Heterocyclic compounds and their use for the treatment of helminthic infections and diseases

Abstract

Provided herein are heterocyclic compounds of Formula (I), Formula (II), Formula (III), Formula (IIIa), Formula (Mb), Formula (IIIc), Formula (Hid), Formula (IV), Formula (IVa), Formula (IVb), and Formula (IVc), and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof, compositions comprising an effective amount of a heterocyclic compound of Formula (I), Formula (II), Formula (III), Formula (IIIa), Formula (Mb), Formula (IIIc), Formula (Hid), Formula (IV), Formula (IVa), Formula (IVb), and Formula (IVc), and methods for treating or preventing heartworm infections and diseases in animals and humans.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of U.S. Provisional Patent Application No. 63,105,013, filed on 23 October 2020, the disclosure of which is incorporated herein by reference in its entirety.

[0002] This specification discloses compounds and methods for the prevention and / or treatment of helminthic infections and diseases caused by helminthic infections. Such compounds for use in such methods are also provided herein. Pharmaceutical compositions containing such compounds for use in such methods for the prevention or treatment of helminthic infections and / or diseases associated with helminthic infections are also disclosed herein. [Background technology]

[0003] Several types of parasites (helmins) exist, the most common worldwide being enteric nematodes or soil-transmitted helmins (STH), schistosomiasis (the parasite that causes schistosomiasis), and filarial worms that cause lymphatic filariasis (LF) and onchocerciasis. Filariasis is a parasitic disease caused by filarial nematodes or roundworms. Filariasis is a host-borne disease transmitted by insect bites. Infectious nematode larvae can be introduced into the human body by being bitten by blood-sucking insects such as mosquitoes or flies. Filariasis can also affect domestic animals such as dogs. In dogs, dirofilariasis, also known as heartworm disease, is caused by nematodes called Dirofilaria immitis and Dirofilaria repens. Dirofilariasis is thought to be prevalent in 49 states in the United States. The vectors are similarly blood-sucking insects, such as mosquitoes.

[0004] The main causes of human filariasis are the human-hosting filarial nematode species Uckereria bancrofti, Brugia malayi, Brugia timori, Onchocerca volvulus, and Mansonella. These nematodes account for the majority of debilitating filarial infections in over 80 developing countries in tropical and subtropical regions, with 1.1 billion people at risk of infection and approximately 150 million infected. All three species are responsible for severe disease conditions resulting in high morbidity and mortality. The infection can cause severe illness in up to 50% of people infected with the nematode.

[0005] Infections with W. bancrofti and B. malayi can often progress to lymphatic filariasis, which in men is seen as hydrocele and / or lymphedema, and in extreme cases as elephantiasis. Infections with O. volvulus can progress to severe dermatitis and / or onchocerciasis, the latter of which is commonly known as river blindness due to visual impairment. Community-led mass medication programs have been designed to control these infections and eliminate them from public health problems.

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

[0007] Two of the main limitations in treating filariasis are (i) the absence of macrofilariatic agents (i.e., those that permanently sterilize the parasite in onchocerciasis), and (ii) the risk of the parasite developing drug resistance. For example, currently available treatments for onchocerciasis include ivermectin, which kills larvae, but has little to no activity against adult Onchocerca volvulus parasites. Therefore, infected patients must be re-treated with ivermectin for several years until the adults die naturally. In addition, in some regions, there is a possibility of signs of resistance to ivermectin within the parasite. Non-patent literature 1. In addition, treatment with ivermectin in patients who are co-infected with (i) Wuchereria bancrofti, Brugia malayi, Brugia timori, and / or Onchocerca volvulus, and (ii) Loa loa, is dangerous. In such co-infected patients, ivermectin treatment can cause severe reactions, including encephalopathy, coma, or even death.

[0008] Heartworm infection, caused by the endoparasite Dirofilaria immitis (D. immitis), can be a life-threatening illness in animals such as dogs and cats. Heartworms have a complex life cycle involving several life stages before maturing into adult worms that eventually infect the pulmonary arteries of host animals. Heartworm transmission also requires mosquitoes to play an intermediate host role in completing this life cycle. For example, the initiation of the heartworm life cycle and transmission process involves a mosquito biting a previously infected dog and ingesting blood containing heartworm microfilariae (larval stage 1). Inside the mosquito, the microfilariae molt over two weeks to become infective larval stage 3 (L3) larvae. When a mosquito bites another dog, the infecting L3 larva enters the host through the bite wound, migrates into the tissue, and usually begins molting within 1-3 days after infection to become a larval stage 4 (L4) larva. Subsequently, the L4 larva continues to migrate within the tissue and molts approximately 50-70 days after infection to become a sexually immature or "juvenile" adult (larval stage 5, immature adult). Sexually mature worms eventually migrate to the dog's heart and lungs, as early as 70 days after infection. Approximately 6-7 months after infection, the D. immitis adult matures, sexually reproduces in the pulmonary artery, produces microfilariae (MFs) that circulate in the dog's blood, and thus completes the heartworm life cycle.

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

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

Problems to be Solved by the Invention

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

Means for Solving the Problems

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

[0013] Formula (I):

Chemical formula

[0014] As used herein, formula (II):

Chemical formula

[0015] As used herein, formula (III): <0001!50>

Chemical formula

[0016] In this specification, formula (IV): [ka] Compounds of the same compound, as well as pharmaceutically acceptable salts, tautomers, isotopologs and stereoisomers thereof, where X, Y, Z, R 1 , R 2 , R 3 and R 4 This is as defined herein.

[0017] In one embodiment, heterocyclic compounds described herein, such as heterocyclic compounds of formula (I), formula (II), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), or formula (IVc), or compounds from Table 1, Table 2, Table 3, Table 4, or Table 5 are provided herein.

[0018] In one embodiment, a pharmaceutical composition is provided herein comprising an effective amount of a heterocyclic compound described herein and a pharmaceutically acceptable carrier, excipient, or medium. In some embodiments, the pharmaceutical composition is suitable for oral, parenteral, mucosal, transdermal, or topical administration.

[0019] In one embodiment, a method for treating a subject infected with helminths is provided herein. In another embodiment, a use of a heterocyclic compound for treating or preventing a helminth infection is provided herein, comprising administering an effective amount of the heterocyclic compound described herein to a subject affected by a helminth infection. In one embodiment, the helminth infection is a filarial infection.

[0020] In one embodiment, a method for treating a subject infected with filarial parasites is provided herein. In another embodiment, a use of a heterocyclic compound for treating or preventing filarial infection is provided herein, comprising administering an effective amount of the heterocyclic compound described herein to a subject affected by filarial infection.

[0021] In certain embodiments, the methods described herein include administering a therapeutically effective amount of a compound of formula (I), (II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), (IVa), (IVb), (IVc) or a compound from Table 1, Table 2, Table 3, Table 4, or Table 5 or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof to a target.

[0022] The compounds of the present invention are useful for treating helminthic diseases, which are classified into tapeworms (Cycetes), roundworms (Nematodes), and trematodes (Platyhelminthes or Trematodes). Non-exclusive examples of filarial nematodes in the family Onchocercidae include species of the genera Brugia (i.e., B. malayi, B. pahangi, B. timori, etc.), Wuchereria (i.e., W. bancrofti, etc.), Dirofilaria (i.e., D. immitis, D. repens, D. ursi, D. tenuis, D. spectans, D. lutrae, etc.), and Dipetalonema (i.e., D. reconditum) Examples include species of the genus Onchocerca (i.e., O. gibsoni, O. gutturosa, O. volvulus, etc.), species of the genus Elaeophora (i.e., E. bohmi, E. elaphi, E. poeli, E. sagitta, E. schneideri, etc.), species of the genus Mansonella (i.e., M. ozzardi, M. perstans, etc.), and species of the genus Loa (i.e., L. loa). In certain embodiments, the filarial parasite is Onchocerca volvulus. In certain embodiments, the filarial parasite is Wuchereria bancrofti. In certain embodiments, the filarial parasite is Brugia malayi. In certain embodiments, the filarial parasite is Brugia timori. In certain embodiments, the filarial parasite is Mansonella.In certain embodiments, the filarial parasite is Dirofilaria immitis.

[0023] In one embodiment, the use of a heterocyclic compound for treating or preventing helminthic infection is provided herein, comprising administering an effective amount of the heterocyclic compound described herein to a subject affected by helminthic infection. In another embodiment, the use of a heterocyclic compound for treating or preventing filarial infection is provided herein, comprising administering an effective amount of the heterocyclic compound described herein to a subject affected by filarial infection.

[0024] In one embodiment, heterocyclic compounds for use as pharmaceuticals are provided herein. In a particular embodiment, heterocyclic compounds for use in a method for treating or preventing helminthic infections are provided herein, the method comprising administering an effective amount of the heterocyclic compound to a subject. In a particular embodiment, heterocyclic compounds for use in a method for treating or preventing filarial worm infections are provided herein, the method comprising administering an effective amount of the heterocyclic compound to a subject.

[0025] In another embodiment, a method for preparing the heterocyclic compounds described herein is provided herein.

[0026] This embodiment can be understood in more detail by referring to the detailed description and examples, which are intended to illustrate non-limiting embodiments. [Brief explanation of the drawing]

[0027] [Figure 1] This shows the life cycle of L. sigmodontis (a rodent filaria nematode), from the microfilaria (L1) stage to the adult stage. [Modes for carrying out the invention]

[0028] definition As used herein, the terms “includes” and “inclusive” are interchangeable. The terms “includes” and “inclusive” should be interpreted as identifying the presence of a specified feature or component, but not excluding the presence or addition of one or more features or components, or groups thereof. Furthermore, the terms “includes” and “inclusive” are intended to include examples encompassed by the term “consisting of.” Therefore, the term “consisting of” may be used instead of the terms “includes” and “inclusive” to provide more specific embodiments of the present invention.

[0029] The term "consists of" means that the subject has at least 90%, 95%, 97%, 98%, or 99% of the defining features or components that constitute it. In another embodiment, the term "consists of" excludes any other features or components from the scope of any subsequent description, except those that are not essential to the technical effect to be achieved.

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

[0031] As used herein and unless otherwise specified, an "alkyl" group is a saturated, partially saturated, or unsaturated linear 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. Typical 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, and -2,3-dimethylbutyl. 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 may be substituted or unsubstituted.Where an alkyl group described herein is said to be "substituted," it means one or more arbitrary substituents as seen in the exemplary compounds and embodiments disclosed herein, as well as halogens; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy; oxo(=O); amino, alkylamino, cycloalkylamino, arylamino, hetero Can be substituted with rosicrylamino, heteroarylamino, heterocycloalkylamino; imino; imide; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio(-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amide; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or -B(OH)2.

[0032] As used herein and unless otherwise specified, the “cycloalkyl” group is a saturated or partially saturated cyclic alkyl group of 3 to 10 carbon atoms having a monocyclic ring or a plurality of fused or crosslinked rings that can 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 is in the range of 3 to 5, 3 to 6, or 3 to 7. Such cycloalkyl groups include, by example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, and 2-methylcyclooctyl, or plurality or crosslinked 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, and adamantyl. Examples of unsaturated cycloalkyl groups include, in particular, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. Cycloalkyl groups can be substituted or unsubstituted. Examples of such substituted cycloalkyl groups include cyclohexanol.

[0033] As used herein and unless otherwise specified, an "aryl" group is an aromatic carbocyclic group of 6 to 14 carbon atoms having a monocyclic ring (e.g., phenyl) or a plurality of fused rings (e.g., naphthyl or anthryl). In some embodiments, the aryl group contains 6 to 14 carbon atoms in the ring portion of the group, and in other embodiments, it contains 6 to 12 or even 6 to 10 carbon atoms. Specific aryl groups include phenyl, biphenyl, naphthyl, and the like. The aryl group may be substituted or unsubstituted. The term "aryl group" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.).

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

[0035] As used herein and unless otherwise specified, “heterocyclyl” refers to an aromatic ring system (also called heteroaryl) or a non-aromatic cycloalkyl (also called heterocycloalkyl) in which 1 to 4 of the ring carbon atoms are independently substituted with heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In some embodiments, the heterocyclyl group contains 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. Heterocyclyls can also be bonded to other groups at any ring atom (i.e., any carbon or heteroatom of the heterocyclic ring). Heterocyclyl groups can be substituted or unsubstituted. Heterocyclyl groups include unsaturated, partially saturated, and saturated ring systems, such as imidazolyl, imidazolinyl, and imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl) groups. The term heterocyclyl includes condensed aromatic and non-aromatic groups, such as 1- and 2-aminotetraline, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxynyl, and benzo[1,3]dioxolyl, among other condensed ring species. This term also includes, but is not limited to, quinuclidyl, bridging polycyclic ring systems containing heteroatoms. Typical examples of heterocyclyl groups include azilidinyl, azetidinyl, azepanil, oxetanyl, pyrrolidyl, and imidazolidinyl (e.g., imidazolidinyl-4-onyl or imidazolidinyl-2).4-Dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranil, dioxolyl, furanil, thiophenyl, pyrrolyl, pyrrolinil, imidazolyl, imidazolinil, pyrazolyl, pyrazolinil, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzoisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinil, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl (e.g., piperazine-2-o Nyl), Morpholinyl, Thiomorpholinyl, Tetrahydropyranyl (e.g., Tetrahydro-2H-pyranyl), Tetrahydrothiopyranyl, Oxathianyl, Dioxyl, Dithianyl, Pyranyl, Pyridyl, Pyrimidyl, Pyridazinyl, Pyrazinyl, Triazinyl, Dihydropyridyl, Dihydrodithinyl, Dihydrodithionyl, 1,4-Dioxaspiro[4.5]decanyl, Homopiperazinyl, Quinuclidyl, Indolyl (e.g., Indole-2-onyl), Isoindolin-1-onyl, Indolinyl, Iso Indolyl, isoindlinyl, azaindolyl, pyrrolopyridyl (e.g., 1H-pyrrolo[2,3-b]pyridyl), indazolyl, indolidinyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazole-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithinyl, benzoxathiini L, benzothiadinyl, benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl (e.g., 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl), azabenzimidazolyl, imidazopyridyl (e.g., 1H-imidazo[4,5-b]pyridyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, 3,Examples include, but are not limited to, 4-dihydroisoquinoline-1(2H)-onyl, quinolidinyl, quinoxalinyl, quinazolinyl, sinnolinyl, phthalazinyl, naphthylidinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiadinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxynyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, tetrahydropyrimidine-2(1H)-one, and tetrahydroquinolinyl groups. Typical non-aromatic heterocyclyl groups do not include condensed ring species containing condensed aromatic groups. Examples of non-aromatic heterocyclyl groups include azilidinyl, azetidinyl, azepanil, pyrrolidyl, imidazolidinyl (e.g., imidazolidine-4-onyl or imidazolidine-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranil, piperidyl, piperazinyl (e.g., piperazine-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranil (e.g., tetrahydro-2H-pyranil), tetrahydrothiopyranil, oxathianil, dithianil, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidine-2(1H)-one. Typical substituted heterocyclyl groups are pyridyl or morpholinyl groups that are monosubstituted or two or more times, and are disubstituted, trisubstituted, tetrasubstituted, pentasubstituted, hexasubstituted, or disubstituted by various substituents, such as those listed below, but are not limited to these.

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

[0037] As used herein and unless otherwise specified, the “aralkyl” group is a radical of the formula :-alkyl-aryl, where alkyl and aryl are as defined above. A substituted aralkyl group may be substituted in the alkyl moiety, the aryl moiety, or both the alkyl and aryl moieties of the group. Typical aralkyl groups include, but are not limited to, the benzyl and phenethyl groups, as well as aralkyl groups in which the aryl group is condensed with a cycloalkyl group, such as indan-4-ylethyl.

[0038] Unless otherwise specified in this specification, a “heterocyclylalkyl” group is a radical of the formula:-alkyl-heterocyclyl, where alkyl and heterocyclyl are defined above. A “heteroarylalkyl” group is a radical of the formula:-alkyl-heteroaryl, where alkyl and heteroaryl are defined above. A “heterocycloalkylalkyl” group is a radical of the formula:-alkyl-heterocycloalkyl, where alkyl and heterocycloalkyl are defined above. A substituted heterocyclylalkyl group may be substituted in the alkyl portion, the heterocyclyl portion, or both the alkyl and heterocyclyl portions of the group. Representative heterocyclylalkyl groups include, but are not limited to, morpholine-4-ylethyl, morpholine-4-ylpropyl, furan-2-ylmethyl, furan-3-ylmethyl, pyridine-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indole-2-ylpropyl.

[0039] As used herein and unless otherwise specified, “halogen” means fluorine, chlorine, bromine, or iodine.

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

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

[0042] As used herein and unless otherwise specified, the “alkoxyalkyl” group is -(alkyl)-O-(alkyl), where alkyl is as defined above.

[0043] As used herein and unless otherwise specified, the “cycloalkyloxy” group is -O-(cycloalkyl), and cycloalkyl is as defined above.

[0044] As used herein and unless otherwise specified, the “aryloxy” group is -O-(aryl), and aryl is as defined above.

[0045] Unless otherwise specified in this specification, a "heterocyclyloxy" group is -O-(heterocyclyl), and a heterocyclyl is defined above. A "heteroaryloxy" group is -O-(heteroaryl), and a heteroaryl is defined above. A "heterocycloalkyloxy" group is -O-(heterocycloalkyl), and a heterocycloalkyl is defined above.

[0046] As used herein and unless otherwise specified, the "amino" group is defined as -NH2, -NH(R # ) or -N(R # )2 radicals, each R # These are independently alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl (e.g., heteroaryl or heterocycloalkyl) or heterocyclylalkyl (e.g., heteroarylalkyl or heterocycloalkylalkyl) groups as defined above, each independently being substituted or unsubstituted.

[0047] In one embodiment, the "amino" group is an "alkylamino" group which is a radical of the formula: -NH-alkyl or -N(alkyl)2, where each alkyl is independently defined above. The terms "cycloalkylamino," "arylamino," "heterocyclylamino," "heteroarylamino," and "heterocycloalkylamino" reflect the above description of "alkylamino" when the term "alkyl" is substituted with "cycloalkyl," "aryl," "heterocyclyl," "heteroaryl," "heterocycloalkyl," etc.

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

[0049] As used herein and unless otherwise specified, the “acyl” group is defined by the formula: -C(O)(R # ) or -C(O)H radical, R # The "formyl" group is defined above. The "formyl" group is a radical with the formula: -C(O)H.

[0050] As used herein and unless otherwise specified, the “amide” group is defined by the 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 # )-C(O)-(R # ) is a radical, and each R # It is defined independently as described above.

[0051] In one embodiment, the "amide" group is represented by the formula: -C(O)-NH2, -C(O)-NH(R # ), -C(O)-N(R # )2 is the "aminocarbonyl" group, and each R # It is defined independently as described above.

[0052] In one embodiment, the "amide" group is represented by the formula: -NH-C(O)H, -NH-C(O)-(R # ), -N(R # )-C(O)H or -N(R # )-C(O)-(R # The radical is the "acylamino" group, and each R # It is defined independently as described above.

[0053] As used herein and unless otherwise specified, the "sulfonylamino" group is defined by the formula: -NHSO2(R # ) or -N(R # )SO2(R # ) is a radical, and each R # This is defined above.

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

[0055] In one embodiment, the “ester” group is an “alkoxycarbonyl” group, which is a radical of the formula:-C(O)-O-(alkyl), where alkyl is defined above. The terms “cycloalkyloxycarbonyl,” “aryloxycarbonyl,” “heterocyclyloxycarbonyl,” “heteroaryloxycarbonyl,” and “heterocycloalkyloxycarbonyl” reflect the above description of “alkoxycarbonyl” when the term “alkoxy” is substituted with “cycloalkyloxy,” “aryloxy,” “heterocyclyloxy,” “heteroaryloxy,” “heterocycloalkyloxy,” etc.

[0056] As used herein and unless otherwise specified, the “carbamate” group is defined by the formulas: -OC(O)-NH2, -OC(O)-NH(R # ), -OC(O)-N(R #)2,-NH-C(O)-O-(R # ) or -N(R # )-C(O)-O-(R # ) is a radical, and each R # It is defined independently as described above.

[0057] As used herein and unless otherwise specified, the “urea” group has the 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 radicals, each R # It is defined independently as described above.

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

[0059] As used herein and unless otherwise specified, the "sulfonyl" group is defined by the formula: -S(O)2R # It is a radical of R # This is defined above.

[0060] As used herein and unless otherwise specified, the "aminosulfonyl" group has the formula: -SO2NH2, -SO2NH(R # ) or -SO2N(R # )2 radicals, each R # It is defined independently as described above.

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

[0062] As used herein, the term “heterocyclic compound” includes the compounds of formula (I), formula (II), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), and formula (IVc), as well as further embodiments of the compounds of formula (I), formula (II), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), and formula (IVc) provided herein. For example, the term “heterocyclic compound” includes the compounds of formula (I), formula (II), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), formula (IVa), formula (IVb), and formula (IVc), and the deuterated compounds of Tables 1, 2, 3, 4, and 5. In one embodiment, the “heterocyclic compound” is a compound listed in Table 1, Table 2, Table 3, Table 4, or Table 5. In certain embodiments, the term “heterocyclic compound” includes pharmaceutically acceptable salts, tautomers, isotopologs, and / or stereoisomers of the heterocyclic compounds provided herein.

[0063] As used herein, the term “pharmaceutically acceptable salt” refers to a salt prepared from a pharmaceutically acceptable, non-toxic acid or base, including inorganic acids and bases, and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of the compounds of formulas (I), (II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), (IVa), (IVb), (IVc), Table 1, Table 2, Table 3, Table 4, or Table 5 include, but are not limited to, metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine), and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethensulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucoic 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 and mesylate salts. Other examples are well known in the art, e.g., Remington's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th See eds., Mack Publishing, Easton PA (1995).

[0064] Unless otherwise stated herein, the terms “stereoisomer” or “stereoisomerically pure” mean one stereoisomer of a heterocyclic compound that is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure compound having one chiral center will substantially be free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers will substantially be free of other diastereomers of the compound. A typical stereoisomerically pure compound contains about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomer of the compound, or about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomer of the compound, or about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomer of the compound, or about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomer of the compound. Heterocyclic compounds may contain chiral centers and may exist as racemates, individual enantiomers or diastereomers, or mixtures thereof. All such isomeric forms, including mixtures thereof, are included within the scope of the embodiments disclosed herein.

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

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

[0067] "Tautomers" refer to isomeric forms of a compound that are in equilibrium with each other. The concentration of each isomer depends on the environment in which the compound is found, and may differ depending on whether the compound is a solid, an organic solution, or an aqueous solution. For example, in an aqueous solution, pyrazole may exhibit the following isomeric forms called tautomers. [ka]

[0068] As will be readily apparent to those skilled in the art, various types of functional groups and other structures can exhibit tautomerism, and all tautomers of the compounds of formulas (I), (II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), (IVa), (IVb), and (IVc) are included within the scope of the present invention.

[0069] It should also be noted that heterocyclic compounds can contain unnatural proportions of atomic isotopes in at least one of their atoms. For example, a compound may contain tritium ( 3 H), Iodine-125( 125 I), Sulfur-35( 35 S) or carbon-14 ( 14 It can be radiolabeled with radioactive isotopes such as C, or carbon-13 ( 13 C) or Nitrogen-15 15 Isotope enrichment can be achieved using N), etc. As used herein, “isotopologs” are isotope-enriched compounds. The term “isotopologs” refers to atoms that have an isotope composition other than the natural isotope composition of that atom. “Isotope enrichment” can also refer to compounds that contain at least one atom that has an isotope composition other than the natural isotope composition of that atom. The term “isotopologs” refers to the amount of each isotope present for a given atom. Radiolabeled and isotope-enriched compounds are useful as therapeutic agents, e.g., cancer and inflammatory drugs, research reagents, e.g., binding assay reagents and diagnostic agents, e.g., in vivo contrast agents. All isotope variations of heterocyclic compounds described herein, whether radioactive or not, are intended to be included within the scope of the embodiments provided herein. In some embodiments, isotopologs of heterocyclic compounds are provided, for example, isotopologs are carbon-13 or nitrogen-15 enriched heterocyclic compounds. As used herein, “deuterated” refers to at least one hydrogen (H) being deuterized (D or 2 This refers to compounds substituted with (indicated by H), meaning the compound is concentrated with deuterium at at least one position. Note that if there is a discrepancy between the depicted structure and the name of that structure, the depicted structure takes precedence.

[0070] As used herein, “inhibit” and “inhibit” mean a relative reduction in a particular response of a specified activity (e.g., insect motility) in the presence of a heterocyclic compound. Inhibition of insect motility, such as that of Onchocerca volvulus, Brugia malayi, and / or Brugia timori, can be determined by the assays described herein.

[0071] As used herein, “to treat” means the overall or partial reduction of one or more of a disorder, disease or condition, or symptoms associated with a disorder, disease or condition, or the slowing or cessation of the further progression or worsening of those symptoms, or the reduction or eradication of the cause of the disorder, disease or condition itself. In one embodiment, the disorder, disorder or condition is a helminthic infection.

[0072] As used herein, “prevent” means a method of delaying and / or preventing, in whole or in part, the onset, recurrence or spread of a disorder, disease or condition; preventing a subject from acquiring a disorder, disease or condition; or reducing the risk of a subject acquiring a disorder, disease or condition. In one embodiment, the disorder, disorder or condition is a helminthic infection.

[0073] In relation to heterocyclic compounds, the term “effective amount” means an amount that can treat or prevent a disorder, disease, condition, or symptoms thereof as disclosed herein. In one embodiment, the disorder, disorder, or condition is a helminth infection.

[0074] The terms “subject” or “patient” include humans and other primates, and domesticated and semi-domesticated animals, including but not limited to poultry, bees, cows, sheep, cattle, goats, pigs, horses, dogs, cats, rabbits, rats, and mice. The term “poultry” includes all types of domesticated birds, including but not limited to chickens, turkeys, ducks, geese, flightless birds, and game birds. In certain embodiments, the subject is a human. In certain embodiments, the subject is a dog. In certain embodiments, the subject is a cat. In certain embodiments, the subject is livestock. In certain embodiments, the subject is a cow. In certain embodiments, the subject is a sheep. In other embodiments, the subject is a goat.

[0075] The terms “combined” or “combined” administration include administration as a mixture, simultaneous administration using separate formulations, and sequential administration in any order.

[0076] As used herein, the terms “helminthic infection” or “helminth infection” refer to infections caused by parasites. Helminthic infections, known as “helminthic diseases” (plural “helminthic diseases”), are any macroparasitic diseases of humans and other animals in which a part of the body is infected with a parasite known as a helminth. There are many species of these parasites, broadly classified into tapeworms, trematodes, and roundworms.

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

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

[0079] As used herein, the terms “microfilaria” or “mf” refer to the initial stage in the life cycle of a particular parasitic nematode. Microfilaria is considered to be the first larval stage, also referred to as L1. The terms “microfilaria,” “mf,” or “L1” are used interchangeably and / or as substitutes.

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

[0081] Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this application pertains.

[0082] Surprisingly, the compounds disclosed herein have been found to be effective in treating helminth infections, such as filarial infections. In vitro and in vivo results demonstrated that the compounds disclosed herein are effective against filarial nematodes. Surprisingly, in some embodiments, the compounds disclosed herein showed different activity between adult and juvenile parasitic nematodes. In some such embodiments, the compounds disclosed herein are selectively effective against adult filarial nematodes (also called macrofilariatic activity). In other embodiments, the compounds disclosed herein are selectively effective against juvenile filarial nematodes (also called microfilariatic activity). Therefore, the compounds disclosed herein may be potent antifilarial agents.

[0083] compound The following equation (I): [ka] Compounds having and pharmaceutically acceptable salts, tautomers, isotopologs and stereoisomers thereof are provided herein, wherein, R 1 These are isoquinoryl; pyrrolopyridyl; 2-pyrimidyl or 2-pyridyl, where 2-pyridyl is a halogen, CN, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 3~7 Cycloalkyl, substituted, or unsubstituted C 6~10 Aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, -OR 5 -SR, -CONR 6 2, -CON(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), -NRCO(C 1~3 Alkyl), -CO (substituted or unsubstituted 3-6 member heterocyclyl), -SO2NR2 and SO2R 5 Substituted with one or more substituents independently selected from; R 2is 2-pyridyl substituted with one or more substituents independently selected from 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 2-pyrimidyl or halogen, substituted or unsubstituted C 1~4 alkyl, substituted or unsubstituted C 6~10 aryl, -OR 5 -SR, -CONR2 and -SO2R 5 or two atoms together with the carbon to which they are attached form a substituted or unsubstituted 5- or 6-membered heterocyclyl; R 3 is H, -CN, substituted or unsubstituted C 1~4 alkyl, (C 1~3 alkyl)O(C 1~3 alkyl)(substituted or unsubstituted C 3~7 cycloalkyl), -(C 1~3 alkyl)OR, (C 1~3 alkyl)(substituted or unsubstituted 3- to 6-membered heterocyclyl), -C(O)(substituted or unsubstituted 3- to 10-membered heterocyclyl), -C(O)OR, substituted or unsubstituted C 6~10 aryl, (C 1~3 alkyl)NR 6 2, -(C 1~3 alkyl)N(C 1~3 alkyl)(substituted or unsubstituted C 3~7 cycloalkyl), CONR 6 2 or -C(O)N(C 1~3 alkyl)NR2; R 4 is H, or substituted or unsubstituted C 1~3 alkyl, or substituted or unsubstituted -(C 1~3 alkyl)C 6~10 aryl; R 5 is H, substituted or unsubstituted C 1~5 alkyl, substituted or unsubstituted C 3~7 cycloalkyl or substituted or unsubstituted 3- to 6-membered heterocyclyl; each R 6 is H, substituted or unsubstituted C 1~5 alkyl, substituted or unsubstituted C 3~6Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl and (C 1~3 Independently selected from alkyl (substituted or unsubstituted 3-6 member heterocyclyl); and Each R is H and substituted or unsubstituted C 1~4 Although selected independently of alkyl, The compound has a structure [ka] The condition is that it is not 4-methyl-N-[4-(4-methyl-2-pyridinyl)-2-thiazolyl]-2-pyridinamine or N-(5-chloropyridin-2-yl)-4-(pyrimidine-2-yl)thiazole-2-amine.

[0084] In one embodiment of the compound of formula (I), R 1 These are isoquinoryl, 1H-pyrrolo[3,2-c]pyridyl, or 1H-pyrrolo[2,3-c]pyridyl.

[0085] In one embodiment of the compound of formula (I), R 1 C is 2-pyrimidyl, and 2-pyrimidyl is either unsubstituted or substituted or unsubstituted. 1~4 Alkyl, substituted, or unsubstituted C 3~7 Cycloalkyl, substituted, or unsubstituted C 6~10 Aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, -OR 5 ,-CONR 6 2, -NRCO(C 1~3 It is substituted with one or more substituents independently selected from alkyl and -CO (substituted or unsubstituted 3-6 member heterocyclyl).

[0086] In one embodiment of the compound of formula (I), R 1 2-pyrimidyl is either unsubstituted or substituted or unsubstituted -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, CF3, cyclopropyl, cyclobutyl, cyclopentyl, -OR 5substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl, -CONR 6 2, -CON(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), -NRCO(C 1~3 It is substituted with one or more substituents independently selected from alkyl, -CO (substituted or unsubstituted 3-6 member heterocyclyl).

[0087] In one embodiment of the compound of formula (I), R 1 2-pyrimidyl is unsubstituted, or substituted or unsubstituted -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, CF3, cyclopropyl, -OR 5 substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl, -CONR 6 It is substituted with one or more substituents independently selected from 2 and -NCH3COCH3.

[0088] In one embodiment of the compound of formula (I), R 1 2-pyridyl is a halogen, -CN, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 3~7 Cycloalkyl, substituted, or unsubstituted C 6~10 Aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, -OR 5 -SR, -CONR 6 2, -CON(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), -NRCO(C 1~3 Alkyl), -CO (substituted or unsubstituted 3-6 member heterocyclyl), -SO2NR2 and SO2R 5 It is substituted with one or more substituents independently selected from the original molecule.

[0089] In some embodiments of the compound of formula (I), R 1 F, Br, Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, CF3, cyclopropyl, cyclobutyl, cyclopentyl, -OR 5 -SR, substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted pyrrolidinonyl, -CONR 6 2, -CON(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), -NRCO(C 1~3 Alkyl), -CO (substituted or unsubstituted 3-6 member heterocyclyl), -SO2NR2 and -SO2R 5 It is 2-pyridyl substituted with one or more substituents independently selected from the above.

[0090] In some embodiments, R 1 is one or more OR 5 It is 2-pyridyl substituted with R. In some such embodiments, R 5 is H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, tetrahydrofuranyl, tetrahydropyranyl, or 1-methylpiperidyl. In some such embodiments, R 5 is H, -CH3, -CH(CH3)2, or tetrahydropyranyl. In some such embodiments, R 5 is H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, piperidyl, 1-methylpiperidyl, tetrahydrofuranil, or tetrahydropyranil. In some such embodiments, R 5 is H or -CH3. In some such embodiments, R 5 is -CH3. In some embodiments, R 5 is -CH(CH3)2. In some such embodiments, R 5is tetrahydropyranyl. In some such embodiments, R 5 It is 1-methylpiperidyl.

[0091] In some embodiments of the compound of formula (I), R 1 is one or more -CONR 6 It is 2-pyridyl substituted with 2. In some such embodiments, each R 6 This is independently a substituted or unsubstituted C selected from H, -CH3, -CH2CH3, -CH2CH2CH3, and -CH(CH3)2. 1~5 Alkyl; substituted or unsubstituted C selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl 3~6 The alkyl and cycloalkyl groups are optionally substituted with one or more substituents independently selected from OH, OCH3, and F. In some embodiments, each R 6 These are independently substituted or unsubstituted C selected from H, -CH(CH3)2. 1~5 Alkyl; substituted or unsubstituted C selected from cyclopentyl and cyclohexyl. 3~6 The molecule is cycloalkyl, and the alkyl and cycloalkyl groups are optionally substituted with one or more substituents independently selected from OH, OCH3, and F.

[0092] In some embodiments, R 1F, Br, Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, CF3, cyclopropyl, cyclobutyl, cyclopentyl, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -SCH3, substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted pyrrolidinonyl, -CONH2, -CONHCH3, -CON(CH 3)2,-CONHCH2CH3,-CON(CH2CH3)2,-CONHCH2CH2CH3,-CONHCH(CH3)2,-CONHCH2CH2OH,-CONHCH2CH2OCH3,-CONHCH(CH3)CH2OH,-CONHCH2CF3,-CONHCH2CH2-pyrrolidyl,-CONH(cyclopropyl),-CONH(cyclobutyl),-CONH(cyclopentyl),-CONH(cyclohexyl),-CO(azetidyl),-CO(piperidyl),-CO(piperazinyl),-CO(morpholinyl),-CONH(CH2)-cyclopropyl,-N(CH3)COCH 3、 2-pyridyls are substituted with one or more substituents independently selected from -SO2N(CH3)2 and -SO2(aziridinyl), and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidyl, piperidyl, and piperazinyl are optionally fluorinated.

[0093] In some embodiments, R 1F, Br, Cl, -CN, -CH3, -CH2CH3, -CH(CH3)2, CF3, cyclopropyl, cyclobutyl, cyclopentyl, -OH, -OCH3, -OCH(CH3)2, -O-tetrahydropyranyl, -SCH3, substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted pyrrolidino -CONH2, -CONHCH(CH3)2, -CONHCH2CH2OH, -CONHCH2CH2OCH3, -CONHCH(CH3)CH2OH, -CONHCH2CF3, -CONHCH2CH2-pyrrolidyl, -CONH(cyclopentyl), -CONH(cyclohexyl), -CO(azetidyl), CO(piperidyl), -CO(piperazinyl), -CO(morpholinyl), -N(CH3)COCH 3、 2-pyridyls are substituted with one or more substituents independently selected from -SO2N(CH3)2 and -SO2(aziridinyl), and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidyl, piperidyl, and piperazinyl are optionally fluorinated.

[0094] In some embodiments, R 1F, Br, Cl, -CN, -CH3, -CH2CH3, -CH(CH3)2, CF3, cyclopropyl, cyclopentyl, -OH, -OCH3, -OCH(CH3)2, -O-tetrahydropyranyl, -SCH3, phenyl; phenyl(COOH); 1-methylpyrazolyl; dihydropyranyl; 1-methyl-piperidyl; piperidyl substituted with COOH, -CONHCH3 or CONHCH2CF3; 1-methyl-piperazinyl; piperidyl substituted with -COC(CH3)2OH and CO-cyclopropyl-CF3; -CONH2, -CON(CH3)2, - 2-pyridyls are substituted with one or more substituents independently selected from CONHCH(CH3)2, -CONHCH2CH2OH, -CONHCH2CH2OCH3, -CONHCH(CH3)CH2OH, -CONHCH2CF3, -CONHCH2CH2-pyrrolidyl, -CONH(cyclopentyl), -CONH(difluorocyclohexyl), -CO(difluoroazetidyl), -CO(difluoropiperidyl), -CO(piperazinyl), -CO(morpholinyl), -N(CH3)COCH3, -SO2N(CH3)2, and -SO2(aziridinyl).

[0095] In some embodiments of the compound of formula (I), R 2 F, Cl, -CN, CH3, -CH2CH3, -CF3, -CHF2, substituted or unsubstituted phenyl, -OR 5 -SR, -SO2R 5 And 2-pyridyl substituted with one or more substituents independently selected from -CONR2. In some embodiments, R 22-pyridyl is substituted with one or more substituents independently selected from F, Cl, -CN, -CH3, -CH2CH3, -CF3, -CHF2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CF3, -O-cyclopropyl, -O-oxetanyl, -O-(1-methylazetidinyl), -O-(1-methylpiperidyl), -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -SCH3, -CONH2, -CONHCH3, -CON(CH3)2, -CONHCH2CH3, -CON(CH2CH3)2, -SO2CH3 and substituted or unsubstituted phenyl. In some such embodiments, R 2 2-pyridyl is substituted with one or more substituents independently selected from F, Cl, -CN, CH3, -CH2CH3, -CF3, -CHF2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2CF3, -O-cyclopropyl, -O-oxetanyl, -O-(1-methylazetidinyl), -O-(1-methylpiperidyl), -O-tetrahydropyranyl, -SCH3, -CONH2, -CON(CH3)2, -SO2CH3 and substituted or unsubstituted phenyl. In some such embodiments, R 2 It is substituted with one or more substituents independently selected from F, Cl, -CN, CH3, -CH2CH3, -CF3, -CHF2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2CF3, -O-cyclopropyl, -O-oxetanyl, -O-(1-methyl-azetidinyl), -O-(1-methyl-piperidyl), -O-tetrahydropyranyl, -SCH3, -CONH2, -CON(CH3)2, -SO2CH3, phenyl, and phenyl substituted with cyclopropyl (COOH).

