Gcn2 and perk kinase inhibitors and methods of use thereof

Abstract

This article describes compounds that are inhibitors of GCN2 kinase or PERK kinase, and methods of using such compounds to treat diseases including those related to GCN2 kinase or PERK kinase.

Description

Technical Field

[0001] [Cross-reference] []

[0002] This application claims priority to U.S. Provisional Application No. 63 / 115,496, filed November 18, 2020, and U.S. Provisional Application No. 63 / 185,846, filed May 7, 2021, each of which is incorporated herein by reference in its entirety. [Sequence List] []

[0003] This application contains a sequence list that has been submitted electronically in ASCII format and is hereby incorporated in its entirety. The ASCII copy was created on October 28, 2021, named DCP-098WO_SL.txt, and is 23,670 bytes in size. Prior Technology

[0004] Cancer cells require a constant supply of nutrients to sustain their abnormal growth and rapid division. As part of these nutrients, amino acids are crucial for supporting the high metabolic demands of tumor cells.

[0005] GCN2 is a serine / threonine protein kinase and one of the eukaryotic initiation factor 2α (eIF2α) kinases. These kinases are key regulators of the integrated stress response (ISR). ISR is crucial for maintaining cellular homeostasis under various stressors and is activated when cells adapt to stress conditions such as hypoxia and amino acid deprivation. ISR is regulated by phosphorylation and activation of eIF2α kinases (including GCN2), which act as early responders to disturbances in cellular homeostasis. Besides GCN2, three other eIF2α kinase families exist: PKR-like ER kinase (PERK), double-stranded RNA-dependent protein kinase (PKR), and heme-regulated eIF2α kinase (HRI). All four eIF2α kinases share broad homology in their kinase catalytic domains but have different regulatory domains. Each eIF2α kinase responds to different environmental and physiological stresses, reflecting its unique regulatory mechanism. PERK kinase is activated under stress conditions including ATP depletion and unfolded protein responses, and similar to GCN2, PERK kinase activation leads to the upregulation of the key ISR transcription factor ATF4.

[0006] Under conditions of essential amino acid restriction or other stressors (UV irradiation, redox stress, or proteasome inhibition), GCN2 phosphorylates eIF2α, which inhibits the formation of novel ternary complexes and thus suppresses mRNA translation initiation. While reducing overall mRNA translation, eIF2α phosphorylation in tumor cells also increases the translation of the ISR transcription factor ATF4, which increases the expression of many stress-responsive genes, including those specifically supplying amino acids to tumor cells: namely, amino acid synthases and transporters mediating amino acid influx into tumor cells. The overexpression of ATF4 in both solid and liquid tumors in humans suggests its important function in tumor progression.

[0007] Asparagine is an important amino acid involved in various biosynthetic pathways that can significantly influence carcinogenesis and tumor biology. All cells require asparagine for protein synthesis and growth. Normal cells obtain most of their required asparagine internally. Compared to normal cells, cancer cells require much higher levels of asparagine for growth and proliferation, cannot produce the necessary amount themselves, and must rely on circulating asparagine for survival. Asparagine synthase (ASNS) catalyzes the synthesis of asparagine from aspartate and glutamic acid. L-asparaginase (ASNase) removes circulating asparagine, thereby depriving cancer cells of a key nutrient and causing their death. The use of L-asparaginase represents the first instance of anticancer therapy targeting specific metabolic features of tumors and is a recognized treatment for childhood acute lymphoblastic leukemia (ALL), but its toxicity limits its use outside this patient population. Compared to normal cells, ASNS is expressed at particularly low levels in many ALL cell lines, making asparagine depletion an effective treatment, attributed to the cells' aberrant dependence on circulating serum asparagine, a nutrient essential for growth. Adverse responses to asparagine enzymes are associated with an increased risk of recurrence. Other hematologic and solid tumors exhibit low levels of ASNS, thus indicating asparagine auxotrophy and asparagine enzyme sensitivity. Conversely, in certain cancer types, ASNS is overexpressed, promoting cell proliferation, chemoresistant behavior, and metastatic activity. In the case of asparagine-resistant cancers, the depletion of blood asparagine via L-asparagine enzymes compensates for this by significantly overexpressing ASNS, effectively negating the effects of chemotherapy. Numerous studies have shown that ASNS is central to cellular responses to amino acid deprivation and other forms of cellular stress. Through transcriptional regulation, the ASNS genome targets two signaling pathways designed to ensure cell survival. The first pathway, called the amino acid response (AAR), is activated by GCN2 kinase under conditions of amino acid availability imbalance. The second pathway, called the unfolded protein response (UPR), is activated by PERK kinase under conditions of increased endoplasmic reticulum stress. Both AAR and UPR pathways converge on eIF2α phosphorylation, leading to a decrease in overall protein synthesis and preferential translation of a selected population of mRNAs, including the translation factor ATF4. ATF4 is a major ASNS-induced factor, functioning as a transactivator via an enhancer element bound to the ASNS promoter.

[0008] GCN2, both in vitro and in vivo, sensitizes cancer cells with low basal ASNS expression levels to the antileukemic drug L-aspartase. Treatment with GCN2 inhibitors sensitizes acute lymphoblastic leukemia cells to L-aspartase by preventing ASNS induction. GCN2 inhibitors and L-aspartase exhibit synergistic antiproliferative effects in cancers with low / deficient ASN. Therefore, combination therapy with GCN2 inhibitors and L-aspartase shows promise for improving outcomes in acute lymphoblastic leukemia and other types of cancer. Acute lymphoblastic leukemia, acute myeloid leukemia, and pancreatic cancer cells are particularly sensitive to combination therapy with L-aspartase and GCN2 inhibitors. Previous studies have demonstrated that the combination therapy of ASNase and GCN2 inhibitors exhibits robust antitumor activity in acute lymphoblastic leukemia, acute myeloid leukemia, and pancreatic cancer cells compared to monotherapy with L-aspartase or GCN2 inhibitors. Therefore, GCN2 inhibitors can represent sensitizers for L-aspartase in the treatment of these tumors. In summary, GCN2 inhibition enhances sensitivity to L-aspartase therapy by preventing ASNS induction in cancer cells with low baseline ASNS expression levels.

[0009] GCN2 inhibition can also be an effective strategy for targeting the tumor microenvironment, including the immune system, such as tryptophan-dependent immune surveillance of tumor cells.

[0010] The tumor microenvironment [TME; a series of extracellular components and stromal cells surrounding tumor cells (endothelial cells, cancer-associated fibroblasts, tumor-associated macrophages, tumor-infiltrating T cells)] is characterized by a lack of oxygen and key nutrients (such as glucose and amino acids), resulting in an overall immunosuppressive environment.

[0011] Many tumors evolve to evade immune surveillance by utilizing their metabolic flexibility and redirecting nutrients for their own benefit. Stromal cells and bone marrow-derived suppressor cells (MDSCs) within tumors create a malnourished environment that suppresses immune function and supports tumor growth.

[0012] Increased tryptophan (an essential amino acid) catabolism, driven by the overexpression of key enzymes in tryptophan metabolism [indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO)], is cellularly driven by the tumor microenvironment, creating an immunosuppressive microenvironment in various cancer types. Local tryptophan depletion is considered a key T-cell immunosuppressive mechanism. In T cells, GCN2 kinase has been identified as a molecular sensor for tryptophan deprivation. Activation of GCN2 through tryptophan depletion can induce apoptosis and reduce T-cell proliferation. GCN2 is a key effector signaling component of IDO / TDO and is considered a metabolic checkpoint for highly tryptophan-dependent T cells.

[0013] The GCN2 pathway is not only crucial for tumor immune escape but also plays an active role in regulating other aspects of the tumor microenvironment. GCN2 attenuation has been shown to prevent amino acid deprivation (AAD)-induced expression of vascular endothelial growth factor (VEGF), which tumors utilize to enhance nutrient supply through increased angiogenesis. Therefore, activation of the GCN2 / ATF4 pathway promotes tumor growth and angiogenesis via AAD-mediated VEGF expression. Elimination of ATF4 or GCN2 expression significantly inhibits in vivo tumor growth.

[0014] Therefore, selective inhibition of GCN2 can increase immune system activity and reduce angiogenesis in the tumor microenvironment. The GCN2-eIF2α-ATF4 pathway is crucial for maintaining metabolic homeostasis of tumor cells under stress and for maintaining the immunosuppressive immune cell microenvironment. The PERK-ATF4 pathway is also crucial for maintaining tumor cell homeostasis under stress. It has been reported that both the GCN2 and PERK signaling pathways are crosstalk regulated, meaning that inhibiting GCN2 can activate PERK as a compensatory mechanism, and vice versa; that is, inhibiting PERK can activate GCN2 as a compensatory mechanism.

[0015] It is necessary to block GCN2 and / or PERK inhibitors that target the pro-tumorigenic state of GCN2 and / or PERK in both the tumor cell (tumor cell autonomous) and tumor immune cell microenvironment. Summary of the Invention

[0016] This article describes compounds exhibiting inhibitory activity against GCN2 (normal control, non-deinhibitory 2) kinase and / or PERK (PKR-like ER kinase) kinase, and methods for treating conditions, including GCN2 or PERK-related diseases.

[0017] In one embodiment, this document describes a compound represented by formula I: [Mode] [I] [] Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: The X1 group is composed of CH and N; the X2 and X3 groups are each independently composed of the following groups: N, CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2, with the restriction that the X2 group is composed of CH and N, and the X3 group is composed of the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; with the restriction that the X2 group is composed of the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2, and the X3 group is composed of CH and N; the X4 group is composed of CR 3 and N; the X10 group is composed of CR 5 and N; the X11 group is composed of CR 7 and N; R R1 is selected from the group consisting of: H, alkyl, (C=O)R13, ​​cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl and sulfonyl; R2 is selected from the group consisting of H and alkyl; R The R3 series is selected from the group consisting of H, alkyl, and halogen; the R4 and R5 series are each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 and R7 series are each independently selected from the group consisting of halogen, H, and alkyl; the R13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, amide, amide, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, Cyanoalkyl and heterocyclic groups, wherein the heterocyclic group is, as appropriate, substituted by one or more independent substituents selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyl, cyano, cyanoalkyl and sulfonyl; A series selected from the group consisting of: substituted 5-membered heteroaryl, substituted 6-membered heteroaryl, pyridinone and substituted aryl ring;The L2 group is selected from the group consisting of direct bonds and alkyl groups, wherein the alkyl group is substituted by (E21)p as appropriate; the E2 group is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonylurea, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen each time it appears; and each p is independently 0, 1, or 2; the limiting condition is that the compound is not: .

[0018] In another embodiment, a pharmaceutical composition is described herein comprising a compound described herein (e.g., a compound of formula I described herein) and a pharmaceutically acceptable carrier or excipient. []

[0019] In another embodiment, this document describes a method for treating a patient in need of a disease caused by an dysregulation of the integrated stress response, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein.

[0020] In another embodiment, this document describes a method for treating a patient in need of a disease caused by dysregulation of the integrated stress response and / or unfolded protein response, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0021] In another embodiment, this document describes a method for modulating the GCN2 kinase activity of a patient in need, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0022] In another embodiment, this document describes a method for activating GCN2 kinase in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0023] In another embodiment, this document describes a method for modulating the PERK kinase activity of a patient in need, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0024] In another embodiment, this document describes a method for activating PERK kinase in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0025] In another embodiment, this document describes a method for inhibiting GCN2 kinase and PERK kinase in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0026] In another embodiment, this document describes a method for modulating the GCN2 kinase activity of a patient in need, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0027] In another embodiment, this document describes a method for inhibiting PERK kinase activity in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0028] In another embodiment, this document describes a method for treating a patient in need of a disease selected from GCN2-related diseases and PERK-related diseases, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0029] In another embodiment, this document describes a method for treating a patient in need of a disease selected from GCN2-related diseases and PERK-related diseases, comprising administering to the patient a therapeutically effective amount of the compound described herein or its pharmaceutically acceptable salt and a therapeutically effective amount of one or more therapeutic agents.

[0030] In another embodiment, a method of treating cancer in a patient in need is described herein, comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of formula I described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. []

[0031] In another embodiment, this document describes a method for treating a patient in need of a condition selected from the group consisting of: melanoma, fibrosarcoma, thyroid cancer, ovarian cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumor, solid tumor, hematogenous cancer, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and other cancers caused by activation of the GCN2 signaling pathway, the method comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of formula I described herein) or a pharmaceutically acceptable salt thereof. Simple Explanation of the Diagram

[0032] Figure 1 depicts the stimulation of ATF4 cells in H929 multiple myeloma cells induced by compound 16.

[0033] Figure 2 depicts the PERK oligomer stimulation plot of compound 16 in HEK293T NanoBRET-based analysis.

[0034] Figure 3 depicts the stimulation of PERK downstream signaling proteins ATF4 and CHOP using actin as an internal reference. The figure shows that, as detected by Western ink dot analysis, compound 16 increases the expression of the PERK signaling pathway in H929 multiple myeloma cells.

[0035] Figure 4 illustrates the fold increase in the expression of compound 16 on PERK pathway target genes ATF4, CHOP, GADD34, GPT2, and VEGFA in H929 multiple myeloma cells, as analyzed by QRT-PCR (compared to the DMSO control).

[0036] Figure 5 illustrates the effect of compound 16 as a single agent on apoptosis pathway readouts in H929 multiple myeloma cells using Western ink dot analysis, including cleaved PARP, cleaved apoptotic protease 7, and cleaved apoptotic protease 3.

[0037] Figures 6A, 6B, 6C, and 6D show the effects of compound 16 as a single agent and in combination with standard of care on cell proliferation of RPMI8226 multiple myeloma cells (Figure 6A), H929 multiple myeloma cells (Figure 6B), GA-10 Burkitts lymphoma cells (Figure 6C), and DOHH-2 follicular lymphoma cells (Figure 6D).

[0038] Figures 7A and 7B illustrate the effect of the combination of compound 16 and asparagine on ATF4 levels in an in vivo PK / PD model, analyzed using the Western ink dot method, and GCN2 activity was measured. The corresponding plasma levels of compound 16 were measured at PD time points of 2, 6, and 10 hours after administration. Figure 7A presents a graph of the results obtained from the PK / PD model study, and Figure 7B presents the results in tabular form.

[0039] Figure 8 illustrates the effect of the combination of compound 16 and asparagine on tumor growth in the MV-4-11 xenograft model. Implementation

[0040] The features and other details of the invention are described more specifically below. Specific terminology used in this specification, examples, and the appended claims is collected herein. These definitions should be read in light of the remainder of the invention and as understood by one skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art. definition

[0041] The definitions set forth in this application are intended to clarify the terminology used throughout this application.

[0042] 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 subject matter belongs. Unless otherwise stated, as used in the specification and the appended claims, the following terms have the meanings assigned to facilitate understanding of the invention.

[0043] When a bond to a substituent is shown to cross with a bond between two atoms in the connecting ring, such a substituent may be bonded to any atom in that ring. If the listed substituents do not indicate that such substituents are bonded to atoms of the remainder of the compound of the specified chemical formula, such substituents may be bonded to any atom of such substituents. Such combinations are permitted when combinations of substituents, substituent positions, and / or variables result in a stable compound.

[0044] As used herein, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” cover a plural reference.

[0045] As used herein, the term "this article" means the entire application.

[0046] As used herein, "deuteration" means that at least one hydrogen atom has been replaced by deuterium. In any sample of a deuterated compound, some discrete molecules of the compound may have hydrogen instead of deuterium at a specified position. However, the percentage of molecules in a deuterated compound having deuterium at a specified position will be much greater than in naturally occurring compounds. Deuterium concentration is increased at the deuteration site.

[0047] As used herein, the terms "optional" or "optionally" mean that an event or situation described below may or may not occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. For example, "optionally substituted alkyl" means both cases where the alkyl group is substituted and cases where the alkyl group is not substituted.

[0048] It should be understood that those skilled in this art can select the substituents and substitution patterns of the revealed compounds to produce chemically stable compounds that can be readily synthesized from readily available starting materials using techniques known in this art and the methods described below. If a substituent is itself substituted by more than one group, it should be understood that these multiple groups can be on the same carbon or on different carbons, as long as a stable structure is produced.

[0049] As used herein, the term "substituted as appropriate" means the substitution of one to six hydrogen atoms in a given structure by a specified substituent, including but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, aryl, cycloalkyl, heterocyclic, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, and -OC(=O)-CH2-O alkyl. Preferably, "substituted as appropriate" means the substitution of one to four hydrogen atoms in a given structure by one of the substituents mentioned above. More preferably, one to three hydrogen atoms are substituted by one of the substituents mentioned above. It should be understood that the substituents may be further substituted.

[0050] As used herein, the term "substituted" refers to a portion of the main chain on one or more carbons having a substituent that replaces hydrogen. It should be understood that "substituted" or "substituted" includes implied limitations, namely that such substitution is based on the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, for example, one that does not spontaneously undergo transformation (such as by recombination, cyclization, elimination, etc.). As used herein, the term "substituted" is used to encompass all permissible substituents in organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. For suitable organic compounds, permissible substituents may be one or more and may be the same or different. For the purposes of this application, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents in organic compounds that satisfy the heteroatom valences described herein.

[0051] Substituents may include any substituents described herein, such as halogens, hydroxyl groups, carbonyl groups (such as carboxyl, alkoxycarbonyl, methyl, or acetyl), alkoxy groups, amino groups, acetamino groups, imine groups, cyano groups, sulfonyl groups, heterocyclic groups, aralkyl groups, heteroaralkyl groups, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that substituents themselves may be substituted where appropriate. For example, substituents of substituted alkyl groups may include substituted and unsubstituted forms of amino, acetamino, sulfonyl, and ether, carboxyl (including carboxylates and esters), -CF3, -CN, and similar groups. Unless specifically stated as "unsubstituted," references to the chemical term herein should be understood to include substituted variants. For example, references to the "aryl" group or part thereof implicitly include both substituted and unsubstituted variants.

[0052] As used herein, the term "alkyl" refers to a fully saturated straight-chain or branched non-aromatic hydrocarbon. Generally, unless otherwise defined, straight-chain or branched alkyl groups have 1 to about 20 carbon atoms, preferably 1 to about 10, and may be, for example, C1-C10 alkyl groups or, for example, C1-C6 alkyl groups. Examples of straight-chain and branched alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl), 2-propyl, n-butyl, secondary butyl, tertiary butyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl and similar groups. Furthermore, the term "alkyl" as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter referring to an alkyl moiety having a substituent replacing one or more hydrogen atoms on the hydrocarbon backbone. "Alkyl" may be substituted, as appropriate.

[0053] The term "CxCy" when used in conjunction with chemical moieties such as acetyl, acetoxy, alkyl, alkenyl, alkynyl, or alkoxy is intended to include groups containing x to y carbons in the chain. For example, the term "CxCy" refers to substituted or unsubstituted saturated hydrocarbon groups containing x to y carbons in the chain, including straight-chain alkyl and branched-chain alkyl groups, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. C0 alkyl indicates hydrogen when the group is terminal, and a single bond when it is internal.

[0054] As used herein, the term "alkoxy" refers to a straight-chain or branched, saturated aliphatic (alkyl) hydrocarbon group bonded to an oxygen atom attached to the core structure. Preferably, the alkoxy group has one to six carbon atoms, i.e., a C1-C6 alkoxy group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tributoxy, pentoxy, 3-methylbutoxy, and similar groups.

[0055] As used herein, the term "alkoxyalkyl" refers to an alkoxy-substituted alkyl group (as defined above) and may be represented by the general formula alkyl-O-alkyl. Examples of alkoxyalkyl groups include, but are not limited to, methyl-O-ethyl- and ethyl-O-ethyl-.

[0056] As used herein, the term "haloalkyl" refers to an alkyl group (as defined above) that has been substituted with one or more halogens. For example, a monohaloalkyl group may have chlorine, bromine, iodine, or fluorine atoms. Dihaloalkyl and polyhaloalkyl groups may have two or more identical or different halogen atoms. Examples of haloalkyl groups include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, and similar groups.

[0057] As used herein, the term "haloalkoxy" refers to a group in which one or more hydrogen atoms of an alkoxy group are substituted with one or more halogens. Representative examples of "haloalkoxy" include, but are not limited to, difluoromethoxy (-OCHF 2), trifluoromethoxy (-OCF 3), or trifluoroethoxy (-OCH 2CF 3).

[0058] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups, wherein each atom of the ring is a carbon. The ring is preferably a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings (fused rings), at least one of which is aromatic; for example, the other ring may be cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic. The term "fused" means the attachment or formation of a second ring by sharing two adjacent atoms with a first ring. The term "fused" is equivalent to the term "condensation." Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrene, phenol, aniline, dihydroindene, dihydrobenzofuranyl, dihydroisobenzofuranyl, indololinyl, isoindololinyl, and similar groups. Unless otherwise specified, the aryl groups described herein may be substituted as appropriate.

[0059] As used herein, the terms "polycyclic," "polycyclic," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic) in which one or more atoms are shared by two adjacent rings, such as "fused rings." Each ring in a polycyclic compound may be substituted or unsubstituted. In some embodiments, each ring in a polycyclic compound contains 3 to 10, preferably 5 to 7, atoms.

[0060] As used herein, the term "acyl" refers to the group -C(=O)-Rw, where Rw is an alkyl group that is substituted as appropriate. Examples of "acyl" include, but are not limited to, cases where Rw is a C1-C10 alkyl (C1-C10 acyl) or a C1-C6-alkyl (C1-C6 acyl). In some embodiments, the substituents that are substituted as appropriate are independently selected from the group consisting of H, OH, alkoxy, cyano, F, and amino groups each time they appear. Other examples of "acyl" include -C(=O)-CH3, -C(=O)-CH2-CH3, -C(=O)-CH2-CH2-CH3, or -C(=O)-CH(CH3)2.

