Methods and compositions for treating fatty liver and viral infections

Abstract

Methods and compositions for treating fatty liver and viral infections are provided. Aspects of the methods include administering to a subject in need thereof an effective amount of a KxL motif binder, such as A27. Compositions for use in the practice of embodiments of the methods are also provided.

Description

Background Art

[0001] Introduction More than 100 million people in the United States have non-alcoholic fatty liver disease (NAFLD) due to metabolic dysfunction associated with obesity. Of these, 10-20% develop a more aggressive form called non-alcoholic steatohepatitis (NASH), which can ultimately cause liver failure and / or liver cancer. Current therapeutic agents are inadequate. There remains a large unmet medical need for therapeutic agents that can prevent and / or reverse NAFLD / NASH.

[0002] Viral infections, such as hepatitis B virus (HBV), alphaviruses such as Venezuelan equine encephalitis virus (VEEV), and coronaviruses (coronavirus 1 and 2) such as severe acute respiratory syndrome (SARS), continue to represent a large unmet medical need.

[0003] Cross References This application claims the benefit of U.S. Provisional Patent Application No. 63 / 344,467, filed May 20, 2022, which is hereby incorporated by reference in its entirety.

Summary of the Invention

[0004] Methods and compositions for treating fatty liver and viral infections are provided. Aspects of the methods include administering to a subject in need thereof an effective amount of a KxL motif binder, such as A27. Compositions for use in the practice of embodiments of the invention are also provided.

[0005] For example, a method of treatment comprising administering to an individual having fatty liver and / or a non-flavivirus viral infection a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formulas I-VI: TIFF2025518536000002.tif54128, is provided.

[0006] In some embodiments, the individual has a viral infection of a non-Flaviviridae virus (e.g., a viral infection of the Hepadnaviridae such as HBV, an alphavirus infection such as ONNV, SFV, VEEV, or CHIKV, a coronavirus infection such as SARS-CoV-2, a paramyxovirus infection such as RSV, an orthomyxovirus infection such as influenza, etc.). In some cases, the individual has a viral infection of hepatitis B virus (HBV), Venezuelan equine encephalitis virus (VEEV), O'nyong'nyong virus (ONNV), SARS-CoV-2, Semliki Forest virus (SFV), or chikungunya virus (CHIKV). In some cases, the individual has a viral infection of hepatitis B virus (HBV), Venezuelan equine encephalitis virus (VEEV), SARS-CoV-2, or chikungunya virus (CHIKV).

[0007] In some embodiments, the compound is co-administered with a second agent, such as an antibiotic and / or an antiviral agent. In some cases, the compound is administered at a concentration in the range of 8 - 100 mg / kg. In some cases, the compound is administered for 3 days or more. In some cases, the compound is A27: is TIFF2025518536000003.tif38128.

[0008] Also, there is also provided a novel compound selected from the group consisting of TIFF2025518536000004.tif186141, for example, a compound or a pharmaceutically acceptable salt thereof.

[0009] Also, a composition, for example, (a) a pharmaceutically acceptable carrier, excipient, or diluent, and (b) a compound selected from the group consisting of TIFF2025518536000005.tif186141 or a pharmaceutically acceptable salt thereof is also provided.

[0010] In some cases, the composition is a medicament for the treatment of fatty liver and, in some cases, for viral infections, such as viral infections of non-flaviviridae (e.g., hepadnavirus infections such as HBV, alphavirus infections such as ONNV, SFV, VEEV, or CHIKV, coronavirus infections such as SARS-CoV-2, paramyxovirus infections such as RSV, orthomyxovirus infections such as influenza).

Brief Description of the Drawings

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BEST MODE FOR CARRYING OUT THE INVENTION

[0012] Definition The term "specific binding" refers to the direct association between two molecules by covalent bonds, electrostatic bonds, hydrophobic bonds, and ionic bonds and / or hydrogen bond interactions (including interactions such as salt bridges and water bridges). Members of specific binding refer to members of a pair of molecules that have binding specificity for each other. The members of a specific binding pair may be of natural origin or may be produced completely or partially synthetically. One member of a pair of molecules has a region or cavity on its surface, which specifically binds to the specific spatial and polar structure of the other member of the pair of molecules and is thus complementary to it. Thus, a pair of members has the property of specific binding to each other. Examples of pairs of members of specific binding are antigen-antibody, biotin-avidin, hormone-hormone receptor, receptor-ligand, enzyme-substrate. The members of the specific binding of a binding pair exhibit high affinity and binding specificity with respect to their binding to each other. Typically, the affinity between a pair of members of specific binding is 10 -6 M or less, for example, 10 -7 M or less, 10 -8 M or less, for example, 10 -9 M or less, 10 -10 M or less, 10 -11 M or less, 10 -12 M or less, 10 -13 M or less, 10 -14 M or less, 10 -15 M or less, including, of K d (dissociation constant). "Affinity" refers to the strength of binding, and an increase in binding affinity correlates with a lower KD. In certain embodiments, affinity is determined by surface plasmon resonance (SPR), for example, as used by a Biacore system. The affinity of one molecule for another molecule is determined, for example, by measuring the binding kinetics of the interaction at 25°C. "Affinity" refers to the strength of binding, and an increase in binding affinity correlates with a lower KD. In certain embodiments, affinity is determined by surface plasmon resonance (SPR), for example, as used by a Biacore system. The affinity of one molecule for another molecule is determined, for example, by measuring the binding kinetics of the interaction at 25°C.

[0013] The methods described herein may include multiple steps. Each step may be executed after a predetermined time has elapsed between steps, as desired. Thus, the time during which each step is executed is 1 second or more, 10 seconds or more, 30 seconds or more, 60 seconds or more, 5 minutes or more, 10 minutes or more, 60 minutes or more, and may include 5 hours or more. In certain embodiments, each subsequent step is performed immediately after the completion of the previous step. In other embodiments, a step may be performed after an incubation or waiting time after the completion of the previous step, for example, a waiting time of several minutes to overnight.

[0014] As used herein, the terms "evaluating," "determining," and "measuring," and "assessing," and "assaying" are used interchangeably and include both quantitative and qualitative determinations.

[0015] The term "separating," as used herein, refers to the physical separation of two elements (e.g., by size or affinity, etc.), as well as the breakdown of one element while the other remains intact.

[0016] Detailed Description Methods and compositions for treating fatty liver and viral infections are provided. Aspects of the methods include administering to a subject in need thereof an effective amount of a KxL motif binder, such as A27. Compositions for use in the practice of embodiments of the invention are also provided.

[0017] Before describing the present invention in more detail, it is to be understood that the invention is not limited to the specific embodiments described, and thus may of course vary. Also, since the scope of the present invention will be limited only by the appended claims, it is to be understood that the terms used herein are for the purpose of describing only specific embodiments and are not intended to be limiting.

[0018] When a range of values is provided, unless the context clearly dictates otherwise, each intervening value, to the tenth of the unit of the lower limit, is included within the invention between the upper and lower limits of that range and any other stated value or intervening value within the stated range. The upper and lower limits of these smaller ranges may independently be included within the smaller ranges, and are also included within the invention, subject to any specific excluded limitations within the stated range. Ranges excluding either or both of those included limits are also included within the invention, if the stated range includes one or both of those limits.

[0019] A particular range is presented herein with the term "about" preceding the numerical value. The term "about" is used herein to provide literal support for the exact number preceding the term and for a number that is near to or approximately the number preceding the term. In determining whether a number is near to or approximately the specifically recited number, a number that is near to or approximately the unrecited number may be a number that provides substantial equivalence to the specifically recited number in the context presented.

[0020] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, representative and exemplary methods and materials are described herein.

[0021] All publications and patents cited herein are incorporated herein by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference, to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention has no right to antedate such publication by virtue of prior invention. Further, the dates of the publications provided may be different from the actual publication dates, which may need to be independently verified.

[0022] It should be noted that, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It should further be noted that the claims may be drafted to exclude any optional element. Accordingly, this description is intended to serve as a precedent for the use of exclusive terms such as "solely" and "only" in connection with the recitation of claim elements, or for the use of "negative" limitations.

[0023] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein can be readily separated from, or combined with, the features of any of several other embodiments without departing from the scope or spirit of the invention. Any recited method can be performed in the order of the recited events, or in any other logically possible order.

[0024] The apparatus and method are described, or will be described, in functional terms for grammatical fluidity, but the claims should not be construed as necessarily limited by the "means" or "step" limitation syntax unless expressly recited under 35 U.S.C. § 112, and should be given the full scope of the meaning and equivalents of the definition provided by the claims under the doctrine of equivalents, and it should be clearly understood that where the claims are expressly recited under 35 U.S.C. § 112, full statutory equivalents under 35 U.S.C. § 112 should be given.

[0025] Methods and compositions for treating fatty liver and viral infections are provided. Aspects of the methods include administering to a subject in need thereof an effective amount of a KxL motif binder, such as A27. Compositions for use in the practice of embodiments of the invention are also provided.

[0026] "Treatment" means that at least one improvement among one or more symptoms related to the target condition that is afflicting the subject is achieved, and the improvement is used in a broad sense to refer to a parameter, for example, at least a reduction in the magnitude of the symptoms related to the target condition being treated. Thus, treatment includes situations where the pathological symptoms or at least the symptoms related thereto are completely inhibited, for example, prevented from occurring, or stopped, for example, terminated, such that an adult mammal no longer suffers from the target condition or at least the symptoms that characterize the impairment thereof. In some examples, "treatment", "treating", etc. refer to obtaining a desired pharmacological and / or physiological effect. The effect can be preventive in terms of completely or partially preventing a disease or its symptoms, and / or can be therapeutic in terms of partial or complete cure of a disease and / or the harmful effects resulting from the disease. "Treatment" can be any treatment of a disease in a mammal, including (a) preventing a disease from occurring in a subject that has a predisposition to the disease but has not yet been diagnosed as having the disease, (b) inhibiting the disease, i.e., preventing its onset, or (c) alleviating the disease, i.e., causing regression of the disease. Treatment can result in various different physical symptoms, for example, regulation of gene expression, restoration of tissues or organs, etc. Treatment of an ongoing disease (treatment that stabilizes or reduces the patient's undesirable clinical symptoms) is carried out in some embodiments. Such treatment can be carried out in the affected tissue before complete loss of function. The subject therapy can be administered during the symptomatic stage of the disease and, in some cases, after the symptomatic stage of the disease.

[0027] Using the methods described herein, any type of subject in need of treatment may be treated. The subjects include mammalian species. Mammalian species that can be treated by the present method include dogs and cats, horses, cows, sheep, etc., as well as primates including humans. The subject methods, compositions, and reagents may also be applied, for example, in experimental investigations to animal models including small mammals such as murine, lagomorphs, etc.

[0028] The terms "recipient", "individual", "subject", "host", and "patient" are used interchangeably herein and refer to any mammalian subject, particularly a human, for which a diagnosis, treatment, or therapy is desired. As used herein for purposes of treatment, "mammal" refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals such as dogs, horses, cats, cows, sheep, goats, pigs, etc. In some embodiments, the mammal is a human. In some embodiments, the individual is not a human (e.g., a non-human mammal).

[0029] The inventors have discovered that A27 and its derivatives can bind to the KxL motif of ApoB and play a role in fatty liver (steatosis, hepatic steatosis). A27 (and derivatives) can be used to reduce steatosis and, thus, can be used to treat fatty liver. Thus, in some embodiments, the individual to which A27 and / or an A27 derivative is delivered has fatty liver.

[0030] As described above, the inventors have discovered that A27 and its derivatives can bind to the KxL motif of ApoB and have also found that it is present in the amphipathic helical domains of viral proteins including hepatitis B surface antigen (HBsAg), non-structural protein (NSP) 1 of Venezuelan equine encephalitis virus (VEEV), NSP1 of onion yellow virus (ONNV), NSP1 of Semliki Forest virus (SFV), NSP1 of chikungunya virus (CHIKV or CHKV), and NSP4 of SARS-CoV-2 (Figure 3). Thus, the compounds described herein (e.g., A27 and its derivatives) can be used to treat viral infections.

[0031] In some embodiments, the viral infection is not a viral infection of the Flaviviridae family (e.g., HCV) (i.e., a non-Flaviviridae infection). In some embodiments, the viral infection is a viral infection of the Hepadnaviridae family (e.g., hepatitis B virus (HBV)). In some cases, the infection is an alphavirus infection (e.g., ONNV, SFV, VEEV, CHIKV, eastern equine encephalitis (EEE), western equine encephalitis (WEE), etc.). In some cases, the infection is a coronavirus infection (e.g., severe acute respiratory syndrome (SARS)-CoV-2). In some cases, the infection is a paramyxovirus family infection (e.g., respiratory syncytial virus (RSV)). In some cases, the infection is an orthomyxovirus family infection (e.g., influenza).

[0032] In some cases, the infection is a hepatitis B virus (HBV) infection, Venezuelan equine encephalitis virus (VEEV) infection, or severe acute respiratory syndrome (SARS)-CoV-2 infection. In some cases, the infection is an HBV infection, VEEV infection, SARS-CoV-2 infection, ONNV infection, SFV infection, or CHIKV infection. In some cases, the infection is an alphavirus infection (e.g., ONNV, eastern equine encephalitis (EEE), western equine encephalitis (WEE), VEEV, CHIKV).

[0033] As summarized above, embodiments of the method employ a KxL motif binder. For example, small molecules that bind to the KxL motif are of interest. Small molecule compounds for natural or synthetic purposes include a number of chemical classes, such as organic molecules, such as small organic compounds having a molecular weight of greater than 50 and less than about 2,500 Daltons. Candidate agents include functional groups for structural interaction with proteins, particularly hydrogen bonding, and typically include at least an amine, carbonyl, hydroxyl, or carboxyl group, preferably including at least two of the functional chemical groups. Candidate agents may include cyclic carbon or heterocyclic structures substituted with one or more of the above functional groups, and / or aromatic or polycyclic aromatic structures. Candidate agents are also found in biomolecules including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs, or combinations thereof. Such molecules can be identified, inter alia, by using the screening protocols described below.

[0034] In some embodiments, the agent is A27 or a derivative thereof (see, e.g., the compounds of Formulas I - III illustrated below). In some of some embodiments, the agent is as disclosed in U.S. Patent Application Publication No. 2012 / 0232062A1 (see, e.g., the compounds of Formulas I - III), the disclosure of which is incorporated herein by reference.

[0035] In some of some embodiments, the agent is TIFF2025518536000006.tif40128 or a derivative thereof (see, e.g., the compounds of Formulas IV - V illustrated below). In some of some embodiments, the agent is as disclosed in International Patent Application Publication No. 2013 / 090929 (see, e.g., the compounds of Formulas IV - V), the disclosure of which is incorporated herein by reference.

[0036] Selective Definitions of Chemical Terms Terms such as those described below are referred to in their conventional meanings. Any terms that are not defined have the meanings recognized in the art.

[0037] As used herein, the term "alkyl" refers to a saturated branched or straight-chain monovalent hydrocarbon group derived by removing one hydrogen atom from a single carbon atom of a parent alkane, either by itself or as part of another substituent. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl such as propane-1-yl or propane-2-yl, and butyl such as butane-1-yl, butane-2-yl, 2-methyl-propane-1-yl, or 2-methyl-propane-2-yl. In some embodiments, the alkyl group contains 1 to 20 carbon atoms. In other embodiments, the alkyl group contains 1 to 10 carbon atoms. In still other embodiments, the alkyl group contains 1 to 6 carbon atoms, for example, 1 to 4 carbon atoms.

[0038] "Alkanil" refers to a saturated branched, straight-chain, or cyclic alkyl group derived by removing one hydrogen atom from a single carbon atom of an alkane, either by itself or as part of another substituent. Typical alkanil groups include, but are not limited to, methanyl; ethanil; propanyl such as propane-1-yl, propane-2-yl (isopropyl), cyclopropane-1-yl; butanyl such as butane-1-yl, butane-2-yl (sec-butyl), 2-methyl-propane-1-yl (isobutyl), 2-methyl-propane-2-yl (t-butyl), cyclobutane-1-yl.

[0039] "Alkylene" generally refers to a branched or unbranched saturated hydrocarbon chain having 1 to 40 carbon atoms, more generally 1 to 10 carbon atoms, and even more generally 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-).

[0040] "Alkenyl", as used by itself or as part of another substituent, refers to an unsaturated branched, straight-chain, or cyclic alkyl group having at least one carbon-carbon double bond, which is derived by removing one hydrogen atom from a single carbon atom of an alkene. The group may be in either the cis or trans conformation with respect to the double bond. Typical alkenyl groups include ethenyl; propenyl such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyl such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, but-1,3-dien-1-yl, but-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobut-1,3-dien-1-yl, etc., but are not limited thereto.

[0041] "Alkynyl", as used by itself or as part of another substituent, refers to an unsaturated branched, straight-chain, or cyclic alkyl group having at least one carbon-carbon triple bond, which is derived by removing one hydrogen atom from a single carbon atom of an alkyne. Typical alkynyl groups include ethynyl; propynyl such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyl such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc., but are not limited thereto.

[0042] "Acyl", as used by itself or as part of another substituent, refers to a -C(O)R 30 group, where R 30is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl as defined herein, and substituted versions thereof. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, piperonyl, propionyl, succinyl, and malonyl.

[0043] The term "aminoacyl" refers to a -C(O)NR 21 R 22 group, where R 21 and R 22 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and R 21 and R 22 optionally together with the nitrogen to which they are attached are linked to form a heterocyclic or substituted heterocyclic group, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0044] "Alkoxy" refers to an -OR 31 group, either by itself or as part of another substituent, where R 31 represents an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy, etc.

[0045] "Alkoxycarbonyl" refers to a -C(O)OR 31 group, either by itself or as part of another substituent, where R 31represents an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, cyclohexyloxycarbonyl, and the like.

[0046] "Aryl" refers to a monovalent aromatic hydrocarbon group derived by removing one hydrogen atom from a single carbon atom of an aromatic ring system, either by itself or as part of another substituent. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, preiadene, pyrene, pyranthrene, rubicene, triphenylene,trinaphthalene, etc. In certain embodiments, the aryl group contains 6 to 20 carbon atoms. In certain embodiments, the aryl group contains 6 to 12 carbon atoms. Examples of aryl groups are phenyl and naphthyl.

[0047] "Arylalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms attached to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced by an aryl group, either by itself or as part of another substituent. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethene-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethene-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like. When a particular alkyl moiety is intended, the nomenclature arylalkanyl, arylalkenyl, and / or arylalkynyl are used. In certain embodiments, the arylalkyl group is (C7~C 30) It is arylalkyl. For example, the alkanil, alkenyl, or alkynyl moiety of the arylalkyl group is (C1 - C 10 ) and the aryl moiety is (C6 - C 20 ). In certain embodiments, the arylalkyl group is (C7 - C 20 ) arylalkyl. For example, the alkanil, alkenyl, or alkynyl moiety of the arylalkyl group is (C1 - C8), and the aryl moiety is (C6 - C 12 ).

[0048] "Arylaryl" refers to a monovalent hydrocarbon group derived by removing one hydrogen atom from a single carbon atom of a ring system in which two or more identical or non - identical aromatic ring systems are directly linked together by single bonds, either by itself or as part of another substituent, and the number of such direct ring junctions is one less than the number of aromatic ring systems involved. Typical arylaryl groups include, but are not limited to, biphenyl, triphenyl, phenyl - naphthyl, binaphthyl, biphenyl - naphthyl, etc. When the number of carbon atoms in the arylaryl group is specified, these numbers refer to the carbon atoms constituting each aromatic ring. For example, (C5 - C 14 ) arylaryl is an arylaryl group in which each aromatic ring contains 5 - 14 carbon atoms, such as biphenyl, triphenyl, binaphthyl, phenylnaphthyl, etc. In certain embodiments, each aromatic ring system of the arylaryl group is independently (C5 - C 14 ) aromatic. In certain embodiments, each aromatic ring system of the arylaryl group is independently (C5 - C 10 ) aromatic. In certain embodiments, each aromatic ring system is the same, such as biphenyl, triphenyl, binaphthyl, trinaphthyl, etc.

[0049] "Cycloalkyl", either by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl group. When a particular level of saturation is intended, the nomenclature "cycloalkanil" or "cycloalkenyl" is used. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc. In certain embodiments, the cycloalkyl group is (C3-C 10 ) cycloalkyl. In certain embodiments, the cycloalkyl group is (C3-C7) cycloalkyl.

[0050] "Cycloheteroalkyl" or "heterocyclyl", either by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or different heteroatoms. Typical heteroatoms that can replace carbon atoms include, but are not limited to, N, P, O, S, Si, etc. When a particular level of saturation is intended, the nomenclature "cycloheteroalkanil" or "cycloheteroalkenyl" is used. Typical cycloheteroalkyl groups include, but are not limited to, groups derived from epoxide, azirine, thiirane, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, etc.

[0051] "Heteroalkyl, heteroalkanil, heteroalkenyl, and heteroalkynyl" each refer to an alkyl, alkanil, alkenyl, and alkynyl group, respectively, in which one or more of the carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or different heteroatom groups. Typical heteroatom groups that can be included in these groups include, -O-, -S-, -S-S-, -O-S-, -NR 37 R 38 -, =N-N=, -N=N-, -N=N-NR 39 R 40 , -PR 41 -, -P(O)2-, -POR 42-, -O-P(O)2-, -S-O-, -S-(O)-, -SO2-, -SnR 43 R 44 - and the like, but not limited thereto, R 37 R 38 R 39 R 40 R 41 R 42 R 43 and R 44 are each independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl.

[0052] "Heteroaryl" refers to a monovalent heteroaromatic radical derived by removing one hydrogen atom from a single atom of a heteroaromatic ring system, either by itself or as part of another substituent. Typical heteroaryl groups include those derived from acridine, alstonine, carbazole, β-carboline, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolidine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, benzodioxole, etc., but are not limited thereto. In certain embodiments, the heteroaryl group is a 5- to 20-membered heteroaryl. In certain embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl. In certain embodiments, the heteroaryl group is derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole, and pyrazine.

[0053] "Heteroarylalkyl" refers to a carbon atom, typically a terminal or sp 3Refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by a heteroaryl group. When a specific alkyl moiety is intended, the nomenclature heteroarylalkanyl, heteroarylalkenyl, and / or heterarylalkynyl is used. In certain embodiments, the heteroarylalkyl group is a 6- to 30-membered heteroarylalkyl, for example, the alkanl, alkenyl, or alkynyl moiety of the heteroarylalkyl is 1- to 10-membered, and the heteroaryl moiety is a 5- to 20-membered heteroaryl. In certain embodiments, the heteroarylalkyl group is a 6- to 20-membered heteroarylalkyl, for example, the alkanl, alkenyl, or alkynyl moiety of the heteroarylalkyl is 1- to 8-membered, and the heteroaryl moiety is a 5- to 12-membered heteroaryl.

[0054] "Aromatic ring system" refers to an unsaturated cyclic or polycyclic ring system having a conjugated π electron system, either by itself or as part of another substituent. Specifically included within the definition of "aromatic ring system" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as fluorene, indane, indene, phenalene, etc. Typical aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, preiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, etc.

[0055] "Heteroaromatic ring system" refers to an aromatic ring system in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or different heteroatoms, either by itself or as part of another substituent. Typical heteroatoms that replace carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically included within the definition of "heteroaromatic ring system" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, arsindole, benzodioxane, benzofuran, chroman, chromene, indole, indoline, xanthene, etc. Typical heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, β-carboline, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolidine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, etc.

[0056] "Substituted" refers to a group in which one or more hydrogen atoms are independently replaced by the same or different substituents. Typical substituents include alkylenedioxy (e.g., methylenedioxy), -M, -R 60 , -O - , =O, -OR 60 , -SR 60 , -S - , =S, -NR 60 R 61 , =NR 60 , -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2O - , -S(O)2OH, -S(O)2R 60 , -OS(O)2O - , -OS(O)2R60 , -P(O)(O - )2, -P(O)(OR 60 )(O - ), -OP(O)(OR 60 )(OR 61 ), -C(O)R 60 ), -C(S)R 60 ), -C(O)OR 60 ), -C(O)NR 60 R 61 ), -C(O)O - ), -C(S)OR 60 ), -NR 62 C(O)NR 60 R 61 ), -NR 62 C(S)NR 60 R 61 ), -NR 62 C(NR 63 )NR 60 R 61 ), and -C(NR 62 )NR 60 R 61 are included, but not limited to these. M is halogen, and R 60 , R 61 , R 62 , and R 63 are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, or optionally R 60 and R 61 together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring, and R 64 and R 65 are independently hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, or optionally R 64 and R 65together with the nitrogen atom to which they are attached, form a cycloheteroalkyl or substituted cycloheteroalkyl ring. In certain embodiments, substituents include -M, -R 60 , =O, -OR 60 , -SR 60 , -S - , =S, -NR 60 R 61 , =NR 60 , -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2R 60 , -OS(O)2O - , -OS(O)2R 60 , -P(O)(O - ), -P(O)(OR 60 )(O - ), -OP(O)(OR 60 )(OR 61 ), -C(O)R 60 , -C(S)R 60 , -C(O)OR 60 , -C(O)NR 60 R 61 , -C(O)O - , -NR 62 C(O)NR 60 R 61 are included. In certain embodiments, substituents include -M, -R 60 , =O, -OR 60 , -SR 60 , -NR 60 R 61 , -CF3, -CN, -NO2, -S(O)2R 60 , -P(O)(OR 60 )(O - ), -OP(O)(OR 60 )(OR 61 ), -C(O)R 60 , -C(O)OR 60 , -C(O)NR 60 R 61 , -C(O)O - are included. In certain embodiments, substituents include -M, -R 60 , =O, -OR 60 , -SR 60 , -NR 60 R61 , -CF3, -CN, -NO2, -S(O)2R 60 , -OP(O)(OR 60 )(OR 61 ), -C(O)R 60 , -C(O)OR 60 , -C(O)O - are exemplified, and R 60 , R 61 , and R 62 are as defined above. For example, the substituted group may have one, two, or three substituents selected from a methylenedioxy substituent, or a halogen atom, a (1-4C) alkyl group, and a (1-4C) alkoxy group.

