Sulfonamides and their use for treating parasitic helminth infections and diseases

Abstract

Provided herein are sulfonamide compounds of Formula I: and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof, wherein R 1 , R 2 , R, A, m, n, and p are as defined herein, compositions comprising an effective amount of a sulfonamide compound, and methods for treating or preventing animal and human filarial infections and diseases.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 147,710, filed February 9, 2021, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] This document discloses compounds and methods for the prevention and / or treatment of parasitic helminth infections and diseases caused by parasitic helminth infections. This document discloses compounds and methods for the prevention and / or treatment of parasitic helminthiasis. This document also provides such compounds for use in such methods. This document further discloses pharmaceutical compositions comprising such compounds for use in such methods for the prevention or treatment of parasitic helminth infections and / or diseases associated with parasitic helminth infections. Background Technology

[0004] There are several types of parasitic worms, the most common worldwide being intestinal nematodes or soil-borne parasitic worms (STH), schistosomes (the parasites that cause schistosomiasis), and filarial worms that cause lymphatic filariasis (LF) and onchocerciasis. Filariasis is a parasitic disease caused by filariasis nematodes or roundworms. It is a vector-borne disease transmitted through insect bites. Infectious larvae of nematodes can be introduced into humans through the bite of blood-sucking insects such as mosquitoes or flies. Filariasis can also affect domestic animals such as dogs. In dogs, diabetic filariasis (also known as heartworm) is caused by nematodes called *Dirofilaria immitis* and *Dirofilaria repens*. Diabetic filariasis is considered endemic in 49 states in the United States. The vector is also blood-sucking insects such as mosquitoes.

[0005] The primary causes of human filariasis are species of the nematodes *Wuchereria bancrofti*, *Brugia malayi*, *Brugia timori*, *Onchocerca volvulus*, and *Mansonella* that host human hosts. *Wuchereria bancrofti*, *Brugia malayi*, and *Onchocerca volvulus* are the most debilitating filariasis infections in over 80 developing countries in tropical and subtropical regions, putting 1.1 billion people at risk of infection, with approximately 150 million already infected. All three species are the root cause of severe pathology, leading to high morbidity and increased mortality. Infection can result in severe morbidity in up to 50% of those infected with these nematodes.

[0006] Infections with *Wuceta banois* and *Brucella malayi* can develop into lymphatic filariasis, often manifesting as hydrocoele and / or lymphedema in men and, in extreme cases, elephantiasis. Onchocerciasis infection can develop into severe dermatitis and / or onchocerciasis, with visual impairment leading to the latter condition commonly known as river blindness. Community-guided large-scale drug administration programs aim to control and eliminate these infections (as a public health issue).

[0007] Current efforts aim to eliminate these parasitic nematodes by using drugs that kill the larvae rather than the adults (such as diethylcarbazine, ivermectin, and albendazole). In countries without a co-endemic onchocerciasis infection (i.e., outside of Africa), the antiparasitic worm drug diethylcarbazine is used against lymphatic filariasis. Ivermectin is used against onchocerciasis. The greatest efficacy of both drugs is against the first-stage larvae found in the bloodstream or dermis. Because the worms can live up to 14 years and are capable of reproduction for most of their lifespan, high coverage (at least 65%) of the population in endemic areas must be treated for many years to prevent the spread of the disease to uninfected individuals.

[0008] Two major limitations in the treatment of filariasis are (i) the lack of macrofilaricidal drugs (or, for onchocerca volvulus, drugs that permanently kill the worms) and (ii) the risk of worms developing resistance. For example, currently available treatments for onchocerca volvulus include ivermectin, which kills worm larvae but has little or no activity against adult onchocerca volvulus parasites. Therefore, infected patients must be treated with ivermectin for several years until the adults die naturally. In addition, in a few areas, there are potential signs of ivermectin resistance within the parasite. Osei-Atweneboana MY et al., Phenotypic Evidence of Emerging Ivermectin Resistance in Onchocerca volvulus, PLoS Negl Trop Dis [PLoS Negled Tropical Diseases] 5(3):e998 (2011). Furthermore, there are risks associated with ivermectin treatment in patients co-infected with (i) *Wuceta banois*, *Brucella malayi*, *Brucella tibenzia*, and / or *Onchocerca salina*; and (ii) *Loa loa*. In such co-infected patients, ivermectin treatment can cause serious reactions, including encephalopathy (leading to coma or even death).

[0009] Heartworm infection caused by the endoparasite *Dirofilaria immitis* (D. immitis) can be a serious and life-threatening disease in animals such as dogs and cats. Heartworms have a complex life cycle involving several stages before they mature into adult worms that eventually infect the pulmonary arteries of their host animals. Heartworm transmission also requires mosquitoes as intermediate hosts to complete this life cycle. For example, the heartworm life cycle and transmission process begins with a mosquito biting a previously infected dog and ingesting blood containing heartworm microfilariae (larval stage 1). Inside the mosquito, the microfilariae molt over a two-week period to become infective larval stage 3 (L3) worms. Once the mosquito bites another dog, the infective L3 worms migrate into the host through the bite wound and migrate into the tissues, where they begin to molt into larval stage 4 (L4) worms (usually within 1 to 3 days after infection). Subsequently, the L4 worm continues to migrate within the tissues and molts into a sexually immature or "adolescent" adult (larval stage 5, immature adult) approximately 50-70 days post-infection. The sexually mature worms eventually migrate to the dog's heart and lungs (as early as 70 days post-infection). Approximately 6-7 months post-infection, the adult *Heartworm* reaches maturity and undergoes sexual reproduction in the pulmonary artery, leading to the production and circulation of microfilariae (MF) in the dog's blood, thus completing the heartworm life cycle.

[0010] The most commonly used heartworm prophylactants are macrolides (MLs), such as ivermectin, moxifloxacin, and slacutane. These agents are administered monthly to kill L3 and L4 canine heartworms acquired by the host within the first 30 days. Their primary action is to interrupt the heartworm life cycle by killing L3 and L4 worms, thus preventing adult formation and subsequent disease. Despite their high effectiveness in preventing heartworm disease, due to the potential of MLs to kill circulating microfilariae, it is recommended that owners test their dogs for existing heartworm infection (i.e., heartworm-positive dogs) before initiating treatment with them. A rapid decrease in the number of microfilariae in the blood can lead to hypersensitivity reactions and circulatory shock (e.g., anaphylactic reactions), presumably due to dead or dying microfilariae. These potential side effects can be life-threatening for dogs and are therefore presented as warnings on many ML product labels. Therefore, the discovery of novel heartworm prophylactants that selectively target L3 and L4 stage worms, compared to those targeting microfilariae, would offer a potential safety advantage. By not killing circulating microfilariae in heartworm-positive dogs, targeted therapy will prevent the side effects known to occur with other heartworm prophylactants that lack selectivity for canine heartworm stages.

[0011] Therefore, alternative and more effective treatments for filariasis are needed.

[0012] Any reference or designation in this application shall not be construed as an admission that the reference is prior art. Summary of the Invention

[0013] This article provides sulfonamide compounds having formula (I):

[0014]

[0015] And its pharmaceutically acceptable salts, tautomers, isotopes, and stereoisomers, of which R 1 R 2 R, A, m, n, and p are as defined in this paper.

[0016] This article provides sulfonamide compounds having formula (Ia):

[0017]

[0018] And its pharmaceutically acceptable salts, tautomers, isotopes, and stereoisomers, of which R 1 R 2 And n is as defined in this article.

[0019] In one respect, this document provides sulfonamide compounds as described in this disclosure, such as sulfonamide compounds having formula (I), formula (Ia) or formula (II), or compounds from Table 1, Table 2, Table 3 or Table 4.

[0020] In one respect, this document provides sulfonamide compounds as described in this disclosure, such as sulfonamide compounds having formula (I), formula (Ia) or formula (II), or compounds from Table 1 or Table 2.

[0021] In one aspect, this document provides pharmaceutical compositions comprising an effective amount of a sulfonamide compound as described herein, and a pharmaceutically acceptable carrier, excipient, or mediator. In some embodiments, the pharmaceutical compositions are suitable for oral, parenteral, mucosal, transdermal, or topical application.

[0022] On one hand, this article provides methods for treating subjects infected with parasitic worms. On the other hand, this article provides the use of sulfonamide compounds for the treatment or prevention of parasitic worm infections, comprising administering an effective amount of a sulfonamide compound as described herein to a subject affected by a parasitic worm infection. In one aspect, the parasitic worm infection is a filarial infection.

[0023] On the one hand, this article provides methods for treating subjects infected with filariasis. On the other hand, this article provides the use of sulfonamide compounds for the treatment or prevention of filariasis infection, including administering an effective amount of the sulfonamide compound as described herein to a subject affected by filariasis infection.

[0024] In some embodiments, the method described herein includes administering to a subject a therapeutically effective amount of a compound having formula (I), (Ia), (II) or a compound from Table 1 or Table 2, Table 3, or Table 4, or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof.

[0025] In some embodiments, the method described herein includes administering to a subject a therapeutically effective amount of a compound having formula (I), (Ia), (II) or a compound from Table 1 or Table 2, or Table 3, or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof.

[0026] The compounds of the present invention can be used to treat parasitic worm diseases, wherein the parasitic worms are divided into cestodes, nematodes (roundworms) and trematodes (flatworms or flukes). Non-restricted examples of filarial nematodes within the family Onchoceridae include the following genera: *Brugia* spp. (i.e., *Brugia pahangi*, *Brugia timeniensis*, etc.), *Wuchereria* spp. (i.e., *Wuchereria bancrofti*, etc.), *Dirofilaria* spp. (*Dirofilaria canis*, *Dirofilaria grosvenorii*, *Dirofilaria ursi*, *Dirofilaria tenuis*, *Dirofilaria spectans*, *Dirofilaria lutrae*, etc.), *Dipetalonema* spp. (i.e., *Dreconditum*, *Dirofilaria repens*, etc.), and *Onchocerca* spp. The genera *Onchocerca gibsoni* (i.e., *Onchocerca gutturosa*, *Onchocerca salina*, etc.), *E. bohmi*, *E. elaphi*, *E. poeli*, *E. sagitta*, *E. schneideri*, etc., *M. ozzardi*, *M. perstans*, etc., and *Loa* species (i.e., *Loa*). In some embodiments, the worm is *Onchocerca salina*. In some embodiments, the worm is *Wuceta banctis*. In some embodiments, the worm is *Brucella malariae*. In some embodiments, the worm is *Brucella tibenziana*. In some embodiments, the worm is *M. mansonia*. In some embodiments, the worm is *Ficus canis*.

[0027] On one hand, this document provides the use of sulfonamide compounds for the treatment or prevention of parasitic worm infections, comprising administering an effective amount of the sulfonamide compound as described herein to a subject affected by a parasitic worm infection. On the other hand, this document provides the use of sulfonamide compounds for the treatment or prevention of filarial infections, wherein these methods comprise administering an effective amount of the sulfonamide compound as described herein to a subject affected by a filarial infection.

[0028] In one aspect, this document provides sulfonamide compounds for use as medicines. In specific embodiments, this document provides sulfonamide compounds for use in methods for treating or preventing parasitic worm infections, the method comprising administering an effective amount of the sulfonamide compound to a subject. In specific embodiments, this document provides sulfonamide compounds for use in methods for treating or preventing filarial infections, the method comprising administering an effective amount of the sulfonamide compound to a subject.

[0029] On the other hand, this article provides a method for preparing sulfonamide compounds as described herein.

[0030] The embodiments of the present invention can be more fully understood by referring to the detailed description and examples, which are intended to illustrate non-limiting embodiments. Attached Figure Description

[0031] Figure 1 The life cycle of L. sigmodontis (a rodent filarial nematode) is shown from microfilariae (L1) to adult stages. Detailed Implementation

[0032] definition

[0033] As used herein, the terms “comprising” and “including” are used interchangeably. The terms “comprising” and “including” should be interpreted as specifying the presence of the stated features or components mentioned, but do not exclude the presence or addition of one or more features or components or groups thereof. Additionally, the terms “comprising” and “including” are intended to include instances covered by the term “consisting of”. Therefore, the term “consisting of” may be used in place of the terms “comprising” and “including” to provide more specific embodiments of the invention.

[0034] The term "composed of" means that the subject matter has at least 90%, 95%, 97%, 98%, or 99% of the features or components of its declared composition. In another embodiment, the term "composed of" excludes any other features or components from any subsequently elaborated scope, except those that are not essential to the desired technical effect.

[0035] As used herein, the term "or" should be interpreted as inclusive "or," meaning any one or any combination thereof. Therefore, "A, B, or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." Exceptions to this definition will only occur when combinations of elements, functions, steps, or behaviors are inherently mutually exclusive in some way.

[0036] As used herein and unless otherwise stated, 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 carbon atoms, 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 alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, etc. An "alkenyl" group 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(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3). Alkyl groups can be substituted or unsubstituted. When the alkyl groups described herein are referred to as “substituted,” they may be substituted with any one or more substituents as seen in the exemplary compounds and examples disclosed herein, and halogens; hydroxyl groups; alkoxy groups; cycloalkyloxy groups, aryloxy groups, heterocyclic alkyloxy groups, heteroaryloxy groups, heterocyclic alkyloxy groups, cycloalkylalkyloxy groups, arylalkyloxy groups, heterocyclic alkyloxy groups, heteroarylalkyloxy groups, heterocyclic alkylalkyloxy groups; oxo (═O); amino groups, alkylamino groups, cycloalkylamino groups, arylamino groups, heterocyclic amino groups, heteroarylamino groups, heterocyclic alkylamino groups; imino groups; imino groups; Amidin; guanidin; enamino; acylamino; sulfonylamino; urea, nitrobenzene; oxime; hydroxyamino; alkoxyamino; arylalkoxyamino; hydrazido; hydrazono; azide; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphono; acyl; formyl; carboxyl; ester; carbamate; acylamino; cyano; isocyanate; isothiocyanate; cyanate; thiocyanate; or -B(OH)2.

[0037] As used herein and unless otherwise stated, a “cycloalkyl” group is a saturated or partially saturated cycloalkyl group having 3 to 10 carbon atoms, having a single ring or multiple fused or bridged rings that may be optionally substituted. In some embodiments, the cycloalkyl group has 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, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, etc., or polycyclic 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, etc. Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, etc. Cycloalkyl groups can be substituted or unsubstituted. Such substituted cycloalkyl groups include, for example, cyclohexanol.

[0038] As used herein and unless otherwise stated, an "aryl" group is an aromatic carbocyclic group having 6 to 14 carbon atoms, comprising a monocyclic ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthracene). In some embodiments, the aryl group contains 6-14 carbons in the ring portion of the group; in other embodiments, it contains 6 to 12 or even 6 to 10 carbon atoms. Specific aryl groups include phenyl, biphenyl, naphthyl, etc. Aryl groups can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.).

[0039] As used herein and unless otherwise stated, a "heteroaryl" group is an aromatic ring system having one to four heteroatoms as ring atoms, wherein the remaining ring atoms are carbon atoms. In some embodiments, the heteroaryl group contains 3 to 6 ring atoms in the ring portion of the group; in other embodiments, it contains 6 to 9 or even 6 to 10 atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In some embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, groups such as pyrrolo, pyrazol, imidazo, triazol, tetrazol, oxazol, isoxazol, benzo[d]isooxazol (e.g., benzo[d]isooxazol), thiazo, pyrrolo, pyridazin, pyrimidin, pyrazin, thienyl, benzothienyl, furanyl, benzofuranyl, indole (e.g., indole-2-one), isoindoline-1-one, azaindoline, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridinyl), inzol, benzo[d]imidazo (e.g., 1H-benzo[d]imidazo), and azabenzimidazol. Imidazolyl (e.g., 1H-imidazo[4,5-b]pyridyl), pyrazolyl, triazolyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolyl, thianaphthalenyl, purine, xanthine, adenine, guanine, quinolinyl, isoquinolinyl, 3,4-dihydroisoquinolin-1(2H)-keto, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. The heteroaryl groups can be substituted or unsubstituted.

[0040] As used herein and unless otherwise stated, a "heterocyclic group" is an aromatic ring system (also called a heteroaryl) or a non-aromatic cycloalkyl (also called a heteroalkyl) in which one to four of the ring carbon atoms are independently substituted by heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In some embodiments, the heterocyclic group comprises 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. The heterocyclic group may also be bonded to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocycle). The heterocyclic group may be substituted or unsubstituted. The heterocyclic group encompasses unsaturated, partially saturated, and saturated ring systems, such as imidazolyl, imidazolinyl, and imidazoalkyl (e.g., imidazoline-4-keto or imidazoline-2,4-diketo) groups. The phrase "heterocyclic group" includes fused-ring substances, including those containing fused aromatic and non-aromatic groups, such as 1- and 2-aminotetrahydronaphthalene, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxacyclopentenyl. The phrase also includes bridging polycyclic systems containing heteroatoms, such as, but not limited to, quinine cyclic groups.Representative examples of heterocyclic groups include, but are not limited to, aziridinyl, aziridinyl, aziridinyl-heptyl, oxadiazinyl, pyrrolyl, imidazoalkyl (e.g., imidazoline-4-one or imidazoline-2,4-diketone), pyrazolyl, thiazoalkyl, tetrahydrothiophene, tetrahydrofuranyl, dioxacyclopentenyl, furanyl, thiophene, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzo[d]isooxazolyl (e.g., benzo[d]isooxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidinyl, piperazinyl (e.g., piperazin-2-one). ), morpholino, thiomorpholino, tetrahydropyrano (e.g., tetrahydro-2H-pyrano), tetrahydrothiarano, oxothiacyclohexyl, dioxyl, dithiaalkyl, pyrano, pyridino, pyrimidino, pyridazino, triazino, dihydropyridino, dihydrodithiinyl, dihydrodithionyl, 1,4-dioxaspiro[4.5]decyl, periperazineso, quininecycloyl, indole (e.g., indole-2-keto), isoindoline-1-keto, dihydroindoline, isoindoline, isoindoline, azaindoline, pyrrolopyridino (e.g., 1H-pyrrolo[2,3-b]pyridino), indazole, indolezineso, benzotriazole Benzyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoimidazolyl (e.g., 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazol-2(3H)-keto), benzofuranyl, benzothiophene, benzothiazolyl, benzooxadiazolyl, benzooxazinyl, benzodithiacinyl, benzooxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiazolyl, benzo[l,3]m-dioxacyclopentenyl, pyrazolopyridyl (e.g., 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl), azabenzimidazolyl, imidazopyridyl (e.g., 1H-imidazolyl) [4,5-b]pyridyl), triazolylpyridyl, isoxazolylpyridyl, purine, xanthine, adenine, guanine, quinolinyl, isoquinolinyl, 3,4-dihydroisoquinolin-1(2H)-one, quinazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthidyl, pteridyl, thianaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazoleyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolylpyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolylpyridyl, tetrahydropyrimidin-2(1H)-one and tetrahydroquinolinyl groups. Representative non-aromatic heterocyclic groups do not include fused-ring substances containing fused aromatic groups.Examples of non-aromatic heterocyclic groups include aziridine, aziridine, aziridine-heptidine, pyrrolidinyl, imidazoalkyl (e.g., imidazoline-4-one or imidazoline-2,4-diketoyl), pyrazolyl, thiazoalkyl, tetrahydrothiophene, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiaranyl, oxothiacyclohexyl, dithiaalkyl, 1,4-dioxaspiro[4.5]decyl, homopiperazinyl, quininecycloyl, or tetrahydropyrimidine-2(1H)-one. Representative substituted heterocyclic groups can be monosubstituted or multisubstituted, such as, but not limited to, pyridyl or morpholinyl groups, which are substituted or disubstituted by various substituents (such as those listed below) 2-, 3-, 4-, 5-, or 6-.

[0041] As used herein and unless otherwise stated, a "cycloalkylalkyl" group is a group having the formula: -alkyl-cycloalkyl, where alkyl and cycloalkyl are as defined above. A substituted cycloalkylalkyl group may be substituted at the alkyl, cycloalkyl, or both alkyl and cycloalkyl moieties of the group. Representative cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl, etc.

[0042] As used herein and unless otherwise stated, an "aralkyl" group is a group having the formula: -alkyl-aryl, where alkyl and aryl are as defined above. A substituted aralkyl group may be substituted at the alkyl, aryl, or both alkyl and aryl moieties of the group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups, as well as aralkyl groups fused to a cycloalkyl group, such as inden-4-ylethyl.

[0043] As used herein and unless otherwise stated, a "heterocyclic alkyl" group is a group having the following formula: -alkyl-heterocyclic, wherein the alkyl and heterocyclic groups are as defined above. A "heteroarylalkyl" group is a group having the following formula: -alkyl-heteroaryl, wherein the alkyl and heteroaryl groups are as defined above. A "heterocyclic alkylalkyl" group is a group having the following formula: -alkyl-heterocyclic alkyl, wherein the alkyl and heterocyclic alkyl groups are as defined above. A substituted heterocyclic alkyl group may be substituted at the alkyl, heterocyclic, or both alkyl and heterocyclic moieties of the group. Representative heterocyclic alkyl groups include, but are not limited to, morpholino-4-ylethyl, morpholino-4-ylpropyl, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indole-2-ylpropyl.

[0044] As used herein and unless otherwise stated, “halogen” means fluorine, chlorine, bromine or iodine.

[0045] As used herein and unless otherwise stated, a “hydroxyalkyl” group is an alkyl group as described above that has been replaced by one or more hydroxyl groups.

[0046] As used herein and unless otherwise stated, an "alkoxy" group is -O-(alkyl), where alkyl is defined above. An "alkylthio" group is -S-(alkyl), where alkyl is defined above.

[0047] As used herein and unless otherwise stated, an "alkoxyalkyl" group is -(alkyl)-O-(alkyl), where alkyl is defined above.

[0048] As used herein and unless otherwise stated, a “cycloalkyloxy” group is -O-(cycloalkyl), where cycloalkyl is defined above.

[0049] As used herein and unless otherwise stated, the "aryloxy" group is -O-(aryl), where aryl is defined above.

[0050] As used herein and unless otherwise stated, a "heterocyclic oxy group" is -O- (heterocyclic group), where the heterocyclic group is defined above. A "heteroaryl oxy group" is -O- (heteroaryl), where the heteroaryl group is defined above. A "heterocyclic alkyl oxy group" is -O- (heterocyclic alkyl), where the heterocyclic alkyl group is defined above.

[0051] As used herein and unless otherwise stated, an "amino" group is a group having the following formula: -NH2, -NH(R) # ), or -N(R # )2, where each R # Independently defined as an alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic (e.g., heteroaryl or heterocycloalkyl), or heterocyclic alkyl (e.g., heteroarylalkyl or heterocycloalkylalkyl) group, each independently being substituted or unsubstituted.

[0052] In one embodiment, the "amino" group is an "alkylamino" group, which is a group having the following formula: -NH-alkyl or –N(alkyl)2, wherein each alkyl group is independently defined above. The terms "cycloalkylamino", "arylamino", "heterocyclicamino", "heteroarylamino", "heterocyclicalkylamino", etc. are similar to the above description of "alkylamino", wherein the term "alkyl" is replaced by "cycloalkyl", "aryl", "heterocyclic", "heteroaryl", "heterocyclic alkyl", etc., respectively.

[0053] As used herein and unless otherwise stated, a “carboxyl” group is a group having the following formula: -C(O)OH.

[0054] As used herein and unless otherwise stated, an "acyl" group is a group having the following formula: -C(O)(R # ) or -C(O)H, where R # As defined above, the "formyl" group is a group having the following formula: -C(O)H.

[0055] As used herein and unless otherwise stated, the "acylamino" group is a group having the following formula: -C(O)-NH2, -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)H # )-C(O)-(R # ), where each R # Defined independently above.

[0056] In one embodiment, the "amide" group is an "amino carbonyl" group, which is a group having the following formula: -C(O)-NH2, -C(O)-NH(R) # ), -C(O)-N(R) # )2, where each R # Defined independently above.

[0057] In one embodiment, the "acylamino" group is an "acylamino" group, which is a group having the following formula: -NH-C(O)H, -NH-C(O)-(R # ), -N(R # -C(O)H, or -N(R)H # )-C(O)-(R # ), where each R # Defined independently above.

[0058] As used herein and unless otherwise stated, the "sulfonylamino" group is a group having the following formula: -NHSO2(R # ) or -N(R # SO2(R) # ), where each R # As defined above.

[0059] As used herein and unless otherwise stated, the "ester" group is a group having the following formula: -C(O)-O-(R # ) or –OC(O)-(R # ), where R # As defined above.

[0060] In one embodiment, the "ester" group is an "alkoxycarbonyl" group, which is a group having the following formula: -C(O)-O-(alkyl), where alkyl is defined above. The terms "cycloalkyloxycarbonyl," "aryloxycarbonyl," "heterocyclic oxycarbonyl," "heteroaryloxycarbonyl," "heterocyclic alkyloxycarbonyl," etc., are similar to the above description of "alkoxycarbonyl," wherein the term "alkoxy" is replaced by "cycloalkyloxy," "aryloxy," "heterocyclic oxy," "heteroaryloxy," "heterocyclic alkyloxy," etc., respectively.

[0061] As used herein and unless otherwise stated, the "carbamate" group is a group having the following formula: -OC(O)-NH2, -OC(O)-NH(R) # ), -OC(O)-N(R) # )2、-NH-C(O)-O-(R # ), or -N(R # )-C(O)-O-(R # ), where each R # Defined independently above.

[0062] As used herein and unless otherwise stated, the "urea" group is a group having the following formula: -NH(CO)NH2, -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, where each R # Defined independently above.

[0063] As used herein and unless otherwise stated, the "sulfinyl" group is a group having the following formula: -S(O)R # , where R # As defined above.

[0064] As used herein and unless otherwise stated, a "sulfonyl" group is a group having the following formula: -S(O)2R # , where R # As defined above.

[0065] As used herein and unless otherwise stated, the "aminosulfonyl" group is a group having the following formula: -SO2NH2, -SO2NH(R # ), or -SO2N(R # )2, where each R # Defined independently above.

[0066] When groups (other than alkyl groups) are referred to herein as “substituted,” they may be substituted by any one or more suitable substituents. Illustrative examples of substituents are those found in the exemplary compounds and examples disclosed herein, as well as halogens; alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, heterocyclic, cycloalkylalkyl, aralkyl, heterocyclic alkyl, heteroarylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, which may optionally be further substituted; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, heterocyclic alkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy, heterocyclic alkylalkyloxy; oxo (═O); oxides (e.g., nitrogen atoms substituted by oxides are referred to as N). -Oxides); amino, alkylamino, cycloalkylamino, arylamino, heterocyclicamino, heteroarylamino, heterocyclicalkylamino; imino; imino; amido; guanidinyl; enamino; acylamino; sulfonylamino; urea, nitrobenzene; oxime; hydroxyamino; alkoxyamino; arylalkoxyamino; hydrazine; acylhydrazine; hydrazine; azide; nitro; thio(-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphonyl oxy; acyl; formyl; carboxyl; ester; carbamate; acylamino; cyano; isocyanate; isothiocyanate; cyanate; thiocyanate; or -B(OH)2.

[0067] As used herein, the term "sulfonamide compound" includes compounds having formula (I), formula (Ia), formula (II), and further examples of compounds having formula (I), formula (Ia), and formula (II) provided herein. For example, the term "sulfonamide compound" includes deuterated compounds having formula (I), formula (Ia), formula (II), and deuterated compounds of Tables 1, 2, 3, or 4. In one embodiment, "sulfonamide compound" is a compound listed in Tables 1, 2, 3, or 4. In some embodiments, the term "sulfonamide compound" includes pharmaceutically acceptable salts, tautomers, isotopes, and / or stereoisomers of the sulfonamide compounds provided herein.