[0061] As used herein, the terms "amine" and "amino group" refer to unsubstituted and substituted amines and their salts, such as portions that can be represented by the following formula: or R 6b independently represents hydrogen, alkyl or cycloalkyl, or the R 6b group together with the attached N atom completes a heterocycle having 4 to 8 atoms in the ring structure.

[0062] As used herein, the terms "acetylamine" and "acetylamine group" refer to groups represented by the following: R7'', R8'', and R10'' each independently represent a hydrogen or hydrocarbon group, or R8'' and R10'' together with the attached N atom form a heterocyclic group with 4 to 8 atoms in the ring structure.

[0063] As used herein, the term "acetaminophen" refers to an amino group as defined above that has been substituted with an acetaminophen group.

[0064] As used herein, the term "aminocarbonyl" refers to a carbonyl group that has been substituted with an amino group.

[0065] As used herein, the term "alkylamine" refers to an amino group as defined above that is substituted with at least one alkyl group.

[0066] As used herein, the term "aminoalkyl" refers to an alkyl group that has been substituted with an amino group.

[0067] As used herein, the term "acetylated alkyl" refers to an alkyl group substituted with an acetylated group.

[0068] As used herein, the term "cyanoalkyl" refers to an alkyl group that has been substituted with a cyano group.

[0069] As used herein, the term "cycloalkoxyalkyl" refers to an alkyl group substituted with a cycloalkoxy group (as defined above) and can be represented by the general formula cycloalkyl-O-alkyl. Examples of cycloalkoxyalkyl groups include, but are not limited to, cyclopropyl-O-methylene- and cyclopropyl-O-ethyl-.

[0070] As used herein, the term "heteroarylalkyl" refers to an alkyl group that has been substituted with a heteroaryl group.

[0071] As used herein, the term "heterocyclic alkyl" refers to an alkyl group that has been substituted with a heterocyclic group.

[0072] As used herein, the term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group.

[0073] As used herein, the term "cycloalkyl," alone or in combination with other terms, refers to a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic, bicyclic, and tricyclic compounds. Generally, unless otherwise defined, monocyclic cycloalkyl compounds have 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms (e.g., C3-C10 cycloalkyl or, for example, C3-C6 cycloalkyl). Examples of monocyclic cycloalkyl compounds include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and similar groups. The second or third ring of a bicyclic or tricyclic cycloalkyl compound may be self-saturated, unsaturated, or aromatic. Cycloalkyl compounds include bicyclic and tricyclic molecules in which one, two, or three or more atoms are shared between the two rings. Cycloalkyl compounds may be further substituted with alkyl, alkenyl, alkoxy, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, and similar groups.

[0074] As used herein, the term "cycloalkylalkyl" refers to an alkyl group that has been substituted with a cycloalkyl group.

[0075] As used herein, the term "cyano" refers to the -CN group.

[0076] As used herein, the term "hydroxyl" or "hydroxyl" refers to the -OH group.

[0077] As used herein, the term "halogen" or "halogen" alone or in combination with other terms means chlorine, fluorine, bromine, and iodine.

[0078] As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Exemplary heteroatoms include nitrogen (N), oxygen (O), sulfur (S), and silicon (Si).

[0079] As used herein, the terms "heterocyclic," "heterocyclic alkyl," "heterocycle," and "heterocyclic" refer to non-aromatic, saturated, or partially saturated ring systems of 3 to 15 members, including monocyclic, polycyclic (e.g., bicyclic, tricyclic) bridged or fused rings, having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)₂, NH, or C(O), with the remaining ring atoms independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. Examples of "heterocyclic alkyl" include, but are not limited to, acryl, oxadiazinyl, imidazolidinyl, pyrrolidyl, and others. Azoxyl, thiazolidinyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, piperidine group, tetrahydropiperanyl, morpholinyl, thio linyl, 1,4-di Alkyl, dioxo-ionized thiomorpholino, oxopyr , oxaperidyl, tetrahydrofuranyl, tetrahydropiperanyl, tetrahydrothiophenyl, dihydropiperanyl, indololinyl, indololinylmethyl, 2-azabicyclo[2.2.2]octyl, acrylinyl, alkyl, Heterocyclic alkyl groups and their N-oxides. The attachment of heterocyclic alkyl substituents can occur via carbon atoms or via heteroatoms. Heterocyclic alkyl groups can be substituted by one or more of the aforementioned groups via one or more suitable groups, depending on the situation. Preferably, "heterocyclic alkyl" refers to a 5- or 6-membered ring selected from the group consisting of: acryl, oxadiazinyl, imidazolidinyl, pyrrolidyl, ... Azoxyl, thiazolidinyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, piperidine , tetrahydropiperanyl, morpholinyl, thiomorpholinyl, 1,4-di Alkyl groups and their N-oxides. More preferably, "heterocyclic alkyl" includes acrylyl, pyrrolidyl, morpholinyl, and piperidinyl. Heterocyclic alkyl groups may be substituted with one or more of the aforementioned groups, depending on the situation.

[0080] As used herein, the term "heteroaryl" refers to a substituted or unsubstituted aromatic monocyclic structure, preferably a 5- to 7-membered ring, more preferably a 5- to 6-membered ring, whose ring structure includes at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The term "heteroaryl" also refers to a substituted or unsubstituted aromatic or partially aromatic ring system containing at least one heteroatom and having two or more cyclic rings (bicyclic, tricyclic, or polycyclic), containing 8 to 20 ring atoms, suitably 5 to 10 ring atoms, which may be covalently linked or fused, wherein two or more atoms are shared by two adjacent rings, wherein at least one of these rings is heteroaromatic, for example, the other cyclic ring may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. These rings may contain N or S atoms, wherein the N or S atom is oxidized as appropriate, or the N atom is quaternarily ammonized as appropriate. All heteroaryl groups are substituted as appropriate. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure. Examples of heteroaryl groups include, but are not limited to: furanyl, thiophene, pyrrole, pyrazolyl, imidazole, etc. azole group, phyrin, iso Azolyl, thiazolyl, isothiazolyl, 1H-tetrazoleyl diazole, triazole, pyridinyl, pyrimidinyl, pyridine Ji, Da Basic, Three Benzyl, benzo[ azole group, benzo[a] azole, benzothiazolyl, benzofuranyl, benzothiophene, benzotriazolyl Base, Tai , thiamethoxamyl, dibenzofuranyl, dibenzothiophenyl, benzimidazolyl, indoleyl, isoindoleyl, indazoleyl, quinolinyl, isoquinolinyl, quinazolinyl, quinolinyl, purineyl, pteridinyl, 9H-carbazolyl, α-carboline, indole Benzyl, benzoisothiazolyl, benzo[] Azolyl, pyrrolopyridyl, furanopyridyl, purine, benzothiadiazole, benzo[] Diazolyl, benzotriazolyl, benzothiadiazolyl, carbazole, dibenzothiaphenyl, acridineyl and similar groups.

[0081] As used herein, the term "sulfonamide" is represented by the following: or Each time R 6c appears, it independently represents hydrogen, alkyl or cycloalkyl, or an R 6c group together with its attached N atom, forming a heterocycle with 4 to 8 atoms in the ring structure.

[0082] As used herein, the term "sulfonyl" refers to the group -S(O)2-R6d, where R6d indicates an alkyl or cycloalkyl group.

[0083] "Combination therapy" refers to treatment that involves administering two or more therapeutic agents, such as a compound of formula I and the enzyme asparaginase (ASNase) or its derivatives, to patients in need.

[0084] The terms "disease," "symptom," and "condition" are used interchangeably in this article.

[0085] "Individual / subject" and "patient" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred. The compounds described herein can be administered not only to mammals such as humans, but also to other mammals, such as animals requiring veterinary treatment, such as livestock (e.g., dogs, cats, and the like), agricultural animals (e.g., cows, sheep, pigs, horses, and the like), and laboratory animals (e.g., rats, mice, guinea pigs, and the like).

[0086] The compounds described herein are suitable for treating GCN2-driven diseases (sometimes abbreviated as "GCN2-related diseases" in this invention), such as cancers [e.g., colorectal cancer (e.g., colorectal cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic duct cancer, pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), duodenal cancer, small bowel cancer, breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer), ovarian cancer (e.g., ovarian epithelial carcinoma, gonadal extragerminal tumor, ovarian germ cell tumor, low-grade malignant potential ovarian tumor), testicular tumors, prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone-dependent prostate cancer, castration-resistant prostate cancer), liver cancer]. (e.g., liver cancer, primary liver cancer, extrahepatic bile duct cancer), thyroid cancer (e.g., medullary thyroid carcinoma), kidney cancer (e.g., renal cell carcinoma (e.g., clear cell renal cell carcinoma), transitional cell carcinoma of the renal pelvis and ureter), uterine cancer (e.g., cervical cancer, endometrial cancer, uterine sarcoma), gestational choriocarcinoma, brain tumors (e.g., medulloblastoma, glioma, pineal astrocytoma, piloastrocytoma, diffuse astrocytoma, degenerative astrocytoma, pituitary adenoma), retinoblastoma, skin cancer (e.g., basal cell carcinoma, malignant melanoma), sarcoma (e.g., rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, spindle cell sarcoma, osteosarcoma), malignant bone tumors, bladder cancer, blood cancers (e.g., multiple myeloma, leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia (including the onset of chronic leukemia)), malignant lymphoma, Hodgkin's disease) [Diseases], chronic myeloproliferative disorders, cancers of unknown primary nucleus, cancer growth inhibitors, cancer metastasis inhibitors, apoptosis promoters, and drugs used to prevent or treat precancerous lesions (such as myelodystrophy syndrome).

[0087] The compounds described herein, such as compounds of formula I as defined herein, may be administered in combination with one or more additional therapeutic agents to treat the conditions described herein, such as the cancers described herein. In some embodiments, the compounds described herein may be used in combination with hormonal therapeutic agents, chemotherapeutic agents, immunotherapeutic agents, agents that inhibit the action of cell growth factors and their receptors (such as PERK inhibitors and autophagy inhibitors, asparagine enzymes (ASNase)) and the like.

[0088] "Pharmaceutical or pharmacologically acceptable" includes molecular entities and compositions that, when administered to animals or humans, do not produce adverse, allergic, or other undesirable reactions. For human administration, the formulation should meet the sterility, pyrogenicity, and general safety and purity standards required by the FDA Office of Biologics Standards.

[0089] As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceutical acceptable excipient" refer to any and all solvents, dispersion media, coatings, isotonics, absorption delay agents, and the like that are compatible with pharmaceutical administration. The use of such media and pharmaceuticals for pharmaceutically active substances is well known in the art. Compositions may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic functions.

[0090] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound as disclosed herein, formulated together with one or more pharmaceutically acceptable carriers.

[0091] As used herein, the term "one or more pharmaceutically acceptable salt(s)" refers to a salt having acidic or basic groups that can be present in the compounds used in the composition. The compounds included in the compositions of this invention, which are inherently basic, can form a wide variety of salts with various inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are acids that form non-toxic acid addition salts, which are salts containing pharmacologically acceptable anions, including but not limited to malates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleate, gentianate, fumarates, gluconates, glucuronides, gluconate dihydrates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl)ate (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthyl)ate). The compounds included in the compositions of the present invention, which are inherently acidic, can form basic salts with a variety of pharmacologically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, specifically calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. The compounds included in the compositions of the present invention, including basic or acidic portions, can also form pharmaceutically acceptable salts with various amino acids. The compounds of the present invention may contain both acidic and basic groups; for example, an amino group and a carboxylic acid group. In such cases, the compounds may exist as acid addition salts, zwitterions, or basic salts.

[0092] The compounds of this invention may contain one or more palmate centers and thus exist in stereoisomers. The term "stereoisomer," as used herein, comprises all enantiomers or diastereomers. Depending on the configuration of the substituents surrounding the stereoforming carbon atom, such compounds may be designated by the symbols "R" or "S," but those skilled in the art will recognize that the structure implicitly represents the palmate center. Such compounds may also be designated by "(+)" and "(-)" based on their optical rotational properties. The compounds described in this invention encompass various stereoisomers of such compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated by the symbol "(±)" in the nomenclature, but those skilled in the art should recognize that the structure implicitly represents the palmate center.

[0093] In this specification, the term "therapeuticly effective amount" means the amount of the compound of the invention that researchers, veterinarians, medical professionals, or other clinicians are seeking to elicit a biological or medical response in a tissue, system, or animal (e.g., a mammal or a human). The compounds described herein are administered in therapeutically effective amounts to treat a condition.

[0094] "Treatment" includes any action that causes improvement in a condition, disease, symptom or similar condition, such as reducing, decreasing, regulating or eliminating it.

[0095] This invention also covers isotopically labeled compounds consistent with those described herein, differing in that one or more atoms have undergone atomic substitutions with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. For example, the compounds of this invention may have one or more deuterium-substituted H atoms.

[0096] Individual enantiomers and diastereomers of the disclosed compounds can be prepared synthetically from commercially available starting materials containing asymmetric or stereosymmetric centers, or by preparing racemic mixtures followed by analytical methods well known to those skilled in the art. Such analytical methods are exemplified by: (1) attaching a mixture of enantiomers to a chiral auxiliary agent, separating the resulting mixture of diastereomers by recrystallization or chromatography, and releasing an optically pure product from the auxiliary agent; (2) forming a salt using an optically active analytical agent; (3) directly separating a mixture of optically enantiomers on a chiral liquid chromatography column; or (4) performing kinetic analysis using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved to their constituent enantiomers by well-known methods such as chiral liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis of unequal mixtures of stereoisomers formed by chemical or enzymatic reactions during the formation of new stereocenters or during the transformation of pre-existing stereocenters is well known in the art. Stereoselective synthesis encompasses both enantioselective and diastereoselective transformations and may involve the use of chiral auxiliaries. For example, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009. compound

[0097] In one embodiment, this document describes a compound represented by formula I: Formula I Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: The X1 group is composed of CH and N; the X2 and X3 groups are each independently composed of the following groups: N, CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2, with the restriction that the X2 group is composed of CH and N, and the X3 group is composed of the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; with the restriction that the X2 group is composed of the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2, and the X3 group is composed of CH and N; the X4 group is composed of CR 3 and N; the X10 group is composed of CR 5 and N; the X11 group is composed of CR 7 and N; R R1 is selected from the group consisting of: H, alkyl, (C=O)R13, ​​cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl and sulfonyl; R2 is selected from the group consisting of H and alkyl; R The R3 series is selected from the group consisting of H, alkyl, and halogen; the R4 and R5 series are each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 and R7 series are each independently selected from the group consisting of halogen, H, and alkyl; the R13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, amide, amide, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, Cyanoalkyl and heterocyclic groups, wherein the heterocyclic group is, as appropriate, substituted by one or more independent substituents selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyl, cyano, cyanoalkyl and sulfonyl; A series selected from the group consisting of: substituted 5-membered heteroaryl, substituted 6-membered heteroaryl, pyridinone and substituted aryl ring;The L2 group is selected from the group consisting of direct bonds and alkyl groups, wherein the alkyl group is substituted by (E21)p as appropriate; the E2 group is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonylurea, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen each time it appears; and each p is independently 0, 1, or 2; the limiting condition is that the compound is not: .

[0098] In some embodiments, the compound is represented by formula IA: Formula IA Or, pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X3 series are selected from the group consisting of: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; X5 series are selected from the group consisting of CR 8 and N; X6 series are selected from the group consisting of CR 9 and N; X7 series are selected from the group consisting of CR 10 and N; X8 series are selected from the group consisting of CR 11 and N; X9 series are selected from the group consisting of CR 8 and N, with the restriction that no more than three of X5, X6, X7, X8, and X9 are N; X10 series are selected from the group consisting of CR 5 and N; X11 series are selected from the group consisting of CR 7 and N; R1 series are selected from the group consisting of: H, alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R4 and R The R5 series are each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 and R7 series are each independently selected from the group consisting of halogen, H, and alkyl; the R8 series are each selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxy, and CN; the R9, R10, and R11 series are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amideamino, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, haloalkyl, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl;R13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, amide, amide, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; L2 series is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein C1-C6... 6. Alkyl groups are optionally substituted with (E 21) p; E 2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E 21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen each time it appears; and each p is independently 0, 1, or 2.

[0099] In some embodiments, the compound is represented by formula IB: Formula IB Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X3 is selected from the group consisting of CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; X4 is selected from the group consisting of CR 3 and N; X5 is selected from the group consisting of CR 8 and N; X6 is selected from the group consisting of CR 9 and N; X7 is selected from the group consisting of CR 10 and N; X8 is selected from the group consisting of CR 11 and N; X9 is selected from the group consisting of CR 8 and N, with the restriction that no more than three of X5, X6, X7, X8, and X9 are N; X10 is selected from the group consisting of CR 5 and N; X11 is selected from the group consisting of CR 7 and N; R R1 is selected from the group consisting of: H, alkyl, (C=O)R13, ​​cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl and sulfonyl; R2 is selected from the group consisting of H and alkyl; R The R3 series is selected from the group consisting of H, alkyl, and halogens; the R4 and R5 series are each independently selected from the group consisting of: halogens, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 and R7 series are each independently selected from the group consisting of halogens, H, and alkyl; the R8 series is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogens, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxy, and CN; the R9, R10, and R The 11-series are each independently selected from the following groups: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamino, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, haloalkyl, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl;R13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, amide, amide, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; L2 series is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein C1-C6... 6. Alkyl groups are optionally substituted with (E 21) p; E 2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E 21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen each time it appears; and each p is independently 0, 1, or 2.

[0100] In some embodiments, the compound is represented by the formula IC: IC Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X2 and X3 are each independently chosen from the following groups: N, CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2, with the restriction that X2 is chosen from groups consisting of CH and N, and X3 is chosen from the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; with the restriction that X2 is chosen from groups consisting of CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2, and X3 is chosen from groups consisting of CH and N; X4 is chosen from groups consisting of CR 3 and N; X5 is chosen from groups consisting of CR 8 and N; X6 is chosen from groups consisting of CR 9 and N; X7 is chosen from groups consisting of CR 10 and N; X8 is chosen from groups consisting of CR 9 and N. The group consisting of 11 and N; the X9 group is selected from the group consisting of CR8 and N, with the restriction that no more than three of X5, X6, X7, X8, and X9 are N; the X10 group is selected from the group consisting of CR5 and N; the X11 group is selected from the group consisting of CR7 and N; the R1 group is selected from the group consisting of H, alkyl, (C=O)R. 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R4 and R The R5 series are each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 and R7 series are each independently selected from the group consisting of halogen, H, and alkyl; the R8 series are each selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxy, and CN; the R9, R10, and R11 series are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, haloalkyl, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl;R13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, amide, amide, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; L2 series is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein C1-C6... 6. Alkyl groups are optionally substituted with (E 21) p; E 2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E 21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen each time it appears; and each p is independently 0, 1, or 2.

[0101] In some embodiments, the compound is represented by formula ID: Formula ID Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X2 and X3 are each independently chosen from the following groups: N, CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2, with the restriction that X2 is chosen from groups consisting of CH and N, and X3 is chosen from the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; with the restriction that X2 is chosen from groups consisting of CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2, and X3 is chosen from groups consisting of CH and N; X4 is chosen from groups consisting of CR 3 and N; X5 is chosen from groups consisting of CR 8 and N; X6 is chosen from groups consisting of CR 9 and N; X7 is chosen from groups consisting of CR 10 and N; X8 is chosen from groups consisting of CR 9 and N. The group consisting of 11 and N; the X9 group is selected from the group consisting of CR8 and N, with the restriction that no more than three of X5, X6, X7, X8, and X9 are N; the X10 group is selected from the group consisting of CR5 and N; the X11 group is selected from the group consisting of CR7 and N; the R1 group is selected from the group consisting of H, alkyl, (C=O)R. 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R4 and R The R5 series are each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 and R7 series are each independently selected from the group consisting of: halogen, H, and alkyl; the R8 series are each selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxy, and CN; the R9, R10, and R11 series are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amideamino, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, haloalkyl, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl;R13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, amide, amide, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; L2 series is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein C1-C6... 6. Alkyl groups are optionally substituted with (E 21) p; E 2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E 21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen each time it appears; and each p is independently 0, 1, or 2.

[0102] In some embodiments, the compound is represented by the formula IE: IE Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X2 series are selected from the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; X5 series are selected from the group consisting of CR 8 and N; X6 series are selected from the group consisting of CR 9 and N; X7 series are selected from the group consisting of CR 10 and N; X8 series are selected from the group consisting of CR 11 and N; X9 series are selected from the group consisting of CR 8 and N, with the restriction that no more than three of X5, X6, X7, X8, and X9 are N; X10 series are selected from the group consisting of CR 5 and N; X11 series are selected from the group consisting of CR 7 and N; R1 series are selected from the following groups: H, alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of: H, alkyl, and halogen; R4 and R The R5 series are each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 and R7 series are each independently selected from the group consisting of halogen, H, and alkyl; the R8 series are each selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxy, and CN; the R9, R10, and R11 series are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, haloalkyl, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl;R13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, amide, amide, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; L2 series is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein C1-C6... 6. Alkyl groups are optionally substituted with (E 21) p; E 2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E 21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen each time it appears; and each p is independently 0, 1, or 2.

[0103] In some embodiments, the compound is represented by the formula IF: Formula IF Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X2 series are selected from the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; X4 series are selected from the group consisting of CR 3 and N; X5 series are selected from the group consisting of CR 8 and N; X6 series are selected from the group consisting of CR 9 and N; X7 series are selected from the group consisting of CR 10 and N; X8 series are selected from the group consisting of CR 11 and N; X9 series are selected from the group consisting of CR 8 and N, with the restriction that no more than three of X5, X6, X7, X8, and X9 are N; X10 series are selected from the group consisting of CR 5 and N; X11 series are selected from the group consisting of CR 7 and N; R1 series are selected from the following groups: H, alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of: H, alkyl, and halogen; R4 and R The R5 series are each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 and R7 series are each independently selected from the group consisting of halogen, H, and alkyl; the R8 series are each selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxy, and CN; the R9, R10, and R11 series are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, haloalkyl, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl;R13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, amide, amide, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; L2 series is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein C1-C6... 6. Alkyl groups are optionally substituted with (E 21) p; E 2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E 21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen each time it appears; and each p is independently 0, 1, or 2.