[0057] Compounds for treating fatty liver and viral infections As summarized above, aspects of the present invention include methods for treating fatty liver and viral infections. In embodiments, the compounds of the present disclosure are isolated compounds. In another embodiment, the isolated compound is at least about 80%, at least about 90% pure, at least about 98% pure, or at least about 99% pure.

[0058] In embodiments, the "salt" of the compounds of the present disclosure includes (1) an acid addition salt formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or an organic acid such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, or (2) a salt formed when an acidic proton present in the compound is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or a coordination compound with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. may be mentioned.

[0059] The term "solvate" as used herein refers to a complex or aggregate formed by one or more molecules of a solute and one or more molecules of a solvent. Such a solvate may be a crystalline solid having a substantially fixed molar ratio of solute and solvent. Representative solvents include, by way of example, water, methanol, ethanol, isopropanol, acetic acid, and the like. When the solvent is water, the solvate formed is a hydrate.

[0060] In some embodiments, the compound of interest comprises a KxL motif binder. Examples of compounds for treating fatty liver and viral infections according to certain embodiments include azaindazole. In some embodiments, the compound is a compound of formula I: TIFF2025518536000007.tif26128, wherein X is C or N, Y is C or N, Z1 is C or N, Z2 is C or N, R1 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted with a substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl, or 6 membered aryl group; C2-C6 alkenyl; substituted or unsubstituted C3-C8 cycloalkyl, -CO-(C3-C8 cycloalkyl), -CO-(C1-C6 alkyl), -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, -SO2-(C1-C6 alkyl), or -SO2-(C3-C8 cycloalkyl) group, or R1 and R2 together form a 12-25 membered heterocycle, or R1 and R5 together form a 12-25 membered heterocycle, L is a bond, -CONH-, -NH-CO-, substituted or unsubstituted C1-C5 alkylene, substituted or unsubstituted C2-C5 heteroalkylene, substituted or unsubstituted 5 membered heteroaryl group, or substituted or unsubstituted 5-7 membered heterocyclyl, C5-C7 cycloalkyl, 5-6 membered heteroaryl, or 6 membered aryl group, or a combination thereof, R2 is -NH2, -NHR', -NR'R', -NHCOR', -NR'COR', -NHSO2R', -NR'SO2R', -NHSO2NH2, -NHSO2NHR', -NHC(O)NH2, -NHC(O)NHR', -N(R')SO2NH2, -N(R)SO2NHR', -N(R')C(O)NH2, and -N(R')C(O)NHR', or a substituted or unsubstituted 5-7 membered heterocyclyl, C5-C7 cycloalkyl, 5-6 membered heteroaryl, or 6 membered aryl group, R3, R4, and R5 are independently hydrogen, halo, -CN, -OH, -OR’, -NH2, -NHR’, -NR’R’, -NHCOR’, -NR’COR’, -NHSO2R’, -NR’SO2R’, -NHSO2NH2, -NHSO2NHR’, -NHC(O)NH2, -NHC(O)NHR’, -N(R’)SO2NH2, -N(R’)SO2NHR’, -N(R’)C(O)NH2, and N(R)C(O)NHR’, -SO2R’, -SO2NH2, SO2NHR’, SO2NR’R’, -CONH2, -CONHR’, -CONR’R’, -CO2H, -CO2R’, or a substituted or unsubstituted C1-C6 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group, R’ is a substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group, or two R’ groups together with the nitrogen atom to which they are attached form a heterocyclic ring.

[0061] In some embodiments, the compound is a compound of formula Ia: TIFF2025518536000008.tif26128, wherein X is C or N, Y is C or N, L is -CO-NH-, -NH-CO-, -CO-NH-CH2-, and -CH2-Y-(CH2) p -, p is an integer of 0 or 1-4, Y is a bond, -O-, or -NH-, and the right side of each L moiety is attached to R2. In one embodiment, L is -CO-NH-. In one embodiment, L is -NH-CO-. In one embodiment, L is -CO-NH-CH2-. In one embodiment, L is -CH2-Y-(CH2) p- wherein p is 1 or an integer from 1 to 4, and Y is -O- or -NH-. In one embodiment, Y is -O-. In one embodiment, Y is -NH-. In one embodiment, p is 0. In one embodiment, p is 1. In one embodiment, p is 2. In one embodiment, p is 3. In one embodiment, p is 4.

[0062] In some embodiments, the compound is a compound of formula Ib: TIFF2025518536000009.tif26128, wherein X is C or N, Y is C or N, R1 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted with a substituted or unsubstituted C3-C8 cycloalkyl, 5- to 8-membered heterocyclyl, or 6-membered aryl group; C2-C6 alkenyl; substituted or unsubstituted C3-C8 cycloalkyl, -CO-(C3-C8 cycloalkyl), -CO-(C1-C6 alkyl), -CO-(C3-C8 cycloheteroalkyl), -CO-(C1-C6 heteroalkyl), -SO2-(C1-C6 cycloalkyl), or -SO2-(C3-C8 cycloalkyl) group; L is a bond, -CONH-, -NH-CO-, a substituted or unsubstituted C1-C5 alkylene, a substituted or unsubstituted C2-C5 heteroalkylene, or a combination thereof; R2 is a substituted or unsubstituted 5- to 7-membered heterocyclyl, C5-C7 cycloalkyl, 5- to 6-membered heteroaryl, or 6-membered aryl group; R5 is R 51 R 52 N-, R 53 (MeSO2)N-, R 54 O-, or a substituted or unsubstituted C1-C6 alkyl; R 51 is hydrogen or C1-C3 alkyl; R 52is a C1-C3 alkyl, substituted or unsubstituted cycloalkyl, aryl, heterocyclyl, or heteroaryl group, and each cycloalkyl, aryl, heterocyclyl, or heteroaryl group contains 6-8 ring atoms, or R 51 and R 52 together with the nitrogen atom to which they are attached form a 6-, 7-, 8-, or 9-membered heterocyclyl ring containing up to 3 heteroatoms substituted by a substituted or unsubstituted benzyl, acyl, or sulfonyl group, R 53 is substituted and unsubstituted C1-C6 alkyl, R 54 is hydrogen, a substituted or unsubstituted benzyl group, branched C3-C8 alkyl, unsubstituted C5-C8 cycloalkyl, or C5-C8 cycloalkyl substituted by one or more linear or branched C1-C4 alkyl groups.

[0063] In some embodiments, the compound is a compound of formula Ic or Id: TIFF2025518536000010.tif47128, wherein, X is C or N, Y is C or N, R1, R 22 、R 23 、R 24 、R 51 、and R 52 are defined as in any of the above (or below) aspects or embodiments.

[0064] In another embodiment, R1 is hydrogen, C1-C5 alkyl, or -(CH2) k -R 11 where k is 1 or 2, and R 11is a C3-C8 cycloalkyl, or a substituted or unsubstituted aryl or heteroaryl group. In another embodiment, R1 is C1-C5 alkyl. In another embodiment, R1 is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, cyclopropylmethyl, or 4-chlorobenzyl. In another embodiment, R1 is methyl. In another embodiment, R1 is 4-chlorobenzyl. In another embodiment, R1 is hydrogen, methyl, or 4-chlorobenzyl. In another embodiment, R1 is hydrogen or methyl. In another embodiment, R1 is hydrogen.

[0065] In another embodiment, L is -CONH-, and the carbon atom of -CO-NH- is bonded to the azaindazole ring.

[0066] In another embodiment, L is a substituted or unsubstituted C1-C5 alkylene or C2-C5 heteroalkylene group. In another embodiment, L is -(CH2) n -, -O-(CH2) n -, or -CH2-O-(CH2) n -, the left side of L is bonded to the azaindazole moiety, and n is 1, 2, 3, or 4. In another embodiment, L is -(CH2) n -. In another embodiment, L is -O-(CH2) n -. In another embodiment, L is -CH2-O-(CH2) n -. In another embodiment, n is 3 or 4. In another embodiment, n is 3 and L is -(CH2) n -. In another embodiment, R1 is 4-chlorobenzyl, L is -CH2-O-(CH2) n -, and n is 2 or 3.

[0067] In another embodiment, R2 is a substituted or unsubstituted piperidinyl, pyrrolidinyl, piperazinyl, or azepanyl group. In another embodiment, R2 is a substituted or unsubstituted piperidin-3-yl or piperidin-4-yl group. In another embodiment, the substituted piperidin-4-yl group is TIFF2025518536000011.tif is 19128, where R 22 is a substituted or unsubstituted C2-C3 alkyl. In another embodiment, R 22 is a C2-C3 alkyl. In another embodiment, R 22 is a substituted ethyl group. In another embodiment, R 22 is -CH2CH2-NR 23 R 24 and R 23 and R 24 are independently C1-C3 alkyl, or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R 23 and R 24 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. In one embodiment within this embodiment, L is -CO-NH-, and the NH moiety is attached to the piperidinyl moiety. In another embodiment, R2 is -NR 23 R 24 and R 23 and R 24 are independently C1-C3 alkyl, or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R 23 and R 24 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. In one embodiment within this embodiment, L is -(CH2) n -, -O-(CH2) n -, or -CH2-O-(CH2)n - and the left side of L is bonded to the azaindazole moiety, and n is 1, 2, 3, or 4.

[0068] In other embodiments, R2 is a 4-piperidinyl group which is TIFF2025518536000012.tif16128, and in the formula, R 25 is a substituent which is H, or a substituted or unsubstituted C1-C3 alkyl which substitutes a carbon or nitrogen atom.

[0069] In some embodiments, the compound is a compound of formula (II): TIFF2025518536000013.tif29128, and in the formula, X is C or N, Y is C or N, R1 is hydrogen, branched or straight-chain C1-C5 alkyl, C2-C 15 alkenyl, unsubstituted or substituted cycloalkyl, -CO-(cycloalkyl), -SO2-(cycloalkyl) group, or -(CH2) n -R 11 or R5 and R1 together form a 12- to 18-membered heterocyclic ring, and n is 1 or 2, R2 is a substituted or unsubstituted piperidinyl, 4-pyridyl, pyrrolidinyl, piperazinyl, benzyl, substituted phenyl, or pyrazolyl group, and R5 is R 51 R 52 N- or R 54 O-, R 51 is H, or substituted or unsubstituted C1-C3 alkyl, and R 52 is C6-C8 cycloalkyl, substituted or unsubstituted straight-chain C1-C3 alkyl, or branched C4-C5 alkyl, or R 51 and R 52Together with the nitrogen atom to which they are attached, form a 6-, 7-, 8-, or 9-membered heterocyclyl ring containing up to 3 heteroatoms, optionally substituted by a substituted or unsubstituted benzylacyl or sulfonyl group other than the azaindazole moiety to which it is already attached, and R 54 is H, a substituted or unsubstituted benzyl group, a branched C3-C8 alkyl, an unsubstituted C5-C8 cycloalkyl, or a C5-C8 cycloalkyl substituted with one or more linear or branched C1-C4 alkyl groups, and R 11 is C5-C8 cycloalkyl, or a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. In various embodiments, the compound of formula II can have R1, R2, and R3 groups as defined below.

[0070] In another embodiment of formula II, R1 is C1-C3 alkyl. In one embodiment, R1 is methyl. In one embodiment, R 11 is cyclohexyl. In one embodiment, R 11 is phenyl substituted with halo. In one embodiment, R 11 is 2-chlorophenyl or 3-chlorophenyl.

[0071] In another embodiment of formula II, R1 is a substituted or unsubstituted 4-piperidinyl or 3-piperidinyl group. In various embodiments, R2 is a 4-piperidinyl group which is TIFF2025518536000014.tif19128, wherein R 22 is a substituted or unsubstituted C2-C3 alkyl. In another embodiment, R 22 is C2-C3 alkyl. In another embodiment, R 22 is a substituted ethyl group. In another embodiment, R 22 is -CH2CH2-NR 23 R 24 and R 23 and R 24 are independently C1-C3 alkyl, or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R23 and R 24 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, one or two methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a pyrrolidinyl, piperidinyl, or azepanyl ring, which may be substituted or unsubstituted. In one embodiment within this embodiment, L is -CO-NH-, and the NH moiety is attached to the piperidinyl moiety. In another embodiment, R2 is -NR 23 R 24 where R 23 and R 24 are independently C1-C3 alkyl, or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R 23 and R 24 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, one or two methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a pyrrolidinyl, piperidinyl, or azepanyl ring, which may be substituted or unsubstituted. In one embodiment within this embodiment, L is -(CH2) n -, -O-(CH2) n -, or -CH2-O-(CH2) n -, the left side of L is attached to the azaindazole moiety, and n is 1, 2, 3, or 4.

[0072] In other embodiments, R2 is a 4-piperidinyl group that is TIFF2025518536000015.tif16128, where R 25 is H, or a substituent that is a substituted or unsubstituted C1-C3 alkyl that replaces a carbon or nitrogen atom.

[0073] In some embodiments, the compound is a compound selected from the following. TIFF2025518536000016.tif56160TIFF2025518536000017.tif197170

[0074] In some embodiments, the compound is a compound of Formula IIa: TIFF2025518536000018.tif32128wherein X is C or N, Y is C or N, R1 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted with a substituted or unsubstituted C3-C8 cycloalkyl, 5- to 8-membered heterocyclyl, or 6-membered aryl group; C2-C6 alkenyl; substituted or unsubstituted C3-C8 cycloalkyl, -CO-(C3-C8 cycloalkyl), -CO-(C1-C6 alkyl), -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, -SO2-(C1-C6 alkyl), or -SO2-(C3-C8 cycloalkyl) group, or R1 and R2 together form a 12- to 25-membered heterocyclic ring, or R1 and R5 together form a 12- to 25-membered heterocyclic ring, R2 is -NH2, -NHR', -NR'R', -NHCOR', -NR'COR', -NHSO2R', -NR'SO2R', -NHSO2NH2, -NHSO2NHR', -NHC(O)NH2, -NHC(O)NHR', -N(R')SO2NH2, -N(R)SO2NHR', -N(R')C(O)NH2, and -N(R')C(O)NHR', or a substituted or unsubstituted 5- to 7-membered heterocyclyl, C5-C7 cycloalkyl, 5- to 6-membered heteroaryl, or 6-membered aryl group.

[0075] In some embodiments, the compound is a compound of Formula IIb: TIFF2025518536000019.tif49128wherein X is C or N, Y is C or N, R1 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted with substituted or unsubstituted C3-C8 cycloalkyl, 5- to 8-membered heterocyclyl, or 6-membered aryl; C2-C6 alkenyl; substituted or unsubstituted C3-C8 cycloalkyl, -CO-(C3-C8 cycloalkyl), -CO-(C1-C6 alkyl), -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, -SO2-(C1-C6 alkyl), or -SO2-(C3-C8 cycloalkyl), or R1 and R2 together form a 12- to 25-membered heterocyclic ring, or R1 and R5 together form a 12- to 25-membered heterocyclic ring, R 22 is hydrogen, substituted or unsubstituted C2-C3 alkyl. In another embodiment, R 22 is C2-C3 alkyl. In another embodiment, R 22 is a substituted ethyl group. In another embodiment, R 22 is -CH2CH2-NR 23 R 24 wherein, R 23 and R 24 are independently C1-C3 alkyl, or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R 23 and R 24 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, one or two methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. In one embodiment within this embodiment, L is -CO-NH-, and the NH moiety is attached to the piperidinyl moiety. In another embodiment, R2 is -NR 23 R 24 wherein, R 23 and R 24 are independently C1-C3 alkyl, or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R 23 and R24 Together with the nitrogen atom to which they are attached, they form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, one or two methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a pyrrolidinyl, piperidinyl, or azepanyl ring, which is substituted or unsubstituted. In one embodiment within this embodiment, L is -(CH2) n -, -O-(CH2) n -, or -CH2-O-(CH2) n -, and the left side of L is attached to the azaindazole moiety, and n is 1, 2, 3, or 4.

[0076] In some embodiments, the compound is a compound of formula IIc: TIFF2025518536000020.tif55128, wherein X is C or N, Y is C or N, X1, X2, X3, X4, and X5 are independently selected from CH or N, Y2 is selected from O or NR', R1 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted with a substituted or unsubstituted C3-C8 cycloalkyl, 5- to 8-membered heteroseryl, or 6-membered aryl group; C2-C6 alkenyl; substituted or unsubstituted C3-C8 cycloalkyl, -CO-(C3-C8 cycloalkyl), -CO-(C1-C6 alkyl), -CO-aryl, -CO-heteroaryl, -CO-heteroseryl, -SO2-(C1-C6 alkyl), or -SO2-(C3-C8 cycloalkyl) group, R2 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted with substituted or unsubstituted C3-C8 cycloalkyl, 5- to 8-membered heterocyclyl, or 6-membered aryl; C2-C6 alkenyl; substituted or unsubstituted C3-C8 cycloalkyl, -CO-(C3-C8 cycloalkyl), -CO-(C1-C6 alkyl), -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, -SO2-(C1-C6 alkyl), or -SO2-(C3-C8 cycloalkyl) group, R3, R4, and R5 are independently hydrogen, hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, CF3, halo, -OH, -OR’, -NH2, -NHR’, -NR’R’, -NHCOR’, -NR’COR’, -NHSO2R’, -NR’SO2R’, -NHSO2NH2, -NHSO2NHR’, -NHC(O)NH2, -NHC(O)NHR’, -N(R’)SO2NH2, -N(R’)SO2NHR’, -N(R’)C(O)NH2, and N(R)C(O)NHR’, -SO2R’, -SO2NH2, SO2NHR’, SO2NR’R’, -CONH2, -CONHR’, -CONR’R’, -CO2H, -CO2R’, or substituted or unsubstituted C1-C6 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group, or together with Y2 form substituted or unsubstituted C3-C8 heteroalkyl, 5- to 8-membered substituted or unsubstituted heterocyclyl, substituted or unsubstituted C3-C8 aryl, or 5- to 8-membered substituted or unsubstituted heteroheteroaryl, R’ is substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group, or two R’ groups together with the nitrogen atom to which they are attached form a heterocyclic ring.

[0077] In some embodiments, the compound is a compound selected from the following. TIFF2025518536000021.tif50128TIFF2025518536000022.tif206160TIFF2025518536000023.tif211160TIFF2025518536000024.tif195160TIFF2025518536000025.tif218160TIFF2025518536000026.tif208160TIFF2025518536000027.tif209141

[0078] In some embodiments, the compound is a compound of formula IId: TIFF2025518536000028.tif47128wherein X is C or N, Y is C or N, X1 is C or N, R1 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted with a substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl, or 6 membered aryl group; C2-C6 alkenyl; substituted or unsubstituted C3-C8 cycloalkyl, -CO-(C3-C8 cycloalkyl), -CO-(C1-C6 alkyl), -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, -SO2-(C1-C6 alkyl), or -SO2-(C3-C8 cycloalkyl) group, or R1 and R2 together form a 12-25 membered heterocyclic ring, or R1 and R5 together form a 12-25 membered heterocyclic ring, R 22 is hydrogen, substituted or unsubstituted C2-C3 alkyl. In another embodiment, R 22 is C2-C3 alkyl. In another embodiment, R 22 is a substituted ethyl group. In another embodiment, R 22 is -CH2CH2-NR 23 R 24 where R 23 and R 24 are independently C1-C3 alkyl, or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R 23and R 24 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, one or two methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. In one embodiment within this embodiment, L is -CO-NH-, and the NH moiety is attached to the piperidinyl moiety. In another embodiment, R2 is -NR 23 R 24 is, and R 23 and R 24 are independently C1-C3 alkyl, or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R 23 and R 24 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, one or two methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. In one embodiment within this embodiment, L is -(CH2) n -, -O-(CH2) n -, or -CH2-O-(CH2) n -, the left side of L is attached to the azaindazole moiety, and n is 1, 2, 3, or 4.

[0079] In some embodiments, the compound is a compound selected from the following. TIFF2025518536000029.tif202140

[0080] In some embodiments, the compound is a compound of formula IIe: TIFF2025518536000030.tif37128, wherein X is C or N, Y is C or N, R1 is hydrogen, branched or straight-chain C1-C5 alkyl, C2-C 15 alkenyl, unsubstituted or substituted cycloalkyl, -CO-(cycloalkyl), -SO2-(cycloalkyl) group, or -(CH2) n -R 11 or R5 and R1 together form a 12- to 18-membered heterocyclic ring, n is 1 or 2, L1 is a 5-membered heteroaryl containing up to 3 heteroatoms selected from the group consisting of O, N, and S, L2 is -CO-NH- where a carbon atom is bonded to L1, or L2 is a 6-membered heteroaryl containing up to 3 heteroatoms selected from the group consisting of O, N, and S, or L2 is a 5-membered cycloalkyl containing up to 3 heteroatoms selected from the group consisting of O, N, and S, L2 is -CO-NH- where a carbon atom is bonded to L1, or L2 is a 6-membered cycloalkyl containing up to 3 heteroatoms selected from the group consisting of O, N, and S, L2 is -CO-NH- where a carbon atom is bonded to L1, L2 is -CO-NH-, and a carbon atom is bonded to L1, L3 is substituted or unsubstituted C1-C3 alkylene, p1 is 0 or 1, p2 is 0, 1, or 2, R2 is 3- or 4-piperidinyl, R5 is -NR 51 R 52 or -OR 54 and R 51 、R 52 、and R 52 are defined by any one of the above formulas, and R1 is methyl. In another embodiment, P1 is 1, and P2 is 0 or 1. In another embodiment, P1 is 0, and P2 is 0 or 1. In another embodiment, P2 is 0. In another embodiment, P2 is 1. In another embodiment, L3 is -CH2-. In other embodiments, the compound of formula IIe has the following formula where R7, R8, and R9 are independently hydrogen, or substituted or unsubstituted C1-C3 alkyl: Having TIFF2025518536000031.tif86170, wherein R 51 , R 52 , and R 52 are defined by any one of the above formulas, and R1 is methyl. In another embodiment, P1 is 1, and P2 is 0 or 1. In another embodiment, P1 is 0, and P2 is 0 or 1. In another embodiment, P2 is 0. In another embodiment, P2 is 1. In another embodiment, L3 is -CH2-. In other embodiments, the compound of formula IIe has the following formula, wherein R7, R8, and R9 are independently hydrogen, or substituted or unsubstituted C1-C3 alkyl.

[0081] In some embodiments, the compound is a compound of formula IIf: TIFF2025518536000032.tif41128, wherein X is C or N, Y is C or N, R1 is hydrogen, branched or straight-chain C1-C5 alkyl, C2-C 15 alkenyl, unsubstituted or substituted cycloalkyl, -CO-(cycloalkyl), -SO2-(cycloalkyl) group, or -(CH2) n -R 11 or R5 and R1 together form a 12- to 18-membered heterocyclic ring, n is 1 or 2, R 51 , R 52 , and R 52 are defined by any one of the above formulas, and R1 is methyl. In another embodiment, P1 is 1, and P2 is 0 or 1. In another embodiment, P1 is 0, and P2 is 0 or 1. In another embodiment, P2 is 0. In another embodiment, P2 is 1. In another embodiment, L3 is -CH2-. In other embodiments, the compound of formula IIf has the following formula, wherein R7, R8, and R9 are independently hydrogen, or substituted or unsubstituted C1-C3 alkyl.

[0082] In some embodiments, the compound is a compound selected from the following. TIFF2025518536000033.tif216160

[0083] In some embodiments, the compound is a compound of Formula IIg: TIFF2025518536000034.tif45128 wherein, X is C or N, Y is C or N, X1 is selected from CH or N, Y2 is selected from O or NR', R1 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted with a substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl, or 6 membered aryl group; C2-C6 alkenyl; substituted or unsubstituted C3-C8 cycloalkyl, -CO-(C3-C8 cycloalkyl), -CO-(C1-C6 alkyl), -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, -SO2-(C1-C6 alkyl), or -SO2-(C3-C8 cycloalkyl) group, or R1 and R2 together form a 12-25 membered heterocycle, or R1 and R5 together form a 12-25 membered heterocycle, R2 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted with a substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl, or 6 membered aryl group; C2-C6 alkenyl, substituted or unsubstituted C3-C8 cycloalkyl, -CO-(C3-C8 cycloalkyl), -CO-(C1-C6 alkyl), -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, -SO2-(C1-C6 alkyl), or -SO2-(C3-C8 cycloalkyl) group, R3, R4, and R5 are independently hydrogen, hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, CF3, halo, -OH, -OR’, -NH2, -NHR’, -NR’R’, -NHCOR’, -NR’COR’, -NHSO2R’, -NR’SO2R’, -NHSO2NH2, -NHSO2NHR’, -NHC(O)NH2, -NHC(O)NHR’, -N(R’)SO2NH2, -N(R’)SO2NHR’, -N(R’)C(O)NH2, and N(R)C(O)NHR’, -SO2R’, -SO2NH2, SO2NHR’, SO2NR’R’, -CONH2, -CONHR’, -CONR’R’, -CO2H, -CO2R’, or a substituted or unsubstituted C1-C6 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group, R’ is a substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group, or two R’ groups together with the nitrogen atom to which they are attached form a heterocyclic ring.