[0068] As used herein, the term "one or more pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases (including inorganic acids and bases as well as organic acids and bases). Suitable pharmaceutically acceptable base addition salts of compounds having formula (I), formula (Ia), formula (II), and the compounds in Tables 1, 2, 3, or 4 include, but are not limited to, metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, and organic salts prepared from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucosamine), 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, vinylsulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroxyethylsulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, viscous 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. Therefore, examples of specific salts include hydrochloride salts and methanesulfonate salts. Others are well known in the field; see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing, Easton, PA (1990) or Remington: The Science and Practice of Pharmacy, 19th edition, Mack Publishing, Easton, PA (1995).

[0069] As used herein and unless otherwise indicated, the terms "stereoisomer" or "stereoisomer-pure" mean a stereoisomer of a sulfonamide compound that is substantially free of other stereoisomers of the compound. For example, a stereoisomer-pure compound having one chiral center will be substantially free of its opposite enantiomers. A stereoisomer-pure compound having two chiral centers will be substantially free of its other diastereomers. Typical stereoisomer-pure compounds contain, by weight, more than about 80% of one stereoisomer of the compound and less than about 20% of other stereoisomers of the compound; more than about 90% of one stereoisomer of the compound and less than about 10% of other stereoisomers of the compound; more than about 95% of one stereoisomer of the compound and less than about 5% of other stereoisomers of the compound; or more than about 97% of one stereoisomer of the compound and less than about 3% of other stereoisomers of the compound. These sulfonamide compounds may have a chiral center and may exist as racemic mixtures, single enantiomers, diastereomers, or mixtures thereof. The examples disclosed herein include all such isomers, including mixtures thereof.

[0070] The embodiments disclosed herein cover the use of pure stereoisomers of such sulfonamide compounds and mixtures thereof. For example, mixtures comprising equal or unequal amounts of enantiomers of a particular sulfonamide compound can 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, New York, 1962); and Wilen, SH., Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, Indiana, 1972).

[0071] It should also be noted that these sulfonamide compounds may include E and Z isomers or mixtures thereof, as well as cis and trans isomers or mixtures thereof. In some embodiments, these sulfonamide compounds are isolated as either E or Z isomers. In other embodiments, these sulfonamide compounds are mixtures of E and Z isomers.

[0072] "Tautomers" refer to the isomers of a compound that exist in equilibrium with each other. The concentration of these isomers will depend on the environment in which the compound is present and will vary depending on, for example, whether the compound is a solid or in an organic solution or an aqueous solution. For example, in aqueous solution, pyrazole can exist in the following isomers, which are referred to as tautomers of each other:

[0073]

[0074] As will be readily understood by those skilled in the art, various functional groups and other structures can exhibit tautomerism, and all tautomers of compounds having formulas (I), (Ia), and (II) are within the scope of this invention.

[0075] It should also be noted that sulfonamide compounds may contain atomic isotopes in non-natural proportions on at least one atom. For example, the compound may contain radioactive isotopes such as tritium ( 3 H), Iodine-125 ( 125 I), sulfur-35( 35 S), or carbon-14 (S), or carbon-14 14 C) Radioactive labeling, or it can be done using carbon-13 ( 13 C), or nitrogen-15 ( 15 N) isotope enrichment. As used herein, an "isotope" is an isotopically enriched compound. The term "isotopically enriched" means having atoms of an isotopic composition other than that of a naturally occurring isotopic composition. "Isotopically enriched" can also refer to a compound containing at least one atom of an isotopic composition other than that of a naturally occurring isotopic composition. The term "isotopic composition" refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds can be used as therapeutic agents (e.g., cancer and inflammation treatments), research reagents (e.g., binding assays), and diagnostic agents (e.g., in vivo imaging agents). All isotopic variants of the sulfonamide compounds described herein, whether or not radioactive, are intended to be covered within the scope of the embodiments provided herein. In some embodiments, isotopes of sulfonamide compounds are provided, for example, isotopes of sulfonamide compounds enriched with carbon-13 or nitrogen-15. As used herein, "deuteration" means that at least one hydrogen (H) has been deuterated (using D or 2H indicates a substitute compound, meaning that the compound is enriched for deuterium at at least one position. It should be noted that if there is a difference between the described structure and the name of the structure, the described structure will be given greater weight.

[0076] As used herein, “inhibit / inhibition” means a relative reduction in a specific response of a given activity (e.g., worm motility) in the presence of a sulfonamide compound. Inhibition of worm motility (e.g., the motility of Onchocerca salina, Brucella malayi, and / or Brucella tiuneensis) can be determined by the assays described herein.

[0077] As used herein, “treatment” means the complete or partial relief of an obstacle, disease, or condition, or the reduction or cessation of the further development or worsening of such symptoms, or the relief or elimination of one or more causes of the obstacle, disease, or condition itself. In one embodiment, the obstacle, disease, or condition is a parasitic worm infection.

[0078] As used herein, “prevention” means delaying and / or preventing the complete or partial onset, recurrence, or spread of a disorder, disease, or condition; preventing a subject from developing a disorder, disease, or condition; or a method of reducing the risk of a subject developing a disorder, disease, or condition. In one embodiment, the disorder, disease, or condition is a parasitic worm infection.

[0079] The term "effective amount" in relation to sulfonamide compounds means an amount sufficient to treat or prevent the impairment, disease, or symptom or symptoms disclosed herein. In one embodiment, the impairment, disease, or symptom is a parasitic worm infection.

[0080] The terms "subject" or "patient" include humans and other primates, as well as domesticated and semi-domesticated animals, including but not limited to poultry, bees, cows, sheep, cattle, goats, pigs, horses, dogs, cats, rabbits, rats, mice, etc. The term "poultry" includes all types of poultry, including but not limited to chickens, turkeys, ducks, geese, katydids, and game birds. In some embodiments, the subject is a human. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. In some embodiments, the subject is livestock. In some embodiments, the subject is a cow. In some embodiments, the subject is a sheep. In another embodiment, the subject is a goat.

[0081] The terms “combination” or “applied in combination” include application as a mixture, simultaneous application with individual formulations, and sequential application in any order.

[0082] As used herein, the term "helminthic infections" refers to infections caused by parasites. Infections caused by parasites (called "helminthiasis," plural "helminthiases") are any major parasitic disease in humans and other animals in which a part of the body is infected with a parasite (called a helminth). These parasites are diverse and are broadly classified into tapeworms, flukes, and roundworms.

[0083] As used in this article, the term "filariasis" refers to a parasitic worm infection caused by filarial nematodes. Non-limiting examples of filarial nematodes within the family Onchocercidae include the following genera: *Brucella* species (i.e., *Brucella malariae*, *Brucella pahangensis*, *Brucella timenensis*, etc.), *Wuce* species (i.e., *Wuce* bancroftianus*, etc.), *Disellus* species (*Disellus canis*, *Disellus creeping*, *Disellus ursinae*, *Disellus pulmonarius*, *D. spectans*, *D. lutrae*, etc.), *Echinopsis* species (i.e., *Echinopsis cryptogamy*, *Echinopsis creeping*, etc.), *Onchocerca* species (i.e., *Onchocerca gigantea*, *Onchocerca laryngoma*, *Onchocerca salina*, etc.), *Tricholoma* species (*E. elaphi*, *E. sagitta*, *E. schneidera*, etc.), *Mansonia* species (i.e., *Mansonia ossii*, *Mansonia comorbidus*, etc.), and *Loa* species (i.e., *Loa*). Infection is the colonization of a host organism by a parasitic species. Human filariasis can cause lymphatic filariasis or onchocerciasis. The term "lymphatic filariasis" refers to infection with nematodes such as *Wuceta banois*, *Brucella malariae*, or *Brucella timenei*. The term "onchocerciasis" refers to infection with the nematode *Onchocerciasis*. Lymphatic filariasis can cause hydroscrotal edema, lymphedema, and elephantiasis. Onchocerciasis can cause skin inflammation and blindness, known as river blindness. In dogs, infection with a nematode species called *Dictyophora canis* or *Dictyophora gravidarum* causes diabetic filariasis. In sheep and goats, infection with a nematode species called *Haemonchus contortus* causes haemonchus filariasis.

[0084] As used interchangeably in this article, the terms "worm" or "nematode" refer to all life stages of an organism, such as egg, unfertilized egg, fertilized egg, larva or juvenile worm, larva in any of the four larval stages (L1, L2, L3, L4), worm in the sexually immature stage (L5 stage), worm in the mature stage, worm in the fully mature stage, adult worm, worm in the pre-parasitic stage, or worm in the parasitic stage.

[0085] As used herein, the term “microfilariae” or “mf” refers to an early stage in the life cycle of certain parasitic nematodes. The microfilariae are considered to be the first larval stage, also known as L1. The terms “microfilariae,” “mf,” or “L1” are used alternatively and / or interchangeably.

[0086] As used in this article, the term "macrofilaria" refers to the adult stage of the life cycle of certain parasitic nematodes.

[0087] Unless otherwise defined, the 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 pertains.

[0088] Surprisingly, the compounds disclosed herein have been found to be effective in treating parasitic worm infections, such as filarial infections. In vitro and in vivo results demonstrate the effectiveness of the compounds disclosed herein against filarial nematodes. In some embodiments, the compounds disclosed herein unexpectedly exhibit different activities between adult and juvenile stages of parasitic nematodes. In some such embodiments, the compounds disclosed herein are selectively effective against adult filarial nematodes (also known as macrofilaricidal activity). In other embodiments, the compounds disclosed herein are selectively effective against juvenile filarial nematodes (also known as microfilaricidal activity). Therefore, the compounds disclosed herein have the potential to be potent antifilarial drugs.

[0089] compound

[0090] This article provides sulfonamide compounds having the following formula (I):

[0091]

[0092] and its pharmaceutically acceptable salts, tautomers, isotopes and stereoisomers,

[0093] in:

[0094] --- is a single or double bond;

[0095] Each A is independently N or CR 1 ;

[0096] Each R 1Independently, it is H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic oxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidin; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each of which may optionally be further substituted.

[0097] R 2 It is a substituted or unsubstituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group;

[0098] R is absent, H is a substituted or unsubstituted alkyl, cycloalkyl, heterocyclic, or CO (substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclic, or heteroaryl);

[0099] m is 0-3;

[0100] n is 0-3; and

[0101] p is 0-3;

[0102] The premise is that m and n are not both 0; and

[0103] When the aforementioned group is referred to as "substituted," it may be substituted by one or more substituents selected from the following: halogen; alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, cycloalkylalkyl, aralkyl, heterocyclic alkyl, heteroarylalkyl, hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; oxo (═O); oxide; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heterocyclic amino, heterocyclic alkyloxy Arylamino; imino; imino; amido; guanidinyl; enamino; acylamino; sulfonylamino; urea, nitrobenzene; oxime; hydroxyamino; alkoxyamino; arylalkoxyamino; hydrazyl; acylhydrazyl; hydrazyl; azide; nitro; thio(-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphonyl oxy; acyl; formyl; carboxyl; ester; carbamate; acylamino; cyano; isocyanate; isothiocyanate; cyanate; thiocyanate; and -B(OH)2; each of which may optionally be further substituted.

[0104] This article further provides sulfonamide compounds having the following formula (I):

[0105]

[0106] and its pharmaceutically acceptable salts, tautomers, isotopes and stereoisomers,

[0107] in:

[0108] --- is a single or double bond;

[0109] Each A is independently N or CR 1 ;

[0110] Each R 1 Independently, it is H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic oxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidin; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; aralkyloxyamino; thio(-SH)sulfonyl; alkylsulfonyl, aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each of which may optionally be further substituted.

[0111] R 2 It is a substituted or unsubstituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group;

[0112] R is absent, H is a substituted or unsubstituted alkyl, cycloalkyl, heterocyclic, or CO (substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclic, or heteroaryl);

[0113] m is 0-3;

[0114] n is 0-3; and

[0115] p is 0-3;

[0116] The premise is that m and n are not both 0; and

[0117] When the aforementioned group is referred to as "substituted," it may be substituted by one or more substituents selected from the following: halogen; alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, cycloalkylalkyl, aralkyl, heterocyclic alkyl, heteroarylalkyl, hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; oxo (═O); oxide; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heterocyclic amino, heterocyclic alkyloxy Arylamino; imino; imino; amido; guanidinyl; enamino; acylamino; sulfonylamino; urea, nitrobenzene; oxime; hydroxyamino; alkoxyamino; arylalkoxyamino; hydrazyl; acylhydrazyl; hydrazyl; azide; nitro; thio(-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphonyl oxy; acyl; formyl; carboxyl; ester; carbamate; acylamino; cyano; isocyanate; isothiocyanate; cyanate; thiocyanate; and -B(OH)2; each of which may optionally be further substituted.

[0118] This article provides sulfonamide compounds having the following formula (Ia):

[0119]

[0120] and its pharmaceutically acceptable salts, tautomers, isotopes and stereoisomers,

[0121] in:

[0122] Each R 1 C is halogen, substituted or unsubstituted, on its own. 1-4 Alkyl, substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic groups, substituted or unsubstituted aryl groups, or –OR;R 2 yes

[0123] a. 2-pyridyl or 3-pyridyl, which is independently substituted by one or more substituents selected from: halogen, CN, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl groups, -OR, and -NR2;

[0124] b. 2-Imidazolyl or 5-imidazolyl, which is independently substituted by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, and (C 1-3 Alkyl groups (substituted or unsubstituted C) 3-6 cycloalkyl);

[0125] c. Pyrazinyl group, which is independently substituted by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl groups, substituted or unsubstituted 3-6 membered heterocyclic groups, –OR and NR2;

[0126] d. Pyrazolyl group, which is unsubstituted or substituted with one or more C groups. 1-4 Alkyl substitution;

[0127] e.2-furanyl, which is unsubstituted or surrounded by one or more C14 groups 1-4 Alkyl substitution;

[0128] Each R is independently H and substituted or unsubstituted C. 1-4 Alkyl or (C 1-3 Alkyl groups (substituted or unsubstituted C) 3-6 cycloalkyl);

[0129] n is 1-3;

[0130] The premise is that the compound is not 5-cyano-N-[5-(trifluoromethyl)-8-quinolinyl]-2-pyridinesulfonamide:

[0131]

[0132] This article further provides sulfonamide compounds having the following formula (Ia):

[0133]

[0134] and its pharmaceutically acceptable salts, tautomers, isotopes and stereoisomers,

[0135] in:

[0136] Each R 1 It is independently a halogen, -CN, or 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 3-6 membered heterocyclic groups, substituted or unsubstituted aryl, or –OR;

[0137] R 2 yes

[0138] a. 2-pyridyl or 3-pyridyl, which is independently substituted by one or more substituents selected from: halogen, CN, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl groups, -OR, and -NR2;

[0139] b. 2-Imidazolyl group, which is independently substituted by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, (C 1-3 Alkyl groups (substituted or unsubstituted C) 3-6 cycloalkyl groups, and substituted or unsubstituted aryl groups;

[0140] c.5-Imidazolyl group, which is independently substituted by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, and (C 1-3 Alkyl groups (substituted or unsubstituted C) 3-6 cycloalkyl);

[0141] d. Pyrazinyl group, which is independently substituted by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl groups, substituted or unsubstituted 3-6 membered heterocyclic groups, –OR and NR2;

[0142] e. pyrazolyl group, which is unsubstituted or substituted or unsubstituted C1 groups. 1-4 Alkyl substitution;

[0143] f.2-furanyl, which is unsubstituted or surrounded by one or more C14 groups. 1-4 Alkyl substitution;

[0144] Each R is independently H and substituted or unsubstituted C. 1-4 Alkyl, (C 1-3 Alkyl groups (substituted or unsubstituted C4 groups) 3-6 cycloalkyl), or substituted or unsubstituted aryloxy groups;

[0145] n is 1-3;

[0146] The premise is that the compound is not 5-cyano-N-[5-(trifluoromethyl)-8-quinolinyl]-2-pyridinesulfonamide:

[0147]

[0148] In one embodiment of the compound having formula (I), m is 2, n is 1, and A is CR. 1 .

[0149] In one embodiment of the compound having formula (I), m is 1, n is 1, and A is CR. 1 .

[0150] In one embodiment of the compound having formula (I), m is 3, n is 0, and A is CR. 1 .

[0151] In one embodiment of the compound having formula (I), m is 2, n is 1, and A is CR1.

[0152] In one embodiment of the compound having formula (I), m is 2, n is 0, and A is CR1.

[0153] In one embodiment of the compound having 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 a compound having formula (I), each R 1 Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: halogen, CN, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, -OR and -NR2.

[0154] In one embodiment of the compound having 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 Cycloalkyl. In one embodiment of a compound having formula (I), each R 1Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: halogen, CN, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, -OR and -NR2.

[0155] In one embodiment of the compound having 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 Cycloalkyl. In one embodiment of a compound having formula (I), each R 1 Independently, it is H, F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, phenyl, pyrrolyl, piperidinyl, piperazinyl, or morpholinyl; and R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: F, Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH2CH3 and -N(CH3)2.

[0156] In one embodiment of the compound having 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 having formula (I), each R 1Independently, it is H, Cl, -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH3, -phenyl, pyrrolyl, piperidinyl, piperazinyl, or morpholinyl; and R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, -cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH2CH3 and -N(CH3)2.

[0157] In one embodiment of a compound having formula (I), where m is 2, n is 1, and A is CR 1 At that time, each R 1 Independently, it is H or Cl; R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the group consisting of -CH3 or -cyclopropyl. In one such embodiment, --- is a single bond; p is 0; and R is -CH3 or cyclopropyl.

[0158] In one embodiment of the compound having 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 a compound having formula (I), each R 1 Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a 2-imidazolium group, which is substituted or unsubstituted by one or more C14 groups. 1-4 Alkyl substitution.

[0159] In one embodiment of the compound having 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 Alkyl group. In one embodiment of a compound having formula (I), each R 1Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a 2-imidazolium group, which is substituted or unsubstituted by one or more C14 groups. 1-4 Alkyl substitution;

[0160] In one embodiment of the compound having 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 having formula (I), each R 1 Independently, it is H, F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, phenyl, pyrrolyl, piperidinyl, piperazinyl, or morpholinyl; and R 2 It is a 2-imidazolium group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 and

[0161] -CF3.

[0162] In one embodiment of a compound having formula (I), where m is 2, n is 1, and A is CR 1 At that time, each R 1 Independently, it is H;R 2 It is a 2-imidazolium group, which is replaced by -CH(CH3)2; --- is a single bond; p is 0; and R is -CH3.

[0163] In one embodiment of the compound having 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 a compound having formula (I), each R 1Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a pyrazolyl group, which is independently substituted by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl groups, substituted or unsubstituted 3-6 membered heterocyclic groups, and -OR.

[0164] In one embodiment of the compound having 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 Alkyl group. In one embodiment of a compound having formula (I), each R 1 Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a pyrazolyl group, which is independently substituted by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl groups, substituted or unsubstituted 3-6 membered heterocyclic groups, and -OR.

[0165] In one embodiment of the compound having formula (I), m is 2, n is 1, and A is CR. 1In 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 having formula (I), each R 1 Independently, it is H, F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, phenyl, pyrrolyl, piperidinyl, piperazinyl, or morpholinyl; and R 2 It is a pyrazolyl group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 and

[0166] -CF3.

[0167] In one embodiment of a compound having formula (I), where m is 2, n is 1, and A is CR 1 At that time, each R 1 Independently, it is H;R 2 It is a pyrazol group, which is replaced by -CH(CH3)2; --- is a single bond; p is 0; and R is -CH3.

[0168] In one embodiment of the compound having 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 a compound having formula (I), each R 1 Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: halogen, CN, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, -OR and -NR2.

[0169] In one embodiment of the compound having 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 Cycloalkyl. In one embodiment of a compound having formula (I), each R 1 Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: halogen, CN, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, -OR and -NR2.

[0170] In one embodiment of the compound having 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 Cycloalkyl. In one embodiment of a compound having formula (I), each R 1 Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: halogen, CN, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, -OR and -NR2.

[0171] In one embodiment of the compound having 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 Cycloalkyl. In one embodiment of a compound having formula (I), each R 1 Independently, it is H, F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, phenyl, pyrrolyl, piperidinyl, piperazinyl, or morpholinyl; and R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: F, Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH2CH3 and -N(CH3)2.

[0172] In one embodiment of the compound having 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 having formula (I), each R 1 Independently, it is H, Cl, -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH3, -phenyl, pyrrolyl, piperidinyl, piperazinyl, or morpholinyl; and R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, -cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH2CH3 and -N(CH3)2.

[0173] In one embodiment of a compound having formula (I), where m is 1, n is 1, and A is CR1 At that time, each R 1 Independently, it is H;R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the group consisting of -CH3 or -N(CH3)2. In one such embodiment, --- is a single bond; p is 0; and R is cyclopropyl.

[0174] In one embodiment of the compound having 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 a compound having formula (I), each R 1 Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a 2-imidazolium group, which is substituted or unsubstituted by one or more C14 groups. 1-4 Alkyl substitution.

[0175] In one embodiment of the compound having 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 Cycloalkyl. In one embodiment of a compound having formula (I), each R 1 Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R2 It is a 2-imidazolium group, which is substituted or unsubstituted by one or more C14 groups. 1-4 Alkyl substitution;

[0176] In one embodiment of the compound having 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 Cycloalkyl. In one embodiment of a compound having formula (I), each R 1 Independently, it is H, F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, phenyl, pyrrolyl, piperidinyl, piperazinyl, or morpholinyl; and R 2 It is a 2-imidazolium group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 and -CF3.

[0177] In one embodiment of a compound having formula (I), where m is 1, n is 1, and A is CR 1 At that time, each R 1 Independently, it is H;R 2 It is a 2-imidazolium group, which is replaced by -CH(CH3)2; --- is a single bond; p is 0; and R is -CH3.

[0178] In one embodiment of the compound having 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 a compound having formula (I), each R 1 Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2It is a pyrazolyl group, which is independently substituted by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl groups, substituted or unsubstituted 3-6 membered heterocyclic groups, and -OR.

[0179] In one embodiment of the compound having 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 Cycloalkyl. In one embodiment of a compound having formula (I), each R 1 Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a pyrazolyl group, which is independently substituted by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl groups, substituted or unsubstituted 3-6 membered heterocyclic groups, and -OR.

[0180] In one embodiment of the compound having 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 having formula (I), each R 1 Independently, it is H, F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, phenyl, pyrrolyl, piperidinyl, piperazinyl, or morpholinyl; and R 2 It is a pyrazolyl group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 and -CF3.

[0181] In one embodiment of a compound having formula (I), where m is 1, n is 1, and A is CR 1 At that time, each R 1 Independently, it is H;R 2 It is a pyrazol group, which is replaced by -CH(CH3)2; --- is a single bond; p is 0; and R is a cyclopropyl group.

[0182] In one embodiment of the compound having 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 a compound having formula (I), each R 1 Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: halogen, CN, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, -OR and -NR2.

[0183] In one embodiment of the compound having 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 Cycloalkyl. In one embodiment of a compound having formula (I), each R 1Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: halogen, CN, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, -OR and -NR2.

[0184] In one embodiment of the compound having 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 Cycloalkyl. In one embodiment of a compound having formula (I), each R 1 Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: halogen, CN, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, -OR and -NR2.

[0185] In one embodiment of the compound having formula (I), m is 3, n is 0, and A is CR. 1In 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 Cycloalkyl. In one embodiment of a compound having formula (I), each R 1 Independently, it is H, F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, phenyl, pyrrolyl, piperidinyl, piperazinyl, or morpholinyl; and R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: F, Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH2CH3 and -N(CH3)2.

[0186] In one embodiment of the compound having 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 having formula (I), each R 1 Independently, it is H, Cl, -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH3, -phenyl, pyrrolyl, piperidinyl, piperazinyl, or morpholinyl; and R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: F, -CH3, -CH2CH3, -CH2CH2CH3, -cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH2CH3 and -N(CH3)2.

[0187] In one embodiment of a compound having formula (I), where m is 3, n is 0, and A is CR 1 At that time, each R 1 Independently, it is H;R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: F, -CH3, or -N(CH3)2. In one such embodiment, --- is a single bond; p is 0; and R is H, -CH3, or cyclopropyl.

[0188] In one embodiment of the compound having 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 a compound having formula (I), each R 1 Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; alkylsulfonyl, aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a 2-imidazolium group, which is substituted or unsubstituted by one or more C14 groups. 1-4 Alkyl, or substituted or unsubstituted aryl.

[0189] In one embodiment of the compound having 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 a compound having formula (I), each R 1 Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a 2-imidazolium group, which is substituted or unsubstituted by one or more C14 groups. 1-4 Alkyl substitution.

[0190] In one embodiment of the compound having 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 a compound having formula (I), each R 1Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a pyrazolyl group, which is independently substituted by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl groups, substituted or unsubstituted 3-6 membered heterocyclic groups, and -OR.

[0191] In one embodiment of the compound having 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 a compound having formula (I), each R 1 Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: halogen, CN, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, -OR and -NR2.

[0192] In one embodiment of the compound having 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 Cycloalkyl. In one embodiment of a compound having formula (I), each R 1Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: halogen, CN, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, -OR and -NR2.

[0193] In one embodiment of the compound having 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 Cycloalkyl. In one embodiment of a compound having formula (I), each R 1 Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: halogen, CN, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, -OR and -NR2.

[0194] In one embodiment of the compound having formula (I), m is 2, n is 0, and A is CR. 1In 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 Cycloalkyl. In one embodiment of a compound having formula (I), each R 1 Independently, it is H, F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, phenyl, pyrrolyl, piperidinyl, piperazinyl, or morpholinyl; and R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: F, Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH2CH3 and -N(CH3)2.

[0195] In one embodiment of the compound having 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 having formula (I), each R 1 Independently, it is H, Cl, -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH3, -phenyl, pyrrolyl, piperidinyl, piperazinyl, or morpholinyl; and R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: F, -CH3, -CH2CH3, -CH2CH2CH3, -cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH2CH3 and -N(CH3)2.

[0196] In one embodiment of a compound having formula (I), where m is 2, n is 0, and A is CR 1 At that time, each R 1 Independently, it is H;R 2 It is a 2-pyridyl group, which is substituted with -CH3. In such an embodiment, --- is a single bond; p is 0; and R is -CH3.

[0197] In one embodiment of the compound having formula (I), m is 2, n is 0, and A is CR. 1In one such embodiment, --- is a single bond. In one embodiment of a compound having formula (I), each R 1 Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a 2-imidazolium group, which is substituted or unsubstituted by one or more C14 groups. 1-4 Alkyl substitution.

[0198] In one embodiment of the compound having 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 a compound having formula (I), each R 1 Independently, H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic alkyloxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidine; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each optionally further substituted; and R 2 It is a pyrazolyl group, which is independently substituted by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl groups, substituted or unsubstituted 3-6 membered heterocyclic groups, and -OR.

[0199] In one embodiment of the compound having formula (Ia), each R 1 C is halogen, substituted or unsubstituted, on its own. 1-4 Alkyl, substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic groups, substituted or unsubstituted aryl groups, or -OR; and R 2It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: halogen, CN, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, -OR and -NR2.

[0200] In one embodiment of the compound having formula (Ia), each R 1 C is halogen, substituted or unsubstituted, on its own. 1-4 Alkyl, substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic groups, substituted or unsubstituted aryl groups, or -OR; and R 2 It is 3-pyridyl, which is independently substituted by one or more substituents selected from the following: halogen, CN, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, -OR and -NR2.

[0201] In one embodiment of the compound having formula (Ia), each R 1 It is independently a halogen, -CN, or 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 3-6 membered heterocyclic groups, substituted or unsubstituted aryl groups, or -OR; and R 2 It is a 2-imidazolium or 5-imidazolium group, which is independently substituted by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, (C 1-3 Alkyl groups (substituted or unsubstituted C) 3-6 cycloalkyl groups, and substituted or unsubstituted aryl groups.

