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 binding agent, such as A27, to treat the subject. Compositions useful for implementing embodiments of the present methods are also provided.

Description

Background Art

[0001] More than 100 million people in the United States have non-alcoholic fatty liver disease (NAFLD), which is caused by obesity-related metabolic dysfunction. Of these, 10%-20% will develop a more aggressive form called non-alcoholic steatohepatitis (NASH), which can ultimately lead to liver failure and / or liver cancer. Current treatments are inadequate. There is still a huge unmet medical need for therapies 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 such as severe acute respiratory syndrome (SARS)-coronavirus 1 and 2 remain large unmet medical needs.

[0003] Cross-references

[0004] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 344,467, filed on May 20, 2022, which is incorporated herein by reference in its entirety. Summary of the invention

[0005] Methods and compositions for treating fatty liver and viral infection are provided. Aspects of the method include administering an effective amount of a KxL motif binder, such as A27, to a subject in need thereof to treat the subject. Compositions for implementing embodiments of the method are also provided.

[0006] For example, a method of treatment is provided, the method comprising administering to an individual having fatty liver and / or non-Flaviveriidae viral infection a therapeutically effective amount of a compound selected from the group consisting of compounds of Formulae I-VI or a pharmaceutically acceptable salt thereof:

[0007]

[0008] In some embodiments, the individual has a non-Flaviveviridae viral infection (e.g., a Hepadnaviridae viral infection such as HBV, an Alphavirus infection such as ONNV, SFV, VEEV, or CHIKV, a Coronaviridae infection such as SARS-CoV-2, a Paramyxoviridae infection such as RSV, an Orthomyxoviridae infection such as influenza, etc. In some cases, the patient has a Hepatitis B virus (HBV), Venezuelan equine encephalitis virus (VEEV), Araraviridae virus (ONNV), SARS-CoV-2, Semliki Forest virus (SFV), or Chikungunya virus (CHIKV) viral infection. In some cases, the individual has a Hepatitis B virus (HBV), Venezuelan equine encephalitis virus (VEEV), SARS-CoV-2, or Chikungunya virus (CHIKV) viral infection.

[0009] In some embodiments, the compound is co-administered with a second agent (e.g., an antibiotic and / or an antiviral agent). In some cases, the compound is administered at a concentration ranging from 8 mg / kg to 100 mg / kg. In some cases, the compound is administered for 3 days or longer. In some cases, the compound is A27:

[0010]

[0011] Also provided are novel compounds, for example, compounds selected from the group consisting of:

[0012]

[0013]

[0014] Compositions are also provided, such as compositions comprising: (a) a pharmaceutically acceptable carrier, excipient, or diluent; and (b) a compound selected from the group consisting of:

[0015]

[0016]

[0017] In some cases, the composition is a medicament for treating fatty liver, and in some cases, the composition is a medicament for treating a viral infection, such as a non-Flaviveviridae viral infection (e.g., a Hepadnaviridae viral infection such as HBV, an Alphavirus infection such as ONNV, SFV, VEEV, or CHIKV, a Coronaviridae infection such as SARS-CoV-2, a Paramyxoviridae infection such as RSV, an Orthomyxoviridae infection such as influenza, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 : A27 inhibits fat accumulation in hepatic cell lines cultured in the presence of supplemented fatty acids. HepG2 cells were cultured in medium supplemented with oleic and palmitic acids to induce steatosis and treated with indicated concentrations of A27 or vehicle for 3 days.

[0019] Figure 2 : A27 inhibits the development of steatosis in high-fat diet mice, as measured by ultrasound. Representative liver ultrasound images of high-fat diet mice treated with 100 mg / kg / day of vehicle (top panel) or A27 (bottom panel) for 4 weeks.

[0020] Figure 3 : Molecular modeling of different amphipathic peptides with KxL motif and their interaction with A27.

[0021] Figure 4 : A27 reduces HBsAg production in engineered human liver tissue infected with HBV.

[0022] Figure 5 : A27 inhibits SARS-CoV-2 in cell culture.

[0023] Figure 6 : A27 inhibits VEEV in cell culture.

[0024] Figure 7 : A proposed scheme for the synthesis of A27 derivatives used in the examples of the present invention.

[0025] Figure 8 : Table showing the functional properties of compounds of Formula I-VI (see, e.g., Examples 2 and 3).

[0026] definition

[0027] The term "specific binding" refers to the direct association between two molecules due to, for example, covalent, electrostatic, hydrophobic and ionic and / or hydrogen bond interactions (including interactions such as salt bridges and water bridges). Specific binding members describe members of a pair of molecules that have binding specificity to each other. The members of a specific binding pair can be naturally derived or produced in whole or in part synthetically. One member of the pair of molecules has an area or cavity on its surface that specifically binds to and is therefore complementary to the specific spatial and polar organization of the other member of the pair of molecules. Therefore, the members of the pair have the property of specifically binding to each other. Examples of specific binding member pairs are antigen-antibody, biotin-avidin, hormone-hormone receptor, receptor-ligand, enzyme substrate-substance. The specific binding members of the binding pair exhibit high affinity and binding specificity for binding to each other. Typically, the affinity between a pair of specific binding members is characterized by K d (dissociation constant) is 10 -6 M or smaller, such as 10 -7 M or smaller, including 10 -8 M or less, for example, 10 -9 M or smaller, 10 -10 M or smaller, 10 -11 M or smaller, 10 -12 M or smaller, 10 -13 M or smaller, 10 -14 M or smaller, including 10 -15M or less. "Affinity" refers to the strength of binding, and increased binding affinity is associated with a lower KD. In one embodiment, affinity is determined by surface plasmon resonance (SPR), for example, as used by a Biacore system. The affinity of a molecule to another molecule is determined by, for example, measuring the binding kinetics of the interaction at 25°C. "Affinity" refers to the strength of binding, and increased binding affinity is associated with a lower KD. In one embodiment, affinity is determined by surface plasmon resonance (SPR), for example, as used by a Biacore system. The affinity of a molecule to another molecule is determined by, for example, measuring the binding kinetics of the interaction at 25°C.

[0028] Methods described herein may include multiple steps. As required, each step may be performed after a predetermined amount of time has passed between steps. Like this, the time between each step may be 1 second or longer, 10 seconds or longer, 30 seconds or longer, 60 seconds or longer, 5 minutes or longer, 10 minutes or longer, 60 minutes or longer and include 5 hours or longer. In certain embodiments, each subsequent step is performed immediately after completing the previous step. In other embodiments, steps may be performed after incubation or waiting time after completing the previous step, for example, a few minutes to overnight waiting time.

[0029] As used herein, the terms "assess," "determine," "measure," and "assess," and "determine" are used interchangeably and include both quantitative and qualitative determinations.

[0030] As used herein, the term "separation" refers to the physical separation of two elements (eg, by size or affinity, etc.) as well as the degradation of one element while leaving the other element intact. DETAILED DESCRIPTION

[0031] Methods and compositions for treating fatty liver and viral infection are provided. Aspects of the method include administering an effective amount of a KxL motif binder, such as A27, to a subject in need thereof to treat the subject. Compositions for implementing embodiments of the method are also provided.

[0032] Before describing the present invention in detail, it should be understood that the present invention is not limited to the specific embodiments described, as these embodiments may of course vary. It should also be understood that the terms used herein are only for the purpose of describing specific embodiments and are not intended to be limiting, as the scope of the present invention will only be limited by the appended claims.

[0033] Where a numerical range is provided, it is understood that each intervening value between the upper and lower limits of the range (based on one-tenth of the unit of the lower limit unless the context clearly dictates otherwise) and any other stated or intervening value in the stated range are included in the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also included in the invention, subject to any explicitly excluded limits in the stated range. Where a range is specified to include one or both limits, ranges excluding one or both of these included limits are also included in the invention.

[0034] Certain ranges appearing herein are presented by preceding the numerical value with the term "about". The term "about" is used herein to provide literal support for the exact number preceding it as well as a number that is close to or approximately the number preceding the term. In determining whether a number is close to or approximately a specifically cited number, the close or approximate unquoted number may be a number that provides a substantial equivalent of the specifically cited number in the context in which it appears.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative illustrative methods and materials are now described.

[0036] All publications and patents cited in this specification are incorporated herein by reference to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference and discloses and describes the methods and / or materials related thereto. 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 is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

[0037] It is noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the claims may be drafted to exclude any optional elements. Thus, this statement is intended to serve as antecedent basis for use of exclusive terminology, such as "only," "only," and the like, in connection with the recitation of claim elements or as a "negative" limitation.

[0038] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features that can be readily separated or combined with the features of any of the other several embodiments without departing from the scope or spirit of the invention. Any recited method may be performed in the order of events recited or in any other order that is logically possible.

[0039] Although the apparatus and method have been or will be described for the sake of grammatical fluency and functional interpretation, it should be clearly understood that unless expressly stated in accordance with 35 U.S.C. §112, the claims should not be interpreted as necessarily being limited in any way to the "means" or "step" limitations, but should be consistent with the full scope of the meaning and equivalents provided by the claims in accordance with the judicial doctrine of equivalents, and in the event that the claims are expressly stated in accordance with 35 U.S.C. §112, they will be given full legal equivalents in accordance with 35 U.S.C. §112.

[0040] Methods and compositions for treating fatty liver and viral infection are provided. Aspects of the method include administering an effective amount of a KxL motif binder, such as A27, to a subject in need thereof to treat the subject. Compositions for implementing embodiments of the method are also provided.

[0041] "Treatment" means achieving at least an improvement in one or more symptoms associated with a target disorder afflicting a subject, wherein improvement is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, such as a symptom associated with the target disorder being treated. Thus, treatment also includes situations in which a pathological condition or at least symptoms associated therewith are completely inhibited, such as prevented from occurring, or stopped, such as terminated, such that an adult mammal no longer suffers from the target disorder or at least symptoms characterizing the injury. In some cases, "treatment", "treating", etc. refer to obtaining a desired pharmacological and / or physiological effect. The effect may be preventive in terms of completely or partially preventing a disease or its symptoms, and / or therapeutic in terms of partially or completely curing a disease and / or adverse effects attributable to a disease. "Treatment" may be any treatment of a mammalian disease, and includes: (a) preventing the onset of the disease in a subject susceptible to the disease but not yet diagnosed with the disease; (b) inhibiting the disease, i.e., arresting its development; or (c) alleviating the disease, i.e., causing regression of the disease. Treatment may result in a variety of different physical manifestations, such as modulation of gene expression, restoration of tissues or organs, etc. In some embodiments, treatment of an ongoing disease occurs, wherein the treatment stabilizes or reduces the patient's undesirable clinical symptoms. Such treatment can be performed before the complete loss of function in the affected tissue. The subject therapy can be administered during the symptomatic stage of the disease, and in some cases after the symptomatic stage of the disease.

[0042] The methods described herein can be used to treat any type of subject in need of treatment. Subjects include mammalian species. Mammalian species that can be treated with the present methods include canines and felines; equines; bovines; sheep; etc., as well as primates, including humans. The subject methods, compositions and reagents can also be applied to animal models, including small mammals, such as murines, lagomorphs, etc., for example in experimental studies.

[0043] The terms "receptor," "individual," "subject," "host," and "patient" are used interchangeably herein and refer to any mammalian subject, particularly a human, in need of diagnosis, treatment, or therapy. "Mammal" for therapeutic purposes refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, and the like. In some embodiments, the mammal is a human. In some embodiments, the individual is not a human (e.g., a non-human mammal).

[0044] The inventors have discovered that A27 and its derivatives can bind to the KxL motif of ApoB, which plays a role in fatty liver (steatosis, hepatic steatosis). A27 (and derivatives) can be used to reduce steatosis and, therefore, can be used to treat fatty liver. Therefore, in some embodiments, the individual to whom A27 and / or A27 derivatives are delivered has fatty liver.

[0045] As described above, the present inventors have discovered that A27 and its derivatives can bind to the KxL motif of ApoB, and found that the KxL motif is also present in the amphipathic helical domain of viral proteins, including hepatitis B surface antigen (HBsAg), nonstructural protein (NSP) 1 of Venezuelan equine encephalitis virus (VEEV), NSP1 of Arara virus (ONNV), NSP1 of Semliki Forest virus (SFV), NSP1 of Chikungunya virus (CHIKV or CHKV), and NSP4 of SARS-CoV-2 ( Figure 3 ). Therefore, the compounds described herein (eg, A27 and its derivatives) can be used to treat viral infections.

[0046] In some embodiments, the viral infection is not a Flaviviridae (e.g., HCV) viral infection (i.e., a non-Flaviviridae infection). In some embodiments, the viral infection is a Hepadnaviridae viral infection (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 Coronaviridae infection (e.g., Severe Respiratory Acute Respiratory Syndrome (SARS)-CoV-2). In some cases, the infection is a Paramyxoviridae infection (e.g., Respiratory Syncytial Virus (RSV)). In some cases, the infection is an Orthomyxoviridae infection (e.g., influenza).

[0047] In some cases, infection is hepatitis B virus (HBV) infection, Venezuelan equine encephalitis virus (VEEV) infection or severe respiratory acute respiratory syndrome (SARS)-CoV-2 infection. In some cases, infection is HBV infection, VEEV infection, SARS-CoV-2 infection, ONNV infection, SFV infection or CHIKV infection. In some cases, infection is alphavirus infection (e.g., ONNV, eastern equine encephalitis (EE), western equine encephalitis (WEE), VEEV, CHIKV).

[0048] As described above, embodiments of the method employ KxL motif binding agents. For example, small molecules that bind to the KxL motif are of interest. Naturally occurring or synthetic small molecule compounds of interest include many chemical categories, such as organic molecules, such as small organic compounds with a molecular weight greater than 50 and less than about 2,500 daltons. Candidate agents include functional groups for interacting with protein structures, particularly hydrogen bonds, and typically include at least amine, carbonyl, hydroxyl or carboxyl groups, preferably at least two functional chemical groups. Candidate agents may include cyclic carbon or heterocyclic structures and / or aromatic or polyaromatic structures substituted by one or more of the above-mentioned functional groups. Candidate agents are also found in biomolecules including peptides, sugars, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs or combinations thereof. Such molecules may be identified, among other means, by using the screening scheme described below.

[0049] In some embodiments, the agent is A27 or a derivative thereof (see, e.g., compounds of Formula I-III, as shown below). In some embodiments, the agent is as disclosed in U.S. Published Patent Application Publication No. US20120232062A1 (see, e.g., compounds of Formula I-III); the disclosure of which is incorporated herein by reference.

[0050] In some embodiments, the agent is

[0051]

[0052] Or a derivative thereof (see, e.g., compounds of Formula IV-V, as shown below). In some embodiments, the agent is as disclosed in International Patent Application Publication No. WO2013090929 (see, e.g., compounds of Formula IV-V); the disclosure of which is incorporated herein by reference.

[0053] Selected Definitions of Chemical Terms

[0054] The following terms are referred to in their conventional sense, as described below. Any undefined term has its art-recognized meaning.

[0055] As used herein, the term "alkyl" by itself or as part of another substituent refers to a saturated branched or straight chain monovalent hydrocarbon group derived by removing a hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl; ethyl; propyl such as prop-1-yl or prop-2-yl; and butyl such as but-1-yl, but-2-yl, 2-methyl-prop-1-yl or 2-methyl-prop-2-yl. In some embodiments, the alkyl group includes 1 to 20 carbon atoms. In other embodiments, the alkyl group includes 1 to 10 carbon atoms. In still other embodiments, the alkyl group includes 1 to 6 carbon atoms, such as 1 to 4 carbon atoms.

[0056] "Alkanyl" by itself or as part of another substituent refers to a saturated branched, straight chain or cyclic alkyl group derived by removing a hydrogen atom from a single carbon atom of an alkane. Typical alkanyl groups include, but are not limited to, methane; ethyl; propane, such as propane-1-yl, propane-2-yl (isopropyl), cyclopropane-1-yl, etc.; butane, such as butane-1-yl, butane-2-yl (sec-butyl), 2-methyl-propane-1-yl (isobutyl), 2-methyl-propane-2-yl (tert-butyl), cyclobutane-1-yl, etc.; and the like.

[0057] "Alkylene" refers to a branched or unbranched saturated hydrocarbon chain, typically having 1 to 40 carbon atoms, more typically 1 to 10 carbon atoms, and even more typically 1 to 6 carbon atoms. The term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-), and the like.

[0058] "Alkenyl" 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 a hydrogen atom from a single carbon atom of an alkene. The group may be in the cis or trans configuration about the double bond. Typical alkenyl groups include, but are not limited to, vinyl; 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-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.; and the like.

[0059] "Alkynyl" 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, but are not limited to, ethynyl; propynyl, such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyl, such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

[0060] "Acyl" by itself or as part of another substituent refers to the group -C(O)R 30 , where R 30is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, aralkyl, heteroalkyl, heteroaryl, heteroarylalkyl, and substituted forms thereof as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, piperonyl, propionyl, succinyl, and malonyl, and the like.

[0061] The term "aminoacyl" refers to the group -C(O)NR 21 R 22 , 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, heterocyclyl, and substituted heterocyclyl, and wherein R 21 and R 22 and optionally linked together with the nitrogen to which it is bound to form a heterocyclyl or substituted heterocyclyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl are as defined herein.

[0062] "Alkoxy" by itself or as part of another substituent refers to the group -OR 31 , 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, and the like.

[0063] "Alkoxycarbonyl" by itself or as part of another substituent refers to the group -C(O)OR 31 , where R 31 represents an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, cyclohexyloxycarbonyl, and the like.

[0064] "Aryl" by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom of an aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrene, acenaphthylene, acetoxyphenanthrene, anthracene, azulene, benzene, In some embodiments, the aryl group comprises 6 to 20 carbon atoms. In some embodiments, the aryl group comprises 6 to 12 carbon atoms. Examples of aryl groups are phenyl and naphthyl.

[0065] "Arylalkyl" by itself or as part of another substituent refers to a radical in which the carbon atom (typically a terminal or sp 3 Acyclic alkyl groups in which one of the hydrogen atoms bonded to a (C-7-carbon atom) is replaced by an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, 2-phenylethene-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, 2-naphthylethene-1-yl, naphthobenzyl, 2-naphthophenylethane-1-yl, etc. When it is intended to use a specific alkyl moiety, the named arylalkyl, arylalkenyl and / or arylalkynyl groups are used. In certain embodiments, the arylalkyl group is (C-7-C 30 ) aralkyl, for example the alkane, alkenyl or alkynyl portion 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 alkane, alkenyl or alkynyl portion of the arylalkyl group is (C1-C8) and the aryl portion is (C6-C 12 ).