[0084] In some embodiments, the compound is a compound selected from the following. TIFF2025518536000035.tif121167TIFF2025518536000036.tif218160TIFF2025518536000037.tif167160

[0085] In some embodiments, the compound is a compound of formula IIh: TIFF2025518536000038.tif51128 where X is C or N, Y is C or N, X1 is selected from CH or N, Y2 is selected from O or NR, R1 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted with a substituted or unsubstituted C3-C8 cycloalkyl, 5- to 8-membered heterocyclyl, or 6-membered aryl group; C2-C6 alkenyl; substituted or unsubstituted C3-C8 cycloalkyl, -CO-(C3-C8 cycloalkyl), -CO-(C1-C6 alkyl), -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, -SO2-(C1-C6 alkyl), or -SO2-(C3-C8 cycloalkyl) group, or R1 and R2 together form a 12- to 25-membered heterocyclic ring, or R1 and R5 together form a 12- to 25-membered heterocyclic ring, R2 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted with a substituted or unsubstituted C3-C8 cycloalkyl, 5- to 8-membered heterocyclyl, or 6-membered aryl group; C2-C6 alkenyl, substituted or unsubstituted C3-C8 cycloalkyl, -CO-(C3-C8 cycloalkyl), -CO-(C1-C6 alkyl), -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, -SO2-(C1-C6 alkyl), or -SO2-(C3-C8 cycloalkyl) group, R3, R4, and R5 are independently hydrogen, hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, CF3, halo, -OH, -OR', -NH2, -NHR', -NR'R', -NHCOR', -NR'COR', -NHSO2R', -NR'SO2R', -NHSO2NH2, -NHSO2NHR', -NHC(O)NH2, -NHC(O)NHR', -N(R')SO2NH2, -N(R')SO2NHR', -N(R')C(O)NH2, and N(R)C(O)NHR', -SO2R', -SO2NH2, SO2NHR', SO2NR'R', -CONH2, -CONHR', -CONR'R', -CO2H, -CO2R', or a substituted or unsubstituted C1-C6 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group, R’ is a substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group, or two R’ groups together with the nitrogen atom to which they are attached form a heterocyclic ring.

[0086] In some embodiments, the compound is a compound selected from the following. TIFF2025518536000039.tif120160TIFF2025518536000040.tif168170TIFF2025518536000041.tif168170TIFF2025518536000042.tif52160

[0087] In some embodiments, the compound is a compound of Formula III: TIFF2025518536000043.tif25128, wherein X is C or N, Y is C or N, Z1 is C or N, Z2 is C or N, R1 is hydrogen, branched or straight-chain C1-C5 alkyl, C2-C 15 alkenyl, unsubstituted or substituted cycloalkyl, -CO-(cycloalkyl), -SO2-(cycloalkyl) group, or -(CH2) n -R 11 or R5 and R1 together form a 12- to 18-membered heterocycle, and n is 1 or 2, R2 is a substituted or unsubstituted phenyl, piperidinyl, 4-pyridyl, pyrrolidinyl, piperazinyl, benzyl, substituted phenyl, or pyrazolyl group, R5 is R 51 R 52 N- or R 54 O-, R 51 is H, or substituted or unsubstituted C1-C3 alkyl, R 52is C6-C8 cycloalkyl, substituted or unsubstituted straight-chain C1-C3 alkyl, or branched C4-C5 alkyl, or R 51 and R 52 together with the nitrogen atom to which they are attached form a 6-, 7-, 8-, or 9-membered heterocyclyl ring optionally substituted by a substituted or unsubstituted benzylacyl or sulfonyl group containing up to 3 heteroatoms other than the azaindazole moiety to which it is already attached, and R 54 is H, a substituted or unsubstituted benzyl group, branched C3-C8 alkyl, unsubstituted C5-C8 cycloalkyl, or C5-C8 cycloalkyl substituted by one or more straight-chain or branched C1-C4 alkyl groups, and R 11 is C5-C8 cycloalkyl, or substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R3 and R5 are independently hydrogen, halo, -CN, -OH, -OR’, -NH2, -NHR’, -NR’R’, -NHCOR’, -NR’COR’, -NHSO2R’, -NR’SO2R’, -NHSO2NH2, -NHSO2NHR’, -NHC(O)NH2, -NHC(O)NHR’, -N(R’)SO2NH2, -N(R’)SO2NHR’, -N(R’)C(O)NH2, and N(R)C(O)NHR’, -SO2R’, -SO2NH2, SO2NHR’, SO2NR’R’, -CONH2, -CONHR’, -CONR’R’, -CO2H, -CO2R’, or a substituted or unsubstituted C1-C6 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group.

[0088] In some embodiments, the compound is a compound selected from the following. TIFF2025518536000044.tif103170

[0089] In some embodiments, the compound is a compound of formula IV: TIFF2025518536000045.tif28128, wherein each X is independently selected from C or N, R 1 is either absent, hydrogen, (C1-C8)alkyl, NR 9 R 10 , halo, amino, -C≡N, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)haloalkyl, (C2-C8)haloalkenyl, (C2-C8)haloalkynyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C1-C8)alkyl(C1-C6)alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, CH(O), C(O)OR 8 , SF5, -OH, -SH, (C1-C6)hydroxyalkyl, (C1-C4)alkylsulfonyl, aminosulfonyl, amino(C1-C4)alkylsulfonyl, or aryl, and R 2 is C(O)NR 11 R 12 , C(O)R 13 , a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, and R 3 is H, (C1-C8)alkyl, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C8)alkoxy, hydroxyl, halo, amino, amide, amino(C1-C8)alkylamide, heterocyclyl, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano, or (C1-C3)haloalkyl, and each R 4 is independently selected from unsubstituted or halo, (C1-C8)alkoxy, (C1-C8)haloalkoxy, S(O)-R 6 , S(O)2, S(O)2-R 6 , S(O)2, C(O)R 6 , C(O)OR 7 , or (C1-C8)alkyl optionally substituted with (C1-C8)cycloalkyl, or both Rs 4together form (C1-C8) cycloalkyl, (C1-C8) substituted cycloalkyl, (C1-C8) heterocycloalkyl, (C1-C8) substituted heterocycloalkyl, (C1-C8) aryl, (C1-C8) substituted aryl, (C1-C8) heteroaryl, or (C1-C8) substituted heteroaryl, R 6 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 7 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 8 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 9 is H, (C1-C8) alkyl, where the (C1-C8) alkyl is unsubstituted or substituted with one or more halos, R 10 is H, (C1-C8) alkyl, where the (C1-C8) alkyl is unsubstituted or substituted with one or more halos, or R 9 and R 10together with the nitrogen atom to which they are attached form a 4- or 5-membered nitrogen-containing heterocyclic ring, which is unsubstituted or substituted with one or more halos, and R is H, (C1-C4) alkyl, (C1-C4) haloalkyl, a 5- or 6-membered heterocyclic ring, or a 5- or 6-membered heteroaryl, R 11 is selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 12 is selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 11 and R 12 together with the nitrogen atom to which they are attached form a 5- to 8-membered nitrogen-containing heterocyclic ring, which is unsubstituted or substituted with OH, halo, =O, or (C1-C8) alkyl, R 13 is OH, O-(C1-C4) alkyl, R 15 is H, (C1-C6) alkyl, (C1-C) haloalkyl, a 4- to 7-membered heterocyclic ring, a 5- to 6-membered heteroaryl, a 3- to 7-membered cycloalkyl, and each of the 4- to 7-membered heterocyclic ring, 5- to 6-membered heteroaryl, 3- to 7-membered cycloalkyl is unsubstituted or substituted at substitutable positions with one or more =O, OH, (C1-C8) alkyl, (C1-C8) haloalkyl, (C1-C8) alkoxy, amino, or (C1-C8) aminoalkyl, R 16is H, (C1-C8)alkyl, or (C1-C8)haloalkyl.

[0090] In some embodiments, the compound is a compound of Formula IVa: TIFF2025518536000046.tif28128, wherein X1 is independently selected from C or N, X2 is independently selected from C or N, X3 is independently selected from C or N, X4 is independently selected from C or N, X5 is independently selected from C or N, R 1 is absent, hydrogen, (C1-C8)alkyl, NR 9 R 10 , halo, amino, -C≡N, (C2-C8)alkenyl, (C2-C8)alkynyl, (C C8)haloalkyl, (C2-C8)haloalkenyl, (C2-C8)haloalkynyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C1-C8)alkyl(C1-C6)alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, CH(O), C(O)OR 8 , SF5, -OH, -SH, (C1-C6)hydroxyalkyl, (C1-C4)alkylsulfonyl, aminosulfonyl, amino(C1-C4)alkylsulfonyl, or aryl, R 2 is C(O)NR 11 R 12 , C(O)R 13 , a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 3is H, (C1-C8)alkyl, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C8)alkoxy, hydroxyl, halo, amino, amide, amino(C1-C8)alkylamide, heterocyclyl, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano, or (C1-C3)haloalkyl, R 4a is H, unsubstituted or selected from halo, (C1-C8)alkoxy, (C1-C8)haloalkoxy, S(O)-R 6 , S(O)2, S(O)2-R 6 , S(O)2, C(O)R 6 , C(O)OR 7 or (C1-C8)alkyl optionally substituted with (C1-C8)cycloalkyl, R 4b is H, unsubstituted or selected from halo, (C1-C8)alkoxy, (C1-C8)haloalkoxy, S(O)-R 6 , S(O)2, S(O)2-R 6 , S(O)2, C(O)R 6 , C(O)OR 7 or (C1-C8)alkyl optionally substituted with (C1-C8)cycloalkyl, or R 4a and R 4b together form (C1-C8)cycloalkyl, (C1-C8)substituted cycloalkyl, (C1-C8)heterocycloalkyl, (C1-C8)substituted heterocycloalkyl, (C1-C8)aryl, (C1-C8)substituted aryl, (C1-C8)heteroaryl, or (C1-C8)substituted heteroaryl, R 6 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4)haloalkyl, and cyano, R 7is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 8 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 9 is H, (C1-C8) alkyl, and the (C1-C8) alkyl is unsubstituted or substituted with one or more halos, R 10 is H, (C1-C8) alkyl, and the (C1-C8) alkyl is unsubstituted or substituted with one or more halos, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- or 5-membered nitrogen-containing heterocycle, and the 4- or 5-membered nitrogen-containing heterocycle is unsubstituted or substituted with one or more halos, and R is H, (C1-C4) alkyl, (C1-C4) haloalkyl, a 5- to 6-membered heterocycle, or a 5- to 6-membered heteroaryl, R 11 is selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 12is selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 11 and R 12 together with the nitrogen atom to which they are attached form a 5- to 8-membered nitrogen-containing heterocyclic ring, and the 5- to 8-membered nitrogen-containing heterocyclic ring is unsubstituted or substituted with OH, halo, =O, or (C1-C8) alkyl, R 13 is OH, O-(C1-C4) alkyl, R 15 is H, (C1-C6) alkyl, (C1-C) haloalkyl, a 4- to 7-membered heterocyclic ring, a 5- to 6-membered heteroaryl, a 3- to 7-membered cycloalkyl, and each of the 4- to 7-membered heterocyclic ring, the 5- to 6-membered heteroaryl, and the 3- to 7-membered cycloalkyl is unsubstituted or substituted at a substitutable position with one or more =O, OH, (C1-C8) alkyl, (C1-C8) haloalkyl, (C1-C8) alkoxy, amino, or (C1-C8) aminoalkyl, R 16 is H, (C1-C8) alkyl, or (C1-C8) haloalkyl.

[0091] In some embodiments, X1 is N. In some embodiments, X1 is C. In some embodiments, X2 is N. In some embodiments, X2 is C. In some embodiments, X3 is N. In some embodiments, X3 is C. In some embodiments, X4 is N. In some embodiments, X4 is C. In some embodiments, X5 is N. In some embodiments, X5 is C.

[0092] In some embodiments, X1 is N, X2 is C, X3 is N, X4 is N, and X5 is C. In some embodiments, X1 is N, X2 is C, X3 is C, X4 is N, and X5 is N. In some embodiments, X1 is C, X2 is N, X3 is C, X4 is C, and X5 is N. In some embodiments, X1 is C, X2 is C, X3 is N, X4 is N, and X5 is C. In some embodiments, X1 is N, X2 is C, X3 is N, X4 is N, and X5 is N.

[0093] In some embodiments, R1 is selected from hydrogen, (C1-C8)alkyl, halo, or haloalkyl. In some examples, R1 is hydrogen. In some examples, R1 is (C1-C8)alkyl, such as methyl, ethyl, propyl, i-propyl, butyl, t-butyl, i-butyl, or pentyl. In certain examples, R1 is methyl. In certain examples, R1 is t-butyl. In some examples, R1 is halo, such as fluoro, chloro, or bromo. In certain examples, R1 is fluoro. In some examples, R1 is haloalkyl, such as CF3, CCl3, or CBr3. In certain examples, R1 is CF3.

[0094] In some embodiments, R 2 is C(O)NR 11 R 12 where R 11 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, and R 12is selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl.

[0095] In some embodiments, R 2 is a 5-membered heteroaryl. In some examples, R 2 is TIFF2025518536000047.tif18128, where Y1 is O, NH, CH2, or S, Y2 is CH or N, Y3 is CH or N.

[0096] In some embodiments, R 11 is H, and R 12 is selected from a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered substituted heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl. In some examples, R 11 is H, and R 12 is a 6-membered heterocyclic ring. In some examples, R 11 is H, and R 12 is a substituted 6-membered heterocyclic ring.

[0097] In a particular example, R 11 is H, and R 12 is a substituted or unsubstituted piperidinyl, pyrrolidinyl, piperazinyl, or azepanyl group. In another embodiment, R 12 is a substituted or unsubstituted piperidin-3-yl or piperidin-4-yl group. In another embodiment, the substituted piperidin-4-yl group is TIFF2025518536000048.tif is 19128, where R 22 is a substituted or unsubstituted C2-C3 alkyl. In another embodiment, R 22 is a C2-C3 alkyl. In another embodiment, R 22 is a substituted ethyl group. In another embodiment, R 22 is -CH2CH2-NR 23 R 24 and R 23 and R 24 are independently C1-C3 alkyl, or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R 23 and R 24 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, one or two methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. In one embodiment within this embodiment, L is -CO-NH-, and the NH moiety is attached to the piperidinyl moiety. In another embodiment, R2 is -NR 23 R 24 and R 23 and R 24 are independently C1-C3 alkyl, or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R 23 and R 24 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, one or two methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. In one embodiment within this embodiment, L is -(CH2) n -, -O-(CH2) n -, or -CH2-O-(CH2)n - and the left side of L is bonded to the azaindazole moiety, and n is 1, 2, 3, or 4.

[0098] In a particular example, R 11 is H, and R 12 is TIFF2025518536000049.tif19128, wherein X6 is N or C, R 22 is substituted or unsubstituted C2-C3 alkyl. In another embodiment, R 22 is C2-C3 alkyl. In another embodiment, R 22 is a substituted ethyl group. In another embodiment, R 22 is -CH2CH2-NR 23 R 24 and R 23 and R 24 are independently C1-C3 alkyl, or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R 23 and R 24 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring.

[0099] In one embodiment within this embodiment, L is -CO-NH-, and the NH moiety is bonded to the piperidinyl moiety. In another embodiment, R2 is -NR 23 R 24 and R 23 and R 24 are independently C1-C3 alkyl, or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R 23 and R 24Together with the nitrogen atom to which they are attached, they form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, one or two methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. In one embodiment within this embodiment, L is -(CH2) n -, -O-(CH2) n -, or -CH2-O-(CH2) n -, the left side of L is attached to the azaindazole moiety, and n is 1, 2, 3, or 4.

[0100] In some embodiments, R 4a is H, unsubstituted or substituted with halo, (C1-C8) alkoxy, (C1-C8) haloalkoxy, or (C1-C8) cycloalkyl, and is any (C1-C8) alkyl. In some embodiments, R 4b is unsubstituted or substituted with halo, (C1-C8) alkoxy, (C1-C8) haloalkoxy, S(O)-R 6 , S(O)2, S(O)2-R 6 , S(O)2, C(O)R 6 , C(O)OR 7 , or H(C1-C8) alkyl substituted with (C1-C8) cycloalkyl, and is any (C1-C8) alkyl. In some embodiments, R 4a is (C1-C8) alkyl. In some embodiments, R 4a is (C1-C8) alkyl substituted with halo. In some examples, R 4a is ethyl substituted with halo.

[0101] In some embodiments, R 4a and R 4bcombine to form (C1-C8) cycloalkyl, (C1-C8) substituted cycloalkyl, (C1-C8) heterocycloalkyl, (C1-C8) substituted heterocycloalkyl, (C1-C8) aryl, (C1-C8) substituted aryl, (C1-C8) heteroaryl, or (C1-C8) substituted heteroaryl. In some examples, R 4a and R 4b combine with the nitrogen to which they are attached to form (C1-C8) heterocycloalkyl. In certain examples, R 4a and R 4b combine with nitrogen to form a 7-membered heterocycloalkyl.

[0102] In some embodiments, the compound is a compound of formula IVb: TIFF2025518536000050.tif31128, wherein X1 is independently selected from C or N, X2 is independently selected from C or N, X3 is independently selected from C or N, X4 is independently selected from C or N, X5 is independently selected from C or N, X6 is independently selected from C or N, R 1 is absent, hydrogen, (C1-C8) alkyl, NR 9 R 10 , halo, amino, -C≡N, (C2-C8) alkenyl, (C2-C8) alkynyl, (C C8) haloalkyl, (C2-C8) haloalkenyl, (C2-C8) haloalkynyl, (C1-C8) alkoxy, (C1-C8) haloalkoxy, (C1-C8) alkyl(C1-C6) alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, CH(O), C(O)OR 8 , SF5, -OH, -SH, (C1-C6) hydroxyalkyl, (C1-C4) alkylsulfonyl, aminosulfonyl, amino(C1-C4) alkylsulfonyl, or aryl, R 2 is C(O)NR11 R 12 、 C(O)R 13 、 a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 3 is H, (C1-C8) alkyl, (C1-C8) alkenyl, (C1-C8) alkynyl, (C1-C8) alkoxy, hydroxyl, halo, amino, amide, amino(C1-C8)alkylamide, heterocyclyl, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano, or (C1-C3) haloalkyl, R 4a is H, unsubstituted or selected from halo, (C1-C8) alkoxy, (C1-C8) haloalkoxy, S(O)-R 6 、 S(O)2、 S(O)2-R 6 、 S(O)2、 C(O)R 6 、 C(O)OR 7 、 or (C1-C8) alkyl optionally substituted with (C1-C8) cycloalkyl, R 4b is H, unsubstituted or selected from halo, (C1-C8) alkoxy, (C1-C8) haloalkoxy, S(O)-R 6 、 S(O)2、 S(O)2-R 6 、 S(O)2、 C(O)R 6 、 C(O)OR 7 、 or (C1-C8) alkyl optionally substituted with (C1-C8) cycloalkyl, or R 4a and R 4b together form (C1-C8) cycloalkyl, (C1-C8) substituted cycloalkyl, (C1-C8) heterocycloalkyl, (C1-C8) substituted heterocycloalkyl, (C1-C8) aryl, (C1-C8) substituted aryl, (C1-C8) heteroaryl, or (C1-C8) substituted heteroaryl, R6 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 7 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 8 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 9 is H, (C1-C8) alkyl, and the (C1-C8) alkyl is unsubstituted or substituted with one or more halos, R 10 is H, (C1-C8) alkyl, and the (C1-C8) alkyl is unsubstituted or substituted with one or more halos, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- or 5-membered nitrogen-containing heterocycle, and the 4- or 5-membered nitrogen-containing heterocycle is unsubstituted or substituted with one or more halos, and R is H, (C1-C4) alkyl, (C1-C4) haloalkyl, a 5- to 6-membered heterocycle, or a 5- to 6-membered heteroaryl, R 11is selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 12 is selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 11 and R 12 together with the nitrogen atom to which they are attached form a 5- to 8-membered nitrogen-containing heterocyclic ring, and the 5- to 8-membered nitrogen-containing heterocyclic ring is unsubstituted or substituted with OH, halo, =O, or (C1-C8) alkyl, R 13 is OH, O-(C1-C4) alkyl, R 15 is H, (C1-C6) alkyl, (C1-C) haloalkyl, a 4- to 7-membered heterocyclic ring, a 5- to 6-membered heteroaryl, a 3- to 7-membered cycloalkyl, and each of the 4- to 7-membered heterocyclic ring, 5- to 6-membered heteroaryl, 3- to 7-membered cycloalkyl is unsubstituted or substituted at substitutable positions with one or more =O, OH, (C1-C8) alkyl, (C1-C8) haloalkyl, (C1-C8) alkoxy, amino, or (C1-C8) aminoalkyl, R 16 is H, (C1-C8) alkyl, or (C1-C8) haloalkyl, R 22 is substituted or unsubstituted C2-C3 alkyl. In another embodiment, R 22 is C2-C3 alkyl. In another embodiment, R 22 is a substituted ethyl group. In another embodiment, R 22is -CH2CH2-NR 23 R 24 wherein R 23 and R 24 are independently C1-C3 alkyl, or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R 23 and R 24 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, one or two methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. In one embodiment within this embodiment, L is -CO-NH-, and the NH moiety is attached to the piperidinyl moiety. In another embodiment, R2 is -NR 23 R 24 wherein R 23 and R 24 are independently C1-C3 alkyl, or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R 23 and R 24 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, one or two methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. In one embodiment within this embodiment, L is -(CH2) n -, -O-(CH2) n -, or -CH2-O-(CH2) n -, the left side of L is attached to the azaindazole moiety, and n is 1, 2, 3, or 4.

[0103] In some embodiments, the compound is a compound selected from the following. TIFF2025518536000051.tif22160TIFF2025518536000052.tif211160TIFF2025518536000053.tif214160TIFF2025518536000054.tif197160TIFF2025518536000055.tif181160

[0104] In some embodiments, the compound is a compound of Formula IVc: TIFF2025518536000056.tif34128wherein X1 is independently selected from C or N, X2 is independently selected from C or N, X3 is independently selected from C or N, X4 is independently selected from C or N, X5 is independently selected from C or N, R 1 is absent, hydrogen, (C1-C8)alkyl, NR 9 R 10 , halo, amino, -C≡N, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)haloalkyl, (C2-C8)haloalkenyl, (C2-C8)haloalkynyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C1-C8)alkyl(C1-C6)alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, CH(O), C(O)OR 8 , SF5, -OH, -SH, (C1-C6)hydroxyalkyl, (C1-C4)alkylsulfonyl, aminosulfonyl, amino(C1-C4)alkylsulfonyl, or aryl, R 2 is hydrogen, (C1-C8)alkyl, NR 9 R 10, halo, amino, -C≡N, (C2-C8) alkenyl, (C2-C8) alkynyl, (C2-C8) haloalkyl, (C2-C8) haloalkenyl, (C2-C8) haloalkynyl, (C1-C8) alkoxy, (C1-C8) haloalkoxy, (C1-C8) alkyl(C1-C6)alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, CH(O), C(O)OR 8 , SF5, -OH, -SH, (C1-C6) hydroxyalkyl, (C1-C4) alkylsulfonyl, aminosulfonyl, amino(C1-C4)alkylsulfonyl, or aryl, R 3 is H, (C1-C8) alkyl, (C1-C8) alkenyl, (C1-C8) alkynyl, (C1-C8) alkoxy, hydroxyl, halo, amino, amide, amino(C1-C8)alkylamide, heterocyclyl, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano, or (C1-C3) haloalkyl, R 4a is H, unsubstituted or selected from halo, (C1-C8) alkoxy, (C1-C8) haloalkoxy, S(O)-R 6 , S(O)2, S(O)2-R 6 , S(O)2, C(O)R 6 , C(O)OR 7 , or (C1-C8) alkyl optionally substituted with (C1-C8) cycloalkyl, R 4b is H, unsubstituted or selected from halo, (C1-C8) alkoxy, (C1-C8) haloalkoxy, S(O)-R 6 , S(O)2, S(O)2-R 6 , S(O)2, C(O)R 6 , C(O)OR 7 , or (C1-C8) alkyl optionally substituted with (C1-C8) cycloalkyl, or R 4a and R 4bcombine to form (C1-C8) cycloalkyl, (C1-C8) substituted cycloalkyl, (C1-C8) heterocycloalkyl, (C1-C8) substituted heterocycloalkyl, (C1-C8) aryl, (C1-C8) substituted aryl, (C1-C8) heteroaryl, or (C1-C8) substituted heteroaryl, R 6 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 7 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 8 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 9 is H, (C1-C8) alkyl, where the (C1-C8) alkyl is unsubstituted or substituted with one or more halos, R 10 is H, (C1-C8) alkyl, where the (C1-C8) alkyl is unsubstituted or substituted with one or more halos, or R 9 and R 10together with the nitrogen atom to which they are attached form a 4- or 5-membered nitrogen-containing heterocycle, which 4- or 5-membered nitrogen-containing heterocycle is unsubstituted or substituted with one or more halos, and R is H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5- or 6-membered heterocycle, or a 5- or 6-membered heteroaryl, R 11 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 12 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 11 and R 12 together with the nitrogen atom to which they are attached form a 5- to 8-membered nitrogen-containing heterocycle, which 5- to 8-membered nitrogen-containing heterocycle is unsubstituted or substituted with OH, halo, =O, or (C1-C8)alkyl, R 13 is OH, O-(C1-C4)alkyl, R 15 is H, (C1-C6)alkyl, (C1-C)haloalkyl, a 4- to 7-membered heterocycle, a 5- to 6-membered heteroaryl, a 3- to 7-membered cycloalkyl, and each of the 4- to 7-membered heterocycle, 5- to 6-membered heteroaryl, 3- to 7-membered cycloalkyl is unsubstituted or substituted at a substitutable position with one or more =O, OH, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, amino, or (C1-C8)aminoalkyl, R 16is H, (C1-C8) alkyl, or (C1-C8) haloalkyl.