[0202] In one embodiment of the compound having formula (Ia), each R 1 C is halogen, substituted or unsubstituted, on its own. 1-4 Alkyl, substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic groups, substituted or unsubstituted aryl groups, or -OR; and R 2 It is a 2-imidazolium or 5-imidazolium group, which is independently substituted by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C3-6 cycloalkyl and (C 1-3 Alkyl groups (substituted or unsubstituted C) 3-6 cycloalkyl).

[0203] In one embodiment of the compound having formula (Ia), each R 1 C is halogen, substituted or unsubstituted, on its own. 1-4 Alkyl, substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic groups, substituted or unsubstituted aryl groups, or -OR; and R 2 It is a pyrazinyl group, which is independently substituted by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl groups, substituted or unsubstituted 3-6 membered heterocyclic groups, and -OR, and NR2. In one embodiment of a compound having formula (Ia), each R is independently -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, or -CH2 (cyclopropyl). In some embodiments of compounds having formula (Ia), n is 1 or 2.

[0204] In one embodiment of the compound having formula (Ia), each R 1 C is halogen, substituted or unsubstituted, on its own. 1-4 Alkyl, substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic groups, substituted or unsubstituted aryl groups, or -OR; and R 2 It is a pyrazolyl group, which is either unsubstituted or substituted with one or more C groups. 1-4 Alkyl substitution. In some examples of compounds having formula (Ia), n is 1 or 2.

[0205] In one embodiment of the compound having formula (Ia), each R 1 C is halogen, substituted or unsubstituted, on its own. 1-4 Alkyl, substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic groups, substituted or unsubstituted aryl groups, or -OR; and R 2 It is 2-furanyl, which is unsubstituted or converted by one or more C14 groups. 1-4 Alkyl substitution. In some examples of compounds having formula (Ia), n is 1 or 2.

[0206] In some embodiments of compounds having formula (Ia), each R 1Independently, it is F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2(cyclopropyl), aziridine, phenyl, pyrrolidine, piperidinyl, piperazinyl, or morpholinyl.

[0207] In some embodiments of compounds having formula (Ia), each R 1 Independently, it is F, Cl, -CH3, -CH2CH3, CF3, cyclopropyl, cyclohexyl, -OCH3-OCH(CH3)2, -OCH2(cyclopropyl), aziridine, phenyl, or morpholino.

[0208] In some embodiments of compounds having formula (Ia), R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: F, Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2-CH2CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH2CH3, -OCH2CH(CH3)2, -NH2, -NHCH3, and -N(CH3)2. In some embodiments of compounds having formula (Ia), R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: F, Cl, -CN, -CH3, -CH(CH3)2, -CH2CH(CH3)2, cyclopropyl, -OCH3, -OCH2CH(CH3)2 and -N(CH3)2.

[0209] In some embodiments of compounds having formula (Ia), R 2 It is a 3-pyridyl group, which is independently substituted by one or more substituents selected from the following: F, Cl, -CN, -CH3, -CH2CH3, and -CF3. In some embodiments of compounds having formula (Ia), R 2 It is a 3-pyridyl group substituted with -CF3.

[0210] In some embodiments of compounds having formula (Ia), R 2 It is a 2-imidazolium group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CF3, cyclopropyl, -CH2CH(CH3)2, phenyl and p-trifluoromethylphenyl.

[0211] In some embodiments of compounds having formula (Ia), R 2It is a 2-imidazolium group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl and -CH2CH(CH3)2.

[0212] In some embodiments of compounds having formula (I), R 2 It is a 2-imidazolium group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CF3, cyclopropyl, -CH2CH(CH3)2, phenyl and p-trifluoromethylphenyl.

[0213] In some embodiments of compounds having formula (I), R 2 It is a 2-imidazolium group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, cyclopropyl and -CH2CH(CH3)2.

[0214] In some embodiments of compounds having formula (Ia), R 2 It is a 5-imidazolium group, which is independently substituted by one or more of the following substituents: -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl and CH2-cyclopropyl.

[0215] In some embodiments of compounds having formula (Ia), R 2 It is a 5-imidazolium group, which is independently substituted by one or more substituents selected from the following: -CH(CH3)2 and -CH2-cyclopropyl.

[0216] In some embodiments of compounds having formula (Ia), R 2 It is 2-pyrazinyl, which is independently substituted by one or more of the following substituents: -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3), -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH(CH3)2, -N(CH3)2, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.

[0217] In some embodiments of compounds having formula (Ia), R 2 It is a 2-pyrazinyl group, which is independently substituted by one or more substituents selected from the following: -CH3, -OCH3, -N(CH3)2 and pyrrolidinyl.

[0218] In one embodiment of a compound having formula (Ia), R 2 It is a pyrazolyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3 and -CH(CH3)2.

[0219] In one embodiment of a compound having formula (Ia), R 2 It is a 2-furanyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, and -CH(CH3)2. In some embodiments of compounds having formula (Ia), n is 1 or 2.

[0220] In some embodiments of compounds having formula (Ia), each R 1 Independently, it is F, Cl, -CH3, -CH2CH2CH3, -CF3, cyclopropyl, cyclohexyl, -OCH3, -OCH(CH3)2, -OCH2(cyclopropyl), aziridine, phenyl, or morpholinyl, and R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: F, Cl, CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH(CH3)2, -NH2, -NHCH3, and -N(CH3)2. In some such embodiments, R 2 It is a 2-pyridyl group, which is independently substituted by one or more substituents selected from the following: F, Cl, CN, -CH3, -CH(CH3)2, -CH2CH(CH3)2, cyclopropyl, -OCH3, -OCH2CH(CH3)2, or -N(CH3)2. In some such embodiments, each R 1 Independently, it is F, Cl, -CH3, -CF3, cyclopropyl, cyclohexyl, -OCH3, -OCH(CH3)2, -OCH2(cyclopropyl), aziridine, phenyl, or morpholino.

[0221] In some embodiments of compounds having formula (Ia), each R 1 Independently, it is F, Cl, -CH3, -CH2CH3, CF3, cyclohexyl, -OCH3, or morpholinyl, and R 2 It is a 3-pyridyl group, which is independently substituted by one or more substituents selected from the following: F, Cl, -CN, -CH3, -CH2CH3, and -CF3. In some embodiments of compounds having formula (Ia), R 2 It is a 3-pyridyl group substituted with -CF3. In some such embodiments, each R 1 It can be F, -CH3, or -OCH3 independently.

[0222] In some embodiments of compounds having formula (Ia), each R1 Independently, it is F, Br, Cl, -CN, -CH3, -CH2CH3, CF3, cyclohexyl, -OCH3, -N(CH3)2, -C(O)CH3, benzoyl, methanesulfonyl, morpholinyl, phenyl, -O-(m-trifluoromethyl)phenyl or p-fluorophenyl, and R 2 It is a 2-imidazolium group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, CH2CH(CH3)2. In some such embodiments, R 2 It is a 2-imidazolium group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CF3, cyclopropyl, -CH2CH(CH3)2, phenyl, and p-trifluoromethylphenyl. In some such embodiments, each R 1 It can be F, Br, Cl, -CN, -CH3, -CH2CH3, CF3, -N(CH3)2, -C(O)CH3, benzoyl, methylsulfonyl, morpholinyl, -OCH3, phenyl, -O-(m-trifluoromethyl)phenyl or p-fluorophenyl.

[0223] In some embodiments of compounds having formula (Ia), each R 1 Independently, it is F, Cl, -CH3, -CH2CH3, CF3, cyclohexyl, -OCH3, or morpholinyl, and R 2 It is a 2-imidazolium group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, and -CH2CH(CH3)2. In some such embodiments, R 2 It is a 2-imidazolium group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, cyclopropyl, and -CH2CH(CH3)2. In some such embodiments, each R 1 It can be F, Cl, -CH3, -CH2CH3, CF3, morpholino, or -OCH3 independently.

[0224] In some embodiments of compounds having formula (Ia), each R 1 Independently, it is F, Cl, -CH3, -CH2CH3, CF3, cyclohexyl, -OCH3, or morpholinyl, and R 2 It is a 5-imidazolium group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, cyclopropyl, and -CH2-cyclopropyl. In some such embodiments, R 2It is a 5-imidazolium group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, and -CH2-cyclopropyl. In some such embodiments, R 2 It is a 5-imidazolium group, which is independently substituted by one or more substituents selected from the following: -CH(CH3)2 and -CH2-cyclopropyl. In some such embodiments, each R 1 It can be either Cl or morpholino.

[0225] In some embodiments of compounds having formula (Ia), each R 1 Independently, it is F, Cl, -CH3, -CH2CH3, CF3, cyclohexyl, -OCH3, or morpholinyl, and R 2 It is a 2-pyrazinyl group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH(CH3)2, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. In some such embodiments, R 2 It is a 2-pyrazinyl group, which is independently substituted by one or more substituents selected from the following: -CH3, -OCH3, -N(CH3)2, and pyrrolidinyl. In some such embodiments, each R 1 It can be either Cl or morpholino.

[0226] In some embodiments of compounds having formula (Ia), each R 1 Independently, it is F, Cl, -CH3, -CH2CH3, CF3, cyclohexyl, -OCH3, or morpholinyl, and R 2 It is a pyrazolyl group, which is either unsubstituted or independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, and -CH(CH3)2. In some such embodiments, R 2 It is a pyrazolyl group, which is either unsubstituted or substituted with -CH3 and -CH(CH3)2. In some such embodiments, each R 1 It is either F or morpholino.

[0227] In some embodiments of compounds having formula (Ia), each R 1 Independently, it is F, Cl, -CH3, -CH2CH3, CF3, cyclohexyl, -OCH3, or morpholinyl, and R 2It is a 2-furanyl group, which is either unsubstituted or independently substituted with one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, and -CH(CH3)2. In some such embodiments, R 2 It is an unsubstituted 2-furanyl group. In some such embodiments, each R 1 It can be F, -CH3, -OCH3, or morpholino group independently.

[0228] This article provides sulfonamide compounds having the following formula (II):

[0229]

[0230] and its pharmaceutically acceptable salts, tautomers, isotopes and stereoisomers,

[0231] in:

[0232] Each R 1 Independently, it is H, halogen, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic groups, substituted or unsubstituted aryl groups, or -OR;

[0233] R 2 yes

[0234] a. pyridyl group, which is unsubstituted or substituted independently by one or more substituents selected from the following: halogen, CN, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted monocyclic heteroaryl, -OR and -NR2;

[0235] b. 2-Imidazolyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, and (C 1-3 Alkyl groups (substituted or unsubstituted C) 3-6 cycloalkyl);

[0236] c. Pyrazinyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl groups, substituted or unsubstituted 3-6 membered heterocyclic groups, -OR and NR2;

[0237] d. Pyrazolyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl groups and substituted or unsubstituted C 3-6 cycloalkyl;

[0238] e. Pyrimidinyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl groups and -OR;

[0239] Each R is independently H, substituted or unsubstituted C. 1-4 Alkyl or (C 1-3 Alkyl groups (substituted or unsubstituted C) 3-6 cycloalkyl);

[0240] n is 1-3;

[0241] And the premise is R 1 and R 2 Not all have been replaced.

[0242] This article further provides sulfonamide compounds having the following formula (II):

[0243]

[0244] and its pharmaceutically acceptable salts, tautomers, isotopes and stereoisomers,

[0245] in:

[0246] Each R 1 It is independently a halogen, -CN, or 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 3-6 membered heterocyclic groups, substituted or unsubstituted aryl, or –OR;

[0247] R 2 yes

[0248] a. pyridyl group, which is unsubstituted or substituted independently by one or more substituents selected from the following: halogen, CN, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted monocyclic heteroaryl, -OR and -NR2;

[0249] b. 2-Imidazolyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, (C 1-3 Alkyl groups (substituted or unsubstituted C) 3-6 cycloalkyl groups, and substituted or unsubstituted aryl groups;

[0250] c. Pyrazinyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl groups, substituted or unsubstituted 3-6 membered heterocyclic groups, -OR and NR2;

[0251] d. Pyrazolyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl groups and substituted or unsubstituted C 3-6 cycloalkyl;

[0252] e. Pyrimidinyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl groups and -OR;

[0253] Each R is independently H and substituted or unsubstituted C. 1-4 Alkyl, (C 1-3 Alkyl groups (substituted or unsubstituted C4 groups) 3-6 cycloalkyl), or substituted or unsubstituted aryloxy groups;

[0254] n is 1-3;

[0255] And the premise is R 1 and R 2 Not all have been replaced.

[0256] In one embodiment of the compound having formula (II), each R 1 Independently, it is H, halogen, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic groups, substituted or unsubstituted aryl groups, or -OR; and R 2 It is a pyridyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: halogen, CN, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted monocyclic heteroaryl, -OR and -NR2.

[0257] In one embodiment of the compound having formula (II), each R 1 Independently, it is 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 3-6 membered heterocyclic group, substituted or unsubstituted aryl, or –OR; and R 2 It is a 2-imidazolium group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, (C 1-3 Alkyl groups (substituted or unsubstituted C) 3-6 cycloalkyl groups, and substituted or unsubstituted aryl groups.

[0258] In one embodiment of the compound having formula (II), each R 1 Independently, it is H, halogen, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic groups, substituted or unsubstituted aryl groups, or –OR; and R 2 It is a 2-imidazolium group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl and (C 1-3 Alkyl groups (substituted or unsubstituted C) 3-6 cycloalkyl).

[0259] In one embodiment of the compound having formula (II), each R 1 Independently, it is H, halogen, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic groups, substituted or unsubstituted aryl groups, or -OR; and R 2 It is a pyrazinyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: substituted or unsubstituted C 1-4Alkyl groups, substituted or unsubstituted 3-6 membered heterocyclic groups, and -OR, and NR2. In one embodiment of a compound having formula (II), each R is independently H, -CH3, -CH2CH3, -CH2CH2CH3, or -CH2CH(CH3)2. In some embodiments of compounds having formula (II), n is 1 or 2.

[0260] In one embodiment of the compound having formula (II), each R 1 Independently, it is H, halogen, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic groups, substituted or unsubstituted aryl groups, or -OR; and R 2 It is a pyrazolyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl groups and substituted or unsubstituted C 3-6 Cycloalkyl.

[0261] In one embodiment of the compound having formula (II), each R 1 Independently, it is H, halogen, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic groups, substituted or unsubstituted aryl groups, or -OR; and R 2 It is a pyrimidinyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: substituted or unsubstituted C 1-4 Alkyl and -OR.

[0262] In some embodiments of compounds having formula (II), each R 1 Independently, it is H, F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. In some examples of compounds having formula (II), each R 1 It can be H, F, Cl, -CH3, -CH2CH3, CF3, cyclohexyl, -OCH3, or morpholinyl.

[0263] In some embodiments of compounds having formula (II), R 2It is a pyridyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: F, Cl, CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -(CH2)CN, -CHF2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, CN-substituted phenyl, F-substituted phenyl, oxadiazolyl, -OCH3, -OCH2CH2CH3, -OCH2CH(CH3)2, -NH2, -NHCH3, and -N(CH3)2. In some embodiments of compounds having formula (II), R 2 It is a pyridyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: F, Cl, CN, CH3, -CH2CH(CH3)2, -C(CH3)3, -(CH2)CN, -CHF2, -CF3, cyclopropyl, phenyl, phenyl substituted with CN, phenyl substituted with F, oxadiazolyl, -OCH3, -OCH2CH(CH3)2 and -N(CH3)2.

[0264] In some embodiments of compounds having formula (II), R 2 It is a 2-imidazolium group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CF3, -CH2CH2CH3, -CH2CH(CH3)2, substituted cyclopropyl, -CH2-cyclopropyl, phenyl and p-trifluoromethylphenyl.

[0265] In some embodiments of compounds having formula (II), R 2 It is a 2-imidazolium group, which is either unsubstituted or substituted independently with one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, substituted cyclopropyl, and -CH2-cyclopropyl. In some embodiments of compounds having formula (II), R 2 It is a 2-imidazolium group, which is unsubstituted or substituted independently by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH(CH3)2, cyclopropyl substituted with one or more F groups, and -CH2-cyclopropyl.

[0266] In some embodiments of compounds having formula (II), R 2 It is 2-pyrazinyl, which is unsubstituted or substituted independently by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3), -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH(CH3)2, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.

[0267] In some embodiments of compounds having formula (II), R 2 It is 2-pyrazinyl, which is either unsubstituted or substituted independently by one or more substituents selected from the following: -CH3, -OCH3 and pyrrolidinyl.

[0268] In some embodiments of compounds having formula (II), R 2 It is a pyrazolyl group, which is unsubstituted or independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3), -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH(CH3)2, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.

[0269] In some embodiments of compounds having formula (II), R 2 It is a pyrazolyl group, which is either unsubstituted or substituted independently by one or more of the following substituents: -CH2CH3 and morpholino.

[0270] In some embodiments of compounds having formula (II), R 2 It is a pyrimidinyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3), -OCH3, -OCH2CH3, -OCH2CH2CH3 and -OCH2CH(CH3)2.

[0271] In some embodiments of compounds having formula (II), R 2 It is a pyrimidinyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: -CH3 and -OCH3.

[0272] In some embodiments of compounds having formula (II), each R 1 Independently, it is H, F, Cl, -CH3, -CH2CH2CH3, -CF3, cyclohexyl, -OCH3, or morpholinyl, and R 2 It is a 2-pyridyl group, which is unsubstituted or substituted independently with one or more substituents selected from the following: F, Cl, CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH(CH3)2, -CF3, CN-substituted phenyl, -NH2, -NHCH3, and -N(CH3)2. In some such embodiments, R 2It is a 2-pyridyl group, which is unsubstituted or independently substituted with one or more substituents selected from the following: F, Cl, CN, -CH3, -CH2CH(CH3)2, cyclopropyl, -OCH3, -OCH2CH(CH3)2, -CF3, a CN-substituted phenyl group, or -N(CH3)2. In some such embodiments, each R 1 Independently, they are H, F, Cl, -CH3, cyclohexyl, and -OCH3.

[0273] In some embodiments of compounds having formula (II), each R 1 Independently, it is H, F, Cl, -CH3, -CH2CH2CH3, -CF3, cyclohexyl, -OCH3, or morpholinyl, and R 2 It is 3-pyridyl, which is unsubstituted or substituted independently by one or more substituents selected from the following: F, Cl, CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CHF2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH(CH3)2, phenyl, phenyl substituted with F, oxadiazolyl, -NH2, -NHCH3 and -N(CH3)2.

[0274] In some embodiments of compounds having formula (II), each R 1 Independently, it is H, F, Cl, -CH3, -CH2CH2CH3, -CF3, cyclohexyl, -OCH3, or morpholinyl, and R 2 It is 3-pyridyl, which is unsubstituted or substituted independently by one or more substituents selected from the following: F, Cl, CN, -CH3, -C(CH3)3, -CHF2, -CF3, -OCH3, cyclopropyl, phenyl, phenyl substituted with F, oxadiazolyl and -NH2.

[0275] In some embodiments of compounds having formula (II), each R 1 Independently, it is H, F, Cl, -CH3, -CH2CH2CH3, -CF3, cyclohexyl, -OCH3, or morpholinyl, and R 2 It is a 4-pyridyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: F, Cl, CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH(CH3)2, phenyl, -NH2, -NHCH3 and -N(CH3)2.

[0276] In some embodiments of compounds having formula (II), each R 1 Independently, it is H, F, Cl, -CH3, -CH2CH2CH3, -CF3, cyclohexyl, -OCH3, or morpholinyl, and R 2 It is 4-pyridyl, which is either unsubstituted or substituted independently by one or more substituents selected from the following: -CH3, cyclopropyl and -CF3.

[0277] In some embodiments of compounds having formula (II), each R 1 Independently, it is 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, and R 2 It is a 2-imidazolium group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CF3, -CH2CH2CH3, -CH2CH(CH3)2, substituted cyclopropyl, -CH2-cyclopropyl, phenyl, and p-trifluoromethylphenyl. In some such embodiments, R 2 It is a 2-imidazolium group, which is unsubstituted or substituted independently with one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CF3, -CH2CH(CH3)2, cyclopropyl substituted with one or more F groups, -CH2-cyclopropyl, phenyl, and p-trifluoromethylphenyl. In some such embodiments, each R 1 It is independently selected from H, F, Br, Cl, -CN, -CH3, -CH2CH3, CF3, -OCH3, -N(CH3)2, -C(O)CH3, phenyl, -O-(m-trifluoromethyl)phenyl, p-fluorophenyl, benzoyl, and methylsulfonyl.

[0278] In some embodiments of compounds having formula (II), each R 1 Independently, it is F, Cl, -CH3, -CH2CH3, CF3, cyclohexyl, -OCH3, or morpholinyl, and R 2 It is a 2-imidazolium group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, substituted cyclopropyl, and -CH2-cyclopropyl. In some such embodiments, R 2 It is a 2-imidazolium group, which is unsubstituted or substituted independently with one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH(CH3)2, cyclopropyl groups substituted with one or more F groups, and -CH2-cyclopropyl groups. In some such embodiments, each R 1Independently, they are H, F, Cl, -CH3, -CH2CH3, CF3, and -OCH3.

[0279] In some embodiments of compounds having formula (II), each R 1 Independently, it is H, F, Cl, -CH3, -CH2CH3, CF3, cyclohexyl, -OCH3, or morpholinyl, and R 2 It is a 2-pyrazinyl group, which is unsubstituted or independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH(CH3)2, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. In some such embodiments, R 2 It is a 2-pyrazinyl group, which is unsubstituted or independently substituted by one or more substituents selected from the following: -CH3, -OCH3, and pyrrolidinyl. In some such embodiments, each R 1 It can be H, Cl, -CH3, -CH2CH3, -OCH3 or morpholino.

[0280] In some embodiments of compounds having formula (II), each R 1 Independently, it is H, F, Cl, -CH3, -CH2CH3, CF3, cyclohexyl, -OCH3, or morpholinyl, and R 2 It is a pyrazolyl group, which is unsubstituted or independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3), -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH(CH3)2, pyrrolidinyl, piperidinyl, piperazineyl, and morpholinyl. In some such embodiments, R 2 It is a pyrazolyl group, which is either unsubstituted or substituted independently by one or more of the following substituents: -CH2CH3 and morpholino.

[0281] In some embodiments of compounds having formula (II), each R 1 Independently, it is H, F, Cl, -CH3, -CH2CH3, CF3, cyclohexyl, -OCH3, or morpholinyl, and R 2 It is a pyrimidinyl group, which is unsubstituted or independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3), -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH(CH3)2, pyrrolidinyl, piperidinyl, piperazineyl, and morpholinyl. In some such embodiments, R 2It is a pyrimidinyl group, which is either unsubstituted or substituted independently by one or more substituents selected from the following: -CH3 and -OCH3.

[0282] The other embodiments provided herein include combinations of at least one of the specific embodiments listed above.

[0283] Representative compounds having formula (I), formula (Ia) and formula (II) are listed in Tables 1 and 2.

[0284] Other representative compounds having formula (I), formula (Ia) and formula (II) are listed in Tables 1, 2, 3 and 4.

[0285] Each compound in Tables 1, 2, and 3 was tested in one or more in vitro parasite motility assays and found to be active in them.

[0286] In another embodiment, each compound in Tables 1, 2, 3 and 4 was tested in one or more in vitro parasite activity assays and found to be active therein.

[0287] Methods for manufacturing compounds

[0288] The sulfonamide compounds having formulas (I), (Ia), and (II), and the sulfonamide compounds listed in Tables 1, 2, and 3, can be prepared using conventional organic synthesis and commercially available starting materials. Additionally, the sulfonamide compounds having formulas (I), (Ia), and (II), and the sulfonamide compounds listed in Tables 1, 2, 3, and 4, can be prepared using conventional organic synthesis and commercially available starting materials. For example, but not limited to, the sulfonamide compounds having formulas (I), (Ia), and (II), and the sulfonamide compounds listed in Tables 1, 2, 3, and 4, can be prepared according to Scheme 1 shown below and as outlined in the examples listed herein. It should be noted that those skilled in the art will understand how to modify the procedures listed in the illustrative schemes and examples to obtain the desired product.

[0289] Option 1

[0290]

[0291] As shown in Scheme 1, compounds having formula (I), formula (Ia), and formula (II), and compounds in Tables 1, 2, 3, and 4 (where R) 1 R 2R, A, m, n, and p (as defined herein) can be prepared from appropriately derived heterocyclic amines (B) and sulfonyl groups (D), wherein LG (leaving group) is Cl or Bt (1H-benzo[d][1,2,3]triazolyl). Compounds having formula I, wherein (B) is a quinolone-8-amine, and (B) is commercially available or can be prepared by known methods (see, for example, J. Heterocyclic Chem., 39, 631 (2002)). Compounds wherein (B) is a hexahydroquinoline-amine or tetrahydroindole-amine, and the compound is commercially available or can be prepared by known methods (see, for example, Org. Biomol. Chem., 2020, 18, 1214-1220). Using, for example, SnCl2 or H2, in the presence of a catalyst (such as Pd / C), in a solvent (such as MeOH or EtOH), and heated at a temperature range of 25°C to 70°C, a suitably substituted 8-nitroquinoline derivative (A) is reduced to provide a derived quinolone-8-amine (B). Sulfonyl chloride (D) (where LG is Cl) is commercially available or can be prepared according to known methods (see, for example, Bull. Korean Chem. Soc., 33, 383 (2012)). In a solvent (such as THF or DMSO), in the presence of a base (such as NaH or CsF), at a temperature range of 0°C to 80°C, a suitably derived (C)-containing R... 2 The thioalkylation of (where X is Cl) provides the intermediate benzylthiol. Subsequently, in a solvent (such as DCM and water), in the presence of an acid (such as HOAc), at a temperature range of -10°C to 25°C, the benzylthiol is oxidatively chlorinated with 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (DCH) or NaOCl to provide a sulfonyl group (D), where LG is Cl. Alternatively, in the presence of SO2Cl2, in a solvent (such as THF), at a temperature range of -78°C to 25°C, or in the presence of SO2 gas, in a solvent (such as Et2O), at a temperature range of -70°C to 25°C, the benzylthiol is oxidatively chlorinated with a suitable derivative of a base (such as nBuLi) containing R. 2 Treatment of a portion (C) (where X is Br), followed by a reaction with NCS in a solvent (such as CHCl3 and water) at a temperature range of 0°C to 25°C, provides a sulfonyl group (D), where LG is Cl. In another method, in a solvent (such as DCM and water), in the presence of an acid (such as HOAc), at a temperature range of 0°C to 25°C, with a suitably derived R from Cl2 gas... 2Treatment of part (C) (where X is SH) yields sulfonyl (D), where LG is Cl. The sulfonyl (D) is prepared according to known methods, where LG is Bt. R is prepared in the presence of SO2 gas, in a solvent (e.g., THF), at a temperature range of -78°C to 0°C, using a suitably derived base (e.g., nBuLi). 2 The treatment of part (C) (where X is H), followed by the addition of N-chlorobenzotriazole in the presence of a base (such as TEA) at a temperature range of 0°C to 25°C, provides a sulfonyl group (D), where LG is benzotriazole. Compounds having formulas (I), (Ia), and (II), and the compounds in Tables 1, 2, 3, and 4, are obtained by treating quinolone-8-amine (B) and the sulfonyl group (D) with a base (such as NaHMDS or pyridine) in a solvent (such as THF or DCM) at a temperature range of -78°C to 130°C.

[0292] On the one hand, this article provides a method for preparing sulfonamide compounds having formula (I):

[0293]

[0294] These methods include making compounds having formula (B):

[0295]

[0296] Contact with compounds having formula (D):

[0297]

[0298] In a solvent, in the presence of a base, under conditions suitable for providing a sulfonamide compound having formula (I), wherein:

[0299] --- is a single or double bond;

[0300] Each A is independently N or CR 1 ;

[0301] Each R 1 Independently, it is H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heterocyclic alkyl, heteroarylalkyl; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclic oxy, heteroaryloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclic alkyloxy, heteroarylalkyloxy; amino, alkylamino, cycloalkylamino, arylamino, heterocyclic amino, heteroarylamino; imino; imino; amidin; alkenylamino; acylamino; sulfonylamino; urea, alkoxyamino; arylalkoxyamino; thio(-SH)sulfonyl; aminosulfonyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; or cyano; each of which may optionally be further substituted.

