH ３ , -OCH(CH ３ ) ２ , -OCH ２ (cyclopropyl), azetidinyl, phenyl or morpholinyl, and R ２ is F, Cl, CN, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH ２ CH (CH ３ ) ２ , cyclopropyl, cyclobutyl, cyclopentyl, -OCH ３ , -OCH ２ CH ３ , -OCH ２ CH ２ CH ３ , -OCH ２ CH (CH ３ ) ２ , -NH ２ , -NHCH ３ and -N(CH ３ ) ２ 11. The compound of claim 10, which is 2-pyridyl substituted with one or more substituents independently selected from:

21. Each R １ are independently F, -CH ３ or -OCH ３ and R ２ But -CF ３ The compound of claim 10, which is 3-pyridyl substituted with

22. Each R １ are independently F, Cl, Br, CN, -CH ３ , -CH ２ CH ３ , -CF ３ , cyclohexyl, -OCH ３ , -N(CH ３ ) ２ , -C(O)CH ３ , benzoyl, methylsulfonyl, morpholinyl, phenyl, -O-(m-trifluoromethyl)phenyl or p-fluorophenyl, and R ２ But -CH ３ , -CH ２ CH ３ , -CH ２ CF ３ , -CH ２ CH ２ CH ３ , cyclopropyl, -CH ２ CH (CH ３ ) ２ 11. The compound of claim 10, which is 2-imidazolyl substituted with one or more substituents independently selected from: phenyl and p-trifluoromethylphenyl.

23. Each R １ is independently Cl or morpholinyl, and R ２ is -CH(CH ３ ) ２ or -CH ２ 11. The compound of claim 10, which is 5-imidazolyl substituted with one or more substituents independently selected from: -cyclopropyl.

24. Each R １ are independently F, Cl, -CH ３ , -CH ２ CH ３ , -CF ３ , cyclohexyl, -OCH ３ or morpholinyl, and R ２ But -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH ２ CH (CH ３ ) ２ , -OCH ３ , -OCH ２ CH ３ , -OCH ２ CH ２ CH ３ , -OCH ２ CH (CH ３ ) ２ , -N(CH ３ ) ２ 11. The compound of claim 10, which is 2-pyrazyl substituted with one or more substituents independently selected from pyrrolidyl, piperidyl, piperazinyl and morpholinyl.

25. Each R １ is independently F or morpholinyl, and R ２ is unsubstituted or -CH ３ and -CH(CH ３ ) ２ 11. The compound of claim 10, which is 2-pyrazolyl substituted with one or more substituents independently selected from:

26. Table 1: The compound according to any one of claims 1 to 10, selected from:

27. Table 2: Any one compound selected from:

28. Table 4: Any one compound selected from:

29. 29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof, and a pharma- ceutically acceptable carrier, excipient or vehicle.

30. 29. A medicament for killing heartworms, comprising a compound according to any one of claims 1 to 28 or a pharma- ceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

31. 29. A medicament for inhibiting heartworm growth or molting, comprising a compound according to any one of claims 1 to 28 or a pharma- ceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

32. A drug for killing heartworms, comprising the compound of Table 3: or a pharma- ceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

33. 1. A drug for inhibiting heartworm growth or molting, comprising the compound of Table 3: or a pharma- ceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

34. 29. A medicament for inhibiting heartworm motility, comprising a compound according to any one of claims 1 to 28 or a pharma- ceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

35. A drug for inhibiting heartworm motility, comprising the compound of Table 3: or a pharma- ceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

36. 29. A medicament for the treatment or prevention of helminth infections and diseases, comprising a compound according to any one of claims 1 to 28 or a pharma- ceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

37. The method of claim 36, wherein the helminth infection is a heartworm infection.

38. 2. A medicament for the treatment or prevention of helminth infections and diseases, comprising: or a pharma- ceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

39. 39. The method of claim 38, wherein the helminth infection is a heartworm infection.

40. 29. A medicament for the treatment or prevention of helminth infections and diseases, comprising a compound according to any one of claims 1 to 28 or a pharma- ceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof, in combination with one or more anti-helminthic drugs.

41. The method of claim 40, wherein the helminth infection is a heartworm infection.

42. TABLE 3 Drugs for the treatment or prevention of helminth infections and diseases, characterized in that they are used in combination with one or more anti-helminthic drugs: or a pharma- ceutically acceptable salt, tautomer, isotope or stereoisomer thereof.

43. The method of claim 42, wherein the helminth infection is a heartworm infection.

44. 43. The method of claim 40 or 42, wherein the anti-helminthic drug is selected from flubendazole, albendazole, mebendazole, thiabendazole, fenbendazole, triclabendazole, ivermectin, abamectin, diethylcarbamazine (DEC), suramin, pyrantel pamoate, levamisole, niclosamide, nitazoxanide, oxyclozanide, praziquantel, emodepside, monepantel, delquantel or pelletierine sulfate.

45. 43. The method of claim 40 or 42, wherein the anti-helminthic drug is a Wolbachia targeted drug.

46. 46. ​​The method of claim 45, wherein the Wolbachia targeted drug is doxycycline.

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