[0105] In some embodiments, the compound is a compound selected from the following. TIFF2025518536000057.tif182161

[0106] In certain embodiments, the compound is as follows. TIFF2025518536000058.tif40128

[0107] In some embodiments, the compound is a compound of formula V: TIFF2025518536000059.tif28128, wherein each X is independently selected from C or N, R 1 is absent, hydrogen, (C1-C8) alkyl, NR 9 R 10 halo, amino, -C≡N, (C2-C8) alkenyl, (C2-C8) alkynyl, (C C8) haloalkyl, (C2-C8) haloalkenyl, (C2-C8) haloalkynyl, (C1-C8) alkoxy, (C1-C8) haloalkoxy, (C1-C8) alkyl(C1-C6) alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, CH(O), C(O)OR 8 SF5, -OH, -SH, (C1-C6) hydroxyalkyl, (C1-C4) alkylsulfonyl, aminosulfonyl, amino(C1-C4) alkylsulfonyl, or aryl, R 2 is C(O)NR 11 R 12 C(O)R 13 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 6-membered heterocycle, 6-membered substituted heterocycle, 6-membered heteroaryl, 6-membered substituted heteroaryl, 5-membered cycloalkyl, or 5-membered substituted cycloalkyl, 6-membered cycloalkyl, or 6-membered substituted cycloalkyl, R 3is H, (C1-C8)alkyl, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C8)alkoxy, hydroxyl, halo, amino, amide, amino(C1-C8)alkylamide, heterocyclyl, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano, or (C1-C3)haloalkyl, each R 4 is independently selected from unsubstituted or halo, (C1-C8)alkoxy, (C1-C8)haloalkoxy, S(O)-R 6 , S(O)2, S(O)2-R 6 , S(O)2, C(O)R 6 , C(O)OR 7 , or (C1-C8)alkyl optionally substituted with (C1-C8)cycloalkyl, or both Rs 4 together form (C1-C8)cycloalkyl, (C1-C8)substituted cycloalkyl, (C1-C8)heterocycloalkyl, (C1-C8)substituted heterocycloalkyl, (C1-C8)aryl, (C1-C8)substituted aryl, (C1-C8)heteroaryl, or (C1-C8)substituted heteroaryl, R 6 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4)haloalkyl, and cyano, R 7 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4)haloalkyl, and cyano, R 8is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 9 is H, (C1-C8) alkyl, and the (C1-C8) alkyl is unsubstituted or substituted with one or more halos, R 10 is H, (C1-C8) alkyl, and the (C1-C8) alkyl is unsubstituted or substituted with one or more halos, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- or 5-membered nitrogen-containing heterocyclic ring, and the 4- or 5-membered nitrogen-containing heterocyclic ring is unsubstituted or substituted with one or more halos, and R is H, (C1-C4) alkyl, (C1-C4) haloalkyl, a 5- to 6-membered heterocyclic ring, or a 5- to 6-membered heteroaryl, R 11 is selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 12 is selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 11 and R 12together with the nitrogen atom to which they are attached form a 5- to 8-membered nitrogen-containing heterocycle, which is unsubstituted or substituted with OH, halo, =O, or (C1-C8)alkyl, R 13 is OH, O-(C1-C4)alkyl, R 15 is H, (C1-C6)alkyl, (C1-C)haloalkyl, a 4- to 7-membered heterocycle, a 5- to 6-membered heteroaryl, a 3- to 7-membered cycloalkyl, each of which is unsubstituted or substituted at substitutable positions with one or more =O, OH, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, amino, or (C1-C8)aminoalkyl, R 16 is H, (C1-C8)alkyl, or (C1-C8)haloalkyl.

[0108] In some embodiments, the compound is a compound of formula Va: TIFF2025518536000060.tif28128, wherein X1 is independently selected from C or N, X2 is independently selected from C or N, X3 is independently selected from C or N, X4 is independently selected from C or N, X5 is independently selected from C or N, R 1 is absent, hydrogen, (C1-C8)alkyl, NR 9 R 10 halo, amino, -C≡N, (C2-C8)alkenyl, (C2-C8)alkynyl, (C C8)haloalkyl, (C2-C8)haloalkenyl, (C2-C8)haloalkynyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C1-C8)alkyl(C1-C6)alkoxy, a 4- to 7-membered heterocyclyl, a 5- to 6-membered heteroaryl, CH(O), C(O)OR 8, SF5, -OH, -SH, (C1-C6) hydroxyalkyl, (C1-C4) alkylsulfonyl, aminosulfonyl, amino(C1-C4) alkylsulfonyl, or aryl, R 2 is C(O)NR 11 R 12 , C(O)R 13 , a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 3 is H, (C1-C8) alkyl, (C1-C8) alkenyl, (C1-C8) alkynyl, (C1-C8) alkoxy, hydroxyl, halo, amino, amide, amino(C1-C8) alkylamide, heterocyclyl, sulfonyl, aminosulfonyl, amino(C1-C8) alkylsulfonyl, cyano, or (C1-C3) haloalkyl, R 4a is H, unsubstituted or halo, (C1-C8) alkoxy, (C1-C8) haloalkoxy, S(O)-R 6 , S(O)2, S(O)2-R 6 , S(O)2, C(O)R 6 , C(O)OR 7 , or selected from any (C1-C8) alkyl optionally substituted with (C1-C8) cycloalkyl, R 4b is H, unsubstituted or halo, (C1-C8) alkoxy, (C1-C8) haloalkoxy, S(O)-R 6 , S(O)2, S(O)2-R 6 , S(O)2, C(O)R 6 , C(O)OR 7 , or selected from any (C1-C8) alkyl optionally substituted with (C1-C8) cycloalkyl, or R 4a and R 4btogether form (C1-C8) cycloalkyl, (C1-C8) substituted cycloalkyl, (C1-C8) heterocycloalkyl, (C1-C8) substituted heterocycloalkyl, (C1-C8) aryl, (C1-C8) substituted aryl, (C1-C8) heteroaryl, or (C1-C8) substituted heteroaryl, R 6 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 7 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 8 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 9 is H, (C1-C8) alkyl, where the (C1-C8) alkyl is unsubstituted or substituted with one or more halos, R 10 is H, (C1-C8) alkyl, where the (C1-C8) alkyl is unsubstituted or substituted with one or more halos, or R 9 and R 10together with the nitrogen atom to which they are attached form a 4- or 5-membered nitrogen-containing heterocyclic ring, which 4- or 5-membered nitrogen-containing heterocyclic ring is unsubstituted or substituted with one or more halos, and R is H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5- or 6-membered heterocyclic ring, or a 5- or 6-membered heteroaryl, R 11 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 12 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 11 and R 12 together with the nitrogen atom to which they are attached form a 5- to 8-membered nitrogen-containing heterocyclic ring, which 5- to 8-membered nitrogen-containing heterocyclic ring is unsubstituted or substituted with OH, halo, =O, or (C1-C8)alkyl, R 13 is OH, O-(C1-C4)alkyl, R 15 is H, (C1-C6)alkyl, (C1-C)haloalkyl, a 4- to 7-membered heterocyclic ring, a 5- to 6-membered heteroaryl, a 3- to 7-membered cycloalkyl, and each of the 4- to 7-membered heterocyclic ring, 5- to 6-membered heteroaryl, 3- to 7-membered cycloalkyl is unsubstituted or substituted at a substitutable position with one or more =O, OH, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, amino, or (C1-C8)aminoalkyl, R 16is H, (C1-C8) alkyl, or (C1-C8) haloalkyl.

[0109] In some embodiments, X1 is N. In some embodiments, X1 is C. In some embodiments, X2 is N. In some embodiments, X2 is C. In some embodiments, X3 is N. In some embodiments, X3 is C. In some embodiments, X4 is N. In some embodiments, X4 is C. In some embodiments, X5 is N. In some embodiments, X5 is C.

[0110] In some embodiments, X1 is N, X2 is C, X3 is N, X4 is N, and X5 is C. In some embodiments, X1 is N, X2 is C, X3 is C, X4 is N, and X5 is N. In some embodiments, X1 is C, X2 is N, X3 is C, X4 is C, and X5 is N. In some embodiments, X1 is C, X2 is C, X3 is N, X4 is N, and X5 is C. In some embodiments, X1 is N, X2 is C, X3 is N, X4 is N, and X5 is N.

[0111] In some embodiments, R1 is selected from hydrogen, (C1-C8) alkyl, halo, or haloalkyl. In some examples, R1 is hydrogen. In some examples, R1 is (C1-C8) alkyl, such as methyl, ethyl, propyl, i-propyl, butyl, t-butyl, i-butyl, or pentyl. In certain examples, R1 is methyl. In certain examples, R1 is t-butyl. In some examples, R1 is halo, such as fluoro, chloro, or bromo. In certain examples, R1 is fluoro. In some examples, R1 is haloalkyl, such as CF3, CCl3, or CBr3. In certain examples, R1 is CF3.

[0112] In some embodiments, R 2is C(O)NR 11 R 12 wherein R 11 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, and R 12 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl.

[0113] In some embodiments, R 2 is a 5-membered heteroaryl. In some examples, R 2 is TIFF2025518536000061.tif18128, wherein Y1 is O, NH, CH2, or S, Y2 is CH or N, Y3 is CH or N.

[0114] In some embodiments, R 11 is H and R 12 is selected from a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered substituted heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl. In some examples, R 11 is H and R 12 is a 6-membered heterocyclic ring. In some examples, R 11 is H and R 12 is a substituted 6-membered heterocyclic ring.

[0115] In a particular example, R 11 is H, and R 12 is a substituted or unsubstituted piperidinyl, pyrrolidinyl, piperazinyl, or azepanyl group. In another embodiment, R 12 is a substituted or unsubstituted piperidin-3-yl or piperidin-4-yl group. In another embodiment, the substituted piperidin-4-yl group is as follows. TIFF2025518536000062.tif19128 wherein R 22 is substituted or unsubstituted C2-C3 alkyl. In another embodiment, R 22 is C2-C3 alkyl. In another embodiment, R 22 is a substituted ethyl group. In another embodiment, R 22 is -CH2CH2-NR 23 R 24 wherein R 23 and R 24 are independently C1-C3 alkyl, or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R 23 and R 24 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, one or two methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. In one embodiment within this embodiment, L is -CO-NH-, and the NH moiety is attached to the piperidinyl moiety. In another embodiment, R2 is -NR 23 R 24 wherein R 23 and R 24 are independently C1-C3 alkyl, or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R 23 and R 24Together with the nitrogen atom to which they are attached, they form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, one or two methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a pyrrolidinyl, piperidinyl, or azepanyl ring, which may be substituted or unsubstituted. In one embodiment within this embodiment, L is -(CH2) n -, -O-(CH2) n -, or -CH2-O-(CH2) n -, the left side of L is attached to the azaindazole moiety, and n is 1, 2, 3, or 4.

[0116] In a particular example, R 11 is H, and R 12 is TIFF2025518536000063.tif19128, where X6 is N or C, R 22 is a substituted or unsubstituted C2-C3 alkyl. In another embodiment, R 22 is a C2-C3 alkyl. In another embodiment, R 22 is a substituted ethyl group. In another embodiment, R 22 is -CH2CH2-NR 23 R 24 and R 23 and R 24 are independently C1-C3 alkyl, or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R 23 and R 24 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, one or two methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a pyrrolidinyl, piperidinyl, or azepanyl ring, which may be substituted or unsubstituted.

[0117] In one embodiment within this embodiment, L is -CO-NH-, and the NH moiety is attached to the piperidinyl moiety. In another embodiment, R2 is -NR 23 R 24 wherein R 23 and R 24 are independently C1-C3 alkyl, or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R 23 and R 24 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, one or two methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a pyrrolidinyl, piperidinyl, or azepanyl ring which is substituted or unsubstituted. In one embodiment within this embodiment, L is -(CH2) n -, -O-(CH2) n -, or -CH2-O-(CH2) n -, the left side of L is attached to the azaindazole moiety, and n is 1, 2, 3, or 4.

[0118] In some embodiments, R 4a is H, unsubstituted or substituted with halo, (C1-C8) alkoxy, (C1-C8) haloalkoxy, or (C1-C8) cycloalkyl, any of (C1-C8) alkyl. In some embodiments, R 4b is H, unsubstituted or substituted with halo, (C1-C8) alkoxy, (C1-C8) haloalkoxy, S(O)-R 6 , S(O)2, S(O)2-R 6 , S(O)2, C(O)R 6 , C(O)OR 7 , or (C1-C8) cycloalkyl, any of (C1-C8) alkyl. In some embodiments, R 4a is (C1-C8) alkyl. In some embodiments, R 4ais (C1-C8) alkyl substituted with halo. In some examples, R 4a is ethyl substituted with halo.

[0119] In some embodiments, R 4a and R 4b together form (C1-C8) cycloalkyl, (C1-C8) substituted cycloalkyl, (C1-C8) heterocycloalkyl, (C1-C8) substituted heterocycloalkyl, (C1-C8) aryl, (C1-C8) substituted aryl, (C1-C8) heteroaryl, or (C1-C8) substituted heteroaryl. In some examples, R 4a and R 4b together with the nitrogen to which they are attached form (C1-C8) heterocycloalkyl. In certain examples, R 4a and R 4b together with nitrogen form a 7-membered heterocycloalkyl.

[0120] In some embodiments, the compound is a compound of formula Vb: TIFF2025518536000064.tif33128, wherein X1 is independently selected from C or N, X2 is independently selected from C or N, X3 is independently selected from C or N, X4 is independently selected from C or N, X5 is independently selected from C or N, X6 is independently selected from C or N, R 1 is absent, hydrogen, (C1-C8) alkyl, NR 9 R 10, halo, amino, -C≡N, (C2-C8) alkenyl, (C2-C8) alkynyl, (C2-C8) haloalkyl, (C2-C8) haloalkenyl, (C2-C8) haloalkynyl, (C1-C8) alkoxy, (C1-C8) haloalkoxy, (C1-C8) alkyl(C1-C6) alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, CH(O), C(O)OR 8 , SF5, -OH, -SH, (C1-C6) hydroxyalkyl, (C1-C4) alkylsulfonyl, aminosulfonyl, amino(C1-C4) alkylsulfonyl, or aryl, R 2 is C(O)NR 11 R 12 , C(O)R 13 , 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 6-membered heterocycle, 6-membered substituted heterocycle, 6-membered heteroaryl, 6-membered substituted heteroaryl, 5-membered cycloalkyl, or 5-membered substituted cycloalkyl, 6-membered cycloalkyl, or 6-membered substituted cycloalkyl, R 3 is H, (C1-C8) alkyl, (C1-C8) alkenyl, (C1-C8) alkynyl, (C1-C8) alkoxy, hydroxyl, halo, amino, amide, amino(C1-C8) alkylamide, heterocyclyl, sulfonyl, aminosulfonyl, amino(C1-C8) alkylsulfonyl, cyano, or (C1-C3) haloalkyl, R 4a is H, unsubstituted or halo, (C1-C8) alkoxy, (C1-C8) haloalkoxy, S(O)-R 6 , S(O)2, S(O)2-R 6 , S(O)2, C(O)R 6 , C(O)OR 7 , or selected from any (C1-C8) alkyl optionally substituted with (C1-C8) cycloalkyl, R 4b is H, unsubstituted or halo, (C1-C8) alkoxy, (C1-C8) haloalkoxy, S(O)-R 6 , S(O)2, S(O)2-R 6, S(O)2, C(O)R 6 , C(O)OR 7 , or is selected from any (C1-C8) alkyl optionally substituted with (C1-C8) cycloalkyl or R 4a and R 4b together form (C1-C8) cycloalkyl, (C1-C8) substituted cycloalkyl, (C1-C8) heterocycloalkyl, (C1-C8) substituted heterocycloalkyl, (C1-C8) aryl, (C1-C8) substituted aryl, (C1-C8) heteroaryl, or (C1-C8) substituted heteroaryl R 6 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano R 7 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano R 8 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano R 9 is H, (C1-C8) alkyl, where the (C1-C8) alkyl is unsubstituted or substituted with one or more halos R 10is H, (C1-C8)alkyl, where the (C1-C8)alkyl is unsubstituted or substituted with one or more halos, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- or 5-membered nitrogen-containing heterocycle, where the 4- or 5-membered nitrogen-containing heterocycle is unsubstituted or substituted with one or more halos, and R is H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5- or 6-membered heterocycle, or a 5- or 6-membered heteroaryl, R 11 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 12 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 11 and R 12 together with the nitrogen atom to which they are attached form a 5- to 8-membered nitrogen-containing heterocycle, where the 5- to 8-membered nitrogen-containing heterocycle is unsubstituted or substituted with OH, halo, =O, or (C1-C8)alkyl, R 13 is OH, O-(C1-C4)alkyl, R 15is H, (C1-C6) alkyl, (C1-C) haloalkyl, a 4- to 7-membered heterocyclic ring, a 5- to 6-membered heteroaryl, or a 3- to 7-membered cycloalkyl, and each of the 4- to 7-membered heterocyclic ring, 5- to 6-membered heteroaryl, and 3- to 7-membered cycloalkyl is unsubstituted or substituted at substitutable positions with one or more =O, OH, (C1-C8) alkyl, (C1-C8) haloalkyl, (C1-C8) alkoxy, amino, or (C1-C8) aminoalkyl, R 16 is H, (C1-C8) alkyl, or (C1-C8) haloalkyl, R 22 is substituted or unsubstituted C2-C3 alkyl. In another embodiment, R 22 is C2-C3 alkyl. In another embodiment, R 22 is a substituted ethyl group. In another embodiment, R 22 is -CH2CH2-NR 23 R 24 wherein R 23 and R 24 are independently C1-C3 alkyl or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R 23 and R 24 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, one or two methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. In one embodiment within this embodiment, L is -CO-NH- and the NH moiety is attached to the piperidinyl moiety. In another embodiment, R2 is -NR 23 R 24 wherein R 23 and R 24 are independently C1-C3 alkyl or C1-C3 alkyl substituted with a C3-C4 cycloalkyl ring, or R 23 and R 24Together with the nitrogen atom to which they are attached, they form a substituted or unsubstituted 5- to 8-membered heterocyclic ring. Suitable substituents for the 5- to 8-membered heterocyclic ring include, but are not limited to, one or two methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5- to 8-membered heterocyclic ring is a pyrrolidinyl, piperidinyl, or azepanyl ring, which may be substituted or unsubstituted. In one embodiment within this embodiment, L is -(CH2) n -, -O-(CH2) n -, or -CH2-O-(CH2) n -, the left side of L is attached to the azaindazole moiety, and n is 1, 2, 3, or 4.

[0121] In some embodiments, the compound is a compound selected from the following. TIFF2025518536000065.tif61156TIFF2025518536000066.tif205160TIFF2025518536000067.tif58160

[0122] In some embodiments, the compound is a compound of formula Vc: TIFF2025518536000068.tif41128, wherein X1 is independently selected from C or N, X2 is independently selected from C or N, X3 is independently selected from C or N, X4 is independently selected from C or N, X5 is independently selected from C or N, R 1 is absent, hydrogen, (C1-C8)alkyl, NR 9 R 10, halo, amino, -C≡N, (C2-C8) alkenyl, (C2-C8) alkynyl, (C1-C8) haloalkyl, (C2-C8) haloalkenyl, (C2-C8) haloalkynyl, (C1-C8) alkoxy, (C1-C8) haloalkoxy, (C1-C8) alkyl(C1-C6)alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, CH(O), C(O)OR 8 , SF5, -OH, -SH, (C1-C6) hydroxyalkyl, (C1-C4) alkylsulfonyl, aminosulfonyl, amino(C1-C4)alkylsulfonyl, or aryl, R 2 is hydrogen, (C1-C8) alkyl, NR 9 R 10 , halo, amino, -C≡N, (C2-C8) alkenyl, (C2-C8) alkynyl, (C1-C8) haloalkyl, (C2-C8) haloalkenyl, (C2-C8) haloalkynyl, (C1-C8) alkoxy, (C1-C8) haloalkoxy, (C1-C8) alkyl(C1-C6)alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, CH(O), C(O)OR 8 , SF5, -OH, -SH, (C1-C6) hydroxyalkyl, (C1-C4) alkylsulfonyl, aminosulfonyl, amino(C1-C4)alkylsulfonyl, or aryl, R 3 is H, (C1-C8) alkyl, (C1-C8) alkenyl, (C1-C8) alkynyl, (C1-C8) alkoxy, hydroxyl, halo, amino, amide, amino(C1-C8)alkylamide, heterocyclyl, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano, or (C1-C3) haloalkyl, R 4a is H, unsubstituted or halo, (C1-C8) alkoxy, (C1-C8) haloalkoxy, S(O)-R 6 , S(O)2, S(O)2-R 6 , S(O)2, C(O)R 6 , C(O)OR 7is selected from (C1-C8) alkyl optionally substituted with (C1-C8) cycloalkyl, R 4b is H, unsubstituted or halo, (C1-C8) alkoxy, (C1-C8) haloalkoxy, S(O)-R 6 , S(O)2, S(O)2-R 6 , S(O)2, C(O)R 6 , C(O)OR 7 is selected from (C1-C8) alkyl optionally substituted with (C1-C8) cycloalkyl, or alternatively R 4a and R 4b together form (C1-C8) cycloalkyl, (C1-C8) substituted cycloalkyl, (C1-C8) heterocycloalkyl, (C1-C8) substituted heterocycloalkyl, (C1-C8) aryl, (C1-C8) substituted aryl, (C1-C8) heteroaryl, or (C1-C8) substituted heteroaryl, R 6 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 7 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 8is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 9 is H, (C1-C8) alkyl, and the (C1-C8) alkyl is unsubstituted or substituted with one or more halos, R 10 is H, (C1-C8) alkyl, and the (C1-C8) alkyl is unsubstituted or substituted with one or more halos, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- or 5-membered nitrogen-containing heterocycle, and the 4- or 5-membered nitrogen-containing heterocycle is unsubstituted or substituted with one or more halos, and R is H, (C1-C4) alkyl, (C1-C4) haloalkyl, a 5- or 6-membered heterocycle, or a 5- or 6-membered heteroaryl, R 11 is selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 12 is selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 11 and R 12together with the nitrogen atom to which they are attached form a 5- to 8-membered nitrogen-containing heterocycle, and the 5- to 8-membered nitrogen-containing heterocycle is unsubstituted or substituted with OH, halo, =O, or (C1-C8)alkyl, R 13 is OH, O-(C1-C4)alkyl, R 15 is H, (C1-C6)alkyl, (C1-C)haloalkyl, a 4- to 7-membered heterocycle, a 5- to 6-membered heteroaryl, or a 3- to 7-membered cycloalkyl, and each of the 4- to 7-membered heterocycle, 5- to 6-membered heteroaryl, and 3- to 7-membered cycloalkyl is unsubstituted or substituted at substitutable positions with one or more =O, OH, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, amino, or (C1-C8)aminoalkyl, R 16 is H, (C1-C8)alkyl, or (C1-C8)haloalkyl.

[0123] In some embodiments, the compound is a compound of formula VI: TIFF2025518536000069.tif24128, wherein R1 is hydrogen; halo, haloalkyl C1-C6 alkyl; C1-C6 alkyl substituted with a substituted or unsubstituted C3-C8 cycloalkyl, 5- to 8-membered heterocyclyl, or 6-membered aryl group; C2-C6 alkenyl; a substituted or unsubstituted C3-C8 cycloalkyl, -CO-(C3-C8 cycloalkyl), -CO-(C1-C6 alkyl), -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, -SO2-(C1-C6 alkyl), or -SO2-(C3-C8 cycloalkyl) group, R 2 is C(O)NR 11 R 12 is C(O)R 13, a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, and R 3 is H, (C1-C8) alkyl, (C1-C8) alkenyl, (C1-C8) alkynyl, (C1-C8) alkoxy, hydroxyl, halo, amino, amide, amino(C1-C8)alkylamide, heterocyclyl, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano, or (C1-C3) haloalkyl, and R 11 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, or alkyl substituted with one or more of a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, and is selected from R 12is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, or an alkyl substituted with one or more of a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl R 11 and R 12 together with the nitrogen atom to which they are attached form a 5- to 8-membered nitrogen-containing heterocyclic ring, and the 5- to 8-membered nitrogen-containing heterocyclic ring is unsubstituted or substituted with OH, halo, =O, or (C1-C8)alkyl, R4 is hydrogen; halo, haloalkyl C1-C6 alkyl; substituted or unsubstituted C3-C8 cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 8-membered aryl, 5- to 8-membered heteroaryl, C1-C6 alkyl substituted with C2-C6 alkenyl; substituted or unsubstituted C3-C8 cycloalkyl, -CO-(C3-C8 cycloalkyl), -CO-(C1-C6 alkyl), -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, -SO2-(C1-C6 alkyl), or -SO2-(C3-C8 cycloalkyl) group.

[0124] In some embodiments, R3 is selected from hydrogen, (C1-C8)alkyl, halo, or haloalkyl. In some examples, R3 is hydrogen. In some examples, R3 is (C1-C8)alkyl, such as methyl, ethyl, propyl, i-propyl, butyl, t-butyl, i-butyl, or pentyl. In certain examples, R3 is methyl. In certain examples, R3 is t-butyl. In some examples, R3 is halo, such as fluoro, chloro, or bromo. In certain examples, R3 is fluoro. In some examples, R3 is haloalkyl, such as CF3, CCl3, or CBr3. In certain examples, R3 is CF3.