[0302] R 2 It is a substituted or unsubstituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group;

[0303] R is absent, H is a substituted or unsubstituted alkyl, cycloalkyl, heterocyclic, or CO (substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclic, or heteroaryl);

[0304] m is 0-3;

[0305] n is 0-3; and

[0306] p is 0-3;

[0307] The premise is that m and n are not both 0.

[0308] In some embodiments, the base is NaHMDS or pyridine. In some embodiments, the solvent is THF or DCM. In some embodiments, the contact is carried out in a temperature range from room temperature to -78°C to 130°C. In some embodiments, LG is Cl or 1H-benzo[d][1,2,3]triazolyl.

[0309] In some embodiments, these methods further include preparing a compound having formula (B):

[0310]

[0311] This method involves reducing a compound having formula (A) with a reducing agent:

[0312]

[0313] In a solvent, under conditions suitable for providing a compound having formula (A).

[0314] In some embodiments, the reducing agent is SnCl2 or H2 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 contact is carried out at a temperature range of 25°C to 70°C.

[0315] In some embodiments, these methods further include preparing a compound having formula (D):

[0316]

[0317] The method includes:

[0318] a) R in the first solvent 2 -X (where X is Cl) is in contact with (4-methoxyphenyl)methanethiol or benzylthiol;

[0319] b) Under conditions suitable for providing a compound having formula (D) (where LG is Cl), the product of step a) is contacted in a second solvent with 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione or NaOCl.

[0320] In some embodiments, the contact in step (a) involves 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 contact in step (a) is carried out at a temperature range of 0°C to 80°C. In some embodiments, the base in step (a) is CsF and the first solvent is DMSO.

[0321] In some embodiments, the method in step (b) further includes 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 contact in step (b) is carried out in a temperature range of -10°C to 25°C.

[0322] In some embodiments, these methods further include preparing a compound having formula (D):

[0323]

[0324] The method includes:

[0325] a) In the first solvent, in the presence of SO2 gas, R 2 -X (where X is Br) comes into contact with a base;

[0326] b) Under conditions suitable for providing a compound having formula (D) (where LG is Cl), the product of step a) is contacted with NCS in a second solvent.

[0327] In one embodiment, the base in step (a) is nBuLi. In one embodiment, the first solvent is Et2O. In some embodiments, the contact in step (a) is carried out in a temperature range of -70°C to 25°C.

[0328] In some embodiments, the second solvent is CHCl3 and water. In some embodiments, the contact in step (b) is carried out at a temperature range of 0°C to 25°C.

[0329] In some embodiments, the base in step (a) is nBuLi. In one embodiment, the first solvent is THF. In some embodiments, the contact in step (a) is carried out in a temperature range of -78°C to 25°C. In some embodiments, the contact between the product of step (a) and SO2Cl2 is carried out in a temperature range of -78°C to 25°C.

[0330] In some embodiments, these methods further include preparing a compound having formula (D):

[0331]

[0332] The method includes, under conditions suitable for providing a compound having the formula (D) (where LG is Cl), in a solvent, in the presence of Cl2 gas, causing R... 2 -X (where X is SH) comes into contact with acid.

[0333] In one embodiment, the acid is HOAc. In one embodiment, the solvent is DCM and water. In some embodiments, the contact is carried out at a temperature range of 0°C to 25°C.

[0334] In some embodiments, these methods further include preparing a compound having formula (D):

[0335]

[0336] The method includes:

[0337] a) In the first solvent, in the presence of SO2 gas, R 2 -X (where X is H) comes into contact with a base;

[0338] b) Under conditions suitable for providing a compound having the formula (D) (where LG is 1H-benzo[d][1,2,3]triazolyl), the product of step a) is contacted with N-chlorobenzotriazole in a second solvent.

[0339] In one embodiment, the base in step (a) is nBuLi. In one embodiment, the first solvent is Et2O. In some embodiments, the contact in step (a) is carried out in a temperature range of -78°C to 0°C.

[0340] In some embodiments, these methods further include 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 contact in step (b) is carried out at a temperature range of 0°C to 25°C.

[0341] How to use

[0342] Sulfonamide compounds (including compounds having formulas (I), (Ia), and (II), and compounds listed in Tables 1, 2, and 3) have medicinal efficacy as a treatment, prevention, or improvement of conditions in animals and humans. Additionally, sulfonamide compounds (including compounds having formulas (I), (Ia), and (II), and compounds listed in Tables 1, 2, 3, and 4) have medicinal efficacy as a treatment, prevention, or improvement of conditions in animals and humans. The sulfonamide compounds provided herein have efficacy for use in the treatment or prevention of all diseases, disorders, or conditions disclosed herein.

[0343] In one aspect, this document provides a method for treating diseases caused by parasitic worm infections. In some embodiments, the compounds described herein are used in human medical treatments, particularly in the treatment of parasitic worm infections. In some embodiments, the compounds provided herein are used in animal medical treatments, particularly in the treatment of parasitic worm infections. In some embodiments, the method comprises administering a therapeutically effective amount of the described compound to a subject suffering from a disease caused by a parasitic worm infection.

[0344] In one aspect, this document provides a method for treating diseases caused by filariasis. In some embodiments, the compounds described herein are used in human medical treatments, particularly in the treatment of filariasis. In some embodiments, the compounds provided herein are used in animal medical treatments, particularly in the treatment of filariasis. In some embodiments, the method comprises administering a therapeutically effective amount of the compound as described to a subject suffering from a disease caused by filariasis.

[0345] In one embodiment, this document provides a method for treating or preventing parasitic worm infections and diseases, 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 some such embodiments, the parasitic worm infection is a filarial infection.

[0346] In one aspect, this article provides a method for treating diseases caused by parasitic worm infections. In some embodiments, a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof is used in human medical therapy, particularly in the treatment of parasitic worm infections. In some embodiments, a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof is used in animal medical therapy, particularly in the treatment of parasitic worm infections. In some embodiments, the method comprises administering a therapeutically effective amount of a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof to a subject suffering from a disease caused by a parasitic worm infection.

[0347] In one aspect, this article provides a method for treating diseases caused by filariasis. In some embodiments, a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof is used in human medical therapy, particularly in the treatment of filariasis. In some embodiments, a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof is used in animal medical therapy, particularly in the treatment of filariasis. In some embodiments, the method comprises administering a therapeutically effective amount of a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof to a subject suffering from a disease caused by filariasis.

[0348] On the other hand, methods for preventing diseases caused by parasitic worm infections are also provided. In some embodiments, a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof is used in human medical therapy, particularly in the prevention of parasitic worm infections. In some embodiments, a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof is used in animal medical therapy, particularly in the prevention of parasitic worm infections. In some embodiments, the method comprises administering to a subject a therapeutically effective amount of a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof to prevent diseases caused by parasitic worm infections.

[0349] On the other hand, methods for preventing diseases caused by filariasis are also provided. In some embodiments, a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof is used in human medical therapy, particularly in the prevention of filariasis infection. In some embodiments, a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof is used in animal medical therapy, particularly in the prevention of filariasis infection. In some embodiments, the method comprises administering to a subject a therapeutically effective amount of a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof to prevent diseases caused by filariasis infection.

[0350] On the other hand, this article provides methods for treating or preventing parasitic diseases. In some embodiments, the parasitic disease is related to worms. In some embodiments, the parasitic disease is caused by worms. In some embodiments, the parasites are classified as cestodes, nematodes (roundworms), and trematodes (flatworms or flukes). In some embodiments, the parasitic disease is related to parasitic worms. In some embodiments, the parasitic disease is related to nematodes. In some embodiments, the nematode is *Wuceta bannes*. In some embodiments, the nematode is *Brucella malayi*. In some embodiments, the nematode is *Brucella tibenzia*. In some embodiments, the nematode is *Onchocerca filariasis*. In some embodiments, the nematode is *Filaria canis*. In some embodiments, the nematode is *Haemaphysema contortus*. In some embodiments, the nematode is *Ascaris lumbricoides*. In some embodiments, the nematode is *Necator americanus*. In another embodiment, the nematode is *Ancylostoma duodenale*. In yet another embodiment, the nematode is *Trichuris trichiura*. In some embodiments, the parasitic disease is related to trematodes. In some embodiments, the parasitic disease is related to the genus *Schistosoma*. In some embodiments, the parasitic disease is related to *Schistosoma mansoni*. In some embodiments, the parasitic disease is enterobiasis, oxyuriasis, ascariasis, hookworm disease, tetanus, dracunculiasis, filariasis, onchocerciasis, schistosomiasis, or whipworm disease. In some embodiments, the parasitic disease is schistosomiasis. In some embodiments, the parasitic disease is uroschistosomiasis. In some embodiments, the parasitic disease is intestinal schistosomiasis. In some embodiments, the parasitic disease is Asian intestinal schistosomiasis. In some embodiments, the parasitic disease is visceral schistosomiasis. In some embodiments, the parasitic disease is acute schistosomiasis. In some embodiments, the parasitic disease is lymphatic filariasis. In some embodiments, the parasitic disease is Bancroftian filariasis. In some embodiments, the parasitic disease is hypodermic filariasis. In some embodiments, the parasitic disease is severe coelomic filariasis. In some embodiments, the parasitic disease is elephantiasis. In some embodiments, the parasitic disease is tropical elephantiasis. In some embodiments, the parasitic disease is onchocerciasis. In some embodiments, malignant filariasis is malignant filariasis in dogs. In some embodiments, malignant filariasis is caused by *Dicarius canis* or *Dicarius creeping*. In some embodiments, the parasitic disease is *Haemaphysalis* infection. In some embodiments, *Haemaphysalis* infection is *Haemaphysalis* infection in sheep and goats. In some embodiments, *Haemaphysalis* infection is caused by *Haemaphysalis contortus*.

[0351] In some aspects, the method includes the step of administering a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof to a subject. In some embodiments, the method includes administering a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof to a subject for no more than fourteen (14) days. In some embodiments, the method includes administering a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof to a subject for no more than seven (7) days. In some embodiments, the subject requires treatment for a parasitic worm infection. In some embodiments, the subject requires treatment for a filarial infection. In some embodiments, the subject has a parasitic worm infection. In some embodiments, the subject is at risk of having a parasitic worm infection. In some embodiments, the subject has a filarial infection. In some embodiments, the subject is at risk of having a filarial infection. In some embodiments, the subject is a pediatric subject. In some embodiments, the subject is less than nine (9) years old. In some embodiments, the subject is less than eight (8) years old. In some embodiments, the subject is pregnant. In some embodiments, the subject is a postpartum woman. In some embodiments, the subject is a woman of childbearing potential. In some embodiments, the subject is an individual attempting to conceive. In some embodiments, the subject is a domestic animal. In some embodiments, the subject is a dog.

[0352] The compounds disclosed herein exhibit efficacy against parasitic worms and therefore have the potential to kill and / or inhibit the growth, molting, or activity of such parasitic worms. The compounds disclosed herein exhibit efficacy against filarial worms and therefore have the potential to kill and / or inhibit the growth, molting, or activity of such filarial worms. Therefore, in one aspect, a method for killing filarial worms is provided, comprising: contacting the filarial worms with an amount of a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof that is effective in killing filarial worms. In another aspect, a method for inhibiting the growth or molting of filarial worms is provided herein, comprising: contacting the filarial worms with an amount of a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof that is effective in inhibiting the growth or molting of filarial worms. In yet another aspect, a method for inhibiting the activity of filarial worms is provided herein, comprising: contacting the filarial worms with an amount of a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof that is effective in inhibiting the activity of filarial worms. In some embodiments, the worm is an egg. In some embodiments, the egg is an unfertilized egg. In some embodiments, the egg is a fertilized egg. In some embodiments, the worm is a larva. In some embodiments, the worm is in a larval or juvenile stage. In some embodiments, the worm is a larva in any of the four larval stages (L1, L2, L3, L4). In some embodiments, the worm is an L1 stage larva or a microfilariae. In some embodiments, the microfilariae are L1 stage larvae. In some embodiments, the worm is an L2 stage larva. In some embodiments, the worm is an L3 stage larva. In some embodiments, the worm is an L4 stage larva. In some embodiments, the worm is in a sexually immature stage (L5 stage). In some embodiments, the worm is mature. In some embodiments, the worm is fully mature. In some embodiments, the worm is in an adult stage. In some embodiments, the worm is in a pre-parasitic stage. In some embodiments, the worm is in a parasitic stage. In some embodiments, the worms are exposed in vivo to a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof. In some embodiments, the worms are exposed in vitro to a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof.

[0353] As discussed herein, the compounds provided herein can be used to treat and prevent certain diseases and disorders in humans and animals. In some embodiments, the sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof is used to treat diseases caused by parasitic worm infections. In some embodiments, the sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof is used to treat diseases caused by filariasis, including but not limited to heartworm disease, ascariasis, whipworm disease, schistosomiasis, schistosomiasis, onchocerciasis, and lymphatic filariasis. In some embodiments, treatment or prevention of such diseases and disorders can be achieved by administering the sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof, alone or as part of a combination therapy, in combination with another active agent. The term "combination" (as in the phrase "combined with another active agent") includes the co-administration of a first agent and a second agent, which may, for example, be dissolved or mixed in the same pharmaceutically acceptable carrier, or the administration of the first agent followed by the second agent, or the administration of the second agent followed by the first agent. Therefore, the methods and compositions of the present invention include methods of combination therapy and combination pharmaceutical compositions. The term "combination therapy" refers to the administration of two or more therapeutic substances, such as compounds described herein, and another drug (e.g., an antihelmintic agent such as ivermectin, albendazole, flubendazole, ethamazol, or emodepside). One or more other drugs may be administered simultaneously with, before, or after a macrolide antibiotic.

[0354] In one embodiment, a method for treating or preventing parasitic worm infection and disease 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 anthelmintics. In some such embodiments, the parasitic worm infection is a filarial infection. In one embodiment, treatment of the parasitic worm infection comprises administering an anthelmintic such as benzimidazole, for example, flubendazole, albendazole, mebendazole, thiabendazole, fenbendazole, or triclofenazole. In one embodiment, treatment of the parasitic worm infection comprises administering one or more anthelmintics, for example, ivermectin, avermectin, dimethoprim (DEC), suramin, pyrantel pamoate, levamisole, niclosamide, nizoxinide, hydroxychlorozadamide, praziquantel, amedas, monepantel, derquantel, or punicic acid sulfate. In some embodiments, a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof is combined with one or more anthelmintics for the treatment of parasitic worm infections. In some embodiments, the anthelmintics are benzimidazoles, such as flubendazole, albendazole, mebendazole, thiabendazole, fenbendazole, or triclofenazole. In some embodiments, the anthelmintics are one or more of ivermectin, avermectin, dimethoprim (DEC), suramin, pyrantel pamoate, levamisole, niclosamide, nizoxinide, hydroxychlorozadamine, praziquantel, ammodendron, mononitrate, dequiterylpyrate, or punicin sulfate. In one embodiment, the anthelmintics are ivermectin, moxifloxacin, or slaquinidine. In some embodiments, a sulfonamide compound or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof is used in a method of treating or preventing filariasis and disease, 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 anthelmintics. In some such embodiments, the anthelmintics are selected from flubendazole, albendazole, mebendazole, thiabendazole, fenbendazole, triclofenazole, ivermectin, avermectin, dimethoprim (DEC), suramin, pyrantel pamoate, levamisole, niclosamide, nizoxinide, hydroxychlorozadamide, praziquantel, ammodendron, mononitrate, dequinoline, or punicin sulfate. In one embodiment, the anthelmintics is a Wolbachia target. In one embodiment, the Wolbachia target is doxycycline.

[0355] Pharmaceutical Compositions and Routes of Administration

[0356] This document provides pharmaceutical compositions comprising an effective amount of a sulfonamide compound as described herein, and a pharmaceutically acceptable carrier, excipient, or mediator. The sulfonamide compound can be administered to a subject in conventional forms of formulations, such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable formulations can be prepared using conventional organic or inorganic additives through commonly used methods. These additives include excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylene pyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), disintegrators (e.g., starch, carboxymethyl cellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), and lubricants (e.g., magnesium stearate, light...). The composition may contain anhydrous silicate, talc, or sodium lauryl sulfate; flavoring agents (e.g., citric acid, menthol, glycine, or orange powder); preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben, or propylparaben); stabilizers (e.g., citric acid, sodium citrate, or acetic acid); suspending agents (e.g., methylcellulose, polyvinylpyrrolidone, or aluminum stearate); dispersants (e.g., hydroxypropyl methylcellulose); diluents (e.g., water); cosolvents (e.g., propylene glycol / tetrahydrofuran polyethylene glycol ether), buffers; copolymers (e.g., poly(lactic-co-glycolic acid), i.e., PLGA); and base waxes (e.g., cocoa butter, white petrolatum, or polyethylene glycol). The effective amount of the sulfonamide compound in the pharmaceutical composition may be at a level that will exert the intended effect; for example, the unit dose for both oral and parenteral administration may be from about 0.005 mg / kg of subject body weight to about 20 mg / kg of subject body weight.

[0357] The dosage of the sulfonamide compound administered to subjects varies considerably and can be determined at the discretion of the healthcare practitioner. Typically, the sulfonamide compound can be administered to subjects at a dose of about 0.5 mg / kg body weight to about 20 mg / kg body weight one to four times daily, but these doses may be varied appropriately based on the subject's age, weight, medical condition, and type of administration. In one embodiment, the dose is about 0.1 mg / kg body weight to about 3 mg / kg body weight, about 0.5 mg / kg body weight to about 2 mg / kg body weight, about 1 mg / kg body weight to about 2 mg / kg body weight, or about 1.5 mg / kg body weight to about 2 mg / kg body weight. In another embodiment, the dose is about 1 mg / kg body weight to about 3 mg / kg body weight. In yet another embodiment, the dose is about 0.5 mg / kg body weight to about 1 mg / kg body weight. In yet another embodiment, the dose is about 1 mg / kg body weight to about 2 mg / kg 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, a single dose is administered daily. In any given case, the amount of sulfonamide compound administered will depend on factors such as the solubility of the active ingredient, the formulation used, and the route of administration. In one embodiment, application at a local concentration provides an intracellular exposure or concentration of about 0.01–10 μM.

[0358] In another embodiment, this document provides a method for treating or preventing a disease or disorder, comprising administering a sulfonamide compound to a subject affected by a parasitic worm infection at a dose of about 1 mg / day to about 1200 mg / day. In another embodiment, this document provides a method for treating or preventing a disease or disorder, comprising administering a sulfonamide compound to a subject affected by a parasitic worm infection at a dose of 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. In one embodiment, a method for treating a disease or disorder comprises administering a sulfonamide compound to a subject affected by a parasitic worm infection at a dose of about 0.375 mg / day to about 750 mg / day. In one embodiment, a method for treating a disease or disorder comprises administering a sulfonamide compound to a subject affected by a parasitic worm infection at a dose of about 0.75 mg / day to about 375 mg / day. In one embodiment, a method of treating a disease or disorder includes administering a sulfonamide compound to a subject affected by a parasitic worm infection at a dose of about 3.75 mg / day to about 75 mg / day. In one embodiment, a method of treating a disease or disorder includes administering a sulfonamide compound to a subject affected by a parasitic worm infection at a dose of about 7.5 mg / day to about 55 mg / day. In one embodiment, a method of treating a disease or disorder includes administering a sulfonamide compound to a subject affected by a parasitic worm infection at a dose of about 18 mg / day to about 37 mg / day.

[0359] In another embodiment, this document provides a unit dose formulation comprising a sulfonamide compound between about 1 mg and 200 mg, about 35 mg and about 1400 mg, about 125 mg and about 1000 mg, about 250 mg and about 1000 mg, or about 500 mg and about 1000 mg. In one embodiment, the unit dose formulation comprises a sulfonamide compound between about 1 mg and 200 mg. In one embodiment, the unit dose formulation comprises a sulfonamide compound between about 35 mg and about 1400 mg. In one embodiment, the unit dose formulation comprises a sulfonamide compound between about 125 mg and about 1000 mg. In one embodiment, the unit dose formulation comprises a sulfonamide compound between about 250 mg and about 1000 mg. In one embodiment, the unit dose formulation comprises a sulfonamide compound between about 500 mg and about 1000 mg.

[0360] In certain embodiments, this document provides unit-dose formulations comprising about 100 mg or 400 mg of a sulfonamide compound.

[0361] In another embodiment, this document provides a unit-dose formulation 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-dose formulation comprises 1 mg of a sulfonamide compound. In one embodiment, the unit-dose formulation comprises 5 mg of a sulfonamide compound. In one embodiment, the unit-dose formulation comprises 10 mg of a sulfonamide compound. In one embodiment, the unit-dose formulation comprises 15 mg of a sulfonamide compound. In one embodiment, the unit-dose formulation comprises 20 mg of a sulfonamide compound. In one embodiment, the unit-dose formulation comprises 25 mg of a sulfonamide compound. In one embodiment, the unit-dose formulation comprises 30 mg of a sulfonamide compound. In one embodiment, a unit dose formulation comprises 35 mg of a sulfonamide compound. In one embodiment, a unit dose formulation comprises 40 mg of a sulfonamide compound. In one embodiment, a unit dose formulation comprises 50 mg of a sulfonamide compound. In one embodiment, a unit dose formulation comprises 70 mg of a sulfonamide compound. In one embodiment, a unit dose formulation comprises 100 mg of a sulfonamide compound. In one embodiment, a unit dose formulation comprises 125 mg of a sulfonamide compound. In one embodiment, a unit dose formulation comprises 130 mg of a sulfonamide compound. In one embodiment, a unit dose formulation comprises 140 mg of a sulfonamide compound. In one embodiment, a unit dose formulation comprises 175 mg of a sulfonamide compound. In one embodiment, a unit dose formulation comprises 200 mg of a sulfonamide compound. In one embodiment, a unit dose formulation comprises 250 mg of a sulfonamide compound. In one embodiment, a unit dose formulation comprises 280 mg of a sulfonamide compound. In one embodiment, a unit dose formulation comprises 350 mg of a sulfonamide compound. In one embodiment, a unit dose formulation comprises 500 mg of a sulfonamide compound. In one embodiment, a unit dose formulation comprises 560 mg of a sulfonamide compound. In one embodiment, a unit dose formulation comprises 700 mg of a sulfonamide compound. In one embodiment, a unit dose formulation comprises 750 mg of a sulfonamide compound. In one embodiment, a unit dose formulation comprises 1000 mg of a sulfonamide compound. In one embodiment, a unit dose formulation comprises 1400 mg of a sulfonamide compound.

[0362] The sulfonamide compound can be administered once, twice, three times, four times or more daily. In certain embodiments, a dose of 600 mg or less is administered as a once-daily dose, and a dose of more than 600 mg is administered twice daily in an amount equal to half of that total daily dose.

[0363] For convenience, the sulfonamide compound can be administered orally. In one embodiment, when administered orally, the sulfonamide compound is taken with food and water. In another embodiment, the sulfonamide compound is dispersed in water or fruit juice (e.g., apple juice or orange juice) and administered orally as a suspension.

[0364] Sulfonamide compounds can also be applied intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, through mucous membranes, by inhalation, or topically to the ear, nose, eye, or skin, or through the eye (i.e., subconjunctival, intravitreal, retrobulbar, or anterior chamber). The method of application is determined by the healthcare practitioner and may depend in part on the site of the medical condition.

[0365] In one embodiment, this document provides a capsule containing a sulfonamide compound but without any additional carrier, excipient, or mediator.

[0366] In another embodiment, this document provides compositions comprising an effective amount of a sulfonamide compound and a pharmaceutically acceptable carrier or medium, wherein the pharmaceutically acceptable carrier or medium may comprise excipients, diluents, or mixtures thereof. In one embodiment, the composition is a pharmaceutical composition.

[0367] The composition may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories, suspensions, gels, rumen devices (e.g., for long-term prophylaxis or controlled release), implants, pour-on formulations, transdermal gels, spot-on formulations, and implants (including devices, gels, liquids (e.g., PLGA)). The composition may be formulated to contain a daily dose in a dosage unit, or a portable portion of a daily dose, which may be a single tablet or capsule or a portable volume of liquid. In one embodiment, the solution is prepared from a water-soluble salt (such as hydrochloride). Typically, all compositions are prepared according to methods known in medicinal chemistry. Capsules can be prepared by mixing a sulfonamide compound with a suitable carrier or diluent and filling an appropriate amount of the mixture into a capsule. Common carriers and diluents include, but are not limited to, inert powdered substances such as various types of starch, powdered cellulose (especially crystalline and microcrystalline cellulose), sugars (such as fructose, mannitol, and sucrose), cereal flours, and similar edible powders.

[0368] Tablets can be prepared by direct compression, wet granulation, or dry granulation. Their formulation typically incorporates diluents, binders, lubricants, disintegrants, and the compound itself. Typical diluents include, for example, different types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts (such as sodium chloride), and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin, and sugars (such as lactose, fructose, glucose, etc.). Natural and synthetic gums are also readily available, including gum arabic, alginate, methylcellulose, polyvinylpyrrolidine, etc. Polyethylene glycol, ethylcellulose, and waxes can also be used as binders.

[0369] To prevent tablets and punches from sticking together in the dye, lubricants may be necessary in tablet formulations. Lubricants can be selected from smooth solids such as talc, magnesium stearate and calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell when wet, causing the tablet to break down and release compounds. Tablet disintegrants include starch, clay, cellulose, alginate, and gums. More specifically, substances such as corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponges, cation exchange resins, alginate, guar gum, citrus pomace, and carboxymethyl cellulose, as well as sodium lauryl sulfate, can be used. Tablets can be coated with sugar as a flavoring agent and sealant, or with film-forming protectants to modify their solubility properties. These compositions can also be formulated into chewable tablets, for example, by using substances such as mannitol in the formulation.

[0370] When sulfonamide compounds are desired for suppository administration, typical bases can be used. Cocoa butter is a traditional suppository base, which can be modified by adding waxes to slightly increase its melting point. Water-miscible suppository bases (especially those containing polyethylene glycol of varying molecular weights) are widely used.

[0371] The action of sulfonamide compounds can be delayed or prolonged through proper formulation. For example, slow-dissolving microspheres of sulfonamide compounds can be prepared and incorporated into tablets or capsules, or used as implantable sustained-release devices. This technology also includes manufacturing microspheres with several different dissolution rates and filling capsules with mixtures of microspheres. Tablets or capsules can be coated with a film that resists dissolution for a predictable period. Even parenteral formulations can be made into long-acting formulations by dissolving or suspending the sulfonamide compound in an oily or emulsified medium, or by adding a certain amount of PLGA (to allow it to disperse slowly in serum).

[0372] Example

[0373] The following examples are provided illustratively and not restrictively. Compound naming uses the automatic name generation tool available in Chemdraw Ultra 17.0 (Cambridgesoft), which generates systematic names of chemical structures supporting the Cahn-Ingold-Prelog rule for stereochemistry. Those skilled in the art can modify the procedures described in the illustrative examples to obtain desired products.

[0374] Abbreviations used:

[0375]

[0376]

[0377]

[0378] Example 1. N-(7-chloroquinoline-8-yl)-3-cyclopropylpyridine-2-sulfonamide

[0379]

[0380] 2-Chloro-3-cyclopropylpyridine. Under nitrogen atmosphere, (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (3.06 g, 4.18 mmol) and potassium carbonate (20.2 g, 146 mmol) were added 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). The mixture was stirred at 100 °C for 24 h. The mixture was concentrated under vacuum. 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 phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography to give 2-chloro-3-cyclopropylpyridine (3.2 g, 20.83 mmol, 49.89% yield).