[0066] "Arylaryl" by itself or as part of another substituent refers to a monovalent hydrocarbon radical derived by removing a hydrogen atom from a single carbon atom of a ring system, wherein two or more of the same or different aromatic ring systems are directly linked together by single bonds, wherein the number of such direct ring links 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, and the like. When specifying the number of carbon atoms in an arylaryl group, the number refers to the carbon atoms contained in each aromatic ring. For example, (C5-C 14 )Arylaryl is an arylaryl group in which each aromatic ring includes 5 to 14 carbons, such as biphenyl, triphenyl, binaphthyl, phenylnaphthyl, etc. In certain embodiments, each aromatic ring of the arylaryl group is independently (C5-C 14 In certain embodiments, each aromatic ring 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.

[0067] "Cycloalkyl" by itself or as part of another substituent refers to a saturated or unsaturated cyclic alkyl group. Where a specific level of saturation is intended, the nomenclature "cycloalkane" or "cycloalkenyl" is used. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. In certain embodiments, a cycloalkyl group is (C3-C 10 In certain embodiments, the cycloalkyl group is a (C3-C7)cycloalkyl.

[0068] "Cycloheteroalkyl" or "heterocyclyl" by itself or as part of another substituent refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or different heteroatoms. Typical heteroatoms used to replace carbon atoms include, but are not limited to, N, P, O, S, Si, and the like. When a specific level of saturation is intended, the nomenclature "cycloheteroalkyl" or "cycloheteroalkenyl" is used. Typical cycloheteroalkane groups include, but are not limited to, groups derived from epoxides, aziridines, thiirane, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like.

[0069] "Heteroalkyl, heteroalkane, heteroalkenyl and heteroalkynyl" by themselves or as part of another substituent refer to alkyl, alkane, alkenyl and alkynyl groups, respectively, in which one or more 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, but are not limited to, --O-, -S-, -SS-, -OS-, -NR 37 R 38-,=NN=,-N=N-,-N=N-NR 39 R 40 , -PR 41 -、-P(O)2-、-POR 42 -, -OP(O)2-, -SO-, -S-(O)-, -SO2-, -SnR 43 R 44 - etc., where R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 and R 44 and R is 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.

[0070] "Heteroaryl" by itself or as part of another substituent refers to a monovalent heteroaromatic radical derived by removing one hydrogen atom from a single atom of a heteroaromatic ring system. Typical heteroaryl radicals include, but are not limited to, radicals derived from acridine, arsindene, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perylene, phenanthridine, o-phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyridine ring, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, benzodioxole, and the like. In certain embodiments, the heteroaryl group is a 5-20 membered heteroaryl. In certain embodiments, the heteroaryl group is a 5-10 membered heteroaryl. In certain embodiments, the heteroaryl group is a group derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.

[0071] "Heteroarylalkyl" by itself or as part of another substituent refers to a group in which the carbon atoms (typically terminal or sp 3In some embodiments, the heteroarylalkyl group is a 6-30 yuan heteroarylalkyl, such as the alkane, alkenyl or alkynyl moiety of heteroarylalkyl is 1-10 yuan, and the heteroaryl moiety is a 5-20 yuan heteroaryl. In some embodiments, the heteroarylalkyl group is a 6-20 yuan heteroarylalkyl, such as the alkane, alkenyl or alkynyl moiety of heteroarylalkyl is 1-8 yuan, and the heteroaryl moiety is a 5-12 yuan heteroaryl.

[0072] "Aromatic ring system" by itself or as part of another substituent refers to an unsaturated cyclic or polycyclic ring system with a conjugated π electron system. The definition of "aromatic ring system" specifically includes fused ring systems in which one or more of the rings is aromatic and one or more of the rings is saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc. Typical aromatic ring systems include, but are not limited to, anthracene, acenaphthene, phenanthracene, anthracene, azulene, benzene, Coronene, fluoranthene, fluorene, hexacene, hexylene, hexene, asymmetric indacene, symmetric indacene, indane, indene, naphthalene, octacene, octacene, octalene, ovalene, pentacene-2,4-diene, pentacene, pentalene, pentylene, perylene, perylene, benzonaphthalene, phenanthrene, phenanthrene, septupene, pyrene, pyranthene, rubrocene, triphenylene, and ternaphthalene, etc.

[0073] "Heteroaromatic ring system" by itself or as part of another substituent 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. Typical heteroatoms used to replace carbon atoms include, but are not limited to, N, P, O, S, Si, and the like. Specifically included in the definition of "heteroaromatic ring system" are fused ring systems in which one or more of the rings is aromatic and one or more of the rings is saturated or unsaturated, such as, for example, arsindenes, benzodioxanes, benzofurans, chromanes, chromenes, indoles, indolines, xanthenes, and the like. Typical heteroaromatic ring systems include, but are not limited to, arsindene, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, dihydroindole, indolizine, isobenzofuran, isochromene, isoindole, isodihydroindole, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perylene, phenanthridine, o-phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyridine ring, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like.

[0074] "Substituted" refers to a group in which one or more hydrogen atoms are independently replaced by the same or different substituents. Typical substituents include, but are not limited to, alkylenedioxy (such as 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)2R 60 、-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 , where M is halogen; R 60 , R 61 , R 62 and R 63 R is independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or R 60 and R 61 optionally together with the nitrogen atom to which they are bound form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and R 64and R 65 R is independently hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or R 64 and R 65 Optionally, together with the nitrogen atom to which they are bound, they form a cycloheteroalkyl or substituted cycloheteroalkyl ring. In certain embodiments, the 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 - )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 - 、-NR 62 C(O)NR 60 R 61 In certain embodiments, the 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 - In certain embodiments, the substituents include -M, -R 60 ,=O,-OR60 、-SR 60 、-NR 60 R 61 , -CF3, -CN, -NO2, -S(O)2R 60 、-OP(O)(OR 60 )(OR 61 )、-C(O)R 60 、-C(O)OR 60 、-C(O)O - , where R 60 , R 61 and R 62 As defined above. For example, the substituted radical may carry a methylenedioxy substituent or one, two or three substituents selected from halogen atoms, (1-4C)alkyl radicals and (1-4C)alkoxy radicals.

[0075] Compounds for treating fatty liver disease and viral infections

[0076] As described above, aspects of the invention include methods for treating fatty liver and viral infections. In an embodiment, 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.

[0077] In embodiments, the "salt" of the compounds of the present disclosure may include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids 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. (1) when the acidic proton in the compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion; or (2) when the acidic proton in the compound is coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.

[0078] As used herein, the term "solvate" refers to a complex or aggregate formed by one or more solute molecules and one or more solvent molecules. Such solvates can be crystalline solids with a substantially fixed molar ratio of solute to solvent. Representative solvents include, for example, water, methanol, ethanol, isopropanol, acetic acid, etc. When the solvent is water, the solvate formed is a hydrate.

[0079] In some embodiments, the compound of interest includes a KxL motif binder. According to certain embodiments, the compound for treating fatty liver and viral infection includes an azaindazole. In some embodiments, the compound is a compound of formula I:

[0080]

[0081] in:

[0082] X is C or N;

[0083] Y is C or N;

[0084] Z1 is C or N;

[0085] Z2 is C or N;

[0086] R1 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted by substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl or 6 membered aryl groups; 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) groups; or R1 and R2 together form a 12-25 membered heterocyclic ring, or R1 and R5 together form a 12-25 membered heterocyclic ring;

[0087] L is a bond, —CONH—, —NH—CO—, a substituted or unsubstituted C1-C5 alkylene group, a substituted or unsubstituted C2-C5 heteroalkylene group, a substituted or unsubstituted 5-membered heteroaryl group, or a substituted or unsubstituted 5-7-membered heterocyclyl group, a C5-C7 cycloalkyl group, a 5-6-membered heteroaryl group, or a 6-membered aryl group; or a combination thereof;

[0088] 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;

[0089] R3, R4 and R5 are independently hydrogen, halogen, -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; and

[0090] 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 bound form a heterocycle.

[0091] In some embodiments, the compound is a compound of Formula Ia:

[0092]

[0093] in:

[0094] X is C or N;

[0095] Y is C or N;

[0096] Where L is -CO-NH-, -NH-CO-, -CO-NH-CH2- and -CH2-Y-(CH2) p—, wherein p is 0 or an integer from 1 to 4 and Y is a bond, —O— or —NH—, wherein the right side of each L portion 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.

[0097] In some embodiments, the compound is a compound of Formula Ib:

[0098]

[0099] in:

[0100] X is C or N;

[0101] Y is C or N;

[0102] R1 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted by substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl or 6 membered aryl groups; 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) groups;

[0103] L is a bond, —CONH—, —NH—CO—, substituted or unsubstituted C1-C5 alkylene, substituted or unsubstituted C2-C5 heteroalkylene, or a combination thereof;

[0104] R2 is a substituted or unsubstituted 5-7 membered heterocyclyl, C5-C7 cycloalkyl, 5-6 membered heteroaryl or 6 membered aryl group;

[0105] R5 is R 51 R 52 N—, R 53 (MeSO2)N—、R 54 O—or substituted or unsubstituted C1-C6 alkyl;

[0106] R 51 is hydrogen or C1-C3 alkyl;

[0107] R 52is C1-C3 alkyl, substituted or unsubstituted cycloalkyl, aryl, heterocyclyl or heteroaryl group, wherein each cycloalkyl, aryl, heterocyclyl or heteroaryl group contains 6 to 8 ring atoms, or R 51 and R 52 Together with the nitrogen atom to which they are bound they form a 6-, 7-, 8- or 9-membered heterocyclyl ring containing up to 3 heteroatoms which is substituted by a substituted or unsubstituted benzyl, acyl or sulfonyl group;

[0108] R 53 is a substituted or unsubstituted C1-C6 alkyl group; and

[0109] R 54 is hydrogen, a substituted or unsubstituted benzyl group, a branched C3-C8 alkyl group, an unsubstituted C5-C8 cycloalkyl group or a C5-C8 cycloalkyl group substituted by one or more linear or branched C1-C4 alkyl groups.

[0110] In some embodiments, the compound is a compound of Formula Ic or Id:

[0111]

[0112] in:

[0113] X is C or N;

[0114] Y is C or N;

[0115] R1, R 22 , R 23 , R 24 , R 51 and R 52 As defined in any aspect or embodiment above (or below).

[0116] In another embodiment, R1 is hydrogen, C1-C5 alkyl or —(CH2) k —R 11 ; k is 1 or 2; and R 11 In another embodiment, R1 is a C3-C8 cycloalkyl or a substituted or unsubstituted aryl or heteroaryl group. In another embodiment, R1 is a 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.

[0117] In another embodiment, L is -CONH-, and the carbon atom of -CO-NH- is bonded to the azaindazole ring.

[0118] 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 —, wherein 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, wherein L is —(CH2) n In another embodiment, R1 is 4-chlorobenzyl, wherein L is -CH2-O-(CH2) n —and n is 2 or 3.

[0119] 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:

[0120]

[0121] Where R 22 is a substituted or unsubstituted C2-C3 alkyl. 22 is a C2-C3 alkyl group. 22 In another embodiment, R 22 is —CH2CH2—NR 23 R 24 , and R 23 and R 24 is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23 and R 24 Together with the nitrogen atom to which they are bonded, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. Within this embodiment, in one embodiment, L is —CO—NH—, wherein the NH portion is bonded to the piperidinyl portion. In another embodiment, R2 is —NR 23 R 24 , and R 23and R 24 is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23 and R 24 Together with the nitrogen atom to which they are bound, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl or azepanyl ring. Within this embodiment, in one embodiment, L is —(CH2) n —、—O—(CH2) n —or—CH2—O—(CH2) n —, wherein the left side of L is bonded to the azaindazole moiety and n is 1, 2, 3 or 4.

[0122] In other embodiments, R2 may be a 4-piperidinyl group, which is:

[0123]

[0124] Where R 25 is H or a substituent which is a substituted or unsubstituted C1-C3 alkyl group substituting a carbon or nitrogen atom.

[0125] In some embodiments, the compound is a compound of Formula II:

[0126]

[0127] in:

[0128] X is C or N;

[0129] Y is C or N;

[0130] R1 is hydrogen, branched or linear 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 12-18 membered heterocyclic ring; n is 1 or 2;

[0131] R2 is a substituted or unsubstituted piperidinyl, 4-pyridinyl, pyrrolidinyl, piperazinyl, benzyl, substituted phenyl or pyrazolyl group; R5 is R 51 R 52 N—or R 54 O—;

[0132] R 51 is H or substituted or unsubstituted C1-C3 alkyl; R 52is a C6-C8 cycloalkyl group, a substituted or unsubstituted linear C1-C3 alkyl group or a branched C4-C5 alkyl group, or R 51 and R 52 Together with the nitrogen atom to which they are bound, they form a 6-, 7-, 8- or 9-membered heterocyclyl ring containing up to 3 heteroatoms, which heterocyclyl ring is optionally substituted with a substituted or unsubstituted benzyl acyl or sulfonyl group in addition to the azaindazole moiety already attached thereto; R 54 R is H, a substituted or unsubstituted benzyl group, a branched C3-C8 alkyl group, an unsubstituted C5-C8 cycloalkyl group or a C5-C8 cycloalkyl group substituted with one or more linear or branched C1-C4 alkyl groups; 11 is C5-C8 cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In various embodiments, the compound of formula II may have R1, R2 and R3 groups as defined below.

[0133] In another embodiment of Formula II, R1 is C1-C3 alkyl. In one embodiment, R1 is methyl. In one embodiment, R 11 In one embodiment, R 11 is a phenyl group substituted with halogen. 11 It is 2-chlorophenyl or 3-chlorophenyl.

[0134] 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:

[0135]

[0136] Where R 22 is a substituted or unsubstituted C2-C3 alkyl. 22 is a C2-C3 alkyl group. 22 In another embodiment, R 22 is —CH2CH2—NR 23 R 24 , and R 23 and R 24 is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23 and R 24Together with the nitrogen atom to which they are bonded, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. Within this embodiment, in one embodiment, L is —CO—NH—, wherein the NH portion is bonded to the piperidinyl portion. In another embodiment, R2 is —NR 23 R 24 , and R 23 and R 24 is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23 and R 24 Together with the nitrogen atom to which they are bound, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl or azepanyl ring. Within this embodiment, in one embodiment, L is —(CH2) n —、—O—(CH2) n —or—CH2—O—(CH2) n —, wherein the left side of L is bonded to the azaindazole moiety and n is 1, 2, 3 or 4.

[0137] In other embodiments, R2 may be a 4-piperidinyl group, which is:

[0138]

[0139] Where R 25 is H or a substituent which is a substituted or unsubstituted C1-C3 alkyl group substituting a carbon or nitrogen atom.

[0140] In some embodiments, the compound is a compound selected from the group consisting of:

[0141]

[0142]

[0143] In some embodiments, the compound is a compound of Formula IIa:

[0144]

[0145] in:

[0146] X is C or N;

[0147] Y is C or N;

[0148] R1 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted by substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl or 6 membered aryl groups; 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) groups; or R1 and R2 together form a 12-25 membered heterocyclic ring, or R1 and R5 together form a 12-25 membered heterocyclic ring;

[0149] 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.

[0150] In some embodiments, the compound is a compound of Formula IIb:

[0151]

[0152] in:

[0153] X is C or N;

[0154] Y is C or N;

[0155] R1 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted by substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl or 6 membered aryl groups; 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) groups; or R1 and R2 together form a 12-25 membered heterocyclic ring, or R1 and R5 together form a 12-25 membered heterocyclic ring;

[0156] Where R 22 is hydrogen, substituted or unsubstituted C2-C3 alkyl. In another embodiment, R 22 is a C2-C3 alkyl group. 22 In another embodiment, R 22 is —CH2CH2—NR23 R 24 , and R 23 and R 24 is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23 and R 24 Together with the nitrogen atom to which they are bonded, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. Within this embodiment, in one embodiment, L is —CO—NH—, wherein the NH portion is bonded to the piperidinyl portion. In another embodiment, R2 is —NR 23 R 24 , and R 23 and R 24 is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23 and R 24 Together with the nitrogen atom to which they are bound, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl or azepanyl ring. Within this embodiment, in one embodiment, L is —(CH2) n —、—O—(CH2) n —or—CH2—O—(CH2) n —, wherein the left side of L is bonded to the azaindazole moiety and n is 1, 2, 3 or 4.

[0157] In some embodiments, the compound is a compound of Formula IIc:

[0158]

[0159] in:

[0160] X is C or N;

[0161] Y is C or N;

[0162] X1, X2, X3, X4 and X5 are independently selected from CH or N;

[0163] Y2 is selected from O or NR';

[0164] R1 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted by substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl or 6 membered aryl groups; 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) groups

[0165] R2 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted by substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl or 6 membered aryl groups; 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) groups.

[0166] R3, R4 and R5 are independently hydrogen, hydrogen; C1-C6 alkyl; substituted C1-C6 alkyl, CF3, halogen, —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, or together with Y2 forms a substituted or unsubstituted C3-C8 cycloalkyl, a 5-8-membered substituted or unsubstituted heterocyclyl, a substituted or unsubstituted C3-C8 aryl, or a 5-8-membered substituted or unsubstituted heteroheteroaryl; and

[0167] 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 bound form a heterocycle.

[0168] In some embodiments, the compound is a compound selected from the group consisting of:

[0169] A27

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178] In some embodiments, the compound is a compound of Formula IId:

[0179]

[0180] in:

[0181] X is C or N;

[0182] Y is C or N;

[0183] X1 is C or N;

[0184] R1 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted by substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl or 6 membered aryl groups; 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) groups; or R1 and R2 together form a 12-25 membered heterocyclic ring, or R1 and R5 together form a 12-25 membered heterocyclic ring;

[0185] Where R 22 is hydrogen, substituted or unsubstituted C2-C3 alkyl. In another embodiment, R 22 is a C2-C3 alkyl group. 22 In another embodiment, R 22 is —CH2CH2—NR 23 R 24 , and R 23 and R 24 is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23 and R 24Together with the nitrogen atom to which they are bonded, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. Within this embodiment, in one embodiment, L is —CO—NH—, wherein the NH portion is bonded to the piperidinyl portion. In another embodiment, R2 is —NR 23 R 24 , and R 23 and R 24 is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23 and R 24 Together with the nitrogen atom to which they are bound, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl or azepanyl ring. Within this embodiment, in one embodiment, L is —(CH2) n —、—O—(CH2) n —or—CH2—O—(CH2) n —, wherein the left side of L is bonded to the azaindazole moiety and n is 1, 2, 3 or 4.