[0104] In some embodiments, the compound is represented by the formula IG: IG Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: The X3 series is selected from the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; the X10 series is selected from the group consisting of CR 5 and N; the X11 series is selected from the group consisting of CR 7 and N; the R1 series is selected from the following groups: H, alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of: H, alkyl, and halogen; R4 and R The R5 series are each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 and R7 series are each independently selected from the group consisting of halogen, H, and alkyl; the R12 series are individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, haloalkyl, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, and heterocyclic alkyl; The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more independent substituents selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, amide, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and Heterocyclic groups, wherein the heterocyclic group is, as appropriate, substituted by one or more independent substituents selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyl, cyano, cyanoalkyl, and sulfonyl; B group is selected from the group consisting of five-membered heteroaryl, six-membered heteroaryl, and pyridinone, wherein the five- or six-membered heteroaryl ring or the pyridinone is, as appropriate, substituted by R12 at each substituted position; L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl, wherein the C1-C6 alkyl is, as appropriate, substituted by (E21)p;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen in each occurrence; and each p is independently 0, 1, or 2.

[0105] In some embodiments, the compound is represented by formula IH: Formula IH Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: The X3 series is selected from the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; the X4 series is selected from the group consisting of CR 3 and N; the X10 series is selected from the group consisting of CR 5 and N; the X11 series is selected from the group consisting of CR 7 and N; the R1 series is selected from the following groups: H, alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of: H, alkyl, and halogen; R4 and R The R5 series are each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 and R7 series are each independently selected from the group consisting of halogen, H, and alkyl; the R12 series are individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, haloalkyl, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, and heterocyclic alkyl; The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more independent substituents selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, amide, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and Heterocyclic groups, wherein the heterocyclic group is, as appropriate, substituted by one or more independent substituents selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyl, cyano, cyanoalkyl, and sulfonyl; B group is selected from the group consisting of five-membered heteroaryl, six-membered heteroaryl, and pyridone, wherein the five- or six-membered heteroaryl ring or pyridone is, as appropriate, substituted by R12 at each substituted position; L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl, wherein the C1-C6 alkyl is, as appropriate, substituted by (E21)p;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen in each occurrence; and each p is independently 0, 1, or 2.

[0106] In some embodiments, the compound is represented by formula IJ: Formula IJ Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X2 and X3 are each independently selected from the following groups: N, CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2, with the restriction that X2 is selected from the group consisting of CH and N, and X3 is selected from the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; with the restriction that X2 is selected from the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2, and X3 is selected from the group consisting of CH and N; X4 is selected from the group consisting of CR 3 and N; X10 is selected from the group consisting of CR 5 and N; X11 is selected from the group consisting of CR 7 and N; R1 is selected from the following groups: H, alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R4 and R The R5 series are each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 and R7 series are each independently selected from the group consisting of halogen, H, and alkyl; the R12 series are individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, haloalkyl, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, heterocyclic, and heterocyclic alkyl;R 13 is selected from the group consisting of: H, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more independent substituents selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, amide, amide, alkoxyalkyl, hydroxyl, hydroxyalkyl, cyano. Cyanoalkyl and heterocyclic groups, wherein the heterocyclic group is, as appropriate, substituted by one or more independent substituents selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; B group selected from the group consisting of five-membered heteroaryl, six-membered heteroaryl, and pyridinone, wherein the five- or six-membered heteroaryl ring or the pyridinone is, as appropriate, substituted at each substituted position by R 12-Substitution; L2 series is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted by (E21)p; E2 series is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl and heterocyclic groups, wherein the heterocyclic groups are optionally substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyl, cyano and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl and halogen each time it appears; and each p is independently 0, 1 or 2.

[0107] In some embodiments, the compound is represented by formula IK: Formula IK Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X2 and X3 are each independently selected from the following groups: N, CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2, with the restriction that X2 is selected from the group consisting of CH and N, and X3 is selected from the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; with the restriction that X2 is selected from the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2, and X3 is selected from the group consisting of CH and N; X4 is selected from the group consisting of CR 3 and N; X10 is selected from the group consisting of CR 5 and N; X11 is selected from the group consisting of CR 7 and N; R1 is selected from the following groups: H, alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R4 and R The R5 series are each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 and R7 series are each independently selected from the group consisting of halogen, H, and alkyl; the R12 series are individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, haloalkyl, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, and heterocyclic alkyl;R 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more independent substituents selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, amide, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and Heterocyclic groups, wherein the heterocyclic group is, as appropriate, substituted by one or more independently selected substituents from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyl, cyano, cyanoalkyl, and sulfonyl; B-groups are selected from the group consisting of five-membered heteroaryl, six-membered heteroaryl, and pyridinone, wherein the five- or six-membered heteroaryl ring or the pyridinone is, as appropriate, substituted at each substituted position by R 12-Substitution; L2 series is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted by (E21)p; E2 series is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl and heterocyclic groups, wherein the heterocyclic groups are optionally substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyl, cyano and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl and halogen each time it appears; and each p is independently 0, 1 or 2.

[0108] In some embodiments, the compound is represented by the formula IL: Formula IL Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: The X2 series is selected from the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; the X10 series is selected from the group consisting of CR 5 and N; the X11 series is selected from the group consisting of CR 7 and N; the R1 series is selected from the following groups: H, alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R4 and R The R5 series are each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 and R7 series are each independently selected from the group consisting of halogen, H, and alkyl; the R12 series are individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, haloalkyl, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, heterocyclic, and heterocyclic alkyl; R The 13-series is selected from the group consisting of: H, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more independent substituents selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, amide, amide, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano. Cyanoalkyl and heterocyclic groups, wherein the heterocyclic group is, as appropriate, substituted by one or more independent substituents selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyl, cyano, cyanoalkyl, and sulfonyl; B group is selected from the group consisting of five-membered heteroaryl, six-membered heteroaryl, and pyridinone, wherein the five- or six-membered heteroaryl ring or the pyridinone is, as appropriate, substituted by R12 at each substituted position; L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are, as appropriate, substituted by (E21)p;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen in each occurrence; and each p is independently 0, 1, or 2.

[0109] In some embodiments, the compound is represented by the formula IM: IM Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: The X2 series is selected from the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; the X4 series is selected from the group consisting of CR 3 and N; the X10 series is selected from the group consisting of CR 5 and N; the X11 series is selected from the group consisting of CR 7 and N; the R1 series is selected from the following groups: H, alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R4 and R The R5 series are each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 and R7 series are each independently selected from the group consisting of halogen, H, and alkyl; the R12 series are individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, haloalkyl, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, and heterocyclic alkyl; The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more independent substituents selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, amide, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and Heterocyclic groups, wherein the heterocyclic group is, as appropriate, substituted by one or more independent substituents selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyl, cyano, cyanoalkyl, and sulfonyl; B group is selected from the group consisting of five-membered heteroaryl, six-membered heteroaryl, and pyridone, wherein the five- or six-membered heteroaryl ring or pyridone is, as appropriate, substituted by R12 at each substituted position; L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl, wherein the C1-C6 alkyl is, as appropriate, substituted by (E21)p;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen in each occurrence; and each p is independently 0, 1, or 2.

[0110] In some embodiments, the compound is represented by the formula IN: IN Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: The X3 series is selected from the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; the X10 series is selected from the group consisting of CR 5 and N; the X11 series is selected from the group consisting of CR 7 and N; the R1 series is selected from the following groups: H, alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R4 and R The R5 series is independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 series is selected from the group consisting of halogen, H, and alkyl; the R7 series is selected from the group consisting of H and F; the R8 series is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy, and CN; the R10 and R11 series are independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; R The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acetyl, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetyl, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; the L2 series is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein C1-C6... 6-alkyl groups are substituted with (E 21) p, depending on the case;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen in each occurrence; and each p is independently 0, 1, or 2.

[0111] In some embodiments, the compound is represented by formula IO: IO Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: The X3 series is selected from the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; the X10 series is selected from the group consisting of CR 5 and N; the X11 series is selected from the group consisting of CR 7 and N; the R1 series is selected from the following groups: H, alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R4 and R The R5 series is independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 series is selected from the group consisting of halogen, H, and alkyl; the R7 series is selected from the group consisting of H and F; the R8 series is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy, and CN; the R10 and R11 series are independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; R The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acetyl, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetyl, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; the L2 series is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein C1-C6... 6-alkyl groups are substituted with (E 21) p, depending on the case;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen in each occurrence; and each p is independently 0, 1, or 2.

[0112] In some embodiments, the compound is represented by formula IP: IP Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X3 series are selected from the group consisting of: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; X10 series are selected from the group consisting of CR 5 and N; X11 series are selected from the group consisting of CR 7 and N; R1 series are selected from the group consisting of: H, alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R4 and R The R5 series is independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 series is selected from the group consisting of halogen, H, and alkyl; the R7 series is selected from the group consisting of H and F; the R8 series is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy, and CN; the R9, R10, and R11 series are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, haloalkyl, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; R The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl and sulfonyl;The L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with (E21)p; the E2 group is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic groups are optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyl, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen each time it appears; and each p is independently 0, 1, or 2.

[0113] In some embodiments, the compound is represented by formula IQ: Formula IQ Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: The X3 series is selected from the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; the X10 series is selected from the group consisting of CR 5 and N; the X11 series is selected from the group consisting of CR 7 and N; the R1 series is selected from the following groups: H, alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R4 and R The R5 series is independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 series is selected from the group consisting of halogen, H, and alkyl; the R7 series is selected from the group consisting of H and F; the R8 series is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy, and CN; the R9, R10, and R11 series are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, haloalkyl, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; R The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acetyl, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetyl, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; the L2 series is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein C1-C6... 6-alkyl groups are substituted with (E 21) p, depending on the case;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen in each occurrence; and each p is independently 0, 1, or 2.

[0114] In some embodiments, the compound is represented by formula I: Formula I Or, pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X1 is selected from the group consisting of CH and N; X2 and X3 are each independently selected from the group consisting of: N, CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2, wherein X2 is selected from the group consisting of CH and N, and X3 is selected from the group consisting of: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; wherein X2 is selected from the group consisting of: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2, and X3 is selected from the group consisting of CH and N; X4 is selected from the group consisting of CR 3 and N; X4 is selected from CR The X10 series is selected from the group consisting of CR5 and N; the X11 series is selected from the group consisting of CR7 and N; the R1 series is selected from the group consisting of H, alkyl, (C=O)R. 13. Alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R4 and R The R5 series are each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 and R7 series are each independently selected from the group consisting of halogen, H, and alkyl; R The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl and sulfonyl;The A series is selected from the group consisting of: substituted 5-membered heteroaryl groups, substituted 6-membered heteroaryl groups, pyridinones, and substituted aryl rings; the L2 series is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with (E21)p; the E2 series is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic groups are optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyl, cyano, and cyanoalkyl; E 21. Each time it appears, it is independently chosen from the following group of constituents: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; and each p is independently 0, 1, or 2; the restriction condition is that the compound is not: .

[0115] In some embodiments, the compound is represented by formula I: Formula I Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X1 is selected from the group consisting of CH and N; X2 is selected from the group consisting of N, CH, COL 2-E 2, and CL 2-E 2; X3 is CN(R 2)-L 2-E 2; X4 is selected from the group consisting of CR 3 and N; X10 is selected from the group consisting of CR 5 and N; X11 is selected from the group consisting of CR 7 and N; R1 is selected from the group consisting of H, alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R4 and R The R5 series are each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 and R7 series are each independently selected from the group consisting of halogen, H, and alkyl; the R13 series are selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, amide, amide, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyan Alkyl and heterocyclic groups, wherein the heterocyclic group is, as appropriate, substituted by one or more independent substituents selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyl, cyano, cyanoalkyl, and sulfonyl; A series is selected from the group consisting of: substituted 5-membered heteroaryl, substituted 6-membered heteroaryl, pyridone, and substituted aryl ring; L2 series is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are, as appropriate, substituted with (E21)p;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen in each occurrence; and each p is independently 0, 1, or 2.

[0116] In one embodiment, this document describes a compound represented by formula I: Formula I Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X1 is CH; X2 and X3 are each independently chosen from the following groups: N, CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2, with the constraint that X2 is chosen from groups consisting of CH and N, and X3 is chosen from the following groups: CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; with the constraint that X2 is chosen from groups consisting of CH, COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2, and X3 is chosen from groups consisting of CH and N; X4 is chosen from groups consisting of CR 3 and N; X10 is chosen from groups consisting of CR 5 and N; X11 is chosen from groups consisting of CR 7 and N; R R1 is selected from the group consisting of: H, alkyl, (C=O)R13, ​​cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl and sulfonyl; R2 is selected from the group consisting of H and alkyl; R The R3 series is selected from the group consisting of H, alkyl, and halogen; the R4 and R5 series are each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 and R7 series are each independently selected from the group consisting of halogen, H, and alkyl; the R13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, amide, amide, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, Cyanoalkyl and heterocyclic groups, wherein the heterocyclic group is, as appropriate, substituted by one or more independent substituents selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyl, cyano, cyanoalkyl and sulfonyl; A series selected from the group consisting of: substituted 5-membered heteroaryl, substituted 6-membered heteroaryl, pyridinone and substituted aryl ring;The L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with (E21)p; the E2 group is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic groups are optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyl, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen each time it appears; and each p is independently 0, 1, or 2.

[0117] In some embodiments, L2 is a direct bond. In some embodiments, L2 is an alkyl group. In some embodiments, L2 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted with (E21)p.

[0118] In some embodiments, X2 is N and X3 is selected from the group consisting of: CH, COL2-E2, CL2-E2 and CN(R2)-L2-E2.

[0119] In some embodiments, X2 is CH and X3 is selected from the group consisting of: N, COL2-E2, CL2-E2 and CN(R2)-L2-E2.

[0120] In some embodiments, X2 is selected from the group consisting of CH, COL2-E2, CL2-E2 and CN(R2)-L2-E2, and X3 is N.

[0121] In some embodiments, X2 is selected from the group consisting of CH, COL 2-E 2, CL 2-E 2 and CN(R 2)-L 2-E 2, and X3 is CH.

[0122] In some embodiments, X2 is selected from the group consisting of N and CH, and X3 is CN(R2)-L2-E2.

[0123] In some embodiments, X2 is N and X3 is CN(R2)-L2-E2.

[0124] In some embodiments, X2 is CH and X3 is CN(R2)-L2-E2.

[0125] In some embodiments, X2 is COL 2-E 2 and X3 is CN(R 2)-L 2-E 2.

[0126] In some embodiments, X2 is CL2-E2 and X3 is CN(R2)-L2-E2.

[0127] In some embodiments, X3 is CN(R2)-L2-E2.

[0128] In some embodiments, X2 is N and X3 is CCH3.

[0129] In some embodiments, X2 is N and X3 is CN(H)CH3.

[0130] In some embodiments, X2 is CH and X3 is N.

[0131] In some embodiments, the X3 series is selected from the group consisting of: R 14 is independently selected from the group consisting of: H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl and cyanoalkyl.

[0132] In some embodiments, R1 is H.

[0133] In some embodiments, R1 is a methyl group.

[0134] In some embodiments, R1 is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic and heterocyclic alkyl.

[0135] In some embodiments, R1 is selected from the group consisting of: R 14 is independently selected from the following group of components each time it appears: H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, and cyanoalkyl.

[0136] In some embodiments, R1 is selected from the group consisting of aryl and heteroaryl groups, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl and heterocyclic groups.

[0137] In some embodiments, R1 is selected from the group consisting of:

[0138] In some embodiments, R1 is selected from the group consisting of (C=O)R13, ​​wherein R13 is selected from the group consisting of H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl and heterocyclic, and wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl and sulfonyl.

[0139] In some embodiments, R1 is selected from the group consisting of: R 14 is independently selected from the following group of components each time it appears: H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, and cyanoalkyl.

[0140] In some embodiments, X1 is N.

[0141] In some embodiments, X1 is CH.

[0142] In some embodiments, the X2 series is selected from the group consisting of: R 14 is independently selected from the following group of components each time it appears: H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, and cyanoalkyl.

[0143] In some embodiments, the X3 series is selected from the group consisting of: R 14 is independently selected from the following group of components each time it appears: H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, and cyanoalkyl.

[0144] In some embodiments, X4 is selected from the group consisting of N and CR3.

[0145] In some embodiments, X 10 is selected from the group consisting of N and CR 5.

[0146] In some embodiments, X 11 is selected from the group consisting of N and CR 7.

[0147] In some embodiments, R3 is selected from the group consisting of H, alkyl groups and halogens.

[0148] In some embodiments, R3 is selected from the group consisting of H, C1-C3 alkyl groups, and halogens. In some embodiments, R3 is a C1-C3 alkyl group.

[0149] In some embodiments, R3 is selected from the group consisting of H, methyl, and F. In some embodiments, R3 is H. In some embodiments, R3 is F. In some embodiments, R3 is Cl. In some embodiments, R3 is methyl.

[0150] In some embodiments, X4 is CH.

[0151] In some embodiments, R4 and R5 are each independently selected from the group consisting of: halogen, H, alkoxy, alkylamine, amino, alkyl, and CN.

[0152] In some embodiments, R4 is F, and R5, R6 and R7 are each H.

[0153] In some embodiments, R6 is F, and R4, R5 and R7 are each H.

[0154] In some embodiments, R4 and R5 are each F, and R6 and R7 are each H.

[0155] In some embodiments, R5 and R6 are each F, and R4 and R7 are each H.

[0156] In some embodiments, R4 and R6 are each F, and R5 and R7 are each H.

[0157] In some embodiments, R4 and R6 are each H, and R5 and R7 are each F.

[0158] In some embodiments, A or B is selected from the group consisting of:

[0159] In some embodiments, A or B is selected from the group consisting of:

[0160] In some embodiments, A is selected from the group consisting of:

[0161] In some embodiments, A is selected from the group consisting of: R 14 is independently selected from the following group of components each time it appears: H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, and cyanoalkyl.

[0162] In some embodiments, A or B is selected from the group consisting of:

[0163] In some embodiments, A is a substituted pyridinone, as appropriate.

[0164] In some embodiments, A is selected from the group consisting of:

[0165] In some embodiments, for The X3 series is selected from the following groups: CH, CL2-E2, CO-L2-E2 and CN(R2)-L2-E2.

[0166] In some embodiments, for X3 is selected from the following groups: CH, CL2-E2, CO-L2-E2 and CN(R2)-L2-E2, where X4 is N or CR3.

[0167] In some embodiments, for X2 is selected from the following groups: CH, CL2-E2, CO-L2-E2 and CN(R2)-L2-E2, where X4 is N or CR3.

[0168] In some embodiments, for The X2 series is selected from the following groups: CH, CL2-E2, CO-L2-E2 and CN(R2)-L2-E2.

[0169] In some embodiments, for The X3 series is selected from the following groups: CH, CL2-E2, COL2-E2 and CN(R2)-L2-E2.

[0170] In some embodiments, for , where X 2 is CH, CL 2-E 2, COL 2-E 2 and CN(R 2)-L 2-E 2, and E 2 is not F.

[0171] In some embodiments, for , where X 3 is CH, CL 2-E 2, COL 2-E 2 and CN(R 2)-L 2-E 2, and E 2 is not F.

[0172] In some embodiments, for , where X 3 is CH, CL 2-E 2, COL 2-E 2 and CN(R 2)-L 2-E 2.

[0173] In some embodiments, for , where X 3 is CH, CL 2-E 2, COL 2-E 2 and CN(R 2)-L 2-E 2.

[0174] In some embodiments, for , where X 2 is CH, CL 2-E 2, COL 2-E 2 and CN(R 2)-L 2-E 2.

[0175] In one embodiment, this document describes a compound represented by formula IR: IR Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X1 series are selected from the group consisting of CH and N; X3 series are selected from the group consisting of: COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; X10 series are selected from the group consisting of CR 5 and N; X11 series are selected from the group consisting of CR 7 and N; R1 series are selected from the group consisting of: alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R4 and R The R5 series is independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 series is selected from the group consisting of halogen, H, and alkyl; the R7 series is selected from the group consisting of H and F; the R10 and R11 series are independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; R The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acetyl, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetyl, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; the R 15 series is selected from the group consisting of alkyl, cycloalkyl, and heterocyclic; the L 2 series is selected from direct bonds and C1-C... The group consisting of 6 alkyl groups, wherein C1-C6 alkyl groups are substituted with (E21)p as appropriate;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen, and each p is independently 0, 1, or 2.

[0176] In one embodiment, this document describes a compound represented by the formula IS: Formula 1-S Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X1 series are selected from the group consisting of CH and N; X3 series are selected from the group consisting of COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; X10 series are selected from the group consisting of CR 5 and N; R1 series are selected from the group consisting of alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R4 and R The R5 series is independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 series is selected from the group consisting of halogen, H, and alkyl; the R7 series is selected from the group consisting of H and F; the R10 and R11 series are independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; R The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acetyl, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetyl, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; the R 15 series is selected from the group consisting of alkyl, cycloalkyl, and heterocyclic; the L 2 series is selected from direct bonds and C1-C... The group consisting of 6 alkyl groups, wherein C1-C6 alkyl groups are substituted with (E21)p as appropriate;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen, and each p is independently 0, 1, or 2.