[0381] 3-Cyclopropyl-2-((4-Methoxybenzyl)thio)pyridine. Cesium fluoride (6.33 g, 41.7 mmol) and 2-chloro-3-cyclopropylpyridine (3.20 g, 20.8 mmol) were added to a mixture of (4-methoxyphenyl)methanethiol (4.82 g, 31.3 mmol) in DMSO (30 mL). 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 under vacuum. The residue was purified by preparative HPLC to give 3-cyclopropyl-2-((4-methoxybenzyl)thio)pyridine (5.6 g, crude).

[0382] 3-Cyclopropylpyridine-2-sulfonyl chloride. At 0 °C, over 0.5 h, a solution of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (DCH) (1.52 g, 7.74 mmol) in DCM (5.6 mL) was added dropwise 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). The mixture was stirred at 0 °C–5 °C for 3 h. The mixture was then poured into water. The aqueous phase was extracted with DCM. The combined organic phases were washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 3-cyclopropylpyridine-2-sulfonyl chloride (562 mg, crude).

[0383] N-(7-chloroquinoline-8-yl)-3-cyclopropylpyridine-2-sulfonamide. Under nitrogen atmosphere at 0 °C, a solution of 3-cyclopropylpyridine-2-sulfonyl chloride (561 mg, 2.58 mmol) in DCM (5.6 mL) was added dropwise to a mixture of 7-chloroquinoline-8-amine (138 mg, 0.774 mmol) in pyridine (5.6 mL). The mixture was stirred at 25 °C for 16 h. The product was isolated and purified (by standard methods) to give N-(7-chloroquinoline-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] + .

[0384] Example 2. N-(7-chloroquinoline-8-yl)-6-(pyrrolidone-1-yl)pyrazine-2-sulfonamide

[0385]

[0386] 2-((4-methoxybenzyl)thio)-6-(pyrrolidine-1-yl)pyrazine. Potassium carbonate (2.59 g, 18.74 mmol) was added to a mixture of 2-chloro-6-[(4-methoxyphenyl)methylthioalkyl]pyrazine (2.50 g, 9.37 mmol) and pyrrolidine (1.33 g, 18.74 mmol) in ACN (30.00 mL). The mixture was stirred at 80 °C for 12 h. The mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography to give 2-[(4-methoxyphenyl)methylthioalkyl]-6-pyrrolidine-1-yl-pyrazine (2.70 g, 8.96 mmol, 96% yield).

[0387] 6-(pyrrolidone-1-yl)pyrazine-2-sulfonyl chloride. A solution of 1,3-dichloro-5,5-dimethylimidazolium-2,4-dione (3.92 g, 19.9 mmol) in DCM (12 mL) was added dropwise to a mixture of 2-[(4-methoxyphenyl)methylthioalkyl]-6-pyrrolidone-1-yl-pyrazine (2.00 g, 6.64 mmol) in DCM (21 mL), water (6 mL), and acetic acid (3 mL) over 1 h at 0 °C. The mixture was stirred at 0 °C for 1.5 h. 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 under vacuum to give 6-pyrrolidone-1-ylpyrazine-2-sulfonyl chloride (1.62 g, crude).

[0388] N-(7-chloroquinoline-8-yl)-6-(pyrrolidine-1-yl)pyrazine-2-sulfonamide. Under N2 protection at -65°C, sodium bis(trimethylsilyl)amino (1M, 6.53 mL) was added to a mixture of 7-chloroquinoline-8-amine (350.00 mg, 1.96 mmol) in THF (10 mL). The mixture was stirred at 25°C for 0.5 h. At -65°C, a solution of 6-pyrrolidine-1-ylpyrazine-2-sulfonyl chloride (1.62 g, 6.53 mmol) in THF (5 mL) was added to the mixture. The mixture was stirred at 25°C for 1 h. The mixture was quenched with water. The product was isolated and purified (by standard methods) to give N-(7-chloro-8-quinolinyl)-6-pyrrolidine-1-yl-pyrazine-2-sulfonamide (229.10 mg, 0.580 mmol, 9% yield, 98.1% purity). MS (ESI) m / z 390.1 [M+1] + .

[0389] Example 3. N-(7-chloroquinoline-8-yl)-3-(dimethylamino)pyrazine-2-sulfonamide

[0390]

[0391] 3-((4-methoxybenzyl)thio)-N,N-dimethylpyrazine-2-amine. A mixture of 2-chloro-3-[(4-methoxyphenyl)methylthioalkyl]pyrazine (3.00 g, 11.3 mmol), N-methylmethylamine (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)methylthioalkyl]-N,N-dimethylpyrazine-2-amine (3.30 g, crude product).

[0392] 3-(Dimethylamino)pyrazine-2-sulfonyl chloride. At 0 °C for 0.5 h, a solution of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (6.65 g, 33.8 mmol) in DCM was added dropwise to a mixture of 3-[(4-methoxyphenyl)methylthioalkyl]-N,N-dimethyl-pyrazine-2-amine (3.10 g, 11.3 mmol) in DCM (21 mL), water (6 mL), and acetic acid (3 mL). 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).

[0393] N-(7-chloroquinoline-8-yl)-3-(dimethylamino)pyrazine-2-sulfonamide. Sodium hexamethyldisilazane (1M, 10.3mL) was added to a mixture of 7-chloroquinoline-8-amine (550.00 mg, 3.08 mmol) in THF (20 mL) at -65 °C under N2 protection. The mixture was stirred at 25 °C for 0.5 h. Then, a solution of 3-(dimethylamino)pyrazine-2-sulfonyl chloride (2.28 g, 10.3 mmol) in THF (10 mL) was added to the mixture at -65 °C. The mixture was stirred at 25 °C for 1 h. The mixture was quenched with water. The product was isolated and purified (by standard methods) to give N-(7-chloro-8-quinoline-3-(dimethylamino)pyrazine-2-sulfonamide (303.00 mg, 0.816 mmol, 27% yield, 98% purity). MS(ESI)m / z 364[M+1] + .

[0394] Example 4. N-(7-chloroquinoline-8-yl)-1-isopropyl-1H-pyrazole-5-sulfonamide

[0395]

[0396] Lithium 1-isopropyl-1H-pyrazole-5-sulfinate. n-BuLi (2.5M, 6.54mL) was added to a solution of 1-isopropyl-1H-pyrazole (1.50g, 13.6mmol) in diethyl ether (50mL) in the presence of SO2 at -70°C. The mixture was stirred at -70°C for 0.5h and then at 0°C for 2h. Excess SO2 was purged and the mixture was stirred at -70°C for 1h. The mixture was then warmed to 20°C. The mixture was filtered, the filter cake was collected and vacuum dried to give lithium 1-isopropyl-1H-pyrazole-5-sulfinate (2.40g, crude product).

[0397] 1-Isopropyl-1H-pyrazole-5-sulfonyl chloride. At 0 °C, 1-isopropyl-1H-pyrazole-5-sulfinate lithium (2.40 g, 13.3 mmol) was added to chloroform (40 mL) and water (50 mL), followed by the fractional addition of N-chlorosuccinimide (2.67 g, 19.9 mmol). The mixture was stirred at 0 °C for 1 h. 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 under vacuum. 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) δ7.62 (d, J = 1.9 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 5.28-5.18 (m, 1H), 1.60 (s, 6H).

[0398] N-(7-chloroquinoline-8-yl)-1-isopropyl-1H-pyrazole-5-sulfonamide. At 0 °C, a mixture of 1-isopropyl-1H-pyrazole-5-sulfonyl chloride (400 mg, 1.92 mmol) in DCM (5 mL) was added to a solution of 7-chloroquinoline-8-amine (205 mg, 1.15 mmol) in pyridine (4.55 g, 57.5 mmol). The mixture was stirred at 25 °C for 8 h. The product was isolated and purified (by standard methods) to give N-(7-chloroquinoline-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] + .

[0399] Example 5. N-(7-chloroquinoline-8-yl)-5-methoxypyrazine-2-sulfonamide

[0400]

[0401] N-(7-chloroquinoline-8-yl)-5-methoxypyrazine-2-sulfonamide. Under nitrogen atmosphere, sodium methoxide (66 mg, 1.69 mmol) was added to a solution of 5-chloro-N-(7-chloroquinoline-8-yl)pyrazine-2-sulfonamide (150 mg, 0.422 mmol) in MeOH (3 mL). The mixture was stirred at 60 °C for 2 h. The product was isolated and purified (by standard methods) to give N-(7-chloroquinoline-8-yl)-5-methoxypyrazine-2-sulfonamide (127.59 mg, 0.354 mmol, 84% yield, 97.3% purity). MS (ESI) m / z 351 [M+1] + .

[0402] Example 6. N-(7-chloroquinoline-8-yl)-6-methoxypyrazine-2-sulfonamide

[0403]

[0404] 2-Chloro-6-((4-methoxybenzyl)thio)pyrazine. Sodium hydride (2.01 g, 50.3 mmol, 60% purity) was added to a mixture of (4-methoxyphenyl)methanethiol (5.18 g, 33.6 mmol, 5 mL) in THF (25 mL). The mixture was stirred at 25 °C for 10 min. Then, at 25 °C, a solution of 2,6-dichloropyrazine (5.00 g, 33.6 mmol) in THF (15 mL) was added dropwise to the mixture while stirring. The resulting mixture was stirred at 25 °C for 3 h. The 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 the 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).

[0405] 2-Methoxy-6-((4-Methoxybenzyl)thio)pyrazine. Sodium methoxide (911 mg, 16.9 mmol) was added to a solution of 2-chloro-6-((4-Methoxybenzyl)thio)pyrazine (3.00 g, 11.25 mmol) in MeOH (20 mL). The mixture was stirred at 60 °C for 16 h. 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 under vacuum. 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).

[0406] 6-Methoxypyrazine-2-sulfonyl chloride. At -5°C for 1 h, a solution of 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (3.38 g, 17.2 mmol) in DCM (12 mL) was added dropwise to a mixture of 2-methoxy-6-((4-methoxybenzyl)thio)pyrazine (1.50 g, 5.7 mmol) in DCM (21 mL), H₂O (6 mL), and acetic acid (3 mL). 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).

[0407] N-(7-chloroquinoline-8-yl)-6-methoxypyrazine-2-sulfonamide. Sodium hexamethyldisilazane (1M, 5.6mL) was added to a mixture of 7-chloroquinoline-8-amine (300 mg, 1.68 mmol) in THF (10 mL) at -65 °C under N2 protection. 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-chloroquinoline-8-yl)-6-methoxypyrazine-2-sulfonamide (97.8 mg, 0.265 mmol, 5% yield, 95.1% purity). MS (ESI) m / z 351 [M+1] + .

[0408] Example 7.1-Ethyl-N-(7-methoxyquinoline-8-yl)-1H-imidazol-2-sulfonamide

[0409]

[0410] 1-((1-ethyl-1H-imidazol-2-yl)sulfonyl)-1H-benzo[d][1,2,3]triazole. Under nitrogen atmosphere at -78°C, a solution of n-butyllithium in hexane (2.5N, 66mL, 164mmol) was added dropwise to a mixture of 1-ethyl-1H-imidazolium (15.0 g, 156 mmol) in THF (450 mL). The resulting reaction mixture was stirred at -78°C for 1 h. Sulfur dioxide was bubbled into the above organometallic reagent in THF at -78°C until the pH of the solution sample was acidic. The mixture was stirred at this temperature for 15 min, then at room temperature for 1 h. N-chlorobenzotriazole (23.0 g, 156 mmol) was added in a single addition, and the mixture was stirred at room temperature for 2 h. TEA (39.4 g, 390 mmol) was added, followed by stirring at room temperature for 16 h. Water (300 mL) was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of 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).

[0411] 7-Methoxyquinoline. Quinoline-7-ol (5.0 g, 34.5 mmol) in dry DMF (200 mL) was added to a slurry of sodium hydride (3.50 g, 86.2 mmol) in dry DMF (100 mL) at 0 °C. The mixture was stirred for 1 h and then warmed to room temperature. Iodimethane (9.80 g, 69.0 mmol) was added and the mixture was stirred for 16 h. 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 a crude product, which was purified by silica gel column chromatography to give the title compound (2.75 g, 17.3 mmol, 50% yield).

[0412] 7-Methoxy-8-nitroquinoline. Cooled 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, maintaining the temperature below 0 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice and neutralized with ammonium hydroxide. The yellow precipitate was filtered to give the desired product (2.80 g, 13.7 mmol, 79% yield).

[0413] 7-Methoxyquinoline-8-amine. Palladium on carbon (200 mg, 10%) was added to a solution of 7-methoxy-8-nitroquinoline (1.00 g, 4.88 mmol) in MeOH (20 mL) and THF (20 mL). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2 h and filtered through diatomaceous earth. The filtrate was concentrated under vacuum to give the desired product (790 mg, 0.25 mmol, 92% yield).

[0414] 1-Ethyl-N-(5-methoxyquinoline-8-yl)-1H-imidazol-2-sulfonamide. Under nitrogen atmosphere at -78°C, a solution of sodium bis(trimethylsilyl)amino in THF (2M, 1.15 mL, 2.30 mmol) was slowly added to a solution of 7-methoxyquinoline-8-amine (200 mg, 1.15 mmol) in THF (5 mL). After stirring the resulting reaction mixture at this temperature for 1 h, 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 h. The reaction mixture was quenched with aqueous ammonium chloride solution 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] + .

[0415] Example 8. 1-Ethyl-N-(3-methylquinoline-8-yl)-1H-imidazol-2-sulfonamide

[0416]

[0417] 1-((1-ethyl-1H-imidazol-2-yl)sulfonyl)-1H-benzo[d][1,2,3]triazole. Under nitrogen atmosphere at -78 °C, a solution of n-BuLi in hexane (2.5 N, 66 mL, 164 mmol) was added dropwise to a solution of 1-ethyl-1H-imidazolium (15.0 g, 156 mmol) in THF (450 mL). The resulting reaction mixture was stirred at -78 °C for 1 h. Sulfur dioxide was bubbled into a solution of the organometallic reagent in THF at -78 °C until the pH of the solution sample was acidic. The mixture was stirred at this temperature for 15 min, then at room temperature for 1 h. N-chlorobenzotriazole (23.0 g, 156 mmol) was added in a single addition, and the mixture was stirred at room temperature for 2 h. Triethylamine (39.4 g, 390 mmol) was added, followed by stirring at room temperature for 16 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous ammonium chloride solution, 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] + .

[0418] 1-Ethyl-N-(3-methylquinoline-8-yl)-1H-imidazol-2-sulfonamide. Under nitrogen atmosphere at -78°C, a solution of sodium bis(trimethylsilyl)amino in THF (2M, 1.25 mL, 2.50 mmol) was slowly added to a solution of 3-methylquinoline-8-amine (200 mg, 1.26 mmol) in THF (5 mL). After stirring the resulting reaction mixture at this temperature for 1 hour, a solution of 1-ethyl-N-(4-methoxyquinoline-8-yl)-1H-imidazol-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). 1 H NMR(400MHz,DMSO-d6)δ8.36(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] + The purity at 214nm is 98.6%, and the purity at 254nm is 96.6%.

[0419] Example 9. N-(6-fluoroquinolin-8-yl)-5-methylpyridine-2-sulfonamide

[0420]

[0421] 2-(benzylthio)-5-methylpyridine. Sodium hydride (60% in mineral oil, 8.28 g, 207 mmol) was added fractionally to a solution of benzyl mercaptan (23.3 g, 188 mmol) in anhydrous THF (200 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h, followed by the fractional addition of 2-chloro-5-methylpyridine (20.0 g, 157 mmol) at 0 °C. The resulting mixture was stirred at 70 °C for 30 h. The reaction mixture was treated with water and 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).

[0422] 5-Methylpyridine-2-sulfonyl chloride. Chlorine gas was bubbled into a solution of 2-(benzylthio)-5-methylpyridine (3.0 g, 50% purity crude product, 6.98 mmol) in acetic acid (20 mL), DCM (20 mL), and water (7 mL) for 0.5 h at 0 °C. The resulting mixture was then stirred at this 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 a crude product (3.2 g), which was proceeded to the next step without further purification.

[0423] 6-Fluoroquinoline-8-amine. Palladium on carbon (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 diatomaceous earth, and the filtrate was concentrated under vacuum to give a crude product (110 mg, 80% purity), which was used for the next step without further purification.

[0424] N-(6-fluoroquinolin-8-yl)-5-methylpyridine-2-sulfonamide. Under nitrogen atmosphere at -78°C, a solution of sodium bis(trimethylsilyl)amino in THF (2 M, 0.50 mL, 1.0 mmol) was slowly added to a solution of 6-fluoroquinolin-8-amine (100 mg, crude) in THF (3 mL). The resulting solution was stirred at -78°C for 1 h. Then, crude 5-methylpyridine-2-sulfonyl chloride (300 mg, crude) was added to the above solution. The resulting solution was stirred at -78°C and then at room temperature for 1 h. The reaction mixture was quenched with aqueous ammonium chloride solution 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, in two steps). MS (ESI) m / z 317.8 [M+1] + .

[0425] Example 10. N-(7-chloroquinoline-8-yl)-3-(dimethylamino)pyridine-2-sulfonamide

[0426]

[0427] Lithium 3-fluoropyridine-2-sulfinate. Butyllithium (2.5 M, 5.5 mL) was added to a solution of 2-bromo-3-fluoropyridine (2.00 g, 11.4 mmol) in diethyl ether (30 mL) at -70 °C. The mixture was stirred at -70 °C for 1 h. Excess sulfur dioxide was purged and the mixture was stirred at -70 °C for 1 h. A yellow solid formed. The mixture was filtered, and the filter cake was vacuum dried to give lithium 3-fluoropyridine-2-sulfinate (1.90 g, crude).

[0428] 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. Then, NCS (3.04 g, 22.7 mmol) was added in portions to the mixture. The mixture was stirred at 0 °C for 1 h. The mixture was extracted with chloroform. The combined organic phases were 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).

[0429] N-(7-chloroquinoline-8-yl)-3-methylpyrazine-2-sulfonamide. Under nitrogen atmosphere at -65°C, sodium bis(trimethylsilyl)amino (1M, 12.3mL) was added dropwise to a mixture of 7-chloroquinoline-8-amine (328mg, 1.84mmol) in THF (20mL). The mixture was stirred at 25°C for 0.5h. Then, under nitrogen atmosphere at -65°C, 3-fluoropyridine-2-sulfonyl chloride (2.00g, 6.13mmol) in THF (10mL) was added dropwise to the above mixture. The mixture was stirred at 25°C for 1h. The mixture was added to saturated ammonium chloride. The aqueous phase was extracted with ethyl acetate. The combined organic phases were 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-chloroquinoline-8-yl)-3-fluoropyridine-2-sulfonamide (500 mg, 1.32 mmol, 22% yield, 89% purity).

[0430] N-(7-chloroquinoline-8-yl)-3-(dimethylamino)pyridine-2-sulfonamide. N-ethyl-N-isopropyl-propane-2-amine (1.44 g, 11.2 mmol) was added to a mixture of N-(7-chloroquinoline-8-yl)-3-fluoropyridine-2-sulfonamide (423 mg, 1.11 mmol) and N-methylmethylamine hydrogen chloride (545 mg, 6.69 mmol) in DMSO (5 mL). The mixture was stirred at 80 °C for 54 h. The product was isolated and purified (by standard methods) to give N-(7-chloroquinoline-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] + .

[0431] Example 11. N-(6-hydroxyquinoline-8-yl)pyridine-2-sulfonamide

[0432]

[0433] N-(6-methoxyquinoline-8-yl)pyridine-2-sulfonamide. Pyridine-2-sulfonyl chloride (305 mg, 1.17 mmol) was added to a solution of 6-methoxyquinoline-8-amine (200 mg, 1.14 mmol) in pyridine (6 mL). The reaction mixture was heated in a microwave at 130 °C for 5 min. 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).

[0434] N-(6-hydroxyquinoline-8-yl)pyridine-2-sulfonamide. Tribromoborane (297 mg, 1.19 mmol) was added to a solution of N-(6-methoxyquinoline-8-yl)pyridine-2-sulfonamide (150 mg, 0.47 mmol) in anhydrous DCM (2 mL). The resulting reaction mixture was heated under reflux for 16 h. The product was isolated and purified (by standard methods) to give the desired product as a pink powder (50 mg, 0.16 mmol, 35% yield). MS (ESI) m / z 302 [M+1] + .

[0435] Example 12. N-(6-fluoroquinoline-8-yl)-3,5-dimethylbenzenesulfonamide

[0436]

[0437] 6-Fluoro-8-nitroquinoline. Propane-1,2,3-triol (14 mL) was preheated to 160 °C for 1 h, 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, followed by dropwise addition of concentrated sulfuric acid (8.4 mL). The reaction mixture was stirred at 150 °C for 45 min. 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 a saturated aqueous sodium carbonate solution, 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, yield: 33%).

[0438] 6-Fluoroquinoline-8-amine. Stannous dichloride (9.40 g, 41.7 mmol) was added to a suspension of 6-fluoro-8-nitroquinoline (4.0 g, 20.8 mmol) in EtOH (100 mL). The mixture was heated to reflux for 2 h. After the reaction was complete, sodium hydroxide (3.5 g, 83.4 mmol) was added to water (100 mL), and the reaction was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated, and 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%).

[0439] N-(6-fluoroquinolin-8-yl)-3,5-dimethylbenzenesulfonamide. 6-fluoroquinolin-8-ylamine (163 mg, 1.0 mmol) was added to a solution of 3,5-dimethylbenzene-1-sulfonyl chloride (180 mg, 1.0 mmol) in pyridine (5 mL). The mixture was stirred overnight at room temperature. 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] + .

[0440] Example 13.3-(N-(5-morpholinoquinolin-8-yl)aminosulfonyl)benzamide

[0441]

[0442] 4-(8-nitroquinoline-5-yl)morpholine. 5-Chloro-8-nitroquinoline (600 mg, 2.88 mmol) was suspended in morpholine (3 mL), and the mixture was irradiated at 100 °C for 10 min using a microwave apparatus. 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).

[0443] 5-Morpholinequinoline-8-amine. Palladium on carbon (100 mg, 10%) was added to a solution of 4-(8-nitroquinoline-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 filtered off, and the filtrate was concentrated to give the desired product, which was used for the next step without further purification (405 mg, yield: 95%, 1.76 mmol).

[0444] 3-Cyano-N-(5-morpholinoquinoline-8-yl)benzenesulfonamide. 3-Cyanobenzene-1-sulfonyl chloride (81 mg, 0.40 mmol) was added to a solution of 5-morpholinoquinoline-8-amine (92 mg, 0.40 mmol) in pyridine (2 mL), and the reaction mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography to give the desired product (118.7 mg, 0.30 mmol, 75% yield).

[0445] 3-(N-(5-morpholinoquinolin-8-yl)aminosulfonyl)benzamide. Potassium carbonate (83 mg, 0.60 mmol) and hydrogen peroxide (31 mg, 0.90 mmol) were added to a solution of 3-cyano-N-(5-morpholinoquinolin-8-yl)benzamide (118.7 mg, 0.30 mmol) in dimethyl sulfoxide (2 mL). The reaction mixture was stirred at room temperature for 2 h. 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] + .

[0446] Example 14. 4-Methyl-N-(6-methylquinoline-8-yl)benzenesulfonamide

[0447]

[0448] 6-Methyl-8-nitroquinoline. Glycerol (3.25 mL, 44.5 mmol) was preheated at 165 °C for 1 h 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 a 10-minute period). The reaction mixture was stirred at 150 °C for 2 h. The resulting reaction mixture was carefully poured into ice-cold water, and the precipitate was collected by filtration. The obtained solid was recrystallized from 10% ethyl acetate and petroleum ether to give the desired product (1 g, 90% purity (by LC-MS), 5.31 mmol, 32% yield).

[0449] 6-Methylquinoline-8-amine. Stannous chloride (4.01 g, 21.27 mmol) was added to a solution of 6-methyl-8-nitroquinoline (1 g, 5.31 mmol) in EtOH (20 mL). The resulting reaction mixture was heated under reflux for 35 min and then cooled to room temperature. The reaction mixture was poured into a 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, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the desired product (800 mg, 5.06 mmol, 94% yield, 90% purity (by LC-MS)).

[0450] 4-Methyl-N-(6-methylquinoline-8-yl)benzenesulfonamide. 4-Methylbenzene-1-sulfonyl chloride (359 mg, 1.89 mmol) was added to a solution of 6-methylquinoline-8-amine (200 mg, 1.26 mmol) in pyridine (6 mL). The resulting reaction mixture was heated in a microwave at 130 °C for 3 min, 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] + .

[0451] Example 15. N-(5-(4-hydroxy-4-phenylpiperidin-1-yl)quinolin-8-yl)-4-methylbenzenesulfonamide

[0452]

[0453] N-(5-(4-hydroxy-4-phenylpiperidin-1-yl)quinoline-8-yl)-4-methylbenzenesulfonamide. Under a nitrogen atmosphere at 110 °C, a mixture of N-(5-bromoquinoline-8-yl)-4-methylbenzenesulfonamide (500 mg, 1.33 mmol), 4-phenylpiperidin-4-ol (1.14 g, 6.65 mmol), tris(dibenzylacetone)palladium (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 overnight. 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] + .

[0454] Example 16. 4-Methyl-N-(3-methylquinoline-8-yl)benzenesulfonamide

[0455]

[0456] 3-Methyl-8-nitroquinoline. Nitric acid (1 mL) was slowly added to a solution of 3-methylquinoline (1 g, 6.99 mmol) in sulfuric acid (2 mL) at -5 °C. The resulting solution was stirred overnight at room temperature. 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 under reflux for 0.5 h, and slowly cooled to room temperature. The mixture was filtered, the filtrate was concentrated, and purified by silica gel column chromatography to give the title compound (309 mg, 1.6 mmol, 23% yield).

[0457] 3-Methyl-quinoline-8-amine. A mixture of 3-methyl-8-nitroquinoline (300 mg, 1.60 mmol) and palladium on carbon (10%, 30 mg) in MeOH (10 mL) was stirred at 25 °C under a hydrogen atmosphere for 3 h. The reaction mixture was then filtered through diatomaceous earth and the residue was washed with MeOH. The reaction mixture was filtered through diatomaceous earth and evaporated under vacuum to give a crude product (250 mg, 1.58 mmol, 99% yield), which was used in the next step without further purification.

[0458] 4-Methyl-N-(3-methylquinoline-8-yl)benzenesulfonamide. 4-Methyl-benzenesulfonyl chloride (420 mg, 2.2 mmol) was added to a solution of 3-methylquinoline-8-amine (172 mg, 1.09 mmol) in pyridine (10 mL). The resulting mixture was heated overnight at 100 °C. The product was isolated and purified (by standard methods) to give the title compound (155.5 mg, 0.50 mmol, 46% yield). MS (ESI) m / z 313.1 [M+1] + .

[0459] Example 17. N-(6-fluoroquinoline-8-yl)-3,5-dimethoxybenzenesulfonamide

[0460]

[0461] 3,5-Dimethoxybenzenesulfonyl chloride. A solution of 2.5N n-butyllithium (2 mL, 5 mmol) was added dropwise to a solution of 1-bromo-3,5-dimethoxy-benzene (1 g, 4.61 mmol) in THF at -78 °C, and the mixture was stirred for 1 hour at the same temperature. Then, sulfonyl chloride (0.42 mL, 5.0 mmol) was 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. The crude product (1.0 g, 50% purity (by LC-MS)) was concentrated under vacuum and proceeded to the next step without further purification.

[0462] 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] + .