[0096] In some embodiments of the compound of formula (I), R 2 R is 2-pyridyl, and the two atoms, together with the carbon to which they are bonded, form a substituted or unsubstituted 5-6 membered heterocycline. In some such embodiments, R 2These are substituted or unsubstituted 2,3-dihydrofl[2,3-c]pyridyl, 2,3-dihydro-1H-pyrrolo[2,3-c]pyridyl, or 1,3-dihydro-2H-pyrrolo[2,3-c]pyridyl-2-one.

[0097] In some embodiments of the compound of formula (I), R 2 These are 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl or 2-pyrimidyl.

[0098] In some embodiments of the compound of formula (I), R 3 H, -CN, -CH3, -CH2CH3, -CH(CH3)3, -CH2OH, -CH2CH2OH, -CH2OCH2-cyclopropyl, -CH2OCH2-cyclobutyl, -CH2CH2O-cyclobutyl, -CH2CH2OCH2-cyclopropyl, -CH2OCH2CH2-cyclopropyl, -CH2N(CH3)2, -CH2-azetidyl, -CH2-piperidyl, -CH2(dimethylmorpholinyl), -CH2(dimethylpiperazyl), -CH2-pyrrolidyl, -CH2(mo -COOH, -CO(dimethylmorpholinyl), -CO(morpholinyl), -CO(1,3-dioxolane-piperidyl), -CO(piperidyl), -CO(pyrrolidyl), -CO(1-methyl-piperazyl), -CO(octahydropyrrolo[1,2-a]pyradyl), -CONHCH2-cyclohexyl, -CONHCH2-tetrahydropyranyl, -CONHCH2-cyclopentyl, -CONH(CH2)2N(CH3)2, -CON(CH3)2, or phenyl. In some embodiments of the compound of formula (I), R 3 The compound is H, -CH3, -CH2OH, -CH2OCH2-cyclopropyl, -CH2-azetidyl, -CH2-piperidyl, or phenyl.

[0099] In some embodiments of the compound of formula (I), R 4 is H, -CH3, or -CH2-phenyl.

[0100] In some embodiments of the compound of formula (I), R 1However, F, Br, Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, CF3, cyclopropyl, cyclobutyl, cyclopentyl, -OR 5 -SR, substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted pyrrolidinonyl, -CONR 6 2, -CON(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), -NRCO(C 1~3 Alkyl), -CO (substituted or unsubstituted 3-6 member heterocyclyl), -SO2NR2 and -SO2R 5 If R is a 2-pyridyl substituted with one or more substituents independently selected from, 2 F, Cl, -CN, -CH3, -CH2CH3, -CF3, -CHF2, substituted or unsubstituted phenyl, -OR 5 -SR, -CONR2 and -SO2R 5 It is 2-pyridyl substituted with one or more substituents independently selected from. In some other such embodiments, R 3H, -CN, -CH3, -CH2CH3, -CH(CH3)3, -CH2OH, -CH2CH2OH, -CH2OCH2-cyclopropyl, -CH2OCH2-cyclobutyl, -CH2CH2O-cyclobutyl, -CH2CH2OCH2-cyclopropyl, -CH2OCH2CH2-cyclopropyl, -CH2N(CH3)2, -CH2-azetidyl, -CH2-piperidyl, -CH2(dimethylmorpholinyl), -CH2(dimethylpiperazyl), -CH2-pyrrolidyl, -CH2(mo -COOH, -CO(dimethylmorpholinyl), -CO(morpholinyl), -CO(1,3-dioxolane-piperidyl), -CO(piperidyl), -CO(pyrrolidyl), -CO(1-methyl-piperazyl), -CO(octahydropyrrolo[1,2-a]pyradyl), -CONHCH2-cyclohexyl, -CONHCH2-tetrahydropyranyl, -CONHCH2-cyclopentyl, -CONH(CH2)2N(CH3)2, -CON(CH3)2, or phenyl. In some other such embodiments, R 4 is H, -CH3, or CH2-phenyl. In some other such embodiments, R 4 In some other such embodiments, R 4 is -CH3. In some other such embodiments, R 4 It is -CH2-phenyl.

[0101] In some embodiments of the compound of formula (I), R 1However, F, Br, Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, CF3, cyclopropyl, cyclobutyl, cyclopentyl, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -SCH3, substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted pyrrolidinonyl, -CONH2, -CONHCH3, -CON(CH 3)2,-CONHCH2CH3,-CON(CH2CH3)2,-CONHCH2CH2CH3,-CONHCH(CH3)2,-CONHCH2CH2OH,-CONHCH2CH2OCH3,-CONHCH(CH3)CH2OH,-CONHCH2CF3,-CONHCH2CH2-pyrrolidyl,-CONH(cyclopropyl),-CONH(cyclobutyl),-CONH(cyclopentyl),-CONH(cyclohexyl),-CO(azetidyl),-CO(piperidyl),-CO(piperazinyl),-CO(morpholinyl),-CONH(CH2)-cyclopropyl,-N(CH3)COCH 3、 If R is substituted with one or more substituents independently selected from -SO2N(CH3)2 and -SO2(aziridinyl), then R 22-pyridyl is substituted with one or more substituents independently selected from F, Cl, -CN, -CH3, -CH2CH3, -CF3, -CHF2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CF3, -O-cyclopropyl, -O-oxetanyl, -O-(1-methylazetidinyl), -O-(1-methylpiperidyl), -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -SCH3, -CONH2, -CONHCH3, -CON(CH3)2, -CONHCH2CH3, -CON(CH2CH3)2, -SO2CH3 and substituted or unsubstituted phenyl. In some such embodiments, R 3 is H, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2OCH2-cyclopropyl, -CH2CH2OCH2-cyclopropyl, -CH2OCH2CH2-cyclopropyl, -CH2-azetidyl, -CH2-piperidyl, or phenyl. In some other such embodiments, R 4 is H, -CH3, or CH2-phenyl. In some other such embodiments, R 4 In some other such embodiments, R 4 is -CH3. In some other such embodiments, R 4 It is -CH2-phenyl.

[0102] In some embodiments of the compound of formula (I), R 1However, F, Br, Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, CF3, cyclopropyl, cyclopentyl, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -O-tetrahydropyranyl, -SCH3, phenyl, phenyl(COOH); pyrrolidinonyl, 1-methylpyrazolyl; dihydropyranyl; 1-methyl-piperidyl; piperidyl substituted with COOH, -CONHCH3 or CONHCH2CF3; 1-methyl-piperazinyl; piperadinyl substituted with COC(CH3)2OH or CO-cyclopropyl-CF3; If R is a 2-pyridyl substituted with one or more substituents independently selected from -CONH2, -CONHCH(CH3)2, -CONHCH2CH2OH, -CONHCH2CH2OCH3, -CONHCH(CH3)CH2OH, -CONHCH2CF3, -CONHCH2CH2-pyrrolidyl, -CONH(cyclopentyl), -CONH(difluorocyclohexyl), -NCH3COCH3, -SO2N(CH3)2, -SO2(aziridinyl), -CO(difluoroazetidyl), CO(difluoropiperidyl), -CO(piperazinyl), and -CO(morpholinyl), 2 2-pyridyl is substituted with one or more substituents independently selected from F, Cl, -CN, -CH3, -CH2CH3, -CF3, -CHF2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2CF3, -O-cyclopropyl, -O-oxetanyl, -O-(1-methylazetidinyl), -O-(1-methylpiperidyl), -O-tetrahydropyranyl, -SCH3, -CONH2, -CON(CH3)2, -SO2CH3, phenyl, and phenyl substituted with cyclopropyl (COOH); R 3 is H, -CH3, -CH2OH, -CH2OCH2-cyclopropyl, -CH2-azetidyl, -CH2-piperidyl, or phenyl; R 4 is H, -CH3, or CH2-phenyl. In some other such embodiments, R 4 In some other such embodiments, R 4 is -CH3. In some other such embodiments, R4 It is -CH2-phenyl.

[0103] In some embodiments of the compound of formula (I), R 1 However, F, Br, Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, CF3, cyclopropyl, cyclopentyl, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -O-tetrahydropyranyl, -SCH3, phenyl, phenyl(COOH); pyrrolidinonyl, 1-methylpyrazolyl; dihydropyranyl; 1-methyl-piperidyl; piperidyl substituted with COOH, -CONHCH3 or CONHCH2CF3; 1-methyl-piperazinyl; piperadinyl substituted with COC(CH3)2OH or CO-cyclopropyl-CF3; If R is a 2-pyridyl substituted with one or more substituents independently selected from -CONH2, -CONHCH(CH3)2, -CONHCH2CH2OH, -CONHCH2CH2OCH3, -CONHCH(CH3)CH2OH, -CONHCH2CF3, -CONHCH2CH2-pyrrolidyl, -CONH(cyclopentyl), -CONH(difluorocyclohexyl), -NCH3COCH3, -SO2N(CH3)2, -SO2(aziridinyl), -CO(difluoroazetidyl), CO(difluoropiperidyl), -CO(piperazinyl), and -CO(morpholinyl), 2 R is 2-pyridyl, and the two atoms, together with the carbon to which they are bonded, form a substituted or unsubstituted 5-6 membered heterocycline. In some such embodiments, R 2 is substituted or unsubstituted 2,3-dihydrofl[2,3-c]pyridyl, 2,3-dihydro-1H-pyrrolo[2,3-c]pyridyl, or 1,3-dihydro-2H-pyrrolo[2,3-c]pyridyl-2-one. In some such embodiments, R 2These are 2,2-dimethyl-2,3-dihydrofl[2,3-c]pyridyl, 1-methyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridyl, 1-methyl-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-c]pyridyl-2-one or 1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridyl; R 3 is H, -CH3, -CH2OH, -CH2OCH2-cyclopropyl, -CH2-azetidyl, -CH2-piperidyl, or phenyl; R 4 is H, -CH3, or CH2-phenyl. In some other such embodiments, R 4 In some other such embodiments, R 4 is -CH3. In some other such embodiments, R 4 It is -CH2-phenyl.

[0104] In some embodiments of the compound of formula (I), R 1 However, if R is a 2-pyridyl substituted with one or more substituents independently selected from -CH3, -CF3, and -NCH3COCH3, 2 These are 2,2-dimethyl-2,3-dihydrofl[2,3-c]pyridyl, 1-methyl-2,2-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridyl, 1-methyl-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-c]pyridyl-2-one or 1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridyl; R 3 H is; R 4 H is H.

[0105] In some embodiments of the compound of formula (I), R 1However, F, Br, Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, CF3, cyclopropyl, cyclopentyl, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -O-tetrahydropyranyl, -SCH3, phenyl, phenyl(COOH); pyrrolidinonyl, 1-methylpyrazolyl; dihydropyranyl; 1-methyl-piperidyl; piperidyl substituted with COOH, -CONHCH3 or CONHCH2CF3; 1-methyl-piperazinyl; piperadinyl substituted with COC(CH3)2OH or CO-cyclopropyl-CF3; - If R is a 2-pyridyl substituted with one or more substituents independently selected from CONH2, -CONHCH(CH3)2, -CONHCH2CH2OH, -CONHCH2CH2OCH3, -CONHCH(CH3)CH2OH, -CONHCH2CF3, -CONHCH2CH2-pyrrolidyl, -CONH(cyclopentyl), -CONH(difluorocyclohexyl), -NCH3COCH3, -SO2N(CH3)2, -SO2(aziridinyl), -CO(difluoroazetidyl), -CO(difluoropiperidyl), -CO(piperazinyl), and -CO(morpholinyl), 2 is 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl. In some such embodiments, R 3 is H, -CH3, -CH2OH, -CH2OCH2-cyclopropyl, -CH2-azetidyl, -CH2-piperidyl, or phenyl; R 4 is H, -CH3, or CH2-phenyl. In some other such embodiments, R 4 In some other such embodiments, R 4 is -CH3. In some other such embodiments, R 4 It is -CH2-phenyl.

[0106] In some embodiments of the compound of formula (I), R 1 However, if R is a 2-pyridyl substituted with one or more substituents independently selected from -CF3 and -NCH3COCH3, 2It is 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl; R 3 H is; R 4 H is H.

[0107] In some embodiments of the compound of formula (I), R 1 However, F, Br, Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, CF3, cyclopropyl, cyclopentyl, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -O-tetrahydropyranyl, -SCH3, phenyl, phenyl(COOH); pyrrolidinonyl, 1-methylpyrazolyl; dihydropyranyl; 1-methyl-piperidyl; piperidyl substituted with COOH, -CONHCH3 or CONHCH2CF3; 1-methyl-piperazinyl; piperadinyl substituted with COC(CH3)2OH or CO-cyclopropyl-CF3; If R is a 2-pyridyl substituted with one or more substituents independently selected from -CONH2, -CONHCH(CH3)2, -CONHCH2CH2OH, -CONHCH2CH2OCH3, -CONHCH(CH3)CH2OH, -CONHCH2CF3, -CONHCH2CH2-pyrrolidyl, -CONH(cyclopentyl), -CONH(difluorocyclohexyl), -NCH3COCH3, -SO2N(CH3)2, -SO2(aziridinyl), -CO(difluoroazetidyl), CO(difluoropiperidyl), -CO(piperazinyl), and -CO(morpholinyl), 2 is 2-pyrimidyl. In some such embodiments, R 3 is H, -CH3, -CH2OH, -CH2OCH2-cyclopropyl, -CH2-azetidyl, -CH2-piperidyl, or phenyl; R 4 is H, -CH3, or CH2-phenyl. In some other such embodiments, R 4 In some other such embodiments, R 4 is -CH3. In some other such embodiments, R 4 is -CH2-phenyl. In some embodiments of the compound of formula (I), R 1However, if it is 2-pyridyl substituted with one or more -CH3 groups, R 2 It is 2-pyrimidyl; R 3 H is; R 4 H is H.

[0108] Further embodiments provided herein include at least one combination of the specific embodiments described above.

[0109] Representative compounds of formula (I) are listed in Table 1.

[0110] The following equation (II): [ka] Compounds having and pharmaceutically acceptable salts, tautomers, isotopologs and stereoisomers thereof are provided herein, wherein, R 1 These are isoquinoryl; pyrrolopyridyl; 2-pyrimidyl or 2-pyridyl, where 2-pyridyl is H, halogen, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 3~7 Cycloalkyl, substituted, or unsubstituted C 6~10 Aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, -OR 5 ,-CONR 6 2, -CON(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), -NRCO(C 1~3 Substituting with one or more substituents independently selected from alkyl and -CO (substituted or unsubstituted 3-6 membered heterocyclyl); R 2 This is H, halogen, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 6~10 Ariel, -OR 5 2-pyridyl substituted with one or more substituents independently selected from -CONR2; R 3 is H, -CN, substituted or unsubstituted C 1~4Alkyl, (C 1~3 Alkyl)O(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), -(C 1~3 (Alkyl) OR, (C 1~3 Alkyl)(substituted or unsubstituted 3-6 member heterocyclyl)-C(O)(substituted or unsubstituted 3-10 member heterocyclyl),-C(O)OR, substituted or unsubstituted C 6~10 Ariel, (C 1~3 Alkyl)NR 6 2, -(C 1~3 Alkyl)N(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), CONR 6 2 or -C(O)N(C 1~3 Alkyl)NR2; R 4 is H or substituted or unsubstituted C 1~3 It is alkyl; R 5 is H, substituted or unsubstituted C 1~5 Alkyl or substituted or unsubstituted 3- to 6-membered heterocyclyl; Each R 6 is H, substituted or unsubstituted C 1~5 Alkyl; substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl and (C 1~3 Independently selected from alkyl (substituted or unsubstituted 3-6 member heterocyclyl); and Each R is H and substituted or unsubstituted C 1~4 Although selected independently of alkyl, R 1 and R 2 If both are 2-pyridyl, then R 1 or R 2 The condition is that one of them is not substituted with H.

[0111] In one embodiment of the compound of formula (II), R 1 It is 2-pyrimidyl.

[0112] In one embodiment of the compound of formula (II), R1 These are isoquinoryl, 1H-pyrrolo[3,2-c]pyridyl, or 1H-pyrrolo[2,3-c]pyridyl.

[0113] In one embodiment of the compound of formula (II), R 1 It is 2-pyridyl, and 2-pyridyl is H, halogen, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 3~7 Cycloalkyl, substituted, or unsubstituted C 6~10 Aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, -OR 5 ,-CONR 6 2, -CON(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), -NRCO(C 1~3 It is substituted with one or more substituents independently selected from alkyl and -CO (substituted or unsubstituted 3-6 membered heterocyclyls).

[0114] In some embodiments of the compound of formula (II), R 1 H, Br, F, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, CF3, cyclopropyl, cyclobutyl, cyclopentyl, -OR 5 , substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl; substituted or unsubstituted pyridadinyl; substituted or unsubstituted pyrazinyl; substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl, -CONR 6 2, -CON(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), -NRCO(C 1~3 It is a 2-pyridyl substituted with one or more substituents independently selected from alkyl and -CO (substituted or unsubstituted 3-6 membered heterocyclyls).

[0115] In some embodiments, R 1 is one or more OR 5It is 2-pyridyl substituted with R. In some such embodiments, R 5 is H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, tetrahydrofuranyl, or tetrahydropyranyl. In some such embodiments, R 5 is H, -CH3, -CH(CH3)2, or tetrahydropyranyl. In some such embodiments, R 5 is H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, piperidyl, 1-methyl-piperidyl, tetrahydrofuranil, or tetrahydropyranil. In some such embodiments, R 5 is H or -CH3. In some such embodiments, R 5 is -CH3. In some embodiments, R 5 is -CH(CH3)2. In some such embodiments, R 5 is tetrahydropyranyl. In some such embodiments, R 5 It is 1-methyl-piperidyl.

[0116] In some embodiments of the compound of formula (II), R 1 is one or more -CONR 6 It is 2-pyridyl substituted with 2. In some such embodiments, each R 6 This is independently a substituted or unsubstituted C selected from H, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. 1~5 Alkyl; substituted or unsubstituted C selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl 3~6 The alkyl and cycloalkyl groups are optionally substituted with one or more substituents independently selected from OH, OCH3, and F. In some embodiments, each R 6 These are independently substituted or unsubstituted C selected from H, CH(CH3)2. 1~5 Alkyl; substituted or unsubstituted C selected from cyclopentyl or cyclohexyl 3~6The molecule is cycloalkyl, and the alkyl and cycloalkyl groups are optionally substituted with one or more substituents independently selected from OH, OCH3, and F.

[0117] In some embodiments, R 1 H, Br, F, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, CF3, cyclopropyl, cyclobutyl, cyclopentyl, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl; substituted or unsubstituted pyridadinyl; substituted or unsubstituted pyrazinyl; substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl, -CONH2, -CONHCH3, -CON(CH3)2, -CONHCH2CH3, -CON(CH2CH3)2, -CONHCH2CH 2-pyridyls are substituted with one or more substituents independently selected from 2CH3, -CONHCH(CH3)2, -CONHCH2CH2OH, -CONHCH2CH2OCH3, -CONHCH(CH3)CH2OH, -CONHCH2CF3, -CONHCH2CH2-pyrrolidyl, -CONH(cyclopropyl), -CONH(cyclobutyl), -CONH(cyclopentyl), -CONH(cyclohexyl), -CONH(CH2)-cyclopropyl, -CO(azetidyl), -CO(piperidyl), -CO(piperazinyl), -CO(morpholinyl), and -NCH3COCH3, wherein cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidyl, piperidyl, and piperazinyl are optionally fluorinated.

[0118] In some embodiments, R 1H, Br, F, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, CF3, cyclobutyl, cyclopentyl, -OH, -OCH3, -OCH(CH3)2, -O-tetrahydropyranyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl; substituted or unsubstituted pyridadinyl; substituted or unsubstituted pyrazinyl; substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl, -CONH2, -CONHCH2CH3, -CONHCH(CH3)2, -CONHCH2CH2OH, -CONHC 2-pyridyls are substituted with one or more substituents independently selected from H2CH2OCH3, -CONHCH(CH3)CH2OH, -CONHCH2CF3, -CONHCH2CH2-pyrrolidyl, -CONH(cyclopropyl), -CONH(cyclopentyl), -CONH(cyclohexyl), -CONH(CH2)-cyclopropyl, -CO(azetidyl), CO(piperidyl), -CO(piperazinyl), -CO(morpholinyl), and -NCH3COCH3, wherein cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidyl, piperidyl, and piperazinyl are optionally fluorinated.

[0119] In some embodiments, R 1This includes H, Br, F, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, CF3, cyclobutyl, cyclopentyl, -OH, -OCH3, -OCH(CH3)2, -O-tetrahydropyranyl, phenyl, phenyl(COOH), phenyl(phenyl), phenyl(CONHCH3), naphthyl; pyridadinyl; pyrazinyl; pyrimidyl; 1-methylpyrazolyl; dihydropyranyl; 1-methyl-piperidyl; piperidyl substituted with COOH, CONHMe or CONHCH2CF3; 1-methyl-piperazinyl; piperidyl substituted with COC(CH3)2OH or CO-cyclopropyl-CF3 2-pyridyls are substituted with one or more substituents independently selected from -CONH2, -CONMe2, -CONHCH2CH3, -CONHCH(CH3)2, -CONHCH2CH2OH, -CONHCH2CH2OCH3, -CONHCH(CH3)CH2OH, -CONHCH2CF3, -CONHCH2CH2-pyrrolidyl, -CONH(cyclopropyl), -CONH(cyclopentyl), -CONH(CH2)-cyclopropyl, -CONH(difluorocyclohexyl), -CO(difluoroazetidyl), CO(difluoropiperidyl), -CO(piperazinyl), -CO(morpholinyl), and -NCH3COCH3.

[0120] In some embodiments of the compound of formula (II), R 2 H, F, methyl, ethyl, substituted or unsubstituted phenyl, -OR 5 And is substituted with one or more substituents independently selected from -CONR2. In some embodiments, R 2 is substituted with one or more substituents independently selected from H, F, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -O-(1-methyl-piperidyl), -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -CONH2, -CONHCH3, -CON(CH3)2, -CONHCH2CH3, -CON(CH2CH3)2 and substituted or unsubstituted phenyl. In some such embodiments, R 2R is substituted with one or more substituents independently selected from H, F, CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -O-(1-methyl-piperidyl), -O-tetrahydropyranyl, -CONH2, -CON(CH3)2, and substituted or unsubstituted phenyl. In some such embodiments, R 2 It is substituted with one or more substituents independently selected from H, F, CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -O-(1-methyl-piperidyl), -O-tetrahydropyranyl, -CONH2, -CON(CH3)2, phenyl, and phenyl substituted with cyclopropyl (COOH).

[0121] In some embodiments of the compound of formula (II), R 3 H, -CN, CH3, -CH2CH3, -CH(CH3)3, -CH2OH, -CH2CH2OH, -CH2OCH2-cyclopropyl, -CH2OCH2-cyclobutyl, -CH2CH2O-cyclobutyl, -CH2CH2OCH2-cyclopropyl, -CH2OCH2CH2-cyclopropyl, -CH2N(CH3)2, -CH2-azetidyl, -CH2-piperidyl, -CH2(dimethylmorpholinyl), -CH2(dimethylpiperazyl), -CH2-pyrrolidyl, -CH2(mo -COOH, -CO(dimethylmorpholinyl), -CO(morpholinyl), -CO(1,3-dioxolane-piperidyl), -CO(piperidyl), -CO(pyrrolidyl), -CO(1-methyl-piperazyl), -CO(octahydropyrrolo[1,2-a]pyradyl), -CONHCH2-cyclohexyl, -CONHCH2-tetrahydropyranyl, -CONHCH2-cyclopentyl, -CONH(CH2)2N(CH3)2, -CON(CH3)2, or phenyl. In some embodiments of the compound of formula (I), R 3H, -CN, -CH3, -CH(CH3)3, -CH2OH, -CH2OCH2-cyclobutyl, -CH2CH2O-cyclobutyl, -CH2OCH2-cyclopropyl, -CH2N(CH3)2, -CH2-azetidyl, -CH2-piperidyl, -CH2(dimethylmorpholinyl), -CH2(dimethylpiperazyl), -CH2-pyrrolidyl, -CH2(morpholinyl), -COOH, -CO(dimethylmorpholinyl), -CO(morpholinyl), -CO(1,3-dioxolane-piperidyl), -CO(piperidyl), -CO(pyrrolidyl), -CO(1-methyl-piperazyl), -CO(octahydropyrrolo[1,2-a]pyradyl), -CONHCH2-cyclohexyl, -CONHCH2-tetrahydropyranyl, -CONHCH2-cyclopentyl, -CONH(CH2)2N(CH3)2, -CON(CH3)2, or phenyl.

[0122] In some embodiments of the compound of formula (II), R 4 This is H, -CH3, or -CH(CH3)2.

[0123] In some embodiments of the compound of formula (II), R 4 is H. In some embodiments of the compound of formula (II), R 4 is CH3. In some embodiments of the compound of formula (II), R 4 This is -CH(CH3)2.

[0124] In one embodiment of the compound of formula (II), R 1 These are isoquinoryl, 1H-pyrrolo[3,2-c]pyridyl, 1H-pyrrolo[2,3-c]pyridyl, and R 2 H, F, methyl, ethyl, substituted or unsubstituted phenyl, -OR 5 And is substituted with one or more substituents independently selected from -CONR2. In some embodiments, R 2is substituted with one or more substituents independently selected from H, F, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -O-(1-methyl-piperidyl), -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -CONH2, -CONHCH3, -CON(CH3)2, -CONHCH2CH3, -CON(CH2CH3)2 and substituted or unsubstituted phenyl. In some embodiments of the compound of formula (II), R 3 is H, CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2OCH2-cyclopropyl, -CH2CH2OCH2-cyclopropyl, -CH2OCH2CH2-cyclopropyl, -CH2-azetidyl, or -CH2-piperidyl. In some other such embodiments, R 4 is H or -CH3. In some other such embodiments, R 4 In some other such embodiments, R 4 is -CH3. In some other such embodiments, R 3 is H, -CH3, -CH2OH, -CH2OCH2-cyclopropyl, -CH2-azetidyl, or -CH2-piperidyl. In some other such embodiments, R 4 H is H.

[0125] In one embodiment of the compound of formula (II), R 1 isoquinoryl, 1H-pyrrolo[3,2-c]pyridyl or 1H-pyrrolo[2,3-c]pyridyl, and R 2 is replaced by H; R 3 is H, CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2OCH2-cyclopropyl, -CH2CH2OCH2-cyclopropyl, -CH2OCH2CH2-cyclopropyl, -CH2-azetidyl or -CH2-piperidyl; R 4 is H or -CH3. In one embodiment, R 3 is H. In one embodiment, R 4 is H. In one embodiment, R 4It is -CH3.

[0126] In some embodiments of the compound of formula (II), R 1 However, H, Br, F, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, CF3, cyclopropyl, cyclobutyl, cyclopentyl, -OR 5 , substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl; substituted or unsubstituted pyridadinyl; substituted or unsubstituted pyrazinyl; substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl, -CONR 6 2, -CON(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), -NRCO(C 1~3 If R is a 2-pyridyl substituted with one or more substituents independently selected from alkyl and -CO (substituted or unsubstituted 3-6 member heterocyclyl), 2 H, F, -CH3, -CH2CH3, substituted or unsubstituted phenyl; -OR 5 And is substituted with one or more substituents independently selected from -CONR2. In some other such embodiments, R 3H, -CN, CH3, -CH2CH3, -CH(CH3)3, -CH2OH, -CH2CH2OH, -CH2OCH2-cyclopropyl, -CH2OCH2-cyclobutyl, -CH2CH2O-cyclobutyl, -CH2CH2OCH2-cyclopropyl, -CH2OCH2CH2-cyclopropyl, -CH2N(CH3)2, -CH2-azetidyl, -CH2-piperidyl, -CH2(dimethylmorpholinyl), -CH2(dimethylpiperazyl), -CH2-pyrrolidyl, -CH2(mo -COOH, -CO(dimethylmorpholinyl), -CO(morpholinyl), -CO(1,3-dioxolane-piperidyl), -CO(piperidyl), -CO(pyrrolidyl), -CO(1-methyl-piperazyl), -CO(octahydropyrrolo[1,2-a]pyradyl), -CONHCH2-cyclohexyl, -CONHCH2-tetrahydropyranyl, -CONHCH2-cyclopentyl, -CONH(CH2)2N(CH3)2, -CON(CH3)2, or phenyl. In some other such embodiments, R 4 is H, -CH3, or -CH(CH3)2. In some other such embodiments, R 4 In some other such embodiments, R 4 is -CH3. In some other such embodiments, R 4 This is -CH(CH3)2.

[0127] In some embodiments of the compound of formula (II), R 1However, H, Br, F, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, CF3, cyclopropyl, cyclobutyl, cyclopentyl, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl; substituted or unsubstituted pyridadinyl; substituted or unsubstituted pyrazinyl; substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl, -CONH2, -CONHCH3, -CON(CH3)2, -CONHCH2CH3, -CON(CH2CH3)2, -CONHCH2CH2CH3 If R is substituted with one or more substituents independently selected from -CONHCH(CH3)2, -CONHCH2CH2OH, -CONHCH2CH2OCH3, -CONHCH(CH3)CH2OH, -CONHCH2CF3, -CONHCH2CH2-pyrrolidyl, -CONH(cyclopropyl), -CONH(cyclobutyl), -CONH(cyclopentyl), -CONH(cyclohexyl), -CONH(CH2)-cyclopropyl, -CO(azetidyl), -CO(piperidyl), -CO(piperazinyl), -CO(morpholinyl), and -NCH3COCH3, 2 is substituted with one or more substituents independently selected from H, F, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -O-(1-methyl-piperidyl), -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -CONH2, -CONHCH3, -CON(CH3)2, -CONHCH2CH3, -CON(CH2CH3)2 and substituted or unsubstituted phenyl. In some such embodiments, R 3H, -CN, CH3, -CH2CH3, -CH(CH3)3, -CH2OH, -CH2CH2OH, -CH2OCH2-cyclopropyl, -CH2OCH2-cyclobutyl, -CH2CH2O-cyclobutyl, -CH2CH2OCH2-cyclopropyl, -CH2OCH2CH2-cyclopropyl, -CH2N(CH3)2, -CH2-azetidyl, -CH2-piperidyl, -CH2(dimethylmorpholinyl), -CH2(dimethylpiperazyl), -CH2-pyrrolidyl, -CH2(mo -COOH, -CO(dimethylmorpholinyl), -CO(morpholinyl), -CO(1,3-dioxolane-piperidyl), -CO(piperidyl), -CO(pyrrolidyl), -CO(1-methyl-piperazyl), -CO(octahydropyrrolo[1,2-a]pyradyl), -CONHCH2-cyclohexyl, -CONHCH2-tetrahydropyranyl, -CONHCH2-cyclopentyl, -CONH(CH2)2N(CH3)2, -CON(CH3)2, or phenyl. In some other such embodiments, R 4 is H, -CH3, or -CH(CH3)2. In some other such embodiments, R 4 In some other such embodiments, R 4 is -CH3. In some other such embodiments, R 4 This is -CH(CH3)2.

[0128] In some embodiments of the compound of formula (II), R 1However, H, Br, F, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, CF3, cyclobutyl, cyclopentyl, -OH, -OCH3, -OCH(CH3)2, -O-tetrahydropyranyl, phenyl, phenyl(COOH), phenyl(phenyl), phenyl(CONHCH3), naphthyl; pyridadinyl; pyrazinyl; pyrimidyl; 1-methylpyrazolyl; dihydropyranyl; 1-methyl-piperidyl; piperidyl substituted with COOH, CONHMe or CONHCH2CF3; 1-methyl-piperazinyl; piperadinyl substituted with COC(CH3)2OH or CO-cyclopropyl-CF3 ;If R is a 2-pyridyl substituted with one or more substituents independently selected from -CONH2, -CONMe2, -CONHCH2CH3, -CONHCH(CH3)2, -CONHCH2CH2OH, -CONHCH2CH2OCH3, -CONHCH(CH3)CH2OH, -CONHCH2CF3, -CONHCH2CH2-pyrrolidyl, -CONH(cyclopropyl), -CONH(cyclopentyl), -CONH(CH2)-cyclopropyl, -CONH(difluorocyclohexyl), -CO(difluoroazetidyl), -CO(difluoropiperidyl), -CO(piperazinyl), -CO(morpholinyl), and -NCH3COCH3, 2 R is substituted with one or more substituents independently selected from H, F, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -O-(1-methyl-piperidyl), -O-tetrahydropyranyl, -CONH2, -CON(CH3)2, phenyl, and phenyl substituted with cyclopropyl (COOH), 1 and R 2 If both are 2-pyridyl, then R 1 or R 2 Either of the following is not substituted with H; and R 3H, -CN, CH3, -CH2CH3, -CH(CH3)3, -CH2OH, -CH2CH2OH, -CH2OCH2-cyclopropyl, -CH2OCH2-cyclobutyl, -CH2CH2O-cyclobutyl, -CH2CH2OCH2-cyclopropyl, -CH2OCH2CH2-cyclopropyl, -CH2N(CH3)2, -CH2-azetidyl, -CH2-piperidyl, -CH2(dimethylmorpholinyl), -CH2(dimethylpiperazyl), -CH2-pyrrolidyl, -CH2(mol -COOH, -CO(dimethylmorpholinyl), -CO(morpholinyl), -CO(1,3-dioxolane-piperidyl), -CO(piperidyl), -CO(pyrrolidyl), -CO(1-methyl-piperazyl), -CO(octahydropyrrolo[1,2-a]pyradyl), -CONHCH2-cyclohexyl, -CONHCH2-tetrahydropyranyl, -CONHCH2-cyclopentyl, -CONH(CH2)2N(CH3)2, -CON(CH3)2, or phenyl; R 4 is H, -CH3, or -CH(CH3)2. In some other such embodiments, R 4 In some other such embodiments, R 4 is -CH3. In some other such embodiments, R 4 This is -CH(CH3)2.

[0129] Further embodiments provided herein include at least one combination of the specific embodiments described above.

[0130] Representative compounds of formula (II) are listed in Tables 2 and 3.

[0131] Each of the compounds listed in Tables 1, 2, and 3 was tested in one or more in vitro parasite motility assays and found to be active.

[0132] The following equation (III): [ka] Compounds having and pharmaceutically acceptable salts, tautomers, isotopologs and stereoisomers thereof are provided herein, wherein, X is CR 3 , N or S; Y is either N or S; Z is CR 3 or S; R 1 is either unsubstituted, or halogen, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 3~7 Cycloalkyl, substituted, or unsubstituted C 6~10 Aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, -OR 5 ,-CONR 6 2-pyridyl substituted with one or more substituents independently selected from 2 and -CO (substituted or unsubstituted 3- to 6-membered heterocyclyls); R 2 is either unsubstituted, or halogen, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 6~10 Ariel, -OR 5 2-pyridyl substituted with one or more substituents independently selected from -CONR2; R 3 is H, substituted or unsubstituted C 1~4 Alkyl or (C 1~3 Alkyl)O(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), (C 1~3 (alkyl) OR; R 4 is H, substituted or unsubstituted C 1~3 It is alkyl; R 5 is H, substituted or unsubstituted C 1~5 They are alkyl or unsubstituted 3-6 member heterocyclines; Each R 6 is H, substituted or unsubstituted C 1~5 Alkyl; substituted or unsubstituted C 3~6Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl and (C 1~3 Independently selected from alkyl (substituted or unsubstituted 3-6 member heterocyclyl); and Each R is H and substituted or unsubstituted C 1~4 It is selected independently of alkyl.

[0133] In one embodiment, the compound is given by formula (IIIa): [ka] The compounds and their pharmaceutically acceptable salts, tautomers, isotopologs, and stereoisomers, where X is N or S and Y is N or S.

[0134] In some embodiments, the compound is of formula (IIIb): [ka] These are compounds, as well as their pharmaceutically acceptable salts, tautomers, isotopologs, and stereoisomers.

[0135] In some embodiments, the compound is of formula (IIIc): [ka] These are compounds, as well as pharmaceutically acceptable salts, tautomers, isotopologs, and stereoisomers.

[0136] In some embodiments, the compound is of formula (IIId): [ka] These are compounds, as well as pharmaceutically acceptable salts, tautomers, isotopologs, and stereoisomers.

[0137] In some embodiments of the compounds of formulas (III), (IIIa), (IIIb), (IIIc), and (IIId), R 1 is either unsubstituted, or halogen, substituted or unsubstituted C1~4 Alkyl, substituted, or unsubstituted C 3~7 Cycloalkyl, substituted, or unsubstituted C 6~10 Aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, -OR 5 ,-CONR 6 2-pyridyl substituted with one or more substituents independently selected from 2 and -CO (substituted or unsubstituted 3- to 6-membered heterocyclyls); R 2 is either unsubstituted, or halogen, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 6~10 Ariel, -OR 5 2-pyridyl substituted with one or more substituents independently selected from -CONR2; R 3 is H, substituted or unsubstituted C 1~4 Alkyl or (C 1~3 Alkyl)O(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), (C 1~3 (alkyl) OR; R 4 is H, substituted or unsubstituted C 1~3 It is alkyl; R 5 is H, substituted or unsubstituted C 1~5 They are alkyl or unsubstituted 3-6 member heterocyclines; Each R 6 is H, substituted or unsubstituted C 1~5 Alkyl; substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl and (C 1~3 Independently selected from alkyl (substituted or unsubstituted 3-6 member heterocyclyl); and Each R is H and substituted or unsubstituted C 1~4 It is selected independently of alkyl.

[0138] In some embodiments of the compounds of formulas (III), (IIIa), (IIIb), (IIIc), and (IIId), R 1C is a halogen, substituted, or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 3~7 Cycloalkyl, substituted, or unsubstituted C 6~10 Aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, -OR 5 ,-CONR 6 2-pyridyl is independently selected from 2 and -CO (substituted or unsubstituted 3- to 6-membered heterocyclyls), and is substituted with one or more substituents or is unsubstituted.