[0177] In one embodiment, this document describes a compound represented by the formula IT: Formula 1-T Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X1 is selected from the group consisting of CH and N; X3 is selected from the group consisting of: COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; R1 is selected from the group consisting of: alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R4 and R The R5 series is independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 series is selected from the group consisting of halogen, H, and alkyl; the R7 series is selected from the group consisting of H and F; the R10 and R11 series are independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; R The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acetyl, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetyl, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; the R 15 series is selected from the group consisting of alkyl, cycloalkyl, and heterocyclic; the L 2 series is selected from direct bonds and C1-C... The group consisting of 6 alkyl groups, wherein C1-C6 alkyl groups are substituted with (E21)p as appropriate;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen, and each p is independently 0, 1, or 2.

[0178] In one embodiment, this document describes a compound represented by the formula IU: Formula 1-U Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X1 series are selected from the group consisting of CH and N; X3 series are selected from the group consisting of: COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; X10 series are selected from the group consisting of CR 5 and N; X11 series are selected from the group consisting of CR 7 and N; R1 series are selected from the group consisting of: alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R The R5 series is selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 series is selected from the group consisting of halogen, H, and alkyl; the R7 series is selected from the group consisting of H and F; the R11 series is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acetyl, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetyl, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; the R 15 series is selected from the group consisting of alkyl, cycloalkyl, and heterocyclic; the L 2 series is selected from direct bonds and C1-C... The group consisting of 6 alkyl groups, wherein C1-C6 alkyl groups are substituted with (E21)p as appropriate;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen, and each p is independently 0, 1, or 2.

[0179] In one embodiment, this document describes a compound represented by formula IV: Formula 1-V Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X1 series are selected from the group consisting of CH and N; X3 series are selected from the group consisting of COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; X10 series are selected from the group consisting of CR 5 and N; R1 series are selected from the group consisting of alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R The R5 series is selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 series is selected from the group consisting of halogen, H, and alkyl; the R7 series is selected from the group consisting of H and F; the R11 series is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acetyl, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetyl, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; the R 15 series is selected from the group consisting of alkyl, cycloalkyl, and heterocyclic; the L 2 series is selected from direct bonds and C1-C... The group consisting of 6 alkyl groups, wherein C1-C6 alkyl groups are substituted with (E21)p as appropriate;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen, and each p is independently 0, 1, or 2.

[0180] In one embodiment, this document describes a compound represented by the formula IW: Formula 1-W Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X1 series are selected from the group consisting of CH and N; X3 series are selected from the group consisting of COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; X11 series are selected from the group consisting of CR 7 and N; R1 series are selected from the group consisting of alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R The R5 series is selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 series is selected from the group consisting of halogen, H, and alkyl; the R7 series is selected from the group consisting of H and F; the R11 series is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acetyl, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetyl, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; the R 15 series is selected from the group consisting of alkyl, cycloalkyl, and heterocyclic; the L 2 series is selected from direct bonds and C1-C... The group consisting of 6 alkyl groups, wherein C1-C6 alkyl groups are substituted with (E21)p as appropriate;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen, and each p is independently 0, 1, or 2.

[0181] In one embodiment, this document describes a compound represented by formula IX: Formula 1-X Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X1 is selected from the group consisting of CH and N; X3 is selected from the group consisting of: COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; R1 is selected from the group consisting of: alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R The 5-series is independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the 6-series is selected from the group consisting of halogen, H, and alkyl; the 7-series is selected from the group consisting of H and F; the 11-series is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acetyl, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetyl, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; the R 15 series is selected from the group consisting of alkyl, cycloalkyl, and heterocyclic; the L 2 series is selected from direct bonds and C1-C... The group consisting of 6 alkyl groups, wherein C1-C6 alkyl groups are substituted with (E21)p as appropriate;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen, and each p is independently 0, 1, or 2.

[0182] In one embodiment, this document describes a representation by formula IY: Formula IY Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X1 is selected from the group consisting of CH and N; X3 is selected from the group consisting of: COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; R1 is selected from the group consisting of: alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R The 5-series is independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the 6-series is selected from the group consisting of halogen, H, and alkyl; the 11-series is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acetyl, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetyl, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; the R 15 series is selected from the group consisting of alkyl, cycloalkyl, and heterocyclic; the L 2 series is selected from direct bonds and C1-C... The group consisting of 6 alkyl groups, wherein C1-C6 alkyl groups are substituted with (E21)p as appropriate;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen, and each p is independently 0, 1, or 2.

[0183] In one embodiment, this document describes a compound represented by formula IZ: Formula IZ Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X1 series are selected from the group consisting of CH and N; X3 series are selected from the group consisting of: COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; X10 series are selected from the group consisting of CR 5 and N; X11 series are selected from the group consisting of CR 7 and N; R1 series are selected from the group consisting of: alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R4 and R The R5 series is independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 series is selected from the group consisting of halogen, H, and alkyl; the R7 series is selected from the group consisting of H and F; the R8 series is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy, and CN; the R10 and R11 series are independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; R The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl and sulfonyl;The L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with (E21)p; the E2 group is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic groups are optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyl, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen each time it appears, and each p is independently 0, 1, or 2.

[0184] In one embodiment, this document describes a compound represented by formula I-AA: Formula I-AA Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X1 series are selected from the group consisting of CH and N; X3 series are selected from the group consisting of COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; X10 series are selected from the group consisting of CR 5 and N; R1 series are selected from the group consisting of alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R4 and R The R5 series is independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 series is selected from the group consisting of halogen, H, and alkyl; the R7 series is selected from the group consisting of H and F; the R8 series is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy, and CN; the R10 and R11 series are independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; R The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl and sulfonyl;The L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with (E21)p; the E2 group is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic groups are optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyl, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen each time it appears, and each p is independently 0, 1, or 2.

[0185] In one embodiment, this document describes a compound represented by formula I-AB: Formula I-AB Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X1 series are selected from the group consisting of CH and N; X3 series are selected from the group consisting of COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; X11 series are selected from the group consisting of CR 7 and N; R1 series are selected from the group consisting of alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R4 and R The R5 series is independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 series is selected from the group consisting of halogen, H, and alkyl; the R7 series is selected from the group consisting of H and F; the R8 series is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy, and CN; the R11 series is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; R The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl and sulfonyl;The L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with (E21)p; the E2 group is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic groups are optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyl, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen each time it appears, and each p is independently 0, 1, or 2.

[0186] In one embodiment, this document describes a compound represented by formula I-AC: Formula 1-AC Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X1 series are selected from the group consisting of CH and N; X3 series are selected from the group consisting of: COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; X10 series are selected from the group consisting of CR 5 and N; X11 series are selected from the group consisting of CR 7 and N; R1 series are selected from the group consisting of: alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R The R5 series is selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 series is selected from the group consisting of halogen, H, and alkyl; the R7 series is selected from the group consisting of H and F; the R8 series is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy, and CN; the R11 series is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; R The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl and sulfonyl;The L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with (E21)p; the E2 group is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic groups are optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyl, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen each time it appears, and each p is independently 0, 1, or 2.

[0187] In one embodiment, this document describes a compound represented by formula I-AD: Formula 1-AD Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X1 series are selected from the group consisting of CH and N; X3 series are selected from the group consisting of COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; X10 series are selected from the group consisting of CR 5 and N; R1 series are selected from the group consisting of alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R The R5 series is selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 series is selected from the group consisting of halogen, H, and alkyl; the R7 series is selected from the group consisting of H and F; the R8 series is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy, and CN; the R11 series is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; R The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acetyl, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetyl, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; the L2 series is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein C1-C6... 6-alkyl groups are substituted with (E 21) p, depending on the case;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen, and each p is independently 0, 1, or 2.

[0188] In one embodiment, this document describes a compound represented by formula I-AE: Equation 1-AE Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X1 series are selected from the group consisting of CH and N; X3 series are selected from the group consisting of COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; X11 series are selected from the group consisting of CR 7 and N; R1 series are selected from the group consisting of alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R The R5 series is selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 series is selected from the group consisting of halogen, H, and alkyl; the R7 series is selected from the group consisting of H and F; the R8 series is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy, and CN; the R11 series is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; R The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acetyl, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetyl, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; the L2 series is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein C1-C6... 6-alkyl groups are substituted with (E 21) p, depending on the case;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen, and each p is independently 0, 1, or 2.

[0189] In one embodiment, this document describes a compound represented by formula I-AF: Formula 1-AF Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X1 is selected from the group consisting of CH and N; X3 is selected from the group consisting of: COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; R1 is selected from the group consisting of: alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R The R5 series is selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 series is selected from the group consisting of halogen, H, and alkyl; the R7 series is selected from the group consisting of H and F; the R8 series is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy, and CN; the R11 series is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; R The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acetyl, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetyl, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; the L2 series is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein C1-C6... 6-alkyl groups are substituted with (E 21) p, depending on the case;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen, and each p is independently 0, 1, or 2.

[0190] In one embodiment, this document describes a compound represented by the formula I-AG: Formula 1-AG Or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X1 is selected from the group consisting of CH and N; X3 is selected from the group consisting of: COL 2-E 2, CL 2-E 2, and CN(R 2)-L 2-E 2; R1 is selected from the group consisting of: alkyl, (C=O)R 13. Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; R2 is selected from the group consisting of H and alkyl; R3 is selected from the group consisting of H, alkyl, and halogen; R The R5 series is selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; the R6 series is selected from the group consisting of halogen, H, and alkyl; the R8 series is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy, and CN; the R11 series is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; The 13 series is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acetyl, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetyl, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl, and sulfonyl; the L2 series is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein C1-C6... 6-alkyl groups are substituted with (E 21) p, depending on the case;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen, and each p is independently 0, 1, or 2.

[0191] In some embodiments, R1 is selected from the group consisting of: R 14 is independently selected from the following group of components each time it appears: H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, and cyanoalkyl.

[0192] In some embodiments, R1 is selected from the group consisting of:

[0193] In some embodiments, R1 is selected from the group consisting of: H, .

[0194] In some embodiments, R1 is selected from the group consisting of:

[0195] In some embodiments, R1 is selected from the group consisting of: R 14 is independently selected from the following group of components each time it appears: H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, and cyanoalkyl.

[0196] In some embodiments, X1 is N. In some embodiments, X1 is CH. In some embodiments, X3 is CN(R2)-L2-E2. In some embodiments, X3 is CN(H)CH3. In some embodiments, X3 is CCH3.

[0197] In some embodiments, the X3 series is selected from the group consisting of: R 14 is independently selected from the following group of components each time it appears: H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, and cyanoalkyl.

[0198] In some embodiments, the X3 series is selected from the group consisting of: R 14 is independently selected from the following group of components each time it appears: H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, and cyanoalkyl.

[0199] In some embodiments, X10 is N and X11 is CR7. In some embodiments, X10 and X11 are N. In some embodiments, X10 is CR5 and X11 is N. In some embodiments, R3 is H, C1-C6 alkyl, and halogen. In some embodiments, R3 is H. In some embodiments, R3 is Me. In some embodiments, R3 is F. In some embodiments, R3 is Cl. In some embodiments, R4 is selected from the group consisting of H, F, Cl, Me, OMe, CF3, and CN. In some embodiments, R5 is selected from the group consisting of H, F, Cl, Me, OMe, CF3, and CN. In some embodiments, R6 and R7 are each independently selected from the group consisting of H, F, Cl, and Me. In some embodiments, R4, R5, R6, and R7 are each independently H or F, and at least one of R4, R5, R6, and R7 is F. In some embodiments, R6 is F; and R4, R5, and R7 are each H. In some embodiments, R4 is F; and R5, R6, and R7 are each H. In some embodiments, R4 and R6 are each F; and R5 and R7 are each H. In some embodiments, R4 and R5 are each F; and R6 and R7 are each H. In some embodiments, R5 and R6 are each F; and R4 and R7 are each H. In some embodiments, R15 is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C6 heterocyclic groups. In some embodiments, R15 is cyclopropyl. In some embodiments, R15 is Me. In some embodiments, R15 is oxonyl. In some embodiments, R15 is oxon-2-yl. In some embodiments, R15 is oxon-3-yl.

[0200] In some embodiments, the compound is selected from the group consisting of: And its pharmaceutically acceptable salts, enantiomers, stereoisomers and tautomers. Treatment methods

[0201] The compounds described herein, such as compounds of formula I as defined herein, can act as therapeutic agents for diseases driven by GCN2 or PERK kinases, and are suitable for treating diseases and conditions in patients in need, such as cancer. Exemplary cancers include, but are not limited to, colorectal cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors, lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic duct cancer, pancreatic endocrine tumors), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), duodenal cancer, small bowel cancer, and breast cancer (e.g., invasive ductal carcinoma, in situ ductal carcinoma). Cancer, including inflammatory breast cancer, ovarian cancer (e.g., ovarian epithelial cancer, extragonadal germ cell tumors, ovarian germ cell tumors, low-grade malignant potential ovarian tumors), testicular tumors, prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone-dependent prostate cancer, castration-resistant prostate cancer), liver cancer (e.g., liver cancer, primary liver cancer, extrahepatic bile duct cancer), thyroid cancer (e.g., medullary thyroid carcinoma), kidney cancer (e.g., renal cell carcinoma (e.g., clear cell renal cell carcinoma), and transitional tumors of the renal pelvis and ureter). Cellular cancers, uterine cancers (e.g., cervical cancer, endometrial cancer, uterine sarcoma), gestational choriocarcinoma, brain tumors (e.g., neuroblastoma, glioma, pineal astrocytoma, piloastrocytoma, diffuse astrocytoma, degenerative astrocytoma, pituitary adenoma), retinoblastoma, skin cancers (e.g., basal cell carcinoma, malignant melanoma, melanoma), sarcomas (e.g., rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, spindle cell sarcoma, osteosarcoma), fibrosarcoma, malignant bone tumors, bladder cancer, hematologic malignancies (e.g., multiple myeloma, leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), including the onset of chronic leukemia), malignant lymphoma, Hodgkin's disease, chronic myeloproliferative disorders, cancers of unknown primary nucleus], ​​cancer growth inhibitors, cancer metastasis inhibitors, apoptosis promoters, and those used for the prevention or treatment of precancerous lesions (e.g., myelodysplastic syndrome).

[0202] In one embodiment, this document also describes a method of treating a disease caused by dysregulation of the integrative stress response in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of formula I described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein. In some embodiments, dysregulation of the integrative stress response and / or the unfolded protein response is caused by GCN2 kinase. In some embodiments, dysregulation of the integrative stress response and / or the unfolded protein response is caused by PERK kinase. In some embodiments, dysregulation of the integrative stress response is caused by GCN2 kinase. In some embodiments, dysregulation of the unfolded protein response is caused by PERK kinase. In some embodiments, dysregulation of the integrative stress response is caused by activation of a kinase selected from the group consisting of PERK kinase and GCN2 kinase. In some embodiments, dysregulation of the integrative stress response is caused by activation of GCN2 kinase. In some embodiments, dysregulation of the integrative stress response is caused by activation of PERK kinase.

[0203] In another embodiment, this document also describes a method for treating a patient in need of a disease caused by dysregulation of the integrative stress response and / or the unfolded protein response, comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of formula I described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, dysregulation of the integrative stress response and / or the unfolded protein response is caused by activation of a kinase selected from the group consisting of PERK kinase and GCN2 kinase. In some embodiments, dysregulation of the integrative stress response is caused by activation of GCN2 kinase. In some embodiments, dysregulation of the unfolded protein response is caused by activation of PERK kinase.

[0204] In another embodiment, this document describes a method for modulating the GCN2 kinase activity of a patient in need, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0205] In another embodiment, this document describes a method for activating GCN2 kinase in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0206] In another embodiment, this document describes a method for modulating the PERK kinase activity of a patient in need, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0207] In another embodiment, this document describes a method for activating PERK kinase in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0208] In another embodiment, this document describes a method for inhibiting GCN2 kinase and PERK kinase in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0209] In another embodiment, this document describes a method for modulating the GCN2 kinase activity of a patient in need, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0210] In another embodiment, this document describes a method for inhibiting PERK kinase activity in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0211] In another embodiment, this document describes a method of treating a patient with cancer in need, comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of formula I described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the cancer is selected from the group consisting of: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, stomach, duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumor, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, choriocarcinoma of pregnancy, brain tumor, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumor, bladder cancer, hematologic malignancy, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and malignant lymphoma. In some embodiments, cancer is selected from the group consisting of: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric and duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumors, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumors, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumors, bladder cancer, hematologic malignancies, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocytic lymphoma, Waldenstrom macroglobulinemia, and malignant lymphoma. In some embodiments, cancer is leukemia. In some embodiments, the cancer is acute myeloid leukemia. In some embodiments, the cancer is acute lymphoblastic leukemia. In some embodiments, the cancer is fibrosarcoma. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is B-cell lymphoma. In some embodiments, the cancer is T-cell lymphoma.

[0212] In one embodiment, a method for treating amyloidosis in a patient in need is described herein, comprising administering to the patient a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In another embodiment, a method for treating light chain amyloidosis in a patient in need is described herein, comprising administering to the patient a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0213] In another embodiment, this document describes a method for treating a patient in need of a disease selected from GCN2-related diseases and PERK-related diseases, comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of formula I described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the disease is a GCN2-related disease. In some embodiments, the disease is a PERK-related disease. In some embodiments, the disease is cancer. In some embodiments, the cancer is selected from the group consisting of: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric and duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumor, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, choriocarcinoma of pregnancy, brain tumor, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumor, bladder cancer, hematologic malignancy, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and malignant lymphoma. In some embodiments, cancer is selected from the group consisting of: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric and duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumors, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumors, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumors, bladder cancer, hematologic malignancies, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocytic lymphoma, Waldenström macroglobulinemia, and malignant lymphoma. In some embodiments, cancer is leukemia. In some embodiments, cancer is acute myeloid leukemia. In some embodiments, the cancer is acute lymphoblastic leukemia. In some embodiments, the cancer is fibrosarcoma. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is B-cell lymphoma. In some embodiments, the cancer is T-cell lymphoma. In some embodiments, the disease is amyloidosis. In some embodiments, the disease is light chain amyloidosis.

[0214] In another embodiment, this document describes a method for treating a patient in need of a disease selected from GCN2-related diseases and PERK-related diseases, comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of formula I described herein) or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more therapeutic agents. In some embodiments, the disease is a GCN2-related disease. In some embodiments, the disease is a PERK-related disease. In some embodiments, the disease is cancer. In some embodiments, the cancer is selected from the group consisting of: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric and duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumors, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, choriocarcinoma of pregnancy, brain tumors, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumors, bladder cancer, hematologic malignancies, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and malignant lymphoma. In some embodiments, cancer is selected from the group consisting of: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric and duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumors, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumors, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumors, bladder cancer, hematologic malignancies, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocytic lymphoma, Waldenström macroglobulinemia, and malignant lymphoma. In some embodiments, cancer is leukemia. In some embodiments, leukemia is acute myeloid leukemia. In some embodiments, the leukemia is acute lymphoblastic leukemia. In some embodiments, the cancer is fibrosarcoma. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is B-cell lymphoma. In some embodiments, the cancer is T-cell lymphoma. In some embodiments, the disease is amyloidosis. In some embodiments, the disease is light chain amyloidosis.In some embodiments, one or more therapeutic agents are selected from the group consisting of: L-aspartame, pegylated aspartame, PERK inhibitor, mTOR inhibitor, immunomodulator, MAPK pathway inhibitor, MEK inhibitor, ERK inhibitor, and Ras inhibitor. In some embodiments, the one or more therapeutic agents are selected from the group consisting of: IMiD agents, proteasome inhibitors, steroids, antiCD38 agents, antiCD20 agents, Bcl-2 inhibitors, PI3K inhibitors, bispecific antibodies, nucleoside analogs, BTK inhibitors, DNA alkylating agents, EZH2 inhibitors, anthracycline, topoisomerase inhibitors, platinum, tyrosine kinase inhibitors, HDAC inhibitors, nuclear export inhibitors, antimicrotubule agents, L-aspartame, pegylated aspartame, PERK inhibitor, mTOR inhibitor, immunomodulator, MAPK pathway inhibitor, MEK inhibitor, ERK inhibitor, and Ras inhibitor.In some embodiments, the one or more therapeutic agents are selected from the group consisting of: L-asparaginase, pegaspargase, calaspargase pegol-mnkl, bortezomib, carfilzomib, ixazomib, thalidomide, pomalidomide, lenalidomide, and dexamethasone. Prednisone, daratumumab, daratumumab / hyaluronidase, isatuximab, rituximab, obinutuzumab, venetoclax, idelalisib, copanlisib, duvelisib, umbralisib, gemcitabine emcitabine, cytarabine, ibrutinib, acalabtinib, zanubrutinib, bendamustine, cyclophosphamide, tazemetostat, doxorubicin, daunorubicin, etoposide, oxaloplatin, carboplatin Latin, cisplatinbosutinib, dasatinib, imatinib, nilotinib, ponatinib, panobinostat, selinexor, vincristine, JZP-458, erythrocyte-encapsulated asparagine, PF745 (JZP-341), asparagine-containing Erwinia chrysanthemi (crisantaspase), Escherichia coli asparagine (colaspase), anti-PD-1 agents, anti-PD-L1 agents, and anti-CTLA4 agents.

[0215] In one embodiment, this document describes a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for treating a patient in need of disease caused by dysregulation of the integrative stress response and / or the unfolded protein response. In some embodiments, dysregulation of the integrative stress response and / or the unfolded protein response is caused by a kinase selected from the group consisting of PERK kinase and GCN2 kinase. In some embodiments, dysregulation of the integrative stress response and / or the unfolded protein response is caused by GCN2 kinase. In some embodiments, dysregulation of the integrative stress response and / or the unfolded protein response is caused by PERK kinase. In some embodiments, dysregulation of the integrative stress response is caused by GCN2 kinase. In some embodiments, dysregulation of the unfolded protein response is caused by PERK kinase. In some embodiments, dysregulation of the integrative stress response is caused by activation of a kinase selected from the group consisting of PERK kinase and GCN2 kinase. In some embodiments, dysregulation of the integrative stress response is caused by activation of GCN2 kinase. In some embodiments, dysregulation of the integrative stress response is caused by activation of PERK kinase. In one embodiment, this document describes a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for modulating GCN2 kinase activity in a patient in need. In one embodiment, this document describes a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for activating GCN2 kinase in a patient in need. In one embodiment, this document describes a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for modulating PERK kinase activity in a patient in need. In one embodiment, this document describes a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for activating PERK kinase in a patient in need.