[0125] In some embodiments, R4 is a 5-membered heteroaryl. In some examples, R 2 is TIFF2025518536000070.tif18128, wherein Y1 is O, NH, CH2, or S, Y2 is CH or N, Y3 is CH or N.

[0126] In certain examples, R4 is furan. In certain examples, R4 is pyrrole. In certain examples, R4 is thiophene. In certain examples, R4 is imidazole. In certain examples, R4 is pyrazole. In certain examples, R4 is oxazole. In certain examples, R4 is isoxazole.

[0127] In certain examples, the compound is TIFF2025518536000071.tif28128.

[0128] In certain examples, the compound is TIFF2025518536000072.tif28128.

[0129] In some embodiments, the target compounds include those described below, which should not be construed as limiting: TIFF2025518536000073.tif182160TIFF2025518536000074.tif194160TIFF2025518536000075.tif179160TIFF2025518536000076.tif176160TIFF2025518536000077.tif191160TIFF2025518536000078.tif181160TIFF2025518536000079.tif183160TIFF2025518536000080.tif194160TIFF2025518536000081.tif174160TIFF2025518536000082.tif193160TIFF2025518536000083.tif196160TIFF2025518536000084.tif203160TIFF2025518536000085.tif200160TIFF2025518536000086.tif197160TIFF2025518536000087.tif172160TIFF2025518536000088.tif197160TIFF2025518536000089.tif192160TIFF2025518536000090.tif184161TIFF2025518536000091.tif50128

[0130] In some embodiments, the agent of the subject is a compound disclosed herein or a pharmaceutically acceptable salt thereof. By way of example, in some cases, the agent of the subject is a compound selected from the group consisting of TIFF2025518536000092.tif207124 or a pharmaceutically acceptable salt thereof (see, e.g., lines 7-10, 21-24, 30, 38-39, 55-56, and 184 of FIG. 8).

[0131] In some cases, the agent of the subject is A compound selected from the group consisting of TIFF2025518536000093.tif69160 or a pharmaceutically acceptable salt thereof (See, for example, lines 23, 30, 39, and 55-56 of FIG. 8).

[0132] In some embodiments, the subject composition comprises (a) a pharmaceutically acceptable carrier, excipient, or diluent, and (b) a compound disclosed herein or a pharmaceutically acceptable salt thereof. By way of illustrative example, in some cases, the subject composition comprises (a) a pharmaceutically acceptable carrier, excipient, or diluent, and (b) A compound selected from the group consisting of TIFF2025518536000094.tif189141 or a pharmaceutically acceptable salt thereof (See, for example, lines 7-10, 21-24, 30, 38-39, 55-56, and 184 of FIG. 8).

[0133] In some such cases, the composition is a medicament for the treatment of fatty liver and / or viral infections, such as viral infections of non-Flaviviridae (e.g., viral infections of Hepadnaviridae such as HBV, alphavirus infections such as ONNV, SFV, VEEV, or CHIKV, coronavirus family infections such as SARS-CoV-2, paramyxovirus family infections such as RSV, orthomyxovirus family infections such as influenza, etc.).

[0134] In those embodiments in which the active agent is administered to a subject, the active agent can be administered to the subject using any convenient administration protocol that can provide the desired activity. Thus, the agent can be incorporated into various formulations, for example, pharmaceutically acceptable vehicles, for therapeutic administration. More specifically, the agents of the present invention can be formulated into pharmaceutical compositions by combination with a suitable pharmaceutically acceptable carrier or diluent, and can be formulated into preparations in solid, semi-solid, liquid, or gaseous forms such as tablets, capsules, powders, granules, ointments (e.g., skin creams), solutions, suppositories, injections, inhalants, and aerosols. Thus, administration of the agent can be achieved by various techniques including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intratracheal, and the like.

[0135] In pharmaceutical dosage forms, the agents may be administered in the form of their pharmaceutically acceptable salts, or they may be used alone, or in suitable association and combination with other pharmaceutically active compounds. The following methods and excipients are merely illustrative and in no way limiting.

[0136] For oral preparations, the agent can be used alone or in combination with suitable additives, such as with conventional additives such as lactose, mannitol, corn starch, or potato starch, with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch, or gelatin, with disintegrants such as corn starch, potato starch, or sodium carboxymethyl cellulose, with lubricants such as talc or magnesium stearate, and optionally with diluents, buffers, wetting agents, preservatives, and flavoring agents, to prepare tablets, powders, granules, or capsules.

[0137] The agent can be formulated into an injectable preparation by dissolving, suspending, or emulsifying it in a vegetable or other similar oil, a synthetic fatty acid glyceride, an ester of a higher fatty acid, or an aqueous or non-aqueous solvent such as propylene glycol, and, if necessary, together with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers, and preservatives.

[0138] The agent can be used in an aerosol preparation administered via inhalation. The compounds of the present invention can be formulated with a pressurized acceptable propellant such as dichlorodifluoromethane, propane, nitrogen.

[0139] Furthermore, the agent can be made into a suppository by mixing it with various bases such as an emulsifying base or a water-soluble base. The compounds of the present invention can be administered rectally via a suppository. The suppository may contain vehicles such as cocoa butter, carbowax, and polyethylene glycol that melt at body temperature but solidify at room temperature.

[0140] Unit dosage forms for oral or rectal administration such as syrups, elixirs, and suspensions may be provided, and each dosage unit, for example, a tablespoonful, a teaspoonful, a tablet, or a suppository, contains a predetermined amount of the composition containing one or more inhibitors. Similarly, unit dosage forms for injection or intravenous administration may contain an inhibitor in the composition as a solution in sterile water, physiological saline, or another pharmaceutically acceptable carrier.

[0141] As used herein, the term "unit dosage form" refers to physically discrete units suitable as unit dosages for human and animal subjects, each unit containing a predetermined amount of the compounds of the present invention calculated to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier, or vehicle. The specifications of the novel unit dosage forms of the present invention depend on the particular compound used, the effect to be achieved, and the pharmacodynamics associated with each compound in the host.

[0142] Pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers, or diluents, are readily available in the public domain. Further, pharmaceutically acceptable auxiliary substances, such as pH adjusters and buffers, tonicity adjusters, stabilizers, wetting agents, etc., are readily available in the public domain.

[0143] When the agent is a polypeptide, polynucleotide, its analog or mimetic, it may be introduced into a tissue or host cell by any number of routes, including viral infection, microinjection, or vesicle fusion. Jet injection may also be used for intramuscular administration, as described by Furth et al., Anal Biochem. (1992) 205:365 - 368. DNA may be coated onto gold microparticles and delivered intradermally by a particle bombardment device or "gene gun", as described in the literature (see, for example, Tang et al. Nature (1992) 356:152 - 154). Here, the gold microprojectiles are coated with DNA and then driven into the skin cells. For therapeutic agents of nucleic acids, as is known in the art, several different delivery vehicles are used, including viral and non - viral vector systems.

[0144] One of ordinary skill in the art will readily appreciate that the dosage levels can vary depending on the particular compound, the nature of the delivery vehicle, etc. The preferred dosage of a given compound can be readily determined by one of ordinary skill in the art by various means.

[0145] "Effective amount" or "effective dosage" refers to an amount that can have a desired effect, such as improvement or delay in the progression of a disease state, altered state, or damaged state, reduction of adiposity, reduction of virus in an individual, etc. The effective amount can be determined based on the individual and is, in part, based on consideration of the symptoms being treated and the result sought. "Therapeutically effective dosage" or "therapeutic dosage" or "therapeutically effective amount" or "therapeutic amount" refers to an amount sufficient to produce a desired clinical result (i.e., achieve therapeutic efficacy). The therapeutically effective dosage can be administered in one or more administrations. The effective amount (e.g., therapeutically effective amount) can be determined by one of ordinary skill in the art using such factors and performing experiments that do not exceed routine experimentation.

[0146] In some embodiments, the treatment (for reducing virus in an individual) results in undetectable levels of viral antigen in the blood of the infected individual, e.g., HBsAg for HBV. In some embodiments, the level of circulating viral antigen, e.g., HBsAg for HBV, (or viral nucleic acid) is reduced by at least 1 log, at least 1 log, at least 2 logs, at least 3 logs or more compared to the baseline pre-treatment level. In some embodiments, the individual achieves seroconversion to a non-positive (for viral antigen) phenotype after treatment. In some embodiments, the individual is tested for the level of virus (e.g., viral nucleic acid, viral antigen, antiviral antibody) after treatment.

[0147] In some cases, an effective amount of the subject agent reduces steatosis (hepatic steatosis). In some cases, the progression of steatosis is blocked and in some cases, steatosis is reduced (i.e., the amount of steatosis observed after administration of the agent will be less than that observed prior to administration). In some cases, steatosis will be reduced by 10% or more (e.g., 20% or more, 35% or more, 50% or more, 70% or more, 85% or more) (i.e., the amount observed will be 90% of the amount present prior to administration). In some cases, steatosis will be reduced by 30% or more (e.g., 50% or more, 70% or more, 85% or more) (i.e., the amount observed will be 70% of the amount present prior to administration). In some cases, steatosis may be reduced by 50% or more.

[0148] The effective dosage (e.g., therapeutically effective dosage) can be expected to be in the range of about 0.001 to about 100 mg / kg body weight per day, in some cases about 0.1 to about 50 mg / kg body weight per day, in some cases about 1 to about 50 mg / kg body weight per day, in some cases about 5 to about 40 mg / kg body weight per day, in some cases about 2 to about 15 mg / kg body weight per day, and in some cases about 25 to about 40 mg / kg body weight per day (for humans). In some cases, the effective dosage is in the range of 5 to 100 mg / kg body weight per day (e.g., 5 to 80, 5 to 50, 5 to 40, 5 to 30, 5 to 20, 5 to 10, 8 to 100, 8 to 80, 8 to 50, 8 to 40, 8 to 30, 8 to 20, 10 to 100, 10 to 80, 10 to 50, 10 to 40, 10 to 30, or 10 to 20 mg / kg body weight). In some cases, the effective dosage is in the range of 8 to 100 mg / kg body weight per day. In some cases, the effective dosage is about 8 mg / kg body weight per day.

[0149] The dosage and frequency can vary depending on the half-life of the agent. Those skilled in the art will understand that such guidelines are adjusted according to the molecular weight of the active agent. The dosage can also vary depending on whether it is a local administration, e.g., intranasal, inhalation, etc., or a systemic administration, e.g., i.m., i.p., i.v., s.c., etc.

[0150] The treatment course can be less than about 12 weeks, less than about 8 weeks, less than about 4 weeks, and can be, for example, 1 to 12 weeks, 2 to 12 weeks, 4 to 12 weeks, 4 to 8 weeks, etc. Administration can be once a week, twice a week, every other day, daily, twice a day, every two weeks, etc., and in some embodiments, it is once a week. In some embodiments, more than one treatment course is administered. In some cases, the treatment course ranges from 1 to 24 weeks (e.g., 1 to 8 weeks, 1 to 4 weeks, about 1 week, about 2 weeks, or about 3 weeks). In some cases, the treatment course ranges from 1 day to 8 weeks (e.g., 1 day to 6 weeks, 1 day to 4 weeks, 1 day to 2 weeks, 1 day to 7 days, 3 days to 8 weeks, 3 days to 6 weeks, 3 days to 4 weeks, 3 days to 2 weeks, or 3 days to 7 days). In some cases, the compound is administered for 2 days or more (e.g., 3 days or more, 4 days or more, 5 days or more, 6 days or more, 7 days or more, 14 days or more, or 1 month or more). In some cases, the compound is administered for 3 days or more.

[0151] The agent of the subject (e.g., A27, A27 derivative, etc.) can be administered to the individual by any route of administration understood in the art, including, but not limited to, oral administration, administration by injection (specific embodiments thereof include intravenous, subcutaneous, intraperitoneal, or intramuscular injection), inhalation, intranasal, or topical administration, either alone or in combination with other agents designed to assist in the treatment of the individual.

[0152] The route of administration should be determined based on several considerations understood by those skilled in the art, including but not limited to the desired physicochemical characteristics of the treatment. The treatment may be provided, for example, at 2 to 8 °C or higher, and formulations useful for parenteral injection may also be prepared. If necessary, preservatives, stabilizers, buffers, antioxidants, and / or other additives may be included. The formulations may include divalent cations (including but not limited to MgCl2, CaCl2, and MnCl2) and / or nonionic surfactants (polysorbate-80 (TWEEN 80 (trademark)), polysorbate-60 (TWEEN 60 (trademark)), polysorbate-40 (TWEEN 40 (trademark)), and polysorbate-20 (TWEEN 20 (trademark)), polyoxyethylene alkyl ethers including but not limited to BRIJ 58 (trademark), BRIJ 35 (trademark), and other nonionic surfactants of the TRITON X-100 (trademark), TRITON X-114 (trademark), NP40 (trademark), Span 85, and PLURONIC (registered trademark) series (e.g., PLURONIC (registered trademark) 121). Any combination of such components forms a particular embodiment of the present disclosure.

[0153] "Pharmaceutically acceptable salts" and "pharmaceutically acceptable esters" mean salts and esters that are pharmaceutically acceptable and have the desired pharmacological properties. Such salts include those that can be formed when acidic protons present in the compound are capable of reacting with inorganic or organic bases. Suitable inorganic salts include those formed with alkali metals such as sodium and potassium, magnesium, calcium, and aluminum. Suitable organic salts include those formed with amine bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Such salts also include acid addition salts formed with inorganic acids (e.g., hydrochloric acid and hydrobromic acid) and organic acids (e.g., acetic acid, citric acid, maleic acid, and alkane and arene sulfonic acids such as methanesulfonic acid and benzenesulfonic acid). Pharmaceutically acceptable esters include esters formed from carboxy, sulfonyloxy, and phosphonoxy groups present in the compound, such as C1-6 alkyl esters. When two acidic groups are present, the pharmaceutically acceptable salt or ester can be a monoacid-mono salt or ester, or a di-salt or ester. Similarly, when more than two acidic groups are present, some or all of such groups can be salified or esterified. The compounds named in the present invention can exist in non-salified or non-esterified form, or in salified and / or esterified form, and the naming of such compounds is intended to include both the original (non-salified and non-esterified) compound and its pharmaceutically acceptable salts and esters. Also, the specific compounds named in the present invention can exist in two or more stereoisomeric forms, and the naming of such compounds is intended to include all individual stereoisomers and all mixtures (whether racemic or not) of such stereoisomers.

[0154] The terms "pharmaceutically acceptable", "physiologically tolerable" and their grammatical variations are used interchangeably when referring to compositions, carriers, diluents, and reagents, and indicate that the material can be administered to or on humans without producing undesirable physiological effects to the extent that would prohibit administration of the composition.

[0155] The terms "co-administer," "co-administering," and "in combination with" include the administration of two or more therapeutic agents (e.g., A27 or any of the compounds described herein, and antiviral agents, target cell-specific antibodies, antibiotics, etc.) within an unspecified time limit, either simultaneously, concurrently, or sequentially. In one embodiment, the agents are present intracellularly or in the body of the subject simultaneously or exert their biological or therapeutic effects simultaneously. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In other embodiments, the therapeutic agents are in separate compositions or unit dosage forms. In certain embodiments, the first agent can be administered before (e.g., minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or sequentially (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the second therapeutic agent.

[0156] Administration of the agent of the subject (e.g., A27 or any of the compounds described herein) may be combined with co - administration of any number of agents such as antiviral agents. Such agents may include, for example, the entry inhibitor myrcludex - b, anti - NTBC antibody, HBV nucleoside analogs (e.g., TDF, TAF, ETC), etc. Administration of the agent of the subject (e.g., A27 or any of the compounds described herein) may be combined with antiviral agents such as, for example, HBsAg release inhibitors (nucleic acid polymers), HBV core inhibitors, siRNA targeting HBV (or HDV), immunomodulators (such as TLR agonists), RT or polymerase inhibitors, therapeutic vaccines, etc. Other antiviral agents may include interferons such as interferon alpha - 2b, peginterferon alpha - 2a, interferon lambda, entecavir, lamivudine, adefovir, telbivudine, tenofovir, sofosbuvir, ledipasvir, ombitasvir, paritaprevir, ritonavir, dasabuvir, grazoprevir, elbasvir, asunaprevir, dectasvir, or beclabuvir.

[0157] The agent of the subject (e.g., A27 or any of the compounds described herein) is optionally formulated with one or more agents that are not essential but enhance activity or otherwise increase the therapeutic effect. These are generally used at the same dosages and routes of administration as used herein, or at about 1 - 99% of the dosages previously used.

[0158] The agent of the subject matter (e.g., A27 or any of the compounds described herein) may be co-administered with other active agents, such as antibiotics, cytokines, antiviral agents. Classes of antibiotics include penicillins, such as penicillin G, penicillin V, methicillin, oxacillin, carbenicillin, nafcillin, ampicillin, etc.; combinations of penicillins with β-lactamase inhibitors, cephalosporins, such as cefaclor, cefazolin, cefuroxime, moxalactam, etc.; carbapenems; monobactams; aminoglycosides; tetracyclines; macrolides; lincosamides; polymyxins; sulfonamides; quinolones; chloramphenicol; metronidazole; spectinomycin; trimethoprim; vancomycin, etc. Cytokines may include, for example, interferon γ, tumor necrosis factor α, interleukin 12, etc. Antiviral agents, such as acyclovir, ganciclovir, etc., may also be used in the treatment.

[0159] Exemplary non-limiting aspects of the present disclosure Aspects including the above-described embodiments of the present subject matter may be beneficial alone or in combination with one or more other aspects or embodiments. Without limiting the foregoing description, certain non-limiting aspects of the present disclosure are provided below (see Sets A and B). As will be apparent to those skilled in the art upon reading the present disclosure, each of the individually numbered aspects may be used or combined with any of the individually numbered aspects preceding or following it. This is intended to provide support for all such combinations of aspects and is not limited to the combinations of aspects explicitly provided below. It will be apparent to those skilled in the art that various changes and modifications may be made without departing from the spirit or scope of the present invention.

[0160] Set A 1. A method of using A27 of a KxL ligand to treat fatty liver. 2. A method of using A27 of a KxL ligand to treat fatty liver and / or viral infection. 3. A method of using A27 of the KxL ligand to treat HBV infection. 4. A method of using A27 of the KxL ligand to treat SARS-CoV-2 infection. 5. A method of using A27 of the KxL ligand to treat VEEV infection. 6. The method of item 1, wherein A27 is administered at 8 mg / kg to 100 mg / kg. 7. The method of item 2, wherein A27 is administered at 8 mg / kg to 100 mg / kg. 8. The method of item 3, wherein A27 is administered at 8 mg / kg to 100 mg / kg. 9. The method of item 4, wherein A27 is administered at 8 mg / kg to 100 mg / kg. 10. The method of item 5, wherein A27 is administered at 8 mg / kg to 100 mg / kg. 11. The methods of items 1 to 5, wherein A27 is administered for 3 days or more. 12. The methods of items 1 to 5, wherein A27 is administered for 7 days or more. 13. The methods of items 1 to 5, wherein A27 is administered for 14 days or more. 14. The methods of items 1 to 5, wherein A27 is administered for 1 month or more. 15. The methods of items 2 to 5, wherein A27 is administered in combination with another antiviral agent. 16. A method of using a derivative of A27 of the KxL ligand to treat fatty liver. 17. A method of using a derivative of A27 of the KxL ligand to treat fatty liver and / or viral infection. 18. A method of using a derivative of A27 of the KxL ligand to treat HBV infection. 19. A method of using a derivative of A27 of the KxL ligand to treat SARS-CoV-2 infection. 20. A method of using a derivative of A27 of the KxL ligand to treat VEEV infection. 21. 22. The methods of items 12 to 16, wherein the A27 derivative is administered in combination with another antiviral agent. 23. The method of items 11 and 18, wherein the antiviral agent is selected from direct-acting antiviral agents (e.g., protease inhibitors, polymerase inhibitors), host-targeted antiviral agents (e.g., interferons), or other agents that modulate the course of viral diseases.