[0463] Example 18. N-(6-phenylquinoline-8-yl)pyridine-2-sulfonamide

[0464]

[0465] Pyridine-2-sulfonyl chloride. Pyridine-2-thiol (5.0 g, 45 mmol) was dissolved in 6N aqueous hydrochloric acid (20 mL), and chlorine gas 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 product).

[0466] N-(6-phenylquinoline-8-yl)pyridine-2-sulfonamide. Pyridine-2-sulfonyl chloride (180 mg, crude) was added to a solution of 6-phenylquinoline-8-amine (120 mg, 0.545 mmol) in pyridine (3 mL). The mixture was stirred overnight at room temperature. The product was isolated and purified (by standard methods) to give the title product (36 mg, 0.1 mmol, yield: 18%). MS (ESI) m / z 362.1 [M+H] + .

[0467] Example 19. 6-Cyanopyridine-2-sulfonic acid quinoline-8-ylamide

[0468]

[0469] 2-Bromo-6-(4-methoxy-benzylthioalkyl)-pyridine. At -15 °C, (4-methoxyphenyl)methanethiol (1.56 g, 10.13 mmol) was added to a suspension of sodium hydride (60% in oil, 1.01 g, 25.32 mmol) in THF (20 mL). 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 h. After 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-methoxy-benzylthioalkyl)-pyridine (1.2 g, 30%). MS (ESI): m / z 309.9 [M+1] + .

[0470] 6-Bromo-pyridine-2-sulfonic acid quinoline-8-ylamide. At -30°C, 2-bromo-6-(4-methoxy-benzylthioalkyl)-pyridine (1.2 g, 3.87 mmol) was added dropwise to concentrated sulfuric acid (12 mL) and stirred continuously at 25°C until a clear solution was obtained. The solution was cooled again to -30°C, and a NaOCl solution (10% aq, 36 mL) was added dropwise to the reaction mixture through a feeding funnel. The reaction mixture was slowly warmed to 25°C and stirred for 2 h. The reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. At 0°C, a crude solution of sulfonyl chloride in DCM (10 mL) was added to a solution of quinoline-8-amine (279 mg, 1.93 mmol) in DCM (15 mL) and pyridine (3 mL, 38.71 mmol), and stirred for 12 h. After 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 Na₂SO₄, filtered, and concentrated under reduced pressure. The crude substance was purified by column chromatography to give the product 6-bromo-pyridine-2-sulfonic acid quinoline-8-ylamide (930 mg, 66%). MS (ESI): m / z 363.8 [M+1] + .

[0471] 6-Cyanopyridine-2-sulfonic acid quinoline-8-ylamide. Zinc cyanide (141.8 mg, 117.41 mmol) was added to a stirred, degassed solution of 6-bromopyridine-2-sulfonic acid quinoline-8-ylamide (400 mg, 1.10 mmol) in DMA (5 mL), followed by the addition of TMEDA (0.052 mL, 0.329 mmol), Pd2(dba)3 (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 mixture 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 Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 6-cyanopyridine-2-sulfonic acid quinoline-8-ylamide (25 mg, 8%). MS(ESI): m / z 311.1[M+1] + .

[0472] Example 20,6-Phenylacetyl-N-(quinolin-8-yl)pyridine-2-sulfonamide

[0473]

[0474] 2-Bromo-3-phenylpyridine. EtOH (5 mL), water (2 mL), and potassium carbonate (802 mg, 5.81 mmol) were added to a stirred solution of 2-bromo-3-iodopyridine (1.5 g m, 5.28 mmol) in toluene (10 mL), followed by the addition of phenylboronic acid (773 mg, 6.34 mmol). The resulting mixture was degassed with argon for 15 min, and Pd(PPh3)4 (305 mg, 0.26 mmol) was added under an inert atmosphere. The resulting mixture was heated to 70 °C for 4 h under an argon atmosphere. The reaction mixture was cooled to 25 °C and diluted with ethyl acetate. The organic matter was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography to give 2-bromo-3-phenylpyridine (250 mg, 20%). MS (ESI): m / z 233.8 [M+1] + .

[0475] 2-{[(4-methoxyphenyl)methyl]thioalkyl}-3-phenylpyridine. CsF (779 mg, 5.13 mmol) was added to a stirred solution of 4-methoxybenzylamine (790 mg, 2.56 mmol) in DMSO (10 mL) at 25 °C, followed by the addition of 2-bromo-3-phenylpyridine (600 mg, 2.56 mmol). The resulting mixture was heated at 80 °C for 3 h. After 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 substance was purified by rapid column chromatography to give 2-{[(4-methoxyphenyl)methyl]thioalkyl}-3-phenylpyridine (600 mg, 76%). MS (ESI): m / z 308.2 [M+1] + .

[0476] 3-Phenyridine-2-sulfonyl chloride. A solution of 2-{[(4-methoxyphenyl)methyl]thioalkyl}-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, followed by stirring under cooling 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%).

[0477] 6-Phenyron-N-(quinoline-8-yl)pyridine-2-sulfonamide. Under an argon atmosphere at 0 °C, a solution of 3-phenylpyridine-2-sulfonyl chloride (65 mg, 0.26 mmol) in DCM (2.5 mL) was added dropwise to a stirred solution of quinoline-8-amine (22 mg, 0.154 mmol) in pyridine (0.3 mL). The reaction mixture was heated to 25 °C and stirred for 16 hours. After 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 material was purified by preparative HPLC to give 6-phenyl-N-(quinoline-8-yl)pyridine-2-sulfonamide (30 mg, 32%). MS (ESI): m / z 362.1 [M+1]+.

[0478] Example 21.4-Cyclopropyl-N-(1,5-Naphthid-4-yl)pyridine-2-sulfonamide

[0479]

[0480] 2-Chloro-4-cyclopropylpyridine. Potassium carbonate (2.51 g, 18.19 mmol) was added to a stirred solution of 4-bromo-2-chloropyridine (1 g, 5.19 mmol) in dioxane (25 mL) and water (2.5 mL), followed by the addition of cyclopropylboronic acid (669 mg, 7.79 mmol). The resulting mixture was degassed with argon and Pd(dppf)Cl2. DCM (381 mg, 0.52 mmol) was added under an inert atmosphere. The resulting mixture was heated at 110 °C for 16 h. After completion, the reaction mixture was cooled to 25 °C and filtered through a diatomaceous earth stencil. 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] + .

[0481] 4-Cyclopropyl-2-{[(4-methoxyphenyl)methyl]thioalkyl}pyridine. CsF (3.2 g, 21.24 mmol) was added to a stirred solution of (4-methoxyphenyl)methanethiol (2.62 g, 16.99 mmol) in DMSO (20 mL) at 25 °C, followed by the addition of 2-chloro-4-cyclopropylpyridine (1.3 g, 8.50 mmol). The resulting mixture was heated at 80 °C for 16 h. After 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 substance was purified by column chromatography to give 4-cyclopropyl-2-{[(4-methoxyphenyl)methyl]thioalkyl}pyridine (2.1 g, 91%). MS (ESI): m / z 271.9 [M+1] + .

[0482] 4-Cyclopropylpyridine-2-sulfonyl chloride. A solution of 4-cyclopropyl-2-{[(4-methoxyphenyl)methyl]thioalkyl}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, followed by stirring under cooling 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%).

[0483] 4-Cyclopropyl-N-(1,5-Naphthid-4-yl)pyridine-2-sulfonamide. Under an argon atmosphere at 0 °C, a solution of 4-cyclopropylpyridine-2-sulfonyl chloride (300 mg, 1.38 mmol) in DCM (3 mL) was added dropwise to a solution of 1,5-naphthid-4-amine (60 mg, 0.41 mmol) in pyridine (3 mL). The reaction mixture was heated to 25 °C and stirred for 16 h. After 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 material was purified by preparative HPLC to give 4-cyclopropyl-N-(1,5-naphthid-4-yl)pyridine-2-sulfonamide (15 mg, 3%). MS (ESI): m / z 327.0 [M+1] + .

[0484] Example 22. N-(3-Cyclopropylquinoline-8-yl)-3-methylpyridine-2-sulfonamide

[0485]

[0486] 3-Cyclopropylquinoline-8-amine. Cyclopropylboronic acid (116 mg, 1.34 mmol) and K3PO4 (333 mg, 1.57 mmol) were added to a stirred solution of 3-bromoquinoline-8-amine (100 mg, 0.45 mmol) in toluene-water (10.5 mL, 20:1) in a sealed tube. The solution was degassed with argon for 10 min, followed by the addition of tricyclohexylphosphine (19 mg, 0.07 mmol) and Pd(OAc)2 (10 mg, 0.05 mmol) (under an inert atmosphere). The resulting mixture was heated at 110 °C for 16 h. After 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-cyclopropylquinoline-8-amine (70 mg, 84%). MS(ESI): m / z 185.1 [M+1] + .

[0487] 3-Methylpyridine-2-sulfonyl chloride. Concentrated H₂SO₄ (6.4 mL) was added dropwise to 2-{[(4-methoxyphenyl)methyl]thioalkyl}-3-methylpyridine (400 mg, 1.63 mmol) (in a round-bottom flask at -20 °C) and stirred continuously for 15 min. NaOCl (24.11 mL, 359.18 mmol) was added over 30 min using a feeding funnel at -20 °C, and then slowly heated to 0 °C over 30 min. After 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 to a minimum volume under reduced pressure and used directly in the next step.

[0488] N-(3-Cyclopropylquinoline-8-yl)-3-methylpyridine-2-sulfonamide. A solution of 3-methylpyridine-2-sulfonyl chloride (104 mg, 0.54 mmol) in DCM (4 mL) was slowly added to a stirred solution of 3-cyclopropylquinoline-8-amine (50 mg, 0.27 mmol) in pyridine (2 mL) at 0 °C. The resulting mixture was warmed to 25 °C and stirred for 16 h. After completion, the reaction mixture was diluted with DCM, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give N-(3-cyclopropylquinoline-8-yl)-3-methylpyridine-2-sulfonamide (24 mg, 26%). MS (ESI): m / z 340.3 [M+1] + .

[0489] Example 23. N-(5-methylquinoline-8-yl)furan-2-sulfonamide

[0490]

[0491] 5-Methyl-8-nitroquinoline. Glycerol (6.5 mL, 89 mmol) was preheated at 165 °C for 1 h 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 min at the same temperature, and the reaction mixture was stirred at 150 °C for 5 h. 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] + .

[0492] 5-Methylquinoline-8-amine. Stannous chloride (8.02 g, 42.55 mmol) was added to a solution of 5-methyl-8-nitroquinoline (2 g, 10.63 mmol) in EtOH (50 mL). The resulting reaction mixture was heated under reflux for 2 h 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. Vacuum concentration was applied to give a crude product (1.5 g, 9.49 mmol, 89.3% yield), which could be used for the next step without further purification. MS (ESI) m / z 159.1 [M+H] + .

[0493] N-(5-methylquinoline-8-yl)furan-2-sulfonamide. Furan-2-sulfonyl chloride (316 mg, 1.89 mmol) was added to a solution of 5-methylquinoline-8-amine (200 mg, 1.26 mmol) in pyridine (6 mL). After microwave irradiation at 130 °C for 3 min, 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). 1 H NMR(400MHz,DMSO-d6)δ10.10(br s,1H),8.77-8.76(m,1H),8.27-8.25(m,1H),7.83(s,1H),7.56-7.51(m,2H),7.17(s,1H),6.55-6.54(m,1H),2.44(s,3H); MS(ESI)m / z 289.0[M+H] +Purity: 97.4% at 214nm, 90.2% at 254nm;

[0494] Example 24. N-(5-fluoroquinoline-8-yl)furan-2-sulfonamide

[0495]

[0496] 5-Fluoroquinoline. Sodium nitrite (934 mg, 13.5 mmol) was added fractionally to a suspension of quinoline-5-amine (1.5 g, 10.4 mmol) in fluoroboric acid (10 mL wt% = 48%) at -5 °C. The mixture was stirred for 1 h and then poured into a solution of 50% ethyl acetate in petroleum ether. The resulting suspension was filtered and the filter cake was air-dried. The collected solid was added to refluxed xylene and stirred under reflux for 2 h, then cooled to 25 °C. The xylene was decanted, and the residue was dissolved in hydrochloric acid (20 mL, 1 N). 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 purified by silica gel chromatography to give the desired compound (1.1 g, 7.43 mmol, 71% yield). MS (ESI) m / z 148.0. [M+H] + .

[0497] 5-Fluoro-8-nitroquinoline. 5-Fluoroquinoline (300 mg, 2.02 mmol) was dissolved in concentrated sulfuric acid (2 mL) at 0 °C, followed by the slow addition of nitric acid (1 mL, 65%) at -5 °C. The mixture was stirred at -5 °C for 1 h, then at 25 °C overnight. The reaction mixture was poured onto ice, and the resulting mixture was alkalized 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 ¹H NMR (400MHz, 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).

[0498] 5-Fluoroquinoline-8-amine. Acetic acid (0.5 mL) was added to a suspension of 5-fluoro-8-nitroquinoline (192 mg, 1.0 mmol) and iron powder (366 mg, 6.0 mmol) in water (8 mL). The mixture was heated at 100 °C for 1.5 h and then cooled to 25 °C. The reaction mixture was alkalized with solid sodium hydroxide and then treated with ethyl acetate under continuous stirring. The collected solid was washed with ethyl acetate and the combined filtrates were 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] + .

[0499] N-(5-fluoroquinoline-8-yl)furan-2-sulfonamide. Furan-2-sulfonyl chloride (113 mg, 0.68 mmol) was added to a solution of 5-fluoroquinoline-8-amine (100 mg, 0.62 mmol) in pyridine (3 mL), and the reaction mixture was microwave-irradiated at 110 °C for 15 min. After removing all volatiles under vacuum, the residue was purified by silica gel column chromatography to give the desired product (54.3 mg, 0.19 mmol, 31% yield). 1 H NMR (400MHz, chloroform-d) δ9.10(s,1H),8.84(dd,J=4.4,1.6Hz,1H),8.40(dd,J=8.8,1.6Hz,1H),7.80-7.77(m,1 H),7.54-7.51(m,1H),7.39(s,1H),7.17(t,J=8.8Hz,1H),7.07(d,J=3.6Hz,1H),6.35(m,1H); MS(ESI)m / z 293.0[M+H] + Purity at 254nm = 99.2%.

[0500] Example 25. N-(5-morpholinoquinoline-8-yl)-1H-pyrazole-4-sulfonamide

[0501]

[0502] 4-(8-nitroquinoline-5-yl)morpholine. 5-Chloro-8-nitroquinoline (600 mg, 2.88 mmol) was suspended in morpholine (3 mL), and the mixture was irradiated with a microwave 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] + .

[0503] 5-Morpholinequinoline-8-amine. Palladium on carbon (100 mg, 10%) was added to a solution of 4-(8-nitroquinoline-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 filtered off, and the filtrate was concentrated to give the desired product, which was used for the next step without further purification (405 mg, yield: 95%, 1.76 mmol). MS (ESI) m / z 230.1 [M+H] + .

[0504] N-(5-morpholinoquinoline-8-yl)-1H-pyrazole-4-sulfonamide. 1H-pyrazole-4-sulfonyl chloride (58 mg, 0.35 mmol) was added to a solution of 5-morpholinoquinoline-8-amine (80 mg, 0.35 mmol) in pyridine (2 mL), and the reaction mixture was stirred at 25 °C for 16 h. The solution was concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography to give the desired product (25.7 mg, 0.072 mmol, 21% yield). 1 ¹H 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 = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 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;

[0505] Example 26. N-(quinazolin-8-yl)pyridine-2-sulfonamide

[0506]

[0507] N-(quinazoline-8-yl)pyridine-2-sulfonamide. Quinazoline-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 h. The reaction was heated at 70 °C for 3 h. The crude product was purified by column chromatography. The crude product was dissolved in MeOH and filtered through a Frit filter to remove insoluble matter, and then purified directly by 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 concentrated to give N-(quinazoline-8-yl)pyridine-2-sulfonamide (27.4 mg, 0.096 mmol, 7.94% yield).1 H NMR (400MHz, DMSO-d6) δppm 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] +

[0508] Example 27. N-(quinolin-8-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-sulfonamide

[0509]

[0510] [1,2,4]triazolo[4,3-a]pyridine-3-sulfonyl chloride. A solution of n-butyllithium in hexane (1.1 mL, 2.75 mmol, 2.5 N) was added dropwise to a solution of 3-bromo-[1,2,4]triazolo[4,3-a]pyridine (530 mg, 2.68 mmol) at -78 °C under nitrogen. The mixture was stirred at -78 °C for 1 h, followed by slow addition of sulfonyl chloride (359 mg, 2.68 mmol). The resulting mixture was stirred at 25 °C for 1 h. 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 crude desired product (430 mg, crude), which was proceeded to the next step without further purification. MS (ESI) m / z 218.0 [M+H] + .

[0511] N-(quinolin-8-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-sulfonamide. N-(quinolin-8-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-sulfonamide (430 mg, crude) was added to a solution of quinolin-8-amine (70 mg, 0.48 mmol) in pyridine (1.5 mL) at 0 °C. The reaction was stirred at 25 °C for 16 h. The reaction was concentrated, and the residue was then purified by high-performance liquid chromatography to give the desired product (5.6 mg, 0.017 mmol, 3.5%). 1H NMR (400MHz, DMSO-d6) δ9.00(d,J=4.4Hz,1H),8.59(d,J=8.4Hz,1H),8.32(d,J=6.4Hz,1H ),7.97(d,J=7.2Hz,1H),7.73-7.52(m,4H),7.38(t,J=8.0Hz,1H),6.70(t,J=7.2Hz,1H). MS(ESI)m / z325.8[M+H] + The purity at 214nm is 98.7%, and the purity at 254nm is 97.3%.

[0512] Example 28. N-(quinolin-8-yl)pyrimidine-4-sulfonamide

[0513]

[0514] Pyrimidine-4-thiol. A mixture of pyrimidine-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 h. 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 / z113.0[M+H] + .

[0515] N-(quinolin-8-yl)pyrimidine-4-sulfonamide. Pre-cooled (-5°C) sodium hypochlorite (10% solution, 1.55M, 78mL, 122.7mmol) was added to a stirred mixture of hydrochloric acid (2N, 89mL) and DCM (118mL) cooled to -5°C (internal temperature), at a rate that kept the temperature below 0°C. Pyrimidine-2-thiol (4.00g, 35.7mmol) was added in small batches 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 minutes. Excess chlorine was quenched by adding cold (0°C) sodium sulfite aqueous solution (1M) until the yellow-green color of the mixture disappeared and iodide test paper (potassium iodide / starch) no longer showed rapid color development. The reaction mixture was then transferred to a separatory funnel (pre-cooled in a refrigerator or with ice water), and the organic layer was rapidly separated and collected in a clean flask. The aqueous phase was rapidly extracted with cold (-10°C) DCM. The organic extracts were combined and dried over magnesium sulfate (under nitrogen atmosphere) and cooled in a dry ice-acetone bath. A solution of sodium bis(trimethylsilyl)amino in THF (2M, 2.1mL, 4.20mmol) (under nitrogen atmosphere at -78°C) was slowly added to a solution of quinoline-8-ylamine (400mg, 2.78mmol) in THF (1mL), and the mixture was stirred for another hour. The pyrimidine-4-sulfonyl chloride solution in the DCM obtained above was then rapidly filtered and added to the above solution. After one hour, the reaction mixture was quenched with aqueous ammonium chloride solution 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 (11.0mg, 0.038mmol, 1% yield). 1 H NMR(400MHz,MeOH-d4)δ9.13,(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),8.05(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] + The purity at 214nm is 97.4%, and the purity at 254nm is 98.0%.

[0516] Example 29. 1-Ethyl-N-(5-methoxyquinoline-8-yl)-1H-imidazol-2-sulfonamide

[0517]

[0518] 1-((1-ethyl-1H-imidazol-2-yl)sulfonyl)-1H-benzo[d][1,2,3]triazole. Under nitrogen atmosphere at -78°C, a solution of n-butyllithium in hexane (2.5N, 66mL, 164mmol) was added dropwise to a solution of 1-ethyl-1H-imidazolium (15.0 g, 156 mmol) in THF (450 mL). The resulting reaction mixture was stirred at -78°C for 1 h. Sulfur dioxide was bubbled into the above organometallic reagent in THF at -78°C until the pH of the solution sample was acidic. The mixture was stirred at this temperature for 15 min, then at 25°C for 1 h. N-chlorobenzotriazole (23.0 g, 156 mmol) was added in a single addition, and the mixture was stirred at 25°C for 2 h. Triethylamine (39.4 g, 390 mmol) was added, followed by stirring at 25°C for 16 h. Water was added and the solution was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous sodium sulfate, and filtered. The residue was concentrated and 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] + .

[0519] 1-Ethyl-N-(5-methoxyquinoline-8-yl)-1H-imidazol-2-sulfonamide. Under nitrogen atmosphere at -78°C, a solution of sodium bis(trimethylsilyl)amino in THF (2M, 1.15 mL, 2.30 mmol) was slowly added to a solution of 5-methoxyquinoline-8-amine (200 mg, 1.15 mmol) in THF (5 mL). After stirring the resulting reaction mixture at this temperature for 1 h, 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 h. The reaction mixture was quenched with aqueous ammonium chloride solution 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). 1H NMR (400MHz, DMSO-d6) δ10.09(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] + The purity at 214nm is 98.6%, and the purity at 254nm is also 98.6%.

[0520] Example 30.5-Methyl-N-(quinoxalo-5-yl)pyridine-2-sulfonamide

[0521]

[0522] 2-(benzylthio)-5-methylpyridine. Sodium hydride (60% from mineral oil, 8.28 g, 207 mmol) was added fractionally to a solution of benzyl mercaptan (23.3 g, 188 mmol) in anhydrous THF (200 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 1 h, and 2-chloro-5-methylpyridine (20.0 g, 157 mmol) was added fractionally at 0 °C. The resulting mixture was stirred at 70 °C for 30 h. 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] + .

[0523] 5-Methylpyridine-2-sulfonyl chloride. Chlorine gas was bubbled into a solution of 2-(benzylthio)-5-methylpyridine (3.0 g, 50% purity, crude product, 6.98 mmol) in acetic acid (20 mL), DCM (20 mL), and water (7 mL) at 0 °C for 30 min. The resulting mixture was then stirred at this 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 a crude product (3.2 g), which was proceeded to the next step without further purification. MS (ESI) m / z 191.9 [M+H] + .

[0524] 5-Methyl-N-(quinoxalo-5-yl)pyridine-2-sulfonamide. Under nitrogen atmosphere at -78°C, a solution of sodium bis(trimethylsilyl)amino in THF (2M, 1.38 mL, 2.76 mmol) was slowly added to a solution of quinoxalo-5-amine (200 mg, 1.38 mmol) in anhydrous THF (3 mL). The mixture was stirred at -78°C for 1 h, followed by the addition of crude 5-methylpyridine-2-sulfonyl chloride (500 mg, crude). The mixture was stirred at 25°C for 1 h. The reaction was quenched with a saturated aqueous ammonium chloride solution 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) δ10.20(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 / z300.8[M+H] + The purity at 214nm is 98.3%, and the purity at 254nm is 98.1%.

[0525] Example 31. 3-Ethyl-N-(5-morpholino-8-quinolinyl)imidazol-4-sulfonamide

[0526]

[0527] (3-Ethylimidazol-4-yl)sulfinyloxylithium. Under nitrogen atmosphere at -70°C, n-butyllithium (54.27 mL, 124.83 mmol) was slowly added to a solution of 1-ethylimidazolium (10 g, 104.03 mmol) in diethyl ether (100 mL). The mixture was stirred at -70°C for 30 min and then at 0°C for 30 min. Excess sulfur dioxide was then bubbled in, and the mixture was stirred at -70°C for 1 h. The mixture was then warmed to 25°C, filtered, and the filter cake was vacuum dried to give crude (3-ethylimidazol-4-yl)sulfinyloxylithium (17 g, crude product).

[0528] 3-Ethylimidazol-4-sulfonyl chloride. NCS (13.66 g, 102.33 mmol) was added to a solution of (3-ethylimidazol-4-yl)sulfinyloxylithium (17 g, crude) in chloroform (100 mL) and water (100 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 h. 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 under vacuum. The crude product was purified by silica gel chromatography to give 3-ethylimidazol-4-sulfonyl chloride (3.5 g, 17.982 mmol, 17.573% yield). LCMS (ESI): m / z 195.0 [M+1] + .

[0529] 3-Ethyl-N-(5-morpholino-8-quinolinyl)imidazolium-4-sulfonamide. A solution of 3-ethylimidazolium-4-sulfonyl chloride (250 mg, 1.28 mmol) in DCM (2 mL) was added to a solution of 5-morpholinoquinolino-8-amine (294.49 mg, 1.28 mmol) in pyridine (8 mL). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by rapid silica gel chromatography to give a crude product, which was further purified by preparative HPLC and then lyophilized to give 3-ethyl-N-(5-morpholino-8-quinolinyl)imidazolium-4-sulfonamide (63.21 mg, 0.1625 mmol, 12.651% yield, 99.6% purity). 1 H NMR (400MHz, DMSO-d6) δ8.82 (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] - .

[0530] Example 32. N-(5-chloro-8-quinolinyl)-3-isopropyl-imidazol-4-sulfonamide

[0531]

[0532] (3-Isopropylimidazol-4-yl)sulfinyloxylithium. Under nitrogen atmosphere at -70°C, n-butyllithium (47.36 mL, 108.93 mmol, 2.5 M in THF) was slowly added to a solution of 1-isopropylimidazolium (10 g, 90.78 mmol) in diethyl ether (150 mL). The mixture was stirred at -70°C for 30 min and then at 0°C for 30 min. Excess sulfur dioxide was then bubbled in, and the mixture was stirred at -70°C for 1 h. The mixture was then warmed to 25°C, filtered, and the filter cake was vacuum dried to give crude (3-isopropylimidazol-4-yl)sulfinyloxylithium (16 g, crude product).

[0533] 3-Isopropylimidazolium-4-sulfonyl chloride. NCS (11.86 g, 88.81 mmol) was added to a solution of (3-isopropylimidazolium-4-yl)sulfinyloxylithium (16 g, 88.81 mmol) in chloroform (100 mL) and water (100 mL) 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 under vacuum. The crude product was purified by silica gel chromatography to give 3-isopropylimidazolium-4-sulfonyl chloride (1.4 g, 6.7092 mmol, 7.5541% yield). 1 H NMR (400MHz, DMSO-d6) δ9.30 (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).

[0534] N-(5-chloro-8-quinolinyl)-3-isopropyl-imidazolium-4-sulfonamide. A solution of 3-isopropylimidazolium-4-sulfonyl chloride (233.65 mg, 1.12 mmol) in DCM (1 mL) was added to a solution of 5-chloroquinolinyl-8-amine (200 mg, 1.12 mmol) in pyridine (4 mL). The mixture was stirred at 25 °C for 16 h. The mixture was diluted with 10% citric acid (50 mL) and 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 the residue, which was purified by preparative HPLC and then lyophilized to give N-(5-chloro-8-quinolinyl)-3-isopropyl-imidazolium-4-sulfonamide (166.84 mg, 0.4670 mmol, 41.709% yield, 98.2% purity). 1H NMR (400MHz, DMSO-d6) δ10.65(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 / z351.1[M+1] + .

[0535] Example 33.3-(cyclopropylmethyl)-N-(5-morpholino-8-quinolinyl)imidazol-4-sulfonamide

[0536]

[0537] 1-(Cyclopropylmethyl)imidazole. Potassium carbonate (109.44 mL, 587.54 mmol) was added to a solution of 1H-imidazole (20 g, 293.77 mmol) in ACN (250 mL), followed by the addition of 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 the residue, which was purified by silica gel chromatography to give 1-(cyclopropylmethyl)imidazole (13 g, 106.41 mmol, 36.222% yield). 1 H NMR (400MHz, CDCl3) δ7.32 (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).