[0216] In one embodiment, this document describes a compound described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein for inhibiting GCN2 kinase and PERK kinase in a patient in need. In one embodiment, this document describes a compound described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein for modulating the activity of GCN2 kinase in a patient in need. In one embodiment, this document describes a compound described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein for inhibiting the activity of PERK kinase in a patient in need.

[0217] In one embodiment, this document describes a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for the treatment of cancer in a patient in need. In some embodiments, cancer is selected from the group consisting of: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric and duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumors, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumors, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumors, bladder cancer, hematologic malignancies, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocytic lymphoma, Waldenström macroglobulinemia, and malignant lymphoma. In some embodiments, cancer is leukemia. In some embodiments, cancer is acute myeloid leukemia. In some embodiments, the cancer is acute lymphoblastic leukemia. In some embodiments, the cancer is fibrosarcoma. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is B-cell lymphoma. In some embodiments, the cancer is T-cell lymphoma.

[0218] In one embodiment, this document describes a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of amyloidosis in a patient in need. In another embodiment, this document describes a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of light-chain amyloidosis in a patient in need.

[0219] In one embodiment, this document describes a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for the treatment of a patient in need of a disease selected from GCN2-related diseases and PERK-related diseases. In some embodiments, the disease is a GCN2-related disease. In some embodiments, the disease is a PERK-related disease. In some embodiments, the disease is cancer. In some embodiments, cancer is selected from the group consisting of: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric and duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumors, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumors, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumors, bladder cancer, hematologic malignancies, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocytic lymphoma, Waldenström macroglobulinemia, and malignant lymphoma. In some embodiments, cancer is leukemia. In some embodiments, cancer is acute myeloid leukemia. In some embodiments, the cancer is acute lymphoblastic leukemia. In some embodiments, the cancer is fibrosarcoma. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is B-cell lymphoma. In some embodiments, the cancer is T-cell lymphoma. In some embodiments, the disease is amyloidosis. In some embodiments, the disease is light chain amyloidosis.

[0220] In one embodiment, this document describes a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for the treatment of a patient in need of a disease selected from GCN2-related diseases and PERK-related diseases. In some embodiments, the disease is a GCN2-related disease. In some embodiments, the disease is a PERK-related disease. In some embodiments, the disease is cancer. In some embodiments, cancer is selected from the group consisting of: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric and duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumors, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumors, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumors, bladder cancer, hematologic malignancies, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocytic lymphoma, Waldenström macroglobulinemia, and malignant lymphoma. In some embodiments, cancer is leukemia. In some embodiments, leukemia is acute myeloid leukemia. In some embodiments, the leukemia is acute lymphoblastic leukemia. In some embodiments, the cancer is fibrosarcoma. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is B-cell lymphoma. In some embodiments, the cancer is T-cell lymphoma. In some embodiments, the disease is amyloidosis. In some embodiments, the disease is light chain amyloidosis. In some embodiments, the one or more therapeutic agents are selected from the group consisting of: IMiD agents, proteasome inhibitors, steroids, antiCD38 agents, antiCD20 agents, Bcl-2 inhibitors, PI3K inhibitors, bispecific antibodies, nucleoside analogs, BTK inhibitors, DNA alkylating agents, EZH2 inhibitors, anthracycline, topoisomerase inhibitors, platinum, tyrosine kinase inhibitors, HDAC inhibitors, nuclear export inhibitors, antimicrotubule agents, L-aspartate aminotransferase, PEGylated aspartate aminotransferase, PERK inhibitors, mTOR inhibitors, immunomodulators, MAPK pathway inhibitors, MEK inhibitors, ERK inhibitors, and Ras inhibitors.In some embodiments, the one or more therapeutic agents are selected from the group consisting of: bortezomib, carfilzomib, ezazoma, thalidomide, lenalidomide, dexamethasone, presbyronone, daratumumab, daratumumab / hyaluronidase, esatuximab, rituximab, atorcizumab, venatura, ederalis, cobancoxib, duvelisib, erblisib, gemcitabine, cytarabine, ibrutinib, acalabutinib, zanubrutinib, bendamustine. Cyclophosphamide, tazestat, doxorubicin, doxorubicin, etoposide, oxaliplatin, carboplatin, cisplatin, bosutinib, dasatinib, imatinib, nilotinib, ponatinib, palbinostat, selinexol, vincristine, L-asparaginase, pegol-mnkl, erythrocyte-encapsulated asparaginase, PF745 (JZP-341), asparaginase from Erwinia chrysanthas, Escherichia coli asparaginase (clapalaminase), anti-PD1, anti-PDL1, and anti-CTLA4.

[0221] The compounds described herein can be administered to patients (animals and humans) requiring treatment at doses that provide optimal therapeutic efficacy. It should be understood that the dosage required for any particular application will vary from patient to patient, not only with the specific compound or composition chosen, but also with the route of administration, the nature of the condition being treated, the patient's age and condition, concurrent drug therapy, any special diet followed by the patient, and other factors that a person skilled in this technique will recognize. The appropriate dosage is ultimately determined by the attending physician. For the treatment of the clinical conditions and diseases mentioned above, the compounds described herein can be administered orally, subcutaneously, topically, non-enterally, by inhalation spray, or rectally in the form of dosage units containing known, non-toxic, and pharmaceutically acceptable carriers, adjuvants, and mediators. Non-enteral administration may include subcutaneous injection, intravenous or intramuscular injection, or infusion techniques.

[0222] Treatment can be continued for extended or shorter periods as needed. The composition can be administered, for example, once to four times or more daily. Appropriate treatment durations may be, for example, at least one week, at least two weeks, at least one month, at least six months, at least one year, or indefinite. Treatment may be terminated when the desired outcome is achieved. Combination therapy

[0223] For example, compounds of Formula I as defined herein, as described herein, can be administered in combination with one or more additional therapeutic agents to treat conditions described herein, such as cancers described herein. For instance, the present invention provides a pharmaceutical composition comprising, for example, compounds of Formula I as defined herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a compound of Formula I as defined herein and one additional therapeutic agent are administered. In some embodiments, a compound of Formula I as defined herein and two additional therapeutic agents are administered. In some embodiments, a compound of Formula I as defined herein and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is separately formulated and administered. For example, a compound of Formula I as defined herein and additional therapeutic agents can be separately formulated and administered. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, such as a pharmaceutical composition comprising a Formula I compound as a therapeutic agent and one or more additional therapeutic agents, such as chemotherapeutic agents. For example, a Formula I compound as defined herein and additional therapeutic agents can be administered in a single formulation. Combination therapy also encompasses other combinations. Although two or more agents in a combination therapy can be administered simultaneously, this is not always the case. For example, the administration of the first agent (or combination of agents) may be minutes, hours, days, or weeks earlier than the administration of the second agent (or combination of agents). Therefore, two or more medications can be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days, or within 2, 3, 4, 5, 6, 7, 8, or 9 weeks, or several weeks. In some cases, even longer time intervals are possible. Although in many cases, the two or more medications used in combination therapy need to be present in the patient's body simultaneously, this is not always the case.

[0224] Combination therapy may also include two or more administrations of one or more of the components of a drug in different sequences. For example, if drug X and drug Y are used together, they can be administered one or more times in any combination, such as in the order of XYX, XXY, YXY, YYX, XXYY, etc.

[0225] Combination therapy may also include two or more administrations of one or more of the same drugs used via different routes of administration. Each of the drugs may be administered independently, in dose units containing known, non-toxic, pharmaceutically acceptable carriers, adjuvants, and mediators, via oral, subcutaneous, topical, non-enteral, inhalation spray, or rectal administration. Non-enteral administration may include subcutaneous injection, intravenous or intramuscular injection, or infusion techniques.

[0226] In some embodiments, the compound of formula I as described herein is combined with asparaginase (ASNase, L-asparaginase) or a derivative thereof. In some embodiments, the asparaginase is obtained from *Erwinia chrysanatas* and is called *Cresanetas* protease or *Erwinia chrysanatas* asparaginase. *Erwinia chrysanatas* asparaginase is marketed under the trademarks Erwinaze® or Erwinase®. In some embodiments, the asparaginase is obtained from *Escherichia coli* and is called clapase. Clapase is marketed under the trademarks Elspar®, Leunase®, Kidrolase®, or Spectrila® (recombinant *Escherichia coli* asparaginase). Polyethylene glycol derivatives of clapase are pegol-mnkl, marketed under the trademark Oncaspar®, and pegol-mnkl, marketed under the trademark Asparlas®. Other asparagine enzyme products currently in preclinical or clinical development include JZP-458 (recombinant Erwinia asparagine enzyme), PF745 (JZP-341), erythrocyte-encapsulated asparagine enzyme (GRASPA®), and Xoncane.

[0227] In some embodiments, compounds of Formula I as defined herein are combined with immunomodulators. In some embodiments, immunomodulation enhances adaptive immune responses. In some embodiments, immunomodulation enhances the activity of antigen-presenting cells. In some embodiments, immunomodulators enhance the antitumor activity of bone marrow cells, including macrophages. In some embodiments, immunomodulation enhances the antitumor activity of natural killer cells. In some embodiments, immunomodulators enhance the activity of effector T cells, including cytotoxic T cells.

[0228] In some embodiments, one or more additional therapeutic agents, which may be MAPK pathway inhibitors, may be administered in combination with the compounds provided herein. Such MAPK pathway inhibitors include, for example, MEK inhibitors, ERK inhibitors, and Ras inhibitors.

[0229] Exemplary MEK inhibitors include, but are not limited to, trametinib, selumetinib, cobimetinib, binimetinib, and their pharmaceutically acceptable salts. Exemplary ERK inhibitors include, but are not limited to, ulixertinib, SCH772984, LY3214996, ravoxertinib, VX-11e, ASN-007, GDC-0994, MK-8353, ASTX-029, LTT462, KO-947, and their pharmaceutically acceptable salts. Exemplary Ras inhibitors include, but are not limited to, AMG-510, MRTX849, ARS-1620, ARS-3248, LY3499446, and their pharmaceutically acceptable salts.

[0230] In some embodiments, the additional therapeutic agent may be an immunomodulatory agent, including but not limited to anti-PD-1 or anti-PDL-1 therapeutic agents, including pembrolizumab, nivolumab, pidilizumab, cemiplimab, atezolizumab, durvalumab, BMS-936559, or avelumab. In some embodiments, the additional therapeutic agent may be an anti-TIM3 (anti-HAVcr2) therapeutic agent, including but not limited to TSR-022 or MBG453; an anti-LAG3 therapeutic agent, including but not limited to relatlimab, LAG525, or TSR-033; an anti-4-1BB (anti-CD37, anti-TNFRSF9) therapeutic agent; a CD40 agonist therapeutic agent, including but not limited to SGN-40, CP-870, 893, or RO7009789; an anti-CD47 therapeutic agent, including but not limited to Hu5F9-G4; an anti-CD20 therapeutic agent; an anti-CD38 therapeutic agent; or a STING agonist, including but not limited to ADU-S100, MK-1454, ASA404, or nitrobenzimidazole. In some embodiments, the additional therapeutic agent may be an anti-CTLA4 agent, including ipilimumab or tremelimumab. In some embodiments, the additional therapeutic agent may be a hypomethylating agent, including but not limited to azoxybicone or decitabine, angiotensin, or other immunomodulatory agents, including but not limited to epidermal growth factor inhibitors, statins, metformin, angiotensin receptor blockers, thalidomide, lenalidomide, polidomide, presbyronone, or dexamethasone. In some embodiments, the additional therapeutic agent may be an immunotherapeutic agent, including targeted therapies, cancer vaccines, and CAR-T cell therapy.

[0231] Compounds of Formula I as described herein may be administered in combination with other known cancer treatments. These other treatments include radiation therapy, anti-microtubule agents, DNA alkylating agents, DNA synthesis inhibitors, DNA intercalating agents, anti-estrogens, anti-androgens, steroids, anti-EGFR agents, kinase inhibitors, mTOR inhibitors, PI3 kinase inhibitors, cyclin-dependent kinase inhibitors, CD4 / CD6 kinase inhibitors, topoisomerase inhibitors, histone deacetylase (HDAC) inhibitors, DNA methylation inhibitors, anti-HER2 agents, anti-angiogenic agents, proteasome inhibitors, PARP (poly-ADP-ribose polymerase) inhibitors, cell cycle regulatory kinase inhibitors, thalidomide, lenalidomide, polidocanol, bortezomib, carfilzomib, itazozomib, daratumumab, daratumumab / hyaluronidase, esatuximab, dexamethasone, and antibody-drug conjugates (ADCs).

[0232] In one embodiment, the additional therapeutic agent may be a chemotherapeutic agent, including but not limited to anti-microtubule agents (e.g., paclitaxel, paclitaxel protein-binding particles for injectable suspensions, including nab-paclitaxel, eribulin, docetaxel, ixabepilone, vincristine, auristatins, or maytansinoids), vinorelbine, DNA alkylating agents (including cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide), and temozolomide). DNA intercalation agents or DNA topoisomerase inhibitors (including anthracyclines such as doxorubicin, pegylated lipid doxorubicin, donomycin, idarubicin, mitoxantrone, or epirubicin, camptothecin such as topotecan, irinotecan, or exatecan), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytadine, gemcitabine, and methotrexate).

[0233] In some embodiments, the additional therapeutic agent may be a kinase inhibitor, including but not limited to erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatinib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, and temsirolimus. us), abemaciclib, LEE011, palbociclib, cabozantinib, ripretinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, nilotinib, ederaris, ibrutinib, BLU-667, Loxo 292, larotrectinib, and quizartinib.

[0234] In some embodiments, such additional therapeutic agents may be anti-estrogens, including but not limited to tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane; and anti-androgens, including but not limited to abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, and cyproterone acetate. acetate; steroid drugs, including but not limited to presbyronone and dexamethasone; PARP inhibitors, including but not limited to neraparib, olaparib, talazoparib, and rucaparib; topoisomerase I inhibitors, including but not limited to irinotecan, camptothecin, eczemaconazole, and toponotecan; topoisomerase II inhibitors, including but not limited to anthracycline, etoposide, etoposide phosphate, and mitoxantrone; histone deacetase (HDAC) inhibitors, including but not limited to vorinostat, romidepsin, panobinostat, and valproic acid. (acid) and belinostat; DNA methylation inhibitors, including but not limited to DZNep and 5-aza-2'-deoxycytidine; proteasome inhibitors, including but not limited to bortezomib and carfilzomib; biologics, including but not limited to trastuzumab, ado-trastuzumab, pertuzumab, cetuximab and panitumumab.

[0235] In some embodiments, the additional therapeutic agent may be an anti-angiogenic agent, including bevacizumab, aflibercept, and AMG386.

[0236] In some embodiments, the additional therapeutic agent may be an antibody-drug conjugate (ADC), including DM1, DM4, MMAE, MMAF or camptothecin payload, brentuximab vedotin and trastuzumab emtansine, radiation therapy, or a therapeutic vaccine, including but not limited to sipuleucel-T.

[0237] In some embodiments, the additional therapeutic agent may be an autophagy inhibitor, including ULK inhibitors, VPS34 inhibitors, PIKfyve inhibitors, PPT1 inhibitors, or lysosomal blockers. In some embodiments, the additional therapeutic agent may be DCC-3116, SAR405, SB02024, hydroxychloroquine, chloroquine, apimod, MRT403, and LYS05.

[0238] In some embodiments, the additional therapeutic agent is selected from luteinizing hormone-releasing hormone (LHRH) analogs, including goserelin and leuprolide.

[0239] In some embodiments, the additional therapeutic agent is selected from the group consisting of: everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, parzopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, Enzastaurin, Vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, Pemetrexed, Erlotinib, Dasatinib, Nilotinib, Decatanib, Panitumumab, Amrubicin, Oregomab, Lep-etu, Nolatrexed, AZD 2171, Batabrine, Atutunab atumtunab), zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR 1KRX-0402, lucanthone, LY 317615, neuradiab, vitespan, Rta 744, alanosine (Sdx) 102), Talenpanel, Atrasentan, XR 311, Romidesin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Irinotecan, Lipid-based Doxorubicin, 5'-Deoxy-5-Fluorouracil, Vincristine, Temozolomide, ZK-304709, Seliciclib; PD0325901, AZD-6244, Capecitabine, L-Glutamic acid,N-[4-[2-(2-amino-4,7-dihydro-4-sideoxy-1H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethyl]benzoyl]-disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258, 3-[5-(methylsulfonylopiperidinylmethyl)-indolyl-j-quinolinone, vatalanib, AG-013736, AVE-0005, [D-Ser(tBu) 6, Azgly

[10] Acetates (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu-Arg-Pro-Azgly-NH2 acetate [C 59H 84N 18O 14-(C 2H 4O 2) x, where x=1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate Acetate), raloxifene, bicalutamide, flutanide, nilutamide, medroxyprogesterone acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl Analide, valproic acid, trichostocin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arsacrine, anagrelide, L-aspartate aminotransferase, BCG, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatinCladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, danomycin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevac, hydroxyurea, idarubicin n), ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, niludamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab Monoclonal antibodies, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesin, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, fluorouracil, deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin ), mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endothelial somatostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasterideCimitidine, Trastuzumab, Denileukin Diftitox, Gefitinib, Bortezomib, Irinotecan, Topotecan, Doxorubicin, Docetaxel, Vinpocetine, Bevacizumab (monoclonal antibody), Erbitux, Cremophor-free Paclitaxel, Epothilone B, BMS-247550, BMS-310705, Traloxifen, 4-Hydroxytamoxifen, Pipendoxifene, ERA-923, Arzoxifene, Fulvestrant, Acolbifene, Lasofoxifene, Idoxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD 184352, Rapamycin, 40-O-(2-hydroxyethyl)-Rapamycin, Temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wortmannin, ZM336372, L-779450, PEG-Figrastim, Dabepoetin, Erythropoietin, Granules Globulin community-stimulating factor, zolendronate, prasone, cetuximab, granulocyte-macrophage community-stimulating factor, histrelin, pegylated interferon α-2a, interferon α-2a, pegylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-aspartate aminotransferase, lenalidomide, gemtuzumab, doxycorticosterone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid acid), ketoconazole, interleukin-2, medroxyprogesterone acetate, immunoglobulin, nitrogen mustard, methylpresone, ibrutinumomab, tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, lipodycinEdwina - Asparagine enzyme, Strontium 89, Cacapitant, Netupitant, NK-1 receptor antagonist, Palonosetron, Aprepitant, Diphenhydramine, Hydroxyzine, Metoclopramide, Lorazepam, Alprazolam, Haloperidol, Droperidol, Dronabinol, Dexamethasone, Methylprestigmine, Prochlorperazine, Granisetron, Ondansetron, Dolastron, Tropisetron, Pegfilgrastim, Erythropoietin, Epoetin Alfa, darbepoetin alfa, ipilumab, and mixtures thereof. Pharmaceutical compositions and kits

[0240] Another aspect of the invention provides pharmaceutical compositions comprising compounds as disclosed herein, formulated with a pharmaceutically acceptable carrier. Specifically, the invention provides pharmaceutical compositions comprising compounds as disclosed herein, formulated with one or more pharmaceutically acceptable carriers. Such formulations include those suitable for oral, rectal, topical, buccal, non-intestinal (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or nebulized administration; however, in any given case, the most suitable form of administration will depend on the extent and severity of the condition being treated and on the nature of the particular compound used. For example, the disclosed compositions may be formulated in unit dose form and / or formulated for oral or subcutaneous administration.

[0241] Exemplary pharmaceutical compositions may be used in pharmaceutical formulations, such as solid, semi-solid, or liquid forms, comprising one or more of the compounds described herein as active ingredients, mixed with an organic or inorganic carrier or excipient suitable for external, enteral, or non-enteral administration. The active ingredient may, for example, be formulated with a commonly used, non-toxic, pharmaceutically acceptable carrier for tablets, pills, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable form of use. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the course or condition of the disease.

[0242] For the preparation of solid compositions such as tablets, the main active ingredient can be mixed with a pharmaceutical carrier such as a known tablet-forming component (such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum) and other pharmaceutical diluents such as water to form a homogeneous mixture of the compounds provided herein or their non-toxic, pharmaceutically acceptable salts. When such preformed compositions are referred to as homogeneous preformed compositions, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily further divided into equivalent dosage forms such as tablets, pills, and capsules.

[0243] In its use in oral administration to solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules and the like), the compositions of the present invention are mixed with any one or more pharmaceutically acceptable carriers and / or adjuncts, such as sodium citrate or dicalcium phosphate: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silica; (2) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) (3) Humectants, such as glycerin; (4) Disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates and sodium carbonate; (5) Solution blockers, such as paraffin; (6) Absorption promoters, such as quaternary ammonium compounds; (7) Wetting agents, such as acetyl alcohol and glyceryl monostearate; (8) Absorbents, such as kaolin and bentonite; (9) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) Colorants. In the case of capsules, tablets and pills, the composition may also contain buffers. Similar types of solid compositions may also be used as fillers in soft-filled and hard-filled gelatin capsules by excipients such as lactose and high molecular weight polyethylene glycol and the like.

[0244] Tablets can be manufactured by selectively compressing or molding them together with one or more auxiliary components. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium glycolate starch or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be manufactured by molding mixtures of the compositions of the present invention moistened with an inert liquid diluent in suitable machinery. Tablets and other solid dosage forms such as sugar-coated pills, capsules, pellets, and granules can be selectively scored or coated and shelled with coatings such as enteric coatings and other coatings well known in pharmaceutical compounding techniques.