[0139] In some embodiments of the compounds of formulas (III), (IIIa), (IIIb), (IIIc), and (IIId), R 1 is either unsubstituted or -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, -OR 5 substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl, -CONR 6 It is a 2-pyridyl substituted with one or more substituents independently selected from 2 and -CO (substituted or unsubstituted 3- to 6-membered heterocyclines).

[0140] In some embodiments, R 1 is either unsubstituted or -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, -OR 5 , substituted or unsubstituted phenyl and -CONR 6 It is a 2-pyridyl substituted with one or more substituents independently selected from 2.

[0141] In some embodiments, R 1 is either unsubstituted or -CH3, -CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, -OR 5 and 2-pyridyl substituted with one or more substituents independently selected from substituted or unsubstituted phenyl compounds.

[0142] In some embodiments, R 1 is either non-substitutive or one or more ORs 5 It is 2-pyridyl substituted with R. In some such embodiments, R 5 is H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, tetrahydrofuranyl, tetrahydropyranyl, or 1-methylpiperidyl. In some such embodiments, R 5 This is H, -CH3, -CH2CH3, -CH(CH3)2, or tetrahydropyranyl.

[0143] In some such embodiments, R 5 is H or -CH3. In some such embodiments, R 5 is -CH3. In some embodiments, R 5 This is -CH(CH3)2.

[0144] In some embodiments of the compounds of formulas (III), (IIIa), (IIIb), (IIIc), and (IIId), R 1 is one or more -CONR 6 It is 2-pyridyl substituted with 2. In some such embodiments, each R 6 is H, substituted or unsubstituted C 1~5 Alkyl; substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl and (C 1~3 A alkyl group is independently selected from (substituted or unsubstituted 3-6 member heterocyclines). In some such embodiments, each R is selected. 6 This is independently a substituted or unsubstituted C selected from H, -CH3, -CH2CH3, -CH2CH2CH3, and -CH(CH3)2. 1~5 Alkyl; substituted or unsubstituted C selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl 3~6The alkyl and cycloalkyl groups are optionally substituted with one or more substituents independently selected from OH, OCH3, and F. In some embodiments, each R 6 These are independently substituted or unsubstituted C selected from H, -CH(CH3)2. 1~5 Alkyl; substituted or unsubstituted C selected from cyclopentyl and cyclohexyl. 3~6 The molecule is cycloalkyl, and the alkyl and cycloalkyl groups are optionally substituted with one or more substituents independently selected from OH, OCH3, and F.

[0145] In some embodiments, R 1 2-pyridyl is either unsubstituted or substituted with one or more substituents independently selected from -CH3, -CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, and substituted or unsubstituted phenyl.

[0146] In some embodiments, R 1 2-pyridyl is either unsubstituted or substituted with one or more substituents independently selected from -CH3, -CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, -OCH3, -OCH(CH3)2, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, and substituted and unsubstituted phenyl compounds.

[0147] In some embodiments, R 1 This is 2-pyridyl, which is either unsubstituted or substituted with one or more substituents independently selected from -CH3, -OCH(CH3)2 and substituted or unsubstituted phenyl compounds.

[0148] In some embodiments of the compounds of formulas (III), (IIIa), (IIIb), (IIIc), and (IIId), R 2-CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, substituted or unsubstituted phenyl, -OR 5 It is a 2-pyridyl substituted with one or more substituents independently selected from -CONR2.

[0149] In some such embodiments, R 2 This is either unsubstituted or 2-pyridyl substituted with one or more substituents independently selected from -CH3, -CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, substituted or unsubstituted phenyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, substituted or unsubstituted phenyl, and -CONR2.

[0150] In some such embodiments, R 2 This is either unsubstituted or 2-pyridyl substituted with one or more substituents independently selected from -CH3, -OCH3, -O-tetrahydrofuranyl and substituted or unsubstituted phenyl.

[0151] In some embodiments of the compounds of formulas (III), (IIIa), (IIIb), (IIIc), and (IIId), R 3 These are H, -CH3, -CH2CH3, -CH(CH3)3, -CH2OH, -CH2CH2OH, -CH2OCH2-cyclopropyl, or -CH2OCH2-cyclobutyl.

[0152] In some embodiments of the compounds of formulas (III), (IIIa), (IIIb), (IIIc), and (IIId), R 3 These are H, -CH3, -CH2CH3, -CH(CH3)3, or -CH2OH.

[0153] In some embodiments of the compounds of formulas (III), (IIIa), (IIIb), (IIIc), and (IIId), R 3is H or -CH3. In some such embodiments, R 3 H is H.

[0154] In some embodiments of the compounds of formulas (III), (IIIa), (IIIb), (IIIc), and (IIId), R 4 is H or -CH3. In some such embodiments, R 4 is H. In some such embodiments, R 4 It is -CH3.

[0155] In some embodiments of the compounds of formulas (III), (IIIa), (IIIb), (IIIc), and (IIId), R 1 However, they are either unsubstituted or -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, -OR 5 substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl, -CONR 6 If R is a 2-pyridyl substituted with one or more substituents independently selected from 2 and -CO (substituted or unsubstituted 3-6 member heterocyclyls), 2 -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, substituted or unsubstituted phenyl, -OR 5 And 2-pyridyl substituted with one or more substituents independently selected from -CONR2. In some other such embodiments, R 3 is H, -CH3, -CH2CH3, -CH(CH3)3, -CH2OH, -CH2CH2OH, -CH2OCH2-cyclopropyl or -CH2OCH2-cyclobutyl. In some such embodiments, R 3 is H or -CH3. In some such embodiments, R 3 is H. In some such embodiments, R 3is -CH3. In some other such embodiments, R 4 is H or -CH3. In some other such embodiments, R 4 In some other such embodiments, R 4 It is -CH3.

[0156] In some embodiments of the compounds of formulas (III), (IIIa), (IIIb), (IIIc), and (IIId), R 1 However, if it is unsubstituted, or 2-pyridyl substituted with one or more substituents independently selected from -CH3, -CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, and substituted or unsubstituted phenyl, then R 2 is unsubstituted or 2-pyridyl substituted with one or more substituents independently selected from -CH3, -OCH3, -O-tetrahydrofuranyl or substituted and unsubstituted phenyl; R 3 is H or -CH3; R 4 is H or -CH3. In some such embodiments, R 3 is H. In some such embodiments, R 3 is -CH3. In some such embodiments, R 4 is H. In some such embodiments, R 4 It is -CH3.

[0157] In some embodiments of the compounds of formulas (III), (IIIa), (IIIb), (IIIc), and (IIId), R 1 However, if it is unsubstituted, or 2-pyridyl substituted with one or more substituents independently selected from -CH3, -OCH(CH3)2 and substituted or unsubstituted phenyl, then R 2is unsubstituted or 2-pyridyl substituted with one or more substituents independently selected from -CH3, -OCH3, -O-tetrahydrofuranyl and substituted or unsubstituted phenyl; R 3 is H or -CH3; R 4 is H or -CH3. In some such embodiments, R 3 is H. In some such embodiments, R 3 is -CH3. In some such embodiments, R 4 is H. In some such embodiments, R 4 It is -CH3.

[0158] Further embodiments provided herein include at least one combination of the specific embodiments described above.

[0159] Representative compounds of formulas (III), (IIIa), (IIIb), (IIIc), and (IIId) are listed in Table 1.

[0160] In one embodiment, the compound is given by formula (IV): [ka] The compound and its pharmaceutically acceptable salts, tautomers, isotopologs and stereoisomers, wherein, X is O or CR 3 and; Y is NR n or CR 3 and; Z is N or NR n and; R 1 is either unsubstituted, or halogen, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 3~7 Cycloalkyl, substituted, or unsubstituted C 6~10 Aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, -OR 5 ,-CONR 62. A 2-pyridyl substituted with one or more substituents independently selected from -CO (substituted or unsubstituted 3-6 member heterocyclyl) and -NR2; R 2 is either unsubstituted, or halogen, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 6~10 Ariel, -OR 5 2-pyridyl substituted with one or more substituents independently selected from -CONR2; R 3 is H, substituted or unsubstituted C 1~4 Alkyl or (C 1~3 Alkyl)O(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), (C 1~3 (alkyl) OR; R 4 is H, substituted or unsubstituted C 1~3 It is alkyl; R 5 is H, substituted or unsubstituted C 1~5 They are alkyl or unsubstituted 3-6 member heterocyclines; Each R 6 is H, substituted or unsubstituted C 1~5 Alkyl; substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl and (C 1~3 Independently selected from alkyl (substituted or unsubstituted 3-6 member heterocyclyl); and Each R is H and substituted or unsubstituted C 1~4 Selected independently of alkyl; Each R n These are H, substituted or unsubstituted C, independently. 1~4 Alkyl or substituted or unsubstituted C 6~10 It is Ariel.

[0161] In some embodiments, the compound is of formula (IVa): [ka] These are compounds, as well as their pharmaceutically acceptable salts, tautomers, isotopologs, and stereoisomers.

[0162] In some embodiments, the compound is of formula (IVb): [ka] These are compounds, as well as their pharmaceutically acceptable salts, tautomers, isotopologs, and stereoisomers.

[0163] In some embodiments, the compound is of formula (IVc): [ka] These are compounds, as well as their pharmaceutically acceptable salts, tautomers, isotopologs, and stereoisomers.

[0164] In some embodiments of the compounds of formula (IV), (IVa), (IVb), and (IVc), R 1 is either unsubstituted, or halogen, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 3~7 Cycloalkyl, substituted, or unsubstituted C 6~10 Aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, -OR 5 ,-CONR 6 2-pyryl is substituted with one or more substituents independently selected from 2 and -CO (substituted or unsubstituted 3- to 6-membered heterocyclyls) and -NR2; R 2 is either unsubstituted, or halogen, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 6~10 Ariel, -OR 5 2-pyridyl substituted with one or more substituents independently selected from -CONR2; R 3 is H, substituted or unsubstituted C 1~4 Alkyl or (C 1~3 Alkyl)O(C 1~3Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), (C 1~3 (alkyl) OR; R 4 is H, substituted or unsubstituted C 1~3 It is alkyl; R 5 is H, substituted or unsubstituted C 1~5 They are alkyl or unsubstituted 3-6 member heterocyclines; Each R 6 is H, substituted or unsubstituted C 1~5 Alkyl; substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl and (C 1~3 Independently selected from alkyl (substituted or unsubstituted 3-6 member heterocyclyl); and Each R is H and substituted or unsubstituted C 1~4 Selected independently of alkyl; Each R n These are H, substituted or unsubstituted C, independently. 1~4 Alkyl or substituted or unsubstituted C 6~10 It is Ariel.

[0165] In some embodiments of the compounds of formula (IV), (IVa), (IVb), and (IVc), R 1 is either unsubstituted or -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, -OR 5 substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl, -CONR 6 2. A 2-pyridyl substituted with one or more substituents independently selected from -CO (substituted or unsubstituted 3- to 6-membered heterocyclyl) and -N(CH3)2.

[0166] In some embodiments, R 1is either unsubstituted or -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, -OR 5 ,-CONR 6 2. 2-pyridyl substituted with one or more substituents independently selected from substituted or unsubstituted phenyl and -N(CH3)2.

[0167] In some embodiments, R 1 is either unsubstituted or -CH3, -CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, -OR 5 , 2-pyridyl substituted with one or more substituents independently selected from substituted or unsubstituted phenyl and -N(CH3)2.

[0168] In some embodiments, R 1 is either non-substitutive or one or more ORs 5 It is 2-pyridyl substituted with R. In some such embodiments, R 5 is H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, tetrahydrofuranyl, tetrahydropyranyl, or 1-methylpiperidyl. In some such embodiments, R 5 is H, -CH3, -CH2CH3, -CH(CH3)2, or tetrahydropyranyl. In some such embodiments, R 5 is H or -CH3. In some such embodiments, R 5 is -CH3. In some embodiments, R 5 This is -CH(CH3)2.

[0169] In some embodiments of the compounds of formula (IV), (IVa), (IVb), and (IVc), R 1 is one or more -CONR 6 It is 2-pyridyl substituted with 2. In some such embodiments, each R 6 is H, substituted or unsubstituted C 1~5 Alkyl; substituted or unsubstituted C3~6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl and (C 1~3 A alkyl group is independently selected from (substituted or unsubstituted 3-6 member heterocyclines). In some such embodiments, each R is selected. 6 This is independently a substituted or unsubstituted C selected from H, -CH3, -CH2CH3, -CH2CH2CH3, and -CH(CH3)2. 1~5 Alkyl; substituted or unsubstituted C selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl 3~6 The alkyl and cycloalkyl groups are optionally substituted with one or more substituents independently selected from OH, OCH3, and F. In some embodiments, each R 6 These are independently substituted or unsubstituted C selected from H, -CH(CH3)2. 1~5 Alkyl; substituted or unsubstituted C selected from cyclopentyl and cyclohexyl. 3~6 The molecule is cycloalkyl, and the alkyl and cycloalkyl groups are optionally substituted with one or more substituents independently selected from OH, OCH3, and F.

[0170] In some embodiments of the compounds of formula (IV), (IVa), (IVb), and (IVc), R 4 is H or -CH3. In some such embodiments, R 4 is H. In some such embodiments, R 4 is -CH3. In some such embodiments, R n is H, -CH3, or an unsubstituted or substituted phenyl. In some such embodiments, R n is H. In some such embodiments, R n is -CH3. In some such embodiments, R n These are unsubstituted or substituted phenyl compounds.

[0171] In some embodiments, compounds of formulas (IV), (IVa), (IVb), and (IVc) are provided herein, R 1This is either unsubstituted or 2-pyridyl substituted with one or more substituents independently selected from -CH3, -OCH(CH3)2, substituted or unsubstituted phenyl, and -N(CH3)2.

[0172] In some embodiments, compounds of formula (IVa) are provided herein, R 1 This is either unsubstituted or 2-pyridyl substituted with one or more substituents independently selected from -CH3, -OCH(CH3)2, substituted or unsubstituted phenyl, and -N(CH3)2.

[0173] In some embodiments, compounds of formulas (IVb) and (IVc) are provided herein, R 1 This is 2-pyridyl, which is either unsubstituted or substituted with one or more substituents independently selected from -CH3, -OCH(CH3)2, substituted or unsubstituted phenyl.

[0174] In some embodiments of the compounds of formula (IV), (IVa), (IVb), and (IVc), R 2 is either unsubstituted, or halogen, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 6~10 Ariel, -OR 5 It is a 2-pyridyl substituted with one or more substituents independently selected from -CONR2.

[0175] In some such embodiments, R 2 -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, substituted or unsubstituted phenyl, -OR 5 It is a 2-pyridyl substituted with one or more substituents independently selected from -CONR2.

[0176] In some such embodiments, R 2This is either unsubstituted or 2-pyridyl substituted with one or more substituents independently selected from -CH3, -CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, substituted or unsubstituted phenyl, and -CONR2.

[0177] In some such embodiments, R 2 This is 2-pyridyl, which is either unsubstituted or substituted with one or more substituents independently selected from -CH3, -OCH3, -OCH(CH3)2, -O-tetrahydrofuranyl and substituted or unsubstituted phenyl.

[0178] In some embodiments of the compounds of formula (IV), (IVa), (IVb), and (IVc), R 3 These are H, -CH3, -CH2CH3, -CH(CH3)3, -CH2OH, -CH2CH2OH, -CH2OCH2-cyclopropyl, or -CH2OCH2-cyclobutyl.

[0179] In some embodiments of the compounds of formula (IV), (IVa), (IVb), and (IVc), R 3 These are H, -CH3, -CH2CH3, -CH(CH3)3, or -CH2OH.

[0180] In some embodiments of the compounds of formula (IV), (IVa), (IVb), and (IVc), R 3 is H or -CH3. In some such embodiments, R 3 H is H.

[0181] In some embodiments of the compounds of formula (IV), (IVa), (IVb), and (IVc), R 4 is H or -CH3. In some such embodiments, R 4 is H. In some such embodiments, R 4 It is -CH3.

[0182] In some embodiments, compounds of formula (IVa) are provided herein, R 2 This is 2-pyridyl, which is either unsubstituted or substituted with one or more substituents independently selected from -CH3, -OCH3, and -OCH(CH3)2.

[0183] In some embodiments, compounds of formulas (IVb) and (IVc) are provided herein, R 2 This is 2-pyridyl, which is either unsubstituted or substituted with one or more substituents independently selected from -CH3, -OCH3, and -O-tetrahydrofuranyl.

[0184] In some embodiments of the compounds of formula (IV), (IVa), (IVb), and (IVc), R 3 is H or -CH3. In some such embodiments, R 3 is H. In some such embodiments, R 4 is H. In some such embodiments, R 4 It is -CH3.

[0185] In some embodiments of the compounds of formula (IV), (IVb), and (IVc), R n is H, -CH3, or an unsubstituted or substituted phenyl. In some such embodiments, R n is H. In some such embodiments, R n is -CH3. In some such embodiments, R n These are unsubstituted or substituted phenyl compounds.

[0186] In some embodiments of the compounds of formula (IV), (IVa), (IVb), and (IVc), R 1 However, they are either unsubstituted or -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, -OR 5substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl, -CONR 6 2. If R is a 2-pyridyl substituted with one or more substituents independently selected from -CO (substituted or unsubstituted 3-6 member heterocyclyl) and -N(CH3)2, 2 -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, substituted or unsubstituted phenyl, -OR 5 And 2-pyridyl substituted with one or more substituents independently selected from -CONR2. In some other such embodiments, R 3 is H, -CH3, -CH2CH3, -CH(CH3)3, -CH2OH, -CH2CH2OH, -CH2OCH2-cyclopropyl or -CH2OCH2-cyclobutyl. In some such embodiments, R 3 is H or -CH3. In some such embodiments, R 3 is H. In some such embodiments, R 3 is -CH3. In some other such embodiments, R 4 is H or -CH3. In some other such embodiments, R 4 In some other such embodiments, R 4 is -CH3. In some such embodiments, R n is H, -CH3, or an unsubstituted or substituted phenyl. In some such embodiments, R n is H. In some such embodiments, R n is -CH3. In some such embodiments, R n It is phenyl.

[0187] In some embodiments of the compounds of formula (IV), (IVa), (IVb), and (IVc), R 1However, if it is unsubstituted, or 2-pyridyl substituted with one or more substituents independently selected from -CH3, -OCH(CH3)2, substituted or unsubstituted phenyl, and -N(CH3)2, then R 2 is unsubstituted or 2-pyridyl substituted with one or more substituents independently selected from -CH3, -OCH3, -OCH(CH3)2, -O-tetrahydrofuranyl and substituted or unsubstituted phenyl; R 3 is H or -CH3; R 4 is H or -CH3. In some such embodiments, R 3 is H. In some such embodiments, R 3 is -CH3. In some such embodiments, R 4 is H. In some such embodiments, R 4 is -CH3. In some such embodiments, R n is H. In some such embodiments, R n is -CH3. In some such embodiments, R n It is phenyl.

[0188] In some embodiments of the compound of formula (IVa), R 1 is unsubstituted or 2-pyridyl substituted with one or more substituents independently selected from -CH3, -OCH(CH3)2, substituted or unsubstituted phenyl, and -N(CH3)2; R 2 is 2-pyridyl, which is either unsubstituted or substituted with one or more substituents independently selected from -CH3, -OCH3, and -OCH(CH3)2; R 3 is H or -CH3; R 4 is H or -CH3. In some such embodiments, R 3 is H. In some such embodiments, R 3 is -CH3. In some such embodiments, R 4 is H. In some such embodiments, R 4It is -CH3.

[0189] In some embodiments of the compounds of formulas (IVb) and (IVc), R 1 is unsubstituted or 2-pyridyl substituted with one or more substituents independently selected from -CH3, -OCH(CH3)2, substituted or unsubstituted phenyl; R 2 is 2-pyridyl, which is either unsubstituted or substituted with one or more substituents independently selected from -CH3, -OCH3, and -O-tetrahydrofuranyl; R 3 is H or -CH3; R 4 is H or -CH3. In some such embodiments, R 3 is H. In some such embodiments, R 3 is -CH3. In some such embodiments, R 4 is H. In some such embodiments, R 4 is -CH3. In some such embodiments, R n is H. In some such embodiments, R n is -CH3. In some such embodiments, R n It is phenyl.

[0190] Further embodiments provided herein include at least one combination of the specific embodiments described above.

[0191] Representative compounds of formulas (IV), (IVa), (IVb), and (IVc) are listed in Tables 4 and 5.

[0192] Method for producing compounds The heterocyclic compounds of formulas (I), (II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), (IVa), (IVb), (IVc), and (IVc) in Tables 1, 2, 3, 4, and 5 can be prepared using conventional organic synthesis and commercially available starting materials. Not limited to, but as an example, the heterocyclic compounds of formulas (I), (II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), (IVa), (IVb), and (IVc) in Tables 1, 2, 3, 4, and 5 can be prepared as outlined in schemes 1, 2, 3, 4, 5, and 6 shown below, and in the examples described herein. Those skilled in the art will know how to modify the procedures described in the explanatory schemes and examples to reach the desired product.

[0193] [ka] As shown in Scheme 1, the compounds of formula (I), formula (II), Table 1, Table 2 and Table 3 (where R 1 , R 2 , R 3 and R 4 A α-haloketone (as defined herein) can be prepared starting from a well-derivativeized α-haloketone (B) and thiourea (D) (where Hal is either Br or Cl). The α-haloketone (B) is commercially available or can be prepared according to known methods (see, for example, K.-w. Jeong et al., European Journal of Medicinal Chemistry 102 (2015) 387-397). For example, an α-haloketone (B) with Hal being Br can be obtained by treating a well-substituted heteroaryl ketone (A) with a brominating agent, such as bromine or pyridinium tribromide with HBr / acetic acid in a solvent such as THF, DCM, or 1-bromopyrrolidine-2,5-dione or NBS in a solvent such as THF, at a temperature in the range of 0°C to 25°C. An α-haloketone with Hal being Cl can be obtained by treating a well-derivativeed heteroaryl ketone (A) with a brominating agent, such as bromine or pyridinium tribromide with HBr / acetic acid in a solvent such as THF, DCM, or NBS. 2Starting from -Br, it can be obtained by Weinreb ketone synthesis using 2-chloro-N-methoxy-N-methylacetamide in a solvent such as THF and in the presence of a base such as nBuLi at a low temperature such as -78°C. Thiourea(D) can be commercially available or prepared according to known methods (ibid.). At a temperature in the range of 25°C to 80°C, in the presence of a base such as NaOH or NaH, benzoyl isothiocyanate can be synthesized using R in a solvent such as EtOH, MeOH, DCM or acetone. 1 Treatment of NH2 yields thiourea(D). The compounds of formula (I), formula (II), Tables 1, 2, and 3 are obtained by treating thiourea(D) with an α-haloketone (B) in a solvent such as EtOH, THF, acetone, or DMF, in the presence of a base such as DIPEA, NaH, NaOH, or Na2CO3, at a temperature in the range of 25°C to 80°C.

[0194] [ka] As shown in Scheme 2, formula (IIIb), the compounds in Table 1 (where R 1 and R 2 (As defined herein) can be prepared starting from appropriately derivatized glycine (E) and amine (C). Substituted glycine (E) can be prepared according to known methods (see, for example, Dhar, TGMurali et al., Bioorganic & Medicinal Chemistry Letters, 12(21), 3125-3128). For example, glycine (E) can be obtained by treating appropriately substituted heteroarylcarboxylic acid (F) with an aminoacetic acid ester in the presence of a base such as DIPEA, a solvent such as DCM or THF, and a coupling agent such as HOBT and EDC, at a temperature in the range of 0°C to 25°C. Amides (G) are then prepared by combining (E) and R in the presence of a coupling agent such as HATU and a solvent such as NMM and DMF, at a temperature in the range of 0°C to 25°C. 1It is obtained by coupling with NH2(C). The compounds of formula (IIIb), Table 1, are obtained by treating amide (G) with Lawson's reagent in a solvent such as toluene at a temperature in the range of 25°C to 110°C.

[0195] [ka] Alternatively, as shown in Scheme 3, formula (IIIc), the compounds in Table 1 (where R 1 and R 2 Compound (as defined herein) can be prepared from commercially available 2,4-dibromothiazole (H) by a series of metal-mediated cross-coupling reactions. For example, 2,4-dibromothiazole (H) can be treated with an organometallic compound (I) (where M is Sn) in a solvent such as DMF at a temperature in the range of 25°C to about 90°C in the presence of a metal catalyst such as Pd(PPh3)2Cl2 to produce compound (J), which can then be treated with an amine (C) in a solvent such as 1,4-dioxane at a temperature in the range of about 25°C to about 110°C in the presence of a metal catalyst and ligand such as Pd2(dba)3 and xanthophos and a base such as Cs2CO3 to obtain compound (IIIc), shown in Table 1.

[0196] [ka] Alternatively, as shown in Scheme 4, formula (IIId), the compounds in Table 1 (where R 1 and R 2Acrylothioamide (K) can be prepared from appropriately substituted acrylothioamide (K), as defined herein. Acrylothioamide (K) can be prepared according to known methods (see, for example, Kuklish, Steven L. et al., Tetrahedron Letters, 56(20), 2605-2607; 2015). For example, substituted nitrile (L) can be treated with acetonitrile in a solvent such as benzene in the presence of a base such as t-BuOK at a temperature in the range of 0°C to 25°C, and then reacted with phosphorus pentasulfide and Na2S in a solvent such as THF at a temperature in the range of 0°C to 25°C to provide acrylothioamide (K). Cyclized aminoisothiazole (M) can be provided by treating acrylothioamide (K) with H2O2 at 25°C in the presence of a solvent such as MeOH. The metal-mediated coupling of aminoisothiazole (M) with heteroaryl halogenated (N) (where Hal is Br) can be carried out in a solvent such as 1,4-dioxane at a temperature in the range of approximately 25°C to approximately 110°C, in the presence of a metal catalyst and ligand such as Pd2(dba)3 and xanthophos or BINAP, and in the presence of a base such as Cs2CO3, to produce the compounds of formula (IIId), Table 1.

[0197] [ka] Alternatively, as shown in Scheme 5, formula (IVa), the compounds in Table 4 (where R 1 and R 2Azidoketones (as defined herein) can be prepared from appropriately substituted azidoketones (O) and isothiocyanates (P). Azidoketones (O) can be prepared according to known methods (see, for example, Harris, Philip A. et al., Journal of Medicinal Chemistry, 48(5), 1610-1619; 2005). For example, azidoketones (O) can be obtained by treating appropriately substituted α-haloketones (B) (where Hal is Br) with NaN3 in a solvent such as EtOH and in the presence of a base such as NaHCO3 at a temperature in the range of 0°C to 25°C. Appropriately substituted isothiocyanates (P) are commercially available or can be prepared according to known methods (see, for example, J. Org. Chem. (2017), 82, 5898-5903). At temperatures ranging from approximately -5 to approximately 20°C, an isothiocyanate (P) is provided by reacting a appropriately substituted amine (C) with thiophosgene in the presence of a base such as DIPEA and in a solvent such as DCM. At temperatures ranging from 0°C to 25°C, the condensation of the isothiocyanate (P) and azidoketone (O) in the presence of PPh3 and in a solvent such as DCM provides the compound of formula (IVa), shown in Table 4.

[0198] [ka] Alternatively, as shown in Scheme 6, the compounds of formula (IVb and IVc) in Table 5 (where R 1 , R 2 and R 3A compound (as defined herein) can be prepared by the condensation of a appropriately substituted N,S-acetal (Q) and hydrazine (R). The N,S-acetal (Q) can be prepared using known methods (see, for example, Surmont, Riccardo et al., Journal of Organic Chemistry, 76(10), 4105-4111; 2011). For example, a ketone (S) can be treated with carbon disulfide and MeI in the presence of a base such as NaH in a solvent such as DMSO or THF at a temperature in the range of about 0°C to 25°C to produce compound (T), which can then be treated with an amine (C) in a solvent such as THF in the presence of a base such as nBuLi at a temperature in the range of 0°C to 25°C to provide the N,S acetal (Q). At temperatures ranging from 0°C to 180°C, the condensation of an N,S acetal (Q) with a appropriately substituted hydrazine (R) in the presence of an acid such as AcOH in a solvent such as tBuOH provides the compounds of formulas (IVb and IVc) and Table 5.

[0199] In one embodiment, equation (I): [ka] A method for preparing the compound of formula (I) is provided herein, wherein the method optionally involves the presence of a base under conditions suitable for providing the compound of formula (B): [ka] The compound of formula (D): [ka] This involves contacting the compound with a solvent, in which, R 1 These are isoquinoryl; pyrrolopyridyl; 2-pyrimidyl or 2-pyridyl, where 2-pyridyl is a halogen, CN, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 3~7 Cycloalkyl, substituted, or unsubstituted C 6~10Aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, -OR 5 -SR, -CONR 6 2, -CON(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), -NRCO(C 1~3 Alkyl), -CO (substituted or unsubstituted 3-6 member heterocyclyl), -SO2NR2 and SO2R 5 Substituted with one or more substituents independently selected from; R 2 This is 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 2-pyrimidyl, or halogen, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 6~10 Ariel, -OR 5 -SR, -CONR2 and -SO2R 5 It is either a 2-pyridyl substituted with one or more substituents independently selected from, or two atoms, together with the carbon to which they are bonded, form a substituted or unsubstituted 5-6 membered heterocycline; R 3 is H, -CN, substituted or unsubstituted C 1~4 Alkyl, (C 1~3 Alkyl)O(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), -(C 1~3 (Alkyl) OR, (C 1~3 Alkyl) (substituted or unsubstituted 3-6 member heterocyclyl), -C(O) (substituted or unsubstituted 3-10 member heterocyclyl), -C(O)OR, substituted or unsubstituted C 6~10 Ariel, (C 1~3 Alkyl)NR 6 2, -(C 1~3 Alkyl)N(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), CONR 6 2 or -C(O)N(C 1~3 Alkyl)NR2; R 4 is H or substituted or unsubstituted C 1~3Alkyl or substituted or unsubstituted-(C 1~3 Alkyl)C 6~10 It is an allele; R 5 is H, substituted or unsubstituted C 1~5 Alkyl, substituted, or unsubstituted C 3~7 It is a cycloalkyl or a substituted or unsubstituted 3-6 member heterocycline; Each R 6 is H, substituted or unsubstituted C 1~5 Alkyl, substituted, or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl and (C 1~3 Independently selected from alkyl (substituted or unsubstituted 3-6 member heterocyclyl); and Each R is H and substituted or unsubstituted C 1~4 Although selected independently of alkyl, The compound must not be 4-methyl-N-[4-(4-methyl-2-pyridinyl)-2-thiazolyl]-2-pyridinamine or N-(5-chloropyridin-2-yl)-4-(pyrimidine-2-yl)thiazole-2-amine.

[0200] In some embodiments, the solvent is EtOH, THF, acetone, or DMF. In some embodiments, the base is DIPEA, NaH, NaOH, or Na2CO3. In some embodiments, the contact is carried out at a temperature in the range of 25°C to 80°C.

[0201] In some embodiments, this method is expressed by formula (B): [ka] The method further comprises preparing a compound of formula (A) under conditions suitable for providing a compound of formula (A): [ka] The process involves contacting the compound with a brominating agent in a solvent, where Hal is Br.

[0202] In some embodiments, the brominating agent is Br2 and the solvent is HBr / acetic acid. In another embodiment, the brominating agent is pyridinium tribromide and the solvent is HBr / acetic acid or THF. In yet another embodiment, the brominating agent is NBS and the solvent is THF or DCM. In yet another embodiment, the brominating agent is 1-bromopyrrolidine-2,5-dione and the solvent is DCM or THF.

[0203] In some embodiments, contact is performed at temperatures ranging from 0°C to 25°C.

[0204] In some embodiments, this method is expressed by formula (B): [ka] The method further comprises preparing a compound of formula (B) in the presence of a base under conditions suitable for providing a compound of formula (B), and R 2 The process involves contacting -Br with 2-chloro-N-methoxy-N-methylacetamide in a solvent, where Hal is Cl.

[0205] In one embodiment, the base is nBuLi. In one embodiment, the solvent is THF. In some embodiments, the contact is carried out at low temperatures. In one embodiment, the contact is carried out at -78°C.

[0206] In some embodiments, this method is expressed by formula (D): [ka] The method further comprises preparing a compound of formula (D) under conditions suitable for providing a compound of formula (D), R 1 This involves contacting NH2 with benzoyl isothiocyanate in a solvent.

[0207] In some embodiments, the method further includes the presence of a base. In one embodiment, the base is NaOH or NaH.

[0208] In one embodiment, the solvent is THF, EtOH, MeOH, DCM, or acetone. In some embodiments, the contact is carried out at a temperature in the range of 25°C to 80°C.

[0209] In another embodiment, equation (IIIb): [ka] A method for preparing a heterocyclic compound is provided herein, in which, X is S; Y is N; R 1 is either unsubstituted, or halogen, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 3~7 Cycloalkyl, substituted, or unsubstituted C 6~10 Aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, -OR 5 ,-CONR 6 2-pyridyl substituted with one or more substituents independently selected from 2 and -CO (substituted or unsubstituted 3- to 6-membered heterocyclyls); R 2 is either unsubstituted, or halogen, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 6~10 Ariel, -OR 5 2-pyridyl substituted with one or more substituents independently selected from -CONR2; R 3 is H, substituted or unsubstituted C 1~4 Alkyl or (C 1~3 Alkyl)O(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), (C 1~3 (alkyl) OR; R 4 is H, substituted or unsubstituted C 1~3 It is alkyl; R 5 is H, substituted or unsubstituted C 1~5They are alkyl or unsubstituted 3-6 member heterocyclines; Each R 6 is H, substituted or unsubstituted C 1~5 Alkyl; substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl and (C 1~3 Independently selected from alkyl (substituted or unsubstituted 3-6 member heterocyclyl); and Each R is H and substituted or unsubstituted C 1~4 It is selected independently of alkyl. This method provides a heterocyclic compound of formula (IIIb) under conditions suitable for providing formula (G). [ka] This involves contacting the compound with Lawson's reagent in a solvent.

[0210] In some such embodiments, the solvent is toluene. In some embodiments, the contact is carried out at a temperature in the range of about 25 to about 110°C.

[0211] In some embodiments, this method is expressed by formula (G): [ka] The method further comprises preparing a compound of formula (G) using a coupling agent under conditions suitable for providing a compound of formula (E): [ka] The compound R 1 This includes coupling with -NH2 in a solvent.

[0212] In some embodiments, the coupling agent is HATU and the solvent is NMM. In yet another embodiment, the solvent is DMF. In some embodiments, the contact is carried out at a temperature in the range of 0°C to 25°C.

[0213] In some embodiments, this method is expressed by formula (E): [ka] The method further comprises preparing a compound of formula (E) using a coupling agent in a solvent in the presence of a base under conditions suitable for providing a compound of formula (E), R 2 This involves contacting the -COOH group with aminoacetic acid.

[0214] In some embodiments, the coupling agents are HOBT and EDC, and the solvent is DCM or DMF. In some embodiments, the base is DIPEA. In some embodiments, the contact is carried out at a temperature in the range of 0°C to 25°C.

[0215] In another embodiment, equation (IIIc): [ka] A method for preparing a heterocyclic compound is provided herein, in which, X is N; Y is S; R 1 is either unsubstituted, or halogen, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 3~7 Cycloalkyl, substituted, or unsubstituted C 6~10 Aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, -OR 5 ,-CONR 6 2-pyridyl substituted with one or more substituents independently selected from 2 and -CO (substituted or unsubstituted 3- to 6-membered heterocyclyls); R 2 is either unsubstituted, or halogen, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 6~10 Ariel, -OR 5 2-pyridyl substituted with one or more substituents independently selected from -CONR2; R 3 is H, substituted or unsubstituted C1~4 Alkyl or (C 1~3 Alkyl)O(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7 Cycloalkyl), (C 1~3 (alkyl) OR; R 4 is H, substituted or unsubstituted C 1~3 It is alkyl; R 5 is H, substituted or unsubstituted C 1~5 They are alkyl or unsubstituted 3-6 member heterocyclines; Each R 6 is H, substituted or unsubstituted C 1~5 Alkyl; substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl and (C 1~3 Independently selected from alkyl (substituted or unsubstituted 3-6 member heterocyclyl); and Each R is H and substituted or unsubstituted C 1~4 It is selected independently of alkyl. This method uses a metal catalyst and a ligand to provide a compound of formula (J) under conditions suitable for providing a compound of formula (IIIc). [ka] The compound R 1 This includes contacting -NH2 in a solvent.

[0216] In some embodiments, the metal catalyst is Pd2(dba)3 and the ligand is xanthophos. In some embodiments, the solvent is 1,4-dioxane and the base is Cs2CO3. In some embodiments, the contact is carried out at a temperature in the range of 25°C to 110°C.

[0217] In some embodiments, this method is expressed by formula (J): [ka] The method further comprises preparing a compound of formula (H): using a metal catalyst under conditions suitable for providing a compound of formula (J). [ka] The compound R 2 - This includes contacting M (where M is Sn).

[0218] In some embodiments, the metal catalyst is Pd(PPh3)2Cl2. In some embodiments, the solvent is DMF, and the contact is carried out at a temperature in the range of 25°C to 90°C.

[0219] In another embodiment, equation (IIId): [ka] A method for preparing a heterocyclic compound is provided herein, in which, Y is N; Z is S, R 1 is either unsubstituted, or halogen, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 3~7 Cycloalkyl, substituted, or unsubstituted C 6~10 Aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, -OR 5 ,-CONR 6 2-pyridyl substituted with one or more substituents independently selected from 2 and -CO (substituted or unsubstituted 3- to 6-membered heterocyclyls); R 2 is either unsubstituted, or halogen, substituted or unsubstituted C 1~4 Alkyl, substituted, or unsubstituted C 6~10 Ariel, -OR 5 2-pyridyl substituted with one or more substituents independently selected from -CONR2; R 3 is H, substituted or unsubstituted C 1~4 Alkyl or (C 1~3 Alkyl)O(C 1~3 Alkyl) (substituted or unsubstituted C) 3~7Cycloalkyl), (C 1~3 (alkyl) OR; R 4 is H, substituted or unsubstituted C 1~3 It is alkyl; R 5 is H, substituted or unsubstituted C 1~5 They are alkyl or unsubstituted 3-6 member heterocyclines; Each R 6 is H, substituted or unsubstituted C 1~5 Alkyl; substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl and (C 1~3 Independently selected from alkyl (substituted or unsubstituted 3-6 member heterocyclyl); and Each R is H and substituted or unsubstituted C 1~4 It is selected independently of alkyl. This method uses a metal catalyst and ligand under conditions suitable for providing a compound of formula (IIId) and formula (M). [ka] The compound R 1 - This involves contacting Hal (where Hal is Br) in a solvent.