[0186] In some embodiments, the compound is a compound selected from the group consisting of:

[0187]

[0188]

[0189] In some embodiments, the compound is a compound of Formula IIe:

[0190]

[0191] in:

[0192] X is C or N;

[0193] Y is C or N;

[0194] R1 is hydrogen, branched or linear 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 12-18 membered heterocyclic ring; n is 1 or 2;

[0195] wherein L1 is a 5-membered heteroaryl group containing up to 3 heteroatoms selected from the group consisting of O, N and S; L2 is —CO—NH—, wherein the carbon atom is attached to L1; or is a 6-membered heteroaryl group containing up to 3 heteroatoms selected from the group consisting of O, N and S; or is a 5-membered cycloalkyl group containing up to 3 heteroatoms selected from the group consisting of O, N and S; L2 is —CO—NH—, wherein the carbon atom is attached to L1; or is a 6-membered cycloalkyl group containing up to 3 heteroatoms selected from the group consisting of O, N and S; L2 is —CO—NH—, wherein the carbon atom is attached to L1;

[0196] L2 is -CO-NH-, where the carbon atom is attached to L1

[0197] L3 is a substituted or unsubstituted C1-C3 alkylene group; p1 is 0 or 1; p2 is 0, 1 or 2; R2 is 3- or 4-piperidinyl;

[0198] R5 is—NR 51 R 52 OR 54 , where R 51 , R 52 and R 52 As defined in any 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:

[0199]

[0200] Where R 51 , R 52 and R 52 As defined in any 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.

[0201] In some embodiments, the compound is a compound of Formula IIf:

[0202]

[0203] X is C or N;

[0204] Y is C or N;

[0205] R1 is hydrogen, branched or linear 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 12-18 membered heterocyclic ring; n is 1 or 2;

[0206] Where R 51 , R 52 and R 52 As defined in any 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.

[0207] In some embodiments, the compound is a compound selected from the group consisting of:

[0208]

[0209]

[0210] In some embodiments, the compound is a compound of Formula IIg:

[0211]

[0212] in:

[0213] X is C or N;

[0214] Y is C or N;

[0215] X1 is selected from CH or N;

[0216] Y2 is selected from O or NR';

[0217] R1 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted by substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl or 6 membered aryl groups; 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) groups; or R1 and R2 together form a 12-25 membered heterocyclic ring, or R1 and R5 together form a 12-25 membered heterocyclic ring;

[0218] R2 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted by substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl or 6 membered aryl groups; 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) groups.

[0219] R3, R4 and R5 are independently hydrogen, hydrogen; C1-C6 alkyl; substituted C1-C6 alkyl, CF3, halogen, —OH, —OR′, —NH2, —NHR′, —NR′R′, —NHCOR′, —NR′COR′, —NHSO2R′, —NR′SO2R′, —NHSO2NH2, —NHSO2NHR′, —NHC(O)NH2, —NHC(O)NHR′, —N(R′)S O2NH2, —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; and

[0220] 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 bound form a heterocycle.

[0221] In some embodiments, the compound is a compound selected from the group consisting of:

[0222]

[0223]

[0224]

[0225] In some embodiments, the compound is of Formula IIh:

[0226]

[0227] in:

[0228] X is C or N;

[0229] Y is C or N;

[0230] X1 is selected from CH or N;

[0231] Y2 is selected from O or NR;

[0232] R1 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted by substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl or 6 membered aryl groups; 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) groups; or R1 and R2 together form a 12-25 membered heterocyclic ring, or R1 and R5 together form a 12-25 membered heterocyclic ring;

[0233] R2 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted by substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl or 6 membered aryl groups; 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) groups.

[0234] R3, R4 and R5 are independently hydrogen, hydrogen; C1-C6 alkyl; substituted C1-C6 alkyl, CF3, halogen, —OH, —OR′, —NH2, —NHR′, —NR′R′, —NHCOR′, —NR′COR′, —NHSO2R′, —NR′SO2R′, —NHSO2NH2, —NHSO2NHR′, —NHC(O)NH2, —NHC(O)NHR′, —N(R′)S O2NH2, —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; and

[0235] 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 bound form a heterocycle.

[0236] In some embodiments, the compound is a compound selected from the group consisting of:

[0237]

[0238]

[0239]

[0240] In some embodiments, the compound is a compound of formula III:

[0241]

[0242] in:

[0243] X is C or N;

[0244] Y is C or N;

[0245] Z1 is C or N;

[0246] Z2 is C or N;

[0247] R1 is hydrogen, branched or linear 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 12-18 membered heterocyclic ring; n is 1 or 2;

[0248] R2 is a substituted or unsubstituted phenyl, piperidinyl, 4-pyridinyl, pyrrolidinyl, piperazinyl, benzyl, substituted phenyl or pyrazolyl group; R5 is R 51 R 52 N—or R 54 O—;

[0249] R 51 is H or substituted or unsubstituted C1-C3 alkyl; R 52 is a C6-C8 cycloalkyl group, a substituted or unsubstituted linear C1-C3 alkyl group or a branched C4-C5 alkyl group, or R 51 and R 52 Together with the nitrogen atom to which they are bound, they form a 6-, 7-, 8- or 9-membered heterocyclyl ring containing up to 3 heteroatoms, which heterocyclyl ring is optionally substituted with a substituted or unsubstituted benzyl acyl or sulfonyl group in addition to the azaindazole moiety already attached thereto; R 54 R is H, a substituted or unsubstituted benzyl group, a branched C3-C8 alkyl group, an unsubstituted C5-C8 cycloalkyl group or a C5-C8 cycloalkyl group substituted with one or more linear or branched C1-C4 alkyl groups; 11 is C5-C8 cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0250] R3 and R5 are independently hydrogen, halogen, -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.

[0251] In some embodiments, the compound is a compound selected from the group consisting of:

[0252]

[0253] In some embodiments, the compound is a compound of Formula IV:

[0254]

[0255] in:

[0256] Each X is independently selected from C or N;

[0257] R 1 is absent, hydrogen, (C1-C8) alkyl, NR 9 R 10 , halogen, 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;

[0258] R 2 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;

[0259] R 3 is H, (C1-C8)alkyl, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C8)alkoxy, hydroxy, halogen, amino, amide, amino(C1-C8)alkylamide, heterocyclic, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano or (C1-C3)haloalkyl;

[0260] Each R 4 independently selected from unsubstituted or halogen-substituted (C1-C8)alkyl, (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; or two R 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;

[0261] 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, halogen, (C1-C4)haloalkyl and cyano;

[0262] 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, halogen, (C1-C4)haloalkyl and cyano;

[0263] 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, halogen, (C1-C4)haloalkyl and cyano;

[0264] R 9 is H, (C1-C8) alkyl, wherein the (C1-C8) alkyl is unsubstituted or substituted by one or more halogens;

[0265] R 10 is H, (C1-C8) alkyl, said (C1-C8) alkyl being unsubstituted or substituted by one or more halogens, or R 9 and R 10 Together with the nitrogen atom to which they are attached, they form a 4- or 5-membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with one or more halogens; R is H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-6-membered heterocyclic ring or 5-6-membered heteroaryl;

[0266] R 11 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0267] R 12 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0268] R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-8 membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with OH, halogen, =0 or (C1-C8)alkyl;

[0269] R 13 is OH, O-(C1-C4)alkyl;

[0270] R 15is H, (C1-C6)alkyl, (C1-C)haloalkyl, 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl, and wherein each of the 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl is unsubstituted or substituted at a substitutable position by one or more =O, OH, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, amino or (C1-C8)aminoalkyl; and

[0271] R 16 is H, (C1-C8) alkyl or (C1-C8) haloalkyl.

[0272] In some embodiments, the compound is a compound of Formula IVa:

[0273]

[0274] in:

[0275] X1 is independently selected from C or N;

[0276] X2 is independently selected from C or N;

[0277] X3 is independently selected from C or N;

[0278] X4 is independently selected from C or N;

[0279] X5 is independently selected from C or N;

[0280] R 1 is absent, hydrogen, (C1-C8) alkyl, NR 9 R 10 , halogen, 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;

[0281] R 2 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;

[0282] R 3 is H, (C1-C8)alkyl, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C8)alkoxy, hydroxy, halogen, amino, amide, amino(C1-C8)alkylamide, heterocyclic, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano or (C1-C3)haloalkyl;

[0283] R 4a is selected from H, unsubstituted or halogen-substituted (C1-C8)alkyl, (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;

[0284] R 4b is selected from H, unsubstituted or halogen-substituted (C1-C8)alkyl, (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;

[0285] 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;

[0286] 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, halogen, (C1-C4)haloalkyl and cyano;

[0287] 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, halogen, (C1-C4)haloalkyl and cyano;

[0288] 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, halogen, (C1-C4)haloalkyl and cyano;

[0289] R 9 is H, (C1-C8) alkyl, wherein the (C1-C8) alkyl is unsubstituted or substituted by one or more halogens;

[0290] R 10 is H, (C1-C8) alkyl, said (C1-C8) alkyl being unsubstituted or substituted by one or more halogens, or R 9 and R 10 Together with the nitrogen atom to which they are attached, they form a 4- or 5-membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with one or more halogens; R is H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-6-membered heterocyclic ring or 5-6-membered heteroaryl;

[0291] R 11 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0292] R 12 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0293] R 11 and R 12Together with the nitrogen atom to which they are attached, they form a 5-8 membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with OH, halogen, =0 or (C1-C8)alkyl;

[0294] R 13 is OH, O-(C1-C4)alkyl;

[0295] R 15 is H, (C1-C6)alkyl, (C1-C)haloalkyl, 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl, and wherein each of the 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl is unsubstituted or substituted at a substitutable position by one or more =O, OH, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, amino or (C1-C8)aminoalkyl; and

[0296] R 16 is H, (C1-C8) alkyl or (C1-C8) haloalkyl.

[0297] 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.

[0298] 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.

[0299] In some embodiments, R1 is selected from hydrogen, (C1-C8) alkyl, halogen or haloalkyl. In some cases, R1 is hydrogen. In some cases, R1 is (C1-C8) alkyl, such as methyl, ethyl, propyl, i-propyl, butyl, t-butyl, i-butyl or pentyl. In some cases, R1 is methyl. In some cases, R1 is t-butyl. In some cases, R1 is halogen, such as fluorine, chlorine or bromine. In some cases, R1 is fluorine. In some cases, R1 is haloalkyl, such as CF3, CCl3 or CBr3. In some cases, R1 is CF3.

[0300] In some embodiments, R 2C(O)NR 11 R 12 , where R 11 is selected from H, (C1-C4) alkyl, (C1-C4) 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; and R 12 is selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, 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.

[0301] In some embodiments, R 2 is a 5-membered heteroaryl. 2 for:

[0302]

[0303] in

[0304] Y1 is O, NH, CH2 or S;

[0305] Y2 is CH or N; and

[0306] Y3 is CH or N.

[0307] In some embodiments, R 11 H and R 12 is selected from 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. In some cases, R 11 H and R 12 is a 6-membered heterocyclic ring. 11 H and R 12 is a substituted 6-membered heterocyclic ring.

[0308] In some cases, R 11 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:

[0309]

[0310] Where R 22 is a substituted or unsubstituted C2-C3 alkyl. 22 is a C2-C3 alkyl group. 22 In another embodiment, R 22 is —CH2CH2—NR 23 R 24 , and R 23 and R 24 is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23 and R 24 Together with the nitrogen atom to which they are bonded, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. Within this embodiment, in one embodiment, L is —CO—NH—, wherein the NH portion is bonded to the piperidinyl portion. In another embodiment, R2 is —NR 23 R 24 , and R 23 and R 24 is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23 and R 24 Together with the nitrogen atom to which they are bound, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl or azepanyl ring. Within this embodiment, in one embodiment, L is —(CH2) n —、—O—(CH2) n —or—CH2—O—(CH2) n —, wherein the left side of L is bonded to the azaindazole moiety and n is 1, 2, 3 or 4.

[0311] In some cases, R 11 H and R 12 for:

[0312]

[0313] wherein X6 is N or C; and

[0314] R22 is a substituted or unsubstituted C2-C3 alkyl. 22 is a C2-C3 alkyl group. 22 In another embodiment, R 22 is —CH2CH2—NR 23 R 24 , and R 23 and R 24 is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23 and R 24 Together with the nitrogen atom to which they are bound, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl or azepanyl ring.

[0315] Within this embodiment, in one embodiment, L is -CO-NH-, wherein the NH portion is bonded to the piperidinyl portion. In another embodiment, R2 is -NR 23 R 24 , and R 23 and R 24 is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23 and R 24 Together with the nitrogen atom to which they are bound, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl or azepanyl ring. Within this embodiment, in one embodiment, L is —(CH2) n —、—O—(CH2) n —or—CH2—O—(CH2) n —, wherein the left side of L is bonded to the azaindazole moiety and n is 1, 2, 3 or 4.

[0316] In some embodiments, R 4a is H, unsubstituted or halogen-substituted (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy or (C1-C8)cycloalkyl. 4b is H, unsubstituted or halogen-substituted (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, S(O)-R 6 、S(O)2、S(O)2-R6 、S(O)2、C(O)R 6 、C(O)OR 7 or (C1-C8) cycloalkyl. In some embodiments, R 4a is (C1-C8) alkyl. 4a is a (C1-C8)alkyl group substituted with halogen. 4a It is an ethyl group substituted by a halogen.

[0317] In some embodiments, R 4a and R 4b Together they 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 cases, R 4a and R 4b Together with the nitrogen to which they are bound, they form a (C1-C8) heterocycloalkyl. 4a and R 4b Together with nitrogen it forms a 7-membered heterocycloalkyl.

[0318] In some embodiments, the compound is a compound of Formula IVb:

[0319]

[0320] in:

[0321] X1 is independently selected from C or N;

[0322] X2 is independently selected from C or N;

[0323] X3 is independently selected from C or N;

[0324] X4 is independently selected from C or N;

[0325] X5 is independently selected from C or N;

[0326] X6 is independently selected from C or N;

[0327] R 1 is absent, hydrogen, (C1-C8) alkyl, NR 9 R 10, halogen, 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;

[0328] R 2 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;

[0329] R 3 is H, (C1-C8)alkyl, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C8)alkoxy, hydroxy, halogen, amino, amide, amino(C1-C8)alkylamide, heterocyclic, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano or (C1-C3)haloalkyl;

[0330] R 4a is selected from H, unsubstituted or halogen-substituted (C1-C8)alkyl, (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;

[0331] R 4b is selected from H, unsubstituted or halogen-substituted (C1-C8)alkyl, (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;

[0332] 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;

[0333] 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, halogen, (C1-C4)haloalkyl and cyano;

[0334] 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, halogen, (C1-C4)haloalkyl and cyano;

[0335] 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, halogen, (C1-C4)haloalkyl and cyano;

[0336] R 9 is H, (C1-C8) alkyl, wherein the (C1-C8) alkyl is unsubstituted or substituted by one or more halogens;

[0337] R 10 is H, (C1-C8) alkyl, said (C1-C8) alkyl being unsubstituted or substituted by one or more halogens, or R 9 and R 10 Together with the nitrogen atom to which they are attached, they form a 4- or 5-membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with one or more halogens; R is H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-6-membered heterocyclic ring or 5-6-membered heteroaryl;

[0338] R 11is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0339] R 12 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0340] R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-8 membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with OH, halogen, =0 or (C1-C8)alkyl;

[0341] R 13 is OH, O-(C1-C4)alkyl;

[0342] R 15 is H, (C1-C6)alkyl, (C1-C)haloalkyl, 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl, and wherein each of the 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl is unsubstituted or substituted at a substitutable position by one or more =O, OH, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, amino or (C1-C8)aminoalkyl; and

[0343] R 16 is H, (C1-C8)alkyl or (C1-C8)haloalkyl; and

[0344] R 22 is a substituted or unsubstituted C2-C3 alkyl. 22 is a C2-C3 alkyl group. 22 In another embodiment, R 22 is —CH2CH2—NR 23 R 24 , and R 23 and R 24 is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23 and R 24Together with the nitrogen atom to which they are bonded, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. Within this embodiment, in one embodiment, L is —CO—NH—, wherein the NH portion is bonded to the piperidinyl portion. In another embodiment, R2 is —NR 23 R 24 , and R 23 and R 24 is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23 and R 24 Together with the nitrogen atom to which they are bound, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl or azepanyl ring. Within this embodiment, in one embodiment, L is —(CH2) n —、—O—(CH2) n —or—CH2—O—(CH2) n —, wherein the left side of L is bonded to the azaindazole moiety and n is 1, 2, 3 or 4.

[0345] In some embodiments, the compound is a compound selected from the group consisting of:

[0346]

[0347]

[0348]

[0349]

[0350]

[0351] In some embodiments, the compound is a compound of Formula IVc:

[0352]

[0353] in:

[0354] X1 is independently selected from C or N;

[0355] X2 is independently selected from C or N;

[0356] X3 is independently selected from C or N;

[0357] X4 is independently selected from C or N;

[0358] X5 is independently selected from C or N;

[0359] R 1 is absent, hydrogen, (C1-C8) alkyl, NR 9 R 10 , halogen, 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;

[0360] R 2 is hydrogen, (C1-C8) alkyl, NR 9 R 10 , halogen, 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;

[0361] R 3 is H, (C1-C8)alkyl, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C8)alkoxy, hydroxy, halogen, amino, amide, amino(C1-C8)alkylamide, heterocyclic, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano or (C1-C3)haloalkyl;

[0362] R 4a is selected from H, unsubstituted or halogen-substituted (C1-C8)alkyl, (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 7or (C1-C8)cycloalkyl;

[0363] R 4b is selected from H, unsubstituted or halogen-substituted (C1-C8)alkyl, (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;

[0364] 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;

[0365] 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, halogen, (C1-C4)haloalkyl and cyano;

[0366] 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, halogen, (C1-C4)haloalkyl and cyano;

[0367] 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, halogen, (C1-C4)haloalkyl and cyano;

[0368] R 9 is H, (C1-C8) alkyl, wherein the (C1-C8) alkyl is unsubstituted or substituted by one or more halogens;

[0369] R 10is H, (C1-C8) alkyl, said (C1-C8) alkyl being unsubstituted or substituted by one or more halogens, or R 9 and R 10 Together with the nitrogen atom to which they are attached, they form a 4- or 5-membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with one or more halogens; R is H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-6-membered heterocyclic ring or 5-6-membered heteroaryl;

[0370] R 11 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0371] R 12 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0372] R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-8 membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted by OH, halogen, =0 or (C1-C8)alkyl;

[0373] R 13 is OH, O-(C1-C4)alkyl;

[0374] R 15 is H, (C1-C6)alkyl, (C1-C)haloalkyl, 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl, and wherein each of the 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl is unsubstituted or substituted at a substitutable position by one or more =O, OH, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, amino or (C1-C8)aminoalkyl; and

[0375] R 16 is H, (C1-C8) alkyl or (C1-C8) haloalkyl.