[0161] Set B 1. A method of treatment comprising administering to an individual having fatty liver and / or a viral infection other than a Flaviviridae virus a therapeutically effective amount of a compound, wherein the compound is (a) A compound of formula I: TIFF2025518536000095.tif26128 or a pharmaceutically acceptable salt thereof (wherein X is C or N, Y is C or N, Z1 is C or N, Z2 is C or N, R1 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted with a substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl, or 6 membered aryl group; C2-C6 alkenyl; a substituted or unsubstituted C3-C8 cycloalkyl, -CO-(C3-C8 cycloalkyl), -CO-(C1-C6 alkyl), -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, -SO2-(C1-C6 alkyl), or -SO2-(C3-C8 cycloalkyl) group, or R1 and R2 together form a 12-25 membered heterocycle, or R1 and R5 together form a 12-25 membered heterocycle, and L is a bond, -CONH-, -NH-CO-, a substituted or unsubstituted C1-C5 alkylene, a substituted or unsubstituted C2-C5 heteroalkylene, a substituted or unsubstituted 5 membered heteroaryl group, or a substituted or unsubstituted 5-7 membered heterocyclyl, C5-C7 cycloalkyl, 5-6 membered heteroaryl, or 6 membered aryl group, or a combination thereof, R2 is -NH2, -NHR', -NR'R', -NHCOR', -NR'COR', -NHSO2R', -NR'SO2R', -NHSO2NH2, -NHSO2NHR', -NHC(O)NH2, -NHC(O)NHR', -N(R')SO2NH2, -N(R)SO2NHR', -N(R')C(O)NH2, and -N(R')C(O)NHR', or a substituted or unsubstituted 5- to 7-membered heterocyclyl, C5-C7 cycloalkyl, 5- to 6-membered heteroaryl, or 6-membered aryl group, R3, R4, and R5 are independently hydrogen, halo, -CN, -OH, -OR', -NH2, -NHR', -NR'R', -NHCOR', -NR'COR', -NHSO2R', -NR'SO2R', -NHSO2NH2, -NHSO2NHR', -NHC(O)NH2, -NHC(O)NHR', -N(R')SO2NH2, -N(R')SO2NHR', -N(R')C(O)NH2, and N(R)C(O)NHR', -SO2R', -SO2NH2, SO2NHR', SO2NR'R', -CONH2, -CONHR', -CONR'R', -CO2H, -CO2R', or a substituted or unsubstituted C1-C6 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group, R' is a substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group, or two R' groups together with the nitrogen atom to which they are attached form a heterocyclic ring), (b) A compound of formula II: TIFF2025518536000096.tif29128 or a pharmaceutically acceptable salt thereof (wherein, X is C or N, Y is C or N, R1 is hydrogen, branched or straight-chain C1-C5 alkyl, C2-C 15 alkenyl, unsubstituted or substituted cycloalkyl, -CO-(cycloalkyl), -SO2-(cycloalkyl) group, or -(CH2) n -R 11or R5 and R1 together form a 12- to 18-membered heterocyclic ring, n is 1 or 2, R2 is a substituted or unsubstituted piperidinyl, 4-pyridyl, pyrrolidinyl, piperazinyl, benzyl, substituted phenyl, or pyrazolyl group, R5 is R 51 R 52 N- or R 54 O-, R 51 is H, or substituted or unsubstituted C1-C3 alkyl, R 52 is C6-C8 cycloalkyl, substituted or unsubstituted straight-chain C1-C3 alkyl, or branched C4-C5 alkyl, or R 51 and R 52 together with the nitrogen atom to which they are attached form a 6-, 7-, 8-, or 9-membered heterocyclyl ring containing up to 3 heteroatoms optionally substituted by a substituted or unsubstituted benzylacyl or sulfonyl group other than the azaindazole moiety to which it is already attached, R 54 is H, a substituted or unsubstituted benzyl group, branched C3-C8 alkyl, unsubstituted C5-C8 cycloalkyl, or C5-C8 cycloalkyl substituted by one or more straight-chain or branched C1-C4 alkyl groups, R 11 is C5-C8 cycloalkyl, or substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl), (c) A compound of formula III: TIFF2025518536000097.tif25128 or a pharmaceutically acceptable salt thereof (wherein, X is C or N, Y is C or N, Z1 is C or N, Z2 is C or N, R1 is hydrogen, branched or straight-chain C1-C5 alkyl, C2-C 15 alkenyl, unsubstituted or substituted cycloalkyl, -CO-(cycloalkyl), -SO2-(cycloalkyl) group, or -(CH2) n -R 11or R5 and R1 together form a 12- to 18-membered heterocyclic ring, n is 1 or 2, R2 is a substituted or unsubstituted phenyl, piperidinyl, 4-pyridyl, pyrrolidinyl, piperazinyl, benzyl, substituted phenyl, or pyrazolyl group, and R5 is R 51 R 52 is N- or R 54 is O-, R 51 is H, or substituted or unsubstituted C1-C3 alkyl, and R 52 is C6-C8 cycloalkyl, substituted or unsubstituted straight-chain C1-C3 alkyl, or branched C4-C5 alkyl, or R 51 and R 52 together with the nitrogen atom to which they are attached form a 6-, 7-, 8-, or 9-membered heterocyclyl ring containing up to 3 heteroatoms, optionally substituted by a substituted or unsubstituted benzyl acyl or sulfonyl group other than the azaindazole moiety to which it is already attached, and R 54 is H, a substituted or unsubstituted benzyl group, branched C3-C8 alkyl, unsubstituted C5-C8 cycloalkyl, or C5-C8 cycloalkyl substituted by one or more straight-chain or branched C1-C4 alkyl groups, and R 11 is C5-C8 cycloalkyl, or substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R3 and R5 are independently hydrogen, halo, -CN, -OH, -OR’, -NH2, -NHR’, -NR’R’, -NHCOR’, -NR’COR’, -NHSO2R’, -NR’SO2R’, -NHSO2NH2, -NHSO2NHR’, -NHC(O)NH2, -NHC(O)NHR’, -N(R’)SO2NH2, -N(R’)SO2NHR’, -N(R’)C(O)NH2, and N(R)C(O)NHR’, -SO2R’, -SO2NH2, SO2NHR’, SO2NR’R’, -CONH2, -CONHR’, -CONR’R’, -CO2H, -CO2R’, or substituted or unsubstituted C1-C6 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group), (d) Compound of formula IV: TIFF2025518536000098.tif28128 or a pharmaceutically acceptable salt thereof, wherein each X is independently selected from C or N, R 1 is absent, hydrogen, (C1-C8)alkyl, NR 9 R 10 , halo, amino, -C≡N, (C2-C8)alkenyl, (C2-C8)alkynyl, (C C8)haloalkyl, (C2-C8)haloalkenyl, (C2-C8)haloalkynyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C1-C8)alkyl(C1-C6)alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, CH(O), C(O)OR 8 , SF5, -OH, -SH, (C1-C6)hydroxyalkyl, (C1-C4)alkylsulfonyl, aminosulfonyl, amino(C1-C4)alkylsulfonyl, or aryl, R 2 is C(O)NR 11 R 12 , C(O)R 13 , 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 6-membered heterocycle, 6-membered substituted heterocycle, 6-membered heteroaryl, 6-membered substituted heteroaryl, 5-membered cycloalkyl, or 5-membered substituted cycloalkyl, 6-membered cycloalkyl, or 6-membered substituted cycloalkyl, R 3 is H, (C1-C8)alkyl, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C8)alkoxy, hydroxyl, halo, amino, amide, amino(C1-C8)alkylamide, heterocyclyl, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano, or (C1-C3)haloalkyl, each R 4 is independently unsubstituted or halo, (C1-C8)alkoxy, (C1-C8)haloalkoxy, S(O)-R 6 , S(O)2, S(O)2-R 6 , S(O)2, C(O)R 6, C(O)OR 7 , or is selected from any (C1-C8) alkyl optionally substituted with a (C1-C8) cycloalkyl, or both Rs 4 together form a (C1-C8) cycloalkyl, (C1-C8) substituted cycloalkyl, (C1-C8) heterocycloalkyl, (C1-C8) substituted heterocycloalkyl, (C1-C8) aryl, (C1-C8) substituted aryl, (C1-C8) heteroaryl, or (C1-C8) substituted heteroaryl, R 6 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 7 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 8 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 9 is H, (C1-C8) alkyl, where the (C1-C8) alkyl is unsubstituted or substituted with one or more halos, R 10 is H, (C1-C8) alkyl, where the (C1-C8) alkyl is unsubstituted or substituted with one or more halos, or R9 and R 10 together with the nitrogen atom to which they are attached form a 4- or 5-membered nitrogen-containing heterocycle, which 4- or 5-membered nitrogen-containing heterocycle is unsubstituted or substituted with one or more halos, and R is H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5- to 6-membered heterocycle, or a 5- to 6-membered heteroaryl, R 11 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 12 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 11 and R 12 together with the nitrogen atom to which they are attached form a 5- to 8-membered nitrogen-containing heterocycle, which 5- to 8-membered nitrogen-containing heterocycle is unsubstituted or substituted with OH, halo, =O, or (C1-C8)alkyl, R 13 is OH, O-(C1-C4)alkyl, R 15 is H, (C1-C6)alkyl, (C1-C)haloalkyl, a 4- to 7-membered heterocycle, a 5- to 6-membered heteroaryl, a 3- to 7-membered cycloalkyl, and each of the 4- to 7-membered heterocycle, 5- to 6-membered heteroaryl, 3- to 7-membered cycloalkyl is unsubstituted or substituted at a substitutable position with one or more =O, OH, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, amino, or (C1-C8)aminoalkyl, R 16 is H, (C1-C8)alkyl, or (C1-C8)haloalkyl), (e) A compound of formula V: TIFF2025518536000099.tif28128 or a pharmaceutically acceptable salt thereof (wherein, each X is independently selected from C or N, R 1 is absent, hydrogen, (C1-C8)alkyl, NR 9 R 10 , halo, amino, -C≡N, (C2-C8)alkenyl, (C2-C8)alkynyl, (C C8)haloalkyl, (C2-C8)haloalkenyl, (C2-C8)haloalkynyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C1-C8)alkyl(C1-C6)alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, CH(O), C(O)OR 8 , SF5, -OH, -SH, (C1-C6)hydroxyalkyl, (C1-C4)alkylsulfonyl, aminosulfonyl, amino(C1-C4)alkylsulfonyl, or aryl, R 2 is C(O)NR 11 R 12 , C(O)R 13 , a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 3 is H, (C1-C8)alkyl, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C8)alkoxy, hydroxyl, halo, amino, amide, amino(C1-C8)alkylamide, heterocyclyl, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano, or (C1-C3)haloalkyl, each R 4is independently selected from unsubstituted or halo, (C1-C8) alkoxy, (C1-C8) haloalkoxy, S(O)-R 6 , S(O)2, S(O)2-R 6 , S(O)2, C(O)R 6 , C(O)OR 7 or is selected from any (C1-C8) alkyl which is either unsubstituted or substituted with halo, (C1-C8) alkoxy, (C1-C8) haloalkoxy, S(O)-R 4 or both Rs together form (C1-C8) cycloalkyl, (C1-C8) substituted cycloalkyl, (C1-C8) heterocycloalkyl, (C1-C8) substituted heterocycloalkyl, (C1-C8) aryl, (C1-C8) substituted aryl, (C1-C8) heteroaryl, or (C1-C8) substituted heteroaryl, R 6 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 7 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 8 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C1-C4) haloalkyl, and cyano, R 9is H, (C1-C8)alkyl, and the (C1-C8)alkyl is unsubstituted or substituted with one or more halos, R 10 is H, (C1-C8)alkyl, and the (C1-C8)alkyl is unsubstituted or substituted with one or more halos, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- or 5-membered nitrogen-containing heterocycle, and the 4- or 5-membered nitrogen-containing heterocycle is unsubstituted or substituted with one or more halos, and R is H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5- or 6-membered heterocycle, or a 5- or 6-membered heteroaryl, R 11 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 12 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 11 and R 12 together with the nitrogen atom to which they are attached form a 5- to 8-membered nitrogen-containing heterocycle, and the 5- to 8-membered nitrogen-containing heterocycle is unsubstituted or substituted with OH, halo, =O, or (C1-C8)alkyl, R 13 is OH, O-(C1-C4)alkyl, R 15is H, (C1-C6)alkyl, (C1-C)haloalkyl, a 4- to 7-membered heterocyclic ring, a 5- to 6-membered heteroaryl, or a 3- to 7-membered cycloalkyl, and each of the 4- to 7-membered heterocyclic ring, 5- to 6-membered heteroaryl, and 3- to 7-membered cycloalkyl is unsubstituted or substituted at a substitutable position with one or more =O, OH, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, amino, or (C1-C8)aminoalkyl, R 16 is H, (C1-C8)alkyl, or (C1-C8)haloalkyl), (f) A compound of formula VI: TIFF2025518536000100.tif24128 or a pharmaceutically acceptable salt thereof (wherein, R1 is hydrogen; halo, haloalkyl C1-C6 alkyl; C1-C6 alkyl substituted with a substituted or unsubstituted C3-C8 cycloalkyl, 5- to 8-membered heterocyclyl, or 6-membered aryl group; C2-C6 alkenyl; substituted or unsubstituted C3-C8 cycloalkyl, -CO-(C3-C8 cycloalkyl), -CO-(C1-C6 alkyl), -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, -SO2-(C1-C6 alkyl), or -SO2-(C3-C8 cycloalkyl) group, R 2 is C(O)NR 11 R 12 、C(O)R 13 、a 5-membered heterocyclic ring, a 5-membered substituted heterocyclic ring, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocyclic ring, a 6-membered substituted heterocyclic ring, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, R 3is H, (C1-C8)alkyl, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C8)alkoxy, hydroxyl, halo, amino, amide, amino(C1-C8)alkylamide, heterocyclyl, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano, or (C1-C3)haloalkyl, R 11 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, or alkyl substituted with one or more of a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl R 12 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl, or alkyl substituted with one or more of a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl R 11 and R 12together with the nitrogen atom to which they are attached form a 5- to 8-membered nitrogen-containing heterocyclic ring, and the 5- to 8-membered nitrogen-containing heterocyclic ring is unsubstituted or substituted with OH, halo, =O, or (C1-C8) alkyl, R4 is hydrogen; halo, haloalkyl C1-C6 alkyl; substituted or unsubstituted C3-C8 cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 8-membered aryl, 5- to 8-membered heteroaryl, C1-C6 alkyl substituted with C2-C6 alkenyl; substituted or unsubstituted C3-C8 cycloalkyl, -CO-(C3-C8 cycloalkyl), -CO-(C1-C6 alkyl), -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, -SO2-(C1-C6 alkyl), or -SO2-(C3-C8 cycloalkyl) group) A method selected from the group consisting of In some embodiments, R3 is selected from hydrogen, (C1-C8) alkyl, halo, or haloalkyl. In some examples, R3 is hydrogen. In some examples, R3 is (C1-C8) alkyl, such as methyl, ethyl, propyl, i-propyl, butyl, t-butyl, i-butyl, or pentyl. In certain examples, R3 is methyl. In certain examples, R3 is t-butyl. In some examples, R3 is halo, such as fluoro, chloro, or bromo. In certain examples, R3 is fluoro. In some examples, R3 is haloalkyl, such as CF3, CCl3, or CBr3. In certain examples, R3 is CF3. 2. The method of 1, wherein the individual has a non-flavivirus viral infection selected from the group consisting of hepatitis B virus (HBV), Venezuelan equine encephalitis virus (VEEV), O'nyong'nyong virus (ONNV), SARS-CoV-2, Semliki Forest virus (SFV), or chikungunya virus (CHIKV). 3. The method of 1, wherein the individual has a viral infection of hepatitis B virus (HBV), Venezuelan equine encephalitis virus (VEEV), O'nyong'nyong virus (ONNV), SARS-CoV-2, Semliki Forest virus (SFV), or chikungunya virus (CHIKV). 4. A method in which an individual has a viral infection of hepatitis B virus (HBV), Venezuelan equine encephalitis virus (VEEV), SARS-CoV-2, or chikungunya virus (CHIKV). 5. A method according to any one of 1 to 4, wherein the compound is co-administered with a second agent. 6. A method according to any one of 2 to 4, wherein the compound is co-administered with a second antiviral agent. 7. A method according to any one of 1 to 6, wherein the compound is administered at a concentration in the range of 8 to 100 mg / kg. 8. A method according to any one of 1 to 7, wherein the compound is administered for 3 days or more. 9. The compound is A27: 10. A method according to any one of 1 to 8, which is TIFF2025518536000101.tif38128. 10. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of TIFF2025518536000102.tif199124. 11. 11. A compound or a pharmaceutically acceptable salt thereof according to claim 10, selected from the group consisting of TIFF2025518536000103.tif68128. 12. (a) A compound or a pharmaceutically acceptable salt thereof according to 10 or 11, and (b) A pharmaceutically acceptable carrier, excipient, or diluent A composition comprising. 13. The composition according to 12, wherein the composition is a medicament for the treatment of fatty liver and / or viral infection.

[0162] The following examples are provided by way of illustration and not by way of limitation.

Examples

[0163] The following examples are presented to provide a complete disclosure and description of the method of making and using the present invention to those skilled in the art, and are not intended to limit the scope that the inventors regard as the invention, nor are they intended to represent that the following experiments are all or the only experiments to be conducted. Although efforts have been made to ensure the accuracy of the numbers used (e.g., amounts, temperatures, etc.), some experimental errors and deviations should be taken into account. Unless otherwise indicated, parts are parts by weight, molecular weight is weight-average molecular weight, temperature is in degrees Celsius, and pressure is atmospheric pressure or approximately atmospheric pressure.

[0164] General methods in molecular and cell biochemistry can be found in standard textbooks such as Molecular Cloning: A Laboratory Manual, 3rd Ed. (Sambrook et al., HaRBor Laboratory Press 2001), Short Protocols in Molecular Biology, 4th Ed. (Ausubel et al. eds., John Wiley & Sons 1999), Protein Methods (Bollag et al., John Wiley & Sons 1996), Nonviral Vectors for Gene Therapy (Wagner et al. eds., Academic Press 1999), Viral Vectors (Kaplift & Loewy eds., Academic Press 1995), Immunology Methods Manual (I. Lefkovits ed., Academic Press 1997), and Cell and Tissue Culture: Laboratory Procedures in Biotechnology (Doyle & Griffiths, John Wiley & Sons 1998), the disclosures of which are incorporated herein by reference. Reagents, cloning vectors, cells, and kits for the methods referred to or related to in the present disclosure are available from commercial sales companies such as BioRad, Agilent Technologies, Thermo Fisher Scientific, Sigma-Aldrich, New England Biolabs (NEB), Takara Bio USA, Inc., and repositories such as Addgene, Inc., American Type Culture Collection (ATCC), etc.

[0165] Example 1 We discovered that the known small molecule A27 can bind to apolipoprotein B (apoB), a lipoprotein involved in cholesterol and lipid droplet formation. Since apoB is involved in the formation of steatosis, we sought to determine whether A27 could regulate the degree of steatosis within cells. Indeed, we discovered that A27 can inhibit the formation of steatosis in cultured hepatocytes. We also discovered that A27 can reduce the development of hepatic steatosis in C57 / BL6 mice fed a high-fat diet.

[0166] We further discovered that apoB contains an amphipathic helical domain with a putative binding motif of A27 (which we call the KxL motif).

[0167] Further studies showed that this KxL motif is also present in the amphipathic helical domain of hepatitis B surface antigen (HBsAg), the non-structural protein (NSP) 1 of Venezuelan equine encephalitis virus (VEEV), and NSP4 of SARS-CoV-2, and we discovered that A27 has antiviral activity against some of these viruses.

[0168] Accordingly, methods for treating fatty liver disease and / or viral infections are provided herein, the methods comprising administering to a subject having fatty liver disease and / or a viral infection an effective amount of A27, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a derivative thereof.

[0169] We discovered that the known small molecule A27 can bind to apolipoprotein B (apoB), a lipoprotein involved in cholesterol and lipid droplet formation. The structure of A27 is as follows. TIFF2025518536000104.tif50128

[0170] Since ApoB is involved in the formation of steatosis, we sought to determine whether A27 could regulate the degree of intracellular steatosis. Indeed, we found that A27 can inhibit the formation of steatosis in cultured hepatocytes, such as HepG2, at a half-maximal effective concentration (EC 50 ) of approximately 0.5 μM (Figure 2).

[0171] Briefly, the fatty medium was prepared by a 1:1 mixture of oleic acid and palmitic acid (Sigma Aldrich) with 10% FFA-free bovine serum albumin (BSA) solution (Sigma Aldrich) in PBS. Essentially, 100 mM oleic acid and palmitic acid were prepared in 99% methanol. Palmitic acid was prepared by shaking at 500 rpm at 50 °C for 20 minutes. 10 mM oleic acid and palmitic acid were incubated with 10% BSA in PBS at 50 °C for 30 minutes. A final concentration of 100 μM FFA mixture was made in the final cell culture medium. Cells were incubated in the fatty medium for 4 days to induce fatty liver. Then, the cells were treated with various concentrations of A27 for 3 days in the presence of the fatty medium. To determine the degree of steatosis, the cells were stained with 1 mg / ml Nile Red solution (Sigma Aldrich) in cell culture medium for 15 minutes at 37 °C and the fluorescence signal was measured (see Figure 1). A dose-dependent decrease in lipid accumulation was observed.

[0172] Furthermore, A27 reduces hepatic steatosis when administered to mice as measured by ultrasound examination of the liver.

[0173] To determine the effect of A27 on hepatic steatosis in vivo, a cohort of C57 / BL6 mice was first pretreated for one day with A27 at 100 mg / kg / day (equivalent to approximately 8 mg / kg / day in human dose based on body surface area allometry conversion) or vehicle control (40% 2-hydroxypropyl-β-cyclodextrin in water), and then placed on a high-fat diet (60% kcal fat content) for four weeks, during which they were continuously treated with A27 or vehicle control. At the end of four weeks, liver ultrasonography was performed to evaluate the degree of hepatic steatosis. As shown in Figure 2, mice on the HFD treated with vehicle showed more hepatic steatosis compared to mice treated with A27. All mice tolerated A27 well.

[0174] We further discovered that apoB contains an amphipathic helical domain with a putative binding motif for A27 (which we call the KxL motif).

[0175] Further studies showed that this KxL motif is also present in the amphipathic helical domain of hepatitis B surface antigen (HBsAg), the non-structural protein (NSP) 1 of Venezuelan equine encephalitis virus (VEEV), and NSP4 of SARS-CoV-2 (Figure 3).

[0176] Next, we discovered that A27 has antiviral activity against HBV and shows a reduction in HBV surface antigen in cells infected with HBV at an EC 50 of approximately 1 μM (Figure 4).

[0177] Next, we discovered that A27 also inhibits SARS-CoV-2 in cell culture. When using the luciferase reporter contained in the infectious clone of SARS-CoV-2 in TMPRSS2-ACE2-Huh7.5 cells, A27 inhibits the genomic replication of SARS-CoV-2 at an EC 50 of 803 nM without evidence of toxicity.

[0178] To determine the in vivo antiviral activity of A27, a cohort of 6- to 8-week-old BALB / c mice was intranasally inoculated with mouse-adapted SARS-CoV-2 (105 TCID50 MA10 SARS-CoV-2 (US_WA-1 / 2020)), and then treated twice daily (total dose of 400 mg / kg / day) for 5 days with an oral daily dose of A27 in the range of 100 mg / kg / day to 200 mg / kg / day (equivalent to approximately 8 mg / kg / day to approximately 32 mg / kg / day in human dose based on body surface area allometry conversion). This resulted in a 1- to 3-log reduction in viral titer compared to mice treated with vehicle (40% 2-hydroxypropyl-β-cyclodextrin in water) (Table 1).

[0179] (Table 1) Viral titers in the lungs of Balb / c mice infected with SARS-CoV-2 treated with STF-3577 compared to vehicle TIFF2025518536000105.tif21161

[0180] We further investigated the potential of A27 in combination with other antiviral agents and found that A27 is synergistic with additives including protease inhibitors (e.g., PF-07321332) and polymerase inhibitor nucleoside analogs (e.g., EIDD2801) against SARS-CoV-2. Thus, A27 can be combined with nirmatrelvir or paxlovid.

[0181] Next, we discovered that A27 also inhibits Venezuelan equine encephalitis virus (VEEV) in cell culture. When using the luciferase reporter contained in the TC83 strain of VEEV in U87-MG cells, we found that A27 inhibits the genomic replication of VEEV at an EC 50 of 7.9 μM without evidence of toxicity.

[0182] Next, we initiated a search for potential derivatives of A27 to further optimize the pharmacokinetic and pharmacodynamic properties. Representative A27 derivatives are the compounds of Formulas I - III (illustrated above), and the proposed scheme for synthesizing more A27 derivatives is shown in Figure 7.

[0183] Example 2 New compounds were generated (Example 2) and tested (Example 3).

[0184] Generation of New Compounds Core Preparation 7 - Pyrazolopyridine Core (Core 1) Compounds having a pyrazolopyridine core were synthesized according to the general reaction scheme above using known synthetic procedures from commercially available difluoropyridine and tert - butyloxyylate. The ketoester was converted to a hydrazone prior to cyclization and methylation. Appropriate R 1 amine substituents were attached using standard SNAr methodology. The tert - butyl ester was hydrolyzed under basic lithium hydroxide conditions, and then the appropriate amide was formed from the amine prepared commercially or using standard alkylation or reductive amination conditions using standard reductive amination conditions from the prepared amine.

[0185] tert - Butyl 2 - (2,6 - Difluoro - 3 - pyridyl) - 2 - oxo - acetate n-Butyllithium solution (9 mL, 95.59 mmol) in hexane was added dropwise over 5 minutes to a clear solution of N-isopropylpropan-2-amine (13.4 mL, 95.59 mmol) in anhydrous THF (90 mL) under a dry nitrogen gas atmosphere at -78 °C (cooled with an acetone dry ice bath). Subsequently, the dry ice and acetone bath were replaced with an ice water bath, and the reaction mixture was stirred at 0 °C for 30 minutes. Then, the ice water bath was replaced again with an acetone dry ice bath. Next, the resulting yellow solution was added dropwise over 30 minutes by cannula transfer to a solution of 2,6-difluoropyridine (7.89 mL, 86.9 mmol) in anhydrous THF (90 mL) under a dry nitrogen gas atmosphere at -78 °C (cooled with an acetone dry ice bath). Subsequently, the reaction mixture was stirred at -78 °C for 1 hour. Finally, a dry solution of di-tert-butyl oxalate (22.32 g, 110.36 mmol) and anhydrous THF (80 mL + 10 mL rinse) was slowly added over 5 minutes by cannula transfer to the flask (the solution was added by flowing it down the side of the flask to avoid a large heat release). Next, the resulting brown mixture was stirred at -78 °C for 1 hour, and then the acetone and dry ice bath were replaced with an ice brine bath. Then, the reaction mixture was stirred at -10 °C for an additional 30 minutes. Next, saturated aqueous ammonium chloride solution (90 mL) was added at -10 °C. Then, the cooling bath was removed and the layers were separated. Then, the aqueous layer was extracted with ethyl acetate (3 × 30 mL). Then, the combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain a brown liquid. Next, the residue was purified by silica gel chromatography using hexane and ethyl acetate (gradient 0 - 10%) to obtain tert-butyl 2-(2,6-difluoro-3-pyridyl)-2-oxo-acetate (12.4 g, 48.5 mmol, 56% yield) as a yellow liquid. 1 1H NMR (500 MHz, CDCl3) δ 8.48 (q, J = 8.3 Hz, 1H), 7.01 (dd, J = 8.3, 2.7 Hz, 1H), 1.59 (s, 9H). LR / MS (ESI) [M - H] calculated: 242.2 [M - H] found: 240.0.

[0186] tert-Butyl (Z)-2-(2,6-difluoropyridin-3-yl)-2-hydrazineylideneacetate TIFF2025518536000108.tif33128 Titanium ethoxide (15.48 mL, 73.85 mmol) and hydrazine monohydrate (3.7 mL, 73.85 mmol) were added in one portion to a solution of tert-butyl 2-(2,6-difluoro-3-pyridyl)-2-oxo-acetate (9 g, 36.92 mmol) in DCM (40 mL) at 23 °C. The reaction mixture was then stirred for 1 h. The resulting yellow mixture was then diluted with DCM (30 mL) and water (45 mL) and stirred for 30 min. Then, saturated aqueous ammonium chloride solution (30 mL) was added. The resulting mixture was then passed through a pad of celite and rinsed with DCM (50 mL). The layers were then separated and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were then dried over sodium sulfate and concentrated under reduced pressure to give tert-butyl (Z)-2-(2,6-difluoropyridin-3-yl)-2-hydrazineylideneacetate (7.5 g, 34.29 mmol, 93% yield) as a yellow solid. 1 H NMR (500 MHz, CDCl3) δ 7.87 (q, J = 8.1 Hz, 1H), 6.97 (ddd, J = 8.1, 2.8, 0.9 Hz, 1H), 1.51 (s, 9H).

[0187] tert-Butyl 6-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate A solution of tert-butyl (2E)-2-(2,6-difluoro-3-pyridyl)-2-hydrazinylidene-acetate (8.8 g, 34.29 mmol) in THF (75 mL) was treated with 60% sodium hydride (1.8 g, 73.73 mmol) at 23 °C. The resulting mixture was stirred at 23 °C for 20 minutes. The flask was then cooled to 0 °C in an ice-water bath. The reaction mixture was then treated with a second portion of 60% sodium hydride (1.8 g, 73.73 mmol). MeI (42.7 mL, 685.83 mmol) was then added dropwise over 5 minutes. The reaction mixture was then stirred for an additional 1 hour while slowly warming the cooling bath to ambient temperature. Saturated aqueous ammonium chloride was then added to the reaction mixture and the layers were separated. The aqueous layer was then extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (15 mL), concentrated under reduced pressure, and purified by silica gel chromatography using 5 - 40% ethyl acetate and hexane to afford tert-butyl 6-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (1.9 g, 6.66 mmol, 19%) as a yellow solid. 1 1H NMR (500 MHz, CDCl3) δ 8.50 (dd, J = 8.6, 7.5 Hz, 1H), 6.92 (dd, J = 8.5, 1.0 Hz, 1H), 4.15 (s, 3H), 1.69 (s, 9H). LR / MS (ESI) calcd for [M + H - tBu - F]: 176.0, found: 177.9.

[0188] tert-butyl 6-(azepan-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate TIFF2025518536000110.tif37128DIPEA (2.63 mL, 15.15 mmol) was added to a mixture of tert-butyl 6-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (1.4 g, 5.05 mmol) and azepane (2.85 mL, 25.25 mmol) in DMSO (50 mL) at 23 °C. The flask was then heated to 150 °C and stirred for 2 hours. The flask was then removed from the heat and then saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture. The layers were then separated and the aqueous layer was extracted with ethyl acetate (3 × 25 mL). The combined organic layers were then washed with brine (3 × 25 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography using 20 - 70% ethyl acetate and hexane to give tert-butyl 6-(azepan-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (1.5 g, 4.24 mmol, 84% yield) as an orange oil. 1 1H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 9.0 Hz, 1H), 6.58 (d, J = 9.0 Hz, 1H), 4.01 (s, 3H), 3.73 (t, J = 6.0 Hz, 4H), 1.88 - 1.78 (m, 4H), 1.66 (s, 9H), 1.55 (dt, J = 6.0, 2.7 Hz, 4H). LR / MS (ESI) [M+H] calcd: 331.4 [M+H] found: 331.2.