[0220] In some embodiments, the metal catalyst is Pd2(dba)3, and the ligand is xanthophos or BINAP. In some embodiments, the solvent is 1,4-dioxane, and the base is Cs2CO3. In some embodiments, the contact is carried out at a temperature in the range of 25°C to 110°C.

[0221] In some embodiments, this method is expressed by formula (M) [ka] The method further comprises preparing a compound of formula (K) under conditions suitable for providing a compound of formula (K): [ka] This involves contacting the compound with H2O2.

[0222] In some embodiments, the solvent is MeOH, and the contact is carried out at 25°C.

[0223] In some embodiments, this method is expressed by formula (K) [ka] The method further comprises preparing a compound of formula (K) under conditions suitable for providing compound R 2 -CN, a) A step of bringing the base into contact with the first solvent and temperature, b) The step of contacting the product from step a) with phosphorus pentasulfide and Na2S in a second solvent. Includes.

[0224] In some embodiments, the first base is t-BuOK and the solvent is benzene or ACN. In one embodiment, the contact in step a) is carried out at a temperature in the range of about 0 to about 25°C.

[0225] In some embodiments, the second solvent is THF. In one embodiment, the contact in step b) is carried out at a temperature ranging from room temperature to about 0 to 25°C.

[0226] In another embodiment, equation (IVa): [ka] A method for preparing a heterocyclic compound is provided herein, in which, X is O; Z is N, R 1 and R 2 This is as defined herein. This method provides a heterocyclic compound of formula (IVa) in a solvent in the presence of PPh3 under conditions suitable for providing a heterocyclic compound of formula (O). [ka] The compound of formula (P): R1-N=C=S (P) This includes contacting the compound with the compound.

[0227] In some embodiments, the solvent is DCM, and the contact is carried out at a temperature in the range of 0°C to 25°C.

[0228] In some embodiments, this method is expressed by formula (O) [ka] The method further comprises preparing a compound of formula (O) in a solvent in the presence of NaN3 under conditions suitable for providing a compound of formula (B): [ka] This involves contacting the compound (where Hal is Br).

[0229] In some embodiments, the solvent is EtOH and the base is NaHCO3. In some embodiments, the contact is carried out at a temperature in the range of 0°C to 25°C.

[0230] In some embodiments, this method is expressed by formula (P) R1-N=C=S (P) The method further comprises preparing a compound of formula (P) using a base in a solvent under conditions suitable for providing a compound of formula (P), and R 1 This includes contacting -NH2 with thiophosgene.

[0231] In some embodiments, the solvent is DCM and the base is DIPEA. In some embodiments, the contact is carried out at a temperature in the range of -5°C to 20°C.

[0232] In another embodiment, formulas (IVb and IVc): [ka] A method for preparing a heterocyclic compound is provided herein, in which, Y is N or NR n and; Z is N or NR n and; R 1 , R 2 and R n This is as defined herein. This method provides heterocyclic compounds of formula (IVb and IVc) under conditions suitable for providing heterocyclic compounds of formula (Q) in a solvent in the presence of an acid. [ka] The compound of formula (R): [ka] This includes contacting the compound with the compound.

[0233] In some embodiments, the solvent is tBuOH and the acid is AcOH. In some embodiments, the contact is carried out at a temperature in the range of 0°C to 180°C.

[0234] In some embodiments, this method is expressed by formula (Q) [ka] The method further comprises preparing a compound of formula (T) in a solvent and a base under conditions suitable for providing a compound of formula (Q). [ka] The compound R 1 This includes contacting -NH2.

[0235] In some embodiments, the solvent is THF and the base is nBuLi. In some embodiments, the contact is carried out at a temperature in the range of 0°C to 25°C.

[0236] In some embodiments, this method is expressed by formula (T) [ka] The method further comprises preparing a compound of formula (T) under conditions suitable for providing a compound of formula (S). [ka] This involves contacting the compound with carbon disulfide and MeI.

[0237] In some embodiments, the base is NaH and the solvent is THF or DMSO. In one embodiment, the contact step is carried out at a temperature in the range of about 0 to about 25°C.

[0238] How to use Heterocyclic compounds, including those of formula (I), formula (II), formula (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), (IVa), (IVb), (IVc), and the compounds in Tables 1, 2, 3, 4, and 5, are useful as pharmaceuticals for treating, preventing, or improving animal and human conditions. The heterocyclic compounds provided herein are useful for use in treating or preventing all diseases, disorders, or conditions disclosed herein.

[0239] In one embodiment, a method for treating a disease caused by helminthiasis is provided herein. In certain embodiments, the compounds described herein are used in human pharmacotherapy, particularly in the treatment of helminthiasis. In certain embodiments, the compounds provided herein are used in animal pharmacotherapy, particularly in the treatment of helminthiasis. In certain embodiments, the method comprises administering a therapeutically effective amount of the compound described to a subject having a disease caused by helminthiasis.

[0240] In one embodiment, a method for treating a disease caused by filariasis is provided herein. In certain embodiments, the compounds described herein are used in human pharmacotherapy, particularly in the treatment of filariasis. In certain embodiments, the compounds provided herein are used in animal pharmacotherapy, particularly in the treatment of filariasis. In certain embodiments, the method comprises administering a therapeutically effective amount of the compound described herein to a subject having a disease caused by filariasis.

[0241] In one embodiment, a method for treating or preventing helminthic infection and disease is provided herein, the method comprising administering an effective amount of a heterocyclic compound or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof to a target. In some such embodiments, the helminthic infection is a filarial worm infection.

[0242] In one embodiment, a method for treating a disease caused by helminthiasis is provided herein. In certain embodiments, a heterocyclic compound or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof is used in human pharmacotherapy, particularly in the treatment of helminthiasis. In certain embodiments, a heterocyclic compound or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof is used in animal pharmacotherapy, particularly in the treatment of helminthiasis. In certain embodiments, the method comprises administering a therapeutically effective amount of a heterocyclic compound or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof to a subject having a disease caused by helminthiasis.

[0243] In one embodiment, a method for treating diseases caused by filarial parasite infection is provided herein. In certain embodiments, heterocyclic compounds or pharmaceutically acceptable salts, tautomers, isotopologs or stereoisomers thereof are used in human pharmacotherapy, particularly in the treatment of filarial parasite infections. In certain embodiments, heterocyclic compounds or pharmaceutically acceptable salts, tautomers, isotopologs or stereoisomers thereof are used in animal pharmacotherapy, particularly in the treatment of filarial parasite infections. In certain embodiments, the method comprises administering a therapeutically effective amount of heterocyclic compounds or pharmaceutically acceptable salts, tautomers, isotopologs or stereoisomers thereof to a subject having a disease caused by filarial parasite infection.

[0244] In another embodiment, a method for preventing diseases caused by helminthiasis is also provided. In certain embodiments, heterocyclic compounds or pharmaceutically acceptable salts, tautomers, isotopologs or stereoisomers thereof are used in human pharmacotherapy, particularly for the prevention of helminthiasis. In certain embodiments, heterocyclic compounds or pharmaceutically acceptable salts, tautomers, isotopologs or stereoisomers thereof are used in animal pharmacotherapy, particularly for the prevention of helminthiasis. In certain embodiments, the method comprises administering a therapeutically effective amount of heterocyclic compounds or pharmaceutically acceptable salts, tautomers, isotopologs or stereoisomers thereof to a subject in order to prevent diseases caused by helminthiasis.

[0245] In another embodiment, a method for preventing diseases caused by filarial parasite infection is also provided. In certain embodiments, heterocyclic compounds or pharmaceutically acceptable salts, tautomers, isotopologs or stereoisomers thereof are used in human pharmacotherapy, particularly for the prevention of filarial parasite infection. In certain embodiments, heterocyclic compounds or pharmaceutically acceptable salts, tautomers, isotopologs or stereoisomers thereof are used in animal pharmacotherapy, particularly for the prevention of filarial parasite infection. In certain embodiments, the method comprises administering a therapeutically effective amount of heterocyclic compounds or pharmaceutically acceptable salts, tautomers, isotopologs or stereoisomers thereof to a subject in order to prevent diseases caused by filarial parasite infection.

[0246] In another embodiment, methods for treating or preventing parasitic diseases are provided herein. In certain embodiments, the parasitic disease is related to worms. In certain embodiments, the parasitic disease is caused by worms. In certain embodiments, the parasites are classified into tapeworms, nematodes (roundworms), and trematodes (flatworms or trematodes). In certain embodiments, the parasitic disease is related to helminths. In certain embodiments, the parasitic disease is related to nematodes. In certain embodiments, the nematode is Wuchereria bancrofti. In certain embodiments, the nematode is Brugia malayi. In certain embodiments, the nematode is Brugia timori. In certain embodiments, the nematode is Onchocerca volvulus. In certain embodiments, the nematode is Dirofilaria immitis. In certain embodiments, the parasitic disease is related to trematodes. In certain embodiments, the parasitic disease is related to the genus Schistosoma. In certain embodiments, the parasitic disease is related to Schistosoma mansoni. In certain embodiments, the parasitic disease is enteric pinworm disease, pinworm disease, roundworm disease, guinea disease, filariasis, onchocerciasis, schistosomiasis, or whipworm disease. In certain embodiments, the parasitic disease is schistosomiasis. In certain embodiments, the parasitic disease is urinary schistosomiasis. In certain embodiments, the parasitic disease is enteric schistosomiasis. In certain embodiments, the parasitic disease is Asian enteric schistosomiasis. In certain embodiments, the parasitic disease is visceral schistosomiasis. In certain embodiments, the parasitic disease is acute schistosomiasis. In certain embodiments, the parasitic disease is lymphatic filariasis. In certain embodiments, the parasitic disease is Bancroftian filariasis. In certain embodiments, the parasitic disease is subcutaneous filariasis. In certain embodiments, the parasitic disease is serosal filariasis. In certain embodiments, the parasitic disease is elephantiasis. In certain embodiments, the parasitic disease is tropical elephantiasis. In certain embodiments, the parasitic disease is onchocerciasis. In certain embodiments, the parasitic disease is dirofilariasis.In certain embodiments, dirofilariasis is dirofilariasis in dogs. In some embodiments, dirofilariasis is caused by Dirofilaria immitis or Dirofilaria repens.

[0247] In certain embodiments, the method of the present invention includes the step of administering a heterocyclic compound or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof to a subject. In certain embodiments, the method includes administering a heterocyclic compound or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof to a subject for a period of 14 days or less. In certain embodiments, the method includes administering a heterocyclic compound or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof to a subject for a period of 7 days or less. In certain embodiments, the subject requires treatment for a helminth infection. In certain embodiments, the subject requires treatment for a filarial infection. In certain embodiments, the subject has a helminth infection. In certain embodiments, the subject is at risk of having a helminth infection. In certain embodiments, the subject has a filarial infection. In certain embodiments, the subject is at risk of having a filarial infection. In certain embodiments, the subject is a pediatric subject. In certain embodiments, the subject is under 9 years of age. In certain embodiments, the subject is under 8 years of age. In certain embodiments, the subject is pregnant. In certain embodiments, the subject is postpartum women. In certain embodiments, the subject is women of childbearing age. In certain embodiments, the subject is an individual who is trying to conceive a child.

[0248] The compounds disclosed herein exhibit efficacy against helminths and therefore have the potential to kill such helminths and / or inhibit their growth, molting, or motility. The compounds disclosed herein exhibit efficacy against filarial parasites and therefore have the potential to kill such filarial parasites and / or inhibit their growth, molting, or motility. Accordingly, in one embodiment, a method for killing filarial parasites is provided, comprising contacting the filarial parasites with a heterocyclic compound or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof effective in killing the filarial parasites. In another embodiment, a method for inhibiting the growth or molting of filarial parasites is provided herein, comprising contacting the filarial parasites with a heterocyclic compound or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof effective in inhibiting the growth or molting of the filarial parasites. In another embodiment, a method for inhibiting the motility of a filarial worm is provided herein, comprising contacting the filarial worm with a heterocyclic compound or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof in an amount effective in inhibiting the motility of the filarial worm. In a particular embodiment, the worm is an egg. In a particular embodiment, the egg is an unfertilized egg. In a particular embodiment, the egg is a fertilized egg. In a particular embodiment, the worm is a larva. In a particular embodiment, the worm is in the larval or juvenile stage. In a particular embodiment, the worm is a larva of any one of four larval stages (L1, L2, L3, L4). In a particular embodiment, the worm is an L1 stage larva or microfilaria. In a particular embodiment, a microfilaria is an L1 stage larva. In a particular embodiment, the worm is an L2 stage larva. In a particular embodiment, the worm is an L3 stage larva. In a particular embodiment, the worm is an L4 stage larva. In certain embodiments, the worm is in the sexually immature stage (L5 stage). In certain embodiments, the worm is mature. In certain embodiments, the worm is fully mature. In certain embodiments, the worm is in the adult stage. In certain embodiments, the worm is in the pre-parasitic stage. In certain embodiments, the worm is in the parasitic stage.In certain embodiments, the insect is in contact with the heterocyclic compound or its pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer inside the object. In certain embodiments, the insect is in contact with the heterocyclic compound or its pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer outside the object.

[0249] As discussed herein, the compounds provided herein are useful for treating and preventing certain diseases and disorders in humans and animals. In certain embodiments, heterocyclic compounds or their pharmaceutically acceptable salts, tautomers, isotopologs or stereoisomers are used to treat diseases resulting from helminthic infections. In certain embodiments, heterocyclic compounds or their pharmaceutically acceptable salts, tautomers, isotopologs or stereoisomers are used to treat diseases resulting from filarial worm infections, including but not limited to heartworm disease, onchocerciasis, and lymphatic filariasis. In certain embodiments, treatment or prevention of such diseases and disorders can be achieved by administering the heterocyclic compound or its pharmaceutically acceptable salts, tautomers, isotopologs or stereoisomers alone or in combination with another activator as part of a combination therapy. The term "combination" in phrases such as "in combination with another activator" includes, for example, the simultaneous administration of a first and second agent that can be dissolved or mixed in the same pharmaceutically acceptable carrier, or the administration of a second agent after the administration of a first agent, or the administration of a first agent after the administration of a second agent. Accordingly, the methods and compositions of the present invention include combination therapeutic treatment methods and combination pharmaceutical compositions. The term "combination therapy" refers to the administration of two or more therapeutic substances, for example, the compounds described herein and another drug (for example, antihelmintic agents such as ivermectin, albendazole, flubendazole, diethylcarbamazine, or emodepside). Other drugs may be administered simultaneously with, before, or after the administration of macrolide antibiotics.

[0250] In one embodiment, a method is provided for the treatment or prevention of helminthic infection and disease, the method comprising administering an effective amount of a heterocyclic compound or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof to a target in combination with one or more antihelmintic agents. In some such embodiments, the helminthic infection is a filarial worm infection. In one embodiment, the treatment of the helminthic infection comprises the administration of an antihelmintic agent such as benzimidazole, e.g., flubendazole, albendazole, mebendazole, thiabendazole, fenbendazole or triclabendazole. In one embodiment, treatment of helminth infection involves the administration of one or more antihelmintic agents, such as ivermectin, abamectin, diethylcarbamazine (DEC), suramin, pyrantel pamoate, levamisole, niclosamide, nitazoxanide, oxyclozanide, praziquantel, emodepside, monepantel, derquantel, or peletierin sulfate. In certain embodiments, heterocyclic compounds or pharmaceutically acceptable salts, tautomers, isotopologs, or stereoisomers thereof are used in combination with one or more antihelmintic agents to treat helminth infection. In some embodiments, the antihelmintic agent is a benzimidazole, such as flubendazole, albendazole, mebendazole, thiabendazole, fenbendazole, or triclabendazole. In some embodiments, the antihelmintic is one or more of ivermectin, abamectin, diethylcarbamazine (DEC), suramin, pyrantel pamoate, levamisole, niclosamide, nitazoxanide, oxyclozanide, praziquantel, emodepside, monepantel, derquantel, or peletierin sulfate. In certain embodiments, a heterocyclic compound or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof is used in a method for the treatment or prevention of filarial worm infection and disease, the method comprising administering an effective amount of the heterocyclic compound or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof to a target in combination with one or more antihelmintic agents.In some such embodiments, the antihelmintic is selected from flubendazole, albendazole, mebendazole, thiabendazole, fenbendazole, triclabendazole, ivermectin, abamectin, diethylcarbamazine (DEC), suramin, pyrantel pamoate, levamisole, niclosamide, nitazoxanide, oxyclozanide, praziquantel, emodepside, monepantel, derquantel, or peretierin sulfate. In one embodiment, the antihelmintic is a Wolbachia-targeting agent. In one embodiment, the Wolbachia-targeting agent is doxycycline.

[0251] Pharmaceutical composition and route of administration Pharmaceutical compositions comprising an effective amount of a heterocyclic compound described herein and a pharmaceutically acceptable carrier, excipient, or medium are provided herein. Heterocyclic compounds can be administered to subjects enterally (e.g., orally, transrectally), topically, or parenterally (e.g., intravenously, intramuscularly, subcutaneously) in conventional 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 include excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), lubricants (e.g., magnesium stearate, light anhydrous silicic acid, talc, or sodium lauryl sulfate), flavorings (e.g., citric acid, menthol, glycine, or orange powder), and preservatives (e.g., sodium benzoate, sodium bisulfite, methyl These can be prepared by commonly used methods using conventional organic or inorganic additives such as parabens or propylparabens, 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 / glycoflor), buffers, copolymers (e.g., poly(lactic acid-co-glycolic acid, i.e., PLGA)), and base waxes (e.g., cocoa butter, white petrolatum, or polyethylene glycol). The effective amount of heterocyclic compound in the pharmaceutical composition can be at a level that can produce the desired effect, for example, about 0.005 mg / kg of body weight to about 20 mg / kg of body weight in unit doses for both oral and parenteral administration.

[0252] The dose of heterocyclic compounds administered to a subject can vary considerably and may be determined at the discretion of the healthcare professional. Generally, heterocyclic compounds can be administered to a subject at doses of approximately 0.5 mg / kg of body weight to approximately 20 mg / kg of body weight, 1 to 4 times a day, but the above dosage may be appropriately adjusted depending on the subject's age, weight, medical condition, and type of administration. In one embodiment, the dose is approximately 0.1 mg / kg of body weight to approximately 3 mg / kg of body weight, approximately 0.5 mg / kg of body weight to approximately 2 mg / kg of body weight, approximately 1 mg / kg of body weight to approximately 2 mg / kg of body weight, or approximately 1.5 mg / kg of body weight to approximately 2 mg / kg of body weight. In one embodiment, the dose is approximately 1 mg / kg of body weight to approximately 3 mg / kg of body weight. In one embodiment, the dose is approximately 0.5 mg / kg of body weight to approximately 1 mg / kg of body weight. In one embodiment, the dose is approximately 1 mg / kg of body weight to approximately 2 mg / kg of body weight. In one embodiment, the dose is approximately 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 body weight of the subject. In one embodiment, one dose is given per day. In any given case, the amount of heterocyclic compound administered may depend on factors such as the solubility of the active ingredient, the formulation used, and the route of administration.

[0253] In another embodiment, a method for treating or preventing a disease or disorder is provided herein, comprising administering a heterocyclic compound to a subject affected by a helminthic infection at a dose of about 1 mg / day to about 1200 mg / day. In yet another embodiment, a method for treating or preventing a disease or disorder is provided herein, comprising administering a heterocyclic compound to a subject affected by a helminthic 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 heterocyclic compound to a subject affected by a helminthic 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 includes administering a heterocyclic compound to a subject affected by helminthiasis at a dose of approximately 0.75 mg / day to approximately 375 mg / day. In one embodiment, a method for treating a disease or disorder includes administering a heterocyclic compound to a subject affected by helminthiasis at a dose of approximately 3.75 mg / day to approximately 75 mg / day. In one embodiment, a method for treating a disease or disorder includes administering a heterocyclic compound to a subject affected by helminthiasis at a dose of approximately 7.5 mg / day to approximately 55 mg / day. In one embodiment, a method for treating a disease or disorder includes administering a heterocyclic compound to a subject affected by helminthiasis at a dose of approximately 18 mg / day to approximately 37 mg / day.

[0254] In another embodiment, unit dosage forms containing about 1 mg to 500 mg or about 500 mg to about 1000 mg of the heterocyclic compound are provided herein. In one embodiment, unit dosage forms containing about 1 mg to 500 mg of the heterocyclic compound are provided herein. In one embodiment, unit dosage forms containing about 500 mg to about 1000 mg of the heterocyclic compound are provided herein. In another embodiment, unit dosage forms containing about 1 mg to 200 mg, about 35 mg to about 1400 mg, about 125 mg to about 1000 mg, about 250 mg to about 1000 mg or about 500 mg to about 1000 mg of the heterocyclic compound are provided herein. In one embodiment, the unit dosage form contains about 1 mg to 200 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains about 35 mg to about 1400 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains about 125 mg to about 1000 mg of the heterocyclic compound. In another embodiment, the unit dosage form contains about 250 mg to about 1000 mg of the heterocyclic compound. In yet another embodiment, the unit dosage form contains about 500 mg to about 1000 mg of the heterocyclic compound.

[0255] In certain embodiments, unit dosage forms comprising about 100 mg or 400 mg of a heterocyclic compound are provided herein.

[0256] In other embodiments, unit dosage forms containing 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 the heterocyclic compound are provided herein. In one embodiment, the unit dosage form contains 1 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains 5 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains 10 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains 15 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains 20 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains 25 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains 30 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains 35 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains 40 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains 50 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains 70 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains 100 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains 125 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains 130 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains 140 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains 175 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains 200 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains 250 mg of the heterocyclic compound. In one embodiment, the unit dosage form contains 280 mg of the heterocyclic compound. In another embodiment, the unit dosage form contains 350 mg of the heterocyclic compound. In another embodiment, the unit dosage form contains 500 mg of the heterocyclic compound. In another embodiment, the unit dosage form contains 560 mg of the heterocyclic compound. In another embodiment, the unit dosage form contains 700 mg of the heterocyclic compound. In another embodiment, the unit dosage form contains 750 mg of the heterocyclic compound. In another embodiment, the unit dosage form contains 1000 mg of the heterocyclic compound. In another embodiment, the unit dosage form contains 1400 mg of the heterocyclic compound.

[0257] Heterocyclic compounds can be administered once, twice, three times, four times, or more than once daily. In certain embodiments, doses of 600 mg or less are administered once daily, and doses exceeding 600 mg are administered twice daily in amounts equal to half of the total daily dose.

[0258] Heterocyclic compounds can be administered orally for convenience. In one embodiment, when administered orally, the heterocyclic compound is administered with food and water. In another embodiment, the heterocyclic compound is dispersed in water or juice (e.g., apple juice or orange juice) and administered orally as a suspension.

[0259] Heterocyclic compounds may also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, transrectally, mucous membrane, by inhalation, topically to the ear, nose, eye or skin, or topically to the eye (i.e., subconjunctival, intravitreous, posterior or anterior chamber). The mode of administration is at the discretion of the healthcare professional and may depend in part on the site of the medical condition.

[0260] In one embodiment, a capsule containing a heterocyclic compound without additional carriers, excipients, or media is provided herein.

[0261] In another embodiment, a composition comprising an effective amount of a heterocyclic compound and a pharmaceutically acceptable carrier or medium is provided herein, the pharmaceutically acceptable carrier or medium may include excipients, diluents, or mixtures thereof. In one embodiment, the composition is a pharmaceutical composition.

[0262] The composition may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories, suspensions, gels, ruminant devices (e.g., for long-term prophylaxis or controlled release), implantable tablets, topical pore-ons, transdermal delivery gels, spot-ons, implantable tablets (including devices), gels, liquids (e.g., PLGA). The composition may be formulated to contain a daily dose or a convenient amount of a daily dose in a dosing unit that may be a single tablet or capsule or a convenient volume of liquid. In one embodiment, the solution is prepared from a water-soluble salt such as hydrochloride. Generally, all compositions are prepared according to methods known in pharmacochemistry. Capsules can be prepared by mixing a heterocyclic compound with a suitable carrier or diluent and filling a capsule with a suitable amount of the mixture. Common carriers and diluents include, but are not limited to, inert powders, such as many different types of starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flour and similar edible powders.

[0263] Tablets can be prepared by direct compression, wet granulation, or dry granulation. The formulations typically include diluents, binders, lubricants, and disintegrants along with the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, phosphoric acid or calcium sulfate, inorganic salts such as sodium chloride, and powdered sugars. Powdered cellulose derivatives are also useful. Typical tablet binders are starch, gelatin, and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginates, methylcellulose, and polyvinylpyrrolidine, are also convenient. Polyethylene glycol, ethylcellulose, and waxes can also serve as binders.

[0264] Lubricants may be necessary in tablet formulations to prevent the tablet and punch from adhering to the dye. Lubricants can be selected from slippery solids such as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell when wet, breaking down the tablet and releasing the compound. Disintegrants include starch, clay, cellulose, algin, and gum. More specifically, for example, corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resin, alginic acid, guar gum, citrus pulp, and carboxymethylcellulose can be used in the same way as sodium lauryl sulfate. Tablets can be coated with sugar as a flavor and sealant, or with a film-forming protective agent to modify the solubility of the tablet. Compositions can also be formulated as chewable tablets by using substances such as mannitol in the formulation.

[0265] When it is desired to administer heterocyclic compounds as suppositories, typical bases can be used. Cocoa butter is a conventional suppository base and can be modified by adding wax to slightly increase its melting point. In particular, water-miscible suppository bases containing polyethylene glycol of various molecular weights are widely used.

[0266] The effects of heterocyclic compounds can be delayed or prolonged by appropriate formulations. For example, slow-dissolving pellets of heterocyclic compounds can be prepared and incorporated into tablets or capsules, or as sustained-release implantable devices. This technique also includes producing pellets with several different dissolution rates and filling mixtures of these pellets into capsules. Tablets or capsules can be coated with a film that withstands dissolution for a predictable period. Parenteral formulations can also be made long-acting by adding an amount of PLGA that allows the heterocyclic compound to dissolve or suspend in an oily or emulsifying medium, or to slowly disperse in serum. [Examples]

[0267] The following examples are presented as illustrations, not as limitations. Compounds are named using the automated name generation tool provided in Chemdraw Ultra 17.0 (Cambridgesoft). This tool generates systematic names for chemical structures in accordance with the Cahn-Ingold-Prelog rule of stereochemistry. Those skilled in the art can modify the procedures described in the descriptive examples to arrive at the desired product.

[0268] [Table 1]

[0269] [Table 2]

[0270] [Table 3]

[0271] Compound Synthesis Example 1. N-(4-methylpyridine-2-yl)-4-(5-methylpyridine-2-yl)thiazole-2-amine [ka] A solution of 2-bromo-1-(5-methylpyridine-2-yl)ethanone (0.214 g, 1 mmol) and 1-phenylthiourea (0.152 g, 1.00 mmol) in EtOH (10 ml) was stirred at 78°C for 1 hour. The reaction mixture was quenched with saturated NaHCO3, washed with ethyl acetate, and then washed with saturated NaCl water. The organic layers were combined, dried on magnesium sulfate, filtered, and concentrated. The crude residue was purified by reverse-phase semi-preparative chromatography. The fraction containing the clean product was loaded onto a Phenomenex Strata-XC ion-exchange column. The column was continuously washed with water and MeOH. The product was isolated and purified by standard methods to obtain N-(4-methylpyridine-2-yl)-4-(5-methylpyridine-2-yl)thiazole-2-amine (0.180 g, 0.637 mmol, yield 63.7%). 1 H NMR(400MHz,DMSO-d6)δ ppm 2.29(s,3H)2.32(s,3H)6.76-6.82(m,1H)6.87-6.92(m,1H)7.55(s,1H)7.65-7.7 2(m,1H)7.86(d,J=8.20Hz,1H)8.17(d,J=5.86Hz,1H)8.41-8.45(m,1H)11.32(br s,1H).LCMS(ESI)m / z 283.4[M+H]+.

[0272] Example 2. N-(4-methylpyridine-2-yl)-4-(pyridine-2-yl)thiazole-2-amine [ka] 1-(4-methylpyridine-2-yl)thiourea. Under a nitrogen atmosphere, a mixture of benzoyl isothiocyanate (5 g, 1.0 mol) and 4-methylpyridine-2-amine (3.3 g, 1.0 mol) in EtOH (50 mL) was stirred at 80°C for 12 hours. The reaction mixture was then poured into ice water and stirred for a further 30 minutes. The benzoylthiourea precipitate was collected by filtration and washed with water. The crude material was dissolved in MeOH and treated with 1N NaOH. The reaction mixture was heated under reflux for 1 hour. After cooling, the reaction mixture was poured into ice water and 1N HCl water was added to produce a pH of approximately 3-4. The reaction mixture was stirred for 30 minutes, and the pH was adjusted to 8-9 using saturated Na2CO3 to obtain a precipitate. This precipitate was collected by filtration, washed with water, and dried to obtain the title compound 1-(4-methylpyridine-2-yl)thiourea (3.2 g, 62%).

[0273] 4-(4-methoxypyridine-2-yl)-N-(4-methylpyridine-2-yl)thiazole-2-amine. A solution of 2-chloro-1-(4-methoxypyridine-2-yl)ethanone (0.186 g, 1 mmol) and 1-(4-methylpyridine-2-yl)thiourea (0.167 g, 1.000 mmol) in EtOH (10 ml) was stirred at 78°C for 1 hour. The reaction mixture was quenched with saturated NaCl water and then washed with ethyl acetate. The product was isolated and purified by standard methods to obtain 4-(4-methoxypyridine-2-yl)-N-(4-methylpyridine-2-yl)thiazole-2-amine (0.25 g, 0.838 mmol, yield 84%). 1 H NMR(400MHz,DMSO-d6)δ ppm 2.29(s,4H)6.76-6.82(m,1H)6.86-6.93(m,3H)7.51(d,J=2.73Hz,1H)7.62 (s,1H)8.13-8.21(m,1H)8.40(d,J=6.25Hz,1H)11.40(s,1H).LCMS(ESI)m / z 299.3[M+H]+.

[0274] Example 3. N-(4-isopropoxypyridine-2-yl)-4-(5-methoxypyridine-2-yl)thiazole-2-amine [ka] 5-Isopropoxypicolinealdehyde. To a mixture of 5-hydroxypicolinealdehyde (9 g, 73.10 mmol) and K2CO3 (10.1 g, 73.10 mmol) in DMF (100 mL), stirred under a nitrogen atmosphere at 25°C, isopropyl iodide (12.4 g, 73.10 mmol) was added dropwise over 30 minutes. The reaction mixture was stirred at 100°C for 3 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The combined organic layer was washed with water and then with brine. It was dried on anhydrous Na2SO4 and concentrated under vacuum. The product was purified by silica gel chromatography to obtain 5-isopropoxypicolinealdehyde (8.5 g, 70% yield).

[0275] 1-(5-isopropoxypyridine-2-yl)ethanol. To a solution of 5-isopropoxypicolinealdehyde (8.5 g, 51.45 mmol) in THF (150 mL) stirred under a nitrogen atmosphere at 0°C, methylmagnesium chloride (25.7 mL, 77.18 mmol) was added dropwise over 15 minutes. The reaction mixture was stirred at 24°C for 16 hours. The reaction was quenched with saturated NH4Cl solution at 0°C and then extracted with Â. The combined organic layers were washed with water and brine, dried on anhydrous Na2SO4, and concentrated under vacuum to obtain 1-(5-isopropoxypyridine-2-yl)ethanol (8.5 g, yield 91%).

[0276] 1-(5-isopropoxypyridine-2-yl)ethanone. To a solution of 2,2,6,6-tetramethylpiperidine-1-oxyl (750 mg, 4.69 mmol) and trichloroisocyanuric acid (12 g, 51.65 mmol) at 0°C, a solution of 1-[5-(1-methylethoxy)pyridine-2-yl]ethanol (8.5 g, 46.96 mmol) dissolved in acetone (100 mL) was added, and the mixture was stirred at 0°C for 10 minutes. The reaction solution was concentrated under vacuum. The residue was stirred with an aqueous solution of NaHCO3, and the resulting solution was extracted with ELISA. The combined organic layers were washed with brine, dried on Na2SO4, and concentrated under reduced pressure to obtain 1-(5-isopropoxypyridine-2-yl)ethanone (5 g), which was used without further purification.

[0277] 2-Bromo-1-(5-isopropoxypyridine-2-yl)ethanone. Under a nitrogen atmosphere at 24°C, pyridinium tripromide (8.9 g, 27.93 mmol) was added all at once to a solution of 1-(5-isopropoxypyridine-2-yl)ethanone (5 g, 27.93 mmol) in THF (50 mL). The reaction mixture was stirred at 24°C for 16 hours. The resulting solid mass was collected by filtration, rinsed with THF, and dried under vacuum to obtain 2-bromo-1-(5-isopropoxypyridine-2-yl)ethanone (4 g), which was used without further purification.

[0278] 4-(5-isopropoxypyridine-2-yl)-N-(3-methylpyridine-2-yl)thiazole-2-amine. 2-bromo-1-(5-isopropoxypyridine-2-yl)ethanone (3.7 g, 14.35 mmol) was added all at once to a solution of 1-(3-methylpyridine-2-yl)thiourea (2 g, 11.95 mmol) in EtOH (50 mL) under a nitrogen atmosphere at 25°C. The reaction mixture was stirred at 80°C for 4 hours. The reaction mixture was poured into ice water and the pH was adjusted to 8 with aqueous ammonia. The resulting crude material was collected by filtration, washed with water, and dried under vacuum. The product was isolated and purified by standard methods to obtain 4-(5-methoxypyridine-2-yl)-N-(3-methylpyridine-2-yl)thiazole-2-amine (1.05 g, yield 27%). MS(ESI)m / z 327.29[M+H] + .

[0279] Example 4.4-(5-methoxypyridine-2-yl)-N-(3-methylpyridine-2-yl)thiazole-2-amine [ka] N-(3-methylpyridine-2-ylcarbamotioil)benzamide. Benzoyl isothiocyanate (16.6 g, 101.71 mmol) was added dropwise to a solution of 3-methylpyridine-2-amine (10 g, 92.47 mmol) in acetone (100 mL) stirred under a nitrogen atmosphere at 24 °C. The reaction mixture was stirred at 70 °C for 3 hours. The reaction mixture was diluted with water and extracted with siRNA. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The crude product was triturated with n-pentane, the solid was collected by filtration, and the product was dried under vacuum to obtain N-(3-methylpyridine-2-ylcarbamotioil)benzamide (20 g, yield 80%).

[0280] 1-(3-methylpyridine-2-yl)thiourea. To a stirred solution of N-(3-methylpyridine-2-yl carbamotiol)benzamide (10 g, 36.90 mmol) in MeOH (100 ml), 50 mL of 1 N NaOH solution was added dropwise at 24 °C. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was poured into ice water, and the pH of the solution was adjusted to neutral with dilute HCl. The resulting solid mass was collected by filtration and dried under vacuum to obtain 1-(3-methylpyridine-2-yl)thiourea (5 g, 29.94 mmol, yield 81%).

[0281] 2-Bromo-1-(5-methoxypyridine-2-yl)ethanone. A solution of 1-(5-methoxypyridine-2-yl)ethanone (3 g, 19.867 mmol) in 33% HBr (10.8 mL) in AcOH stirred at 0°C was met with dropwise addition of a suspension of pyridinium tribromide (8.2 g, 25.827 mmol) in AcOH (210 mL). The reaction mixture was stirred at 24°C for 5 hours. The reaction mixture was diluted with Et2O, and the solution was kept in a refrigerator at -4°C for 16 hours. The resulting crude material was collected by filtration, washed with Et2O, and dried under vacuum to obtain 2-bromo-1-(5-methoxypyridine-2-yl)ethanone (4 g), which was used in the next step without purification. MS(ESI) m / z 230.36[M+1] + .

[0282] 4-(5-methoxypyridine-2-yl)-N-(3-methylpyridine-2-yl)thiazole-2-amine. 2-bromo-1-(5-methoxypyridine-2-yl)ethanone (3.7g, 14.35 mmol) was added all at once to a solution of 1-(3-methylpyridine-2-yl)thiourea (2g, 11.95 mmol) in EtOH (50 mL) stirred under a nitrogen atmosphere at 24°C. The reaction mixture was stirred at 80°C for 4 hours. The reaction mixture was poured into ice water and the pH was adjusted to 10 with aqueous ammonia. The crude material was collected by filtration, washed with water (10 mL), and dried under vacuum. The product was isolated and purified by standard methods to obtain 4-(5-methoxypyridine-2-yl)-N-(3-methylpyridine-2-yl)thiazole-2-amine (1.3 g, yield 37%). MS(ESI)m / z 299.22[M+H] + .

[0283] Example 5.4-(5-methoxypyridine-2-yl)-N-(5-(tetrahydro-2H-pyran-4-yloxy)pyridine-2-yl)thiazole-2-amine [ka] Tetrahydro-2H-pyran-4-ylmethanesulfonate. Methanesulfonyl chloride (10.1 g, 89.2 mmol) was added dropwise to a stirred, cooled solution of tetrahydro-2H-pyran-4-ol (7.00 g, 68.6 mmol) and TEA (20.7 g, 206 mmol) in DCM (50 mL). The mixture was stirred at 24 °C for 16 hours. The reaction mixture was partitioned between water and DCM. The organic layer was separated, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel chromatography to obtain the desired product (6.4 g, 35.6 mmol, 52%).

[0284] 5-(tetrahydro-2H-pyran-4-yloxy)pyridine-2-amine. To a solution of tetrahydro-2H-pyran-4-ylmethanesulfonate (4.00 g, 22.2 mmol) in N,N-dimethylformamide (20 mL), 6-aminopyridine-3-ol (2.93 g, 26.7 mmol) and K2CO3 (9.2 g, 66.7 mmol) were added. The mixture was stirred at 100°C for 16 hours. The reaction was cooled to 24°C, filtered, and the inorganic salts were removed. The filtrate was partitioned between water and DCM. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (1.25 g, 6.44 mmol, yield 29%).

[0285] N-(5-(tetrahydro-2H-pyran-4-yloxy)pyridine-2-ylcarbamoteoyl)benzamide. Benzyl thioisocyanate (1.05 g, 6.44 mmol) was added to a solution of 5-(tetrahydro-2H-pyran-4-yloxy)pyridine-2-amine (1.25 g, 6.44 mmol) in DCM (10 mL). The mixture was stirred at 24 °C for 4 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.60 g, 4.48 mmol, yield 69%).