[0376] In some embodiments, the compound is a compound selected from the group consisting of:

[0377]

[0378] In certain embodiments, the compound is:

[0379]

[0380] In some embodiments, the compound is of Formula V:

[0381]

[0382] in:

[0383] Each X is independently selected from C or N;

[0384] R 1 is absent, hydrogen, (C1-C8) alkyl, NR 9 R 10 , halogen, 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;

[0385] R 2 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;

[0386] R 3 is H, (C1-C8)alkyl, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C8)alkoxy, hydroxy, halogen, amino, amide, amino(C1-C8)alkylamide, heterocyclic, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano or (C1-C3)haloalkyl;

[0387] Each R 4 independently selected from unsubstituted or halogen-substituted (C1-C8)alkyl, (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; or two R 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;

[0388] 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, halogen, (C1-C4)haloalkyl and cyano;

[0389] 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, halogen, (C1-C4)haloalkyl and cyano;

[0390] 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, halogen, (C1-C4)haloalkyl and cyano;

[0391] R 9 is H, (C1-C8) alkyl, wherein the (C1-C8) alkyl is unsubstituted or substituted by one or more halogens;

[0392] R 10 is H, (C1-C8) alkyl, said (C1-C8) alkyl being unsubstituted or substituted by one or more halogens, or R 9 and R 10 Together with the nitrogen atom to which they are attached, they form a 4- or 5-membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with one or more halogens; R is H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-6-membered heterocyclic ring or 5-6-membered heteroaryl;

[0393] R11 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0394] R 12 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0395] R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-8 membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted by OH, halogen, =0 or (C1-C8)alkyl;

[0396] R 13 is OH, O-(C1-C4)alkyl;

[0397] R 15 is H, (C1-C6)alkyl, (C1-C)haloalkyl, 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl, and wherein each of the 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl is unsubstituted or substituted at a substitutable position by one or more =O, OH, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, amino or (C1-C8)aminoalkyl; and

[0398] R 16 is H, (C1-C8) alkyl or (C1-C8) haloalkyl.

[0399] In some embodiments, the compound is of Formula Va:

[0400]

[0401] in:

[0402] X1 is independently selected from C or N;

[0403] X2 is independently selected from C or N;

[0404] X3 is independently selected from C or N;

[0405] X4 is independently selected from C or N;

[0406] X5 is independently selected from C or N;

[0407] R 1 is absent, hydrogen, (C1-C8) alkyl, NR 9 R 10 , halogen, 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;

[0408] R 2 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;

[0409] R 3 is H, (C1-C8)alkyl, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C8)alkoxy, hydroxy, halogen, amino, amide, amino(C1-C8)alkylamide, heterocyclic, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano or (C1-C3)haloalkyl;

[0410] R 4a is selected from H, unsubstituted or halogen-substituted (C1-C8)alkyl, (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;

[0411] R 4b is selected from H, unsubstituted or halogen-substituted (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, S(O)-R 6 、S(O)2、S(O)2-R6 、S(O)2、C(O)R 6 、C(O)OR 7 or (C1-C8)cycloalkyl;

[0412] 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;

[0413] 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, halogen, (C1-C4)haloalkyl and cyano;

[0414] 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, halogen, (C1-C4)haloalkyl and cyano;

[0415] 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, halogen, (C1-C4)haloalkyl and cyano;

[0416] R 9 is H, (C1-C8) alkyl, wherein the (C1-C8) alkyl is unsubstituted or substituted by one or more halogens;

[0417] R 10 is H, (C1-C8) alkyl, said (C1-C8) alkyl being unsubstituted or substituted by one or more halogens, or R 9 and R 10 Together with the nitrogen atom to which they are attached, they form a 4- or 5-membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with one or more halogens; R is H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-6-membered heterocyclic ring or 5-6-membered heteroaryl;

[0418] R 11 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0419] R 12 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0420] R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-8 membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted by OH, halogen, =0 or (C1-C8)alkyl;

[0421] R 13 is OH, O-(C1-C4)alkyl;

[0422] R 15 is H, (C1-C6)alkyl, (C1-C)haloalkyl, 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl, and wherein each of the 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl is unsubstituted or substituted at a substitutable position by one or more =O, OH, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, amino or (C1-C8)aminoalkyl; and

[0423] R 16 is H, (C1-C8) alkyl or (C1-C8) haloalkyl.

[0424] 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.

[0425] 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.

[0426] In some embodiments, R1 is selected from hydrogen, (C1-C8) alkyl, halogen or haloalkyl. In some cases, R1 is hydrogen. In some cases, R1 is (C1-C8) alkyl, such as methyl, ethyl, propyl, i-propyl, butyl, t-butyl, i-butyl or pentyl. In some cases, R1 is methyl. In some cases, R1 is t-butyl. In some cases, R1 is halogen, such as fluorine, chlorine or bromine. In some cases, R1 is fluorine. In some cases, R1 is haloalkyl, such as CF3, CCl3 or CBr3. In some cases, R1 is CF3.

[0427] In some embodiments, R 2 C(O)NR 11 R 12 , where R 11 is selected from H, (C1-C4) alkyl, (C1-C4) 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; and R 12 is selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, 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.

[0428] In some embodiments, R 2 is a 5-membered heteroaryl. 2 for:

[0429]

[0430] in

[0431] Y1 is O, NH, CH2 or S;

[0432] Y2 is CH or N; and

[0433] Y3 is CH or N.

[0434] In some embodiments, R 11 H and R 12 is selected from 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. In some cases, R 11 H and R 12 is a 6-membered heterocyclic ring. 11 H and R 12 is a substituted 6-membered heterocyclic ring.

[0435] In some cases, R 11 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:

[0436]

[0437] Where R 22 is a substituted or unsubstituted C2-C3 alkyl. 22 is a C2-C3 alkyl group. 22 In another embodiment, R 22 is —CH2CH2—NR 23 R 24 , and R 23 and R 24 is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23 and R 24 Together with the nitrogen atom to which they are bonded, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. Within this embodiment, in one embodiment, L is —CO—NH—, wherein the NH portion is bonded to the piperidinyl portion. In another embodiment, R2 is —NR 23 R 24 , and R 23 and R 24is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23 and R 24 Together with the nitrogen atom to which they are bound, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl or azepanyl ring. Within this embodiment, in one embodiment, L is —(CH2) n —、—O—(CH2) n —or—CH2—O—(CH2) n —, wherein the left side of L is bonded to the azaindazole moiety and n is 1, 2, 3 or 4.

[0438] In some cases, R 11 H and R 12 for:

[0439]

[0440] wherein X6 is N or C; and

[0441] R 22 is a substituted or unsubstituted C2-C3 alkyl. 22 is a C2-C3 alkyl group. 22 In another embodiment, R 22 is —CH2CH2—NR 23 R 24 , and R 23 and R 24 is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23 and R 24 Together with the nitrogen atom to which they are bound, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl or azepanyl ring.

[0442] Within this embodiment, in one embodiment, L is -CO-NH-, wherein the NH portion is bonded to the piperidinyl portion. In another embodiment, R2 is -NR 23 R 24 , and R 23 and R 24 is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23and R 24 Together with the nitrogen atom to which they are bound, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl or azepanyl ring. Within this embodiment, in one embodiment, L is —(CH2) n —、—O—(CH2) n —or—CH2—O—(CH2) n —, wherein the left side of L is bonded to the azaindazole moiety and n is 1, 2, 3 or 4.

[0443] In some embodiments, R 4a is H, unsubstituted or halogen-substituted (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy or (C1-C8)cycloalkyl. 4b is H, unsubstituted or halogen-substituted (C1-C8)alkyl, (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. In some embodiments, R 4a is (C1-C8) alkyl. 4a is a (C1-C8)alkyl group substituted with halogen. 4a It is an ethyl group substituted by a halogen.

[0444] In some embodiments, R 4a and R 4b Together they 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 cases, R 4a and R 4b Together with the nitrogen to which they are bound, they form a (C1-C8) heterocycloalkyl. 4a and R 4b Together with nitrogen it forms a 7-membered heterocycloalkyl.

[0445] In some embodiments, the compound is of Formula Vb:

[0446]

[0447] in:

[0448] X1 is independently selected from C or N;

[0449] X2 is independently selected from C or N;

[0450] X3 is independently selected from C or N;

[0451] X4 is independently selected from C or N;

[0452] X5 is independently selected from C or N;

[0453] X6 is independently selected from C or N;

[0454] R 1 is absent, hydrogen, (C1-C8) alkyl, NR 9 R 10 , halogen, 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;

[0455] R 2 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;

[0456] R 3 is H, (C1-C8)alkyl, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C8)alkoxy, hydroxy, halogen, amino, amide, amino(C1-C8)alkylamide, heterocyclic, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano or (C1-C3)haloalkyl;

[0457] R 4a is selected from H, unsubstituted or halogen-substituted (C1-C8)alkyl, (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;

[0458] R 4b is selected from H, unsubstituted or halogen-substituted (C1-C8)alkyl, (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;

[0459] 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;

[0460] 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, halogen, (C1-C4)haloalkyl and cyano;

[0461] 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, halogen, (C1-C4)haloalkyl and cyano;

[0462] 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, halogen, (C1-C4)haloalkyl and cyano;

[0463] R 9 is H, (C1-C8) alkyl, wherein the (C1-C8) alkyl is unsubstituted or substituted by one or more halogens;

[0464] R 10 is H, (C1-C8) alkyl, said (C1-C8) alkyl being unsubstituted or substituted by one or more halogens, or R 9 and R 10 Together with the nitrogen atom to which they are attached, they form a 4- or 5-membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with one or more halogens; R is H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-6-membered heterocyclic ring or 5-6-membered heteroaryl;

[0465] R 11 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0466] R 12 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0467] R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-8 membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted by OH, halogen, =0 or (C1-C8)alkyl;

[0468] R 13 is OH, O-(C1-C4)alkyl;

[0469] R 15 is H, (C1-C6)alkyl, (C1-C)haloalkyl, 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl, and wherein each of the 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl is unsubstituted or substituted at a substitutable position by one or more =O, OH, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, amino or (C1-C8)aminoalkyl; and

[0470] R 16 is H, (C1-C8)alkyl or (C1-C8)haloalkyl; and

[0471] R 22is a substituted or unsubstituted C2-C3 alkyl. 22 is a C2-C3 alkyl group. 22 In another embodiment, R 22 is —CH2CH2—NR 23 R 24 , and R 23 and R 24 is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23 and R 24 Together with the nitrogen atom to which they are bonded, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl, or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl, or azepanyl ring. Within this embodiment, in one embodiment, L is —CO—NH—, wherein the NH portion is bonded to the piperidinyl portion. In another embodiment, R2 is —NR 23 R 24 , and R 23 and R 24 is independently C1-C3 alkyl or C1-C3 alkyl substituted by a C3-C4 cycloalkyl ring, or R 23 and R 24 Together with the nitrogen atom to which they are bound, they form a substituted or unsubstituted 5-8 membered heterocyclic ring. Suitable substituents for the 5-8 membered heterocyclic ring include, but are not limited to, 1 or 2 methyl, hydroxymethyl, methoxymethyl or hydroxyl groups. In another embodiment, the 5-8 membered heterocyclic ring is a substituted or unsubstituted pyrrolidinyl, piperidinyl or azepanyl ring. Within this embodiment, in one embodiment, L is —(CH2) n —、—O—(CH2) n —or—CH2—O—(CH2) n —, wherein the left side of L is bonded to the azaindazole moiety and n is 1, 2, 3 or 4.

[0472] In some embodiments, the compound is a compound selected from the group consisting of:

[0473]

[0474]

[0475] In some embodiments, the compound is a compound of formula Vc:

[0476]

[0477] in:

[0478] X1 is independently selected from C or N;

[0479] X2 is independently selected from C or N;

[0480] X3 is independently selected from C or N;

[0481] X4 is independently selected from C or N;

[0482] X5 is independently selected from C or N;

[0483] R 1 is absent, hydrogen, (C1-C8) alkyl, NR 9 R 10 , halogen, 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;

[0484] R 2 is hydrogen, (C1-C8) alkyl, NR 9 R 10 , halogen, 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;

[0485] R 3 is H, (C1-C8)alkyl, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C8)alkoxy, hydroxy, halogen, amino, amide, amino(C1-C8)alkylamide, heterocyclic, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano or (C1-C3)haloalkyl;

[0486] R 4ais selected from H, unsubstituted or halogen-substituted (C1-C8)alkyl, (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;

[0487] R 4b is selected from H, unsubstituted or halogen-substituted (C1-C8)alkyl, (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;

[0488] 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;

[0489] 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, halogen, (C1-C4)haloalkyl and cyano;

[0490] 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, halogen, (C1-C4)haloalkyl and cyano;

[0491] 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, halogen, (C1-C4)haloalkyl and cyano;

[0492] R 9 is H, (C1-C8) alkyl, wherein the (C1-C8) alkyl is unsubstituted or substituted by one or more halogens;

[0493] R 10 is H, (C1-C8) alkyl, said (C1-C8) alkyl being unsubstituted or substituted by one or more halogens, or R 9 and R 10 Together with the nitrogen atom to which they are attached, they form a 4- or 5-membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with one or more halogens; R is H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-6-membered heterocyclic ring or 5-6-membered heteroaryl;

[0494] R 11 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0495] R 12 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0496] R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-8 membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted by OH, halogen, =0 or (C1-C8)alkyl;

[0497] R 13 is OH, O-(C1-C4)alkyl;

[0498] R 15 is H, (C1-C6)alkyl, (C1-C)haloalkyl, 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl, and wherein each of the 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl is unsubstituted or substituted at a substitutable position by one or more =O, OH, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, amino or (C1-C8)aminoalkyl; and

[0499] R16 is H, (C1-C8) alkyl or (C1-C8) haloalkyl.

[0500] In some embodiments, the compound is a compound of Formula VI:

[0501]

[0502] in:

[0503] R1 is hydrogen; halogen, haloalkyl, C1-C6 alkyl; C1-C6 alkyl substituted by substituted or unsubstituted C3-C8 cycloalkyl, 5-8-membered heterocyclyl or 6-membered aryl groups; 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) groups;

[0504] R 2 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;

[0505] R 3 is H, (C1-C8)alkyl, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C8)alkoxy, hydroxy, halogen, amino, amide, amino(C1-C8)alkylamide, heterocyclic, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano or (C1-C3)haloalkyl;

[0506] R 11 alkyl substituted by one or more of H, (C1-C4) alkyl, (C1-C4) haloalkyl, 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, or 5-membered heterocycle, 5-membered heterocycle, 5-membered heteroaryl, 5-membered heteroaryl, 6-membered heterocycle, 6-membered heterocycle, 6-membered heteroaryl, 6-membered heteroaryl, 5-membered cycloalkyl or 5-membered substituted cycloalkyl, 6-membered cycloalkyl or 6-membered substituted cycloalkyl

[0507] R12 alkyl substituted by one or more of H, (C1-C4) alkyl, (C1-C4) haloalkyl, 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, or 5-membered heterocycle, 5-membered heterocycle, 5-membered heteroaryl, 5-membered heteroaryl, 6-membered heterocycle, 6-membered heterocycle, 6-membered heteroaryl, 6-membered heteroaryl, 5-membered cycloalkyl or 5-membered substituted cycloalkyl, 6-membered cycloalkyl or 6-membered substituted cycloalkyl

[0508] R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-8 membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with OH, halogen, =0 or (C1-C8)alkyl; and

[0509] R4 is hydrogen; halogen, haloalkyl, C1-C6 alkyl; substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl, C1-C6 alkyl substituted by 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.

[0510] In some embodiments, R3 is selected from hydrogen, (C1-C8) alkyl, halogen or haloalkyl. In some cases, R3 is hydrogen. In some cases, R3 is (C1-C8) alkyl, such as methyl, ethyl, propyl, i-propyl, butyl, t-butyl, i-butyl or pentyl. In some cases, R3 is methyl. In some cases, R3 is t-butyl. In some cases, R3 is halogen, such as fluorine, chlorine or bromine. In some cases, R3 is fluorine. In some cases, R3 is haloalkyl, such as CF3, CCl3 or CBr3. In some cases, R3 is CF3.

[0511] In some embodiments, R4 is a 5-membered heteroaryl. 2 for:

[0512]

[0513] in

[0514] Y1 is O, NH, CH2 or S;

[0515] Y2 is CH or N; and

[0516] Y3 is CH or N.

[0517] In some cases, R4 is furan. In some cases, R4 is pyrrole. In some cases, R4 is thiophene. In some cases, R4 is imidazole. In some cases, R4 is pyrazole. In some cases, R4 is oxazole. In some cases, R4 is isoxazole.

[0518] In some cases, the compound is:

[0519]

[0520] In some cases, the compound is:

[0521]

[0522] In some embodiments, compounds of interest include those shown below, but these compounds are not considered limiting.

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542] In some embodiments, the subject agent is a compound disclosed herein or a pharmaceutically acceptable salt thereof. As an example, in some cases, the subject agent is a compound selected from the group consisting of:

[0543]

[0544]

[0545] (See, e.g., Figure 8 7-10, 21-24, 30, 38-39, 55-56, and 184).

[0546] In some cases, the subject agent is a compound selected from the group consisting of:

[0547]

[0548] (See, e.g., Figure 8 23, 30, 39, and 55-56 of the ).

[0549] 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. As an example, in some cases, the subject composition comprises: (a) a pharmaceutically acceptable carrier, excipient, or diluent; and (b) a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of:

[0550]

[0551] (See, e.g., Figure 8 7-10, 21-24, 30, 38-39, 55-56, and 184).