[0189] 6-(Azepan-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid A solution of tert-butyl 6-(azepan-1-yl)-1-methyl-pyrazolo[3,4-b]pyridine-3-carboxylate (1.47 g, 4.46 mmol) in DCM (15 mL) was treated with TFA (10.23 mL, 133.7 mmol) at 23 °C and stirred for 4 h. The mixture was then concentrated under reduced pressure. The resulting orange solid was redissolved in DCM (5 mL) and toluene (3 mL) and concentrated once again under reduced pressure to afford 6-(azepan-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (1 g, 3.63 mmol, 95% yield) as an orange solid. 1 H NMR (500 MHz, CDCl3) δ 8.22 (d, J = 9.3 Hz, 1H), 6.75 (d, J = 9.4 Hz, 1H), 4.15 (s, 3H), 3.80 (t, J = 5.9 Hz, 4H), 1.89 (p, J = 5.3 Hz, 4H), 1.62 (p, J = 2.7 Hz, 4H). LR / MS (ESI) [M + H] calcd: 275.3 [M + H] found: 275.0.

[0190] tert-butyl 4-(6-(azepan-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamido)piperidine-1-carboxylate A solution of 6-(azepan-1-yl)-1-methyl-pyrazolo[3,4-b]pyridine-3-carboxylic acid (1.23 g, 4.47 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (1 g, 4.92 mmol) in DMF (18 mL) was treated with DIPEA (2.72 mL, 15.64 mmol) at 23 °C. Then, HATU (2.5 g, 6.7 mmol) was added and the reaction was stirred for 3 h. The reaction was then diluted with ethyl acetate (50 mL), washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The resulting orange solid was purified by silica gel chromatography using 20 - 60% hexane and ethyl acetate to give tert-butyl 4-(6-(azepan-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamido)piperidine-1-carboxylate (1.7 g, 3.57 mmol, 80% yield) as an orange solid. 1 1H NMR (500 MHz, CDCl3) δ 8.22 (d, J = 9.1 Hz, 1H), 6.58 (d, J = 9.0 Hz, 1H), 4.18 - 3.97 (m, 3H), 3.95 (s, 3H), 3.73 (t, J = 6.1 Hz, 4H), 2.02 (dt, J = 12.9, 4.2 Hz, 2H), 1.83 (dq, J = 8.9, 4.9 Hz, 4H), 1.57 (qt, J = 7.9, 4.2 Hz, 4H), 1.47 (s, 9H). LR / MS (ESI) calculated for [M+H]: 457.6, found: 457.3.

[0191] 6-(Azepan-1-yl)-1-methyl-N-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide TIFF2025518536000113.tif 44128 TFA (24.91 mL, 325.51 mmol) was added to a solution of tert-butyl 4-[[6-(azepan-1-yl)-1-methyl-pyrazolo[3,4-b]pyridine-3-carbonyl]amino]piperidine-1-carboxylate (3 g, 6.51 mmol) in DCM (26 mL) at ambient temperature (23 °C) and stirred for 2 h. The mixture was then concentrated under reduced pressure. The resulting orange solid was redissolved in DCM and toluene and reconcentrated under reduced pressure. The crude product was then further purified by silica gel chromatography using 0 - 10% methanol and DCM to give 6-(azepan-1-yl)-1-methyl-N-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (2.1 g, 5.65 mmol, 87% yield) as a pale yellow solid. 1 H NMR (500 MHz, MeOD) δ 8.11 (d, J = 9.1 Hz, 1H), 6.70 (d, J = 9.1 Hz, 1H), 4.19 (tt, J = 10.7, 4.1 Hz, 1H), 3.95 (s, 3H), 3.76 (t, J = 6.1 Hz, 4H), 3.52 - 3.44 (m, 2H), 3.17 (td, J = 12.8, 3.1 Hz, 2H), 2.25 - 2.16 (m, 2H), 1.92 - 1.87 (m, 2H), 1.84 (hept, J = 3.9 Hz, 4H), 1.56 (p, J = 2.7 Hz, 4H). LR / MS (ESI) [M + H] calcd: 357.5 [M + H] found: 357.1.

[0192] General Reductive Amination for NSP4 Benzyl Derivative Compounds Sodium triacetoxyborohydride (1.4 eq) was added to a solution of 6-(azepan-1-yl)-1-methyl-N-(4-piperidyl)pyrazolo[3,4-b]pyridine-3-carboxamide (1 eq) and benzaldehyde derivative (1.5 eq) in anhydrous DCE (0.25 M) under a nitrogen atmosphere. The reaction mixture was then stirred for 3 h. Then, saturated aqueous sodium bicarbonate was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were then dried over sodium sulfate and concentrated under reduced pressure. The crude product was then dissolved in a small amount of methanol using heat to aid dissolution. The flask was then placed in an ice bath. Solid product began to crystallize out of the solution. The product was then filtered and washed with more methanol.

[0193] 6-(Azepan-1-yl)-1-methyl-N-(1-(4-methylbenzyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide TIFF2025518536000115.tif50128 1 H NMR (500 MHz, MeOD) δ 8.11 (d, J = 9.1 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 6.72 (d, J = 9.1 Hz, 1H), 4.29 (s, 2H), 4.17 (dt, J = 17.8, 7.4 Hz, 1H), 3.95 (s, 3H), 3.78 (t, J = 6.1 Hz, 4H), 3.52 (dt, J = 11.5, 4.8 Hz, 2H), 3.25 - 3.07 (m, 2H), 2.40 (s, 3H), 2.32 - 2.08 (m, 2H), 2.00 - 1.77 (m, 6H), 1.57 (p, J = 2.7 Hz, 4H). LR / MS (ESI) [M + H] calcd: 461.6 [M + H] found: 461.2.

[0194] 6-(Azepan-1-yl)-N-(1-(4-chlorobenzyl)piperidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide TIFF2025518536000116.tif501281 H NMR (500 MHz, MeOD) δ 8.12 (d, J = 9.1 Hz, 1H), 7.52 (dd, J = 7.5, 1.8 Hz, 1H), 7.39 (dd, J = 7.8, 1.5 Hz, 1H), 7.30 (td, J = 7.5, 1.5 Hz, 1H), 7.26 (td, J = 7.6, 1.9 Hz, 1H), 6.71 (d, J = 9.1 Hz, 1H), 3.95 (s, 3H), 3.98 - 3.89 (m, 1H), 3.78 (t, J = 6.1 Hz, 4H), 3.69 (s, 2H), 2.97 (d, J = 11.9 Hz, 2H), 2.31 (t, J = 11.5 Hz, 2H), 1.96 (d, J = 12.8 Hz, 2H), 1.85 (s, 4H), 1.72 (qd, J = 11.8, 3.8 Hz, 2H), 1.57 (p, J = 2.7 Hz, 4H). LR / MS (ESI) [M + H] calculated value: 482.0 [M + H] measured value: 481.1.

[0195] 6-(Azepan-1-yl)-N-(1-(4-fluorobenzyl)piperidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide TIFF2025518536000117.tif50128 1 H NMR (500 MHz, DMSO) δ 8.07 (d, J = 9.1 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.18 - 7.10 (m, 2H), 6.73 (d, J = 9.1 Hz, 1H), 3.89 (s, 3H), 3.78 (tdd, J = 11.4, 8.3, 4.3 Hz, 1H), 3.72 (t, J = 6.1 Hz, 4H), 3.44 (s, 2H), 2.79 (d, J = 11.1 Hz, 2H), 2.01 (td, J = 11.8, 2.6 Hz, 2H), 1.77 (d, J = 5.8 Hz, 4H), 1.76 - 1.69 (m, 2H), 1.63 (qd, J = 11.9, 3.8 Hz, 2H), 1.48 (p, J = 2.7 Hz, 4H). LR / MS (ESI) [M + H] calculated value: 465.6 [M + H] measured value: 465.3.

[0196] Synthesis of 6-(azepan-1-yl)-1-methyl-N-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide To a solution of 6-(azepan-1-yl)-1-methyl-N-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (0.5 mmol) in DMF (5 mL), 2-bromoethanol (1.0 g, 5 mmol), Cs2CO3, and NaI were added. After stirring at 70 °C for 4 h, the reaction solution was diluted with EtOAc and washed with water and brine. The organic layer was dried (MgSO4) and the solvent was evaporated to dryness under reduced pressure to give crude 6-(azepan-1-yl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide.

[0197] Synthesis of 6-(azepan-1-yl)-1-methyl-N-(1-(2-(pyrrolidin-1-yl)ethyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide To a solution of 6-(azepan-1-yl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (0.2 mmol) in CH2Cl (5 mL), MsCl (4 mmol) and TEA (1.5 mmol) were added. After stirring at room temperature for 30 min, the solvent was evaporated to dryness under reduced pressure. The crude mesylate was then dissolved in DMF (2 mL), pyrrolidine (4 mmol), Cs2CO3 (1.0 mmol), and NaI (0.5 mmol) were added, and the mixture was stirred at 80 °C for 16 h and purified by reverse-phase prep-HPLC to give the title product. 1 H NMR (CDCl3 and CD3OD, δ ppm): 8.18 (d, 1H), 6.58 (d, 1H), 4.02 (s, 3H), 3.91 - 3.48 (m, 12H), 3.11 - 2.95 (m, 4H), 2.80 - 1.95 (m, 9H), 1.82 - 1.72 (m, 4H), and 1.49 - 1.47 (m, 4H).

[0198] 7-Pyrazolopyridine core (Core 11) Compounds that did not have an amidoline linker were synthesized from commercially available 6-chloro-1H-pyrazolo[3,4-b]pyridine. The core was halogenated using N-iodosuccinimide and then methylated with iodomethane. The azepane moiety was attached using standard SNAr chemistry, and then the core was converted to a boronic pinacol ester according to well-established literature procedures. The boronic acid was reacted with an appropriate halogenated aryl using standard Suzuki-Miyaura coupling conditions to obtain the desired target.

[0199] 7-Pyrazolopyridine core (Core 3) TIFF2025518536000121.tif67160Compounds having a pyrazolopyridine core with a 5,6-substitution pattern were synthesized according to the general reaction procedure provided. 1-Methyl-1H-pyrazolo[3,4-b]pyridin-6-ol was synthesized from commercially available 1-methyl-1H-pyrazol-5-amine using known condensation chemistry. Treatment of this core with N-bromosuccinimide resulted in bromination at the 5-position. The bromine was converted to a methyl ester using well-established palladium-mediated carbonylation chemistry. After basic hydrolysis of the ester, standard reductive amination was performed using an appropriate R 2 amine. To attach the desired R 2 substituent, the core was treated with phosphoryl chloride and an appropriate amine was inserted using standard SNAr conditions.

[0200] Azaindole core (Core 6) TIFF2025518536000122.tif57156Compounds containing a 7-azaindole core were synthesized from commercially available 6-bromo-7-azaindole. A methyl ester was attached using standard Friedel-Crafts acylation conditions, and then the indole was methylated using sodium hydride and methyl iodide. Appropriate R 1The amine was attached using backward Hartwig chemistry catalyzed by RuPhos Pd G3. Basic hydrolysis of the methyl ester, followed by reductive amination with the appropriate amine (R 2 ) gave the desired target.

[0201] TIFF2025518536000123.tif116155Indazole core (cores 5 and 12) Compounds containing an indazole core were synthesized by the above general procedure using known literature procedures. Functionalized indazoles (e.g., X = CF3) can be obtained from the appropriate 2-nitrotoluene. After methylating the core with iodomethane, the nitrile was hydrolyzed under acidic conditions to give the carboxylic acid. The appropriate R 2 amide was inserted using HATU in DMF under standard amide coupling reaction conditions. The desired R 1 substituents were attached using standard backward Hartwig conditions catalyzed by RuPhos Pd G3 to give the desired compound.

[0202] Triazolopyridine core (core 4) The triazolopyridine core was synthesized using known literature conditions. Hydrolysis of the ethyl ester with lithium hydroxide gave the carboxylic acid, which could then be coupled with the appropriate R 2 amine to give the desired amide. The desired R 1 substituents were attached using an amine under standard backward Hartwig amination conditions catalyzed by Pd2(dba)3 and BINAP.

[0203] Pyrazolopyridine (core 9) TIFF2025518536000124.tif881545Compounds containing a 5 - pyrazolopyridine core were synthesized from ethyl 2-(5 - bromo - 3 - nitropyridin - 2 - yl)acetate according to literature procedures. The appropriate R 1The substituents were attached using a suitable amine and standard backward Hartwig amination conditions catalyzed by RuPhos Pd G3. Lithium hydroxide was used to hydrolyze the ethyl ester to the carboxylic acid, and then the desired R 2 Amides were formed from amide couplings promoted by HATU.

[0204] Naphthyridine (core 10) TIFF2025518536000125.tif54156 Commercially available 2,6-dichloronaphthyridine was obtained and compounds containing the naphthyridine core were synthesized. The desired R 1 The amine substituents were inserted using standard SNAr conditions, and then the methyl ester was attached using a standard palladium-catalyzed carbonylation reaction. After hydrolyzing the methyl ester to the carboxylic acid, the appropriate R 2 The desired product was obtained by amide coupling with the appropriate amine.

[0205] Pyridopyrimidine core (core 14) TIFF2025518536000126.tif69165 2,6-Dichloropyridopyrimidine was synthesized according to well-established literature procedures. R 1 was inserted using standard SNAr conditions with a suitable amine. The methyl ester was attached using standard palladium-catalyzed carbonylation chemistry using carbon monoxide. After hydrolyzing the ester to the carboxylic acid, the desired R 2 Amide coupling was performed using the appropriate amine to obtain the desired amide.

[0206] Pyridopyrimidine (core 15) TIFF2025518536000127.tif65165 Ethyl 6-chloropyrido[3,2-d]pyrimidine-2-carboxylate was synthesized according to previously published literature. The appropriate R 1The substituent was attached by an SNAr reaction using an appropriate amine. Hydrolysis of the methyl ester gave the carboxylic acid, which was then coupled to tert-butyl 4-aminopiperidine-1-carboxylate using HATU. The Boc group was removed using 4M HCl in dioxane. The resulting HCl salt was then subjected to either reductive amination using an appropriate R 2 aldehyde or alkylation reaction using an appropriate R 2 halide or triflate.

[0207] Quinoline core (core 7) The substituted hydroxyquinoline core was synthesized using the procedures reported in the literature previously. The hydroxy group was converted to a triflate and could be replaced with a compound containing an amine for R 1 or alkylated using standard alkylation conditions for a compound having an ether linkage for R 1 . The ester was then reacted with hydrazine followed by condensation with o-phenylcarbonochloridothioate and aminocyclohexanol and subsequent EDC-mediated cyclization to obtain an oxadiazole-linked derivative.

[0208] R 1 General procedure for SNAr alkylation: All R 1 SNAr alkylation was carried out as described in the following representative examples using various commercially available amines.

[0209] TIFF2025518536000129.tif26128DIPEA (3 equivalents) was added to a mixture of tert-butyl 6-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (1 equivalent) and azepane (5 equivalents) in DMSO (0.01 M) at 23 °C. Subsequently, the flask was heated to 150 °C for 2 hours. Then, the flask was removed from the heating, and then an aqueous saturated ammonium chloride solution was added to the reaction mixture. Then, the layers were separated, and the aqueous layer was extracted with ethyl acetate (×3). Then, the combined organic layers were washed with brine (×3), dried over sodium sulfate, and concentrated under reduced pressure. Then, the crude product was purified by silica gel chromatography using 20 - 70% ethyl acetate and hexane to obtain tert-butyl 6-(azepan-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (yield 84%) as an orange oil.

[0210] R 2 General procedure for reductive amination: All reductive aminations were carried out using various commercially available amines as described in the following representative examples.

[0211] A solution of 6-(azepan-1-yl)-1-methyl-pyrazolo[3,4-b]pyridine-3-carboxylic acid (1 equivalent) and tert-butyl 4-aminopiperidine-1-carboxylate (1.1 equivalents) in DMF (0.2 M, 34128) was treated with DIPEA (3.5 equivalents) and HATU (1.5 equivalents) added at once at 23 °C. The solution was then stirred overnight. The reaction mixture was then diluted with ethyl acetate (100 mL) and washed with brine (3 × 30 mL) in a separatory funnel. The recovered organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting brown crude product was then purified by silica gel chromatography using 10 - 50% ethyl acetate and hexane to obtain tert-butyl 4-[[6-(azepan-1-yl)-1-methyl-pyrazolo[3,4-b]pyridin-3-carbonyl]amino]piperidine-1-carboxylate (79% yield) as a yellow solid.

[0212] Amines not commercially available were prepared using standard literature procedures for alkylation or reductive amination. Representative and illustrative reactions are provided below.

[0213] Representative example of an alkylation reaction: TIFF2025518536000131.tif17155 Step 1: tert-Butyl N-(4-piperidyl)carbamate (1 equiv), 1-(2-chloroethyl)pyrrolidine; hydrochloride (1.1 equiv), and K2CO3 (3 equiv) were suspended in DMF (0.5 M) at 23 °C. The reaction mixture was warmed to 60 °C over 18 h. The reaction mixture was cooled to RT, diluted with ethyl acetate, and washed with 50% brine (x3). The organic layer was dried over anhydrous sodium sulfate, evaporated to give a crude residue, which was purified on a 50 g silica column with Biotage Selekt eluting with a gradient of 0 - 20% (0.5 M NH3) MeOH in DCM. The desired product (monitored by TLC) was found to elute at ~20%, and the appropriate fractions were combined and concentrated to give the desired tert-butyl N-[1-(2-pyrrolidin-1-ylethyl)-4-piperidyl]carbamate (47% yield) as an orange solid.

[0214] Step 2: To a solution of tert-butyl N-[1-(2-pyrrolidin-1-ylethyl)-4-piperidyl]carbamate (1 equiv) in 1,4-dioxane (0.34 M) was added 4 M HCl in dioxane (4 equiv). The mixture was stirred at 23 °C for 3 h. The reaction mixture was concentrated to give 1-(2-pyrrolidin-1-ylethyl)piperidin-4-amine (90% yield) as the solid yellow hydrochloride.

[0215] Representative examples of reductive amination: TIFF2025518536000132.tif12158tert-Butyl N-(4-piperidyl)carbamate (1 eq) was suspended in DCM (0.4 M), 4-fluorobenzaldehyde (1 eq) was added, followed by 3 drops of acetic acid. The reaction mixture was aged at 23 °C for 1 h, then sodium triacetoxyborohydride (2 eq) was added. The reaction mixture was stirred at this temperature for 1 h and then quenched by the addition of water. The reaction mixture was washed with additional portions of DCM and saturated sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and purified by Biotage Selekt using a 0 - 10% MeOH gradient in DCM over a 50 g silica column. The appropriate fractions were combined and concentrated to give the desired tert-butyl N-[1-[(4-fluorophenyl)methyl]-4-piperidyl]carbamate (95% yield) as a white solid.

[0216] Example 3 Testing of New Compounds The following results are shown in Figure 8. The concentration at which virus replication is reduced by 50% is the EC50. The concentration at which cell viability is reduced by 50% is the CC50. Activity key: A = < 1 μM, B = 1 - 5 μM, C = 5 - 10 μM, D = > 10 μM (blank = undetermined).

[0217] SARS-CoV-2 To evaluate the antiviral activity against SARS-CoV-2, Huh7.5-ACE2-TMPRSS2 cells were infected with SARS-CoV-2-Nluc at an MOI of 0.05 for 1 h and then washed once with PBS before the addition of the compound. The cells were incubated for 48 h and luciferase activity, used as a surrogate measure of virus replication, was measured using the Nano-Glo luciferase assay and the signal was normalized to untreated cells. Cell viability was determined by the presto blue assay.

[0218] Dengue virus (DENV) HuH-7 cells were cultured in DMEM (Corning) containing 10% FBS and seeded at a density of 10,000 cells / well in 96-well white clear-bottom plates (Greiner / Corning) one day before infection. The cells were infected with 50 μl of DENV2-Renilla luciferase reporter virus (C38-Rluc2A-C-prM-E-NS region) in DMEM without FBS at 37 °C, 5% CO2, and an MOI of 0.01 for 1 hour. After 1 hour, 50 μl of the compound was directly added to the wells (final volume of 100 μl per well) in triplicate at final concentrations of 10 μM, 2.5 μM, 625 nM, 156 nM, 39 nM, and 9.76 nM (4-fold dilution), and then incubated at 37 °C, 5% CO2 for 48 hours. 0.4% DMSO was used as a negative control. After 48 hours, the medium was removed, the cells were washed once with 200 μl of PBS, and then 30 μl of 1× lysis buffer (Promega, catalog number E2820) was added to each well. The cells were incubated on a rocking shaker (300 RPM) for 30 minutes to ensure complete lysis. Then, 50 μl of Renilla substrate (Promega, catalog number E2820) was added to each well using a syringe needle, and the luminescence readout was performed using a Spark luminescence module (Tecan) with an integration time of 1 second.

[0219] The viability assay was performed in parallel as described above, but 96-well black clear-bottom plates (Greiner / Corning) were used. Forty-eight hours after treatment, 100 μl / well of PrestoBlue viability reagent (Thermo Fisher Scientific) was added according to the manufacturer's instructions. The cells were incubated at 37 °C, 5% CO2 for 1 hour, and the readout was performed at 560 / 590 nm (excitation / emission) using the fluorescence module of a Spark plate reader (Tecan).

[0220] Chikungunya virus (CHIKV) The CKV181-nLuc and MAYV-nLuc reporter viruses were generated as described in Ramjag, A. et al. A high-throughput screening assay to identify inhibitory antibodies targeting alphavirus release. Virol. J. 19, 170 (2022). The nanoluciferase (nLuc) reporter gene was engineered and inserted into the 5’ end of E2 of the CHIKV vaccine strain 181 / clone 25 (CKV181-nLuc) or the MAYV infectious clone. The reporter viruses were genetically back-generated and titrated. Human U2OS cells in 96-well plates were infected with CKV181-nLuc or MAYV-nLuc at an MOI of 0.5 and treated with serial dilutions of individual compounds at 1 hpi. At 24 hpi, 25 μl of the culture supernatant per well was transferred to a fresh luciferase assay plate and mixed with the substrate for nLuc. In parallel, the cells were lysed and intracellular ATP was quantified using the CellTiter-Glo® Luminescent Cell Viability Assay. Control cells were treated with DMSO and their viability and virus production were set to 100%.

[0221] Example 4 Orthomyxoviridae (e.g., influenza) The PR8 virus (ATCC-VR-1469) adapted to tissue culture was purchased from ATCC. Confluent MDCK cells in a 12-well plate were infected with approximately 70 p.f.u. of the virus and incubated at 37 °C for 1 hour. The cells were then washed with a 50:50 mixture of PBS and 2× virus growth DMEM containing 1.2% agarose and the final concentration of oseltamivir or the test compound at 100 nM or 1 μM. The plates were harvested after 72 hours, stained with crystal violet, and the plaques were counted. Treatment with STF-00203577-001, STF-00204266-001, STF-00204657-001, or STF-00204460-001 resulted in smaller-sized plaques compared to the wells treated with oseltamivir. Thus, the compounds disclosed herein, including those tested in this example, can be used to treat individuals having an Orthomyxoviridae infection (e.g., influenza).

[0222] Paramyxoviridae (e.g., RSV) The RSV-luc5 virus was purchased from https: / / www.viratree.com / product / rsv-luc5 / . HeLa cells were plated overnight in a 96-well black clear-bottom plate at 5,000 cells / well. The cells were infected with RSV-luc5 for 1 hour. The cells were then treated with various concentrations of the compound for 3 days. Luciferase activity was measured using Bright-Glo luciferase as a readout of virus replication. Treatment with STF-00203577-001, STF-00204266-001, STF-00204657-001, or STF-00204460-001 significantly inhibited RSV replication with EC50 values of 1.1, 1.88, 2.52, and 1.11 μM, respectively. Thus, the compounds disclosed herein, including those tested in this example, can be used to treat individuals having a Paramyxoviridae infection (e.g., RSV).

[0223] In at least some of the above embodiments, one or more elements used in an embodiment can be used interchangeably in another embodiment as long as replacement is technically feasible. Those skilled in the art should understand that various other omissions, additions, and modifications can be made to the above methods and structures without departing from the scope of the claimed subject matter. All such modifications and changes are intended to fall within the scope of the subject matter defined by the appended claims.

[0224] Generally, the terms used in this specification and especially in the appended claims (e.g., the body of the appended claims) are generally intended to be open terms (e.g., the term "including" should be construed as "including but not limited to", the term "having" should be construed as "having at least", the term "includes" should be construed as "including but not limited to", etc.), which will be understood by those skilled in the art. When a specific number of introduced claim recitations are intended, such intent is explicitly recited within the claims, and in the absence of such a recitation, those skilled in the art will further understand that such intent does not exist. For example, by way of illustration, the following appended claims may include the use of introductory phrases such as "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be construed to mean that the introduction of a claim recitation by the indefinite article "a" or "an" limits a particular claim scope that includes such introduced claim recitation to an embodiment that includes only one such recitation. The same claim may include an introductory phrase such as "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" means "at least one" or "one or more"); the same also applies to the use of definite articles used to introduce claim recitations. Additionally, even if a specific number of introduced claim recitations are explicitly recited, those skilled in the art will recognize that such recitation should be construed to mean at least the recited number (e.g., a bare recitation of "two recitations" without other modifiers means at least two recitations, or two or more recitations). Further, when a convention similar to "at least one of A, B, and C, etc." is used, generally such a construction is intended in the sense that those skilled in the art will understand the convention (e.g., a system having "at least one of A, B, and C" includes, but is not limited to, a system having only A, only B, only C, both A and B, both A and C, both B and C, and / or all of A, B, and C).When a convention similar to “at least one of A, B, or C, etc.” is used, generally, such a configuration is intended in the sense that a person skilled in the art would understand the convention (for example, “a system having at least one of A, B, or C” includes, but is not limited to, a system having only A, only B, only C, both A and B, both A and C, both B and C, and / or both A, B, and C, etc.). Regardless of the specification, claims, or drawings, it will be further understood by those skilled in the art that substantially any disjunctive and / or phrase presenting two or more alternative terms is to be understood as contemplating the possibility of including one of the terms, any of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B”.