[0286] 1-(5-(tetrahydro-2H-pyran-4-yloxy)pyridine-2-yl)thiourea. N-(5-(tetrahydro-2H-pyran-4-yloxy)pyridine-2-ylcarbamoteoyl)benzamide (900 mg, 2.52 mmol) was dissolved in NaOH water (2.5 M, 10 mL), and the mixture was stirred at 80°C for 1 hour. The reaction was cooled to 0°C, and the precipitate was collected by filtration. The filtration cake was washed with water and dried to obtain the desired product (560 mg, 2.21 mmol, yield 88%).

[0287] 4-(5-methoxypyridine-2-yl)-N-(5-(tetrahydro-2H-pyran-4-yloxy)pyridine-2-yl)-thiazole-2-amine. 2-bromo-1-(5-methoxypyridine-2-yl)ethanone hydrobromide (99 mg, 0.316 mmol) was added to a solution of 1-(5-(tetrahydro-2H-pyran-4-yloxy)pyridine-2-yl)thiourea (80 mg, 0.316 mmol) in EtOH (5 mL). The mixture was stirred at 24°C for 1 hour. The product was isolated and purified by standard methods to obtain (56 mg, 0.146 mmol, yield 46%). MS(ESI) m / z 385.1[M+H] + .

[0288] Example 6. N-(4-isopropoxypyridine-2-yl)-4-(5-methoxypyridine-2-yl)thiazole-2-amine [ka] 4-Isopropoxypyridine-2-amine. Sodium propane-2-olate (63.7 g, 777.0 mmol) was added to a solution of 4-chloropyridine-2-amine (10 g, 77.7 mmol) in DMSO (500 mL) under a nitrogen atmosphere at 24 °C, and the reaction solution was stirred at 150 °C for 4 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried on anhydrous Na₂SO₄, and concentrated under vacuum. The crude product was purified by silica gel chromatography to obtain 4-isopropoxypyridine-2-amine (7 g, 59% yield).

[0289] N-(4-isopropoxypyridine-2-ylcarbamotioil)benzamide. Benzoyl isothiocyanate (10.7 g, 65.78 mmol) was added dropwise to a solution of 4-isopropoxypyridine-2-amine (10 g, 65.78 mmol) in THF (100 mL) under a nitrogen atmosphere at 24 °C. The reaction mixture was stirred at 70 °C for 3 hours. The reaction mixture was diluted with water. The product was collected by filtration, washed with water, and dried under vacuum to obtain N-(4-isopropoxypyridine-2-ylcarbamotioil)benzamide (12 g, yield 58%), which was used in the next step without further purification.

[0290] 1-(4-isopropoxypyridine-2-yl)thiourea. At 24°C, 1N NaOH (20mL) was added to a solution of N-(4-isopropoxypyridine-2-yl carbamotioyl)benzamide (6g, 19.04 mmol) in MeOH (50mL), and the mixture was stirred at 80°C for 2 hours. The reaction mixture was poured into ice water and the pH was adjusted to 7 with 1N HCl. The resulting crude material was collected by filtration, washed with water, and dried under vacuum to obtain 1-(4-isopropoxypyridine-2-yl)thiourea (3.5g, yield 87%).

[0291] N-(4-isopropoxypyridine-2-yl)-4-(5-methoxypyridine-2-yl)thiazole-2-amine. Under a nitrogen atmosphere at 24°C, 2-bromo-1-(5-methoxypyridine-2-yl)ethanone (2.2 g, 9.478 mmol) was added all at once to a solution of 1-(4-isopropoxypyridine-2-yl)thiourea (2 g, 9.478 mmol) in EtOH (50 ml). The reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was poured into ice water and adjusted to pH 10 with aqueous ammonia. The product was isolated and purified by standard methods to obtain N-(4-isopropoxypyridine-2-yl)-4-(5-methoxypyridine-2-yl)thiazole-2-amine (2.5 g, yield 78%). MS(ESI) m / z 343.20[M+H] + .

[0292] Example 7.6-(2-((3-methylpyridine-2-yl)amino)thiazole-4-yl)nicotinamide [ka] 6-(2-bromoacetyl)nicotinamide. Bromine (0.147 ml, 2.85 mmol) was added to a suspension of 6-acetylnicotinonitrile (0.416 g, 2.85 mmol) in 33% HBr (5 ml) of AcOH. The reaction mixture was stirred at 70°C for 1 hour. The reaction mixture was quenched with saturated NaHCO3 and then washed with ethyl acetate. The organic phases were combined and washed with saturated NaCl water. The organic layer was dried on magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain 6-(2-bromoacetyl)nicotinamide (0.577 g, 2.374 mmol, yield 83%). 1 H NMR(400MHz,DMSO-d6)δ ppm 5.06(s,2H)7.83(br.s.,1H)8.35(br.s.,1H)8.41(dd,J=8.20,1.56Hz,1H)9.12(d,J=1.95Hz,1H);MS(ESI)m / z 243.0[M+H] + .

[0293] 6-(2-((3-methylpyridine-2-yl)amino)thiazole-4-yl)nicotinamide. A solution of 6-(2-bromoacetyl)nicotinamide (0.243 g, 1 mmol) and 1-(3-methylpyridine-2-yl)thiourea (0.167 g, 1.000 mmol) in EtOH (10 ml) was stirred at 78°C for 1 hour. The reaction mixture was purified using reverse-phase semi-preparative HPLC. The fraction containing the clean product was loaded onto a Phenomenex Strata-XC ion-exchange column. The column was continuously washed with water and MeOH. The product was isolated and purified by standard methods to obtain 6-(2-((3-methylpyridine-2-yl)amino)thiazole-4-yl)nicotinamide (0.125 g, 0.401 mmol, yield 40.1%). 1H NMR(400MHz,DMSO-d6)δ ppm 2.38(s,3H)6.93(dd,J=7.42,5.08Hz,1H)7.54-7.62(m,2H)7.80(s,1H)8.11(d,J=8.20Hz,1H)8.16(s,1 H)8.20(d,J=3.12Hz,1H)8.32(dd,J=8.20,1.95Hz,1H)9.05(d,J=2.34Hz,1H)10.58(s,1H).MS(ESI)m / z 312.2[M+H]+.

[0294] Example 8. N,N-dimethyl-6-(2-((3-methylpyridine-2-yl)amino)thiazole-4-yl)nicotinamide [ka] 6-Bromo-N,N-dimethylnicotinamide. 6-bromonicotinic acid (5.00 g, 24.8 mmol) and dimethylamine hydrochloride (3.03 g, 37.1 mmol) were dissolved in THF (100 mL) and 4-methylmorpholine (7.51 g, 74.3 mmol) was added. Next, EDCI (5.7 g, 29.7 mmol) and HOBt (4 g, 29.7 mmol) were added to the mixture. The mixture was stirred under nitrogen at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was poured into water, and the aqueous phase was extracted with SiO2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography to obtain 6-bromo-N,N-dimethylnicotinamide (5 g, crude).

[0295] 6-(1-ethoxyvinyl)-N,N-dimethylnicotinamide. A mixture of 6-bromo-N,N-dimethylnicotinamide (5.00 g, 21.8 mmol) and tributyl(1-ethoxyvinyl) stannane (8.67 g, 24.0 mmol) in acetonitrile (100 mL) was mixed with CuI (623 mg, 3.27 mmol) and Pd(PPh3)2Cl2 (1.5 g, 2.18 mmol) under nitrogen. This mixture was stirred under nitrogen at 90°C for 48 hours. The mixture was poured into water and potassium fluoride (2 g) was added. The mixture was filtered through a Celite pad and the filter cake was washed with SiO2. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography to provide 6-(1-ethoxyvinyl)-N,N-dimethylnicotinamide (5.00 g, 15.9 mmol, 73% yield, 70% purity).

[0296] 6-(2-bromoacetyl)-N,N-dimethylnicotinamide. NBS (1.45 g, 8.17 mmol) was added in several portions at 0°C to a mixture of 6-(1-ethoxyvinyl)-N,N-dimethylnicotinamide (2.57 g, 8.17 mmol) in THF (49 mL) and water (16 mL). The mixture was stirred at 26°C for 0.5 hours. The mixture was poured into water, and the aqueous phase was extracted with SiO2. The combined organic phases were washed with brine, dried on anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 6-(2-bromoacetyl)-N,N-dimethylnicotinamide (3.3 g, crude).

[0297] N-((3-methylpyridine-2-yl)carbamotioil)benzamide. To a solution of benzoyl chloride (2.00 g, 14.2 mmol) in acetone (20 mL), ammonia thiocyanate (291 mg, 17.1 mmol) was added under nitrogen. This mixture was stirred at 60°C for 1 hour. A solution of 3-methylpyridine-2-amine (1.54 g, 14.2 mmol) in acetone (5 mL) was added dropwise to the above mixture under nitrogen at 20°C. The mixture was stirred at 60°C for 2 hours. The mixture was poured into water, and the aqueous phase was extracted with ELISA. The combined organic phases were washed with brine, dried on anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by silica gel chromatography to obtain N-((3-methylpyridine-2-yl)carbamotioil)benzamide (1.8 g, crude).

[0298] 1-(3-methylpyridine-2-yl)thiourea. A solution of N-((3-methylpyridine-2-yl)carbamoteoyl)benzamide (1.30 g, 4.79 mmol) in MeOH (40 mL) was added to a solution of NaOH (1 g, 26.0 mmol) in water (10 mL). The mixture was stirred at 80°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and 1N HCl was added to the mixture until a pH of 7 was obtained. The residue was diluted with water. The aqueous phase was extracted with ELISA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to obtain 1-(3-methylpyridine-2-yl)thiourea (850 mg, crude).

[0299] N,N-dimethyl-6-(2-((3-methylpyridin-2-yl)amino)thiazole-4-yl)nicotinamide. A mixture of 6-(2-bromoacetyl)-N,N-dimethylnicotinamide (2.50 g, 6.46 mmol) in EtOH (50 mL) was mixed with 1-(3-methylpyridin-2-yl)thiourea (1.00 g, 5.38 mmol). This mixture was stirred under nitrogen at 80°C for 1 hour. The product was isolated and purified by standard methods to obtain N,N-dimethyl-6-[2-[(3-methyl-2-pyridyl)amino]thiazole-4-yl]pyridin-3-carboxamide (1.53 g, 4.40 mmol, yield 82%, purity 97.5%). MS(ESI): m / z 340.2[M+1] + .

[0300] Example 9. N-(3-methylpyridine-2-yl)-4-(5-((tetrahydro-2H-pyran-4-yl)oxy)pyridine-2-yl)thiazole-2-amine. [ka] Tetrahydro-2H-pyran-4-ylmethanesulfonate. To a cooled solution of tetrahydro-2H-pyran-4-ol (7.00 g, 68.6 mmol) and TEA (20.7 g, 206 mmol) stirred in DCM (50 mL), methanesulfonyl chloride (10.1 g, 89.2 mmol) was added dropwise. The mixture was stirred at 24 °C for 16 hours. The reaction solution was partitioned between water and DCM. The organic layer was separated, dried on anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel chromatography to obtain the desired product (6.4 g, 35.6 mmol, 52%).

[0301] 2-Bromo-5-((tetrahydro-2H-pyran-4-yl)oxy)pyridine. 6-bromopyridine-3-ol (4.0 g, 23 mmol) was dissolved in DMF (45 mL) and K2CO3 (6.35 g, 46 mmol) and tetrahydro-2H-pyran-4-ylmethanesulfonate (6.2 g, 34.5 mmol) were added. The mixture was stirred at 100°C for 16 hours. Water was added, and the reaction mixture was extracted with DCM. The combined organic phase was washed with water and brine, dried on magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the desired product (3.6 g, 14 mmol, 61%).

[0302] 2-Chloro-1-(5-((tetrahydro-2H-pyran-4-yl)oxy)pyridine-2-yl)ethanone. A solution of 2-bromo-5-((tetrahydro-2H-pyran-4-yl)oxy)pyridine (0.84 g, 3.2 mmol) in THF (20 mL) was added to a solution of nBuLi in THF (1.3 mL, 2.5 M, 3.2 mmol) at -78 °C and stirred for 2 hours. To this mixture, 2-chloro-N-methoxy-N-methylacetamide (0.88 g, 6.4 mmol) in THF (5 mL) was added, and the solution was stirred for a further 4 hours at -78 °C. After quenching the reaction with saturated NH4Cl water, RINKAN was added. The organic layer was washed with water and brine, dried on magnesium sulfate, filtered, and concentrated. The crude product was purified by column chromatography using silica gel to obtain the desired product (0.30 g, 1.18 mmol, 36%).

[0303] N-(3-methylpyridine-2-yl)-4-(5-((tetrahydro-2H-pyran-4-yl)oxy)pyridine-2-yl)thiazole-2-amine. 2-chloro-1-(5-((tetrahydro-2H-pyran-4-yl)oxy)pyridine-2-yl)ethanone (0.302 g, 1.18 mmol) was added to a solution of 1-(3-methylpyridine-2-yl)thiourea (0.197 g, 1.2 mmol) in EtOH (8 mL). The reaction mixture was refluxed for 1 hour. The solvent was removed under reduced pressure. The product was isolated and purified by standard methods to obtain the title compound (0.065 g, 0.17 mmol, yield 14%). MS(ESI) m / z 369.1[M+H] + .

[0304] Example 10. 4-(5-fluoropyridine-2-yl)-N-(4-(trifluoromethyl)pyridine-2-yl)-thiazole-2-amine [ka] 4-(5-fluoropyridine-2-yl)-N-(4-(trifluoromethyl)pyridine-2-yl)thiazole-2-amine. 2-bromo-1-(5-fluoropyridine-2-yl)ethane-1-one hydrobromide (203 mg, 0.678 mmol) and DIPEA (0.118 ml, 0.678 mmol) were added to a solution of 1-(4-(trifluoromethyl)pyridine-2-yl)thiourea (100 mg, 0.452 mmol) in EtOH (5 ml), and the mixture was stirred at 85°C for 4 hours. A precipitate formed, and after the reaction mixture was cooled, it was filtered. The product was isolated and purified by standard methods to obtain 4-(5-fluoropyridine-2-yl)-N-(4-(trifluoromethyl)pyridine-2-yl)thiazole-2-amine (95 mg, 0.276 mmol, yield 61.1%). 1H NMR(300MHz,DMSO-d6)δ 11.82(s,1H),8.65-8.54(m,2H),8.02(dd,J=8.8,4.6Hz,1H),7.83(td,J=8.8,3. 0Hz,1H),7.69(s,1H),7.43(s,1H),7.26(dd,J=5.4,1.5Hz,1H).LCMS(APCI):m / z 341.1[M+H] + .

[0305] Example 11. N-(5-isopropyl-4-(trifluoromethyl)pyridine-2-yl)-4-(pyridine-2-yl)thiazole-2-amine [ka] 5-Bromo-4-(trifluoromethyl)pyridine-2-amine. To a stirred solution of 4-(trifluoromethyl)pyridine-2-amine (10 g, 61.72 mmol) in DCM (100 mL), NBS (10.98 g, 61.72 mmol) was added all at once under a nitrogen atmosphere at 24 °C. The resulting mixture was stirred for 2 hours. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, dried on anhydrous Na₂SO₄, and concentrated under vacuum. The product was purified by silica gel column chromatography to obtain 5-bromo-4-(trifluoromethyl)pyridine-2-amine (10 g, 67% yield).

[0306] 5-(propa-1-en-2-yl)-4-(trifluoromethyl)pyridine-2-amine. 5-bromo-4-(trifluoromethyl)pyridine-2-amine (5 g, 20.83 mmol), 4,4,5,5-tetramethyl-2-(propa-1-en-2-yl)-1,3,2-dioxaborolane (5.25 g, 31.25 mmol), and K2CO3 (8.62 g, 62.49 mmol) were added all at once to a degassed solution of [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with DCM (1.52 g, 2.08 mmol). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was filtered through a Celite pad and rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 5-(propa-1-en-2-yl)-4-(trifluoromethyl)pyridine-2-amine (3.5 g, yield 83%).

[0307] 5-Isopropyl-4-(trifluoromethyl)pyridine-2-amine. A solution of 5-(propa-1-en-2-yl)-4-(trifluoromethyl)pyridine-2-amine (10 g, 92.47 mmol) in EtOH (100 mL) was mixed with Pd / C (0.3 equivalents) under a nitrogen atmosphere, and the solution was hydrogenated at 40 psi for 16 hours using a Parr shaker. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under vacuum to obtain 5-isopropyl-4-(trifluoromethyl)pyridine-2-amine (6 g, 60% yield).

[0308] N-(5-isopropyl-4-(trifluoromethyl)pyridine-2-ylcarbamotioil)benzamide. Benzoyl isothiocyanate (4.8 g, 29.11 mmol) was added dropwise to a solution of 5-isopropyl-4-(trifluoromethyl)pyridine-2-amine (5.4 g, 26.47 mmol) in THF (60 mL) under a nitrogen atmosphere at 24 °C. The reaction mixture was stirred at 70 °C for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried on anhydrous sodium 2 SO4, and concentrated under vacuum to obtain N-(5-isopropyl-4-(trifluoromethyl)pyridine-2-ylcarbamotioil)benzamide (4.9 g, yield 50%).

[0309] 1-(5-isopropyl-4-(trifluoromethyl)pyridine-2-yl)thiourea. To a solution of N-(5-isopropyl-4-(trifluoromethyl)pyridine-2-yl carbamotiol)benzamide (4.8 g, 13.07 mmol) in MeOH stirred at 24°C, 20 mL of 1N NaOH solution was added, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was poured into ice water and neutralized with dilute HCl. The resulting crude material was collected by filtration, washed with water, and dried under vacuum to obtain 1-(5-isopropyl-4-(trifluoromethyl)pyridine-2-yl)thiourea (3.1 g, 90% yield).

[0310] N-(5-isopropyl-4-(trifluoromethyl)pyridine-2-yl)-4-(pyridine-2-yl)thiazole-2-amine. To a solution of 1-(5-isopropyl-4-(trifluoromethyl)pyridine-2-yl)thiourea (2 g, 76.04 mmol) in EtOH (20 mL) stirred under a nitrogen atmosphere at 24°C, 2-bromo-1-(5-methoxypyridine-2-yl)ethanone (1.5 g, 76.04 mmol) was added all at once, and the solution was stirred at 80°C for 4 hours. The reaction mixture was poured into ice water and the pH was adjusted to 10 with aqueous ammonia. The product was collected by filtration, washed with water, and dried under vacuum. The product was isolated and purified by standard methods to obtain N-(5-isopropyl-4-(trifluoromethyl)pyridine-2-yl)-4-(pyridine-2-yl)thiazole-2-amine (1.6 g, 57% yield). MS(ESI)m / z 365.23[M+H] + .

[0311] Example 12.6-(4-(pyridine-2-yl)thiazole-2-ylamino)pyridine-3-ol [ka] 6-(4-(pyridine-2-yl)thiazole-2-ylamino)pyridine-3-ol. To a solution of N-(5-methoxypyridine-2-yl)-4-(pyridine-2-yl)thiazole-2-amine (0.150 g, 0.528 mmol) in DCM (20 ml), BBr3 (1 M in DCM) (3.17 ml, 3.17 mmol) was added. The reaction mixture was stirred at 40°C for 15 hours. The reaction mixture was quenched with saturated NaHCO3 and diluted with siRNA. The layers were separated, and the organic phase was washed with saturated NaCl water. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified using reverse-phase semi-preparative HPLC. The fraction containing the clean product was loaded onto a Phenomenex Strata-XC ion-exchange column. The column was sequentially washed with water and MeOH, and the product was eluted with 5% ammonium hydroxide in MeOH. The eluent containing the product was concentrated under reduced pressure to obtain 6-(4-(pyridine-2-yl)thiazole-2-ylamino)pyridine-3-ol (0.145 g, 0.536 mmol, yield 102%). The free base was dissolved in THF (20 mL), and the hydrochloride salt (1.2 equivalents in 1 M diethyl ether) was added. The product was isolated and purified by standard methods to obtain 6-(4-(pyridine-2-yl)thiazole-2-ylamino)pyridine-3-ol HCl salt. MS(ESI) m / z 271.4[M+H] + .

[0312] Example 13. N-(3,5-dimethylpyridine-2-yl)-4-(pyridine-2-yl)thiazole-2-amine [ka] N-(3,5-dimethylpyridine-2-yl)-4-(pyridine-2-yl)thiazole-2-amine. A solution of 2-bromo-1-(pyridine-2-yl)ethanone (0.200 g, 1 mmol) and 1-(3,5-dimethylpyridine-2-yl)thiourea (0.181 g, 1.000 mmol) in EtOH (10 ml) was stirred at 78°C for 1 hour. The reaction mixture was quenched with saturated NaCl, washed with ethyl acetate, and then washed additionally with saturated NaCl water. The organic layers were combined, dried on magnesium sulfate, filtered, and concentrated. The crude residue was purified by reverse-phase semi-preparative HPLC. The fraction containing the clean product was loaded onto a Phenomenex Strata-XC ion-exchange column. The column was washed sequentially with water and MeOH. The product was isolated and purified by standard methods to obtain N-(3,5-dimethylpyridine-2-yl)-4-(pyridine-2-yl)thiazole-2-amine (0.083 g, 0.294 mmol, yield 29.4%). MS(ESI)m / z 282.36[M+H] + .

[0313] Example 14. 5-Methyl-N-(4-methylpyridine-2-yl)-4-(pyridine-2-yl)thiazole-2-amine [ka] 5-Methyl-N-(4-methylpyridine-2-yl)-4-(pyridine-2-yl)thiazole-2-amine. A solution of 2-chloro-1-(pyridine-2-yl)propan-1-one (0.170 g, 1 mmol) and 1-(4-methylpyridine-2-yl)thiourea (0.167 g, 1.000 mmol) in EtOH (10 ml) was stirred at 75°C for 15 hours. The reaction mixture was quenched with saturated NaCl water and washed with ethyl acetate. The organic phases were combined and washed with saturated NaCl water. The organic layers were dried over magnesium sulfate, filtered, and concentrated. The product was isolated and purified by standard methods to obtain 5-methyl-N-(4-methylpyridine-2-yl)-4-(pyridine-2-yl)thiazole-2-amine (0.120 g, 0.425 mmol, yield 42.5%); MS(ESI) m / z 283.2[M+H]+ .

[0314] Example 15. 4-(pyridine-2-yl)-N-(1H-pyrrolo[3,2-b]pyridine-5-yl)thiazole-2-amine [ka] 4-(pyridine-2-yl)-N-(1H-pyrrolo[3,2-b]pyridine-5-yl)thiazole-2-amine. A solution of 1-(1H-pyrrolo[3,2-b]pyridine-5-yl)thiourea (0.192 g, 1 mmol) and 2-bromo-1-(pyridine-2-yl)ethanone (0.200 g, 1.000 mmol) in EtOH (10 ml) was stirred at 78°C for 24 hours. The reaction mixture was concentrated, the product isolated, and purified by standard methods to obtain 4-(pyridine-2-yl)-N-(1H-pyrrolo[3,2-b]pyridine-5-yl)thiazole-2-amine (0.120 g, 0.409 mmol, yield 40.9%). LC-MS (ESI): m / z 294.2 [M+H] + .

[0315] Example 16. 2-((4-(pyridine-2-yl)thiazole-2-yl)amino)isonicotinamide [ka] 2-((4-(pyridine-2-yl)thiazole-2-yl)amino)isonicotinamide. 2-thioureidoisonicotinamide (200 mg, 1.019 mmol) was stirred in EtOH (2 ml) under a nitrogen atmosphere at 24°C. 2-bromo-1-(pyridine-2-yl)ethane-1-one hydrobromide (286 mg, 1.019 mmol) was added, and the reaction mixture was stirred at 80°C for 4 hours. The reaction mixture was poured into ice water and the pH was adjusted to 10 with aqueous ammonia. The product was isolated and purified by standard methods to obtain 2-((4-(pyridine-2-yl)thiazole-2-yl)amino)isonicotinamide (79 mg, 0.266 mmol, yield 26.1%). 1H NMR(300MHz,DMSO-d6)δ 11.64(s,1H),8.60(d,J=4.4Hz,1H),8.43(d,J=5.3Hz,1H),8.17(s,1H),7.99(d,J=7.8Hz,1H),7.88(td, LCMS(ESI):m / z 298.1[M+H] + .

[0316] Example 17. 2-((4-(pyridine-2-yl)thiazole-2-yl)amino)-N-(2,2,2-trifluoroethyl)isonicotinamide [ka] 2-((4-(pyridine-2-yl)thiazole-2-yl)amino)-N-(2,2,2-trifluoroethyl)isonicotinamide. To a stirred solution of 2-((4-(pyridine-2-yl)thiazole-2-yl)amino)isonicotinic acid (100 mg, 0.335 mmol) in DMF (2 ml), TEA (0.047 ml, 0.335 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosfinan 2,4,6-trioxide (0.200 ml, 0.335 mmol), and 2,2,2-trifluoroethane-1-amine hydrochloride (45.4 mg, 0.335 mmol) were added. The resulting reaction mixture was stirred at 25°C for 14 hours. The product was isolated and purified by standard methods to obtain 2-((4-(pyridine-2-yl)thiazole-2-yl)amino)-N-(2,2,2-trifluoroethyl)isonicotinamide (14 mg, 0.037 mmol, yield 11.01%). 1H NMR(300MHz,DMSO-d6)δ 11.68(s,1H),9.35(t,J=6.2Hz,1H),8.61(d,J=4.6Hz,1H),8.48(d,J=5.3Hz,1H),8.05-7. 82(m,2H),7.70(s,1H),7.53(s,1H),7.39-7.23(m,2H),4.24-4.01(m,2H).LCMS(ESI):m / z 380.0[M+H] + .

[0317] Example 18. N-Isopropyl-2-((4-(pyridine-2-yl)thiazole-2-yl)amino)isonicotinamide [ka] N-isopropyl-2-((4-(pyridin-2-yl)thiazole-2-yl)amino)isonicotinamide. 2-((4-(pyridin-2-yl)thiazole-2-yl)amino)isonicotinic acid, hydrobromide (50 mg, 0.132 mmol) and HATU (75 mg, 0.198 mmol) were suspended in DMF (659 μl), then DIPEA (69.1 μl, 0.396 mmol) was added, and the reaction mixture was stirred for 10 minutes. Isopropylamine (13.55 μl, 0.158 mmol) was added, and the reaction mixture was stirred for 16 hours. The product was isolated and purified by standard methods to obtain N-isopropyl-2-((4-(pyridin-2-yl)thiazole-2-yl)amino)isonicotinamide (30 mg, 0.088 mmol, yield 67.0%). 1 H NMR(300MHz,DMSO-d6)δ 11.60(s,1H),8.59(ddd,J=4.8,1.8,1.0Hz,1H),8.46(d,J=7.8Hz,1H),8.41(d,J=5.3Hz,1H),7.98(dt,J=7.9,1.1Hz,1H),7.88( td,J=7.7,1.8Hz,1H),7.67(s,1H),7.51-7.43(m,1H),7.37-7.24(m,2H),4.19-3.97(m,1H),1.18(d,J=6.6Hz,6H).MS(ESI):m / z 340.2[M+H] + .

[0318] Example 19. (4-(6-((4-(pyridine-2-yl)thiazole-2-yl)amino)pyridine-3-yl)piperazine-1-yl)(1-(trifluoromethyl)cyclopropyl)methanone [ka] (4-(6-((4-(pyridine-2-yl)thiazole-2-yl)amino)pyridine-3-yl)piperazine-1-yl)(1-(trifluoromethyl)cyclopropyl)methanone. N-ethyl-N-isopropylpropan-2-amine (340 mg, 2.63 mmol) was added to a solution of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (135 mg, 0.876 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (500 mg, 1.314 mmol) in DMF (1.00 ml), and the mixture was stirred at 25°C for 10 minutes. Next, N-(5-(piperazine-1-yl)pyridine-2-yl)-4-(pyridine-2-yl)thiazole-2-amine (326 mg, 0.964 mmol) dissolved in DMF (1 ml) was added to the stirred solution. The solution was then stirred at 25°C for 5 hours. The reaction mixture was then diluted with DCM and washed with 10% LiCl solution. The organic layer was passed through a hydrophobic frit and organic matter was removed under vacuum. The product was isolated and purified by standard methods to obtain (4-(6-((4-(pyridine-2-yl)thiazole-2-yl)amino)pyridine-3-yl)piperazine-1-yl)(1-(trifluoromethyl)cyclopropyl)methanone (112 mg, 0.234 mmol, yield 26.7%). 1H NMR(300MHz,DMSO-d6)δ 11.19(s,1H),8.59(ddd,J=4.8,1.8,0.9Hz,1H),8.07-7.92(m,2H),7.87(td,J=7.6,1.8Hz,1H),7.63-7.48(m,2H),7.30(ddd, LCMS(ESI):m / z 475.1[M+H] + .

[0319] Example 20.1-(6-((4-(pyridine-2-yl)thiazole-2-yl)amino)pyridine-3-yl)piperidine-3-carboxylic acid [ka] 1-(6-((4-(pyridin-2-yl)thiazole-2-yl)amino)pyridin-3-yl)piperidine-3-carboxylic acid. A suspension of 2-bromo-1-(pyridin-2-yl)ethane-1-one hydrobromide (546 mg, 1.944 mmol) and 1-(6-thioureidopyridin-3-yl)piperidine-3-carboxylic acid (545 mg, 1.944 mmol) was heated in EtOH (20 ml) at 85°C for 5 hours. A precipitate was formed, and a saturated solution of NaHCO3 was added until the pH became neutral, and the precipitate was dissolved. The product was isolated and purified by standard methods to obtain 1-(6-((4-(pyridin-2-yl)thiazole-2-yl)amino)pyridin-3-yl)piperidine-3-carboxylic acid (350 mg, 0.881 mmol, yield 45.3%). 1H NMR(300MHz,DMSO-d6)δ 12.31(s,1H),11.16(s,1H),8.68-8.50(m,1H),8.04-7.92(m,2H),7.87(td,J=7.7,1.8Hz,1H),7.57 (s,1H),7.49(dd,J=9.0,2.9Hz,1H),7.30(ddd,J=7.4,4.8,1.3Hz,1H),7.06(d,J=9.0Hz,1H),3.69- 3.38(m,2H),2.93(dd,J=12.0,9.4Hz,1H),2.78(ddd,J=12.2,9.7,3.3Hz,1H),2.59(tq,J=6.8,3.7H z,1H),1.90(dt,J=12.5,4.0Hz,1H),1.82-1.70(m,1H),1.58(tt,J=13.6,6.9Hz,2H).LCMS(ESI):m / z 382.1[M+H] + .

[0320] Example 21. 2-Hydroxy-2-methyl-1-(4-(6-((4-(pyridine-2-yl)thiazole-2-yl)amino)pyridine-3-yl)piperazine-1-yl)propan-1-one [ka] 2-Hydroxy-2-methyl-1-(4-(6-((4-(pyridine-2-yl)thiazole-2-yl)amino)pyridine-3-yl)piperazine-1-yl)propan-1-one. N-ethyl-N-isopropylpropan-2-amine (354 mg, 2.74 mmol) was added to a solution of 2-hydroxy-2-methylpropanoic acid (95 mg, 0.913 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (520 mg, 1.369 mmol) in DMF (1.0 ml), and the mixture was stirred at 24°C for 10 minutes. N-(5-(piperazin-1-yl)pyridine-2-yl)-4-(pyridine-2-yl)thiazole-2-amine (340 mg, 1.0 mmol) dissolved in DMF (1 ml) was added to a stirred solution. The solution was then stirred at 24°C for 5 hours. Next, the reaction mixture was diluted with DCM and washed with 10% LiCl solution. The organic layer was then passed through a hydrophobic frit to remove organic matter under vacuum. The product was isolated and purified by standard methods to obtain 2-hydroxy-2-methyl-1-(4-(6-((4-(pyridine-2-yl)thiazole-2-yl)amino)pyridine-3-yl)piperazin-1-yl)propan-1-one (98 mg, 0.224 mmol, yield 24.54%). 1 H NMR(300MHz,DMSO-d6)δ 11.17(s,1H),8.59(ddd,J=4.8,1.8,1.0Hz,1H),8.07-7.91(m,2H),7.87(td,J=7.6,1.8Hz,1H),7.57(s,1H),7.53(dd,J=9.0,2.9Hz,1H) ,7.30(ddd,J=7.4,4.7,1.3Hz,1H),7.07(d,J=9.0Hz,1H),5.45(s,1H),3.31(s,18H),3.10(t,J=5.1Hz,4H),1.35(s,5H).LCMS(ESI):m / z 425.1[M+H] + .

[0321] Example 22.1-(6-((4-(pyridine-2-yl)thiazole-2-yl)amino)pyridine-3-yl)-N-(2,2,2-trifluoroethyl)piperidine-3-carboxamide [ka] 1-(6-((4-(pyridine-2-yl)thiazole-2-yl)amino)pyridine-3-yl)-N-(2,2,2-trifluoroethyl)piperidine-3-carboxamide. 1-(6-((4-(pyridine-2-yl)thiazole-2-yl)amino)pyridine-3-yl)piperidine-3-carboxylic acid hydrobromide (300 mg, 0.649 mmol) and HATU (370 mg, 0.973 mmol) were dissolved in DMF (2 ml), to which DIPEA (0.340 ml, 1.947 mmol) was added, and the mixture was stirred at 24°C for 10 minutes. 2,2,2-trifluoroethane-1-amine (77 mg, 0.779 mmol) was added to the stirred solution, and the solution was stirred at 24°C for 5 hours. The reaction mixture was diluted with DCM and washed with 10% LiCl solution. The organic layer was passed through a hydrophobic frit, and organic matter was removed under vacuum. The product was isolated and purified by standard methods to obtain 1-(6-((4-(pyridine-2-yl)thiazole-2-yl)amino)pyridine-3-yl)-N-(2,2,2-trifluoroethyl)piperidine-3-carboxamide (173 mg, 0.374 mmol, yield 57.7%). 1 1H NMR (300MHz, DMSO-d6)δ 11.15(s,1H),8.69-8.48(m,2H),8.03-7.92(m,2H),7.87(td,J=7.7,1.8Hz,1H ),7.57(d,J=0.7Hz,1H),7.50(dd,J=9.0,2.9Hz,1H),7.30(ddd,J=7.4,4.8,1.3 Hz,1H),7.06(d,J=9.0Hz,1H),4.19-3.71(m,2H),3.56(dd,J=23.5,11.3Hz,2H ),2.96-2.53(m,3H),1.96-1.70(m,2H),1.57(q,J=11.7Hz,2H).LCMS(ESI):m / z 463.2[M+H] + .

[0322] Example 23. 5-(piperidine-1-ylmethyl)-4-(pyridine-2-yl)-N-(4-(trifluoromethyl)pyridine-2-yl)thiazole-2-amine [ka] 5-(piperidine-1-ylmethyl)-4-(pyridine-2-yl)-N-(4-(trifluoromethyl)pyridine-2-yl)thiazole-2-amine. 4-(pyridine-2-yl)-2-((4-(trifluoromethyl)pyridine-2-yl)amino)thiazole-5-carbaldehyde (25 mg, 0.071 mmol) and powdered molecular sieve were dissolved in DCE (5 ml), to which piperidine (0.021 ml, 0.214 mmol) and AcOH (4.09 μl, 0.071 mmol) were added. The mixture was stirred under reflux for 3 hours. After cooling to 24°C, sodium triacetoxyborohydride (30.2 mg, 0.143 mmol) was added, and the reaction mixture was stirred at 24°C for 4 hours. The product was isolated and purified by standard methods to obtain 5-(piperidine-1-ylmethyl)-4-(pyridine-2-yl)-N-(4-(trifluoromethyl)pyridine-2-yl)thiazole-2-amine (20 mg, 0.046 mmol, yield 64.8%). 1 H NMR(300MHz, methanol-d4)δ 8.67(d,J=4.6Hz,1H),8.55(d,J=5.4Hz,1H),8.16(d,J=8.0Hz,1H),7.98(t,J=7.9Hz,1H),7.50-7.37(m,1H),7.31( s,1H),7.19(d,J=5.4Hz,1H),4.45(s,2H),3.19-2.83(m,4H),1.92-1.74(m,4H),1.71-1.52(m,2H).LCMS(ESI):m / z 420.2[MH].

[0323] Example 24. (4-(pyridine-2-yl)-2-((4-(trifluoromethyl)pyridine-2-yl)amino)thiazole-5-yl)methanol [ka] (4-(pyridine-2-yl)-2-((4-(trifluoromethyl)pyridine-2-yl)amino)thiazole-5-yl)methanol. At 24°C, lithium borohydride (0.032 g, 1.471 mmol) was added to a solution of ethyl 4-(pyridine-2-yl)-2-((4-(trifluoromethyl)pyridine-2-yl)amino)thiazole-5-carboxylate and hydrobromide (0.233 g, 0.490 mmol) in dioxane (9.80 ml). The reaction mixture was stirred at 70°C for 18 hours. The product was isolated and purified by standard methods to obtain (4-(pyridine-2-yl)-2-((4-(trifluoromethyl)pyridine-2-yl)amino)thiazole-5-yl)methanol (48 mg, 0.136 mmol, yield 27.8%). MS(ESI): m / z 353.1[MH]. 1 H NMR(300MHz,DMSO-d6)δ 11.60(br s,1H),8.63(ddd,J=4.9,1.9,1.0Hz,1H),8.58(d,J=5.4Hz,1H),8.00(d,J=8.0Hz,1H),7.91(td,J=7.7,1.8Hz,1H), 7.40(s,1H),7.31(ddd,J=7.4,4.8,1.3Hz,1H),7.23(d,J=4.9Hz,1H),5.82(t,J=5.7Hz,1H),5.06(d,J=5.3Hz,2H).