[0538] [3-(cyclopropylmethyl)imidazol-4-yl]sulfinyloxylithium. Under nitrogen atmosphere at -70°C, n-butyllithium (55.52 mL, 127.69 mmol) was slowly added to a solution of 1-(cyclopropylmethyl)imidazolium (13 g, 106.41 mmol) in diethyl ether (200 mL). The mixture was stirred at -70°C for 30 min and then at 0°C for 30 min. 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, filtered, and the filter cake was vacuum dried to give crude [3-(cyclopropylmethyl)imidazol-4-yl]sulfinyloxylithium (20 g, crude product) (containing [1-(cyclopropylmethyl)imidazol-4-yl]sulfinyloxylithium), which can be used directly without further purification.

[0539] 3-(cyclopropylmethyl)imidazolium-4-sulfonyl chloride. At 0 °C, NCS (13.89 g, 104.08 mmol) was added to a solution of [3-(cyclopropylmethyl)imidazolium-4-yl]sulfinyloxylithium (20 g, crude) (containing [1-(cyclopropylmethyl)imidazolium-4-yl]sulfinyloxylithium) in chloroform (100 mL) and water (100 mL). 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 under vacuum. The crude product was purified by silica gel chromatography to give crude 3-(cyclopropylmethyl)imidazolium-4-sulfonyl chloride (1 g, crude) (containing 1-(cyclopropylmethyl)imidazolium-4-sulfonyl chloride). 1 H NMR (400MHz, DMSO-d6) δ9.18 (d, J = 1.5 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 4.20 (d, J = 7.5 Hz, 2H), 1.58-1.45 (m, 1H), 0.59-0.45 (m, 4H).

[0540] 3-(cyclopropylmethyl)-N-(5-morpholino-8-quinolinyl)imidazol-4-sulfonamide. Add 211.75 mg, 0.9600 mmol of 3-(cyclopropylmethyl)imidazol-4-sulfonyl chloride (containing 1-(cyclopropylmethyl)imidazol-4-sulfonyl chloride) in DCM (1 mL) to a solution of 5-morpholinoquinolino-8-amine (220 mg, 0.9600 mmol) in pyridine (4 mL). Stir the mixture at 25 °C for 16 hours. Dilute the mixture with 10% citric acid (50 mL) and extract the resulting mixture 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 the residue, which was purified by preparative HPLC and then lyophilized to give 3-(cyclopropylmethyl)-N-(5-morpholino-8-quinolinyl)imidazol-4-sulfonamide (42.14 mg, 0.0971 mmol, 10.122% yield, 95.3% purity). 1HNMR(400MHz,DMSO-d6)δ10.42-10.02(m,1H),8.80(dd,J1=4.1,J2=1.5Hz,1H),8.49(dd,J 1=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,1 H),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] +

[0541] Example 34.1-(cyclopropylmethyl)-N-(5-morpholino-8-quinolinyl)imidazol-4-sulfonamide

[0542]

[0543] [1-(cyclopropylmethyl)imidazol-4-yl]sulfinyloxylithium. Under nitrogen atmosphere at -70°C, n-butyllithium (55.52 mL, 127.69 mmol) was slowly added to a solution of 1-(cyclopropylmethyl)imidazolium (13 g, 106.41 mmol) in diethyl ether (200 mL). The mixture was stirred at -70°C for 30 min and then at 0°C for 30 min. 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, filtered, and the filter cake was vacuum dried to give crude [1-(cyclopropylmethyl)imidazol-4-yl]sulfinyloxylithium (which also contains [3-(cyclopropylmethyl)imidazol-4-yl]sulfinyloxylithium), which could be used directly without further purification.

[0544] 1-(cyclopropylmethyl)imidazolium-4-sulfonyl chloride. NCS (13.89 g, 104.08 mmol) was added to a solution of [1-(cyclopropylmethyl)imidazolium-4-yl]sulfinyloxylithium (20 g, crude) (containing [3-(cyclopropylmethyl)imidazolium-4-yl]sulfinyloxylithium) in chloroform (100 mL) and water (100 mL) 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 under vacuum. The crude product was purified by silica gel chromatography to give crude 1-(cyclopropylmethyl)imidazolium-4-sulfonyl chloride (1 g, crude) (also containing 3-(cyclopropylmethyl)imidazolium-4-sulfonyl chloride). 1 H NMR (400MHz, DMSO-d6) δ9.18 (d, J = 1.5 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 4.20 (d, J = 7.5 Hz, 2H), 1.58-1.45 (m, 1H), 0.59-0.45 (m, 4H).

[0545] 1-(cyclopropylmethyl)-N-(5-morpholino-8-quinolinyl)imidazol-4-sulfonamide. Add 1-(cyclopropylmethyl)imidazol-4-sulfonyl chloride (211.75 mg, 0.9600 mmol) (containing a solution of 3-(cyclopropylmethyl)imidazol-4-sulfonyl chloride) in DCM (1 mL) to a solution of 5-morpholinoquinolino-8-amine (220 mg, 0.9600 mmol) in pyridine (4 mL). Stir the mixture at 25 °C for 16 hours. Dilute the mixture with 10% citric acid (50 mL) and extract the resulting mixture 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 the residue, which was purified by preparative HPLC and then lyophilized to give 1-(cyclopropylmethyl)-N-(5-morpholino-8-quinolinyl)imidazol-4-sulfonamide (6.19 mg, 0.0143 mmol, 72.242% yield, 95.7% purity). 1H NMR (400MHz, MeOH-d4) δ8.80 (dd, J1=4.1, J2=1.6Hz, 1H), 8.57 (dd, J1=8.5, J2=1.5Hz, 1 H),7.80(d,J=1.3Hz,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] + .

[0546] Example 35.1-Cyclopropyl-N-(5-morpholino-8-quinolinyl)imidazol-2-sulfonamide

[0547]

[0548] (1-Cyclopropylimidazol-2-yl)sulfinyloxylithium. Under nitrogen atmosphere at -70°C, n-butyllithium (48.25 mL, 110.97 mmol) was slowly added to a solution of 1-cyclopropylimidazolium (10 g, 92.47 mmol) in diethyl ether (150 mL). The mixture was stirred at -70°C for 30 min and then at 0°C for 30 min. 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, filtered, and the filter cake was vacuum dried to give crude (1-cyclopropylimidazol-2-yl)sulfinyloxylithium (16 g, crude product) (also containing (3-cyclopropylimidazol-4-yl)sulfinyloxylithium).

[0549] 1-Cyclopropylimidazolium-2-sulfonyl chloride. At 0 °C, NCS (11.99 g, 89.82 mmol) was added to a solution of (1-cyclopropylimidazolium-2-yl)sulfinyloxylithium (16 g, crude) (containing (3-(cyclopropylmethyl)imidazolium-4-yl)sulfinyloxylithium) in chloroform (100 mL) and water (100 mL). 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 under vacuum. The crude product was purified by silica gel chromatography to give crude 1-cyclopropylimidazolium-2-sulfonyl chloride (1 g, crude) (containing 3-cyclopropylimidazolium-4-sulfonyl chloride).

[0550] 1-Cyclopropyl-N-(5-morpholino-8-quinolinyl)imidazol-2-sulfonamide. A solution of 1-cyclopropylimidazol-2-sulfonyl chloride (277.66 mg, 1.34 mmol) (containing 3-cyclopropylimidazol-4-sulfonyl chloride) in DCM (1 mL) was added to a solution of 5-morpholinoquinolino-8-amine (256.72 mg, 1.12 mmol) in pyridine (4 mL). The mixture was stirred at 25 °C for 16 h. The mixture was diluted with 10% citric acid (50 mL) and 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 the residue, which was purified by rapid silica gel chromatography to give the crude product. It was further purified by preparative HPLC and then lyophilized to give 1-cyclopropyl-N-(5-morpholino-8-quinolinyl)imidazol-2-sulfonamide (23.42 mg, 0.0586 mmol, 5.2308% yield, 99.9% purity). 1 H NMR (400MHz, methanol-d4) δ8.86 (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] + .

[0551] Example 36. 3-Methyl-N-(2-methylisoindoline-4-yl)pyridine-2-sulfonamide

[0552]

[0553] 2-Methyl-4-nitroisoindoline. TEA (1.44 g, 14.24 mmol) was added to a solution of 1,2-bis(bromomethyl)-3-nitro-benzene (2.00 g, 6.47 mmol) and methylamine (2 M, 3.6 mL). The mixture was stirred at 25 °C under N2 for 0.5 h. Methylamine (2 M, 15.0 mL) was added to the mixture. The mixture was stirred again at 25 °C under N2 for 1 h. The mixture was concentrated under vacuum. 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 under vacuum. The residue was purified by column chromatography to give 2-methyl-4-nitroisoindoline (200 mg, 1.05 mmol, 16% yield, 93.3% purity). MS (ESI): m / z 179.2 [M+1]+.

[0554] 2-Methylisoindoline-4-amine. Pd / C (40 mg) was added to a solution of 2-methyl-4-nitro-isoindoline (200 mg, 1.12 mmol) in 2,2,2-trifluoroethanol (10 mL). The mixture was stirred at 45 °C for 3 h under H2 (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give 2-methylisoindoline-4-amine (150 mg, crude). MS (ESI): m / z 149.0 [M+1] + .

[0555] 3-Methyl-N-(2-methylisoindoline-4-yl)pyridine-2-sulfonamide. A mixture of 3-methylpyridine-2-sulfonyl chloride (400 mg, 1.61 mmol) in DCM (5 mL) was added to a solution of 2-methylisoindoline-4-amine (143 mg, 0.966 mmol) in pyridine (3.83 g, 48.40 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 3 h under N2. The mixture was concentrated. The residue was diluted with brine and the aqueous phase was extracted with DCM. The combined organic phases were 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-methylisoindoline-4-yl)pyridine-2-sulfonamide (120.74 mg, 0.330 mmol, 34% yield, 95.5% purity, FA). 1H NMR (400MHz, CD3OD-d4) δ8.50-8.39(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] + .

[0556] Example 37. 3-Fluoro-N-(1,2,3,4-tetrahydroquinoline-8-yl)pyridine-2-sulfonamide

[0557]

[0558] Lithium 3-fluoropyridine-2-sulfinate. n-BuLi (2.5 M, 13.09 mL) was added to a solution of 2-bromo-3-fluoropyridine (4.8 g, 27.27 mmol) in diethyl ether (100 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, the filter cake was collected and vacuum dried to give lithium 3-fluoropyridine-2-sulfinate (4 g, crude).

[0559] 3-Fluoropyridine-2-sulfonyl chloride. NCS (4.79 g, 35.87 mmol) was added fractionally to a solution of lithium 3-fluoropyridine-2-sulfinate (4 g) in chloroform (50 mL) and water (50 mL) 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 chloroform. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 3-fluoropyridine-2-sulfonyl chloride (3 g, 13.19 mmol, 86% purity).

[0560] 1,2,3,4-Tetrahydroquinoline-8-amine. Platinum dioxide (0.4 g, 1.76 mmol) was added to a solution of quinoline-8-amine (10 g, 69.36 mmol) in acetic acid (50 mL) under nitrogen. The suspension was degassed under vacuum and purged several times with hydrogen. The mixture was stirred at 30 °C for 40 h under hydrogen (20 psi). The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by silica gel chromatography to give 1,2,3,4-tetrahydroquinoline-8-amine (9.4 g, 63.43 mmol, 91.44% yield). 1H NMR (400MHz, DMSO-d6) δ6.34 (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).

[0561] 3-Fluoro-N-(1,2,3,4-tetrahydroquinoline-8-yl)pyridine-2-sulfonamide. Under nitrogen atmosphere at 0 °C, 2 g (8.79 mmol) of 3-fluoropyridine-2-sulfonyl chloride dissolved in DCM (5 mL) was slowly added to a solution of 1,2,3,4-tetrahydroquinoline-8-amine (1.30 g, 8.79 mmol) in pyridine (10 mL). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure to give a residue, which was then diluted with water. The 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-tetrahydroquinoline-8-yl)pyridine-2-sulfonamide (1.6 g, crude). The crude product was ground with MeOH for 30 min, then the mixture was filtered and the filter cake was ground with water containing 20% ​​ACN for 10 min. The mixture was lyophilized to give 3-fluoro-N-(1,2,3,4-tetrahydroquinoline-8-yl)pyridine-2-sulfonamide (150.21 mg, 482.87 μmol, 14.84% yield, 98.8% purity). 1 H NMR (400MHz, DMSO-d6) δ9.77(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=7.6 Hz,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 / z308.1[M+1] + .

[0562] Example 38. 3-Methyl-N-(1-methylindoline-7-yl)pyridine-2-sulfonamide

[0563]

[0564] Lithium 3-methylpyridine-2-sulfinate. Under nitrogen atmosphere at -70°C, n-BuLi (2.5 M, 27.90 mL) was slowly added. 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, the filter cake was collected and vacuum dried to give lithium 3-methylpyridine-2-sulfinate (12 g, crude product).

[0565] 3-Methylpyridine-2-sulfonyl chloride. NCS (14.73 g, 110.31 mmol) was added in portions to a mixture of lithium 3-methylpyridine-2-sulfinate (12 g, 1 equivalent) in chloroform (50 mL) and water (50 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The 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).

[0566] 1-Methyl-7-nitroindoline. Sodium cyanoborohydride (7.13 g, 113.53 mmol) was added in portions to a solution of 1-methyl-7-nitro-1H-indoline (5 g, 28.38 mmol) in acetic acid (50 mL) at 25 °C. The mixture was stirred at 70 °C for 48 h. 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).

[0567] 1-Methylindoline-7-amine. Under nitrogen atmosphere, Pd / C (600 mg, 10% purity) and Pd(OH)₂ / C (600 mg, 4.27 mmol) were added to a solution of 1-methyl-7-nitroindoline (6.5 g, 1 equivalent) in MeOH (100 mL). The mixture was then stirred at 25 °C under hydrogen (15 psi) for 4 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC to give 1-methylindoline-7-amine (2.16 g, 14.34 mmol, 97% purity). 1 ¹H 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); 1-methylindoline-7-amine (0.72 g, 4.62 mmol, 95% purity) was obtained as a red oil.1 H NMR (400MHz, DMSO-d6) δ7.05 (d, J=3.2Hz, 1H), 6.82 (dd, J1=7.6, J2=0.4Hz, 1H), 6.80 (d ,J=7.6Hz,1H),6.37(d,J=7.2Hz,1H),6.21(d,J=3.2Hz,1H),4.82(s,2H),4.05(s,3H).

[0568] N-(1-Methylindololin-7-yl)acetamide. Sodium cyanoborohydride (3.87 g, 61.56 mmol) was added fractionally to a solution of 1-methylindololin-7-amine (1.86 g, 12.31 mmol) in acetic acid (30 mL). The mixture was stirred at 60 °C for 48 h. 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 under vacuum. The residue was purified by silica gel chromatography to give N-(1-methylindololin-7-yl)acetamide (1.1 g, 5.78 mmol, 46.96% yield).

[0569] 1-Methylindololin-7-amine. Under nitrogen atmosphere, thionyl chloride (450.26 mg, 3.78 mmol, 274.55 μL) was added to a mixture of N-(1-methylindololin-7-yl)acetamide (0.9 g, 4.73 mmol) in MeOH (15 mL). The mixture was stirred at 75 °C for 3 h. The mixture was concentrated to give a residue, saturated sodium carbonate was added to the residue, and the residue was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1-methylindololin-7-amine (0.7 g). 1 H NMR (400MHz, CDCl3) δ6.72-6.68(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).

[0570] 3-Methyl-N-(1-methylindoline-7-yl)pyridine-2-sulfonamide. Under nitrogen atmosphere at 0 °C, 3-methylpyridine-2-sulfonyl chloride (840.48 mg) in DCM (10 mL) was slowly added to a mixture of 1-methylindoline-7-amine (0.65 g, 4.39 mmol) in pyridine (10 mL). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC to give 3-methyl-N-(1-methylindoline-7-yl)pyridine-2-sulfonamide (430.07 mg, 1.36 mmol, 31.03% yield, 96% purity). 1 H NMR (400MHz, DMSO-d6) δ8.57(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,1 H), 6.49 (d, J = 8.0Hz, 1H), 6.34 (t, J = 7.2Hz, 1H), 3.26 (t, J = 8.8Hz, 2H), 3.01 (s, 3H), 2.82 (t, J = 8.4Hz, 2H), 2.45 (s, 3H); MS (ESI): m / z 304.1[M+1] + .

[0571] Example 39. 3-Methyl-N-(2-methyl-1,2,3,4-tetrahydroisoquinoline-8-yl)pyridine-2-sulfonamide

[0572]

[0573] 8-(3-methylpyridin-2-sulfonamido)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester. To a solution of 8-amino-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (1.2 g, 4.83 mmol) in pyridine (20 mL), 3-methylpyridin-2-sulfonyl chloride (926 mg) dissolved in DCM (10 mL) was added. The mixture was stirred at 25 °C for 16 h. 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 the residue. The residue was purified by silica gel chromatography to give 8-[(3-methyl-2-pyridinyl)sulfonamido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.7 g).

[0574] 3-Methyl-N-(1,2,3,4-tetrahydroisoquinoline-8-yl)pyridine-2-sulfonamide. Trifluoromethanesulfonic acid (4.62 g, 40.52 mmol, 3 mL) was slowly added to a solution of tert-butyl 8-[(3-methyl-2-pyridyl)sulfonamide]-3,4-dihydro-1H-isoquinoline-2-carboxylate (0.9 g, 2.23 mmol) in DCM (15 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 1 h. The mixture was concentrated under reduced pressure to give 3-methyl-N-(1,2,3,4-tetrahydroisoquinoline-8-yl)pyridine-2-sulfonamide (1 g, crude, trifluoromethanesulfonate).

[0575] 3-Methyl-N-(2-methyl-1,2,3,4-tetrahydroisoquinoline-8-yl)pyridine-2-sulfonamide. Triethylamine (400 mg, 3.96 mmol, 550.55 μL) was added to a mixture of 3-methyl-N-(1,2,3,4-tetrahydroisoquinoline-8-yl)pyridine-2-sulfonamide (1 g, crude, trifluoromethanesulfonate) in MeOH (10 mL). 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 h. 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 h. The mixture was concentrated under reduced pressure to give a residue, and saturated sodium carbonate was added. The mixture was extracted with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC to give 3-methyl-N-(2-methyl-3,4-dihydro-1H-isoquinoline-8-yl)pyridine-2-sulfonamide (556.67 mg, 1.70 mmol, 97% purity). 1 H NMR (400MHz, DMSO-d6) δ8.52(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] + .

[0576] Example 40. N-(1-Cyclopropyl-1,2,3,4-Tetrahydroquinoline-8-yl)-3-(Dimethylamino)pyridine-2-sulfonamide

[0577]

[0578] N-(1-cyclopropyl-1,2,3,4-tetrahydroquinoline-8-yl)-3-(dimethylamino)pyridine-2-sulfonamide. Sodium cyanoborohydride (662 mg, 10.53 mmol) was added to a solution of 3-(dimethylamino)-N-(1,2,3,4-tetrahydroquinoline-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). The mixture was stirred at 25 °C for 32 h. The mixture was concentrated. The residue was poured into sodium bicarbonate and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was ground with MeOH. The filter cake and filtrate were combined and subsequently 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-tetrahydroquinoline-8-yl)-3-(dimethylamino)pyridine-2-sulfonamide (414.09 mg, 1.06 mmol, 50.42% yield, 95.5% purity). 1 H NMR(400MHz, DMSO-d6)8.78(brs,1H),8.21(dd,J1=4.3,J2=1.1Hz,1H),7.77(dd,J 1=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] + .

[0579] Example 41.1-Isopropyl-N-(2-methyl-1,2,3,4-tetrahydroisoquinoline-8-yl)-1H-pyrazole-5-sulfonamide

[0580]

[0581] 1,2,3,4-Tetrahydroisoquinoline-8-amine. Platinum dioxide (0.2 g, 0.881 mmol) was added to a solution of isoquinoline-8-amine (5 g, 34.68 mmol) in acetic acid (30 mL) under nitrogen atmosphere. The suspension was degassed under vacuum and purged several times with hydrogen. The mixture was stirred at 25 °C for 16 h under hydrogen (50 psi). The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 1,2,3,4-tetrahydroisoquinoline-8-amine (10 g, crude product, acetic acid). 1 H NMR (400MHz, DMSO-d6) δ6.91(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).

[0582] 8-Amino-3,4-Dihydroisoquinoline-2(1H)-formate tert-butyl ester. Under nitrogen atmosphere at 0 °C, di-tert-butyl dicarbonate (9.75 g, 44.67 mmol, 10.26 mL) was slowly added to a mixture of 1,2,3,4-tetrahydroisoquinoline-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). The mixture was stirred at 15 °C for 2 h. The 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 the residue. The residue was purified by silica gel chromatography to give 8-amino-3,4-dihydroisoquinoline-2(1H)-formate tert-butyl ester (5.9 g, 23.76 mmol). 1 H NMR (400MHz, CDCl3) δ7.01 (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).

[0583] 8-(1-Isopropyl-1H-pyrazole-5-sulfonamido)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester. Under nitrogen atmosphere at 0 °C, 1-isopropyl-1H-pyrazole-5-sulfonyl chloride (588 mg, 2.82 mmol) dissolved in DCM (2 mL) was slowly added to a solution of 8-amino-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (700 mg, 2.82 mmol) in pyridine (8 mL). The mixture was stirred at 15 °C for 16 h. The mixture was diluted with 10% citric acid and 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 the 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).

[0584] 8-(1-Isopropyl-1H-pyrazole-5-sulfonamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl ester. Under nitrogen atmosphere and at 0°C, trifluoroacetic acid (3.08 g, 27.01 mmol, 2.00 mL) was slowly added 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). The mixture was stirred at 0°C for 0.5 h. The mixture was concentrated under reduced pressure to give 8-(1-isopropyl-1H-pyrazole-5-sulfonamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl ester (1.2 g, crude, trifluoroacetic acid).

[0585] 1-Isopropyl-N-(2-methyl-1,2,3,4-tetrahydroisoquinoline-8-yl)-1H-pyrazole-5-sulfonamide. TEA (307.46 mg, 3.04 mmol) and acetic acid (24.88 mg, 0.414 mmol) were added to a mixture of tert-butyl 8-(1-isopropyl-1H-pyrazole-5-sulfonamide)-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). The mixture was stirred at 15 °C for 30 min, followed by the addition of sodium cyanoborohydride (520.75 mg, 8.29 mmol) in portions, and the mixture was stirred at 15 °C for 2 h. The mixture was concentrated under reduced pressure to give the 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 the residue. The residue was purified by preparative HPLC to give 1-isopropyl-N-(2-methyl-1,2,3,4-tetrahydroisoquinoline-8-yl)-1H-pyrazole-5-sulfonamide (177.35 mg, 0.509 mmol, 96% purity). 1 H NMR (400MHz, DMSO-d6) δ8.14(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 ),5.15-5.05(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] + .

[0586] Example 42. N-(1-Cyclopropyl-1,2,3,4-Tetrahydroquinoline-8-yl)-3-methylpyridine-2-sulfonamide

[0587]

[0588] 3-Methyl-N-(1,2,3,4-tetrahydroquinoline-8-yl)pyridine-2-sulfonamide. Under nitrogen atmosphere at 0 °C, 3-methylpyridine-2-sulfonyl chloride (1 g, 5.22 mmol) dissolved in DCM (5 mL) was slowly added to a solution of 1,2,3,4-tetrahydroquinoline-8-amine (773.37 mg, 5.22 mmol) in pyridine (8 mL). The mixture was stirred at 15 °C for 16 h. The mixture was diluted with 10% citric acid and 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 the residue. The residue was purified by silica gel chromatography to give 3-methyl-N-(1,2,3,4-tetrahydroquinoline-8-yl)pyridine-2-sulfonamide (1 g, 3.30 mmol, 63.17% yield).

[0589] N-(1-Cyclopropyl-1,2,3,4-Tetrahydroquinoline-8-yl)-3-methylpyridine-2-sulfonamide. Under nitrogen atmosphere and at 0°C, sodium cyanoborohydride (621.40 mg, 9.89 mmol) was added in portions to a mixture of 3-methyl-N-(1,2,3,4-tetrahydroquinoline-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). The mixture was stirred at 40°C for 16 h. The mixture was concentrated under reduced pressure to give a residue, which was then 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-tetrahydroquinoline-8-yl)-3-methylpyridine-2-sulfonamide (203.15 mg, 0.562 mmol, 17.05% yield, 95% purity). 1 H NMR (400MHz, DMSO-d6) δ9.03(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=2.8 Hz,2H),6.55-6.51(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] + .

[0590] Example 43. N-(2-Cyclopropylisoindoline-4-yl)-1-isopropyl-1H-imidazol-2-sulfonamide

[0591]

[0592] 1,2-Bis(bromomethyl)-3-nitrobenzene. Benzoyl peroxide (456.69 mg, 1.89 mmol) and 1-bromopyrrolidine-2,5-dione (22.37 g, 125.69 mmol) were added to a solution of 1,2-dimethyl-3-nitrobenzene (9.5 g, 62.85 mmol) in tetrachloromethane (50 mL) at 10 °C. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated to give 1,2-bis(bromomethyl)-3-nitrobenzene (18 g, crude product).

[0593] 2-Cyclopropyl-4-nitroisoindoline. A mixture of cyclopropylamine (3.33 g, 58.26 mmol, 4.04 mL) in THF (20 mL) was added to a solution of 1,2-bis(bromomethyl)-3-nitrobenzene (18 g, 58.26 mmol) and TEA (11.79 g, 116.52 mmol, 16.22 mL) in THF (80 mL). The reaction mixture was stirred at 10 °C for 2 hours. The reaction mixture was concentrated to give a crude product. The crude product was purified twice by silica gel chromatography to give 2-cyclopropyl-4-nitroisoindoline (1.5 g, crude product). 1 H 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] + .

[0594] 2-Cyclopropylisoindoline-4-amine. Palladium / carbon (500 mg, 10% purity) was added to a solution of 2-cyclopropyl-4-nitroisoindoline (1.4 g, crude) in MeOH (20 mL). The suspension was degassed under vacuum and purged three times with hydrogen, then stirred at 45 °C for 1 hour under hydrogen (15 psi). The reaction mixture was filtered, and the filtrate was concentrated to give the 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). 1H 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] + .

[0595] N-(2-Cyclopropylisoindoline-4-yl)-1-isopropyl-1H-imidazol-2-sulfonamide. At 0 °C, a solution of 1-isopropyl-1H-imidazol-2-sulfonyl chloride (452.68 mg, 2.17 mmol) in DCM (3 mL) was added dropwise to a mixture of 2-cyclopropylisoindoline-4-amine (0.35 g, 1.81 mmol) in pyridine (5 mL). The mixture was stirred at 20 °C for 16 h. 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 under vacuum to give the crude product. The crude product was ground with MeOH and then lyophilized to give N-(2-cyclopropylisoindoline-4-yl)-1-isopropyl-1H-imidazol-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] + .

[0596] Example 44. N-(7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-8-yl)-3-methylpyridine-2-sulfonamide

[0597]

[0598] 8-Amino-5-bromo-3,4-dihydroisoquinoline-2(1H)-formate tert-butyl ester. Under nitrogen atmosphere at 0 °C, N-bromosuccinimide (716.75 mg, 4.03 mmol) dissolved in DMF (3 mL) was slowly added to a solution of 8-amino-5-bromo-3,4-dihydroisoquinoline-2(1H)-formate (1 g, 4.03 mmol) in DMF (10 mL). The mixture was stirred at 15 °C for 2 h. 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 the residue. The residue was purified by silica gel chromatography to give 8-amino-5-bromo-3,4-dihydroisoquinoline-2(1H)-formate tert-butyl ester (1.2 g, 3.67 mmol, 91.07% yield). 1 H NMR (400MHz, CDCl3) δ7.24(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).