[0225] In addition, when a feature or aspect of the present disclosure is described from the perspective of a Markush group, it will be recognized by those skilled in the art that thereby the present disclosure is also described from the perspective of any individual member or subgroup of members of the Markush group.

[0226] As will be understood by those skilled in the art, for any purpose, for example, from the perspective of providing a written description, all ranges disclosed herein also encompass any possible sub-ranges and combinations of those sub-ranges. Any listed range sufficiently indicates that the same range can be decomposed into at least equal halves, thirds, fourths, fifths, tenths, etc., and can be readily recognized as enabling such decomposition. As a non-limiting example, each range considered herein can be readily decomposed into, for example, the lower third, the middle third, and the upper third. As will also be understood by those skilled in the art, all terms such as "maximum", "at least", "greater than", "less than", etc. include the recited numbers and refer to ranges that can later be decomposed into sub-ranges as described above. Finally, as will be understood by those skilled in the art, a range includes each individual member. Thus, for example, a group having 1 to 3 items refers to a group having 1, 2, or 3 items. Similarly, a group having 1 to 5 items refers to a group having 1, 2, 3, 4, or 5 items, and so on.

[0227] The above-described inventions have been described in some detail by way of illustration and example for the purpose of a clear understanding. However, it will be readily apparent to those skilled in the art that certain changes and modifications can be made to those inventions without departing from the spirit or scope of the appended claims in light of the teachings of the present invention.

[0228] Accordingly, the foregoing merely illustrates the principles of the present invention. Those skilled in the art will appreciate that, although not explicitly described or illustrated herein, various arrangements embodying the principles of the present invention and falling within its spirit and scope can be devised. Further, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the present invention and the concepts contributed by the inventor to further the art, and are to be construed as not being limited to such specifically recited examples and conditions. Additionally, all descriptions in this specification of the principles, aspects, and embodiments of the present invention, as well as specific examples thereof, are intended to encompass both their structural and functional equivalents. Moreover, such equivalents are intended to include both currently known equivalents and equivalents developed in the future, i.e., any elements developed to perform the same function regardless of structure. Further, what is disclosed herein is not intended to be dedicated to the public whether or not such disclosure is expressly recited in the claims.

[0229] Accordingly, it is not intended that the scope of the present invention be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the present invention are embodied by the appended claims. In the claims, 35 U.S.C. § 112(f) or 35 U.S.C. § 112, ¶ 6 is expressly defined such that it is recited in a claim only when the exact phrase "means for" or the exact phrase "step for" begins such limitation in that claim, and 35 U.S.C. § 112(f) or 35 U.S.C. § 112, ¶ 6 is not recited when such exact phrase is not used for limitation in the claim.

Claims

1. A pharmaceutical composition for treating an individual having fatty liver and / or a nonflaviviral viral infection, comprising a therapeutically effective amount of a compound, wherein the compound is (g) Compounds of formula I: or a pharmaceutically acceptable salt thereof (in the formula, X is either C or N, Y is either C or N, Z １ is C or N, Z ２ is C or N, R １ is hydrogen; C １ -C ６ -alkyl; substituted or unsubstituted C ３ -C ８ -cycloalkyl, 5- to 8-membered heterocyclyl, or 6-membered aryl group-substituted C １ -C ６ -alkyl; C ２ -C ６ -alkenyl; substituted or unsubstituted C ３ -C ８ -cycloalkyl, -CO-(C ３ -C ８ -cycloalkyl), -CO-(C １ -C ６ -alkyl), -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, -SO ２ -(C １ -C ６ -alkyl), or -SO ２ -(C ３ -C ８ -cycloalkyl) group, or R １ and R ２ together form a 12- to 25-membered heterocyclic ring, or R １ and R ５ together form a 12- to 25-membered heterocyclic ring, and L represents bonded, -CONH-, -NH-CO-, substituted, or unsubstituted C. １ ~C ５ Alkylene, substituted or unsubstituted C ２ ~C ５ Heteroalkylenes, substituted or unsubstituted 5-membered heteroaryl groups, or substituted or unsubstituted 5- to 7-membered heterocyclines, C ５ ~C ７ A cycloalkyl group, a 5-6 membered heteroaryl group, a 6-membered aryl group, or a combination thereof. R ２ is, -NH ２ , -NHR', -NR'R', -NHCOR', -NR'COR', -NHSO ２ R', -NR'SO ２ R', -NHSO ２ NH ２ , - NHSO ２ NHR', -NHC(O)NH ２ , -NHC(O)NHR', -N(R')SO ２ NH ２ , -N(R)SO ２ NHR', -N(R')C(O)NH ２ , and -N(R')C(O)NHR', or substituted or unsubstituted 5- to 7-membered heterocyclyls, C ５ ~C ７ It is a cycloalkyl group, a 5-6 membered heteroaryl group, or a 6-membered aryl group. R ３ , R ４ , and R ５ These are independently hydrogen, halo, -CN, -OH, -OR', and -NH ２ , -NHR', -NR'R', -NHCOR', -NR'COR', -NHSO ２ R', -NR'SO ２ R', -NHSO ２ NH ２ , - NHSO ２ NHR', -NHC(O)NH ２ , -NHC(O)NHR', -N(R')SO ２ NH ２ , -N(R')SO ２ NHR', -N(R')C(O)NH ２ , and N(R)C(O)NHR', -SO ２ R', -SO ２ NH ２ SO ２ NHR', SO ２ NR'R', -CONH ２ , -CONHR', -CONR'R', -CO ２ H, -CO ２ R', or substituted or unsubstituted C １ ~C ６ Alkyl, C ３ ~C ８ It is a cycloalkyl, aryl, heteroaryl, or heterocyclyl group. R' is a substituted or unsubstituted C. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C ８ (either a cycloalkyl, aryl, heteroaryl, or heterocyclyl group, or two R' groups that, together with the nitrogen atom to which they are bonded, form a heterocyclic ring.) (h) Compounds of formula II: or a pharmaceutically acceptable salt thereof (in the formula, X is either C or N, Y is either C or N, R １ is hydrogen, branched or straight-chain C １ to C ５ alkyl, C ２ to C １５ alkenyl, unsubstituted or substituted cycloalkyl, -CO-(cycloalkyl), -SO ２ -(cycloalkyl) group, or -(CH ２ ) ｎ -R １１ or R ５ and R １ together form a 12- to 18-membered heterocyclic ring, and n is 1 or 2. R ２ These are substituted or unsubstituted piperidinyl, 4-pyridyl, pyrrolidinyl, piperazinyl, benzyl, substituted phenyl, or pyrazolyl groups. R ５ is R ５１ R ５２ N- or R ５４ is O-, R ５１ is H, or substituted or unsubstituted C １ ~C ３ It is alkyl, R ５２ C ６ ~C ８ Cycloalkyl, substituted or unsubstituted linear C １ ~C ３ Alkyl or branched C ４ ~C ５ It is alkyl, or R ５１ and R ５２ Together with the nitrogen atoms to which they are bonded, they form a 6, 7, 8, or 9-membered heterocyclyl ring containing up to three heteroatoms, which may be substituted by substituted or unsubstituted benzylacyl or sulfonyl groups other than the azindazole moiety to which it is already bonded, R ５４ H, a substituted or unsubstituted benzyl group, a branched C ３ ~C ８ Alkyl, unsubstituted C ５ ~C ８ Cycloalkyl, or one or more linear or branched C atoms １ ~C ４ C substituted with alkyl group ５ ~C ８ It is a cycloalkyl, R １１ C ５ ~C ８ (A cycloalkyl, or a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl) (i) Compounds of formula III: or a pharmaceutically acceptable salt thereof (in the formula, X is either C or N, Y is either C or N, Z １ is C or N, Z ２ is C or N, R １ This is hydrogen, branched or straight-chain carbon. １ ~C ５ Alkyl, C ２ ~C １５ Alkenyl, unsubstituted or substituted cycloalkyl, -CO-(cycloalkyl), -SO ２ -(cycloalkyl) group, or -(CH ２ ) ｎ -R １１ is it R ５ and R １ These elements combine to form a 12-18 member heterocycle, where n is 1 or 2. R ２ R is a substituted or unsubstituted phenyl, piperidinyl, 4-pyridyl, pyrrolidinyl, piperazinyl, benzyl, substituted phenyl, or pyrazolyl group, ５ R ５１ R ５２ N- or R ５４ It is O-, R ５１ is H, or substituted or unsubstituted C １ ~C ３ It is alkyl, R ５２ C ６ ~C ８ Cycloalkyl, substituted or unsubstituted linear C １ ~C ３ Alkyl or branched C ４ ~C ５ It is alkyl, or R ５１ and R ５２ Together with the nitrogen atoms to which they are bonded, they form a 6, 7, 8, or 9-membered heterocyclyl ring containing up to three heteroatoms, which may be substituted by substituted or unsubstituted benzylacyl or sulfonyl groups other than the azindazole moiety to which it is already bonded, R ５４ H, a substituted or unsubstituted benzyl group, a branched C ３ ~C ８ Alkyl, unsubstituted C ５ ~C ８ Cycloalkyl, or one or more linear or branched C atoms １ ~C ４ C substituted with alkyl group ５ ~C ８ It is a cycloalkyl, R １１ C ５ ~C ８ A cycloalkyl, or a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, R ３ and R ５ These are independently hydrogen, halo, -CN, -OH, -OR', and -NH ２ , -NHR', -NR'R', -NHCOR', -NR'COR', -NHSO ２ R', -NR'SO ２ R', -NHSO ２ NH ２ , - NHSO ２ NHR', -NHC(O)NH ２ , -NHC(O)NHR', -N(R')SO ２ NH ２ , -N(R')SO ２ NHR', -N(R')C(O)NH ２ , and N(R)C(O)NHR', -SO ２ R', -SO ２ NH ２ SO ２ NHR', SO ２ NR'R', -CONH ２ , -CONHR', -CONR'R', -CO ２ H, -CO ２ R', or substituted or unsubstituted C １ ~C ６ Alkyl, C ３ ~C ８ (A cycloalkyl, aryl, heteroaryl, or heterocyclyl group) (j) Compound of formula IV: or a pharmaceutically acceptable salt thereof (in the formula, Each X is independently selected from C or N. R １ It does not exist, or hydrogen, (C １ ~C ８ ) alkyl, NR ９ R １０ , halo, amino, -C≡N, (C ２ ~C ８ ) Alkenil, (C ２ ~C ８ ) Alkinyl, (CC C ８ ) Haloalkyl, (C ２ ~C ８ ) Haloalkenyl, (C ２ ~C ８ ) Haloalkynyl, (C １ ~C ８ ) Alkoxy, (C １ ~C ８ ) Haloalkoxy, (C １ ~C ８ ) Alkyl (C １ ~C ６ ) Alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, CH(O), C(O)OR ８ SF ５ , -OH, -SH, (C １ ~C ６ ) Hydroxyalkyl, (C １ ~C ４ ) alkylsulfonyl, aminosulfonyl, amino(C １ ~C ４ ) Alkyl sulfonyl or aryl, R ２ C(O)NR １１ R １２ , C(O)R １３ , a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl R ３ H, (C １ ~C ８ ) alkyl, (C １ ~C ８ ) Alkenil, (C １ ~C ８ ) Alkinyl, (C １ ~C ８ ) Alkoxy, hydroxyl, halo, amino, amide, amino (C １ ~C ８ ) alkylamide, heterocyclyl, sulfonyl, aminosulfonyl, amino(C １ ~C ８ ) alkylsulfonyl, cyano, or (C １ ~C ３ ) is a haloalkyl, Each R ４ Independently, non-substituted or halo, (C １ ~C ８ ) Alkoxy, (C １ ~C ８ ) Haloeyecoxy, S(O)-R ６ , S(O) ２ , S(O) ２ -R ６ , S(O) ２ , C(O)R ６ , C(O)OR ７ , or (C １ ~C ８ ) Either substituted with a cycloalkyl group (C １ ~C ８ ) Selected from alkyl, or both R ４ Together, (C １ ~C ８ ) Cycloalkyl, (C １ ~C ８ ) Substituted cycloalkyl, (C １ ~C ８ ) Heterocycloalkyl, (C １ ~C ８ ) Substituted heterocycloalkyl, (C １ ~C ８ ) Aryl, (C １ ~C ８ ) Substitute aryl, (C １ ~C ８ ) heteroaryl, or (C １ ~C ８ ) form a substituted heteroaryl, R ６ H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C １ ~C ４ ) Haloalkyl and cyano, R ７ H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C １ ~C ４ ) Haloalkyl and cyano, R ８ H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C １ ~C ４ ) Haloalkyl and cyano, R ９ H, (C １ ~C ８ ) is alkyl, and the above (C １ ~C ８ ) Alkyl is either unsubstituted or substituted with one or more halos. R １０ H, (C １ ~C ８ ) is alkyl, and the above (C １ ~C ８ ) Alkyl is either unsubstituted or substituted with one or more halos, or R ９ and R １０ These, together with the nitrogen atoms to which they are bonded, form a four- or five-membered nitrogen-containing heterocycle, and the four- or five-membered nitrogen-containing heterocycle is either unsubstituted or substituted with one or more halos, where R is H, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) a haloalkyl, a 5-6 membered heterocyclic, or a 5-6 membered heteroaryl, R １１ H, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Selected from haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 6-membered heterocycle, 6-membered substituted heterocycle, 6-membered heteroaryl, 6-membered substituted heteroaryl, 5-membered cycloalkyl, or 5-membered substituted cycloalkyl, 6-membered cycloalkyl, or 6-membered substituted cycloalkyl, R １２ H, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Selected from haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 6-membered heterocycle, 6-membered substituted heterocycle, 6-membered heteroaryl, 6-membered substituted heteroaryl, 5-membered cycloalkyl, or 5-membered substituted cycloalkyl, 6-membered cycloalkyl, or 6-membered substituted cycloalkyl, R １１ and R １２ These, together with the nitrogen atoms to which they are bonded, form a 5-8 member nitrogen-containing heterocycle, and the 5-8 member nitrogen-containing heterocycle is either unsubstituted or contains OH, halo, =O, or (C １ ~C ８ ) Substituted with alkyl, R １３ is OH, O-(C １ ~C ４ ) is alkyl, R １５ H, (C １ ~C ６ ) alkyl, (C １ ~C) Haloalkyl, 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl, where each of the 4-7 membered heterocycle, 5-6 membered heteroaryl, and 3-7 membered cycloalkyl is unsubstituted or has one or more =O, OH, (C １ ~C ８ ) alkyl, (C １ ~C ８ ) Haloalkyl, (C １ ~C ８ ) Alkoxy, amino, or (C １ ~C ８ ) It is substituted with aminoalkyl at a replaceable position, R １６ H, (C １ ~C ８ ) alkyl, or (C １ ~C ８ (It is a haloalkyl) (k) Compound of formula V: or a pharmaceutically acceptable salt thereof (in the formula, Each X is independently selected from C or N. R １ It does not exist, or hydrogen, (C １ ~C ８ ) alkyl, NR ９ R １０ , halo, amino, -C≡N, (C ２ ~C ８ ) Alkenil, (C ２ ~C ８ ) Alkinyl, (CC C ８ ) Haloalkyl, (C ２ ~C ８ ) Haloalkenyl, (C ２ ~C ８ ) Haloalkynyl, (C １ ~C ８ ) Alkoxy, (C １ ~C ８ ) Haloalkoxy, (C １ ~C ８ ) Alkyl (C １ ~C ６ ) Alkoxy, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, CH(O), C(O)OR ８ SF ５ , -OH, -SH, (C １ ~C ６ ) Hydroxyalkyl, (C １ ~C ４ ) alkylsulfonyl, aminosulfonyl, amino(C １ ~C ４ ) Alkyl sulfonyl or aryl, R ２ C(O)NR １１ R １２ , C(O)R １３ , a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl R ３ H, (C １ ~C ８ ) alkyl, (C １ ~C ８ ) Alkenil, (C １ ~C ８ ) Alkinyl, (C １ ~C ８ ) Alkoxy, hydroxyl, halo, amino, amide, amino (C １ ~C ８ ) alkylamide, heterocyclyl, sulfonyl, aminosulfonyl, amino(C １ ~C ８ ) alkylsulfonyl, cyano, or (C １ ~C ３ ) is a haloalkyl, Each R ４ Independently, non-substituted or halo, (C １ ~C ８ ) Alkoxy, (C １ ~C ８ ) Haloeyecoxy, S(O)-R ６ , S(O) ２ , S(O) ２ -R ６ , S(O) ２ , C(O)R ６ , C(O)OR ７ , or (C １ ~C ８ ) Either substituted with a cycloalkyl group (C １ ~C ８ ) Selected from alkyl, or both R ４ Together, (C １ ~C ８ ) Cycloalkyl, (C １ ~C ８ ) Substituted cycloalkyl, (C １ ~C ８ ) Heterocycloalkyl, (C １ ~C ８ ) Substituted heterocycloalkyl, (C １ ~C ８ ) Aryl, (C １ ~C ８ ) Substitute aryl, (C １ ~C ８ ) heteroaryl, or (C １ ~C ８ ) form a substituted heteroaryl, R ６ H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C １ ~C ４ ) Haloalkyl and cyano, R ７ H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C １ ~C ４ ) Haloalkyl and cyano, R ８ H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, halo, (C １ ~C ４ ) Haloalkyl and cyano, R ９ H, (C １ ~C ８ ) is alkyl, and the above (C １ ~C ８ ) Alkyl is either unsubstituted or substituted with one or more halos. R １０ H, (C １ ~C ８ ) is alkyl, and the above (C １ ~C ８ ) Alkyl is either unsubstituted or substituted with one or more halos, or R ９ and R １０ These, together with the nitrogen atoms to which they are bonded, form a four- or five-membered nitrogen-containing heterocycle, and the four- or five-membered nitrogen-containing heterocycle is either unsubstituted or substituted with one or more halos, where R is H, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) a haloalkyl, a 5-6 membered heterocyclic, or a 5-6 membered heteroaryl, R １１ H, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Selected from haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 6-membered heterocycle, 6-membered substituted heterocycle, 6-membered heteroaryl, 6-membered substituted heteroaryl, 5-membered cycloalkyl, or 5-membered substituted cycloalkyl, 6-membered cycloalkyl, or 6-membered substituted cycloalkyl, R １２ H, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Selected from haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 6-membered heterocycle, 6-membered substituted heterocycle, 6-membered heteroaryl, 6-membered substituted heteroaryl, 5-membered cycloalkyl, or 5-membered substituted cycloalkyl, 6-membered cycloalkyl, or 6-membered substituted cycloalkyl, R １１ and R １２ These, together with the nitrogen atoms to which they are bonded, form a 5-8 member nitrogen-containing heterocycle, and the 5-8 member nitrogen-containing heterocycle is either unsubstituted or contains OH, halo, =O, or (C １ ~C ８ ) Substituted with alkyl, R １３ is OH, O-(C １ ~C ４ ) is alkyl, R １５ H, (C １ ~C ６ ) alkyl, (C １ ~C) Haloalkyl, 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl, where each of the 4-7 membered heterocycle, 5-6 membered heteroaryl, and 3-7 membered cycloalkyl is unsubstituted or has one or more =O, OH, (C １ ~C ８ ) alkyl, (C １ ~C ８ ) Haloalkyl, (C １ ~C ８ ) Alkoxy, amino, or (C １ ~C ８ ) It is substituted with aminoalkyl at a replaceable position, R １６ H, (C １ ~C ８ ) alkyl, or (C １ ~C ８ ) being haloalkyl), as well as (l) Compounds of formula VI: or a pharmaceutically acceptable salt thereof (in the formula, R １ is hydrogen; halo, haloalkyl C １ ~C ６ Alkyl; substituted or unsubstituted C ３ ~C ８ C is substituted with a cycloalkyl, a 5- to 8-membered heterocyclyl, or a 6-membered aryl group. １ ~C ６ Alkyl; C ２ ~C ６ Alkenyl; Substituted or unsubstituted C ３ ~C ８ Cycloalkyl, -CO-(C ３ ~C ８ Cycloalkyl), -CO-(C １ ~C ６ Alkyl), -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, -SO ２ - (C １ ~C ６ Alkyl), or -SO ２ - (C ３ ~C ８ It is a cycloalkyl group, R ２ C(O)NR １１ R １２ , C(O)R １３ , a 5-membered heterocycle, a 5-membered substituted heterocycle, a 5-membered heteroaryl, a 5-membered substituted heteroaryl, a 6-membered heterocycle, a 6-membered substituted heterocycle, a 6-membered heteroaryl, a 6-membered substituted heteroaryl, a 5-membered cycloalkyl, or a 5-membered substituted cycloalkyl, a 6-membered cycloalkyl, or a 6-membered substituted cycloalkyl R ３ H, (C １ ~C ８ ) alkyl, (C １ ~C ８ ) Alkenil, (C １ ~C ８ ) Alkinyl, (C １ ~C ８ ) Alkoxy, hydroxyl, halo, amino, amide, amino (C １ ~C ８ ) alkylamide, heterocyclyl, sulfonyl, aminosulfonyl, amino(C １ ~C ８ ) alkylsulfonyl, cyano, or (C １ ~C ３ ) is a haloalkyl, R １１ H, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Selected from alkyl groups substituted with one or more of the following: haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 6-membered heterocycle, 6-membered substituted heterocycle, 6-membered heteroaryl, 6-membered substituted heteroaryl, 5-membered cycloalkyl, or 5-membered substituted cycloalkyl, 6-membered cycloalkyl, or 6-membered substituted cycloalkyl, or alkyl groups substituted with one or more of the following: 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 6-membered heterocycle, 6-membered heterocycle, 6-membered heteroaryl, 6-membered substituted heteroaryl, 5-membered cycloalkyl, or 5-membered substituted cycloalkyl, 6-membered cycloalkyl, or 6-membered substituted cycloalkyl. R １２ H, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Selected from alkyl groups substituted with one or more of the following: haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 6-membered heterocycle, 6-membered substituted heterocycle, 6-membered heteroaryl, 6-membered substituted heteroaryl, 5-membered cycloalkyl, or 5-membered substituted cycloalkyl, 6-membered cycloalkyl, or 6-membered substituted cycloalkyl, or alkyl groups substituted with one or more of the following: 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 6-membered heterocycle, 6-membered heterocycle, 6-membered heteroaryl, 6-membered substituted heteroaryl, 5-membered cycloalkyl, or 5-membered substituted cycloalkyl, 6-membered cycloalkyl, or 6-membered substituted cycloalkyl. R １１ and R １２ These, together with the nitrogen atoms to which they are bonded, form a 5-8 member nitrogen-containing heterocycle, and the 5-8 member nitrogen-containing heterocycle is either unsubstituted or contains OH, halo, =O, or (C １ ~C ８ ) Substituted with alkyl, R ４ is hydrogen; halo, haloalkyl C １ ~C ６ Alkyl; substituted or unsubstituted C ３ ~C ８ Cycloalkyl, 5-8 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl, C ２ ~C ６ C substituted with alkenyl １ ~C ６ Alkyl; substituted or unsubstituted C ３ ~C ８ Cycloalkyl, -CO-(C ３ ~C ８ Cycloalkyl), -CO-(C １ ~C ６ Alkyl), -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, -SO ２ - (C １ ~C ６ Alkyl), or -SO ２ - (C ３ ~C ８ (It is a cycloalkyl group.) A pharmaceutical composition selected from the group consisting of the following.

2. The pharmaceutical composition according to claim 1, wherein the individual has a nonflaviviral viral infection selected from the group consisting of Hepadnaviridae viral infections, alphavirus infections, coronavirus infections, paramyxoviridae infections, and orthomyxoviridae infections.

3. The pharmaceutical composition according to claim 1, wherein the individual has a viral infection with hepatitis B virus (HBV), Venezuelan encephalitis virus (VEEV), Onyonnyon virus (ONNV), SARS-CoV-2, Semryki Forest virus (SFV), or Chikungunya virus (CHIKV).

4. The pharmaceutical composition according to claim 1, wherein the individual has a viral infection with hepatitis B virus (HBV), Venezuelan encephalitis virus (VEEV), SARS-CoV-2, or chikungunya virus (CHIKV).

5. The pharmaceutical composition according to claim 1, wherein the compound is co-administered to the individual together with the second agent.

6. The pharmaceutical composition according to claim 2, wherein the compound is co-administered to the individual together with a second antiviral agent.

7. The pharmaceutical composition according to claim 1, wherein the compound is administered to the individual at a concentration in the range of 8 to 100 mg / kg.

8. The pharmaceutical composition according to claim 1, wherein the compound is administered to the individual for three days or more.

9. The aforementioned compound is A27: The pharmaceutical composition according to claim 1. A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of

10. .

11. A compound according to claim 10 or a pharmaceutically acceptable salt thereof, selected from the group consisting of

11. .

12. (a) The compound according to claim 10 or 11 or a pharmaceutically acceptable salt thereof, and (b) A pharmaceutically acceptable carrier, excipient, or diluent A composition containing the following:

13. The composition according to claim 12, which is a pharmaceutical for the treatment of fatty liver and / or viral infection.

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