[0245] Compositions for inhalation or inhalation include solutions and suspensions, as well as powders, in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the compositions of this invention, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuranol, fatty acid esters of polyethylene glycol and sorbitol, cyclodextrins, and mixtures thereof.

[0246] In addition to the compositions of the present invention, the suspension may also contain, for example, ethoxylated isostearyl alcohol, polyethylene oxide sorbitol and dehydrated sorbitol ester, microcrystalline cellulose, aluminum hydroxide, bentonite, agar-agar and tragali, and mixtures thereof as suspending agents.

[0247] The preparation for administration via rectal or vaginal administration can be presented in suppository form. The suppository can be prepared by mixing the composition of the present invention with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax or salicylate, and is solid at room temperature but liquid at body temperature and will therefore melt in the body cavity and release the active agent.

[0248] Dosage forms for transdermal administration of the compositions of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants that may be required.

[0249] In addition to the compositions of the present invention, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, tragali, cellulose derivatives, polyethylene glycol, polysiloxane, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0250] In addition to the compositions of the present invention, powders and sprays may also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. Sprays may further contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane and propane).

[0251] The compositions and compounds of this invention can alternatively be administered via aerosols. This is achieved by preparing aqueous aerosols, liposome formulations, or solid particles containing the compounds. Non-aqueous suspensions (e.g., fluorocarbon propellants) can be used. Sonic aerosols can be used because they minimize the exposure of the agent to shear forces that could lead to degradation of the compounds contained in the compositions of this invention. Typically, aqueous aerosols are manufactured by formulating an aqueous solution or suspension of the compositions of this invention with conventionally pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary depending on the specific requirements of the compositions of this invention, but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol); harmless proteins, such as serum albumin; dehydrated sorbitol esters; oleic acid; lecithin; amino acids, such as glycine; buffers; salts; sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0252] The pharmaceutical compositions of the present invention, applicable to non-enteral administration, comprise the compositions of the present invention and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions just before use. Such sterile powders may contain antioxidants, buffers, antibacterial agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

[0253] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions provided herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate) and cyclodextrins. Appropriate flowability can be maintained, for example, by using coating materials such as lecithin, by maintaining the desired particle size in the case of a dispersion, and by using surfactants.

[0254] In another embodiment, an enteric pharmaceutical formulation is provided, comprising the disclosed compound and an enteric-coated material, and a pharmaceutically acceptable carrier or excipient thereof. The enteric-coated material refers to a polymer that is substantially insoluble in the acidic environment of the stomach and primarily soluble in intestinal fluid at a specific pH. The small intestine is part of the gastrointestinal tract (intestine) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is approximately 5.5, the pH of the jejunum is approximately 6.5, and the pH of the terminal ileum is approximately 7.5.

[0255] Therefore, the enteric material is insoluble, for example up to a pH of about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Examples of enteric-coated materials include cellulose acetate phthalate (CAP); hydroxypropyl methylcellulose phthalate (HPMCP); polyvinyl acetate phthalate (PVAP); hydroxypropyl methylcellulose succinate (HPMCAS); cellulose benzotriacyl acetate; hydroxypropyl methylcellulose succinate; cellulose succinate; cellulose hexahydrophthalic acid cellulose acetate; cellulose propionate phthalate; cellulose maleate cellulose acetate; cellulose acetate butyrate; cellulose acetate propionate; copolymers of methyl methacrylate and methyl methacrylate; copolymers of methyl acrylate, methyl methacrylate and methacrylate; copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series); ethyl methacrylate-methyl methacrylate-ethyl chlorotrimethylammonium acrylate copolymers; natural resins such as corn gluten, shellac and copal colophorium; and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit...). L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric. The solubility of each of the above materials is known or readily measurable in vitro. The foregoing materials are a list of possible materials, but those skilled in the art who will benefit from this invention will recognize that it is incomplete and that other enteric-coated materials exist that satisfy the objectives described herein.

[0256] Advantageously, this article provides kits for consumers, for example, who require cancer treatment. These kits include suitable dosage forms such as those described above; and instructions describing the use of the dosage form to mediate, reduce, or prevent inflammation. The instructions will guide consumers or medical personnel to administer the dosage form according to dosing patterns known to those skilled in the art. These kits can be advantageously packaged and sold as single or multiple kit units. An example of such kits is the so-called blister pack. Blister packs are well-known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a relatively rigid sheet of material covered with a foil of a preferred transparent plastic material. During the packaging process, a groove is formed in the plastic foil. The groove has the size and shape of the tablet or capsule to be packaged. The tablet or capsule is then placed in the groove, and the relatively rigid sheet of material is sealed against the plastic foil on the foil side opposite to the direction in which the groove was formed. As a result, the tablets or capsules are sealed in a groove between the plastic foil and the sheet. Preferably, the sheet is strong enough that pressure can be manually applied to the groove to create an opening in the sheet at the groove location for removal of the tablets or capsules from the blister pack. The tablets or capsules can then be removed through this opening.

[0257] Memory aids may need to be provided on the kit, for example, by numbering the tablets or capsules adjacent to each other, with the number corresponding to the number of days in the regimen for which the prescribed tablets or capsules should be taken. Another example of such memory aids is a calendar printed on a card, such as "Week 1, Monday, Tuesday, ... etc.; Week 2, Monday, Tuesday, ... etc." Other variations of memory aids are obvious. A "daily dose" can be a single tablet or capsule or several tablets or capsules to be taken on a specified date. Furthermore, the first compound of the daily dose may consist of one tablet or capsule, while the second compound of the daily dose may consist of several tablets or capsules, and vice versa. The memory aid should reflect this. [Example]

[0258] The compounds described herein can be prepared in various ways based on the teachings contained herein and the synthetic procedures disclosed in this art. In the description of the synthetic methods described below, it should be understood that, unless otherwise indicated, all proposed reaction conditions, including solvent selection, reaction atmosphere, reaction temperature, experimental duration, and processing procedures, can be selected as standard conditions for that reaction. Those skilled in organic synthesis will understand that the functional groups present on various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions should be readily apparent to those skilled in this art, and therefore, alternative methods are indicated. The starting materials used in the examples are commercially available or readily prepared from known materials by standard methods.

[0259] The accompanying abbreviations are used in this invention and have the following accompanying definitions: "AcOH" is acetic acid, "ADP" is adenosine diphosphate, "AgNO3" is silver nitrate, "ASNase" is asparagine enzyme, "Boc" is tributyl carbonate, "CDI" is carbodiimidazole, "conc" is concentrated, "Cs2CO3" is cesium carbonate, "CuI" is copper iodide (I), "DBU" is 1,8-diazabicyclo[5.4.0]undecyl-7-ene, "DCC" is N,N'-bicyclohexylcarbodiimide, "DCE" is dichloroethane, "DCM" is dichloromethane, "DIAD" is diisopropyl azodicarbonate, "DIEA" is N,N-diisopropylethylamine, and "DMA" is N... N-Dimethylacetamide, "DMAP" is 4-(dimethylamino)pyridine, "DMF" is N,N-dimethylmethamide, "dppf" is 1,1'-bis(diphenylphosphino)ferrocene, "DMSO" is dimethyl sulfoxide, "EDTA" is ethylenediaminetetraacetic acid, "ESI" is electrospray ionization, "EtOAc" is ethyl acetate, "EtOH" is ethanol, "GST" is glutathione S-transferase, "h" is hours, "HBTU" is hexafluorophosphate (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium), "H2" is hydrogen, "HCl" is hydrochloric acid, "Hex" is hexane, "H2O" is water, "HOBt" is hydroxybenzotriazole, "IC50" is half-maximum inhibition concentration, "K2CO" is... "3" represents potassium carbonate, "KOAc" represents potassium acetate, "K3PO4" represents potassium phosphate, "NaBH4" represents sodium borohydride, "LAH" represents lithium aluminum hydride, "LiOH" represents lithium hydroxide, "MeCN" represents acetonitrile, "MeOH" represents methanol, "Me4tBuXPhos" represents di-tertiary butyl(2',4',6'-triisopropyl-3,4,5,6-tetramethyl-[1,1'-biphenyl]-2-yl)phosphine, "MgSO4" represents magnesium sulfate, "MHz" represents megahertz, "min" represents min, "MnO2" represents manganese oxide (IV), "MS" represents mass spectrometry, "NADH" represents nicotinamide adenine dinucleotide, "Na" represents sodium, "NaH" represents sodium hydride, "NaHCO3" represents sodium bicarbonate, "NaNO2" represents sodium nitrite, "NaOMe" represents sodium methoxide, "Na2SO4" represents sodium hydroxide ... 4" represents sodium sulfate, "NBS" represents N-bromosuccinimide, "NCS" represents N-chlorosuccinimide, "NH 4Cl" represents ammonium chloride, "NH 2OH" represents hydroxylamine, "NMP" represents N-methyl-2-pyrrolidone, "NMR" represents nuclear magnetic resonance, "PBS" represents phosphate-buffered saline, "Pd / C" represents palladium / carbon, and "Pd 2(dba) 3" represents triphenylmethyleneacetone dipalladium(O)."Pd(OAc)2" is palladium(II) acetate, "Pd(PPh3)4" is tetrakis(triphenylphosphine)palladium(O), "Pd(dppf)Cl2" is 1,1-bis(diphenylphosphine)ferrocene-palladium(II) dichloride, "Preparative HPLC" is preparative high-performance liquid chromatography, "PCl3" is phosphorus trichloride, "Ph3P" is triphenylphosphine, "PhPOCl2" is phenylphosphine dichloride, "PMB" is p-methoxybenzyl, "POCl3" is phosphorus oxychloride, "PyBOP" is benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate, "rt" is room temperature, also known as "ambient temperature", which is understood to consist of a series of normal laboratory temperatures in the range of 15 to 25°C, "satd." is saturated, "SDS" is sodium dodecyl sulfate, "SFC" is supercritical fluid chromatography, "S "NAr" represents nucleophilic aromatic substitution, "SOCl 2" represents thionyl chloride, "T 3P" represents n-propane phosphoric anhydride, "TEA" represents triethylamine, "TFA" represents trifluoroacetic acid, "THF" represents tetrahydrofuran, "Xantphos" represents 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopiperanan, "X-Phos" represents 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, and "ZnCl 2" represents zinc chloride.

[0260] In the following examples and corresponding figures, "Compound 16" refers to the compound described as Example 16 in Table I below. [General Chemical Reactions] []

[0261] The exemplary compounds described herein can be obtained by the general synthetic methods illustrated in the following procedures, intermediate preparations and accompanying examples. [Synthesis Process] [] [process] [1]

[0262] Process 1 Description of Borate [1.4] Exemplary preparation. The compound is prepared by an oxygen borylation reaction known to those skilled in the art. [1.1] (commercially available, synthesized as described in WO2013134298 or by a person skilled in this technique) reacts with bis(pinacolyl) diborone (at high temperature using a palladium catalyst such as Pd(dppf)Cl2, a suitable base such as KOAc, in a 1,4-di (Palladium-mediated reaction in a suitable solvent of alkane) to obtain the compound [1.2], which is related to sulfonyl chloride [2.3] The reaction (see process 2) yields the compound. [1.4]. Alternatively, compounds [1.1] Reaction with sulfonyl chloride [2.3], sulfonamide was obtained [1.3], which is converted to borate ester under the oxygen borylation reaction conditions known to those skilled in the art. [1.4]. [] [process] [2]

[0263] Procedure 2 explains sulfonyl chloride [2.3] Exemplary preparation. The bromide is prepared by a Pd-catalyzed coupling reaction (e.g., using Pd₂(dba)₃, XantPhos, phenylmethanethiol, in the presence of a base such as DIEA, in a solvent such as toluene, and at high temperature). [2.1a] (Ring A: substituted aryl, five- or six-membered heteroaryl, commercially available or synthesized by someone skilled in this technique) converted to thioethers [2.2a]. Based on the general reaction conditions reported in Synthesis, 2006, 24, 4131-4134 and Bioorg. Med. Chem., 2017, 25, 3447-3460, thioethers... [2.2a] Smooth oxidation (e.g., by a combination of NCS and dilute HCl, 1,3-dichloro-5,5-dimethylhydantoin) yields the corresponding sulfonyl chloride. [2.3]. Alternatively, sulfonyl chloride [2.3] Self-amine [2.1b] (Ring A: substituted aryl, five- or six-membered heteroaryl, commercially available or synthesized by a person skilled in this technique) is prepared by starting with diazotization followed by Cu-mediated chlorination of the resulting intermediate (under general reaction conditions reported in Org. Proc. Res. Dev., 2009, 5, 875-879). [process] [3] []

[0264] Process 3 describes the intermediate products [3.9] Illustrative preparation of (X 21 = O, NR 2). The compound is prepared in the presence of a base such as piperidine. [3.1] (Commercially available or synthesized by someone skilled in this technique) reacts with ethyl 2-bromoacetate to give pyridopyrimidine ketone. [3.2]. The compound is subjected to high temperatures in a polar aprotic solvent such as NMP in the presence of a base such as DIEA. [3.2] Reacts with amine R 1NHP (P = protecting group or H) to give [3.3]. Compounds [3.3] Reacts with POCl3 to obtain [3.4], which is converted into an intermediate by reacting with an alkoxide (E 2-L 2-OH / Na) or an amine (E 2-L 2-NHR 2). [3.9](X 21 = O, NR 2). In another embodiment, pyridopyrimidine ketone [3.2] It reacts with POCl3, and the resulting intermediate then undergoes a substitution reaction with an amine (R1NH2) to give the intermediate. [3.9](X 21-L 2-E 2= NHR 1). Alternatively, intermediates [3.9] Self-contained compounds [3.5] The preparation was carried out according to the general reaction conditions reported in WO2018153373, CN105481858 and CN105968108. Bromine was used in AcOH to prepare the solution. [3.5] Bromination was carried out to obtain bromide. [3.6], which is converted into chloride by treatment with POCl 3. [3.7]. The intermediate was then reacted with an alkoxide (E 2-L 2-OH / Na) or an amine (E 2-L 2-NHR 2) to form the intermediate. [3.7] converted into compounds [3.8](X 21 = O, NR 2). Compound [3.8] Transformed into intermediates [3.9] is carried out in a two-step process, including: (i) sulfide oxidation in a suitable solvent such as DCM in the presence of an oxidant such as mCPBA at rt to obtain the corresponding sulfide and (ii) condensation of the sulfide with amine R 1NHP (P = protecting group or H). [process] [4] []

[0265] Process 4 Explanation [I] Illustrative preparation of the compound. In the presence of a Pd catalyst such as Pd(PPh3)4 or Pd(dppf)Cl2, the intermediate was prepared... [3.9] (Prepared as described in process 3, X 21 = O, NR 2) and borate ester [1.4] Condensation yields the formula [I] Compound. Alternatively, under palladium-mediated oxoborylation reaction conditions... [3.9] Reacted with bis(pinacolyl)diboron to give a borate intermediate. [4.1]. Boron esters are produced by the Suzuki reaction, known to those skilled in the art. [4.1] with bromide [1.3] The reaction yields formula... [I] compounds. In another embodiment, under Pd-catalyzed coupling conditions... [3.9] with borate esters [1.2] Reaction (Suzuki reaction) yields compound [4.2]. Aniline is produced in the presence of a base such as pyridine. [4.2] with sulfonamides [2.3] The reaction yields the formula... [I] Compounds. In formula... [I] When the compound contains a nitrogen-protecting group P such as Boc or PMB, it can be used under acidic conditions (TFA or HCl at 1,4-di) (in an alkane) removing the protecting group to obtain the corresponding amine (formula) [I] compound). [process] [5] []

[0266] Process 5 Explanation [I] Illustrative preparation of compounds. In the presence of a Pd catalyst such as Pd(PPh3)4 or Pd(dppf)Cl2... [5.1] (Y = OSO 2CF 3, X 21 = direct bond, as described in WO2013134243, WO2013029084 and J. Med. Chem., 2015, 58, 4165-4179) and borate esters [1.2] The Suzuki reaction occurs to give aniline. [5.5]. Similarly, under Pd-catalyzed coupling conditions, the compound... [5.1](Y = OSO 2CF 3, X 21 = direct bond) and borate esters [1.4] Reaction (Suzuki reaction), providing compounds [5.6]. Alternatively, [5.6] Aniline can be used [5.5] with sulfonamides [2.3] The compound is prepared by the coupling reaction of sulfadiazine. [5.6] The conversion to compound I is carried out in a two-step process, comprising: (i) sulfide oxidation in a suitable solvent such as DCM in the presence of an oxidant such as mCPBA at rt, thereby obtaining the corresponding sulfide, and (ii) condensation of the sulfide with an amine R 1NH 2. Alternatively, compound I can be converted by... [5.6] It is obtained by direct substitution reaction with amine R 1NH 2 at high temperature.

[0267] In another embodiment, the compound was oxidized with mCPBA. [5.1](Y = H, X 21 = direct bond, commercially available or synthesized as described in WO2013134243, WO2013029084 and J. Med. Chem., 2015, 58, 4165-4179), the resulting intermediate then undergoes a substitution reaction with an amine R 1NH 2, generally carried out in an aprotic solvent at a temperature between rt and 150 °C, to give the compound [5.2]. Based on the general reaction conditions reported in WO2013134243, WO2013029084 and J. Med. Chem., 2015, 58, 4165-4179, [5.2] Bromination (e.g., with NBS or Br2 / HOAc) yields bromides. [5.3](X 21 = direct bond). Compound [5.3] with borate esters [1.2] Compounds were obtained by Pd-catalyzed coupling reaction (Suzuki reaction) in the presence of Pd catalysts such as Pd(PPh3)4 or Pd(dppf)Cl2. [5.4], which is related to sulfonyl chloride [2.3] The reaction yields the corresponding sulfadiazine (formula...). [I] compounds). Alternatively, formula [I] The compound can be directly derived from the Suzuki reaction. [5.3] with borate esters [1.4] Preparation. [process] [6]

[0268] Process 6 describes the intermediate products [6.5] Exemplary preparation. The compound is prepared under Wittig reaction conditions known to those skilled in the art. [6.1] (commercially available or synthesized by someone skilled in this technique) reacts with 3-(triphenyl-15-phosphine)propionitrile to give the compound [6.2]. Compounds [6.2] DBU-promoted cyclization under microwave irradiation at high temperature yields 1,6- 2-Pyridine [6.3]. Using NBS [6.3] Bromination yields intermediate. [6.4], which is converted into a compound by a substitution reaction with amine R 1NHP at high temperature. [6.5]. [process] [7]

[0269] Process 7 describes the intermediate products [7.6] Exemplary preparation of (X 21 = O, NH). The compound is prepared at high temperature in the presence of a suitable base such as sodium alkoxide and in a protic solvent such as 2-ethoxyethanol. [7.1] (commercially available or synthesized by someone skilled in this technique) and phenylacetonitrile [7.2] (Commercially available or synthesized by someone skilled in this technique) reaction, to obtain [7.4a](R = NH₂). According to the general reaction conditions reported in Synlett, 2001, 5, 643-645, the intermediate is... [7.4a](R = NH₂) reacts with DMF-dimethylacetal, followed by reduction with NaBH₄ to give [7.5a](X 21 = NH). The compound is reduced with ammonium chloride under mild reducing conditions (such as zinc or iron metals). The nitro substituent of [7.5a] yields an aniline derivative. [7.6]. In another embodiment, the compound is reacted at high temperature in a protic solvent such as EtOH in the presence of a base such as piperidine. [7.1]With ester [7.3] (Commercially available or synthesized by someone skilled in this technique) reaction, to obtain [7.4b](R = OH). The intermediate is prepared under standard phototensive conditions (e.g., in the presence of Ph 3P and DIAD). [7.4b] Reacts with alcohols (E 2-L 2-OH) to provide ethers [7.5b](X 21= O), via reduction with ammonium chloride in the presence of zinc or iron. The nitro functional group of [7.5b] converts it into a compound. [7.6]. [process] [8]

[0270] Process 8 Explanation [I] Illustrative preparation of the compound. The compound was prepared from trifluoromethanesulfonate according to the general reaction conditions reported in WO2013134298 and WO2018229629. [8.1] (X 21 = direct bond) Start the preparation of aniline in 2 steps [8.3]. Trifluoromethanesulfonate [8.1] (synthesized as described in J. Med. Chem., 2015, 58, 4165-4179) with borate esters The Suzuki reaction of [1.2] yielded [8.2]. Chloride is produced at high temperature in the presence of an alkali such as DIEA. [8.2] Reacts with R 1NHP (P = protecting group) to give compound [8.3], by means of sulfonyl chloride [2.3] The reaction converts it into sulfonamide. [8.5]. In another embodiment, the compound [8.5] ​​is achieved through bromide [6.5] (See intermediates described in process 6) [6.5] Preparation) and borate ester [1.4] Suzuki coupling reaction is used to prepare it. Alternatively, it can be prepared by... [7.6](X 21 = O, NH, see intermediates described in process 7) [7.6] Preparation) and sulfonyl chloride [2.3] reaction yields sulfamethoxam. [8.4], by means of palladium catalysts such as Pd₂(dba)₃ or Pd(OAc)₂ and metal ligands such as XantPhos or tert-butylXphos, in the presence of bases such as Cs₂CO₃, in the presence of 1,4-di The alkane is converted into a compound by reacting it with an amine R 1NHP (P = protecting group) in a suitable solvent. [8.5], thus obtaining the intermediate. [8.5]. Removal [8.5] ​​Protection base provision [I] [Compound.] In the case of a compound containing a nitrogen protecting group P such as Boc or PMB, the protecting group can be used under acidic conditions (TFA or HCl at 1,4-diphenyl ether). (from alkane) to obtain the corresponding amine (formula) [I] compound). [process] [9] []