[0324] Example 25. 5-((cyclopropylmethoxy)methyl)-4-(pyridine-2-yl)-N-(4-(trifluoromethyl)pyridine-2-yl)thiazole-2-amine [ka] 5-((cyclopropylmethoxy)methyl)-4-(pyridine-2-yl)-N-(4-(trifluoromethyl)pyridine-2-yl)thiazole-2-amine. (bromomethyl)cyclopropane (65.8 mg, 0.487 mmol), cesium carbonate (159 mg, 0.487 mmol), and potassium iodide (135 mg, 0.812 mmol) were placed in a 7 mL sealed tube containing acetone (3 ml) and heated at 75°C for 5 minutes. Next, (4-(pyridine-2-yl)-2-((4-(trifluoromethyl)pyridine-2-yl)amino)thiazole-5-yl)methanol (143 mg, 0.406 mmol) was added, and the mixture was heated for 16 hours. The product was isolated and purified by standard methods to obtain 5-((cyclopropylmethoxy)methyl)-4-(pyridine-2-yl)-N-(4-(trifluoromethyl)pyridine-2-yl)thiazole-2-amine (51 mg, 0.119 mmol, yield 29.4%). UPLC-MS(ESI): m / z 407.1[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ 8.72(d,J=5.2Hz,1H),8.69-8.62(m,1H),8.08(d,J=8.0Hz,1H),7.95(td,J=7.7,1.8Hz,1H),7.73(s,1H),7.39(d,J=5.0Hz,1H) ),7.39-7.28(m,2H),5.87(t,J=5.7Hz,1H),5.11(d,J=5.7Hz,2H),4.57(d,J=6.8Hz,2H),1.50-1.24(m,1H),0.68-0.42(m,4H).

[0325] Example 26. N-{5-[(cyclobutylmethoxy)methyl]-4-(pyridine-2-yl)-1,3-thiazole-2-yl}-4-methylpyridine-2-amine [ka] Ethyl 2-bromo-3-oxo-3-(pyridine-2-yl)propanoate. To a stirred solution of ethyl 3-oxo-3-(pyridine-2-yl)propanoate (1 g, 5.18 mmol) in 30 ml of CHCl3 at 0°C, bromine (0.27 mL, 5.18 mmol) dissolved in 5 mL of CHCl3 was added dropwise, and the mixture was stirred at 0-5°C for 15 minutes. Upon completion, the reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3. Next, the organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain ethyl 2-bromo-3-oxo-3-(pyridine-2-yl)propanoate (1.3 g, crude). MS(ESI): m / z 272.0[M+1] + .

[0326] Ethyl 2-[(4-methylpyridine-2-yl)amino]-4-(pyridine-2-yl)-1,3-thiazole-5-carboxylate. To a stirred solution of (4-methylpyridine-2-yl)thiourea (500 mg, 2.99 mmol) in EtOH (50 mL), ethyl 2-bromo-3-oxo-3-(pyridine-2-yl)propanoate (1.3 g, 2.99 mmol) was added, and the resulting mixture was heated under reflux for 16 hours. After completion, it was cooled to 25°C and poured onto crushed ice. Next, it was stirred for a further 30 minutes, and the pH was adjusted to 8 with Na2CO3 solution. The resulting crude product was filtered and washed with cold water. The crude material was dissolved in 10% MeOH:DCM, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was triturated with Et2O to obtain 2-[(4-methylpyridine-2-yl)amino]-4-(pyridine-2-yl)-1,3-thiazole-5-carboxylate ethyl (850 mg, 83%). MS(ESI): m / z 341.0[M+1] + .

[0327] {2-[(4-methylpyridine-2-yl)amino]-4-(pyridine-2-yl)-1,3-thiazole-5-yl}methanol. To a stirred solution of ethyl 2-[(4-methylpyridine-2-yl)amino]-4-(pyridine-2-yl)-1,3-thiazole-5-carboxylate (300 mg, 0.88 mmol) in 20 ml of THF at -78°C, LiEt3BH (superhydride, 1 M in THF, 3.53 mL, 3.53 mmol) was added dropwise, and the mixture was stirred at -78°C for 30 minutes. Next, it was warmed to 25°C and stirred for 16 hours. The reaction mixture was cooled to -78°C, and further LiEt3BH (superhydride, 1 M in THF, 3.53 ml, 3.53 mmol) was added, and the mixture was stirred at 25°C for 4 hours. Upon completion, the reaction mixture was cooled to -10°C, quenched with saturated NH4Cl aqueous solution, and extracted with siRNA. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. After purifying the crude compound by column chromatography, trituration with Et2O was performed to obtain {2-[(4-methylpyridine-2-yl)amino]-4-(pyridine-2-yl)-1,3-thiazole-5-yl}methanol (190 mg, 72%). MS(ESI): m / z 299.4[M+1] + .

[0328] N-{5-[(cyclobutylmethoxy)methyl]-4-(pyridine-2-yl)-1,3-thiazole-2-yl}-4-methylpyridine-2-amine. To a stirred solution of {2-[(4-methylpyridine-2-yl)amino]-4-(pyridine-2-yl)-1,3-thiazole-5-yl}methanol (100 mg, 0.34 mmol) in DCM (10 ml) at 0°C, PBr3 (0.02 ml, 0.17 mmol) was added dropwise, and the mixture was stirred at 25°C for 20 minutes. Cyclobutylmethanol (3.53 ml, 36.91 mmol) was added, and the mixture was stirred at 25°C for 30 minutes. NaOH (1 M, 2.7 mL, 2.7 mmol) was added, and the mixture was stirred at 25°C for 2 hours. After completion, the reaction mixture was evaporated under reduced pressure and diluted with ethyl acetate. The organic layer was washed with NaHCO3 solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by standard methods to obtain N-{5-[(cyclobutylmethoxy)methyl]-4-(pyridine-2-yl)-1,3-thiazole-2-yl}-4-methylpyridine-2-amine (25 mg, 20%). MS(ESI): m / z 367.2[M+1] + .

[0329] Example 27. N-[5-tert-butyl-4-(pyridine-2-yl)-1,3-thiazole-2-yl]-4-methylpyridine-2-amine [ka] 2-Bromo-3,3-dimethyl-1-(pyridine-2-yl)butan-1-one. To a stirred solution of 3,3-dimethyl-1-(pyridine-2-yl)butan-1-one (200 mg, 1.29 mmol) in AcOH (2 ml), 33% HBr (1 ml) in AcOH was added at 0°C, followed by dropwise addition of bromine (1.54 ml, 1.54 mmol) in AcOH. The resulting mixture was heated to 25°C and stirred for 2 hours. The reaction mixture was diluted with water and extracted with ELISA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired compound, 2-bromo-3,3-dimethyl-1-(pyridine-2-yl)butan-1-one (300 mg, 91%). MS(ESI): m / z 256.0[M+1] + .

[0330] N-[5-tert-butyl-4-(pyridine-2-yl)-1,3-thiazole-2-yl]-4-methylpyridine-2-amine. (4-methylpyridine-2-yl)thiourea (198 mg, 1.181 mmol) was added to a stirred solution of 2-bromo-3,3-dimethyl-1-(pyridine-2-yl)butan-1-one (300 mg, 1.18 mmol) in DMF (5 ml). The resulting mixture was heated in a sealed tube at 90°C for 16 hours. The reaction mixture was cooled to 24°C and poured onto crushed ice. The resulting solution was adjusted to pH 8 with Na2CO3 solution and extracted with ELISA. The combined organic matter was washed with brine, dried over Na2SO4, and concentrated to obtain the crude compound. The crude aggregate was purified by prep-HPLC to obtain N-[5-tert-butyl-4-(pyridine-2-yl)-1,3-thiazole-2-yl]-4-methylpyridine-2-amine (16 mg, 4%). MS(ESI): m / z 325.3[M+1] + .

[0331] Example 28. 4-Butyl-N-[4-(pyridine-2-yl)-1,3-thiazole-2-yl]pyridine-2-amine [ka] 4-Butylpyridine. To a stirred solution of LDA (2M in THF, 40.3 mL, 80.6 mmol) in 50 mL of THF, a solution of 4-methylpyridine (5 g, 53.76 mmol) in 15 mL of THF was added dropwise under an argon atmosphere at -78°C. The mixture was stirred at -78°C for 1 hour. A solution of N-iodopropane (5.74 mL, 59.14 mmol) in 15 mL of THF was added over 45 minutes at -78°C. The reaction mixture was slowly warmed to 25°C and stirred for 2 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with RINKAN. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude mass was purified by column chromatography to obtain 4-butylpyridine (6 g, 82%). MS(ESI): m / z 135.9[M+1] + .

[0332] 4-Butylpyridine-1-ium-1-olate. 4-Butylpyridine (3 g, 22.22 mmol) was dissolved in DCM (100 ml) at 0°C, and mCPBA (77%, 9.9 g, 22.22 mmol) was gradually added at 0°C. The resulting mixture was heated to 25°C and stirred for 5 hours. Upon completion, the reaction mixture was diluted with DCM, washed sequentially with saturated NaHCO3 water, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 4-Butylpyridine-1-ium-1-olate (1.9 g, 56%). MS(ESI): m / z 151.8[M+1] + .

[0333] 4-Butyl-N-tert-butylpyridine-2-amine. To a stirred solution of 4-butylpyridine-1-ium-1-olate (1.8 g, 11.92 mmol) in trifluorotoluene (75 ml) at 0°C under an argon atmosphere, tBuNH2 (6.2 ml, 59.60 mmol) was added dropwise. Tosylic acid anhydride (7.8 g, 23.84 mmol) was added all at once, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude mass was purified by column chromatography to obtain 4-butyl-N-tert-butylpyridine-2-amine (1.3 g, 53%). MS(ESI): m / z 207.4[M+1] + .

[0334] 4-Butylpyridine-2-amine. 4-Butyl-N-tert-butylpyridine-2-amine (1.2 g, 5.82 mmol) was dissolved in TFA (25 ml) and heated at 65°C for 3 hours. The reaction mixture was evaporated under reduced pressure and diluted with ice-water. The aqueous portion was adjusted to pH 8 with saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mass was purified by column chromatography to obtain 4-butylpyridine-2-amine (500 mg, 66%). MS(ESI): m / z 150.7[M+1] + .

[0335] 1-Benzoyl-3-(4-butylpyridine-2-yl)thiourea. Benzoyl isothiocyanate (597 mg, 3.66 mmol) was added to a stirred solution of 4-butylpyridine-2-amine (500 mg, 3.33 mmol) in acetone (10 mL) under an argon atmosphere. The reaction mixture was stirred at 25°C for 3 hours and concentrated under reduced pressure. The crude mixture was purified by column chromatography to obtain 1-benzoyl-3-(4-butylpyridine-2-yl)thiourea (500 mg, 48%). MS(ESI): m / z 314.1[M+1] + .

[0336] (4-Butylpyridine-2-yl)thiourea. 1-Benzoyl-3-(4-Butylpyridine-2-yl)thiourea (500 mg, 1.59 mmol) was dissolved in 10% NaOH aqueous solution (5 mL) and stirred at 25°C for 15 minutes. The reaction mixture was heated under reflux for 15 minutes and then cooled to 0°C. The pH was adjusted to 4 with HCl aqueous solution, and then to 8-9 with saturated KHCO3 aqueous solution. The resulting mixture was stirred at 0°C for 15 minutes. The crude product was filtered, washed with cold water, and dried under vacuum to obtain (4-Butylpyridine-2-yl)thiourea (220 mg, 64%). MS(ESI): m / z 210.2[M+1] + .

[0337] 4-butyl-N-[4-(pyridin-2-yl)-1,3-thiazole-2-yl]pyridine-2-amine. 2-bromo-1-(pyridin-2-yl)ethane-1-one hydrobromide (160 mg, 0.57 mmol) was added to a stirred solution of (4-butylpyridine-2-yl)thiourea (120 mg, 0.57 mmol) in EtOH (3 ml). The resulting mixture was heated under reflux for 16 hours. The reaction mixture was cooled to 25°C, poured over crushed ice, and adjusted to pH 8 with Na2CO3 solution. The crude product was filtered, washed with cold water, and dried under vacuum. The crude was purified by column chromatography to obtain 4-butyl-N-[4-(pyridin-2-yl)-1,3-thiazole-2-yl]pyridine-2-amine (85 mg, 43%). MS(ESI): m / z 310.7[M+1] + .

[0338] Example 29. N-[4-(3-methylpyridine-2-yl)-1,3-thiazole-2-yl]-4-phenylpyridine-2-amine [ka] 4-Phenylpyridine-2-amine. To a stirred solution of 4-bromopyridine-2-amine (1.5 g, 8.67 mmol) in dioxane (40 ml) and water (8 ml), K2CO3 (1.8 g, 13.0 mmol) and phenylboronic acid (1.27 g, 10.40 mmol) were added. The resulting mixture was purged with argon for 15 minutes, and Pd(dppf)Cl2 (317 mg, 0.43 mmol) was added under an inert atmosphere. The resulting mixture was heated at 100°C for 16 hours. 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 Na2SO4, filtered, and concentrated under reduced pressure. The crude mass was purified by column chromatography to obtain 4-phenylpyridine-2-amine (1.2 g, 81%). MS(ESI): m / z 171.1[M+1] + .

[0339] (4-phenylpyridine-2-yl)thiourea. To a stirred solution of 4-phenylpyridine-2-amine (1.5 g, 8.82 mmol) in acetone (20 mL), benzoyl isothiocyanate (1.44 g, 8.82 mmol) was added, and the resulting mixture was stirred at 25°C for 1 hour. The suspension was cooled in an ice-water bath, diluted with ice-water, and stirred for 10 minutes. A precipitate formed, which was filtered, washed with cold water, and dried under vacuum. The crude compound was suspended in NaOH water, stirred at 25°C for 10 minutes, and then heated under reflux for another 10 minutes. The reaction mixture was cooled to 0°C, adjusted to pH 4 with aqueous HCl, and then adjusted to pH 8-9 with aqueous saturated KHCO3. The mixture was stirred at 0°C for 15 minutes. The crude product was filtered, washed with cold water, and dried under vacuum to obtain (4-phenylpyridine-2-yl)thiourea (2 g, 99%). MS(ESI): m / z 230.1[M+1] + .

[0340] N-[4-(3-methylpyridine-2-yl)-1,3-thiazole-2-yl]-4-phenylpyridine-2-amine. (4-phenylpyridine-2-yl)thiourea (194 mg, 0.85 mmol) was added to a stirred solution of 2-bromo-1-(3-methylpyridine-2-yl)ethane-1-one (250 mg, 0.85 mmol) in EtOH (5 mL). The resulting mixture was heated under reflux for 4 hours. Next, the reaction mixture was cooled to 25 °C, poured into ice water, and adjusted to pH 8 with Na2CO3. The material thus formed was filtered and dried. The crude compound was purified by column chromatography to obtain N-[4-(3-methylpyridine-2-yl)-1,3-thiazole-2-yl]-4-phenylpyridine-2-amine (100 mg, 34%). MS(ESI): m / z 345.1[M+1] + .

[0341] Example 30. N-[4-(4-methylpyridine-2-yl)-1,3-thiazole-2-yl]-3-phenylpyridine-2-amine [ka] 2-Bromo-1-(4-methylpyridine-2-yl)ethane-1-one. A stirred solution of 1-(4-methylpyridine-2-yl)ethane-1-one (1 g, 7.41 mmol) in ice AcOH (10 mL) was prepared by adding HBr (33%, 5 mL) in AcOH. The resulting mixture was cooled to 0°C, and bromine (1 M, 8.9 mL, 8.9 mmol) in AcOH was added. The resulting mixture was slowly warmed to 25°C and stirred for 2 hours. The crude product was filtered, washed with Et2O and pentane, and dried under vacuum to obtain 2-bromo-1-(4-methylpyridine-2-yl)ethane-1-one hydrobromic acid (1.6 g, 73%). MS(ESI): m / z 213.9[M+1] + .

[0342] 3-Phenylpyridine-2-amine. To a stirred solution of 3-bromopyridine-2-ylamine (2 g, 11.56 mmol) in dioxane (40 ml) and water (8 ml), K2CO3 (2.4 g, 17.34 mmol) and phenylboronic acid (1.69 g, 13.87 mmol) were added. The resulting mixture was purged with argon for 15 minutes, and Pd(dppf)Cl2 (423 mg, 0.58 mmol) was added under an inert atmosphere. The resulting mixture was heated at 100°C for 16 hours, cooled to 24°C, and diluted with phenylpyridine-2-amine. The organic matter was washed with water and brine, dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude mass was purified by column chromatography to obtain 3-phenylpyridine-2-amine (1.8 g, 91%). MS(ESI): m / z 171.1[M+1] + .

[0343] (3-phenylpyridine-2-yl)thiourea. To a stirred solution of 3-phenylpyridine-2-amine (1.8 g, 10.59 mmol) in acetone (20 mL), benzoyl isothiocyanate (1.73 g, 10.59 mmol) was added, and the resulting mixture was stirred at 25°C for 1 hour. The suspension was cooled in an ice-water bath, diluted with ice-water, and stirred for 15 minutes. The precipitate was filtered, washed with cold water, and dried under vacuum. The crude compound (3.5 g) was suspended in 10% NaOH aqueous solution (20 mL), stirred at 25°C for 15 minutes, and then heated under reflux for another 15 minutes. The reaction mixture was cooled to 0°C, adjusted to pH 4 with aqueous HCl, and then adjusted to pH 8-9 with saturated aqueous KHCO3. The mixture was stirred at 0°C for 15 minutes. The solid was filtered, washed with cold water, and dried under vacuum to obtain (3-phenylpyridine-2-yl)thiourea (2.2 g, 90%). MS(ESI): m / z 230.1[M+1] + .

[0344] N-[4-(4-methylpyridine-2-yl)-1,3-thiazole-2-yl]-3-phenylpyridine-2-amine. To a stirred solution of 2-bromo-1-(4-methylpyridine-2-yl)ethane-1-one (250 mg, 0.85 mmol) in EtOH (5 mL), (3-phenylpyridine-2-yl)thiourea (194 mg, 0.85 mmol) was added. The resulting mixture was heated under reflux for 4 hours, then cooled to 25°C, poured into ice-water, and the pH was adjusted to 8 by adding Na2CO3 solution. The material thus formed was filtered and dried. The crude compound was purified by column chromatography to obtain N-[4-(4-methylpyridine-2-yl)-1,3-thiazole-2-yl]-3-phenylpyridine-2-amine (150 mg, 51%). MS(ESI): m / z 345.1[M+1] + .

[0345] Example 31. 4-Methyl-N-[4-(3-phenylpyridine-2-yl)-1,3-thiazole-2-yl]pyridine-2-amine [ka] N-methoxy-N-methyl-3-phenylpyridine-2-carboxamide. To a stirred solution of 3-phenylpyridine-2-carboxylic acid (1 g, 5.02 mmol) in DMF (20 mL), EDC.HCl (1.4 g, 9.04 mmol) and HOBt (814 mg, 6.02 mmol) were added, followed by the addition of N,O-dimethylhydroxylamine hydrochloride (539 mg, 5.52 mmol) and TEA (1.3 ml, 10.04 mmol). The resulting mixture was stirred at 25°C for 3 hours. The reaction mixture was quenched and extracted with RINKAN. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain N-methoxy-N-methyl-3-phenylpyridine-2-carboxamide (650 mg, 53%). MS(ESI): m / z 242.7[M+1] + .

[0346] 1-(3-phenylpyridine-2-yl)ethane-1-one. A solution of N-methoxy-N-methyl-3-phenylpyridine-2-carboxamide (630 mg, 2.807 mmol) in dry THF (8 mL) was cooled to -10°C, and MeMgBr (3 M in Et2O, 1.7 mL, 5.1 mmol) was added. The mixture was stirred at -10°C for a further 1 hour. The reaction mixture was quenched with saturated NH4Cl solution and extracted with siRNA. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude mass was purified by column chromatography to obtain 1-(3-phenylpyridine-2-yl)ethane-1-one (220 mg, 43%). MS(ESI): m / z 197.9[M+1] + .

[0347] 2-Bromo-1-(3-phenylpyridine-2-yl)ethane-1-one. A stirred solution of 1-(3-phenylpyridine-2-yl)ethane-1-one (210 mg, 1.06 mmol) in ice AcOH (2.1 ml) was prepared by adding HBr (33%, 1.1 ml) in AcOH. The resulting mixture was cooled to 0°C, and bromine (1 M, 1.28 ml, 1.28 mmol) in AcOH was added. The resulting mixture was slowly warmed to 25°C and stirred for 2 hours. The product was filtered, washed with Et2O and pentane, and dried under vacuum to obtain 2-bromo-1-(3-phenylpyridine-2-yl)ethane-1-one hydrobromide (250 mg, 66%). MS(ESI): m / z 276.1[M+1] + .

[0348] 4-methyl-N-[4-(3-phenylpyridine-2-yl)-1,3-thiazole-2-yl]pyridine-2-amine. 2-bromo-1-(3-phenylpyridine-2-yl)ethane-1-one hydrobromide (250 mg, 0.7 mmol) was stirred in EtOH (8 mL), to which (4-methylpyridine-2-yl)thiourea (117 mg, 0.7 mmol) was added. The resulting mixture was heated under reflux for 4 hours. Next, the reaction mixture was cooled to 25°C, poured into ice-water, and adjusted to pH 8 with Na2CO3 solution. The crude material was filtered, dried, and purified by column chromatography to obtain 4-methyl-N-[4-(3-phenylpyridine-2-yl)-1,3-thiazole-2-yl]pyridine-2-amine (150 mg, 62%). MS(ESI): m / z 345.1[M+1] + .

[0349] Example 32. 4-(pyrazine-2-yl)-N-[4-(pyridine-2-yl)-1,3-thiazole-2-yl]pyridine-2-amine [ka] N-[4-(pyrazine-2-yl)pyridine-2-yl]carbamate tert-butyl. To a stirred solution of 2-bromopyrazine (500 mg, 3.15 mmol) in dioxane (10 mL) and water (1 mL), K2CO3 (651 mg, 4.72 mmol) was added while purging with argon at 25°C, followed by the addition of N-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]carbamate tert-butyl (1.2 g, 3.77 mmol) and [(t-Bu)3P]BF4 (18.24 mg, 0.06 mmol). After 10 minutes, Pd(OAc)2 (35 mg, 0.16 mmol) was added, and the resulting mixture was heated at 100°C for 16 hours 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 on anhydrous Na2SO4, and concentrated. The crude product was purified by column chromatography to obtain N-[4-(pyrazine-2-yl)pyridine-2-yl]carbamate tert-butyl (500 mg, 58%). MS(ESI): m / z 273.3[M+1] + .

[0350] 4-(pyrazine-2-yl)pyridine-2-amine. To a stirred solution of N-[4-(pyrazine-2-yl)pyridine-2-yl]carbamate tert-butyl (500 mg, 1.84 mmol) in 1,4-dioxane (10 mL), 4N HCl (4.6 mL) in dioxane was added at 0°C under an argon atmosphere. The reaction mixture was stirred at 25°C for 4 hours. After the starting material was completely consumed, volatile substances were removed under reduced pressure. The resulting residue was dissolved in RINKAN and washed with saturated NaHCO3 solution, water, and then a salt solution. The organic layer was evaporated to obtain 4-(pyrazine-2-yl)pyridine-2-amine (280 mg, 88%). MS(ESI): m / z 173.2[M+1] + .

[0351] [4-(pyrazine-2-yl)pyridine-2-yl]thiourea. Benzoyl isothiocyanate (255 mg, 1.57 mmol) was added to a stirred solution of 4-(pyrazine-2-yl)pyridine-2-amine (270 mg, 0.87 mmol) in acetone (10 mL) under an argon atmosphere at 25°C. The reaction mixture was stirred at 25°C for 45 minutes, cooled to 0°C, and then water (5 mL) was added, and the mixture was stirred for 10 minutes. The solution was extracted with ethyl acetate, washed with brine, dried on anhydrous Na2SO4, and concentrated under reduced pressure. The resulting crude product was dissolved in 10% NaOH solution (5 mL), stirred at 25°C for 10 minutes, and then refluxed for a further 30 minutes. The reaction mixture was cooled to 0°C, 1N HCl solution was added dropwise to adjust the pH to 4, and then saturated NaHCO3 solution was added to adjust the pH to 8. The solid was filtered, washed with cold water, and dried under vacuum to obtain [4-(pyrazine-2-yl)pyridine-2-yl]thiourea [250 mg, 69%]. MS(ESI): m / z 231.9 [M+1] + .

[0352] 4-(pyrazine-2-yl)-N-[4-(pyridine-2-yl)-1,3-thiazole-2-yl]pyridine-2-amine. A solution of [4-(pyrazine-2-yl)pyridine-2-yl]thiourea (250 mg, 1.08 mmol) and 2-bromo-1-(pyridine-2-yl)ethane-1-one (304 mg, 1.08 mmol) in EtOH (5 mL) was heated under reflux for 18 hours. The reaction mixture was poured into ice water and stirred for 30 minutes. The reaction mixture was adjusted to pH 8 with Na2CO3 solution, the resulting solid was filtered, and washed with water. The solid was dried under vacuum and purified by column chromatography to obtain 4-(pyrazine-2-yl)-N-[4-(pyridine-2-yl)-1,3-thiazole-2-yl]pyridine-2-amine (120 mg, 33%). MS(ESI): m / z 333.1[M+1] + .

[0353] Example 33. 4-Methyl-N-[4-(pyridine-2-yl)-5-(pyrrolidine-1-ylmethyl)-1,3-thiazole-2-yl]pyridine-2-amine [Chem.] 4-Methyl-N-[4-(pyridin-2-yl)-5-(pyrrolidin-1-ylmethyl)-1,3-thiazol-2-yl]pyridin-2-amine. To a stirred solution of 4-methyl-N-[4-(pyridin-2-yl)-1,3-thiazol-2-yl]pyridin-2-amine (100 mg, 0.37 mmol) in EtOH (10 ml) were added pyrrolidine (0.3 ml, 3.73 mmol) and aqueous HCHO (37%) (0.3 ml, 3.73 mmol), and the mixture was heated at 80 °C for 2 h. When complete, the reaction mixture was cooled to 25 °C and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by prep-HPLC to give 4-methyl-N-[4-(pyridin-2-yl)-5-(pyrrolidin-1-ylmethyl)-1,3-thiazol-2-yl]pyridin-2-amine (65 mg, 49%). MS (ESI): m / z 352.1 [M+1] + .

[0354] Example 34. 4-Methyl-N-[4-(3-methylpyridin-2-yl)-5-phenyl-1,3-thiazol-2-yl]pyridin-2-amine [Chem.] 1-(3-Methylpyridin-2-yl)-2-phenyl ethan-1-one. To a stirred solution of 3-methylpyridine-2-carbonitrile (1 g, 8.46 mmol) in dry THF (30 ml) was added benzylmagnesium bromide (1 M in THF, 16.9 ml, 16.9 mmol) dropwise at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organics were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude mass was purified by column chromatography to give 1-(3-methylpyridin-2-yl)-2-phenyl ethan-1-one (1.2 g, 67%). MS (ESI): m / z 212.2 [M+1] + .

[0355] 2-Bromo-1-(3-methylpyridine-2-yl)-2-phenylethane-1-one. To a stirred solution of 1-(3-methylpyridine-2-yl)-2-phenylethane-1-one (300 mg, 1.42 mmol) in ice AcOH (3 ml), HBr (33%, 1.5 ml) in AcOH was added, and the mixture was cooled to 0°C. Bromine (1 M, 2.84 ml, 2.84 mmol) in AcOH was added, and the resulting mixture was heated to 25°C and stirred for 2 hours. The crude product was filtered, washed with Et2O, and dried to obtain 2-bromo-1-(3-methylpyridine-2-yl)-2-phenylethane-1-one hydrobromide (350 mg, 71%). MS(ESI): m / z 292.1[M+2] + .

[0356] 4-Methyl-N-[4-(3-methylpyridine-2-yl)-5-phenyl-1,3-thiazole-2-yl]pyridine-2-amine. (4-methylpyridine-2-yl)thiourea (112 mg, 0.676 mmol) was added to a stirred solution of 1-(3-methylpyridine-2-yl)-2-phenylethane-1-one hydrobromide (250 mg, 0.68 mmol) in EtOH (10 ml) at 25°C. The resulting mixture was heated under reflux for 16 hours. The reaction mixture was cooled to 25°C and poured onto crushed ice. The pH was adjusted to 8 with Na2CO3 solution and extracted with ELISA. The combined organic compounds were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 4-methyl-N-[4-(3-methylpyridine-2-yl)-5-phenyl-1,3-thiazole-2-yl]pyridine-2-amine (110 mg, 45%). MS(ESI): m / z 359.3[M+1] + .

[0357] Example 35. N-[5-ethyl-4-(pyridine-2-yl)-1,3-thiazole-2-yl]-4-methylpyridine-2-amine [ka] N-methoxy-N-methylpyridine-2-carboxamide. To a stirred solution of pyridine-2-carboxylic acid (1 gm, 8.12 mmol) in DMF (20 mL), EDC·HCl (2.27 gm, 14.62 mmol) and HOBt (1.3 gm, 9.75 mmol) were added. Next, under an argon atmosphere at 25°C, N,O-dimethylhydroxylamine hydrochloride (875 mg, 8.93 mmol) was added, followed by TEA (2.2 mL, 16.25 mmol). The reaction mixture was stirred at 25°C for 3 hours and quenched with water. The aqueous portion was extracted with RINKAN. The combined organic layers were washed with brine, dried on anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain N-methoxy-N-methylpyridine-2-carboxamide (650 mg, 48%). MS(ESI): m / z 166.8[M+1] + .

[0358] 1-(pyridine-2-yl)butan-1-one. To a stirred solution of N-methoxy-N-methylpyridine-2-carboxamide (600 mg, 3.61 mmol) in dry THF (8 mL), n-propyl MgBr (2.4 mL, 7.22 mmol, 3 M in THF) was added under an argon atmosphere at -10°C. The reaction mixture was stirred at 0°C for 1 hour and quenched with saturated NH4Cl solution. The solution was extracted with Âti, the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 1-(pyridine-2-yl)butan-1-one (160 mg, 33%). MS(ESI): m / z 150.1[M+1] + .

[0359] 2-Bromo-1-(pyridin-2-yl)butan-1-one. To a solution of 1-(pyridin-2-yl)butan-1-one (180 mg, 1.21 mmol) in glacial AcOH (1.8 mL) was added 33% HBr in AcOH (0.9 mL) at 0 °C. Next, bromine (1.4 mL, 1.45 mmol, of 1 M) in AcOH was added dropwise and the reaction mixture was stirred at 25 °C for 4 h. The reaction solution was cooled to 0 °C and quenched with saturated NaHCO3 solution. The solution was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 2-bromo-1-(pyridin-2-yl)butan-1-one (120 mg, 43%). MS (ESI): m / z 228.0, 230.0 [M+1] + .

[0360] (4-Methylpyridin-2-yl)thiourea. To a stirred solution of 4-methylpyridin-2-amine (10 g, 92.59 mmol) in acetone (150 mL) was added benzoyl isothiocyanate (15.09 mL, 92.59 mmol) and the resulting mixture was stirred at 25 °C for 1 h. The suspension was cooled in an ice-bath, diluted with ice-water (20 mL) and stirred for 15 min. The precipitate was filtered off, washed with cold water and dried under vacuum. The crude compound (23 g) was suspended in 10% aqueous NaOH (115 mL), stirred at 25 °C for 15 min and then heated to reflux for a further 15 min. The reaction mixture was cooled to 0 °C, adjusted to pH 4 with aqueous HCl and then to pH 8 - 9 with saturated aqueous KHCO3. The mixture was stirred at 0 °C for 15 min. The solid was filtered off, washed with cold water and dried under vacuum to give (4-methylpyridin-2-yl)thiourea (11 g, 71%). MS (ESI): m / z 168.1 [M+1] + .

[0361] N-[5-ethyl-4-(pyridin-2-yl)-1,3-thiazole-2-yl]-4-methylpyridine-2-amine. (4-methylpyridine-2-yl)thiourea (88 mg, 0.53 mmol) was added to a solution of EtOH (5 mL) and 2-bromo-1-(pyridin-2-yl)butan-1-one (120 mg, 0.53 mmol), and the mixture was heated under reflux for 18 hours. Next, the reaction mixture was poured into ice water and stirred for 30 minutes. The reaction mixture was adjusted to pH 8 with Na2CO3 solution, the obtained material was filtered, and washed with water. The crude product was dried under vacuum and purified by column chromatography to obtain N-[5-ethyl-4-(pyridin-2-yl)-1,3-thiazole-2-yl]-4-methylpyridine-2-amine (100 mg, 64%). MS(ESI):m / z 297.1[M+1] + .

[0362] Example 36. 5-((dimethylamino)methyl)-4-(pyridine-2-yl)-N-(4-(trifluoromethyl)pyridine-2-yl)thiazole-2-amine [ka] 5-((dimethylamino)methyl)-4-(pyridin-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)thiazole-2-amine. A mixture of 5-(chloromethyl)-4-(pyridin-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)thiazole-2-amine (0.05 g, 0.135 mmol) and dimethylamine was added to MeOH (0.081 ml, 0.162 mmol) in THF and stirred at 25°C for 16 hours. The mixture was concentrated under vacuum and purified by preparative HPLC to obtain acetate, which was filtered through an SCX column, and the filtrate was concentrated to obtain 5-((dimethylamino)methyl)-4-(pyridin-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)thiazole-2-amine (9 mg, 0.024 mmol, 17.59%). MS(ESI): m / z 379.9[M+1] + . 1H NMR(300MHz, methanol-d4)δ 8.63(ddd,J=4.9,1.8,0.9Hz,1H),8.54(d,J=5.3Hz,1H),8.02(dt,J=8.0,1.1Hz,1H),7.8 9(td,J=7.7,1.8Hz,1H),7.40-7.28(m,2H),7.21-7.13(m,1H),4.23(s,2H),2.39(s,6H).

[0363] Example 37. 5-(((3S,5R)-3,5-dimethylpiperazine-1-yl)methyl)-4-(pyridine-2-yl)-N-(4-(trifluoromethyl)pyridine-2-yl)thiazole-2-amine [ka] 5-(((3S,5R)-3,5-dimethylpiperazine-1-yl)methyl)-4-(pyridine-2-yl)-N-(4-(trifluoromethyl)pyridine-2-yl)thiazole-2-amine. 4-(pyridine-2-yl)-2-((4-(trifluoromethyl)pyridine-2-yl)amino)thiazole-5-carbaldehyde (100 mg, 0.285 mmol) and powdered molecular sieve were dissolved in DCE (5 ml) and (2R,6S)-2,6-dimethylpiperazine-1-carboxylate tert-butyl (184 mg, 0.856 mmol) and AcOH (0.016 ml, 0.285 mmol) were added. The mixture was stirred under reflux for 3 hours. After cooling to 25°C, sodium triacetoxyborohydride (121 mg, 0.571 mmol) was added, and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was washed with water. The organic layer was separated, dried over Na2SO4, filtered, and the solvent was removed under vacuum. The BOC-protected product was dissolved in DCM (2 ml), and HCl (1 ml, 4.00 mmol, 4 M in dioxane) was added. After 2 hours, the reaction mixture was concentrated under reduced pressure, the solid was dissolved in MeOH (5 ml), and filtered through an SCX-2 column. The product was washed with 20 ml of MeOH and 2 M ammonia / MeOH to obtain the free base. The filtrate was concentrated under reduced pressure and purified by preparative HPLC to obtain the expected product as acetate. The solid was dissolved in MeOH (5 ml), filtered through an SCX-2 column, and washed with 20 ml of MeOH and 2 M ammonia / MeOH to obtain 5-(((3S,5R)-3,5-dimethylpiperazine-1-yl)methyl)-4-(pyridine-2-yl)-N-(4-(trifluoromethyl)pyridine-2-yl)thiazole-2-amine (40 mg, 0.089 mmol, 31.2%). MS(ESI): m / z 449.1[M+1] + . 1H NMR(300MHz, methanol-d4)δ 8.58(dd,J=19.1,5.1Hz,2H),8.02-7.81(m,2H),7.38-7.27(m,2H),7.16(d,J=5.3Hz, 1H),4.19(s,2H),2.93(d,J=9.4Hz,5H),1.75(t,J=11.3Hz,2H),1.05(d,J=6.3Hz,6H).

[0364] Example 38. 4-(pyridine-2-yl)-2-((4-(trifluoromethyl)pyridine-2-yl)amino)thiazole-5-carboxylic acid [ka] 4-(pyridine-2-yl)-2-((4-(trifluoromethyl)pyridine-2-yl)amino)thiazole-5-carboxylic acid. To a stirred solution of ethyl 4-(pyridine-2-yl)-2-((4-(trifluoromethyl)pyridine-2-yl)amino)thiazole-5-carboxylic acid and HBr (900 mg, 1.894 mmol) in EtOH (8 ml), an aqueous solution of NaOH (189 mg, 4.73 mmol, 5 ml) was added, and the reaction mixture was stirred at 60°C for 16 hours. After completion, the organic solvent was removed under reduced pressure, and the pH was adjusted to 4 with dilute HCl. The crude product was filtered, dried, and triturated with EtOH to obtain the final compound 4-(pyridine-2-yl)-2-((4-(trifluoromethyl)pyridine-2-yl)amino)thiazole-5-carboxylic acid (550 mg, 1.486 mmol, 78%). MS(ESI):m / z 366.7[M+1] + . 1 H NMR(300MHz,DMSO-d6)δ 12.21(s,1H),8.79(d,J=5.1Hz,1H),8.68(d,J=5.3Hz,1H),8.42(d,J=8.1Hz,1H), 8.31(td,J=7.8,1.7Hz,1H),7.78-7.69(m,1H),7.45(s,1H),7.37(d,J=5.4Hz,1H).

[0365] Example 39. (4-(pyridine-2-yl)-2-((4-(trifluoromethyl)pyridine-2-yl)amino)thiazole-5-yl)(pyrrolidine-1-yl)methanone [ka] (4-(pyridine-2-yl)-2-((4-(trifluoromethyl)pyridine-2-yl)amino)thiazole-5-yl)(pyrrolidine-1-yl)methanone. 4-(pyridine-2-yl)-2-((4-(trifluoromethyl)pyridine-2-yl)amino)thiazole-5-carboxylic acid (50 mg, 0.136 mmol) and TEA (0.058 ml, 0.409 mmol) were stirred in DMF (0.5 ml), to which 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosfinan 2,4,6-trioxide (0.081 ml, 0.273 mmol) and then pyrrolidine (0.023 ml, 0.273 mmol) were added. The reaction was stirred at 25°C for 2 hours. Once complete, it was poured onto ice, filtered, washed with water, and triturated with EtOH to yield the final compound (4-(pyridine-2-yl)-2-((4-(trifluoromethyl)pyridine-2-yl)amino)thiazole-5-yl)(pyrrolidine-1-yl)methanone (40 mg, 0.095 mmol, 69.3%). MS(ESI): m / z 419.7[M+1] + . 1 H NMR(300MHz,DMSO-d6)δ 12.00(s,1H),8.57(dd,J=11.6,5.1Hz,2H),8.03-7.85(m,2H),7.39(s,1H),7.37-7.27(m, 2H),3.49(t,J=6.9Hz,2H),3.06(t,J=6.6Hz,2H),1.83(q,J=6.7Hz,2H),1.78-1.61(m,2H).