[0552] In some such cases, the composition is a medicament for treating fatty liver and / or a viral infection, such as a non-Flaviveviridae viral infection (e.g., a Hepadnaviridae viral infection such as HBV, an Alphavirus infection such as ONNV, SFV, VEEV, or CHIKV, a Coronaviridae infection such as SARS-CoV-2, a Paramyxoviridae infection such as RSV, an Orthomyxoviridae infection such as influenza, etc.).

[0553] In those embodiments where an active agent is administered to a subject, any convenient administration regimen that can produce the desired activity can be used to administer the active agent to the subject. Therefore, the medicament can be incorporated into a variety of preparations, for example, a pharmaceutically acceptable vehicle, for therapeutic administration. More particularly, the medicament of the present invention can be formulated into a pharmaceutical composition by combining with a suitable pharmaceutically acceptable carrier or diluent, and can be formulated into a preparation in solid, semisolid, liquid or gaseous form, such as tablets, capsules, powders, granules, ointments (e.g., skin creams), solutions, suppositories, injections, inhalants, and aerosols. Therefore, the administration of the medicament can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intratracheal, etc. administration.

[0554] 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 appropriate association and combination with other pharmaceutically active compounds. The following methods and excipients are merely exemplary and non-limiting.

[0555] For oral formulations, the medicament can be used alone or in combination with suitable additives to make tablets, powders, granules or capsules, for example, in combination with conventional additives such as lactose, mannitol, corn starch or potato starch; binders such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch or gelatin; disintegrants such as corn starch, potato starch or sodium carboxymethyl cellulose; lubricants such as talc or magnesium stearate; and, if necessary, in combination with diluents, buffers, wetting agents, preservatives and flavoring agents.

[0556] The medicaments can be formulated into injection preparations by dissolving, suspending or emulsifying them in an aqueous or non-aqueous solvent (such as vegetable oil or other similar oils, synthetic fatty acid glycerides, higher fatty acid esters or propylene glycol); and if necessary, adding conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.

[0557] The medicament can be used in an aerosol formulation for administration by inhalation. The compounds of the present invention can be formulated into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen and the like.

[0558] In addition, the medicament can be mixed with a variety of bases (such as emulsified bases or water-soluble bases) to form a suppository. The compound of the present invention can be administered rectally via a suppository. The suppository may include a carrier (such as cocoa butter, carbowax, and polyethylene glycol) that melts at body temperature but solidifies at room temperature.

[0559] Unit dosage forms for oral or rectal administration, such as syrups, elixirs, and suspensions, may be provided, wherein each dosage unit (e.g., teaspoon, tablespoon, tablet, or suppository) contains a predetermined amount of a composition containing one or more inhibitors. Similarly, unit dosage forms for injection or intravenous administration may contain the inhibitor in a composition as a solution in sterile water, physiological saline, or another pharmaceutically acceptable carrier.

[0560] As used herein, the term "unit dosage form" refers to physically discrete units suitable as unit doses for human and animal subjects, each unit containing a predetermined amount of the compound of the present invention, calculated in an amount sufficient to produce the desired effect in combination with a pharmaceutically acceptable diluent, carrier or carrier. The specifications of the novel unit dosage form of the present invention depend on the specific compound employed and the effect to be achieved, as well as the pharmacodynamics associated with each compound in the host.

[0561] Pharmaceutically acceptable excipients such as carriers, adjuvants, vehicles or diluents are readily available. In addition, pharmaceutically acceptable auxiliary substances such as pH adjusters and buffers, tonicity adjusters, stabilizers, wetting agents, etc. are readily available.

[0562] When the agent is a polypeptide, a polynucleotide, an analog thereof or a mimetic, it can be introduced into a tissue or a host cell by any number of approaches, including viral infection, microinjection or vesicle fusion. As described in Furth et al., Anal Biochem. (1992) 205:365-368, jet injection can also be used for intramuscular administration. DNA can be coated on gold particles and delivered intradermally by a particle bombardment device or a "gene gun" described in the literature (see, for example, Tang et al., Nature (Nature) (1992) 356:152-154), wherein gold microbullets are coated with DNA and then bombard skin cells. For nucleic acid therapeutic agents, a variety of different delivery vectors can be used, including viral and non-viral vector systems known in the art.

[0563] Those skilled in the art will readily appreciate that dosage levels may vary depending on the function of the particular compound, the nature of the delivery vehicle, etc. The preferred dosage for a given compound is readily determined by those skilled in the art in a variety of ways.

[0564] "Effective amount" or "effective dose" refers to an amount capable of having a desired effect, such as improving or delaying the progression of a diseased, degenerative or damaged condition, reducing fatty degeneration, reducing viruses, etc. in an individual. The effective amount can be determined on an individual basis and will be based in part on considerations of the symptoms to be treated and the results sought. A "therapeutically effective dose" or "therapeutic dose" or "therapeutically effective amount" or "therapeutic amount" is an amount sufficient to achieve the desired clinical result (i.e., to achieve therapeutic efficacy). A therapeutically effective dose can be administered in one or more administrations. An effective amount (e.g., a therapeutically effective amount) can be determined by one of ordinary skill in the art employing such factors and using no more than routine experimentation.

[0565] In some embodiments, treatment (reducing the virus in an individual) results in undetectable levels of viral antigens (e.g., HBsAg for HBV) in the blood of infected individuals. In some embodiments, the level of circulating viral antigens (e.g., HBsAg for HBV (or viral nucleic acid)) is reduced by at least 1 log relative to the baseline pre-treatment level; and can be reduced by at least 1 log, at least 2 logs, at least 3 logs or more. In some embodiments, individuals achieve seroconversion to a non-positive (for viral antigens) phenotype after treatment. In some embodiments, after treatment, individuals are tested for viral levels (e.g., viral nucleic acids, viral antigens, antiviral antibodies).

[0566] In some cases, the subject agent of an effective amount will reduce steatosis (liver steatosis). In some cases, the progression of steatosis will be blocked, and in some cases, steatosis will be reduced (i.e., the amount of steatosis observed after administration of the agent will be less than the amount observed before administration). In some cases, steatosis will be reduced by 10% (i.e., the amount observed will be 90% of the amount present before administration) or more (e.g., 20% or more, 35% or more, 50% or more, 70% or more, 85% or more). In some cases, steatosis will be reduced by 30% (i.e., the amount observed will be 70% of the amount present before administration) or more (e.g., 50% or more, 70% or more, 85% or more). In some cases, steatosis will be reduced by 50% or more.

[0567] An effective dose (e.g., a therapeutically effective dose) can be expected to be in the range of about 0.001 mg / kg body weight / day to about 100 mg / kg body weight / day (for humans), in some cases about 0.1 mg / kg body weight / day to about 50 mg / kg body weight / day, in some cases about 1 mg / kg body weight / day to about 50 mg / kg body weight / day, in some cases about 5 mg / kg body weight / day to about 40 mg / kg body weight / day, in some cases about 2 mg / kg body weight / day to about 15 mg / kg body weight / day, and in some cases about 25 mg / kg body weight / day to about 40 mg / kg body weight / day. In some cases, an effective dose is in the range of 5 mg / kg body weight / day to 100 mg / kg body weight / day (e.g., 5 mg / kg body weight / day to 80 mg / kg body weight / day, 5 mg / kg body weight / day to 50 mg / kg body weight / day, 5 mg / kg body weight / day to 40 mg / kg body weight / day, 5 mg / kg body weight / day to 30 mg / kg body weight / day, 5 mg / kg body weight / day to 20 mg / kg body weight / day, 5 mg / kg body weight / day to 10 mg / kg body weight / day, 8 mg / kg body weight / day to 100 mg / kg body weight / day, 8 mg / kg body weight / day to 80 mg / kg body weight / day, 8 mg / kg body weight / day to 100 mg / kg body weight / day In some cases, the effective dose is in the range of 8 mg / kg body weight / day to 100 mg / kg body weight / day, 10 mg / kg body weight / day to 80 mg / kg body weight / day, 10 mg / kg body weight / day to 50 mg / kg body weight / day, 10 mg / kg body weight / day to 40 mg / kg body weight / day, 10 mg / kg body weight / day to 30 mg / kg body weight / day, or 10 mg / kg body weight / day to 20 mg / kg body weight / day). In some cases, the effective dose is in the range of 8 mg / kg body weight / day to 100 mg / kg body weight / day. In some cases, the effective dose is about 8 mg / kg body weight / day.

[0568] Dosage and frequency may vary depending on the half-life of the agent. Those skilled in the art will appreciate that such guidelines will be adjusted for the molecular weight of the active agent. Dosage may also vary for topical administration, such as intranasal, inhalation, etc., or for systemic administration, such as im, ip, iv, sc, etc.

[0569] The course of treatment 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, once every other day, once a day, twice a day, once every two weeks, etc., and in some embodiments, once a week. In some embodiments, more than one course of treatment is administered. In some cases, the course of treatment is in the range of 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 course of treatment is in the range of 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 longer (e.g., 3 days or longer, 4 days or longer, 5 days or longer, 6 days or longer, 7 days or longer, 14 days or longer, or 1 month or longer). In some cases, the compound is administered for 3 days or longer.

[0570] The subject agents (e.g., A27, A27 derivatives, etc.), alone or in combination with other agents designed to assist in the treatment of an individual, can be administered to an individual by any route of administration known in the art, including, but not limited to, oral administration, administration by injection (specific examples of which include intravenous, subcutaneous, intraperitoneal or intramuscular injection), administration by inhalation, intranasal or topical administration.

[0571] The route of administration should be determined based on a number of considerations known to those skilled in the art, including, but not limited to, the desired physicochemical characteristics of the treatment. Treatments, for example, at 2°C to 8°C or higher can be provided while also allowing the formulation to be used for parenteral injection. Preservatives, stabilizers, buffers, antioxidants, and / or other additives may be included as appropriate. The formulation may contain divalent cations (including, but not limited to, MgCl2, CaCl2, and MnCl2) and / or nonionic surfactants (including, but not limited to, polysorbate-80 (TWEEN 80 TM ), polysorbate-60 (TWEEN 60 TM ), polysorbate-40 (TWEEN 40 TM ) and polysorbate 20 (TWEEN 20 TM ) Polyoxyethylene alkyl ethers, including but not limited to BRIJ 58 TM 、BRIJ 35 TM And other non-ionic surfactants such as TRITONX-100 TM 、TRITONX-114 TM 、NP40 TM , Span 85 and Series (e.g. 121). Any combination of such components constitutes a specific embodiment of the present disclosure.

[0572] "Pharmaceutically acceptable salts" and "pharmaceutically acceptable esters" mean salts and esters that are pharmaceutically acceptable and have the desired pharmacological properties. Such salts include salts formed when acidic protons that may be 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 organic bases such as amine bases, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. 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 alkanesulfonic acids and arenesulfonic acids, such as methanesulfonic acid and benzenesulfonic acid). Pharmaceutically acceptable esters include esters formed by carboxyl, sulfonyloxy and phosphonyloxy groups present in the compound, such as C1-6 alkyl esters. When two acidic groups are present, the pharmaceutically acceptable salt or ester may be a monoacid monosalt or ester or a disalt or ester; and similarly, when more than two acidic groups are present, some or all of such groups may be salified or esterified. The compounds named in the present invention may exist in a non-salified or non-esterified form, or in a salified and / or esterified form, and the naming of such compounds is intended to include the original (non-salified and non-esterified) compound and its pharmaceutically acceptable salts and esters. Moreover, certain compounds named in the present invention may exist in more than one stereoisomeric form, and the naming of such compounds is intended to include all single stereoisomers and all mixtures of such stereoisomers (whether racemic or otherwise).

[0573] The terms "pharmaceutically acceptable," "physiologically tolerable," and grammatical variations thereof, when referring to compositions, carriers, diluents, and agents, are used interchangeably and mean that these materials are capable of being administered to a human or human body without producing adverse physiological effects to an extent that would prohibit administration of the composition.

[0574] The terms "co-administered", "co-administered with", and "in combination with" include the simultaneous, concurrent, or sequential administration of two or more therapeutic agents (e.g., A27 or any compound described herein and an antiviral agent, a target cell-specific antibody, an antibiotic, etc.) without specific time limits. In one embodiment, the agents are present in a cell or in a subject at the same time, or exert their biological or therapeutic effects at the same time. 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 may be administered prior to (e.g., a few 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), concomitantly with, or after (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) administration of the second therapeutic agent.

[0575] The administration of the subject agent (e.g., A27 or any compound described herein) can be combined with the co-administration of any number of agents such as antiviral agents. Such agents may include, for example, entry inhibitors myrcludex-b, anti-NTBC antibodies, HBV nucleoside analogs (e.g., TDF, TAF, ETC), etc. The administration of the subject agent (e.g., A27 or any compound described herein) can be combined with antiviral agents such as HBsAg release inhibitors (nucleic acid polymers), HBV core inhibitors, siRNA targeting HBV (or HDV), immunomodulators (TLR agonists, etc.), RT or polymerase inhibitors, therapeutic vaccines, etc. Other antiviral agents may include interferons, including interferon alpha-2b, pegylated interferon alpha-2a, interferon-λ, entecavir, lamivudine, adefovir, telbivudine, tenofovir, sofosbuvir, ledipasvir, ombitasvir, pariperivir, ritonavir, dasabuvir, gezoprevir, elbavir, anaprevir, daclatasvir, or belabuvir.

[0576] The subject agent (e.g., A27 or any compound described herein) is not necessarily but optionally formulated with one or more agents that enhance activity or otherwise increase therapeutic effect. These are generally used in the same dosages and administration routes as used herein, or 1% to 99% of those used to date.

[0577] The subject agent (e.g., A27 or any compound described herein) can be co-administered with other active agents, such as antibiotics, cytokines, antiviral agents, etc. Antibiotic classes include penicillins, such as penicillin G, penicillin V, methicillin, oxacillin, carbenicillin, nafcillin, ampicillin, etc.; penicillins in combination with: β-lactamase inhibitors, cephalosporins, such as cefaclor, cefazolin, cefuroxime, ramoxef, etc.; carbapenems; monobactams; aminoglycosides; tetracyclines; macrolides; lincomycins; polymyxins; sulfonamides; quinolones; chloramphenicol; metronidazole; spectinomycin; trimethoprim; vancomycin; etc. Cytokines, such as interferon gamma, tumor necrosis factor alpha, interleukin 12, etc., may also be included. Antiviral agents, such as acyclovir, ganciclovir, etc., may also be used in treatment.

[0578] EXEMPLARY NON-LIMITING ASPECTS OF THE DISCLOSURE

[0579] Aspects of the present subject matter described above, alone or in combination with one or more other aspects or embodiments, including embodiments, may be beneficial. Without limiting the foregoing description, certain non-limiting aspects of the present disclosure are provided below (see Group A and Group B). As will be apparent to those of ordinary skill in the art after reading the present disclosure, each of the individually numbered aspects may be used or combined with any of the previously or subsequently individually numbered aspects. This is intended to provide support for the combination of all such aspects, and is not limited to the combination of the various aspects explicitly provided below. It is apparent to those of ordinary skill in the art that various changes and modifications may be made without departing from the spirit or scope of the present invention.

[0580] Group A

[0581] 1. Method for treating fatty liver using KxL ligand A27.

[0582] 2. Methods for treating fatty liver and / or viral infection using KxL ligand A27.

[0583] 3. Methods for treating HBV infection using KxL ligand A27.

[0584] 4. Methods of using KxL ligand A27 to treat SARS-CoV-2 infection.

[0585] 5. Methods for treating VEEV infection using KxL ligand A27.

[0586] 6. The method according to 1, wherein A27 is administered at 8 mg / kg to 100 mg / kg.

[0587] 7. The method according to 2, wherein A27 is administered at 8 mg / kg to 100 mg / kg.

[0588] 8. The method according to 3, wherein A27 is administered at 8 mg / kg to 100 mg / kg.

[0589] 9. The method according to 4, wherein A27 is administered at 8 mg / kg to 100 mg / kg.

[0590] 10. The method according to 5, wherein A27 is administered at 8 mg / kg to 100 mg / kg.

[0591] 11. The method according to 1 to 5, wherein A27 is administered for 3 days or longer.

[0592] 12. The method according to 1 to 5, wherein A27 is administered for 7 days or longer.

[0593] 13. The method according to 1 to 5, wherein A27 is administered for 14 days or longer.

[0594] 14. The method according to 1 to 5, wherein A27 is administered for 1 month or longer.

[0595] 15. The method according to 2 to 5, wherein A27 is administered in combination with another antiviral agent.

[0596] 16. A method for treating fatty liver using KxL ligand A27 derivatives.

[0597] 17. A method for treating fatty liver and / or viral infection using KxL ligand A27 derivatives.

[0598] 18. A method for treating HBV infection using KxL ligand A27 derivatives.

[0599] 19. Methods of using KxL ligand A27 derivatives to treat SARS-CoV-2 infection.

[0600] 20. A method of treating VEEV infection using a KxL ligand A27 derivative. twenty one.

[0602] 22. The method according to 12-16, wherein the A27 derivative is administered in combination with another antiviral agent.

[0603] 23. The method according to 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 progression of viral diseases.