[0271] Process 9 Explanation [I] Illustrative preparation of compounds. The aldehyde is prepared at high temperature in the presence of a base such as DIEA and in a polar solvent such as NMP. [9.1a] (commercially available or synthesized by someone skilled in the art, X 21 = direct bond, O, NH) reacts with guanidine carbonate to give 6-bromoquinazolin-2-amine. [9.2a]. Using Sandmeier reaction conditions known to those skilled in the art (e.g., X = I: amyl nitrite, CuI, and CH₂I₂), the compound... [9.2a] transformed into [9.3a](X = Cl, I). [9.3a] (X = Cl or I) reacts with amine R 1NH 2 at high temperature to obtain S NAr. [9.4a](X 1 = N, according to the general reaction conditions reported in WO2018046739, WO2006039718, US20090197862, and J. Med. Chem., 2006, 49, 5671-5686). In another embodiment, the primary amine is reacted at high temperature in the presence of a base such as DIEA. [9.1b] (commercially available or synthesized by a person skilled in this technique, X 21 = direct bond, O, NH) reacts with ethyl 2,2-dimethoxyethyl acetate, followed by acid-mediated cyclization and trifluorination with trifluoromethanesulfonic anhydride to give trifluoromethanesulfonate. [9.2b]. When R3 is H, any obtained The regioisomers of [9.2b] can be separated by appropriate methods such as SFC purification, crystallization, or chromatography. Following the general reaction conditions reported in ACS Med. Chem. Lett., 2015, 6, 31-36, trifluoromethanesulfonate is obtained via a S NAr reaction at high temperature. [9.2b] Reacts with amine R 1NH 2 to give [9.4b](X 1= CH). Commercially available. [9.2c](X1=N, X3=CH and R3=H: 6-bromoquinazolin-2-amine, and X1=CH, X3=CH and R3=H: 7-bromoisoquinolin-3-amine) react with acid anhydrides ((R13(CO))2O) at high temperature to give acetylamine. [9.4](X1 = N or CH; R1 = (CO)R13). Under the Suzuki reaction conditions, [9.4a] [9.4b] and [9.4c] and boronic acid esters [1.2] Palladium-catalyzed coupling yielded intermediates. [9.5a]、 [9.5b] [and] [9.5c]. Under reaction conditions known to those skilled in this technique, [9.5a]、 [9.5b] and [9.5c] with sulfonyl chloride The coupling of [2.3] yields the formula [I] Compound. Or, formula: [I] The compound can be coupled via a palladium-catalyzed reaction (Suzuki reaction) from... [9.2c]、 [9.4a] [9.4b] and [9.4c] and boronic acid esters [1.4] is used to prepare it. [process]

[10]

[0272] Mode [I] The compound can be prepared as described in procedure 10. In the presence of a base such as DIEA, commercially available 2,6-dichloropyridinium[3,2-d]pyrimidine ( [10.1]) reacts with amine R 1NH 2 (commercially available or synthesized by someone skilled in this technique) to give an intermediate. [10.2]. Chloride [10.2] with borate esters [1.2] Palladium-catalyzed coupling reaction (Suzuki reaction) yields aniline. [10.3]. Aniline [10.3] with sulfonyl chloride [2.3] The reaction is provided by formula [I] Compound. Or, formula: [I] The compound can be self-chlorinated under Suzuki reaction conditions. [10.2] and borate esters [1.4] Direct preparation. [process]

[11] []

[0273] Mode [I] The compound can be prepared as described in procedure 11. The amine is prepared under palladium-mediated Suzuki coupling conditions. [11.1] (commercially available or synthesized by those skilled in the art) and borate esters [1.4] The reaction yields compound I (R 1 = H). In another embodiment, the amine is made... [11.1] Under amide coupling conditions (e.g., HATU and DMAP in the presence of DIEA), the reaction with carboxylic acid R13COOH, or with amide chloride R13COCl in the presence of a base such as pyridine, yields [11.2]. The intermediate was prepared under Suzuki reaction conditions. [11.2] with borate esters [1.2] The reaction yielded the compound. [11.3], which is transmitted via sulfonyl chloride [2.3] It reacts to form compound I. Alternatively, formula I... [I] The compound can be generated under the Suzuki reaction conditions. [11.2] with borate esters [1.4] Direct preparation. [process]

[12]

[0274] Mode The intermediate of [12.5] can be prepared as described in process 12. Commercially available 5-bromo-2-chloroisocyanuric acid (B2C) is prepared under Pd / Cu-catalyzed Sonogashira cross-coupling conditions (e.g., in the presence of a palladium catalyst such as Pd(PPh3)2Cl2, in the presence of a Cu(I) catalyst such as CuCl or CuI, in the presence of a base such as triethylamine, in a suitable solvent such as DMF / THF, at a temperature between rt and 120°C). [12.1]) and 3-nitrobenzylene [12.2] (Commercially available or synthesized by someone skilled in this technique) reaction to obtain acetylene. [12.3]. In the presence of a suitable base such as NaOAc, the intermediate is made... [12.3] Reacts with hydroxylamine hydrochloride to give oxime. [12.4]. N-oxides [12.5] The synthesis procedure reported in US20190270742 is based on the method of cyclization using AgNO3 electrophilic metal catalysis. [12.4] is used to prepare it. [process]

[13] []

[0275] Mode [I] The compound can be prepared as described in procedure 13. N-oxide [12.5] (See process 12 for details) [12.5] Preparation) copper-catalyzed direct amination, at high temperature, in an aprotic solvent such as toluene, in the presence of a catalyst such as CuI, reacted with amine E2-L2-NHR2 (according to the general reaction conditions reported in J. Org. Chem., 2017, 82, 8933-8942), yielding [13.1](X 21 = NR 2). According to the synthesis procedure reported in US20190270742, N-oxides were synthesized in the presence of PCl 3. [13.1] transformed into a compound [13.2]. Under mild reducing conditions (reactions with ammonium chloride in the presence of metals such as zinc or iron), [13.2] Nitro reduction to aniline [13.3], which is due to its interaction with sulfonyl chloride [2.3] The reaction is converted to the corresponding sulfonamide. [13.4]. Finally, those familiar with this technique already know... [13.4] The Pd-catalyzed coupling reaction with R1NH2 (Buchwald reaction) yields the formula... [I] Compound. [process]

[14]

[0276] Mode [14.6] The intermediate can be prepared as described in process 14. Commercially available methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (Methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate) is prepared under Pd / Cu catalytic conditions known to those skilled in the art. [14.1]) and 3-nitrophenylacetylene [12.2] (Commercially available or synthesized by those skilled in this technique) reaction (soybean curd reaction), yielding [14.2]. Ester hydrolyzed with LiOH (aqueous solution). [14.2] The corresponding acid was obtained. [14.3]. According to the general reaction conditions reported in Org. Lett., 2006, 8, 5517-5520, acid... [14.3] Acid-promoted intramolecular cyclization yields [14.4]. Intermediate substances [14.4] At high temperature, in glacial acetic acid, it is converted to NH4OAc. [14.5]. According to the general reaction conditions reported in WO2018113584, the compound was... [14.5] Reacts with PhPOCl₂ to give an intermediate. [14.6]. [process]

[15]

[0277] Mode [I] The compound can be prepared as described in procedure 15. Following the general reaction conditions reported in WO2018113584, in the presence of Ag₂CO₃, it is prepared using the alkylating agent E₂L₂-I. [14.5] (See process 14 for details) [14.5] was prepared by O-alkylation to obtain [15.1a](X 21= O). Alternatively, according to the general reaction conditions reported in WO2014037750, the chloride is substituted by a substitution reaction at high temperature in the presence of a base such as DIEA in a polar aprotic solvent such as NMP. [14.6] Reacts with alcohols (E₂-L₂-OH) or amines (E₂-L₂-NHR₂) to give [15.1b](X 21 = O, NR 2). Alternatively, under Pd catalytic coupling conditions, chloride is... [14.6] (Prepared in process 14) reacts with boric acid or borate ester E 2-L 2-B(OR) 2 (commercially available or synthesized by a person skilled in this technique) (Suzuki reaction) to obtain [15.1c](X 21 = direct bond). Palladium-catalyzed hydrogenation or mild reduction conditions (zinc or iron metal with ammonium chloride) [15.1a]、 [15.1b] and Nitro reduction of [15.1c] yields aniline. [15.2]. When [15.1c] When a double or triple bond is present at L2-E2, this moiety, along with the nitro group, can be completely reduced under palladium-catalyzed hydrogenation conditions to obtain... [15.2]. Under sulfonamide coupling conditions known to those skilled in the art, aniline is... [15.2] with sulfonyl chloride [2.3] reaction to obtain sulfamethoxam [15.3]. Finally, formula [I] The compound can be oxidized by mCPBA. [15.3] The intermediate was then prepared by reacting the obtained intermediate with amine R 1NH 2 via an S NAr reaction. [process]

[16]

[0278] Mode The intermediate of [16.6] can be prepared as described in process 16. Commercially available 5-amino-2-chloroisocyanuric acid ( [16.1]) and 3-nitro-aldehyde [16.2] (Commercially available or synthesized by someone skilled in this technique) reaction, to obtain [16.3]. According to the general reaction conditions reported in WO2018113584, oxidation is carried out using an oxidizing agent such as MnO2. [16.3], obtained [16.4]. Intermediate substances [16.4] The reaction of amine R1NH2 with Pd-catalyzed coupling reaction known to those skilled in the art (Barch reaction) yields [16.5], which can react with POCl3 to give the intermediate chloride. [16.6]. [process]

[17] []

[0279] Mode [I] The compound can be prepared as described in procedure 17. The chloride is prepared by substitution reaction. [16.6] (Prepared as described in procedure 16) reacts with an alcohol (E₂-L₂-OH) or an amine (E₂-L₂-NHR₂) to give [17.1a](X 21= O) or [17.b](X 21 = NR 2). Alternatively, [17.1c](X 21 = direct key) can be self-contained [16.6] It is prepared by a Pd-coupling reaction (Suzuki reaction) with boric acid or borate ester (E2-L2-B(OR)2). The reaction is carried out via palladium-catalyzed hydrogenation or under mild reducing conditions (zinc or iron metal with ammonium chloride). [17.1a] [、] [17.1b] and Nitro reduction of [17.1c] yields aniline. [17.2]. When [17.1c] When a double or triple bond is present at L2-E2, this moiety, along with the nitro group, can be completely reduced under palladium-catalyzed hydrogenation conditions to obtain... [17.2]. Finally, aniline [17.2] with sulfonyl chloride [2.3] Under sulfamethoxam coupling conditions, the following formula was obtained. [I] Compound. In another embodiment, commercially available 2-chloro-5-iodoisocyanate (2-chloro-5-iodoisocyanate) was reacted under the general reaction conditions reported in Tetrahedron Lett., 2010, 51, 785-760. [17.3]) and various benzo[a]amidine [17.4] (commercially available or synthesized by someone skilled in this technique) undergoes a ligandless copper-catalyzed Ullmann reaction to obtain [17.5](X 21-L 2-E 2= H). Pd-catalyzed coupling reaction, known to those skilled in the art, is used to pyridopyrimidine... [17.5] Reacts with amine R 1NH 2 to give [17.6]. The reaction is carried out via palladium-catalyzed hydrogenation or under mild reducing conditions (zinc or iron metal with ammonium chloride). The nitro reduction of [17.6] yields aniline. [17.7]. Aniline [17.7] with sulfonyl chloride The coupling reaction of sulfadiazine [2.3] yields the formula... [I] Compound. [Preparation of intermediates and final compounds.] []

[0280] The accompanying compound was prepared using the synthetic procedures and methods described herein and methods known to those skilled in the art: [General Method] [A] [Oxyborylation reaction] [] Example [A1]: 2-Fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)aniline

[0281] Potassium acetate (14.4 g, 147 mmol), 5-bromo-2-fluoro-4-methylaniline (10.0 g, 49 mmol), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (17.4 g, 69 mmol) were reacted with Ar to form potassium acetate (14.4 g, 147 mmol), 5-bromo-2-fluoro-4-methylaniline (10.0 g, 49 mmol), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (17.4 g, 69 mmol). The mixture in 150 mL of alkyl was degassed for 10 minutes. PdCl₂ (dppf) (1.79 g, 2.5 mmol) was added and the reaction mixture was heated at 110 °C for 6 hours. The reaction was cooled to rt and filtered through a diatomaceous earth mat. The filtrate was removed under reduced pressure and the residue was purified by silica gel column chromatography (0 to 50% EtOAc / hexane and 1% EtOAc / DCM) to give 6.2 g, 50% yield, a brown solid of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)aniline. 1H NMR (500 MHz, DMSO-d 6): δ 7.12 (d, J = 10.4 Hz, 1H), 6.78 (d, J = 12.8 Hz, 1H), 4.86 (s, 2H), 2.29 (s, 3H), 1.26 (s, 12H); MS (ESI) m / z: 252.2 (M+H+).

[0282] Use the general method A described above to prepare the intermediates listed in Table A. [surface] [A.] [] Instance number product Yield (%) 1H NMR (400 or 500 MHz, DMSO-d 6): δ MS (m / z: M+H+) A2 96 No data available 234.2 A3 61 6.85 (m, 1H), 6.78 (m, 1H), 6.65 (m, 1H), 4.90 (brs, 2H), 1.27 (s, 12H). 238.1 A4 62 7.13 (d, J = 9.8 Hz, 1H), 6.94 (m, 2H), 6.82 (t, J = 6.3 Hz, 1H), 5.09 (s, 2H), 1.24 (s, 12H). 238.1 A5 88 6.77 (d, J = 2.0 Hz, 1H), 6.42 (m, 2H), 5.42 (s, 2H), 1.27 (s, 12H). 238.2 A6 78 6.86 (m, 2H), 6.76 (d, J = 6.8 Hz, 1H), 5.02 (s, 2H), 1.28 (s, 12H). 238.2 A7 crude product No data available 256.2 A8 36 6.59 (m, 2H), 5.20 (brs, 2H), 1.28 (s, 12H). 256.1 A9 33 No data available 256.2 A10 93 7.09 (m,1H), 6.94 (m, 1H), 5.00 (s, 2H), 1.28 (s, 12H). 256.2 A11 crude product 7.1.3 (d, J = 9.8 Hz,1H), 6.94 (m, 1H), 6.82 (m, 1H), 5.09 (s, 2H), 1.24 (s, 12H). 238.1 A12 61 6.88 (t, J = 8.8 Hz, 1H), 6.77 (m, 1H), 5.10 (brs, 2H), 1.28 (s, 12H). 256.0 A13 65 6.74 (d, J = 2.4 Hz, 1H), 6.37 (dd, J = 2.4 and 12.4 Hz, 1H), 5.10 (brs, 2H), 2.18 (d, J = 2.0 Hz, 3H), 1.28 (s, 12H). 252.1 A14 40 6.88 (d, J = 7.8 Hz, 1H), 6.71 (m, 1H), 4.7 (brs, 2H), 2.05 (s, 3H), 1.26 (s, 12H). 252.3 A15 81 6.80 (d, J = 4.6 Hz, 2H), 6.75 (m, 1H), 4.80 (s, 2H), 3.65 (s, 3H), 1.29 (s, 12H). 250.2 A16 38 6.84 (d, J = 2.8 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H), 6.61 (m, 1H), 4.6 (brs, 2H), 3.59 (s, 3H), 1.25 (s, 12H). 250.1 A17 76 6.86 (m, 2H), 6.71 (m, 1H), 4.7 (brs, 2H), 2.20 (s, 3H), 1.28 (s, 12H). 234.2 A18 60 7.31 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 2.4 Hz, 1H), 6.64 (dd, J = 1.6及8.4 Hz, 1H), 5.80 (brs, 2H), 1.28 (s, 12H). 288.1 A19 62 7.22 (t, J = 8.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.57 (d, J = 6.8 Hz, 1H), 5.50 (brs, 2H), 1.27 (s, 12H). 287.8 A20 46 6.99 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 2.8 Hz, 1H), 6.60 (dd, J = 3.2 and 8.8 Hz, 1H), 5.20 (brs, 2H), 1.28 (s, 12H). 254.0 A21 43 6.99 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 6.4 Hz, 1H), 6.77 (d, J = 6.8 Hz, 1H), 5.25 (brs, 2H), 1.28 (s, 12H). 254.1 A22 78 7.29 (m, 1H), 6.92 (m, 2H), 5.93 (s, 2H), 1.30 (s, 12H). 245.2 A23 42 6.85 (d, J = 1.2 Hz, 1H), 6.69 (s, 1H), 6.67 (m, 1H), 5.41 (brs, 2H), 1.27 (s, 12H) No information [General Method] [B] [:condensation] [] Example [B1]: 7-Methyl-2-(methylthio)pyrido[2,3-d]pyrimidine

[0283] A solution of 4-amino-2-(methylthio)pyrimidine-5-carboxaldehyde (3.0 g, 18 mmol) in acetone (50 mL) was treated with K₂CO₃ (3.1 g, 22 mmol). The reaction was heated to 65 °C overnight. The reaction was filtered while hot, and the filtrate was cooled to rt and the solvent evaporated. The residue was recrystallized from water. The solid was filtered and washed with hexane (20 mL) to give 7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidine (3.1 g, 93% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d 6): δ 9.40 (s, 1H), 8.42 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 2.71 (s, 3H), 2.63 (s, 3H). [General Method] [C] [:replace] [] Example [B2]:N,7-Dimethylpyrido[2,3-d]pyrimidin-2-amine

[0284] Heating 7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidine ( ) in a sealed tube at 80°C [B1] (1.00 g, 0.52 mmol) was dissolved overnight in N-methylamine (33% in ethanol, 8 mL). The reaction was cooled to rt and then concentrated under reduced pressure to give N,7-dimethylpyridano[2,3-d]pyrimidine-2-amine (0.62 g, 68% yield) as an orange solid. This substance was used in the next reaction without further purification. MS (ESI) m / z: 175.2 (M+H+). [General Method] [D] [:halogenation] [(Br)] [or] [I)] Example [B3]: 6-Bromo-N,7-dimethylpyrido[2,3-d]pyrimidin-2-amine

[0285] N,7-dimethylpyrido[2,3-d]pyrimidin-2-amine was added in batches at rt. [B2], 0.62 g, 0.36 mmol) in a solution of NBS (0.67 g, 0.38 mmol) in DCM (7.5 mL). The reaction mixture was stirred overnight at rt. The reaction mixture was cooled to 0 °C and stirred for 15 min. The solid was filtered off and washed with cold DCM (15 mL) to give 6-bromo-N,7-dimethylpyridano[2,3-d]pyrimidin-2-amine (0.48 g, 53% yield). ¹H NMR (500 MHz, DMSO-d 6): δ 9.07 (s, 1H), 8.47 (s, 1H), 7.84 (s, 1H), 2.90 (d, J = 4.7 Hz, 3H), 2.68 (s, 3H); MS (ESI) m / z: 253.0 (M+H+) and 255.0. [General Method] [E] [:condensation] [] Example [B4]: 7-Methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-ol

[0286] A suspension of 4-amino-2-(methylthio)pyrimidine-5-carboxaldehyde (45 g, 266 mmol) in water (600 mL) was treated with NaOH (21 g, 530 mmol). 1-Hydroxyprop-2-one (23 g, 319 mmol) was added, and the reaction mixture was then heated to 55 °C and maintained for 4 hours. The reaction was cooled to 0 °C, and concentrated HCl was added dropwise under the same conditions until the pH was approximately 3–4. The reaction was stirred at 0 °C for 30 min, and the solid was then filtered to obtain 51 g (93% yield) of 7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidine-6-ol as a yellow solid. 1H NMR (500 MHz, DMSO-d 6): δ 10.8 (s, 1H), 9.28 (s, 1H), 7.53 (s, 1H), 2.57 (s, 3H), 2.56 (s, 3H); MS (ESI) m / z: 208.2 (M+H +). [General Method] [F] [:activation] [] Example [B5]: 7-Methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl ester of trifluoromethanesulfonate

[0287] 7-Methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-ol was stirred at 0°C. A suspension of [B4] (20 g, 97 mmol) and DIEA (37 g, 290 mmol) in DCM (500 mL) was prepared. A solution of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (34 g, 97 mmol) in DCM (130 mL) was slowly added. The reaction mixture was slowly heated to rt over 3 hours. The reaction mixture was quenched with saturated NaHCO3 (aqueous solution, 500 mL) and then filtered through a diatomaceous earth mat. The filtrate was extracted with DCM (3 × 100 mL) and the combined organic matter was washed with water (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was suspended in hexane and the solid was filtered off to obtain 7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl trifluoromethanesulfonic acid (23 g,...