[0599] 8-Amino-5-bromo-7-chloro-3,4-dihydroisoquinoline-2(1H)-formate tert-butyl ester. A mixture of 8-amino-5-bromo-3,4-dihydroisoquinoline-2(1H)-formate tert-butyl ester (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 h. 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 the residue. The residue was purified by silica gel chromatography to give 8-amino-5-bromo-7-chloro-3,4-dihydroisoquinoline-2(1H)-formate tert-butyl ester (1 g, 2.77 mmol, 75.40% yield). 1 H NMR (400MHz, CDCl3) δ7.40 (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).

[0600] 8-Amino-7-chloro-3,4-dihydroisoquinoline-2(1H)-formate tert-butyl ester. A mixture of 8-amino-5-bromo-7-chloro-3,4-dihydroisoquinoline-2(1H)-formate tert-butyl ester (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 h. 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 min. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to give 8-amino-7-chloro-3,4-dihydroisoquinoline-2(1H)-formate tert-butyl ester (0.3 g, 1.06 mmol, 91.36% yield). MS (ESI): m / z 227.0 [M-55] + .

[0601] 7-Chloro-8-(3-methylpyridin-2-sulfonamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl ester. Under nitrogen atmosphere at -70°C, sodium bis(trimethylsilyl)amino (1M, 0.8mL) was slowly added to a solution of 0.15 g, 0.53 mmol, crude 8-amino-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate in 10 mL of THF. The mixture was stirred at 15°C for 30 min, and then 3-methylpyridin-2-sulfonyl chloride (101.66 mg, 0.53 mmol) dissolved in 2 mL of THF was slowly added at -70°C, followed by stirring at 15°C for 2 h. The mixture was then slowly quenched with saturated ammonium chloride (5 mL) at -20°C and 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 the residue. The residue was purified by silica gel chromatography to give tert-butyl 7-chloro-8-(3-methylpyridin-2-sulfonamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.1 g, crude). MS (ESI): m / z 438.0 [M+1] + .

[0602] N-(7-chloro-1,2,3,4-tetrahydroisoquinoline-8-yl)-3-methylpyridine-2-sulfonamide (trifluoroacetate). Trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL) was slowly added to a solution of tert-butyl 7-chloro-8-(3-methylpyridine-2-sulfonamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.18 g, 0.41 mmol, crude) in DCM (4 mL) at 0 °C. The mixture was stirred at 15 °C for 2 h. The mixture was concentrated under reduced pressure to give N-(7-chloro-1,2,3,4-tetrahydroisoquinoline-8-yl)-3-methylpyridine-2-sulfonamide (trifluoroacetate). MS (ESI): m / z 338.0 [M+1] + .

[0603] N-(7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-8-yl)-3-methylpyridine-2-sulfonamide. TEA (71.89 mg, 0.71 mmol) was slowly added to a solution of N-(7-chloro-1,2,3,4-tetrahydroisoquinoline-8-yl)-3-methylpyridine-2-sulfonamide (0.2 g, crude) (trifluoroacetate) in MeOH (10 mL) 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 h. The 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 the residue. The residue was purified by preparative HPLC to give N-(7-chloro-2-methyl-3,4-dihydro-1H-isoquinoline-8-yl)-3-methyl-pyridine-2-sulfonamide (14.01 mg, 0.04 mmol, 6.46% yield, 96% purity). 1 H NMR (400MHz, CDCl3) δ8.53(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 / z352.1[M+1] + .

[0604] Example 45.1-(2,2,2-trifluoroethyl)-N-[5-[3-(trifluoromethyl)phenoxy]-8-quinolinyl]imidazol-2-

[0605] sulfonamide

[0606]

[0607] 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 slowly added in portions under an inert atmosphere. The resulting reaction mixture was allowed to reach room temperature and stirred continuously for 16 h. The reaction mixture was poured into crushed ice. The resulting precipitate 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]+.

[0608] 8-Nitro-5-[3-(trifluoromethyl)phenoxy]quinoline. Under an argon atmosphere at room temperature, K₂CO₃ (6.85 g, 49.5 mmol) was added to a stirred solution of 5-bromo-8-nitro-quinoline (5 g, 19.84 mmol) in dry DMF (50 mL), followed by the addition of 3-trifluoromethylphenol (6.4 g, 39.68 mmol). 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 / hexane) to give 8-nitro-5-[3-(trifluoromethyl)phenoxy]quinoline (3.5 g, 53%) as a pale yellow solid. MS (ESI): m / z 335.37 [M+1]+.

[0609] 5-[3-(trifluoromethyl)phenoxy]quinoline-8-amine. NH4Cl (238 mg, 4.49 mmol) and Fe powder (838 mg, 14.97 mmol) were added to a stirred solution (24 mL, 3:2:1 ratio) of 8-nitro-5-[3-(trifluoromethyl)phenoxy]quinoline (1 g, 2.99 mmol) in THF-EtOH-H2O. The resulting mixture was heated at 80 °C for 4 h. After completion, the reaction mixture was filtered through a diatomaceous earth stencil 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 hexane) to give 5-[3-(trifluoromethyl)phenoxy]quinoline-8-amine (700 mg, 77%) as a yellow solid. MS (ESI): m / z 305.4 [M+1]+.

[0610] 1-(2,2,2-trifluoroethyl)-1H-imidazol-2-thiol. At 0 °C, 1-[(2-oxo-1,2-dihydropyridin-1-yl)thiocarbonyl]-1,2-dihydropyridin-2-one (12.8 g, 55.6 mmol) was added in portions to a stirred solution of 2,2,2-trifluoroethane-1-amine (5 g, 50.5 mmol) in DCM (50 mL). The resulting mixture was heated to 10 °C and stirred for 3 h. 2,2-diethoxyethane-1-amine (10 g, 75.2 mmol) was added under cooling 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. After completion, the reaction mixture was concentrated under reduced pressure, diluted with water, adjusted to pH approximately 8 with 1(N) NaOH aqueous solution, 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 substance was purified by column chromatography (25%–30% EtOAc-Hex) to give 1-(2,2,2-trifluoroethyl)-1H imidazole-2-thiol (3 g, 33%, in two steps) as a white solid. MS (ESI): m / z 183.3 [M+1]+.

[0611] 1-(2,2,2-trifluoroethyl)-1H-imidazol-2-sulfonyl chloride. 1.5 g (8.2 mmol) of 1-(2,2,2-trifluoroethyl)-1H-imidazol-2-thiol was placed in a double-necked round-bottom flask and cooled to -10 °C. Concentrated H₂SO₄ (40 mL) was slowly added under cooling. NaOCl (70 mL) was added over a 30-minute period at -15 °C, followed by stirring for another 0.5 h. Afterward, 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-imidazol-2-sulfonyl chloride (as a DCM solution), which was used immediately for the next step without further purification. MS (ESI): m / z 249.3 [M+1]+.

[0612] 1-(2,2,2-trifluoroethyl)-N-[5-[3-(trifluoromethyl)phenoxy]-8-quinolinyl]imidazolium-2-sulfonamide. Under an argon atmosphere, 1-(2,2,2-trifluoroethyl)-1H-imidazolium-2-sulfonyl chloride (DCM solution) was added dropwise to a stirred solution of 5-[700 mg, 2.31 mmol]quinolinium-8-amine at 0 °C in pyridine (4 mL, 49.6 mmol) and DCM (10 mL). The reaction mixture was slowly warmed to room temperature and stirred for 2 h. After 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 hexane) to give 1-(2,2,2-trifluoroethyl)-N-[5-[3-(trifluoromethyl)phenoxy]-8-quinolinyl]imidazol-2-sulfonamide (680 mg, 62%). 1 H NMR (400MHz, DMSO-d6) δ5.44(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=7.8Hz,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]+.

[0613] Example 46. N-(5-cyano-8-quinolinyl)-1-ethyl-imidazol-2-sulfonamide

[0614]

[0615] 8-Nitroquinoline-5-carboxynitrile. Zinc cyanide (371 mg, 3.16 mmol) was added to a stirred, degassed solution of 5-bromo-8-nitroquinoline (200 mg, 0.791 mmol) in DMF (4 mL), followed by the addition of DIPEA (0.2 mL, 1.18 mmol), Pd(dba)₂ (136 mg, 0.24 mmol), and Xphos (113 mg, 0.24 mmol). The resulting mixture was heated at 100 °C for 0.5 h under MW irradiation. 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 Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (20%–25% EtOAc, in hexane) to give 8-nitroquinoline-5-carboxynitrile (75 mg, 47%) as a grayish-white solid. MS(ESI): m / z 200.3 [M+1] + .

[0616] 8-Aminoquinoline-5-carboxynitrile. 10% Pd-C (33 mg) was added to a stirred solution of 8-nitroquinoline-5-carboxynitrile (85 mg, 0.43 mmol) in MeOH (5 mL). The resulting mixture was hydrogenated at room temperature for 16 h under balloon pressure. After completion, the reaction mixture was filtered through a diatomaceous earth septum, and the filtrate was concentrated under reduced pressure. The crude material was purified by combiflash chromatography (20%–25% EtOAc, in hexane) to give 8-aminoquinoline-5-carboxynitrile (40 mg, 55%) as a colorless gel. MS (ESI): m / z 170.18 [M+1]+.

[0617] Ethyl isothiocyanate. 1-[(2-oxo-1,2-dihydropyridin-1-yl)thiocarbonyl]-1,2-dihydropyridin-2-one (28.4 g, 122 mmol) was added in portions to a stirred solution of ethylamine (5 g, 55.5 mL, 110.92 mmol, in 2 M THF) in DCM (300 mL) and stirred at room temperature for 3 h. After completion, the reaction mixture was evaporated to dryness to give ethane isothiocyanate as a brown solid (7.7 g, crude product), which was used directly in the next step without further purification.

[0618] 1-Ethylimidazol-2-thiol. 2,2-Diethoxyethyl-1-amine (19.3 mL, 133.06 mmol) was added dropwise to a stirred solution of isothiocyanate ethane (7.7 g, 88.70 mmol, crude) in toluene (40 mL) at room temperature and stirred for 2 h. Then, concentrated HCl (7.5 mL) was added to the reaction mixture and stirred at 110 °C for 3 h. After completion, the reaction mixture was evaporated to dryness and the residue was diluted with water (40 mL). The aqueous fraction was alkalized to pH approximately 8 with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic fractions 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-ethylimidazol-2-thiol (10 g, 70%, 2 steps) as a brown solid. MS(ESI): m / z 129.2 [M+1] - .

[0619] 1-Ethylimidazol-2-sulfonyl chloride. 150 mg (1.72 mmol) of 1-ethylimidazol-2-thiol was placed in a double-necked round-bottom flask and cooled to -10 °C. Concentrated H₂SO₄ (3 mL) was slowly added dropwise (while continuously stirring) and stirred for another 10 min at -10 °C. The reaction mixture was cooled to -15 °C, and NaOCl (9 mL) was added dropwise over 30 min. The mixture was stirred for another 30 min at -10 °C. After 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 (in a pre-cooled flask), filtered through a sintered funnel, and partially concentrated at low temperature to obtain 1-ethylimidazol-2-sulfonyl chloride (as a DCM solution), which was used directly in the next step without further purification.

[0620] N-(5-Cyano-8-quinolinyl)-1-ethyl-imidazolium-2-sulfonamide. Under an argon atmosphere, 1-ethylimidazolium-2-sulfonyl chloride (crude product, DCM solution) was added dropwise to a stirred solution of 8-aminoquinoline-5-carboxynitrile (50 mg, 0.296 mmol) at 0 °C in pyridine (1 mL, 0.6 mmol) and DCM (4 mL). The mixture was then stirred at 0 °C–room temperature for 2 h. After completion, the solution 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-quinolinyl)-1-ethyl-imidazolium-2-sulfonamide (20 mg, 21%). 1¹H NMR (400MHz, DMSO-d⁶) δ 1.32 (t, J = 7.2Hz, 3H), 4.40 (q, J = 7.2Hz, 2H), 7.01 (s, 1H), 7.50 (s, 1H), 7.84 (dd, J = 4.6, 8.4Hz, 2H), 8.15 (d, J = 7.9Hz, 1H), 8.46 (d, J = 8.4Hz, 1H), 9.03 (d, J = 3.4Hz, 1H) [NH protons not observed]. MS (ESI): m / z 328.0 [M+1]⁺.

[0621] Example 47. 1-Phenyl-N-[5-(trifluoromethyl)-8-quinolinyl]imidazol-2-sulfonamide

[0622]

[0623] 8-Bromo-5-(trifluoromethyl)quinoline. Glycerol (1.5 g, 16.3 mmol) was heated to 160 °C for 1 h. It was then 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, with sulfuric acid (95%–98%, 1.8 g, 18.4 mmol) added dropwise, and the mixture was heated at 150 °C for 45 min. 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 Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (20%–25% EtOAc, in hexane) to give 8-bromo-5-(trifluoromethyl)quinoline (600 mg, 26%) as a colorless, colloidal substance. MS(ESI): m / z 276.0 [M+1] + .

[0624] 5-(trifluoromethyl)quinoline-8-amine. Benzophenone imine (395 mg, 2.18 mmol) was added to a stirred, degassed solution of 8-bromo-5-(trifluoromethyl)quinoline (500 mg, 1.82 mmol) in toluene (8 mL), followed by the addition of Cs₂CO₃ (289 mg, 2.72 mmol), Pd(OAc)₂ (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 diatomaceous earth stencil, 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 HCl aqueous solution. The resulting mixture was stirred at room temperature for 3 h. It was then alkalized with a saturated NaHCO₃ aqueous solution 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 hexane) to give 5-(trifluoromethyl)quinoline-8-amine (310 mg, 80%) as an orange solid. MS (ESI): m / z 200.3 [M+1] + .

[0625] Isothiocyanate-based benzene. 1-[(2-oxo-1,2-dihydropyridin-1-yl)thiocarbonyl]-1,2-dihydropyridin-2-one (2.9 g, 12.90 mmol) was added in portions to a stirred solution of aniline (1 g, 10.73 mmol) in DCM (30 mL) and stirred at room temperature for 3 h. After completion, the reaction mixture was concentrated under reduced pressure to give a brown solid, 1.5 g, crude, which was used directly in the next step without further purification.

[0626] 1-Phenylidene-2-thiol. 2,2-Diethoxyethyl-1-amine (2.2 g, 16.66 mmol) was added dropwise to a stirred solution of isothiocyanate benzene (1.5 g, 11.12 mmol, crude) in toluene (15 mL) and stirred for 2 h. Then concentrated HCl (1 mL) was added to the reaction mixture and stirred at 110 °C for 3 h. After completion, the reaction mixture was evaporated to dryness and the residue was diluted with water (40 mL). The aqueous fraction was alkalized to pH approximately 8 with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic fractions 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-phenylimidazol-2-thiol (1.2 g, 63%, 2 steps) as a colorless, colloidal substance. MS(ESI): m / z 177.0 [M+1] + .

[0627] 1-Phenylidene-2-sulfonyl chloride. 1-Phenylidene-2-thiol (300 mg, 1.70 mmol) was placed in a two-necked round-bottom flask and cooled to -10 °C. Concentrated H₂SO₄ (5 mL) was slowly added dropwise (while continuously stirring) and stirred for another 10 min at -10 °C. The reaction mixture was cooled to -15 °C, and NaOCl (15 mL) was added dropwise over 30 min. The mixture was stirred for another 30 min at -10 °C. After 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 (in a pre-cooled flask), filtered through a sintered funnel, and partially concentrated at low temperature to obtain 1-phenylimidazolium-2-sulfonyl chloride (as a DCM solution), which was used directly in the next step without further purification.

[0628] 1-Phenylidene-N-[5-(trifluoromethyl)-8-quinolinyl]imidazolium-2-sulfonamide. Under an argon atmosphere, 1-phenylimidazolium-2-sulfonyl chloride (crude product, DCM solution) was added dropwise to a stirred solution of 5-(trifluoromethyl)quinolinyl-8-amine (200 mg, 0.943 mmol) at 0 °C in pyridine (1 mL, 12.6 mmol) and DCM (5 mL). The mixture was then stirred at 0 °C–room temperature for 2 h. After completion, the mixture was diluted with water (25 mL) and extracted with DCM (2 x 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 hexane) to give 1-phenyl-N-[5-(trifluoromethyl)-8-quinolinyl]imidazolium-2-sulfonamide (75 mg, 19%) as a grayish-white solid. MS(ESI): m / z 418.8 [M+1] + .

[0629] Example 48. 1-Ethyl-N-(4-phenyl-8-quinolinyl)imidazol-2-sulfonamide

[0630]

[0631] 8-Nitro-4-phenyl-quinoline. Under an argon atmosphere, K₂CO₃ (82 mg, 0.59 mmol) was added to a stirred, degassed solution of 4-bromo-8-nitro-quinoline (200 mg, 0.791 mmol) in dioxane-H₂O (5.5 mL, 10:1), followed by the addition of phenylboronic acid (58 mg, 0.48 mmol) and Pd(dppf)Cl₂ (15 mg, 0.02 mmol). 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 Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (80%–100% EtOAc, in hexane) to give 8-nitro-4-phenyl-quinoline (75 mg, 76%) as a grayish-white solid. MS(ESI): m / z 251.0 [M+1] +

[0632] 4-Phenylono-8-amine. NH4Cl (297 mg, 5.6 mmol) and zinc powder (182 mg, 2.8 mmol) were added to a stirred solution (24 mL, 1:1 ratio) of 8-nitro-4-phenyl-quinoline (140 mg, 0.56 mmol) in THF-EtOH and stirred at room temperature for 2 h. After completion, the reaction mixture was filtered through a diatomaceous earth saddle 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 hexane) to give 4-phenylquinoline-8-amine (100 mg, 81%) as a gray solid. MS (ESI): m / z 221.3 [M+1]+.

[0633] 1-Ethyl-N-(4-phenyl-8-quinolinyl)imidazolium-2-sulfonamide. Under an argon atmosphere, 1-ethylimidazolium-2-sulfonyl chloride (crude product, DCM solution) was added dropwise to a stirred solution of 4-phenylquinolinyl-8-amine (80 mg, 0.363 mmol) at 0 °C in pyridine (1 mL, 12.6 mmol) and DCM (4 mL). The mixture was then stirred at 0 °C–room temperature for 2 h. After completion, the 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-quinolinyl)imidazolium-2-sulfonamide (70 mg, 51%) as a grayish-white solid. MS (ESI): m / z 379.2 [M+1] + .

[0634] Example 49. 1-Ethyl-N-(5-methanesulfonyl-8-quinolinyl)imidazol-2-sulfonamide

[0635]

[0636] 5-Methanesulfonyl-8-nitro-quinoline. Sodium methanesulfinate (73 mg, 0.71 mmol) was added to a stirred, degassed solution of 5-bromo-8-nitro-quinoline (150 mg, 0.595 mmol) in DMSO (8 mL) under an inert atmosphere, followed by the addition of copper iodide (11 mg, 0.06 mmol) and L-proline (14 mg, 0.12 mmol). The resulting mixture was heated at 100 °C for 16 h in a sealed tube. 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 Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (5%–10% EtOAc, in hexane) to give 5-methanesulfonyl-8-nitro-quinoline (45 mg, 30%) as a grayish-white solid. MS (ESI): m / z 253.2 [M+1] + .

[0637] 5-Methanesulfonylquinoline-8-amine. NH4Cl (95 mg, 1.78 mmol) and zinc powder (117 mg, 1.78 mmol) were added to a stirred solution (10 mL, 1:1 ratio) of 5-methanesulfonyl-8-nitro-quinoline (90 mg, 0.35 mmol) in THF-EtOH and stirred at 10 °C for 0.5 h. After completion, the reaction mixture was filtered through a diatomaceous earth bed 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 hexane) to give 5-methanesulfonylquinoline-8-amine (75 mg, 94%) as a gray solid. MS (ESI): m / z 223.2 [M+1] + .

[0638] 1-Ethyl-N-(5-methanesulfonyl-8-quinolinyl)imidazolium-2-sulfonamide. NaH (27.0 mg, 0.676 mmol) was added to a stirred solution of 5-methanesulfonylquinolinyl-8-amine (75 mg, 0.34 mmol) in THF (5 mL) at 0 °C, and the mixture was stirred for 15 min at the same temperature. The resulting mixture was heated at 80 °C for 30 min and cooled to 0 °C. 1-Ethylimidazolium-2-sulfonyl chloride (crude product, DCM solution) was added dropwise under an argon atmosphere. The reaction mixture was stirred at 0 °C–room temperature for 2 h. After 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-methanesulfonyl-8-quinolinyl)imidazolium-2-sulfonamide (10 mg, 8%). 1 H NMR (400MHz, DMSO-d6) δ1.33(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]+.

[0639] Example 50. N-(6-fluoro-8-quinolinyl)-1-[4-(trifluoromethyl)phenyl]imidazol-2-sulfonamide

[0640]

[0641] 6-Fluoro-8-nitro-quinoline. 4-Fluoro-2-nitro-aniline (10.0 g, 64.06 mmol) and arsenic pentoxide hydrate (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 h. The reaction mixture was then heated to 120 °C for 90 min. It was cooled to ambient temperature and poured into an ice / water mixture (200 mL) and filtered. Ammonia was added dropwise to adjust the pH to approximately 6, and the mixture was extracted with DCM. 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 (10% EtOAc, in hexane) to give 6-fluoro-8-nitro-quinoline (6.5 g, 53%) as a yellow solid. MS (ESI): m / z 193.2 [M+1]+.

[0642] 6-Fluoroquinoline-8-amine. NH4Cl (1.43 g, 26.8 mmol) and Fe powder (4.98 g, 89.3 mmol) were added to a stirred solution (42 mL, 3:2:1 ratio) of 6-fluoro-8-nitro-quinoline (3.43 g, 17.86 mmol) in THF-EtOH-H2O and stirred at 90 °C for 2 h. After completion, the reaction mixture was filtered through a diatomaceous earth stencil 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 hexane) to give 6-fluoroquinoline-8-amine (1.5 g, 52%) as a brown solid. MS (ESI): m / z 163.3 [M+1]+.

[0643] 1-Isothiocyanate-4-(trifluoromethyl)benzene. 1-[(2-oxo-1,2-dihydropyridin-1-yl)thiocarbonyl]-1,2-dihydropyridin-2-one (1.58 g, 6.83 mmol) was added in portions to a stirred solution of 4-(trifluoromethyl)aniline (1 g, 6.21 mmol) in DCM (20 mL) and stirred at room temperature for 3 h. After completion, the reaction mixture was concentrated under reduced pressure to give 1-isothiocyanate-4-(trifluoromethyl)benzene (1.2 g, crude) as a brown solid, which was used directly in the next step without further purification.

[0644] 1-[4-(trifluoromethyl)phenyl]imidazol-2-thiol. 2,2-Diethoxyethyl-1-amine (1.28 g, 8.87 mmol) was added dropwise to a stirred solution of 1-isothiocyanate-4-(trifluoromethyl)benzene (1.2 g, 5.91 mmol, crude) in toluene (10 mL) at room temperature and stirred for 2 h. Concentrated HCl (2 mL) was added to the reaction mixture and stirred at 100 °C for 16 h. After completion, the reaction mixture was evaporated to dryness and the residue was diluted with water. The aqueous fraction was alkalized to pH approximately 8 with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic fractions 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]imidazol-2-thiol (1.2 g, 83%, 2 steps) as a grayish-white solid. MS (ESI): m / z 245.3 [M+1] + .

[0645] 1-[4-(trifluoromethyl)phenyl]imidazol-2-sulfonyl chloride. 1-[4-(trifluoromethyl)phenyl]imidazol-2-thiol (300.0 mg, 1.23 mmol) was cooled to -10 °C, and 10 mL of 1 (N) HCl was added dropwise (while stirring continuously) for 10 min. NaOCl (18 mL) was added dropwise over 30 min, and stirring continued for anothe...

Claims

1. A compound having formula (Ia) (Ia), Or its pharmaceutically acceptable salt. in: Each R 1 Independently, it is -F, -Cl, -Br, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2(cyclopropyl), aziridine, -N(CH3)2, -C(O)CH3, benzoyl, methylsulfonyl, phenyl, -O-(m-trifluoromethyl)phenyl or p-fluorophenyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; R 2 yes The pyrazinyl group is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3), -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH(CH3)2, -N(CH3)2, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl; and n is 1 - 3.

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

3. The compound according to claim 1, wherein each R 1 Independently, it is -F, -Cl, -Br, -CN, -CH3, -CH2CH3, -CF3, cyclopropyl, cyclohexyl, -OCH3, -OCH(CH3)2, -OCH2(cyclopropyl), aziridine, -N(CH3)2, -C(O)CH3, benzoyl, methylsulfonyl, phenyl, -O-(m-trifluoromethyl)phenyl, p-fluorophenyl, or morpholino.

4. The compound according to claim 1, wherein R 2 It is 2-pyrazinyl, which is independently substituted by one or more of the following substituents: -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3), -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH(CH3)2, -N(CH3)2, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.

5. The compound according to claim 1, wherein R 2 It is 2-pyrazinyl, which is independently substituted by one or more of the following substituents: -CH3, -OCH3 and pyrrolidinyl.

6. The compound according to claim 1, wherein each R 1 Independently, it is -F, -Cl, -CH3, cyclopropyl, cyclohexyl, -OCH3, -OCH(CH3)2, -OCH2(cyclopropyl), aziridine, phenyl, or morpholino.

7. The compound according to claim 1, wherein each R 1 Independently, it is -F, -Cl, -CH3, -CH2CH3, -CF3, cyclohexyl, -OCH3, or morpholinyl, and R 2 It is a 2-pyrazinyl group, which is independently substituted by one or more substituents selected from the following: -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH(CH3)2, -N(CH3)2, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.

8. The compound according to claim 1, wherein R 2 It is a 2-pyrazinyl group, which is independently substituted by one or more substituents selected from the following: -CH3, -OCH3, -N(CH3)2, and pyrrolidinyl.

9. The compound according to claim 1, wherein each R 1 It is independently -Cl or morpholino.

10. The compound according to claim 1, wherein the compound is selected from: Or its pharmaceutically acceptable salt.

11. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1-10 and a pharmaceutically acceptable carrier, excipient or mediator.

12. Use of the compound according to any one of claims 1-10, or 3-methyl-N-(quinoline-8-yl)pyrazine-2-sulfonamide or N-(quinoline-8-yl)pyrazine-2-sulfonamide, in the preparation of a medicament for treating filariasis in an individual.

13. The use according to claim 12, wherein the treatment comprises inhibiting the growth or molting of filarial worms, killing filarial worms, or inhibiting filarial movement.

14. Use of the compound according to any one of claims 1-10, or 3-methyl-N-(quinoline-8-yl)pyrazine-2-sulfonamide or N-(quinoline-8-yl)pyrazine-2-sulfonamide, in the preparation of a medicament for treating or preventing parasitic worm infections or diseases.

15. The use according to claim 14, wherein the parasitic worm infection is a filarial infection.

16. The use according to claim 15, wherein the drug is intended to be administered in combination with one or more anthelmintics to treat or prevent parasitic worm infection or disease.

17. The use according to claim 16, wherein the parasitic worm infection is a filarial infection.

18. The use according to claim 16, wherein the insect repellent is selected from flubendazole, albendazole, mebendazole, thiabendazole, fenbendazole, trichlorobendazole, ivermectin, abamectin, dimethoprim (DEC), suramin, pyrantel pamoate, levamisole, niclosamide, nizoxinide, hydroxychlorozadamide, praziquantel, amedas, mononitrate, dequiteryl, and punicic acid sulfate.

19. The use according to claim 16, wherein the insect repellent is a Wolbachia target.

20. The use according to claim 19, wherein the Wolbachia target is doxycycline.

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