[0604] Group B

[0605] 1. A method of treatment comprising: administering to an individual with fatty liver and / or non-Flaviveriidae viral infection a therapeutically effective amount of a compound selected from the group consisting of:

[0606] (a) Compounds of formula I:

[0607]

[0608] or a pharmaceutically acceptable salt thereof, wherein:

[0609] X is C or N;

[0610] Y is C or N;

[0611] Z1 is C or N;

[0612] Z2 is C or N;

[0613] R1 is hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted by substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl or 6 membered aryl groups; 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) groups; or R1 and R2 together form a 12-25 membered heterocyclic ring, or R1 and R5 together form a 12-25 membered heterocyclic ring;

[0614] L is a bond, —CONH—, —NH—CO—, a substituted or unsubstituted C1-C5 alkylene group, a substituted or unsubstituted C2-C5 heteroalkylene group, a substituted or unsubstituted 5-membered heteroaryl group, or a substituted or unsubstituted 5-7-membered heterocyclyl group, a C5-C7 cycloalkyl group, a 5-6-membered heteroaryl group, or a 6-membered aryl group; or a combination thereof;

[0615] 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;

[0616] R3, R4 and R5 are independently hydrogen, halogen, -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; and

[0617] 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 bound form a heterocycle;

[0618] (b) Compounds of formula II:

[0619]

[0620] or a pharmaceutically acceptable salt thereof, wherein:

[0621] X is C or N;

[0622] Y is C or N;

[0623] R1 is hydrogen, branched or linear 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 12-18 membered heterocyclic ring; n is 1 or 2;

[0624] R2 is a substituted or unsubstituted piperidinyl, 4-pyridinyl, pyrrolidinyl, piperazinyl, benzyl, substituted phenyl or pyrazolyl group;

[0625] R5 is R 51 R 52 N—or R 54 O—;

[0626] R 51 is H or substituted or unsubstituted C1-C3 alkyl; R 52is a C6-C8 cycloalkyl group, a substituted or unsubstituted linear C1-C3 alkyl group or a branched C4-C5 alkyl group, or R 51 and R 52 Together with the nitrogen atom to which they are bound, they form a 6-, 7-, 8- or 9-membered heterocyclyl ring containing up to 3 heteroatoms, which heterocyclyl ring is optionally substituted with a substituted or unsubstituted benzyl acyl or sulfonyl group in addition to the azaindazole moiety already attached thereto; R 54 R is H, a substituted or unsubstituted benzyl group, a branched C3-C8 alkyl group, an unsubstituted C5-C8 cycloalkyl group or a C5-C8 cycloalkyl group substituted with one or more linear or branched C1-C4 alkyl groups; 11 is C5-C8 cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0627] (c) Compounds of formula III:

[0628]

[0629] or a pharmaceutically acceptable salt thereof, wherein:

[0630] X is C or N;

[0631] Y is C or N;

[0632] Z1 is C or N;

[0633] Z2 is C or N;

[0634] R1 is hydrogen, branched or linear 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 12-18 membered heterocyclic ring; n is 1 or 2;

[0635] R2 is a substituted or unsubstituted phenyl, piperidinyl, 4-pyridinyl, pyrrolidinyl, piperazinyl, benzyl, substituted phenyl or pyrazolyl group; R5 is R 51 R 52 N—or R 54 O—;

[0636] R 51 is H or substituted or unsubstituted C1-C3 alkyl; R 52 is a C6-C8 cycloalkyl group, a substituted or unsubstituted linear C1-C3 alkyl group or a branched C4-C5 alkyl group, or R 51 and R 52Together with the nitrogen atom to which they are bound, they form a 6-, 7-, 8- or 9-membered heterocyclyl ring containing up to 3 heteroatoms, which heterocyclyl ring is optionally substituted with a substituted or unsubstituted benzyl acyl or sulfonyl group in addition to the azaindazole moiety already attached thereto; R 54 R is H, a substituted or unsubstituted benzyl group, a branched C3-C8 alkyl group, an unsubstituted C5-C8 cycloalkyl group or a C5-C8 cycloalkyl group substituted with one or more linear or branched C1-C4 alkyl groups; 11 is C5-C8 cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0637] R3 and R5 are independently hydrogen, halogen, -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;

[0638] (d) Compounds of formula IV:

[0639]

[0640] or a pharmaceutically acceptable salt thereof, wherein:

[0641] Each X is independently selected from C or N;

[0642] R 1 is absent, hydrogen, (C1-C8) alkyl, NR 9 R 10 , halogen, 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;

[0643] R 2 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;

[0644] R 3 is H, (C1-C8)alkyl, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C8)alkoxy, hydroxy, halogen, amino, amide, amino(C1-C8)alkylamide, heterocyclic, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano or (C1-C3)haloalkyl;

[0645] Each R 4 independently selected from unsubstituted or halogen-substituted (C1-C8)alkyl, (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; or two R 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;

[0646] 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, halogen, (C1-C4)haloalkyl and cyano;

[0647] 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, halogen, (C1-C4)haloalkyl and cyano;

[0648] R8 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, halogen, (C1-C4)haloalkyl and cyano;

[0649] R 9 is H, (C1-C8) alkyl, wherein the (C1-C8) alkyl is unsubstituted or substituted by one or more halogens;

[0650] R 10 is H, (C1-C8) alkyl, said (C1-C8) alkyl being unsubstituted or substituted by one or more halogens, or R 9 and R 10 Together with the nitrogen atom to which they are attached, they form a 4- or 5-membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with one or more halogens; R is H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-6-membered heterocyclic ring or 5-6-membered heteroaryl;

[0651] R 11 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0652] R 12 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0653] R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-8 membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with OH, halogen, =0 or (C1-C8)alkyl;

[0654] R 13 is OH, O-(C1-C4)alkyl;

[0655] R 15is H, (C1-C6)alkyl, (C1-C)haloalkyl, 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl, and wherein each of the 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl is unsubstituted or substituted at a substitutable position by one or more =O, OH, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, amino or (C1-C8)aminoalkyl; and

[0656] R 16 is H, (C1-C8)alkyl or (C1-C8)haloalkyl;

[0657] (e) Compounds of formula V:

[0658]

[0659] or a pharmaceutically acceptable salt thereof, wherein:

[0660] Each X is independently selected from C or N;

[0661] R 1 is absent, hydrogen, (C1-C8) alkyl, NR 9 R 10 , halogen, 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;

[0662] R 2 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;

[0663] R 3is H, (C1-C8)alkyl, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C8)alkoxy, hydroxy, halogen, amino, amide, amino(C1-C8)alkylamide, heterocyclic, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano or (C1-C3)haloalkyl;

[0664] Each R 4 independently selected from unsubstituted or halogen-substituted (C1-C8)alkyl, (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; or two R 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;

[0665] 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, halogen, (C1-C4)haloalkyl and cyano;

[0666] 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, halogen, (C1-C4)haloalkyl and cyano;

[0667] 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, halogen, (C1-C4)haloalkyl and cyano;

[0668] R 9 is H, (C1-C8) alkyl, wherein the (C1-C8) alkyl is unsubstituted or substituted by one or more halogens;

[0669] R 10 is H, (C1-C8) alkyl, said (C1-C8) alkyl being unsubstituted or substituted by one or more halogens, or R 9 and R 10 Together with the nitrogen atom to which they are attached, they form a 4- or 5-membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with one or more halogens; R is H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-6-membered heterocyclic ring or 5-6-membered heteroaryl;

[0670] R 11 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0671] R 12 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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;

[0672] R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-8 membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with OH, halogen, =0 or (C1-C8)alkyl;

[0673] R 13 is OH, O-(C1-C4)alkyl;

[0674] R 15 is H, (C1-C6)alkyl, (C1-C)haloalkyl, 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl, and wherein each of the 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl is unsubstituted or substituted at a substitutable position by one or more =O, OH, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, amino or (C1-C8)aminoalkyl; and

[0675] R 16 is H, (C1-C8)alkyl or (C1-C8)haloalkyl; and

[0676] (f) Compound of formula VI:

[0677]

[0678] or a pharmaceutically acceptable salt thereof, wherein:

[0679] R1 is hydrogen; halogen, haloalkyl, C1-C6 alkyl; C1-C6 alkyl substituted by substituted or unsubstituted C3-C8 cycloalkyl, 5-8-membered heterocyclyl or 6-membered aryl groups; 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) groups;

[0680] R 2 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;

[0681] R 3 is H, (C1-C8)alkyl, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C8)alkoxy, hydroxy, halogen, amino, amide, amino(C1-C8)alkylamide, heterocyclic, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano or (C1-C3)haloalkyl;

[0682] R 11 alkyl substituted by one or more of H, (C1-C4) alkyl, (C1-C4) haloalkyl, 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, or 5-membered heterocycle, 5-membered heterocycle, 5-membered heteroaryl, 5-membered heteroaryl, 6-membered heterocycle, 6-membered heterocycle, 6-membered heteroaryl, 6-membered heteroaryl, 5-membered cycloalkyl or 5-membered substituted cycloalkyl, 6-membered cycloalkyl or 6-membered substituted cycloalkyl

[0683] R 12alkyl substituted by one or more of H, (C1-C4) alkyl, (C1-C4) haloalkyl, 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, or 5-membered heterocycle, 5-membered heterocycle, 5-membered heteroaryl, 5-membered heteroaryl, 6-membered heterocycle, 6-membered heterocycle, 6-membered heteroaryl, 6-membered heteroaryl, 5-membered cycloalkyl or 5-membered substituted cycloalkyl, 6-membered cycloalkyl or 6-membered substituted cycloalkyl

[0684] R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-8 membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with OH, halogen, =0 or (C1-C8)alkyl; and

[0685] R4 is hydrogen; halogen, haloalkyl, C1-C6 alkyl; substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl, 5-8 membered aryl, 5-8 membered heteroaryl, C1-C6 alkyl substituted by 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.

[0686] In some embodiments, R3 is selected from hydrogen, (C1-C8) alkyl, halogen or haloalkyl. In some cases, R3 is hydrogen. In some cases, R3 is (C1-C8) alkyl, such as methyl, ethyl, propyl, i-propyl, butyl, t-butyl, i-butyl or pentyl. In some cases, R3 is methyl. In some cases, R3 is t-butyl. In some cases, R3 is halogen, such as fluorine, chlorine or bromine. In some cases, R3 is fluorine. In some cases, R3 is haloalkyl, such as CF3, CCl3 or CBr3. In some cases, R3 is CF3.

[0687] 2. The method of 1, wherein the individual has a non-Flaviveviridae viral infection selected from the group consisting of a Hepadnaviridae viral infection, an Alphavirus infection, a Coronaviridae infection, a Paramyxoviridae infection, and an Orthomyxoviridae infection.

[0688] 3. The method of claim 1, wherein the individual has a viral infection with hepatitis B virus (HBV), Venezuelan equine encephalitis virus (VEEV), Arara virus (ONNV), SARS-CoV-2, Semliki Forest virus (SFV), or Chikungunya virus (CHIKV).

[0689] 4. The method of claim 1, wherein the individual has a viral infection with hepatitis B virus (HBV), Venezuelan equine encephalitis virus (VEEV), SARS-CoV-2, or chikungunya virus (CHIKV).

[0690] 5. The method according to any one of 1 to 4, wherein the compound is co-administered with a second agent.

[0691] 6. The method according to any one of 2 to 4, wherein the compound is co-administered with a second antiviral agent.

[0692] 7. The method according to any one of 1 to 6, wherein the compound is administered at a concentration ranging from 8 mg / kg to 100 mg / kg.

[0693] 8. The method according to any one of 1 to 7, wherein the compound is administered for 3 days or longer.

[0694] 9. The method according to any one of 1 to 8, wherein the compound is A27:

[0695]

[0696] 10. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of:

[0697]

[0698] 11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:

[0699]

[0700] 12. A composition comprising:

[0701] (a) the compound according to 10 or 11 or a pharmaceutically acceptable salt thereof; and

[0702] (b) a pharmaceutically acceptable carrier, excipient or diluent.

[0703] 13. The composition according to 12, wherein the composition is a drug for treating fatty liver and / or viral infection.

[0704] The following examples are offered by way of illustration and not by way of limitation.

[0705] Examples

[0706] The following examples are presented to provide a person of ordinary skill in the art with a complete disclosure and description of how to make and use the invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the following experiments are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to the numbers used (such as quantities, temperatures, etc.), but some experimental errors and deviations should be considered. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is degrees Celsius, and pressure is at or near atmospheric pressure.

[0707] General methods in molecular and cellular biochemistry can be found in standard textbooks such as Molecular Cloning: A Laboratory Manual, 3rd edition (Sambrook et al., Harbor Laboratory Press 2001); Short Protocols in Molecular Biology, 4th edition (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 1996). 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 mentioned in or related to the present disclosure are available from commercial suppliers such as BioRad, Agilent Technologies, Thermo Fisher Scientific, Sigma-Aldrich, New England Biolabs (NEB), Takara Bio USA, Inc., etc., and from repositories such as, for example, Addgene, Inc., American Type Culture Collection (ATCC), etc.

[0708] Example 1

[0709] We found that a known small molecule, A27, binds to apolipoprotein B (apoB), a lipoprotein involved in cholesterol and lipid droplet formation. Because apoB has been implicated in the development of steatosis, we sought to determine whether A27 could modulate the extent of steatosis in cells. Indeed, we found that A27 inhibited the development of steatosis in cultured hepatocytes. We also found that A27 reduced the development of hepatic steatosis in C57 / BL6 mice fed a high-fat diet.

[0710] We further discovered that apoB contains an amphipathic helical domain with a putative binding motif for A27 that we termed the KxL motif.

[0711] Further studies showed that this KxL motif is also present in the amphipathic helical domain of hepatitis B surface antigen (HBsAg), nonstructural protein (NSP) 1 of VEEV, and NSP4 of SARS-CoV-2, and we found that A27 has antiviral activity against several of these viruses.

[0712] Therefore, provided herein is a method for treating fatty liver disease and / or viral infection, comprising administering an effective amount of A27 or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a derivative thereof to a subject having fatty liver disease and / or viral infection.

[0713] We found that a known small molecule, A27, can bind to apolipoprotein B (apoB), a lipoprotein involved in cholesterol and lipid droplet formation. The structure of A27 is:

[0714]

[0715] Since ApoB has been implicated in the development of steatosis, we sought to determine whether A27 could modulate the extent of steatosis in cells. Indeed, we found that A27 inhibited the development of steatosis in cultured hepatocytes, such as HepG2, with a 50% effective concentration (EC 50 ) is about 0.5 μM ( Figure 2 ).

[0716] Briefly, adipogenic medium was prepared by a 1:1 mixture of oleic acid and palmitic acid (Sigma Aldrich) with a 10% FFA-free bovine serum albumin (BSA) solution (Sigma Aldrich) in PBS. Basically, 100 mM oleic acid and palmitic acid were prepared in 99% methanol. Palmitic acid was prepared by shaking at 500 rpm for 20 minutes at 50°C. 10 mM oleic acid and palmitic acid were incubated with 10% BSA in PBS at 50°C for 30 minutes. A mixture of FFAs was made at a final concentration of 100 uM in the final cell culture medium. Cells were incubated in adipogenic medium for 4 days to induce fatty liver. Cells were then treated with different concentrations of A27 for 3 days in the presence of adipogenic medium. To determine the extent of steatosis, cells were stained with 1 mg / ml Nile red solution (Sigma Aldrich) in cell culture medium at 37°C for 15 minutes and the fluorescence signal was measured (see Figure 1 ). A dose-dependent reduction in lipid accumulation was observed.

[0717] Furthermore, when administered in mice, A27 reduced hepatic steatosis as measured by liver ultrasound.

[0718] To determine the effect of A27 against hepatic steatosis in vivo, a cohort of C57 / BL6 mice was first pretreated with 100 mg / kg / day of A27 (equivalent to a human dose of approximately 8 mg / kg / day based on allometric conversion of body surface area) or vehicle control (40% 2-hydroxypropyl-β-cyclodextrin in water) for 1 day, then placed on a high-fat diet (60% kcal fat content) for 4 weeks and continued to be treated with A27 or vehicle control during this time. At the end of the 4 weeks, liver ultrasound was performed to assess the degree of hepatic steatosis. Figure 2 As shown, HFD mice treated with vehicle showed more hepatic steatosis compared with mice treated with A27. A27 was well tolerated by all mice.

[0719] We further discovered that apoB contains an amphipathic helical domain with a putative binding motif for A27 that we termed the KxL motif.

[0720] Further studies have shown that this KxL motif is also present in the amphipathic helical domain of hepatitis B surface antigen (HBsAg), the nonstructural protein (NSP) 1 of VEEV, and NSP4 of SARS-CoV-2 ( Figure 3 ).

[0721] We subsequently found that A27 had antiviral activity against HBV, showing a reduction in HBV surface antigen in HBV-infected cells, EC 50 About 1 μM ( Figure 4 ).

[0722] We subsequently found that A27 also inhibited SARS-CoV-2 in cell culture. Using a luciferase reporter containing a SARS-CoV-2 infectious clone in TMPRSS2-ACE2-Huh7.5 cells, A27 inhibited SARS-CoV-2 genome replication, EC 50 was 803 nM without any evidence of toxicity.

[0723] To determine the in vivo antiviral activity of A27, 6- to 8-week-old BALB / c mouse cohorts were inoculated intranasally with mouse-adapted SARS-CoV-2 (105TCID50MA10SARS-CoV-2 (US_WA-1 / 2020)) and then treated with oral daily doses of A27 ranging from 100 mg / kg / day to 200 mg / kg / day, twice a day (400 mg / kg / day total dose) for 5 days (equivalent to human doses of about 8 mg / kg / day to about 32 mg / kg / day, based on allometric conversion of body surface area). This resulted in a 1 to 3 log reduction in viral titers compared to mice treated with vehicle (40% 2-hydroxypropyl-β-cyclodextrin in water) (Table 1).

[0724]

[0725] We further explored the potential of combining A27 with other antiviral agents and found that A27 has synergistic effects with protease inhibitors against SARS-CoV-2 (e.g., PF-07321332) and additive effects with polymerase inhibitor nucleoside analogs (e.g., EIDD2801). Therefore, A27 can be combined with nematevir or parovird.

[0726] We subsequently found that A27 also inhibited Venezuelan equine encephalitis virus (VEEV) in cell culture. Using a luciferase reporter from the TC83 strain containing VEEV in U87-MG cells, we found that A27 inhibited VEEV genome replication, EC 50 was 7.9 μM without any evidence of toxicity.

[0727] We then began to explore potential derivatives of A27 to further optimize its pharmacokinetic and pharmacodynamic properties. Representative A27 derivatives are compounds of Formula I to III (as shown above), and the proposed scheme for synthesizing more A27 derivatives is as follows Figure 7 shown.

[0728] Example 2

[0729] New compounds were generated (Example 2) and tested (Example 3).

[0730] Generate new compounds

[0731] Core preparation

[0732] 7-Pyrazolopyridine core (core 1)

[0733]

[0734] Compounds bearing a pyrazolopyridine core are synthesized from commercially available difluoropyridine and tert-butyl oxalate using known synthetic procedures according to the general reaction scheme described above. The ketoester is converted to a hydrazone prior to cyclization and methylation. Appropriate R 1 The amine substituent is installed using standard SNAr methods. The tert-butyl ester is hydrolyzed under basic lithium hydroxide conditions and then the appropriate amide is formed using standard reductive amination conditions from amines that are either commercially available or prepared using standard alkylation or reductive amination conditions.