[0366] Example 40. N-(5-isopropyl-4-(trifluoromethyl)pyridine-2-yl)-5-methyl-4-(pyridine-2-yl)thiazole-2-amine [ka] N-(5-isopropyl-4-(trifluoromethyl)pyridine-2-yl)-5-methyl-4-(pyridine-2-yl)thiazole-2-amine. To a stirred solution of 1-(5-isopropyl-4-(trifluoromethyl)pyridine-2-yl)thiourea (170 mg, 0.646 mmol) in EtOH (2 ml), 2-bromo-1-(pyridine-2-yl)propan-1-one (138 mg, 0.646 mmol) was added, and the mixture was stirred at 85°C for 3 hours. The reaction mixture was cooled to 25°C and filtered. The HBr salt was neutralized by dissolving 150 mg in 10 ml of MeOH and then adding 0.200 ml of NET3. Water was added, and the precipitate was filtered to obtain N-(5-isopropyl-4-(trifluoromethyl)pyridine-2-yl)-5-methyl-4-(pyridine-2-yl)thiazole-2-amine (85 mg, 0.220 mmol, 34.1%). MS(ESI): m / z 379.1[M+1] + . 1 H NMR(300MHz,DMSO-d6)δ 11.46(s,1H),8.69-8.55(m,2H),8.01-7.93(m,1H),7.87(td,J=7.7,1.8Hz,1H),7.37(s,1H) ,7.28(ddd,J=7.5,4.8,1.3Hz,1H),3.12(p,J=7.0Hz,1H),2.75(s,3H),1.31(d,J=6.8Hz,6H).

[0367] Example 41. 2-((5-(((2S,6R)-2,6-dimethylmorpholino)methyl)-4-(pyridine-2-yl)thiazole-2-yl)amino)-N-(2,2,2-trifluoroethyl)isonicotinamide [ka] 2-((5-(((2S,6R)-2,6-dimethylmorpholino)methyl)-4-(pyridine-2-yl)thiazole-2-yl)amino)-N-(2,2,2-trifluoroethyl)isonicotinamide. 2-((5-(chloromethyl)-4-(pyridine-2-yl)thiazole-2-yl)amino)-N-(2,2,2-trifluoroethyl)isonicotinamide (140 mg, 0.327 mmol) was stirred in a mixture of acetonitrile (1 ml) and MeOH (1.00 ml). TEA (0.091 ml, 0.654 mmol) and (2S,6R)-2,6-dimethylmorpholine (0.081 ml, 0.654 mmol) were added. The reaction mixture was stirred at 50°C for 2 hours. Upon completion, the solvent was removed under reduced pressure, and the crude compound was purified by column chromatography to obtain the final compound 2-((5-(((2S,6R)-2,6-dimethylmorpholino)methyl)-4-(pyridine-2-yl)thiazole-2-yl)amino)-N-(2,2,2-trifluoroethyl)isonicotinamide (90 mg, 0.178 mmol, 54.3%). MS(ESI): m / z 506.8[M+1] + . 1 1H NMR (300MHz, DMSO-d6)δ 11.48(s,1H),9.36(t,J=6.3Hz,1H),8.63(dt,J=4.6,1.7Hz,1H),8.46(d,J=5. 3Hz,1H),7.98(dt,J=8.0,1.1Hz,1H),7.88(td,J=7.7,1.9Hz,1H),7.52(s,1H) ,7.36-7.25(m,2H),4.22(s,2H),4.17-4.02(m,2H),3.82(ddd,J=11.0,5.5,3. 2Hz,2H),3.58(d,J=8.1Hz,2H),2.87(d,J=11.0Hz,2H),1.11(d,J=6.3Hz,6H).

[0368] Example 42. 4-(pyridine-2-yl)-2-((4-(trifluoromethyl)pyridine-2-yl)amino)thiazole-5-carbonitrile [ka] 4-(pyridine-2-yl)-2-((4-(trifluoromethyl)pyridine-2-yl)amino)thiazole-5-carbonitrile. 1-(4-(trifluoromethyl)pyridine-2-yl)thiourea (72.3 mg, 0.327 mmol) was added to a stirred solution of 2-bromo-3-oxo-3-(pyridine-2-yl)propanenitrile and HBr (100 mg, 0.327 mmol) in EtOH (1 ml), and the reaction mixture was stirred at 85°C for 2 hours. After completion, it was filtered and the solid was washed with EtOH. The crude product was dissolved in 10 ml of 10% EtOH:DCM and washed with saturated NaHCO3 solution. The organic layer was concentrated and dried to provide the final compound 4-(pyridine-2-yl)-2-((4-(trifluoromethyl)pyridine-2-yl)amino)thiazole-5-carbonitrile (39 mg, 0.108 mmol, 33.1%). MS(ESI): m / z 347.8[M+1] + . 1 H NMR(300MHz,DMSO-d6)δ 12.70(s,1H),8.78-8.66(m,2H),8.11-7.98(m,2H),7.57-7.47(m,1H),7.44(d,J=5.2Hz,2H).

[0369] Example 43.2-((5-methyl-4-(pyridine-2-yl)thiazol-2-yl)amino)-N-(2,2,2-trifluoroethyl)isonicotinamide [ka] 2-((5-methyl-4-(pyridine-2-yl)thiazole-2-yl)amino)-N-(2,2,2-trifluoroethyl)isonicotinamide. To a stirred solution of 2-((5-methyl-4-(pyridine-2-yl)thiazole-2-yl)amino)isonicotinic acid hydrobromide (200 mg, 0.509 mmol) in DMF (2 ml), N-ethyl-N-isopropylpropan-2-amine (0.266 ml, 1.526 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (290 mg, 0.763 mmol) were added, and the reaction mixture was then stirred at 25°C for 10 minutes. Subsequently, 2,2,2-trifluoroethane-1-amine (0.080 ml, 1.017 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. Upon completion, the reaction mixture was poured onto ice, filtered, washed with water, and dried. The solid product was triturated with MeOH to obtain the desired final compound, 2-((5-methyl-4-(pyridine-2-yl)thiazole-2-yl)amino)-N-(2,2,2-trifluoroethyl)isonicotinamide (55 mg, 0.140 mmol, 27.5%). MS(ESI): m / z 394[M+1] + . 1H NMR(300MHz,DMSO-d6)δ 11.46(s,1H),9.33(t,J=6.2Hz,1H),8.68-8.56(m,1H),8.43(dd,J=5.3,0.8Hz,1H),7.99(dt,J=8.0,1.1Hz ,1H),7.87(td,J=7.7,1.8Hz,1H),7.48(t,J=1.1Hz,1H),7.36-7.24(m,2H),4.22-4.02(m,2H),2.75(s,3H).

[0370] Example 44. 5-Methyl-4-(pyridine-2-yl)-N-(4-((tetrahydro-2H-pyran-4-yl)oxy)pyridine-2-yl)thiazole-2-amine [ka] 5-Methyl-4-(pyridine-2-yl)-N-(4-((tetrahydro-2H-pyran-4-yl)oxy)pyridine-2-yl)thiazole-2-amine. Pd2(dba)3 (151 mg, 0.165 mmol) was added to a degassed solution of xanthophos (191 mg, 0.330 mmol), Na2CO3 (175 mg, 1.650 mmol), 5-methyl-4-(pyridine-2-yl)thiazole-2-amine hydrobromide (494 mg, 1.815 mmol), and 2-bromo-4-((tetrahydro-2H-pyran-4-yl)oxy)pyridine (426 mg, 1.650 mmol) in dioxane (10 ml). The reaction vial was sealed and heated at 130°C for 16 hours. The crude reaction mixture was adsorbed onto silica and purified by column chromatography to obtain the product. The pure fraction was collected, and the solvent was evaporated to obtain 5-methyl-4-(pyridine-2-yl)-N-(4-((tetrahydro-2H-pyran-4-yl)oxy)pyridine-2-yl)thiazole-2-amine (132 mg, 0.358 mmol, yield 21.71%). MS(ESI): m / z 369.2[M+1] + . 1 1H NMR (300MHz, DMSO-d6)δ 10.96(s,1H),8.73-8.50(m,1H),8.10(d,J=5.8Hz,1H),7.97(d,J=7.9Hz,1H ),7.86(td,J=7.7,1.9Hz,1H),7.27(s,1H),6.74-6.50(m,2H),4.64(dt,J=8 .8,4.5Hz,1H),3.86(dd,J=10.5,5.8Hz,2H),3.51(ddd,J=11.8,9.4,2.8Hz, 2H),2.73(s,3H),2.02(d,J=12.5Hz,2H),1.63(dtd,J=13.0,9.0,3.9Hz,2H).

[0371] Example 45. 5-Ethyl-4-(pyridine-2-yl)-N-(6-(trifluoromethyl)pyridine-2-yl)thiazole-2-amine [ka] 5-ethyl-4-(pyridine-2-yl)-N-(6-(trifluoromethyl)pyridine-2-yl)thiazole-2-amine. A solution of 1-(6-(trifluoromethyl)pyridine-2-yl)thiourea (150 mg, 0.678 mmol), 2-bromo-1-(pyridine-2-yl)butan-1-one (170 mg, 0.746 mmol), and DIPEA (0.130 ml, 0.746 mmol) in EtOH (4 mL) was heated at 80°C for 2 hours in a 7 ml sealed tube. The resulting solution was directly adsorbed onto the minimum amount of silica and purified by column chromatography. Next, the pure fraction was collected and the solvent was removed to obtain 5-ethyl-4-(pyridine-2-yl)-N-(6-(trifluoromethyl)pyridine-2-yl)thiazole-2-amine (152 mg, 0.434 mmol, 64.0%). MS(ESI): m / z 350.9[M+1] + . 1 H NMR(300MHz,DMSO-d6)δ 11.64(s,1H),8.63(ddd,J=4.8,1.9,1.0Hz,1H),8.03-7.91(m,2H),7.87(td,J=7.7,1.9Hz,1H),7 .43-7.33(m,2H),7.29(ddd,J=7.4,4.8,1.3Hz,1H),3.33(q,J=7.4Hz,2H),1.28(t,J=7.4Hz,3H).

[0372] Example 46. N-(3-methyl-2-pyridyl)-4-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]thiazole-2-amine [ka] 5-(2,2,2-trifluoroethoxy)pyridine-2-carbonitride. To a stirred, ice-cold solution of 5-fluoropyridine-2-carbonitride (650 mg, 5.32 mmol) in NMP (10 mL), NaH (60% in mineral oil, 332 mg, 7.98 mmol) was added at 0°C under an argon atmosphere. The resulting mixture was stirred at 24°C for 5 minutes and cooled to 0°C. Trifluoroethanol (0.8 mL, 10.64 mmol) was added, and the resulting mixture was warmed to 24°C. The reaction mixture was heated at 90°C for 4 hours. After completion, the reaction mixture was quenched with an aqueous solution of Na2CO3 and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 5-(2,2,2-trifluoroethoxy)pyridine-2-carbonitrile (750 mg, 69%). MS(ESI): m / z 203.1[M+1] + .

[0373] 1-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]etanone. To a stirred solution of 5-(2,2,2-trifluoroethoxy)pyridine-2-carbonitride (750 mg, 3.713 mmol) in THF (15 mL), MeMgBr (3 M in THF, 2.5 ml, 7.50 mmol) was added dropwise at 0°C under an argon atmosphere, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with aqueous NH4Cl solution and extracted with RINKAN. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 1-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]etanone (250 mg, 31%). MS(ESI): m / z 220.2[M+1] + .

[0374] 2-Bromo-1-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]ethanone. To a stirred solution of 1-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]ethanone (250 mg, 1.14 mmol) in ice AcOH (3 mL), HBr (1.5 mL) in ice AcOH was added dropwise at 0°C under an argon atmosphere. A solution of bromine in AcOH (1 M in AcOH, 1.4 mL, 1.4 mmol) was added dropwise to the reaction mixture at 0°C, and the resulting mixture was stirred at 24°C for 2 hours. The crude product was filtered, washed with Et2O, and dried to obtain 2-bromo-1-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]ethanone (550 mg, 62%). MS(ESI): m / z 298.2[M+1] + .

[0375] (3-methyl-2-pyridyl)thiourea. To a stirred solution of 3-methylpyridine-2-amine (20 g, 185.01 mmol) in acetone (200 ml), benzoyl isothiocyanate (25.1 mL, 185.01 mmol) was added, and the resulting mixture was stirred at 24°C for 2 hours. The suspension was cooled in an ice-water bath, diluted with ice-water (50 ml), and stirred for 15 minutes. The precipitate was filtered, washed with cold water, and dried under vacuum. The crude compound (45 g) was suspended in 10% NaOH water (150 mL), stirred at 24°C for 15 minutes, and then heated under reflux for another 15 minutes. The reaction mixture was cooled to 0°C, adjusted to pH 4 with aqueous HCl, and then adjusted to pH 8-9 with saturated aqueous KHCO3. The mixture was stirred at 0°C for 15 minutes. The crude product was filtered, washed with cold water, and dried under vacuum to obtain (3-methyl-2-pyridyl)thiourea (26 g, 84%). MS(ESI): m / z 168.0[M+1] + .

[0376] N-(3-methyl-2-pyridyl)-4-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]thiazole-2-amine. 2-bromo-1-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]ethenone hydrobromide (160 mg, 0.417 mmol) was added to a stirred solution of (3-methyl-2-pyridyl)thiourea (70 mg, 0.417 mmol) in EtOH (5 ml). The resulting mixture was heated under reflux for 4 hours. The reaction mixture was cooled to 24°C and poured onto crushed ice. The pH was adjusted to 8 with an aqueous solution of Na2CO3 and extracted with ELISA. The combined organic portion was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain N-(3-methyl-2-pyridyl)-4-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]thiazole-2-amine (74 mg, 48%). MS(ESI): m / z 367.1[M+1] + .

[0377] Example 47.2-[[4-(5-ethoxy-2-pyridyl)thiazole-2-yl]amino]pyridine-3-carbonitrile [ka] 4-(5-ethoxy-2-pyridyl)thiazole-2-amine. Thiourea (47 mg, 0.615 mmol) was added to a stirred solution of 2-bromo-1-(5-ethoxy-2-pyridyl)ethenone hydrobromide (200 mg, 0.615 mmol) in EtOH (5 ml). The resulting mixture was heated under reflux for 4 hours. The reaction mixture was cooled to 24°C and poured onto crushed ice. The pH was adjusted to 8 with Na2CO3 solution and extracted with siRNA. The combined organic portion was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude mass was triturated with Et2O to obtain 4-(5-ethoxy-2-pyridyl)thiazole-2-amine (110 mg, 81%). MS(ESI): m / z 222.3[M+1] + .

[0378] 2-[[4-(5-ethoxy-2-pyridyl)thiazole-2-yl]amino]pyridine-3-carbonitrile. To a stirred solution of 2-bromopyridine-3-carbonitrile (55 mg, 3.04 mmol) in 1,4-dioxane (5 mL), 4-(5-ethoxy-2-pyridyl)thiazole-2-amine (81 mg, 0.365 mmol) and Cs2CO3 (198 mg, 0.608 mmol) were added, and the mixture was degassed in a sealed tube with argon for 10 minutes. Under an inert atmosphere, xanthophos (35 mg, 0.061 mmol) was added, followed by the addition of Pd2(dba)3 (28 mg, 0.03 mmol). The resulting mixture was heated at 90°C for 16 hours. After completion, the reaction mixture was cooled to 24°C, diluted with water, and extracted with Âr. 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 obtain 2-[[4-(5-ethoxy-2-pyridyl)thiazole-2-yl]amino]pyridine-3-carbonitrile (40 mg, 41%). MS(ESI): m / z 324.3[M+1] + .

[0379] Example 48. N-[5-(methoxymethyl)-4-(3-methylpyridine-2-yl)-1,3-thiazole-2-yl]-4-methylpyridine-2-amine [ka] Ethyl 3-(3-methylpyridine-2-yl)-3-oxopropanoate. To a stirred solution of 1-(3-methylpyridine-2-yl)ethane-1-one (2 g, 14.79 mmol) in diethyl carbonate (120 mL), NaH (60% in mineral oil, 3.55 g, 88.76 mmol) was gradually added at 24°C. The resulting mixture was heated at 90°C for 4 hours. After completion, the reaction mixture was cooled to 24°C, quenched with a mixture of AcOH (8.4 mL) and Et2O (84 mL), filtered through a short Celite pad, and washed with ethyl phosphate. The filtrate was concentrated under reduced pressure, and the crude compound was purified by column chromatography to obtain ethyl 3-(3-methylpyridine-2-yl)-3-oxopropanoate (2.8 g, 91%). MS(ESI): m / z 208.2[M+1] + .

[0380] Ethyl 2-bromo-3-(3-methylpyridine-2-yl)-3-oxopropanoate. To a stirred solution of ethyl 3-(3-methylpyridine-2-yl)-3-oxopropanoate (1 g, 4.83 mmol) in CHCl3 (30 mL), bromine (0.23 mL, 4.35 mmol) in CHCl3 (10 mL) was added dropwise over 15 minutes at 0°C. After completion, the reaction mixture was diluted with DCM. The organic layer was carefully washed with saturated aqueous NaHCO3, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain ethyl 2-bromo-3-(3-methylpyridine-2-yl)-3-oxopropanoate (1.3 g, crude). MS(ESI): m / z 286.0[M+1] + .

[0381] 4-(3-methylpyridine-2-yl)-2-[(4-methylpyridine-2-yl)amino]-1,3-thiazole-5-carboxylate ethyl. To a stirred solution of (4-methylpyridine-2-yl)thiourea (762 mg, 4.56 mmol) in EtOH (30 mL), 2-bromo-3-(3-methylpyridine-2-yl)-3-oxopropanoate ethyl (1.3 g, 4.56 mmol) was added, and the resulting mixture was heated under reflux for 3 hours. After completion, the reaction mixture was cooled to 24°C, poured into ice water, and stirred for a further 30 minutes. The resulting solution was adjusted to pH 8 with aqueous Na2CO3 and extracted with ethyl. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by column chromatography to obtain 4-(3-methylpyridine-2-yl)-2-[(4-methylpyridine-2-yl)amino]-1,3-thiazole-5-carboxylate ethyl (1.05 g, 61% in 2 steps). MS(ESI): m / z 354.9[M+1] + .

[0382] [4-(3-methylpyridine-2-yl)-2-[(4-methylpyridine-2-yl)amino]-1,3-thiazole-5-yl]methanol. To a stirred solution of ethyl 4-(3-methylpyridine-2-yl)-2-[(4-methylpyridine-2-yl)amino]-1,3-thiazole-5-carboxylate (500 mg, 1.41 mmol) in 15 mL of THF, LiEt3BH (superhydride, 1 M in THF, 5.65 mL, 5.65 mmol) was added dropwise under an argon atmosphere at -78°C. The resulting mixture was stirred at -78°C for 30 minutes and then stirred at 24°C for a further 1 hour. As some starting material remained, it was cooled again to -78°C, and further LiEt3BH (superhydride, 1 M in THF, 5.65 mL, 5.65 mmol) was added dropwise. The reaction mixture was heated to 24°C and stirred for a further 2 hours. Once complete, it was cooled to -10°C, quenched with saturated NH4Cl aqueous solution, and extracted with siRNA. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by column chromatography to obtain [4-(3-methylpyridine-2-yl)-2-[(4-methylpyridine-2-yl)amino]-1,3-thiazole-5-yl]methanol (350 mg, 79%). MS(ESI): m / z 313.3[M+1] + .

[0383] N-[5-(methoxymethyl)-4-(3-methylpyridine-2-yl)-1,3-thiazole-2-yl]-4-methylpyridine-2-amine. To a stirred solution of [4-(3-methylpyridine-2-yl)-2-[(4-methylpyridine-2-yl)amino]-1,3-thiazole-5-yl]methanol (100 mg, 0.32 mmol) in DCM (10 mL), PBr3 (0.015 mL, 0.16 mmol) was added dropwise at 0°C, and the mixture was stirred at 24°C for 30 minutes. NaOH aqueous solution (103 mg in 2.8 mL of water) was added, and the mixture was stirred at 24°C for 2 hours. After completion, the reaction mixture was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and water. The resulting solution was neutralized with aqueous NaHCO3 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 compound was purified by prep-HPLC to obtain N-[5-(methoxymethyl)-4-(3-methylpyridine-2-yl)-1,3-thiazole-2-yl]-4-methylpyridine-2-amine (15 mg, 14%). MS(ESI): m / z 327.4[M+1] + .

[0384] Example 49. 4-(pyridin-2-yl)-N-(pyrimidine-2-yl)thiazole-2-amine [ka] 1-(pyrimidine-2-yl)thiourea. Benzoyl isothiocyanate (1.632 g, 10.00 mmol) was added to a solution of pyrimidine-2-amine (0.951 g, 10 mmol) in THF (5 ml). The reaction was stirred at 60°C for 1 hour, and the resulting material was removed by filtration. Next, the crude product was stirred with NaOH (20.00 ml, 50.0 mmol) at 60°C for 1 hour, and the pH was adjusted to 8 with HCl. The crude product was collected by filtration to obtain 1-(pyrimidine-2-yl)thiourea (0.85 g, 5.51 mmol, yield 55.1%). MS(ESI)m / z 154.9[M+H] + .

[0385] 4-(pyridin-2-yl)-N-(pyrimidine-2-yl)thiazole-2-amine. A solution of 2-bromo-1-(pyridin-2-yl)ethanone (0.200 g, 1 mmol) and 1-(pyrimidine-2-yl)thiourea (0.154 g, 1.000 mmol) in EtOH (10 mL) was stirred at 78 °C for 1 hour. The reaction mixture was purified by reverse-phase semi-preparative HPLC. The fraction containing the clean product was loaded onto an ion-exchange column. The column was successively washed with water and MeOH. The product was eluted with a 5% ammonium hydroxide eluent in MeOH, and the eluent containing the product was concentrated under reduced pressure to obtain 4-(pyridin-2-yl)-N-(pyrimidine-2-yl)thiazole-2-amine (0.034 g, 0.133 mmol, yield 13.32%). MS(ESI)m / z 256.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)d ppm 7.06(t,J=5.08Hz,1H)7.32(dd,J=7.42,5.08Hz,1H)7.75(s,1H)7.84-7.93(m,1H)7.9 9(d,J=8.20Hz,1H)8.60(dd,J=4.69,0.78Hz,1H)8.67(d,J=5.47Hz,2H)11.89(s,1H).

[0386] Example 50. N-(4-methylpyridine-2-yl)-4-(pyrimidine-2-yl)thiazole-2-amine [ka] 2-Bromo-1-(pyrimidine-2-yl)ethanone. To a solution of 1-(pyrimidine-2-yl)ethanone (0.5 g, 4.09 mmol) in 33% HBr (2 ml, 4.09 mmol) in AcOH at 0°C, dibromine (0.720 g, 4.50 mmol) was added. The reaction mixture was then stirred at 75°C for 2 hours. The reaction mixture was cooled to 24°C, and Et2O was added. The product was collected by filtration to obtain 2-bromo-1-(pyrimidine-2-yl)ethanone hydrobromide (0.7 g, 3.48 mmol, yield 85%). MS(ESI) m / z 201.2[M+H] + .

[0387] N-(4-methylpyridine-2-yl)-4-(pyrimidine-2-yl)thiazole-2-amine. A solution of 2-bromo-1-(pyrimidine-2-yl)ethanone hydrobromide (0.201 g, 1 mmol) and 1-(4-methylpyridine-2-yl)thiourea (0.167 g, 1.000 mmol) in EtOH (10 ml) was stirred at 78°C for 2 hours. The reaction mixture was purified by reverse-phase semi-preparative HPLC. The fraction containing the clean product was loaded onto an ion-exchange column. The column was successively washed with water and MeOH. The product was eluted with a 5% ammonium hydroxide eluent in MeOH, and the eluent containing the product was concentrated under reduced pressure to obtain N-(4-methylpyridine-2-yl)-4-(pyrimidine-2-yl)thiazole-2-amine (0.068 g, 0.252 mmol, yield 25.2%). MS(ESI)m / z 270.4[M+H] + . 1 H NMR(400MHz,DMSO-d6)d ppm 2.29(s,3H)6.79(d,J=5.47Hz,1H)6.83(s,1H)7.39(t,J=4.88Hz,1H)7.87(s,1H)8.18(d,J=5.08Hz,1H)8.84(d,J=4.69Hz,2H)11.61(s,1H).

[0388] Example 51. 4-(5-methoxypyridine-2-yl)-N-(4-methylpyridine-2-yl)thiazole-2-amine [ka] 2-Chloro-1-(5-methoxypyridine-2-yl)ethanone. To a solution of 2-bromo-5-methoxypyridine (1 g, 5.32 mmol) in hexane (60 ml), Et2O (30 ml), and THF (30 ml) at -78°C, 1.6 N nBuLi (3.66 ml, 5.85 mmol) in hexane was added dropwise. After 10 minutes, 2-chloro-N-methoxy-N-methylacetamide (0.951 g, 6.91 mmol) in THF (2 mL) was added. The reaction mixture was stirred at -78°C for 15 minutes and then warmed to 24°C. The reaction mixture was quenched with saturated NaCl water and washed with ethyl acetate. The organic phases were combined and washed with saturated NaCl water. The organic layer was dried on magnesium sulfate, filtered, and concentrated. The crude product was purified by column chromatography. Concentration of the desired fraction yielded 2-chloro-1-(5-methoxypyridine-2-yl)ethanone (0.8 g, 4.31 mmol, 81% yield). MS(ESI)m / z 186.0[M+H] + .

[0389] 4-(5-methoxypyridine-2-yl)-N-(4-methylpyridine-2-yl)thiazole-2-amine. A solution of 2-chloro-1-(5-methoxypyridine-2-yl)ethanone (0.186 g, 1 mmol) and 1-(4-methylpyridine-2-yl)thiourea (0.167 g, 1.000 mmol) in EtOH (10 ml) was stirred at 78°C for 1 hour. The reaction mixture was concentrated. The crude product was purified by reverse-phase semi-preparative HPLC. The fraction containing the clean product was loaded onto an ion-exchange column. The column was successively washed with water and MeOH. The product was eluted with a 5% ammonium hydroxide eluent in MeOH, and the eluent containing the product was concentrated under reduced pressure to obtain 4-(5-methoxypyridine-2-yl)-N-(4-methylpyridine-2-yl)thiazole-2-amine (0.015 g, 0.050 mmol, yield 5.03%); m / z 299.3[M+H] + . 1H NMR(400MHz,DMSO-d6)d ppm 2.29(s,3H)6.78(dd,J=5.47,0.78Hz,1H)6.89(s,1H)7.43(s,1H)7.45-7.51(m,1H )7.91(d,J=8.59Hz,1H)8.17(d,J=5.47Hz,1H)8.31(d,J=3.12Hz,1H)11.34(s,1H).

[0390] Example 52. N-(3-(azetidine-1-ylsulfonyl)pyridine-2-yl)-4-(5-isopropoxypyridine-2-yl)thiazole-2-amine [ka] 2-Bromo-5-isopropoxypyridine. A mixture of 6-bromopyridine-3-ol (10 g, 57.47 mmol) and 2-iodopropane (19.54 g, 114.94 mmol) in acetonitrile (120 mL) was mixed with K2CO3 (21.41 mL, 114.94 mmol). The mixture was stirred at 80°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain the residue. The residue was purified by column chromatography to obtain 2-bromo-5-isopropoxypyridine (12 g, 55.535 mmol, yield 96.631%). LCMS (ESI): m / z 218.0 [M+1] + .

[0391] 2-(1-ethoxyvinyl)-5-isopropoxypyridine. A mixture of tributyl(1-ethoxyvinyl) stannane (20.06 g, 55.53 mmol), 2-bromo-5-isopropoxypyridine (12 g, 55.53 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (1.95 g, 2.78 mmol), and cuprous iodide (528.83 mg, 2.78 mmol) in 1,4-dioxane (200 mL) was stirred at 110 °C for 16 hours under a nitrogen atmosphere. The residue was purified by column chromatography to obtain 2-(1-ethoxyvinyl)-5-isopropoxypyridine (5.5 g, 20.67 mmol, yield 37.22%). LCMS(ESI): m / z 208.2[M+1]+ .

[0392] 2-Bromo-1-(5-isopropoxypyridine-2-yl)ethanone. A solution of 2-(1-ethoxyvinyl)-5-isopropoxypyridine (5.5 g, 26.54 mmol) in THF (75 mL) and water (25 mL) was prepared by adding NBS (4.72 g, 26.54 mmol) at 0°C. The mixture was stirred at 0°C for 20 minutes. The residue was poured into water. The aqueous phase was extracted with ELISA, the combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography to obtain 2-bromo-1-(5-isopropoxypyridine-2-yl)ethanone (5.5 g, 21.30 mmol, yield 80.30%). LCMS(ESI): m / z 258.0[M+1] + .

[0393] N-(3-(azetidine-1-ylsulfonyl)pyridine-2-yl)-4-(5-isopropoxypyridine-2-yl)thiazole-2-amine. 1-(3-(azetidine-1-ylsulfonyl)pyridine-2-yl)thiourea (464.27 mg, 1.7 mmol) was added to a mixture of 2-bromo-1-(5-isopropoxypyridine-2-yl)ethanone (440 mg, 1.70 mmol) in EtOH (5 mL). The mixture was stirred at 80°C for 1 hour. The residue was purified by column chromatography to obtain the crude product. The crude product was triturated with MeOH and DMF to obtain N-(3-(azetidine-1-ylsulfonyl)pyridine-2-yl)-4-(5-isopropoxypyridine-2-yl)thiazole-2-amine (396.52 mg, 0.92 mmol, yield 53.84%). LC-MS (ESI): m / z 432.1 [M+1] + . 1H NMR(400MHz,DMSO-d6)10.13(s,1H),8.71(dd,J1=1.4,J2=4.8Hz,1H),8.28-8.20(m,2H),7.92(d,J=8.8Hz,1H),7.62(s,1H),7.43(dd,J1 =2.9,J2=8.7Hz,1H),7.29(dd,J1=4.8,J2=7.8Hz,1H),4.75-4.69(m,1H),3.83(t,J=7.6Hz,4H),2.16-2.01(m,2H),1.30(d,J=6.0Hz,6H).

[0394] Example 53. N-methyl-N-(5-(trifluoromethyl)-2-((4-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)pyridine-3-yl)acetamide [ka] A mixture of 5-(1-ethoxyvinyl)-1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine (2.6 g, 13.22 mmol), tributyl(1-ethoxyvinyl) stannan (5.73 g, 15.86 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (241.82 mg, 0.3300 mmol) in 1,4-dioxane (2 mL) was stirred at 100°C for 16 hours under a nitrogen atmosphere. The mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to obtain 1-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)ethanone (1 g, 4.43 mmol, yield 33.55%). MS(ESI): 205.1 m / z[M+1] + . 1 H NMR(400MHz, CDCl3)δ=7.79(d,J=0.63Hz,1H),7.63(s,1H),2.90(s,2H),2.81(s,3H),2.63(s,3H),1.28(s,6H).

[0395] 2-Bromo-1-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)ethanone. 1-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)ethanone (750 mg, 3.67 mmol) was dissolved in THF (10 mL) and phenyltrimethylammonium tribromide (1380.27 mg, 3.67 mmol) was added. The mixture was stirred under nitrogen at 60°C for 21 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography to obtain 2-bromo-1-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)etanone (260 mg, 0.85 mmol, yield 23.25%). MS(ESI): 283.8, 285.8 m / z [M+1] + . 1 H NMR(400MHz, CDCl3)δ=7.81(s,1H),7.63(s,1H),4.78(s,2H),2.92(s,2H),2.84(s,3H),1.30(s,6H).

[0396] Methyl (5-(trifluoromethyl)-2-((4-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)pyridine-3-yl)carbamate tert-butyl (321.7 mg, 0.92 mmol) was added to a solution of 2-bromo-1-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)ethanone (260 mg, 0.9200 mmol) in EtOH (3 mL). The mixture was stirred at 80°C for 1 hour. The reaction mixture was concentrated under reduced pressure and the solvent was removed. The residue was purified by column chromatography to obtain methyl(5-(trifluoromethyl)-2-((4-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)pyridine-3-yl)carbamate tert-butyl (400 mg, 0.70 mmol, yield 77.0%). LCMS(ESI): 535.3 m / z[M+1] + .

[0397] N 3 -methyl-5-(trifluoromethyl)-N 2 -(4-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)thiazole-2-yl)pyridine-2,3-diamine. To a solution of methyl(5-(trifluoromethyl)-2-((4-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)pyridine-3-yl)carbamate tert-butyl (400 mg, 0.7500 mmol) in ethyl 3 -methyl-5-(trifluoromethyl)-N 2-(4-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)thiazole-2-yl)pyridine-2,3-diamine hydrochloride was obtained (280 mg, 0.58 mmol, yield 77.95%). MS(ESI) 435.3 m / z [M+1] + .

[0398] N-methyl-N-(5-(trifluoromethyl)-2-((4-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)pyridine-3-yl)acetamide. N 3 -methyl-5-(trifluoromethyl)-N 2 A solution of -(4-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)thiazole-2-yl)pyridine-2,3-diamine hydrochloride (280 mg, 0.5900 mmol) in DMF (3 mL) was mixed with TEA (0.41 mL, 2.97 mmol), followed by the addition of acetyl acetate (121.4 mg, 1.19 mmol). The mixture was stirred at 40°C for 16 hours. Acetyl acetate (60.7 mg, 0.5900 mmol) was added, and the mixture was stirred at 40°C for a further 24 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, purified by prep-HPLC, and then freeze-dried to obtain N-methyl-N-(5-(trifluoromethyl)-2-((4-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)pyridine-3-yl)acetamide (74.47 mg, 0.15 mmol, yield 26.28%, purity 95.5%). LCMS(ESI): 477.1 m / z[M+1] + . 1 H NMR(400MHz,DMSO-d6)δ=8.75-8.63(m,1H),8.23(s,0.5H),8.01(s,0.4H),7.76(d,J=6.4Hz,1H),7.67(s,1H),7.4 4-7.40(m,1H),3.28(s,1.5H),3.09(s,1.6H),2.87(s,2H),2.70(s,3H),2.22(s,1.4H),1.74(s,1.6H),1.21(s,6H)

[0399] Example 54. N-methyl-N-(5-(trifluoromethyl)-2-((4-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)pyridine-3-yl)acetamide [ka] 5-Chloro-1,3,3-trimethyl-1H-pyrrolo[2,3-c]pyridine-2(3H)-one. To a mixture of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2(3H)-one (1.2 g, 7.12 mmol) in DMF (40 mL), NaH (1.42 g, 35.59 mmol) was added at 0°C. The mixture was stirred at 25°C for 1 hour. The mixture was cooled to 0°C, and iodomethane (5.05 g, 35.59 mmol) was added. The mixture was stirred at 25°C for 2 hours. The mixture was cooled and slowly poured into ice water. The aqueous phase was extracted with ELISA, the combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography to obtain 5-chloro-1,3,3-trimethyl-1H-pyrrolo[2,3-c]pyridine-2(3H)-one (1.3 g, 6.17 mmol, yield 86.69%). LCMS(ESI): m / z 211.2[M+1] + .

[0400] 5-(1-Ethoxyvinyl)-1,3,3-trimethyl-1H-pyrrolo[2,3-c]pyridin-2(3H)-one. A mixture of 5-chloro-1,3,3-trimethyl-1H-pyrrolo[2,3-c]pyridin-2(3H)-one (1.3 g, 6.17 mmol), tributyl(1-ethoxyvinyl)stannane (2.67 g, 7.41 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.45 g, 0.62 mmol) in 1,4-dioxane (20 mL) was stirred at 100 °C for 16 h under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 5-(1-ethoxyvinyl)-1,3,3-trimethyl-1H-pyrrolo[2,3-c]pyridin-2(3H)-one (1.2 g, 4.87 mmol, yield 78.95%). LCMS(ESI): m / z 247.2 [M+1] + .

[0401] 5-(2-Bromoacetyl)-1,3,3-trimethyl-1H-pyrrolo[2,3-c]pyridin-2(3H)-one. NBS (0.69 g, 3.9 mmol) was added to a solution of 5-(1-ethoxyvinyl)-1,3,3-trimethyl-1H-pyrrolo[2,3-c]pyridin-2(3H)-one (1.2 g, 3.9 mmol) in THF (15 mL) and water (5 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min. The residue was poured into water. The aqueous phase was extracted with EtOAc, the combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography to give 5-(2-bromoacetyl)-1,3,3-trimethyl-1H-pyrrolo[2,3-c]pyridin-2(3H)-one (1.1 g, 3.70 mmol, yield 94.97%). LCMS(ESI): m / z 297.0 [M+1] + .

[0402] Methyl (5-(trifluoromethyl)-2-((4-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)pyridine-3-yl)carbamate tert-butyl. Methyl (2-thioureido-5-(trifluoromethyl)pyridine-3-yl)carbamate tert-butyl (636.7 mg, 1.82 mmol) was added to a solution of 5-(2-bromoacetyl)-1,3,3-trimethyl-1H-pyrrolo[2,3-c]pyridine-2(3H)-one (900 mg, 3.03 mmol) in EtOH (15 mL). The mixture was stirred at 80°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain crude methyl(5-(trifluoromethyl)-2-((4-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)pyridine-3-yl)carbamate tert-butyl (1.6 g, 2.91 mmol, yield 96.29%). MS(ESI): m / z 549.3[M+1] + .

[0403] A solution of 1,3,3-trimethyl-5-(2-((3-(methylamino)-5-(trifluoromethyl)pyridine-2-yl)amino)thiazole-4-yl)-1H-pyrrolo[2,3-c]pyridine-2(3H)-one was prepared. A solution of methyl(5-(trifluoromethyl)-2-((4-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)pyridine-3-yl)carbamate tert-butyl (1.4 g, 2.55 mmol) in HCl (20 mL, 80 mmol) in ethyl acetate was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was poured into a solution of NaHCO3. The aqueous phase was extracted with ethyl acetate, the combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography to obtain 1,3,3-trimethyl-5-(2-((3-(methylamino)-5-(trifluoromethyl)pyridine-2-yl)amino)thiazole-4-yl)-1H-pyrrolo[2,3-c]pyridine-2(3H)-one (620 mg, 1.37 mmol, yield 53.68%). MS(ESI): m / z 449.2[M+1] + .