Claims

1. A compound represented by Formula I, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: Formula I X1 is a group composed of CH and N; X2 and X3 are each independently chosen from the following groups: N, CH, CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2, with the restriction that X2 is a group composed of CH and N, and X3 is a group composed of the following groups: CH, CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; or with the restriction that X2 is a group composed of the following groups: CH, CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2, and X3 is a group composed of CH and N; X4 is a group composed of CR3 and N; X10 is a group composed of CR5 and N; X11 is a group composed of CR7 and N. R1 is selected from the group consisting of: H, alkyl, (C=O)R13, ​​cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, acetylamine, acetyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl and heterocyclic, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, acetylamine, amine, aminoalkyl, acetyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, cyanoalkyl and sulfonyl; R2 is selected from the group consisting of H and alkyl. R3 is selected from the group consisting of H, alkyl, and halogens; R4 and R5 are each independently selected from the group consisting of: halogens, H, alkoxy, alkylamino, amino, alkyl, haloalkyl, and CN; R6 and R7 are each independently selected from the group consisting of halogens, H, and alkyl; R13 is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl. Each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more independent substituents selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, amide, amide, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl and heterocyclic groups, wherein the heterocyclic group is, as appropriate, substituted by one or more independent substituents selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyl, cyano, cyanoalkyl and sulfonyl; the A group is selected from the group consisting of: substituted 5-membered heteroaryl, substituted 6-membered heteroaryl, pyridone and substituted phenyl ring; the L2 group is selected from the group consisting of direct bonds and alkyl groups, wherein the alkyl group is, as appropriate, substituted with (E21)p;E2 is selected from the group consisting of: hydroxyl, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, amide, amide, haloalkoxy, haloalkyl, and heterocyclic groups, wherein the heterocyclic group is substituted, as appropriate, by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amide, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, syloxy, cyano, and cyanoalkyl; E21 is independently selected from the group consisting of: H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen each time it appears; and each p is independently 0, 1, or 2; the limiting condition is that the compound is not: . ; 2. The compound of claim 1, or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, is: (i) a compound represented by formula IA: Formula IA or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X3 is selected from the group consisting of CH, CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; X5 is selected from the group consisting of CR8 and N; X6 is selected from the group consisting of CR9 and N; X7 is selected from the group consisting of CR10 and N; X8 is selected from the group consisting of CR11 and N; X9 is selected from the group consisting of CR8 and N, with the restriction that no more than three of X5, X6, X7, X8, and X9 are N; R8 is selected from the group consisting of: alkoxy, alkylamine, cycloalkoxy, cycloalkylamine, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxyl, and CN; R9, R10, and R11 are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamino, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; and L2 is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (ii) Compounds represented by formula IB: Formula IB or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X3 is selected from the group consisting of CH, CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; X5 is selected from the group consisting of CR8 and N; The X6 series is selected from the group consisting of CR9 and N; the X7 series is selected from the group consisting of CR10 and N; the X8 series is selected from the group consisting of CR11 and N; the X9 series is selected from the group consisting of CR8 and N, with the restriction that no more than three of X5, X6, X7, X8, and X9 are N; the R8 series is selected from the group consisting of: alkoxy, alkylamine, cycloalkoxy, cycloalkylamine, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxyl, and CN; R9, R10, and R11 are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamino, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; and L2 series are selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (iii) Compounds represented by formula IC: formula IC or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X5 series are selected from the group consisting of CR8 and N; X6 series are selected from the group consisting of CR9 and N; X7 series are selected from the group consisting of CR10 and N;The X8 group is selected from the group consisting of CR11 and N; the X9 group is selected from the group consisting of CR8 and N, with the restriction that no more than three of X5, X6, X7, X8, and X9 are N; the R8 group is selected from the group consisting of: alkoxy, alkylamine, cycloalkoxy, cycloalkylamine, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxyl, and CN; R9, R10, and R11 are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamino, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; and L2 series are selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (iv) Compounds represented by formula ID: Formula ID or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X5 series are selected from the group consisting of CR8 and N; X6 series are selected from the group consisting of CR9 and N; X7 series are selected from the group consisting of CR10 and N; X8 series are selected from the group consisting of CR11 and N; The X9 group is selected from the group consisting of CR8 and N, with the restriction that no more than three of X5, X6, X7, X8, and X9 are N; the R8 group is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxy, and CN; R9, R10, and R11 are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; and the L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (v) Compounds represented by formula IE: Formula IE or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X2 is selected from the group consisting of CH, CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; X5 is selected from the group consisting of CR8 and N; X6 is selected from the group consisting of CR9 and N; X7 is selected from the group consisting of CR10 and N; X8 is selected from the group consisting of CR11 and N; X9 is selected from the group consisting of CR8 and N, with the restriction that no more than three of X5, X6, X7, X8, and X9 are N;R8 is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxyl, and CN; R9, R10, and R11 are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; and L2 is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (vi) Compounds represented by formula IF: Formula IF or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X2 is selected from the group consisting of CH, CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; X5 is selected from the group consisting of CR8 and N; X6 is selected from the group consisting of CR9 and N; X7 is selected from the group consisting of CR10 and N; X8 is selected from the group consisting of CR11 and N; X9 is selected from the group consisting of CR8 and N, with the restriction that no more than three of X5, X6, X7, X8, and X9 are N; R8 is selected from the group consisting of: alkoxy, alkylamine, cycloalkoxy, cycloalkylamine, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxyl, and CN; R9, R10, and R11 are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamino, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; and L2 series are selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (vii) Compounds represented by formula IG: Formula IG or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X3 series are selected from the group consisting of CH, CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; R12 is individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamino, halogen, cyano, haloalkyl, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic and heterocyclic alkyl;The B group is selected from the group consisting of five-membered heteroaryl, six-membered heteroaryl and pyridinone, wherein the five-membered or six-membered heteroaryl ring or the pyridinone is substituted at each substituted position by R12; and the L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted by (E21)p as appropriate; (viii) Compounds represented by formula IH: Formula IH or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein: the X3 group is selected from the group consisting of CH, CO-L2-E2, C-L2-E2 and CN(R2)-L2-E2; R12 is individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamyl, halogen, cyano, haloalkyl, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic and heterocyclic alkyl; B series is selected from the group consisting of five-membered heteroaryl, six-membered heteroaryl and pyridone, wherein the five- or six-membered heteroaryl ring or the pyridone is substituted by R12 at each substituted position as appropriate; and L2 series is selected from the group consisting of direct bond and C1-C6 alkyl, wherein the C1-C6 alkyl is substituted by (E21)p as appropriate; (ix) Compounds represented by formula IJ: Formula IJ or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein: R12 is individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamino, halogen, cyano, haloalkyl, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic and heterocyclic alkyl; B series is selected from the group consisting of five-membered heteroaryl, six-membered heteroaryl and pyridone, wherein the five- or six-membered heteroaryl ring or the pyridone is substituted by R12 at each substituted position as appropriate; and L2 series is selected from the group consisting of direct bond and C1-C6 alkyl, wherein the C1-C6 alkyl is substituted by (E21)p as appropriate; (x) Compounds represented by formula IK: Formula IK or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein: R12 is individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamino, halogen, cyano, haloalkyl, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic and heterocyclic alkyl; B is selected from the group consisting of five-membered heteroaryl, six-membered heteroaryl and pyridinone, wherein the five-membered or six-membered heteroaryl ring or the pyridinone is substituted by R12 at each substituted position as appropriate;The L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (xi) Compounds represented by the formula IL: Formula IL or its pharmaceutically acceptable salts, enantiomers, stereoisomers or tautomers, wherein: The X2 group is selected from the group consisting of CH, CO-L2-E2, C-L2-E2 and CN(R2)-L2-E2; R12 is individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamino, halogen, cyano, haloalkyl, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic and heterocyclic alkyl; B series is selected from the group consisting of five-membered heteroaryl, six-membered heteroaryl and pyridinone, wherein the five-membered or six-membered heteroaryl ring or the pyridinone is substituted by R12 at each substituted position as appropriate; and L2 series is selected from the group consisting of direct bond and C1-C6 alkyl, wherein the C1-C6 alkyl is substituted by (E21)p as appropriate; (xii) Compounds represented by formula IM: Formula IM or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein: X2 series is selected from the group consisting of CH, CO-L2-E2, C-L2-E2 and CN(R2)-L2-E2; R12 is individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamyl, halogen, cyano, haloalkyl, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic and heterocyclic alkyl; B series is selected from the group consisting of five-membered heteroaryl, six-membered heteroaryl and pyridone, wherein the five- or six-membered heteroaryl ring or the pyridone is substituted by R12 at each substituted position as appropriate; and L2 series is selected from the group consisting of direct bond and C1-C6 alkyl, wherein the C1-C6 alkyl is substituted by (E21)p as appropriate; (xiii) Compounds represented by formula IN: Formula IN or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein: The X3 group is selected from the group consisting of CH, CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; the R7 group is selected from the group consisting of H and F; the R8 group is selected from the group consisting of: alkoxy, alkylamine, cycloalkoxy, cycloalkylamine, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyl, and CN;R10 and R11 are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl and heterocyclic alkyl; R13 is selected from the group consisting of: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl and heteroarylalkyl. Each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, amide, amide, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl and heterocyclic groups, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyloxy, cyano, cyanoalkyl and sulfonyl; and the L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are, as appropriate, substituted by (E21)p; (xiv) Compounds represented by formula IO: Formula IO or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein: The X3 group is selected from the group consisting of CH, CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; the R7 group is selected from the group consisting of H and F; the R8 group is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyl, and CN; R10 and R11 are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl;The R13 group is selected from the following compositional groups: H, alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclic, heterocyclic alkyl, aryl, heteroaryl, and heteroarylalkyl. Each of the aryl and heteroaryl groups is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, amide, amide, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl and heterocyclic groups, wherein the heterocyclic group is, as appropriate, substituted by one or more substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, amide, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, septyloxy, cyano, cyanoalkyl and sulfonyl; and the L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are, as appropriate, substituted by (E21)p; (xv) Compounds represented by formula IP: Formula IP or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein: The X3 group is selected from the group consisting of CH, CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; the R7 group is selected from the group consisting of H and F; the R8 group is selected from the group consisting of: alkoxy, alkylamine, cycloalkoxy, cycloalkylamine, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyl, and CN; R9, R10, and R11 are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamino, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; and L2 is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (xvi) Compounds represented by formula IQ: Formula IQ or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X3 is selected from the group consisting of CH, CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; R7 is selected from the group consisting of H and F; The R8 group is selected from the following groups: alkoxy, alkylamine, cycloalkoxy, cycloalkylamine, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyl, and CN;R9, R10, and R11 are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamino, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; and L2 is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (xvii) Compounds represented by Formula I: Formula I or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: L2 is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (xviii) Compounds represented by Formula I: Formula I Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X2 is selected from the group consisting of N, CH, CO-L2-E2, and C-L2-E2; X3 is CN(R2)-L2-E2; and L2 is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; or (xix) a compound represented by Formula I: Formula I or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X1 is CH; and L2 is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate.

3. The compound of claim 1 or 2, or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: (i) R1 is selected from: the group consisting of: , wherein R14 is independently selected from the group consisting of: H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl and cyanoalkyl each time it appears; or the group consisting of: or the group consisting of: H, ; Or a group consisting of: ; or a group consisting of: wherein R14 is independently selected from the group consisting of H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl and cyanoalkyl each time it appears; and / or (ii) X4 is CR3, wherein R3 is selected from the group consisting of H, methyl and F; and / or (iii) X10 is CR5 and X11 is CR7, X10 and X11 are N, or X10 is CR5 and X11 is N; and / or (iv) R4 and R5 are each independently selected from the group consisting of H, F, Cl, Me, OMe, CF3 and CN; and / or (v) R6 and R7 are each independently selected from the group consisting of H, F, Cl, Me; and / or (vi) R4, R5, R6 and R7 are each independently H or F, wherein at least one of R4, R5, R6 and R7 is F.

4. The compound of claim 1, or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: (i) X1 is N or CH; (ii) X2 is a group consisting of N and CH; and X3 is CN(R2)-L2-E2; (iii) X3 is CN(R2)-L2-E2 or CN(H)CH3; or (iv) X2 is N and X3 is CCH3 or X2 is CH and X3 is N.

5. The compound of claim 1, or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: (i) X2 is selected from the group consisting of: wherein R14 is independently selected from the group consisting of H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl and cyanoalkyl in each occurrence; or (ii) X3 is selected from: the group consisting of: wherein R14 is independently selected from the group consisting of H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl and cyanoalkyl in each occurrence; or the group consisting of: wherein R14 is independently selected from the group consisting of H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl and cyanoalkyl in each occurrence.

6. The compound of claim 1, or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: (i) A or B is selected from: the group consisting of: ; or the group consisting of: ; (ii) Series A is selected from: the group consisting of: ; or the group consisting of: wherein R14 is independently selected from the group consisting of: H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, and cyanoalkyl in each occurrence; or (iii) Series A or B is selected from: the group consisting of: ; or the group consisting of:

7. The compound of claim 1, or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, is: (i) a compound represented by formula IR: formula IR or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X3 is selected from the group consisting of CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; R7 is selected from the group consisting of H and F; R10 and R11 are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamino, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; R15 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclic; and L2 is selected from the group consisting of direct bonds and C1-C6 alkyl, wherein the C1-C6 alkyl is substituted by (E21)p as appropriate; (ii) Compounds represented by formula IS: Formula 1-S Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X3 is selected from the group consisting of CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; R7 is selected from the group consisting of H and F; R15 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclic groups; and L2 is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (iii) A compound represented by formula IT: Formula 1-T or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X3 is selected from the group consisting of CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; R7 is selected from the group consisting of H and F; R15 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclic groups; and L2 is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (iv) Compounds represented by formula IU: Formula 1-U or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X3 is selected from the group consisting of CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; R7 is selected from the group consisting of H and F; The R11 group is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamino, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; the R15 group is selected from the group consisting of alkyl, cycloalkyl, and heterocyclic groups; and the L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate;(v) Compounds represented by Formula IV: Formulas 1-V or their pharmaceutically acceptable salts, enantiomers, stereoisomers or tautomers, wherein: X3 is selected from the group consisting of CO-L2-E2, C-L2-E2 and CN(R2)-L2-E2; R7 is selected from the group consisting of H and F; R11 is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamino, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl and heterocyclic alkyl; R15 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclic groups; and L2 is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (vi) Compounds represented by formula IW: Formula 1-W or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X3 is selected from the group consisting of CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; X11 is selected from the group consisting of CR7 and N; R7 is selected from the group consisting of H and F; R11 is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamino, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl and heterocyclic alkyl; R15 is selected from the group consisting of alkyl, cycloalkyl and heterocyclic; and L2 is selected from the group consisting of direct bonds and C1-C6 alkyl, wherein the C1-C6 alkyl is substituted by (E21)p as appropriate; (vii) Compounds represented by formula IX: Formulas 1-X or their pharmaceutically acceptable salts, enantiomers, stereoisomers or tautomers, wherein: X3 is selected from the group consisting of CO-L2-E2, C-L2-E2 and CN(R2)-L2-E2; The R7 group is selected from the group consisting of H and F; the R11 group is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamyl, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; the R15 group is selected from the group consisting of alkyl, cycloalkyl, and heterocyclic groups; and the L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate;(viii) Compounds represented by formula IY: Formula 1-Y or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X3 is selected from the group consisting of CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; R11 is selected from the group consisting of hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamino, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; R15 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclic groups; and L2 is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (ix) Compounds represented by formula IZ: Formula IZ or its pharmaceutically acceptable salts, enantiomers, stereoisomers or tautomers, wherein: X3 is selected from the group consisting of CO-L2-E2, C-L2-E2 and CN(R2)-L2-E2; R7 is selected from the group consisting of H and F; R8 is selected from the group consisting of: alkoxy, alkylamine, cycloalkoxy, cycloalkylamine, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyl and CN; R10 and R11 are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamino, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; and L2 is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (x) Compounds represented by formula I-AA: Formula I-AA or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X3 is selected from the group consisting of CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; R7 is selected from the group consisting of H and F; R8 is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyl, and CN; R10 and R11 are each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl;Furthermore, L2 is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (xi) Compounds represented by formula I-AB: Formula I-AB or its pharmaceutically acceptable salts, enantiomers, stereoisomers or tautomers, wherein: X3 is selected from the group consisting of CO-L2-E2, C-L2-E2 and CN(R2)-L2-E2; R7 is selected from the group consisting of H and F; R8 is selected from the group consisting of: alkoxy, alkylamine, cycloalkoxy, cycloalkylamine, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy and CN; R11 is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamino, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl and heterocyclic alkyl; and L2 is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (xii) Compounds represented by formula I-AC: Formula 1-AC or its pharmaceutically acceptable salts, enantiomers, stereoisomers or tautomers, wherein: X3 is selected from the group consisting of CO-L2-E2, C-L2-E2 and CN(R2)-L2-E2; R7 is selected from the group consisting of H and F; The R8 group is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyl, and CN; The R11 group is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; and the L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (xiii) Compounds represented by formula I-AD: Formula I-AD or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: The X3 group is selected from the group consisting of CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; the R7 group is selected from the group consisting of H and F; the R8 group is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyl, and CN;R11 is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acetamino, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; and L2 is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (xiv) Compounds represented by formula I-AE: Formula I-AE or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: X3 is selected from the group consisting of CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; R7 is selected from the group consisting of H and F; The R8 group is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyl, and CN; The R11 group is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; and the L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate; (xv) Compounds represented by formula I-AF: Formula I-AF or its pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers, wherein: The X3 group is selected from the group consisting of CO-L2-E2, C-L2-E2, and CN(R2)-L2-E2; the R7 group is selected from the group consisting of H and F; the R8 group is selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyl, and CN; the R11 group is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; and the L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with (E21)p as appropriate; (xvi) Compounds represented by formula I-AG: Formula 1-AG or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein: X3 is selected from the group consisting of CO-L2-E2, C-L2-E2 and CN(R2)-L2-E2;The R8 group is selected from the following groups: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyl, and CN; the R11 group is selected from the following groups: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amide, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclic, alkoxycarbonyl, and heterocyclic alkyl; and the L2 group is selected from the group consisting of direct bonds and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are substituted with (E21)p as appropriate.

8. The compound of claim 4, or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: (i) R1 is selected from the group consisting of: wherein R14 is independently selected from the group consisting of: H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl and cyanoalkyl each time it appears; or from the group consisting of: ; or from the group consisting of: H, ; Or a group consisting of: ; or a group consisting of: wherein R14 is independently selected from the group consisting of: H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl and cyanoalkyl each time it appears; and / or (ii) X1 is N or CH; (iii) X3 is CN(R2)-L2-E2, or selected from the group consisting of: wherein R14 is independently selected from the group consisting of: H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl and cyanoalkyl each time it appears; or selected from the group consisting of: wherein R14 is independently selected from the group consisting of: H, alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl and cyanoalkyl each time it appears; and / or (iv) R5 is selected from the group consisting of: H, F, Cl, Me, OMe, CF3 and CN; and / or (v) R6 and R7 are each independently selected from the group consisting of H, F, Cl, Me, and / or (vi) R4, R5, R6 and R7 are each independently H or F, and at least one of R4, R5, R6 and R7 is F; and / or (vii) R15 is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 heterocyclic groups.

9. A compound selected from the group consisting of: and its pharmaceutically acceptable salts, enantiomers, stereoisomers and tautomers.

10. A pharmaceutical composition comprising a compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

11. Use of a compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition of claim 10, for the preparation of an agent for treating diseases associated with GCN2 kinase or PERK kinase.

12. Use of a compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, or a pharmaceutical composition of claim 10, for the preparation of an agent for: (i) treating diseases caused by dysregulation of the integrated stress response and / or unfolded protein response; (ii) modulating the activity of GCN2 kinase; (iii) activating GCN2 kinase; (iv) modulating the activity of PERK kinase; (v) activating PERK kinase; (vi) inhibiting GCN2 kinase and inhibiting PERK kinase; (vii) inhibiting the activity of GCN2 kinase; (viii) inhibiting the activity of PERK kinase; (ix) treating cancer; (x) treating amyloidosis; (xi) treating light chain amyloidosis; (xii) treating diseases selected from GCN2-related diseases and PERK-related diseases; or (xiii) treating diseases selected from GCN2-related diseases and PERK-related diseases. The treatment further comprises administering a therapeutically effective amount of one or more therapeutic agents, wherein the one or more therapeutic agents are selected from the group consisting of: (1) IMiD agents, proteasome inhibitors, steroids, antiCD38 agents, antiCD20 agents, Bcl-2 inhibitors, PI3K inhibitors, bispecific antibodies, nucleoside analogs, BTK inhibitors, DNA alkylating agents, EZH2 inhibitors, anthracycline, topoisomerase inhibitors, platinum, tyrosine kinase inhibitors, HDAC inhibitors, nuclear export inhibitors, antimicrotubule agents, L-aspartate aminotransferase, PEGylated aspartate aminotransferase, PERK inhibitors, mTOR inhibitors, immunomodulators, MAPK pathway inhibitors, MEK inhibitors, ERK inhibitors, and Ras inhibitors;Or (2) L-asparagase, pegaspargase, calaspargase pegol-mnkl, bortezomib, carfilzomib, ixazomib, thalidomide, pomalidomide, lenalidomide, dexamethasone, prednisone, daratumumab (daratumumab), daratumumab / hyaluronidase, isatuximab, rituximab, obinutuzumab, venetoclax, idelalisib, copanlisib, duvelisib, umbralisib, gemcitabine, cytarabine Cytarabine, ibrutinib, acalabtinib, zanubrutinib, bendamustine, cyclophosphamide, tazemetostat, doxorubicin, daunorubicin, etoposide, oxaloplatin, carboplatin, cisplatin-potassium Cisplatinbosutinib, dasatinib, imatinib, nilotinib, ponatinib, panobinostat, selinexor, vincristine, JZP-458, erythrocyte-encapsulated asparagine, PF745 (JZP-341), asparagine-containing Erwinia chrysanthemi (crisantaspase), Escherichia coli asparagine (colaspase), anti-PD-1 agents, anti-PD-L1 agents, and anti-CTLA-4 agents.

13. As used in request item 12, wherein: This medication is intended to treat in patients with conditions resulting from dysregulation of the integrated stress response and / or unfolded protein response, wherein such dysregulation is caused by kinases selected from the group consisting of PERK kinases and GCN2 kinases; or the cancer is selected from the group consisting of: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumors, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumors, retinal tumors. Cellular tumors, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumors, bladder cancer, blood cancers, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocytic lymphoma, Waldenström macroglobulinemia, and malignant lymphoma; or selected from GCN2-related diseases and PERK-related diseases, the disease is amyloidosis or light chain amyloidosis.

14. As requested in claim 12, wherein the agent is used to treat cancer, wherein the cancer is selected from the group consisting of: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric and duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumor, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumor, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumor, bladder cancer, blood cancer, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocytic lymphoma, Waldenström macroglobulinemia, and malignant lymphoma.

15. As claimed in claim 12, wherein the medicine is used to treat amyloidosis.

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