[0735] 2-(2,6-Difluoro-3-pyridyl)-2-oxo-acetic acid tert-butyl ester

[0736]

[0737] Under a nitrogen dry atmosphere, at -78 ° C (cooled with an acetone dry ice bath), a solution of n-butyl lithium in hexane (9 mL, 95.59 mmol) was added dropwise to a clear solution of N-isopropylpropane-2-amine (13.4 mL, 95.59 mmol) in anhydrous THF (90 mL) over 5 minutes. The dry ice and acetone baths were then replaced with ice-water baths, and the reaction mixture was stirred at 0 ° C for 30 minutes. The ice-water bath was then replaced with an acetone dry ice bath again. The resulting yellow solution was then added dropwise to a solution of 2,6-difluoropyridine (7.89 mL, 86.9 mmol) in anhydrous THF (90 mL) at -78 ° C (cooled with an acetone dry ice bath) via cannula transfer over 30 minutes under a nitrogen dry atmosphere. The reaction mixture was then stirred at -78 ° C for 1 hour. Finally, di-tert-butyl oxalate (22.32 g, 110.36 mmol) and a dry solution of anhydrous THF (80 mL + 10 mL flushing solution) were slowly added to the flask over 5 minutes via cannula transfer (add solution so that it flows down from the side of the flask to avoid a large amount of heat release). The resulting brown mixture was then stirred at -78 ° C for 1 hour, and acetone and dry ice bath were replaced with an ice-salt bath. The reaction mixture was then stirred for another 30 minutes at -10 ° C. Saturated aqueous ammonium chloride solution (90 mL) was then added at -10 ° C. The cooling bath was then removed, and each layer was separated. The aqueous layer was then extracted with ethyl acetate (3 x 30 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to produce a brown liquid. The residue was then purified via silica gel chromatography using n-hexane and ethyl acetate (gradient 0% to 10%) to provide tert-butyl 2-(2,6-difluoro-3-pyridinyl)-2-oxo-acetate (12.4 g, 48.5 mmol, 56% yield) as a yellow liquid. 1 H NMR (500 MHz, CDCl3) δ8.48 (q, J = 8.3 Hz, 1H), 7.01 (dd, J = 8.3, 2.7 Hz, 1H), 1.59 (s, 9H). LR / MS (ESI) [MH] calculated value: 242.2 [MH] found value: 240.0.

[0738] (Z)-tert-Butyl 2-(2,6-difluoropyridin-3-yl)-2-hydrazonoacetate

[0739]

[0740] At 23 ° C, ethyl titanate (15.48mL, 73.85mmol) and hydrazine monohydrate (3.7mL, 73.85mmol) are added to a solution of 2-(2,6-difluoro-3-pyridyl)-2-oxo-tert-butyl acetate (9g, 36.92mmol) in DCM (40mL) at one time. Then the reaction mixture is stirred for 1 hour. Then the resulting yellow mixture is diluted in DCM (30mL) and water (45mL) and stirred for 30 minutes. Then saturated aqueous ammonium chloride solution (30mL) is added. Then the resulting mixture is passed through a diatomaceous earth pad and rinsed with DCM (50mL). Then each layer is separated, and the aqueous layer is extracted with ethyl acetate (3x 20mL). The combined organic layers were then dried over sodium sulfate and concentrated under reduced pressure to provide (Z)-tert-butyl 2-(2,6-difluoropyridin-3-yl)-2-hydrazonoacetate (7.5 g, 34.29 mmol, 93% yield) as a yellow solid. 1 H NMR (500MHz, CDCl3) δ7.87 (q, J=8.1Hz, 1H), 6.97 (ddd, J=8.1, 2.8, 0.9Hz, 1H), 1.51 (s, 9H).

[0741] 6-Fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid tert-butyl ester

[0742]

[0743] At 23 ° C, a solution of (2E)-2-(2,6-difluoro-3-pyridyl)-2-hydrazono-acetic acid tert-butyl ester (8.8 g, 34.29 mmol) in THF (75 mL) was treated with 60% sodium hydride (1.8 g, 73.73 mmol). 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 another hour while the cooling bath was slowly warmed to the ring temperature. A saturated aqueous ammonium chloride solution was then added to the reaction mixture, and the layers were separated. The aqueous layer was then extracted with ethyl acetate (3 x 15 mL). The combined organic layers were then washed with brine (15 mL), concentrated under reduced pressure, and purified via silica gel chromatography using 5%-40% ethyl acetate and hexanes to provide 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. 1HNMR (500 MHz, CDCl3) δ8.50 (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) [M+H-tBu-F] calculated value: 176.0 [M+H-tBu-F] found value: 177.9.

[0744] 6-(Azepan-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid tert-butyl ester

[0745]

[0746] At 23 ° C, DIPEA (2.63 mL, 15.15 mmol) was added to a mixture of 6-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid tert-butyl ester (1.4 g, 5.05 mmol) and azepane (2.85 mL, 25.25 mmol) in DMSO (50 mL). The flask was then heated to 150 ° C and stirred for 2 hours. The flask was then removed from the heat and saturated aqueous ammonium chloride solution (50 mL) was then added to the reaction mixture. The layers were then separated and the aqueous layer was extracted with ethyl acetate (3 x 25 mL). The combined organic layer was then washed with brine (3 x 25 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was then purified via silica gel chromatography using 20%-70% ethyl acetate and hexanes to provide 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 H NMR (500 MHz, CDCl3) δ8.05 (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] calculated value: 331.4 [M+H] found value: 331.2.

[0747] 6-(Azepan-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid

[0748]

[0749] At 23 ° C, a solution of 6- (azepane -1- base) -1- methyl - pyrazolo [3,4-b] pyridine -3- carboxylic acid tert-butyl ester (1.47g, 4.46mmol) in DCM (15mL) was treated with TFA (10.23mL, 133.7mmol) and stirred for 4 hours. The reaction mixture was then concentrated under reduced pressure. The resulting orange solid was then redissolved in DCM (5mL) and toluene (3mL) and concentrated under reduced pressure again to give 6- (azepane -1- base) -1- methyl -1H- pyrazolo [3,4-b] pyridine -3- carboxylic acid (1g, 3.63mmol, 95% yield) as an orange solid. 1 H NMR (500 MHz, CDCl3) δ8.22 (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] calculated value: 275.3 [M+H] found value: 275.0.

[0750] tert-Butyl 4-(6-(azepan-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamido)piperidine-1-carboxylate

[0751]

[0752] 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. HATU (2.5 g, 6.7 mmol) was then added and the reaction was stirred for 3 hours. 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 then purified via silica gel chromatography using 20%-60% hexanes and ethyl acetate to afford 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. 1H NMR (500 MHz, CDCl3) δ8.22 (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) [M+H] calculated value: 457.6 [M+H] found value: 457.3.

[0753] 6-(Azepan-1-yl)-1-methyl-N-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

[0754]

[0755] At ambient temperature (23 ° C), TEA (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 DOM (26 mL) and allowed to stir for 2 hours. The mixture was then concentrated under reduced pressure. The resulting orange solid was then redissolved in DCM and toluene and reconcentrated under reduced pressure. The crude product was then further purified via silica gel chromatography using 0-10% methanol and DCM to provide 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 light yellow solid. 1 HNMR (500 MHz, MeOD) δ8.11 (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] calculated value: 357.5 [M+H] found value: 357.1.

[0756] General reductive amination of NSP4 benzyl derivative compounds

[0757]

[0758] Under nitrogen atmosphere, sodium triacetoxyborohydride (1.4 eq) was added to a solution of 6-(azepan-1-yl)-1-methyl-N-(4-piperidinyl)pyrazolo[3,4-b]pyridine-3-carboxamide (1 eq) and a benzaldehyde derivative (1.5 eq) in anhydrous DCE (0.25 M). The reaction mixture was then stirred for 3 hours. Saturated aqueous sodium bicarbonate solution was then 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. Heat was then used to dissolve the crude product in a small amount of methanol to aid dissolution. The flask was then placed in an ice bath. The solid product began to crystallize out of the solution. The product was then filtered and rinsed with more methanol.

[0759] 6-(Azepan-1-yl)-1-methyl-N-(1-(4-methylbenzyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

[0760]

[0761] 1 H NMR(500MHz,MeOD)δ8.11(d,J=9.1Hz,1H),7.40(d,J=8.2Hz,2H),7.33(d,J=7.9Hz,2H),6 .72(d,J=9.1Hz,1H),4.29(s,2H),4.17(dt,J=17.8,7.4Hz,1H),3.95(s,3H),3.78(t,J=6 .1Hz, 4H), 3.52 (dt, J=11.5, 4.8Hz, 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=2.7Hz, 4H). LR / MS (ESI) [M+H] calculated value: 461.6 [M+H] found value: 461.2.

[0762] 6-(Azepan-1-yl)-N-(1-(4-chlorobenzyl)piperidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

[0763]

[0764] 1H NMR (500MHz, MeOD) δ8.12(d,J=9.1Hz,1H),7.52(dd,J=7.5,1.8Hz,1H),7.39(dd,J=7.8,1.5Hz,1H),7.30(t d,J=7.5,1.5Hz,1H),7.26(td,J=7.6,1.9Hz,1H),6.71(d,J=9.1Hz,1H),3.95(s,3H),3.98–3.89(m,1H),3.7 8 (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] found value: 481.1.

[0765] 6-(Azepan-1-yl)-N-(1-(4-fluorobenzyl)piperidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

[0766]

[0767] 1 H NMR (500MHz, DMSO) δ8.07(d,J=9.1Hz,1H),8.01(d,J=8.3Hz,1H),7.37–7.29(m,2H),7.18–7.10(m,2H ),6.73(d,J=9.1Hz,1H),3.89(s,3H),3.78(tdd,J=11.4,8.3,4.3Hz,1H),3.72(t,J=6.1Hz,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] found value: 465.3.

[0768] Synthesis of 6-(azepan-1-yl)-1-methyl-N-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

[0769]

[0770] 2-bromoethanol (1.0 g, 5 mmol), CsCO and NaI were added 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). After stirring at 70 ° C for 4 hours, 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 provide crude 6-(azepan-1-yl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide.

[0771] 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

[0772]

[0773] 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) was added MsCl (4 mmol) and TEA (1.5 mmol). After stirring at room temperature for 30 minutes, 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 stirred at 80 °C for 16 hours to provide the title product, which was purified by reverse phase preparative HPLC.

[0774] 1 H NMR (CDCl3 and CD3OD, δppm):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).

[0775] 7-Pyrazolopyridine core (core 11)

[0776]

[0777] Compounds without an amide linker were synthesized from commercially available 6-chloro-1H-pyrazolo[3,4-b]pyridine. The core was halogenated using N-iodosuccinamide and then methylated with iodomethane. The azepane moiety was installed using standard SNAr chemistry and the core was then converted to the boronic acid pinacol ester following established literature procedures. The boronic acid was reacted with the appropriate aryl halide using standard Suzuki-Miyaura coupling conditions to provide the desired target.

[0778] 7-Pyrazolopyridine core (core 3)

[0779]

[0780] The general reaction procedures provided are followed to synthesize compounds bearing a pyrazolopyridine core with a 5,6 substitution pattern. 1-Methyl-1H-pyrazolo[3,4-b]pyridine-6-ol is synthesized from commercially available 1-methyl-1H-pyrazol-5-amine using known condensation chemistry. Treatment of the core with N-bromosuccinamide results in bromination at the 5-position. The bromine is converted to the methyl ester using established palladium-mediated carbonylation chemistry. Alkaline hydrolysis of the ester is performed followed by reaction with the appropriate R 2 The amines were subjected to standard reductive amination. To install the desired R 2 To replace the groups, the core was treated with phosphorus oxychloride and the appropriate amine was inserted using standard SNAr conditions.

[0781]

[0782] Azaindole Core (Core 6)

[0783] Compounds containing a 7-azaindole core were synthesized from commercially available 6-bromo-7-azaindole. The methyl ester was installed using standard Friedel-Crafts acylation conditions, followed by methylation of the indole using sodium hydride and iodomethane. The appropriate R was installed using Buchwald-Hartwig chemistry catalyzed by RuPhos Pd G3. 1 Amine. The methyl ester is subjected to alkaline hydrolysis and then reacted with an appropriate amine (R 2 ) Evolutionary reductive amination to obtain the desired target.

[0784]

[0785] Indazole core (core 5 and 12)

[0786] Compounds containing an indazole core were synthesized via the general procedure described above using known literature procedures. Functionalized indazoles (e.g., where X=CF3) can be obtained from appropriate 2-nitrotoluene. After methylation of the core with iodomethane, the nitrile is hydrolyzed under acidic conditions to give the carboxylic acid. The appropriate R is inserted via standard amide coupling reaction conditions using HATU in DMF.2 The desired R was installed using standard Buchwald-Hartwig conditions catalyzed by RuPhos Pd G3. 1 Substituents are added to obtain the desired compounds.

[0787] Triazolopyridine core (core 4)

[0788] The triazolopyridine core was synthesized using known literature conditions. The ethyl ester was hydrolyzed with lithium hydroxide to give the carboxylic acid which was then reacted with the appropriate R 2 The desired R is installed using an amine under standard Buchwald-Hartwig amidation conditions catalyzed by Pd2(dba)3 and BINAP. 1 Substituent.

[0789] Pyrazolopyridine (core 9)

[0790]

[0791] Compounds containing a 5-pyrazolopyridine core were synthesized from ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate following literature procedures. The appropriate R was installed using standard Buchwald-Hartwig amination conditions with the appropriate amine and catalyzed by RuPhos Pd G3. 1 The ethyl ester was hydrolyzed to the carboxylic acid using lithium hydroxide, followed by amide coupling facilitated by HATU to form the desired R 2 Amide.

[0792] Naphthyridine (core 10)

[0793]

[0794] Commercially available 2,6-dichloronaphthyridine was obtained to synthesize compounds containing a naphthyridine core. Standard SNAr conditions were used to insert the desired R 1 The amine substituent is then used to install the methyl ester using a standard palladium-catalyzed carbonylation reaction. The methyl ester is hydrolyzed to the carboxylic acid and then reacted with the appropriate R 2 The amines undergo amide coupling to give the desired products.

[0795] Pyridopyrimidine core (core 14)

[0796]

[0797] 2,6-Dichloropyridopyrimidine was synthesized following established literature procedures. Under standard SNAr conditions, R was inserted with an appropriate amine. 1 The methyl ester is installed using standard palladium-catalyzed carbonylation chemistry with carbon monoxide. The ester is hydrolyzed to the carboxylic acid and then the desired R 2Amines undergo amide coupling to give the desired amides.

[0798] Pyridopyrimidine core (core 15)

[0799]

[0800] Ethyl 6-chloropyrido[3,2-d]pyrimidine-2-carboxylate was synthesized according to previously published literature. The appropriate R 1 The methyl ester was hydrolyzed to give the carboxylic acid which was then coupled with tert-butyl 4-aminopiperidine-1-carboxylate using HATU. The Boc group was removed using 4M HCl in dioxane. The resulting HCl salt was then reacted with the appropriate R 2 Aldehydes can be reductively aminized or reacted with appropriate R 2 Halides or trifluoromethanesulfonates are used for alkylation reactions.

[0801] Quinoline core (core 7)

[0802]

[0803] Substituted hydroxyquinoline cores were synthesized using previously reported literature procedures. The hydroxyl group could be converted to a triflate and replaced with a 1 Compounds containing amines at R 1 Compounds with ether linkages can be alkylated using standard alkylation conditions. The ester can then be reacted with hydrazine, followed by condensation with chloromethylthiophenyl ester and aminocyclohexanol, and subsequently subjected to EDC-mediated cyclization to afford the oxadiazole-linked derivative.

[0804] R 1 General procedure for SNAr alkylation:

[0805] All R were performed as described in the following representative examples using a variety of commercially available amines. 1 SNAr alkylation.

[0806]

[0807] At 23 ° C, DIPEA (3 equivalents) is added to a mixture of 6-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid tert-butyl ester (1 equivalent) and azepan (5 equivalents) in DMSO (0.01M). The flask is then heated to 150 ° C and continued for 2 hours. The flask is then removed from the heat, and a saturated aqueous ammonium chloride solution is then added to the reaction mixture. The layers are then separated, and the aqueous layer is extracted using ethyl acetate (x 3). The combined organic layer is then washed with brine (x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is then purified via silica gel chromatography using 20%-70% ethyl acetate and hexane to provide 6- (azepan-1-yl) -1-methyl -1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid tert-butyl ester (84% yield) as an orange oil.

[0808] R 2 General procedure for reductive amination:

[0809] All reductive aminations were performed as described in the representative examples below using a variety of commercially available amines.

[0810]

[0811] 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 (0.2M) was treated with DIPEA (3.5 equivalents), and HATU (1.5 equivalents) was added at 23°C. The solution was then stirred overnight. The reaction mixture was then diluted with ethyl acetate (100mL) and washed with brine (3x 30mL) in a separatory funnel. The collected organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting brown crude product was then purified via 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]pyridine-3-carbonyl]amino]piperidine-1-carboxylate (79% yield) as a yellow solid.

[0812] Amines that are not commercially available are prepared using standard literature procedures for alkylation or reductive amination. Representative example reactions are provided below.

[0813] Representative examples of alkylation reactions:

[0814]

[0815] Step 1: at 23 ℃, tert-butyl N-(4-piperidinyl)carbamate (1 equivalent), 1-(2-chloroethyl) pyrrolidine hydrochloride (1.1 equivalents) and K2CO3 (3 equivalents) are suspended in DMF (0.5M). The reaction is warmed to 60 ℃ for 18 hours. The reaction is cooled to room temperature, diluted with ethyl acetate and washed with 50% brine (x3). The organic layer is dried over anhydrous sodium sulfate and evaporated to obtain a crude residue, which is purified on a 50g silica column on Biotage Selekt with a gradient elution of 0-20% (0.5MNH3) MeOH in DCM. It is found that the desired product (monitored by TLC) is eluted by about 20%, and appropriate fractions are combined and concentrated to obtain the desired N-[1-(2-pyrrolidin-1-ylethyl)-4-piperidinyl] tert-butyl carbamate (47% yield) as an orange solid.

[0816] Step 2: To a solution of tert-butyl N-[1-(2-pyrrolidin-1-ylethyl)-4-piperidinyl]carbamate (1 eq) in 1,4-dioxane (0.34 M) was added 4M HCl in dioxane (4 eq). The mixture was stirred at 23 °C for 3 hours. The reaction was concentrated to afford 1-(2-pyrrolidin-1-ylethyl)piperidin-4-amine (90% yield) as a solid yellow hydrochloride.