[0404] N-methyl-N-(5-(trifluoromethyl)-2-((4-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)pyridine-3-yl)acetamide. Acetyl acetate (177.56 mg, 1.74 mmol) was added to a mixture of 1,3,3-trimethyl-5-(2-((3-(methylamino)-5-(trifluoromethyl)pyridine-2-yl)amino)thiazole-4-yl)-1H-pyrrolo[2,3-c]pyridine-2(3H)-one (600 mg, 1.34 mmol) and TEA (406.15 mg, 4.01 mmol) in DMF (3 mL). The mixture was stirred at 40°C for 36 hours. The mixture was concentrated under vacuum, the residue was tritulated with MeOH, and dried by freeze-drying to obtain N-methyl-N-(5-(trifluoromethyl)-2-((4-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)pyridine-3-yl)acetamide (256.38 mg, 0.51 mmol, yield 38.32%). LCMS(ESI): m / z 491.1[M+1] + 1 H NMR(400MHz,DMSO-d6)11.78-11.36(m,1H),8.77-8.65(m,1H),8.35(s,1H),8.29-8.00(m,2H),7.71- 7.64(m,1H),3.29(s,1.4H),3.22(s,3H),3.10(s,1.5H),2.23(s,1.2H),1.74(s,1.5H),1.33(s,6H).

[0405] Example 55. N-(6-((4-(4-isopropoxypyridine-2-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)-N-methylacetamide [ka] 2-Bromo-4-isopropoxypyridine. K2CO3 (15.89 g, 114.94 mmol) was added to a mixture of 2-bromopyridine-4-ol (10.0 g, 57.47 mmol) and 2-iodopropane (10 g, 57.47 mmol) in acetonitrile (120 mL). The mixture was stirred at 80°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to obtain 2-bromo-4-isopropoxypyridine (10 g, 46.27 mmol, yield 80.52%). 1 H NMR(400MHz, CDCl3)δ=8.07(d,J=5.9Hz,1H),6.89(d,J=2.2Hz,1H),6.66(dd,J1=2.3,J2=5.8Hz,1H),4.56-4.50(m,1H),1.29(d,J=6.1Hz,6H).

[0406] 2-(1-ethoxyvinyl)-4-isopropoxypyridine. A mixture of 2-bromo-4-isopropoxypyridine (6 g, 27.77 mmol), tributyl(1-ethoxyvinyl) stannan (10.03 g, 27.77 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.97 g, 1.39 mmol), and copper(I) iodide (264.42 mg, 1.39 mmol) in 1,4-dioxane (150 mL) was stirred at 110 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography to obtain 2-(1-ethoxyvinyl)-4-isopropoxypyridine (6 g, 28.94 mmol, yield 104.25%). 1 H NMR(400MHz,CDCl3)δ=8.36(d,J=5.7Hz,1H),7.20(d,J=2.4Hz,1H),6.69(dd,J1=2.6,J2=5.6Hz,1H),4.7 0-4.64(m,1H),4.35(d,J=2.0Hz,1H),3.97(q,J=7.0Hz,2H),1.44(t,J=7.0Hz,3H),1.37(d,J=6.0Hz,7H).

[0407] 2-Bromo-1-(4-isopropoxypyridine-2-yl)ethanone. To a solution of 2-(1-ethoxyvinyl)-4-isopropoxypyridine (6 g, 28.95 mmol) in THF (90 mL) and water (30 mL), NBS (5.15 g, 28.95 mmol) was added at 0°C. The mixture was stirred at 0°C for 20 minutes. The residue was poured into water. The aqueous phase was extracted with ELISA, the combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography to obtain 2-bromo-1-(4-isopropoxypyridine-2-yl)ethanone (3 g, 11.62 mmol, yield 40.15%). 1 H NMR(400MHz,CDCl3)δ=8.45(d,J=5.6Hz,1H),7.57(d,J=2.6Hz,1H),6.96(dd ,J1=2.6,J2=5.6Hz,1H),4.85(s,2H),4.75-4.69(m,1H),1.41-1.36(m,6H).

[0408] (6-((4-(4-isopropoxypyridine-2-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)(methyl)carbamate tert-butyl. Methyl (6-thioureido-5-(trifluoromethyl)pyridine-3-yl)carbamate tert-butyl (678.7 mg, 1.94 mmol) was added to a mixture of 2-bromo-1-(4-isopropoxypyridine-2-yl)ethanone (500 mg, 1.94 mmol) in EtOH (5 mL). The mixture was stirred at 80°C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography to obtain (6-((4-(4-isopropoxypyridine-2-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)(methyl)carbamate tert-butyl (850 mg, 1.67 mmol, yield 86.11%). LCMS(ESI): m / z 510.2[M+1] + .

[0409] N2-(4-(4-isopropoxypyridine-2-yl)thiazole-2-yl)-N5-methyl-3-(trifluoromethyl)pyridine-2,5-diamine. A mixture of (6-((4-(4-isopropoxypyridine-2-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)(methyl)carbamate tert-butyl (720 mg, 1.41 mmol) in HCl (20.0 mL, 80 mmol) in ethylethanol at 0°C was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain N2-(4-(4-isopropoxypyridine-2-yl)thiazole-2-yl)-N5-methyl-3-(trifluoromethyl)pyridine-2,5-diamine (350 mg, 0.78 mmol, yield 55.55%, HCl).

[0410] N-(6-((4-(4-isopropoxypyridine-2-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)-N-methylacetamide. To a mixture of N2-(4-(4-isopropoxypyridine-2-yl)thiazole-2-yl)-N5-methyl-3-(trifluoromethyl)pyridine-2,5-diamine (800 mg, 1.79 mmol) in DMF (10 mL), acetyl acetate (732.67 mg, 7.18 mmol) and TEA (1 mL, 7.18 mmol) were added. The mixture was stirred at 30°C for 16 hours. The reaction mixture was concentrated under reduced pressure. After purifying the residue by prep-HPLC, it was freeze-dried. To the solid in THF (5 mL), a solution of NaOH (5 mL, 20 mmol) in water (5 mL) was added, and the mixture was stirred at 20°C for 16 hours. The mixture was poured into water, the aqueous phase was extracted with siRNA, the combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was tritulated with MTBE and then freeze-dried to obtain N-(6-((4-(4-isopropoxypyridine-2-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)-N-methylacetamide (186.7 mg, 0.41 mmol, yield 22.93%). LCMS(ESI): 452.3 m / z[M+1] + . 1H NMR(400MHz,DMSO-d6)δ=8.29(d,J=5.5Hz,1H),8.22(s,1H),7.70-7.56(m,2H),7.33(s,1H),6.74(d ,J=2.2Hz,1H),4.90-4.80(m,1H),3.11(s,3H),2.18(s,0.2H),1.80(s,2.8H),1.34(d,J=6.0Hz,6H).

[0411] Example 56. N-(6-((4-(5-isopropoxypyridine-2-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)-N-methylacetamide [ka] Methyl (6-thioureido-5-(trifluoromethyl)pyridine-3-yl)carbamate tert-butyl. To a solution of (6-isothiocyanato-5-(trifluoromethyl)pyridine-3-yl)(methyl)carbamate tert-butyl (2.5 g, 7.5 mmol) in DCM (20 mL), NH4OH (1.16 mL, 7.5 mmol) was added. The mixture was stirred at 20 °C for 1 hour, concentrated under vacuum, and dried by freeze-drying to obtain methyl (6-thioureido-5-(trifluoromethyl)pyridine-3-yl)carbamate tert-butyl (1.9 g, 5.423 mmol, yield 72.306%). 1 H NMR(DMSO-d6,400MHz)δ 9.43-9.12(m,2H),8.58(d,J=2.3Hz,1H),8.20(d,J=2.4Hz,1H),3.24(s,3H),1.41(s,9H);LCMS(ESI):m / z 351.1[M+1] + .

[0412] (6-((4-(5-isopropoxypyridine-2-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)(methyl)carbamate tert-butyl. Methyl (6-thioureido-5-(trifluoromethyl)pyridine-3-yl)carbamate tert-butyl (407.22 mg, 1.16 mmol) was added to a solution of 2-bromo-1-(5-isopropoxypyridine-2-yl)ethanone (300 mg, 1.16 mmol) in EtOH (10 mL). The mixture was stirred at 80°C for 1 hour. The mixture was concentrated under vacuum to obtain (6-((4-(5-isopropoxypyridine-2-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)(methyl)carbamate tert-butyl (600 mg, 1.1775 mmol, yield 101.31%). LCMS (ESI): m / z 509.9 [M+1] + .

[0413] N 2 -(4-(5-isopropoxypyridine-2-yl)thiazole-2-yl)-N 5 -Methyl-3-(trifluoromethyl)pyridine-2,5-diamine. To a solution of crude (6-((4-(5-isopropoxypyridine-2-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)(methyl)carbamate tert-butyl (600 mg, 1.18 mmol) in 10 mL of ethyl phosphate, HCl (10 mL, 40 mmol, 4 M) in ethyl phosphate was added. The mixture was stirred at 35°C for 2 hours. The mixture was cooled and concentrated under reduced pressure. The residue was poured into saturated NaHCO3 water. The aqueous phase was extracted with ethyl phosphate, the combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography and N 2 -(4-(5-isopropoxypyridine-2-yl)thiazole-2-yl)-N 5- Methyl-3-(trifluoromethyl)pyridine-2,5-diamine was obtained (320 mg, 0.7816 mmol, yield 66.374%). 1H NMR(DMSO-d6,400MHz)δ 9.92-9.62(m,1H),8.25(d,J=2.8Hz,1H),7.98(d,J=2.5Hz,1H),7.94(d,J=8.6Hz,1H),7.46(dd,J1=8.8,J2=2.9H z,1H),7.35(s,1H),7.31(d,J=2.6Hz,1H),4.76-4.70(m,1H),2.76(s,3H),1.30(d,J=6.0Hz,6H);LCMS(ESI):m / z 410.0[M+1] + .

[0414] N-(6-((4-(5-isopropoxypyridine-2-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)-N-methylacetamide. N 2 -(4-(5-isopropoxypyridine-2-yl)thiazole-2-yl)-N 5 Acetyl acetate (299.22 mg, 2.93 mmol) was added to a solution of -methyl-3-(trifluoromethyl)pyridin-2,5-diamine (300 mg, 0.7300 mmol) and TEA (0.25 mL, 3.66 mmol) in DMF (1 mL). The mixture was stirred at 30°C for 6 hours. The mixture was concentrated, the residue was triturated with DMF (5 mL), and then filtered. Next, the filtered cake was triturated again with DMF (2 mL) and then filtered. The filtered cake was dried by freeze-drying to obtain N-[6-[[4-(5-isopropoxy-2-pyridyl)thiazole-2-yl]amino]-5-(trifluoromethyl)-3-pyridyl]-N-methyl-acetamide (181.23 mg, 0.3982 mmol, yield 54.346%). 1 H NMR(DMSO-d6,400MHz)δ 8.62-8.52(m,1H),8.28(d,J=2.7Hz,1H),8.16(s,1H),7.99(d,J=8.8Hz,1H),7.50-7.43(m,2H),4.78-4.72 (m,1H),3.38(s,0.6H),3.17(s,2.3H),2.21(s,0.6H),1.82(s,2.3H),1.31(d,J=6.0Hz,6H);LCMS(ESI):m / z 452.2[M+1]+ .

[0415] Example 57. N-(2-((4-(2,2-dimethyl-2,3-dihydrofluoro[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)-N-methylacetamide [ka] 1-(5-bromo-2-chloropyridine-4-yl)-2-methylpropan-2-ol. To a solution of 5-bromo-2-chloro-4-methylpyridine (24 g, 116.24 mmol) in THF (200 mL), LDA (69.74 mL, 139.49 mmol, 2 M in THF) was added at 0°C. The mixture was stirred at 0°C for 1 hour. Next, acetone (13.5 g, 232.48 mmol) was added dropwise to the mixture at 0°C, and the mixture was stirred at 25°C for 3 hours. The mixture was poured into NH4Cl (300 mL) at 0°C. The aqueous phase was extracted with ELISA, the combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography to obtain 1-(5-bromo-2-chloropyridine-4-yl)-2-methylpropan-2-ol (18 g, 46.948 mmol, yield 40.389%). LCMS(ESI): m / z 263.9[M+1] + .

[0416] 5-Chloro-2,2-dimethyl-2,3-dihydrofl[2,3-c]pyridine. To a solution of 1-(5-bromo-2-chloro-4-pyridyl)-2-methyl-propan-2-ol (17 g, 64.26 mmol) in toluene (200 mL), cuprous iodide (1.22 g, 6.43 mmol), 8-hydroxyquinoline (1.4 g, 9.64 mmol), and cesium carbonate (41.87 g, 128.52 mmol) were added. The mixture was stirred at 120 °C for 16 hours, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography to obtain 5-chloro-2,2-dimethyl-2,3-dihydrofl[2,3-c]pyridine (4 g, 20.367 mmol, yield 31.695%). 1H NMR(400MHz,DMSO-d6)δ 7.83(s,1H),7.35(s,1H),3.07(s,2H),1.43(s,6H).LCMS(ESI):m / z 184.1[M+1] + .

[0417] 5-(1-ethoxyvinyl)-2,2-dimethyl-2,3-dihydrofl[2,3-c]pyridine. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.59 g, 2.18 mmol) was added to a solution of 5-chloro-2,2-dimethyl-2,3-dihydrofl[2,3-c]pyridine (4 g, 21.78 mmol) and tributyl(1-ethoxyvinyl) stannane (9.44 g, 26.14 mmol) in 1,4-dioxane (40 mL) under nitrogen. The mixture was stirred at 100°C for 16 hours. Next, tributyl(1-ethoxyvinyl) stannane (7.36 mL, 21.78 mmol) was added, and the mixture was stirred at 100°C for a further 6 hours. The mixture was filtered, and the filtrate was concentrated under vacuum. The mixture was purified by column chromatography to obtain 5-(1-ethoxyvinyl)-2,2-dimethyl-3H-flu[2,3-c]pyridine (1.9 g, 6.8451 mmol, yield 31.424%). 1 H NMR(400MHz,DMSO-d6)δ 8.01(d,J=0.7Hz,1H),7.51(s,1H),5.14(s,1H),4.24(d,J=1.3Hz,1H),3.90(q ,J=7.0Hz,2H),3.06(s,2H),1.43(s,6H),1.35(t,J=7.0Hz,3H);LCMS(ESI):m / z 220.1[M+1] + .

[0418] 2-Bromo-1-(2,2-dimethyl-2,3-dihydrofluor[2,3-c]pyridine-5-yl)ethanone. 1-bromopyrrolidine-2,5-dione (1.54 g, 8.66 mmol) was added to a solution of 5-(1-ethoxyvinyl)-2,2-dimethyl-3H-fluor[2,3-c]pyridine (1.9 g, 8.66 mmol) in 20 mL of water and 60 mL of THF at 0°C. The mixture was stirred at 0°C for 20 minutes. The mixture was poured into water. The aqueous phase was extracted with ELISA, the combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography to obtain 2-bromo-1-(2,2-dimethyl-2,3-dihydrofluor[2,3-c]pyridine-5-yl)ethanone (1.6 g, 4.324 mmol, yield 49.904%). 1 H NMR(400MHz,DMSO-d6)δ 8.17(d,J=0.6Hz,1H),7.97(d,J=0.6Hz,1H),4.91(s,2H),3.15(s,2H),1.47(s,6H);LCMS(ESI):m / z 270.0[M+1] + .

[0419] (2-((4-(2,2-dimethyl-2,3-dihydrofluoro[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)(methyl)carbamate tert-butyl. Methyl (2-thioureido-5-(trifluoromethyl)pyridine-3-yl)carbamate tert-butyl (389.12 mg, 1.11 mmol) was added to a solution of 2-bromo-1-(2,2-dimethyl-2,3-dihydrofluoro[2,3-c]pyridine-5-yl)ethanone (300 mg, 1.11 mmol) in EtOH (5 mL). The mixture was stirred at 80°C for 1 hour. A solid precipitated and was filtered. The filtrate was concentrated under vacuum, then triturated with Â(5 mL) and filtered. The filtered cakes were combined and dried under vacuum to obtain (2-((4-(2,2-dimethyl-2,3-dihydrofluoro[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)(methyl)carbamate tert-butyl (500 mg, 0.7957 mmol, yield 71.644%). 1 H NMR(400MHz,DMSO-d6)δ 11.57-11.52(m,1H),8.67(s,1H),8.24(s,1H),8.19(s,1H),8.15(d,J=2.0Hz ,1H),7.93(s,1H),3.30(s,2H),3.14(s,3H),1.51(s,6H),1.46-1.15(m,9H).

[0420] N2-(4-(2,2-dimethyl-2,3-dihydrofluor[2,3-c]pyridine-5-yl)thiazole-2-yl)-N3-methyl-5-(trifluoromethyl)pyridine-2,3-diamine hydrochloride. To a solution of crude N-[2-[[4-(2,2-dimethyl-3H-fluor[2,3-c]pyridine-5-yl)thiazole-2-yl]amino]-5-(trifluoromethyl)-3-pyridyl]-N-methylcarbamate tert-butyl (500 mg, 0.9600 mmol) in HCl (10 mL, 40 mmol, 4 M) in HCl was added in HCl. The mixture was stirred at 20°C for 1 hour and concentrated under vacuum to obtain N2-[4-(2,2-dimethyl-3H-fluoro[2,3-c]pyridine-5-yl)thiazole-2-yl]-N3-methyl-5-(trifluoromethyl)pyridine-2,3-diamine hydrochloride (400 mg, 0.8736 mmol, yield 91.122%). LCMS(ESI): m / z 422.1[M+1] + .

[0421] N-(2-((4-(2,2-dimethyl-2,3-dihydrofluor[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)-N-methylacetamide. A mixture of N2-[4-(2,2-dimethyl-3H-fluor[2,3-c]pyridine-5-yl)thiazole-2-yl]-N3-methyl-5-(trifluoromethyl)pyridine-2,3-diamine hydrochloride (400 mg, 0.9500 mmol) and TEA (288.13 mg, 2.85 mmol) in DMF (3 mL) was mixed with acetic anhydride (145.34 mg, 1.42 mmol). The mixture was stirred at 40°C for 16 hours. The mixture was concentrated under vacuum. After purifying the residue by prep-HPLC, it was freeze-dried to obtain N-[2-[[4-(2,2-dimethyl-3H-fluoro[2,3-c]pyridine-5-yl)thiazole-2-yl]amino]-5-(trifluoromethyl)-3-pyridyl]-N-methyl-acetamide (213.29 mg, 0.4501 mmol, yield 47.419%). LCMS(ESI): m / z 464.1[M+1] + . 1H NMR(400MHz,DMSO-d6)11.77-11.40(m,1H),8.78-8.63(m,1H),8.29-8.01(m,3H),7.68(d,J=2.9 Hz,1H),3.28(s,1.4H),3.18(s,2H),3.09(s,1.5H),2.23(s,1.3H),1.74(s,1.6H),1.48(s,6H).

[0422] Example 58. N-(6-((4-(2,2-dimethyl-2,3-dihydrofluoro[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)-N-methylacetamide [ka] (6-((4-(2,2-dimethyl-2,3-dihydrofluor[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)(methyl)carbamate tert-butyl. Methyl (6-thioureido-5-(trifluoromethyl)pyridine-3-yl)carbamate tert-butyl (389.12 mg, 1.11 mmol) was added to a solution of 2-bromo-1-(2,2-dimethyl-2,3-dihydrofluor[2,3-c]pyridine-5-yl)ethanone (300 mg, 1.11 mmol) in EtOH (5 mL). The mixture was stirred at 80°C for 1 hour and concentrated under vacuum to obtain crude (6-((4-(2,2-dimethyl-2,3-dihydrofluoro[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)(methyl)carbamate tert-butyl (580 mg, crude). LCMS (ESI): m / z 521.9 [M+1] + .

[0423] N 2 -(4-(2,2-dimethyl-2,3-dihydrofluor[2,3-c]pyridine-5-yl)thiazole-2-yl)-N 5-Methyl-3-(trifluoromethyl)pyridine-2,5-diamine. Crude (6-((4-(2,2-dimethyl-2,3-dihydrofluoro[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)(methyl)carbamate tert-butyl (580 mg, crude) was dissolved in 10 mL of HCl in HCl (10 mL, 40 mmol, 4 M) in HCl. The mixture was stirred at 20°C for 1 hour, concentrated under vacuum, and the residue was triturated with 10 mL of HCl and stirred for 1 hour. The suspension was filtered, and the filter cake was dried under vacuum. 2 -(4-(2,2-dimethyl-2,3-dihydrofluor[2,3-c]pyridine-5-yl)thiazole-2-yl)-N 5 -Methyl-3-(trifluoromethyl)pyridine-2,5-diamine was obtained (600 mg, crude). LCMS(ESI): m / z 422.1[M+1] + .

[0424] N-(6-((4-(2,2-dimethyl-2,3-dihydrofluor[2,3-c]pyridine-5-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)-N-methylacetamine. To a mixture of N2-[4-(2,2-dimethyl-3H-fluor[2,3-c]pyridine-5-yl)thiazole-2-yl]-N5-methyl-3-(trifluoromethyl)pyridine-2,5-diamine hydrochloride (550 mg, 1.2 mmol) and TEA (364.63 mg, 3.6 mmol) in DMF (3 mL), acetyl acetate (159.41 mg, 1.56 mmol) was added. The mixture was stirred at 40°C for 16 hours and concentrated under vacuum. After purifying the residue by prep-HPLC, it was freeze-dried to obtain N-[6-[[4-(2,2-dimethyl-3H-fluoro[2,3-c]pyridine-5-yl)thiazole-2-yl]amino]-5-(trifluoromethyl)-3-pyridyl]-N-methyl-acetamide (242.98 mg, 0.5138 mmol, yield 42.773%). LCMS(ESI): m / z 464.1[M+1] + . 1H NMR(400MHz,DMSO-d6)8.64-8.50(m,1H),8.18-8.05(m,2H),7.96(s,1H),7.36(s,1H), 3.38(s,0.6H),3.16(s,2.3H),3.12(s,2H),2.21(s,0.5H),1.81(s,2.3H),1.47(s,6H).

[0425] Example 59. 1-(2-((4-(4-isopropoxypyridine-2-yl)thiazole-2-yl)amino)-5-(trifluoromethyl)pyridine-3-yl)pyrrolidine-2-one [ka] 1-(2-azido-5-(trifluoromethyl)pyridine-3-yl)pyrrolidine-2-one. 1-(2-chloro-5-(trifluoromethyl)pyridine-3-yl)pyrrolidine-2-one (2.8 g, 10.58 mmol) was added to a solution of sodium azide (2.06 g, 31.74 mmol) in DMSO (30 mL). The mixture was stirred at 100°C for 16 hours and then poured into saturated NaHCO3 water. The aqueous phase was extracted with ELISA, the comb...

Claims

1. Equation (I) 【Chemistry 1】 (In the formula, R １ is 2-pyridyl, and the 2-pyridyl is -CN, substituted or unsubstituted C １～４ alkyl, substituted or unsubstituted C ３～７ cycloalkyl, substituted or unsubstituted C ６～１０ aryl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted 3- to 6-membered heterocyclyl, -OR ５ , -SR, -CONR ６ ２ , -CON(C １～３ alkyl)(substituted or unsubstituted C ３～７ cycloalkyl), -NRCO(C １～３ alkyl), -CO(substituted or unsubstituted 3- to 6-membered heterocyclyl), -SO ２ NR ２ , and SO ２ R ５ is substituted with one or more substituents independently selected from; R ２ This includes halogens, -CN, substituted or unsubstituted C １～４ Alkyl, substituted, or unsubstituted C ６～１０ aryl, -OR ５ , -SR, -CONR ２ , and -SO ２ R ５ 2-pyridyl substituted with one or more substituents independently selected from, Alternatively, R2 is 2-pyridyl, and the two substituents of the 2-pyridyl, together with the carbon to which they are attached, form a substituted or unsubstituted 5-6 membered heterocycline; R ３ is H, -CN, substituted or unsubstituted C １～４ Alkyl, (C １～３ Alkyl)O(C １～３ Alkyl) (substituted or unsubstituted C) ３～７ Cycloalkyl), (C １～３ (Alkyl) OR, (C １～３ Alkyl) (substituted or unsubstituted 3-6 member heterocyclyl), C(O) (substituted or unsubstituted 3-10 member heterocyclyl), -C(O)OR, substituted or unsubstituted C ６～１０ Ariel, (C １～３ Alkyl) NR ６ ２ , (C １～３ Alkyl)N(C １～３ Alkyl) (substituted or unsubstituted C) ３～７ Cycloalkyl), CONR ６ ２ , or -C(O)N(C １～３ Alkyl) NR ２ And; R ４ is H, substituted or unsubstituted C １～３ Alkyl, or substituted or unsubstituted (C １～３ Alkyl) C ６～１０ It is an allele; R ５ is H, substituted or unsubstituted C １～５ Alkyl, substituted, or unsubstituted C ３～７ It is a cycloalkyl, or a substituted or unsubstituted 3- to 6-membered heterocycline; Each R ６ is H, substituted or unsubstituted C １～５ Alkyl; substituted or unsubstituted C ３～６ Cycloalkyl, substituted or unsubstituted 3-6 member heterocyclyl, and (C １～３ Independently selected from alkyl) (substituted or unsubstituted 3-6 member heterocyclyl); and Each R is H and substituted or unsubstituted C １～４ (Selected independently of alkyl) A compound, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog or stereoisomer thereof, provided that it is not 4-methyl-N-[4-(4-methyl-2-pyridinyl)-2-thiazolyl]-2-pyridineamine or N-(5-chloropyridin-2-yl)-4-(pyrimidine-2-yl)thiazole-2-amine.

2. R １ -CN, -CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ ien-CH ２ CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ CF ３ Cyclopropyl, cyclobutyl, cyclopentyl, -OR ５ -SR, substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted pyrrolidinonyl, -CONR ６ ２ , -CON(C １～３ Alkyl) (substituted or unsubstituted C) ３～７ Cycloalkyl), -NRCO(C １～３ Alkyl), -CO (substituted or unsubstituted 3-6 membered heterocyclyl), -SO ２ NR ２ , and -SO ２ R ５ The compound according to claim 1, or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof, which is 2-pyridyl substituted with one or more substituents independently selected from the above.

3. R ５ H, -CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof, which is tetrahydrofuranil, tetrahydropyranil, or 1-methylpiperidyl.

4. R ５ H, -CH ３ , -CH(CH ３ ) ２ The compound according to claim 3, or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof, which is tetrahydropyranil or 1-methylpiperidyl.

5. Each R ６ is independently selected from H, substituted or unsubstituted C １～５ alkyl, and substituted or unsubstituted C ３～６ cycloalkyl, wherein the C １～５ alkyl and C ３～６ cycloalkyl are optionally substituted with one or more substituents independently selected from OH, OCH ３ , and F, a compound or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof according to any one of claims 1 to 4.

6. The foregoing R ６ 's C １～５ alkyl is selected from -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , and -CH(CH ３ ), ２ and the compound according to claim 5 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

7. Said C １～５ Alkyl is -CH(CH ３ ) ２ The compound according to claim 5, or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

8. Said C ３～６ The cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and is a compound according to claim 5 or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

9. Said C ３～６ The cycloalkyl is selected from cyclopentyl and cyclohexyl, and is the compound according to claim 5 or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof.

10. R １ -CN, -CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ ien-CH ２ CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ CF ３ Cyclopropyl, cyclobutyl, cyclopentyl, -OH, -OCH ３ , -OCH ２ CH ３ , -OCH ２ CH ２ CH ３ , -OCH(CH ３ ) ２ -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -SCH ３ substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted pyrrolidinonyl, -CONH ２ , -CONH ２ , -CONHCH ３ , -CON(CH ３ ) ２ , -CONHCH ２ CH ３ , -CON(CH ２ CH ３ ) ２ , -CONHCH ２ CH ２ CH ３ , -CONHCH(CH ３ ) ２ , -CONHCH ２ CH ２ OH, -CONHCH ２ CH ２ OCH ３ , -CONHCH(CH ３ )CH ２ OH, -CONHCH ２ CF ３ , -CONHCH ２ CH ２ -pyrrolidyl, -CONH(cyclopropyl), -CONH(cyclobutyl), -CONH(cyclopentyl), -CONH(cyclohexyl), -NCH ３ COCH ３ , -SO ２ N(CH ３ ) ２ , -SO ２ 2-pyridyl substituted with one or more substituents independently selected from (aziridinyl), -CO(azethinyl), CO(piperidyl), -CO(piperazinyl), and -CO(morpholinyl), wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azethinyl, piperidyl, and piperazinyl are optionally fluorinated, the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof.

11. R １ -CN, -CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ ien-CH ２ CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CF ３ Cyclopropyl, cyclopentyl, -OH, -OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ ) ２ , -O-tetrahydropyranyl, -SCH ３ substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted pyrrolidinonyl, -CONH ２ , -CONHCH(CH ３ ) ２ , -CONHCH ２ CH ２ OH, -CONHCH ２ CH ２ OCH ３ , -CONHCH(CH ３ )CH ２ OH, -CONHCH ２ CF ３ , -CONHCH ２ CH ２ -pyrrolidil, -CONH (cyclopentyl), -CONH (cyclohexyl), -NCH ３ COCH ３ , -SO ２ N(CH ３ ) ２ , -SO ２ 2-pyridyl substituted with one or more substituents independently selected from (aziridinyl), -CO(azethinyl), -CO(piperidyl), -CO(piperazinyl), and -CO(morpholinyl), wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azethinyl, piperidyl, and piperazinyl are optionally fluorinated, the compound according to claim 10 or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof.

12. R １ -CN, -CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ ien-CH ２ CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ CF ３ Cyclopropyl, cyclopentyl, -OH, -OCH ３ , OCH ２ CH ３ , -OCH(CH ３ ) ２ , -O-tetrahydropyranyl, -SCH ３ phenyl, phenyl(COOH), pyrrolidinonyl, 1-methylpyrazolyl, dihydropyranyl, 1-methyl-piperidyl, -COOH-substituted piperidyl, -CONHCH ３ Piperidyl substituted with -CON(CH ３ ) ２ Piperidyl substituted with -CONHCH ２ CF ３ Piperidyl, 1-methyl-piperazinyl, -COC(CH) substituted with ３ ) ２ OH-substituted piperazinyl, -CO-cyclopropyl-CF ３ Piperazinyl substituted with -CONH ２ , -CON(CH ３ ) ２ , -CONHCH(CH ３ ) ２ , -CONHCH ２ CH ２ OH, -CONHCH ２ CH ２ OCH ３ , -CONHCH(CH ３ )CH ２ OH, -CONHCH ２ CF ３ , -CONHCH ２ CH ２ -pyrrolidyl, -CONH (cyclopentyl), -CONH (difluorocyclohexyl), -NCH ３ COCH ３ , -SO ２ N(CH ３ ) ２ , -SO ２ The compound according to claim 11, or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof, which is 2-pyridyl substituted with one or more substituents independently selected from (aziridinyl), -CO(difluoroazethinyl), CO(difluoropiperidyl), -CO(piperazinyl), and -CO(morpholinyl).

13. R ２ F, Cl, -CN, -CH ３ ien-CH ２ CH ３ , -CF ３ ,-CHF ２ substituted or unsubstituted phenyl, -OR ５ , -SR, -CONR ２ , and -SO ２ R ５ A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof, which is 2-pyridyl substituted with one or more substituents independently selected from thereto.

14. R ５ H, -CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ ien-CH ２ CF ３ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof, which is cyclopropyl, oxetanyl, 1-methyl-azetidinyl, piperidyl, 1-methyl-piperidyl, tetrahydrofuranil, or tetrahydropyranil.

15. R ５ is, -CH ３ ien-CH ２ CH ３ , -CH(CH ３ ) ２ ,-CHF ２ ien-CH ２ CF ３ The compound according to any one of claims 1 to 13, which is cyclopropyl, oxetanyl, 1-methyl-azetidinyl, 1-methyl-piperidyl, or tetrahydropyranil, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog or stereoisomer.

16. R ５ is H or -CH ３ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

17. R ２ F, Cl, -CN, -CH ３ ien-CH ２ CH ３ , -CF ３ ,-CHF ２ , -OCH ３ , -OCH ２ CH ３ , -OCH ２ CH ２ CH ３ , -OCH(CH ３ ) ２ , -OCH ２ CF ３ -O-cyclopropyl, -O-oxetanyl, -O-(1-methylazetidinyl), -O-(1-methylpiperidyl), -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -SCH ３ , -CONH ２ , -CONHCH ３ , -CON(CH ３ ) ２ , -CONHCH ２ CH ３ , -CON(CH ２ CH ３ ) ２ , -SO ２ CH ３ The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof, which is 2-pyridyl substituted with one or more substituents independently selected from substituted or unsubstituted phenyl.

18. R ２ F, Cl, -CN, -CH ３ ien-CH ２ CH ３ , -CF ３ ,-CHF ２ , -OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ ) ２ , -OCH ２ CF ３ -O-cyclopropyl, -O-oxetanyl, -O-(1-methylazetidinyl), -O-(1-methylpiperidyl), -O-tetrahydropyranyl, -SCH ３ , -CONH ２ , -CON(CH ３ ) ２ , -SO ２ CH ３ The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof, which is 2-pyridyl substituted with one or more substituents independently selected from substituted or unsubstituted phenyl.

19. R ２ F, Cl, -CN, -CH ３ ien-CH ２ CH ３ , -CF ３ ,-CHF ２ , -OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ ) ２ , -OCH ２ CF ３ -O-cyclopropyl, -O-oxetanyl, -O-(1-methylazetidinyl), -O-(1-methylpiperidyl), -O-tetrahydropyranyl, -SCH ３ , -CONH ２ , -CON(CH ３ ) ２ , -SO ２ CH ３ The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof, which is 2-pyridyl substituted with one or more substituents independently selected from phenyl and phenyl substituted with cyclopropyl (COOH).

20. R ２ The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof, wherein the compound is 2-pyridyl, and the two substituents of the 2-pyridyl, together with the carbon to which they are bonded, form a substituted or unsubstituted 5- to 6-membered heterocycline.

21. R ２ The compound according to claim 20, or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof, wherein is substituted or unsubstituted 2,3-dihydrofl[2,3-c]pyridyl, 2,3-dihydro-1H-pyrrolo[2,3-c]pyridyl, or 1,3-dihydro-2H-pyrrolo[2,3-c]pyridyl-2-one.

22. R ３ H, -CN, -CH ３ ien-CH ２ CH ３ , -CH(CH ３ ) ３ ien-CH ２ OH, -CH ２ CH ２ OH, -CH ２ OCH ２ -Cyclopropyl, -CH ２ OCH ２ -Cyclobutyl, -CH ２ CH ２ O-cyclobutyl, -CH ２ CH ２ OCH ２ -Cyclopropyl, -CH ２ OCH ２ CH ２ -Cyclopropyl, -CH ２ N(CH ３ ) ２ ien-CH ２ -Azethinyl, -CH ２ -Piperidyl, -CH ２ (dimethylmorpholinyl), -CH ２ (Dimethylpiperazyl), -CH ２ -pyrrolidil, -CH ２ (Morpholinyl), -COOH, -CO(dimethylmorpholinyl), -CO(morpholinyl), -CO(1,3-dioxolane-piperidyl), -CO(piperidyl), -CO(pyrrolidyl), -CO(1-methyl-piperazyl), -CO(octahydropyrrolo[1,2-a]pyradyl), -CONHCH ２ -Cyclohexyl, -CONHCH ２ -Tetrahydropyranyl, -CONHCH ２ -Cyclopentyl, -CONH(CH ２ ) ２ N(CH ３ ) ２ , -CON(CH ３ ) ２ A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof, which is phenyl.

23. R ４ is H or -CH ３ or CH ２ - A compound according to any one of claims 1 to 22, which is phenyl, or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof.

24. A compound according to claim 1, or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof, selected from the following: Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23

25. A compound selected from the following, or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof. Table 24

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or medium.

27. A drug for killing filarial parasites, comprising a compound described in any one of claims 1 to 25 or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof.

28. A drug for inhibiting the growth or molting of filarial worms, comprising a compound described in any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, or stereoisomer.

29. A chemical agent for killing filarial parasites, comprising a compound selected from the following, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, or stereoisomer. Table 25 Table 26

30. A drug for inhibiting the growth or molting of filarial worms, comprising a compound selected from the following, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, or stereoisomer. Table 27 Table 28

31. An agent for inhibiting the motility of filarial parasites, comprising a compound described in any one of claims 1 to 25 or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

32. A drug for inhibiting the motility of filarial parasites, comprising a compound selected from the following, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, or stereoisomer. Table 29 Table 30

33. An agent for the treatment or prevention of helminthic infection and disease, comprising a compound described in any one of claims 1 to 25 or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof.

34. Agents for the treatment or prevention of helminthic infections and diseases, comprising compounds selected from the following or pharmaceutically acceptable salts, tautomers, isotopologs, or stereoisomers thereof. Table 31 Table 32

35. A drug for the treatment or prevention of helminthic infection and disease, wherein the drug comprises a compound described in any one of claims 1 to 25 or a pharmaceutically acceptable salt, tautomer, isotopolog or stereoisomer thereof, and is used to be administered in combination with one or more antihelmintic agents.

36. A drug for the treatment or prevention of helminthic infection and disease, characterized in that the drug comprises a compound selected from the following or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof, and is used in combination with one or more antihelmintic drugs. Table 33 Table 34

37. The agent according to any one of claims 33 to 36, wherein the helminth infection is a filarial parasite infection.

38. The agent according to claim 35 or 36, wherein the one or more antihelmintic agents are selected from flubendazole, albendazole, mebendazole, thiabendazole, fenbendazole, triclabendazole, ivermectin, abamectin, diethylcarbamazine (DEC), suramin, pyrantel pamoate, levamisole, niclosamide, nitazoxanide, oxyclozanide, praziquantel, emodepside, monepantel, derquantel, or peretierin sulfate.

39. The agent according to claim 35 or 36, wherein the one or more antihelmintic agents are Wolbachia-targeting agents.

40. The agent according to claim 39, wherein the Wolbachia-targeting agent is doxycycline.

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