[0817] Representative examples of reductive amination:

[0818]

[0819] N-(4-piperidyl) tert-butyl carbamate (1 equivalent) is suspended in DCM (0.4M), and 4-fluorobenzaldehyde (1 equivalent) is added, followed by 3 drops of acetic acid. The reaction is matured at 23 ° C for 1 hour, followed by the addition of sodium triacetoxyborohydride (2 equivalents). The reaction is stirred at this temperature for 1 hour, followed by the addition of water quenching. The reaction mixture is washed with DCM and saturated sodium bicarbonate of an additional portion. The organic portion is dried over anhydrous sodium sulfate, and purified on a 50g silica column on Biotage Selekt with a gradient of 0-10% MeOH in DCM. Appropriate fractions are merged and concentrated to obtain the desired N-[1-[(4-fluorophenyl) methyl]-4-piperidyl] tert-butyl carbamate (95% yield) as a white solid.

[0820] Example 3

[0821] Testing new compounds

[0822] The following results are Figure 8Depicted in. The concentration at which viral 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 = not determined yet).

[0823] SARS-CoV-2

[0824] To assess the antiviral activity against SARS-CoV-2, Huh7.5-ACE2-TMPRSS2 cells were infected with SARS-CoV2-Nluc at MOI 0.05 for 1 hour and then washed once with PBS before adding the compound. The cells were incubated for 48 hours and luciferase activity was measured using the Nano-Gio luciferase assay, which was used as a surrogate measure of viral replication, and the signal was normalized for cells without drug treatment. Cell viability was determined by presto blue assay.

[0825] Dengue virus (DENV)

[0826] HuH-7 cells were cultured in DMEM (Corning) containing 10% FBS and seeded in 96-well clear bottom white plates (Greiner / Corning) at a density of 10.000 cells / well the day before infection. In DMEM without FBS, cells were infected with 50ul DENV2-Sea Renilla luciferase reporter virus (C38-Rluc2A-C-prM-E-NS region) at MOI 0.01 for 1 hour at 37°C, 5% CO2. After 1 hour, 50ul compounds were added directly to the wells (100ul final volume per well) in triplicate at a final concentration of 10uM, 2.5uM, 625nM, 156nM, 39nM and 9.76nM (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, take out culture medium, wash cells once with 200ul PBS, and then add 30ul 1x lysis buffer (Promega, catalog number: E2820) to each hole.Cells are incubated for 30 minutes in a rocking shaker (300RPM) to ensure complete lysis.Afterwards, 50ul sea renilla substrate (Promega, catalog number: E2820) is added to each hole using a syringe needle, and luminescence reading is carried out with 1 second integration time in a Spark luminescent module (Tecan).

[0827] Viability assays were performed in parallel as described above, but using 96-well clear bottom black plates (Greiner / Corning). 48 hours after treatment, 100 ul / well of PrestoBlue Viability Reagent (Thermo Fisher Scientific) was replaced according to the manufacturer's instructions. Cells were incubated at 37°C, 5% CO2 for 1 hour and read at 560 / 590 nm (excitation / emission) using the fluorescence module of the Spark plate reader (Tecan).

[0828] Chikungunya virus (CHIKV)

[0829] 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). Journal of Virology (Virol. J.) 19, 170 (2022). The nanoluciferase (nLuc) reporter gene was engineered to the 5' end of E2 in CHIKV vaccine strain 181 / clone 25 (CKV181-nluc) or MAYV infectious clone. Reporter viruses were generated by reverse genetics and titrated. Human U2OS cells in 96-well plates were inoculated 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 culture supernatant per well was transferred to a fresh luciferase assay plate and mixed with substrate for nLuc. In parallel, cells were lysed and intracellular ATP was quantified with Luminescent cell viability assay was used for quantification. Control cells were treated with DMSO and their viability and virus yield were set to 100%.

[0830] Example 4

[0831] Orthomyxoviridae (eg, influenza)

[0832] Tissue culture adapted PR8 virus (ATCC-VR-1469) was purchased from ATCC. Confluent MDCK cells in 12-well plates were infected with approximately 70 p.fu of virus and incubated at 37°C for 1 hour. The cells were then washed with PBS and a 50:50 mixture of 1.2% agarose:2x virus growth DMEM containing oseltamivir or test compounds at a final concentration of 100 nM or 1 uM. The plates were harvested after 72 hours, stained with crystal violet and plaques were counted. Compared to the wells treated with oseltamivir, treatment with STF-00203577-001, STF-00204266-001, STF-00204657-001 or STF-00204460-001 resulted in smaller plaques. Therefore, the compounds disclosed herein, including those tested in this example, can be used to treat individuals with Orthomyxoviridae infections (e.g., influenza).

[0833] Paramyxoviridae (eg, RSV)

[0834] RSV-luc5 virus was purchased from https: / / www.viratree.com / product / rsv-luc5 / . HeLa cells were plated in 96-well black transparent bottom plates at 5,000 cells / well overnight. The cells were infected with RSV-Luc5 for 1 hour. The cells were then treated with various concentrations of compounds for 3 days. Luciferase activity was measured using Bright-Glo luciferase as a readout of viral replication. Treatment with STF-00203577-001, STF-00204266-001, STF-00204657-001 or STF-00204460-001 significantly inhibited RSV replication, with EC50s of 1.1 μM, 1.88 μM, 2.52 μM, and 1.11 μM, respectively. Therefore, the compounds disclosed herein, including those tested in this example, can be used to treat individuals with Paramyxoviridae infections (e.g., RSV).

[0835] In at least some of the previously described embodiments, one or more elements used in an embodiment may be used interchangeably in another embodiment unless such replacement is technically infeasible. It will be appreciated by those skilled in the art that various other omissions, additions, and modifications may 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 as defined in the appended claims.

[0836] Those skilled in the art will understand that, in general, the terms used herein, especially in the appended claims (e.g., the bodies of the appended claims), are generally intended as "open" terms (e.g., the term "including" should be interpreted as "including but not limited to", the term "having" should be interpreted as "having at least", the term "includes" should be interpreted as "including but not limited to", etc.). Those skilled in the art will further understand that if a specific number of claim recitations is intended to be introduced, such intent will be explicitly stated in the claim, and in the absence of such a statement, such intent is absent. For example, to aid understanding, the following appended claims may contain the use of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of these phrases should not be interpreted as implying that the introduction of a claim recitation by the indefinite article "a" or "an" will limit any particular claim that includes such introduced claim recitation to multiple embodiments that include only one such recitation, even if the same claim includes the introductory phrases "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" should generally be interpreted as meaning "at least one" or "one or more"); the same applies to the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly referenced, those skilled in the art will recognize that such reference should be interpreted as indicating at least the number of references (e.g., a simple reference of "two references" without other modifiers means at least two references, or two or more references). Furthermore, where a convention similar to “at least one of A, B, and C, etc.” is used, generally, those skilled in the art will use such construction in the sense of understanding the convention (e.g., “a system having at least one of A, B, and C” will include, but is not limited to, A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). Where a convention similar to “at least one of A, B, or C, etc.” is used, generally, those skilled in the art will use such construction in the sense of understanding the convention (e.g., “a system having at least one of A, B, or C” will include, but is not limited to, A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). Those skilled in the art will further understand that almost any non-connective word and / or phrase that proposes two or more optional terms, whether in the specification, claims, or drawings, should be understood to cover the possibility of including one of the terms, either of the terms, or both of the terms. For example, the phrase “A or B” should be understood to include the possibility of “A” or “B” or “A and B”.

[0837] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0838] As will be understood by those skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily identified as fully describing and enabling the same range to be decomposed into at least equal half, one-third, one-quarter, one-fifth, one-tenth, etc. As a non-limiting example, each range discussed herein can be easily decomposed into a lower third, a middle third, and an upper third, etc. As will be understood by those skilled in the art, all languages ​​such as "at most", "at least", "greater than", "less than", etc. include the cited numbers, and refer to the ranges that can be subsequently decomposed into sub-ranges as described above. Finally, as will be understood by those skilled in the art, the range includes each individual member. Therefore, for example, a group with 1-3 articles refers to a group with 1, 2 or 3 articles. Similarly, a group with 1-5 articles refers to a group with 1, 2, 3, 4 or 5 articles, and so on.

[0839] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent to one of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

[0840] Therefore, the above only illustrates the principle of the present invention.It should be understood that those skilled in the art will be able to design various arrangements, which, although not explicitly described or shown in this article, embody the principle of the present invention and are included in its spirit and scope.In addition, all examples and conditional language described in this article are mainly intended to help readers understand the principles of the present invention and the concepts contributed by the inventor to promote this field, and should be interpreted as not being limited to such specific examples and conditions.In addition, all statements describing the principles, aspects and embodiments of the present invention and their specific examples are intended to cover both their structural equivalents and functional equivalents.In addition, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, that is, any element that performs the same function developed, regardless of the structure.In addition, regardless of whether such disclosure is explicitly described in the claims, any content disclosed herein is not intended to be dedicated to the public.

[0841] Therefore, the scope of the present invention is not intended to be limited to the exemplary embodiments shown and described herein. Instead, 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 explicitly defined as a limitation only when the exact phrase "means for..." or the exact phrase "step for..." is recorded at the beginning of a limitation in the claims, and 35 U.S.C. §112(f) or 35 U.S.C. §112(6) will not be cited if a limitation in the claims does not use such exact phrases.

Claims

1. A method of treatment, comprising: Administering to an individual with fatty liver and / or non-Flaviveriidae viral infection a therapeutically effective amount of a compound selected from the group consisting of: (g) Compounds of formula I: 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 by substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl or 6 membered aryl groups; 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) groups; or R1 and R2 together form a 12-25 membered heterocyclic ring, or R1 and R5 together form a 12-25 membered heterocyclic ring; L is a bond, —CONH—, —NH—CO—, a substituted or unsubstituted C1-C5 alkylene group, a substituted or unsubstituted C2-C5 heteroalkylene group, a substituted or unsubstituted 5-membered heteroaryl group, or a substituted or unsubstituted 5-7-membered heterocyclyl group, a C5-C7 cycloalkyl group, a 5-6-membered heteroaryl group, or a 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, halogen, -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; and 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 bound form a heterocycle; (h) Compounds of formula II: or a pharmaceutically acceptable salt thereof, wherein: X is C or N; Y is C or N; R1 is hydrogen, branched or linear 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 12-18 membered heterocyclic ring; n is 1 or 2; R2 is a substituted or unsubstituted piperidinyl, 4-pyridinyl, 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 a C6-C8 cycloalkyl group, a substituted or unsubstituted linear C1-C3 alkyl group or a branched C4-C5 alkyl group, or R 51 and R 52 together with the nitrogen atom to which they are bound, form a 6-, 7-, 8- or 9-membered heterocyclyl ring containing up to 3 heteroatoms, said heterocyclyl ring being optionally substituted with a substituted or unsubstituted benzyl acyl or sulfonyl group in addition to the azaindazole moiety already attached thereto; R 54 R is H, a substituted or unsubstituted benzyl group, a branched C3-C8 alkyl group, an unsubstituted C5-C8 cycloalkyl group or a C5-C8 cycloalkyl group substituted with one or more linear or branched C1-C4 alkyl groups; 11 is C5-C8 cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; (i) Compound of formula III: 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 linear 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 12-18 membered heterocyclic ring; n is 1 or 2; R2 is a substituted or unsubstituted phenyl, piperidinyl, 4-pyridinyl, 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 a C6-C8 cycloalkyl group, a substituted or unsubstituted linear C1-C3 alkyl group or a branched C4-C5 alkyl group, or R 51 and R 52 together with the nitrogen atom to which they are bound, form a 6-, 7-, 8- or 9-membered heterocyclyl ring containing up to 3 heteroatoms, said heterocyclyl ring being optionally substituted with a substituted or unsubstituted benzyl acyl or sulfonyl group in addition to the azaindazole moiety already attached thereto; R 54 R is H, a substituted or unsubstituted benzyl group, a branched C3-C8 alkyl group, an unsubstituted C5-C8 cycloalkyl group or a C5-C8 cycloalkyl group substituted with one or more linear or branched C1-C4 alkyl groups; 11 is C5-C8 cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R3 and R5 are independently hydrogen, halogen, -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; (j) Compounds of formula IV: 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 , halogen, 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 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, hydroxy, halogen, amino, amide, amino(C1-C8)alkylamide, heterocyclic, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano or (C1-C3)haloalkyl; Each R 4 independently selected from unsubstituted or halogen-substituted (C1-C8)alkyl, (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; or two R 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, halogen, (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, halogen, (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, halogen, (C1-C4)haloalkyl and cyano; R 9 is H, (C1-C8) alkyl, wherein the (C1-C8) alkyl is unsubstituted or substituted by one or more halogens; R 10 is H, (C1-C8) alkyl, said (C1-C8) alkyl being unsubstituted or substituted by one or more halogens, or R 9 and R 10 Together with the nitrogen atom to which they are attached, they form a 4- or 5-membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with one or more halogens; R is H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-6-membered heterocyclic ring or 5-6-membered heteroaryl; R 11 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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 Together with the nitrogen atom to which they are attached, they form a 5-8 membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with OH, halogen, =0 or (C1-C8)alkyl; R 13 is OH, O-(C1-C4)alkyl; R 15 is H, (C1-C6)alkyl, (C1-C)haloalkyl, 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl, and wherein each of the 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl is unsubstituted or substituted at a substitutable position by one or more =O, OH, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, amino or (C1-C8)aminoalkyl; and R 16 is H, (C1-C8)alkyl or (C1-C8)haloalkyl; (k) Compounds of formula V: 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 , halogen, 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 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, hydroxy, halogen, amino, amide, amino(C1-C8)alkylamide, heterocyclic, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano or (C1-C3)haloalkyl; Each R 4 independently selected from unsubstituted or halogen-substituted (C1-C8)alkyl, (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; or two R 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, halogen, (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, halogen, (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, halogen, (C1-C4)haloalkyl and cyano; R 9 is H, (C1-C8) alkyl, wherein the (C1-C8) alkyl is unsubstituted or substituted by one or more halogens; R 10 is H, (C1-C8) alkyl, said (C1-C8) alkyl being unsubstituted or substituted by one or more halogens, or R 9 and R 10 Together with the nitrogen atom to which they are attached, they form a 4- or 5-membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with one or more halogens; R is H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-6-membered heterocyclic ring or 5-6-membered heteroaryl; R 11 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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 is selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, 5-membered heterocycle, 5-membered substituted heterocycle, 5-membered heteroaryl, 5-membered substituted heteroaryl, 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 Together with the nitrogen atom to which they are attached, they form a 5-8 membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with OH, halogen, =0 or (C1-C8)alkyl; R 13 is OH, O-(C1-C4)alkyl; R 15 is H, (C1-C6)alkyl, (C1-C)haloalkyl, 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl, and wherein each of the 4-7 membered heterocycle, 5-6 membered heteroaryl, 3-7 membered cycloalkyl is unsubstituted or substituted at a substitutable position by one or more =O, OH, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, amino or (C1-C8)aminoalkyl; and R 16 is H, (C1-C8)alkyl or (C1-C8)haloalkyl; and (1) Compound of formula VI: or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen; halogen, haloalkyl, C1-C6 alkyl; C1-C6 alkyl substituted by substituted or unsubstituted C3-C8 cycloalkyl, 5-8-membered heterocyclyl or 6-membered aryl groups; 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) groups; R 2 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, hydroxy, halogen, amino, amide, amino(C1-C8)alkylamide, heterocyclic, sulfonyl, aminosulfonyl, amino(C1-C8)alkylsulfonyl, cyano or (C1-C3)haloalkyl; R 11 alkyl substituted by one or more of H, (C1-C4) alkyl, (C1-C4) haloalkyl, 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, or 5-membered heterocycle, 5-membered heterocycle, 5-membered heteroaryl, 5-membered heteroaryl, 6-membered heterocycle, 6-membered heterocycle, 6-membered heteroaryl, 6-membered heteroaryl, 5-membered cycloalkyl or 5-membered substituted cycloalkyl, 6-membered cycloalkyl or 6-membered substituted cycloalkyl R 12 alkyl substituted by one or more of H, (C1-C4) alkyl, (C1-C4) haloalkyl, 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, or 5-membered heterocycle, 5-membered heterocycle, 5-membered heteroaryl, 5-membered heteroaryl, 6-membered heterocycle, 6-membered heterocycle, 6-membered heteroaryl, 6-membered heteroaryl, 5-membered cycloalkyl or 5-membered substituted cycloalkyl, 6-membered cycloalkyl or 6-membered substituted cycloalkyl R 11 and R 12 Together with the nitrogen atom to which they are attached, they form a 5-8 membered nitrogen-containing heterocyclic ring which is unsubstituted or substituted with OH, halogen, =0 or (C1-C8)alkyl; and R4 is hydrogen; halogen, haloalkyl, C1-C6 alkyl; substituted or unsubstituted C3-C8 cycloalkyl, 5-8 membered heterocyclyl, 5-8 membered aryl, 5-8 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; In some embodiments, R3 is selected from hydrogen, (C1-C8) alkyl, halogen or haloalkyl; in some cases, R3 is hydrogen; in some cases, R3 is (C1-C8) alkyl, such as methyl, ethyl, propyl, i-propyl, butyl, t-butyl, i-butyl or pentyl; in some cases, R3 is methyl; in some cases, R3 is t-butyl; in some cases, R3 is halogen, such as fluorine, chlorine or bromine; in some cases, R3 is fluorine; in some cases, R3 is haloalkyl, such as CF3, CCl3 or CBr3; in some cases, R3 is CF3.

2. The method of claim 1, wherein the individual has a non-Flaviveviridae viral infection selected from the group consisting of a Hepadnaviridae viral infection, an Alphavirus infection, a Coronaviridae infection, a Paramyxoviridae infection, and an Orthomyxoviridae infection.

3. The method of claim 1, wherein the individual has a viral infection with hepatitis B virus (HBV), Venezuelan equine encephalitis virus (VEEV), Arara virus (ONNV), SARS-CoV-2, Semliki Forest virus (SFV), or Chikungunya virus (CHIKV).

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

5. The method of any one of claims 1 to 4, wherein the compound is co-administered with a second agent.

6. The method of any one of claims 2 to 4, wherein the compound is co-administered with a second antiviral agent.

7. The method according to any one of claims 1 to 6, wherein the compound is administered at a concentration ranging from 8 mg / kg to 100 mg / kg.

8. The method of any one of claims 1 to 7, wherein the compound is administered for 3 days or longer.

9. The method according to any one of claims 1 to 8, wherein the compound is A27:

10. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of:

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

12. A composition comprising: (a) a compound according to claim 10 or claim 11 or a pharmaceutically acceptable salt thereof; as well as (b) a pharmaceutically acceptable carrier, excipient or diluent.

13. The composition according to claim 12, wherein the composition is a drug for treating fatty liver and / or viral infection.

Images