CN117321037A

CN117321037A - GCN2 and PERK kinase inhibitors and methods of use thereof

Info

Publication number: CN117321037A
Application number: CN202180090945.5A
Authority: CN
Inventors: D·L·弗林; P·卡尼; J·兹维克; G·阿尔·安; S·贾韦德; Y·M·安; K·斯托尔茨; B·勒布尔多内克
Original assignee: Deciphera Pharmaceuticals LLC
Current assignee: Deciphera Pharmaceuticals LLC
Priority date: 2020-11-18
Filing date: 2021-11-17
Publication date: 2023-12-29

Abstract

Described herein are compounds that are inhibitors of GCN2 kinase or PERK kinase, and methods of treating diseases, including diseases associated with GCN2 kinase or PERK kinase, with such compounds.

Description

GCN2 and PERK kinase inhibitors and methods of use thereof

Cross Reference to Related Applications

The present application claims priority from U.S. provisional application 63/115,496 filed on 11/18 and U.S. provisional application 63/185,846 filed on 5/7 of 2021, each of which is incorporated herein by reference in its entirety.

Sequence listing

The present application contains a sequence listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy was created at 2021, 10-28, named DCP-098WO_SL.txt and is 23,670 bytes in size.

Background

Cancer cells need to be continuously supplied with nutrients to maintain their abnormal growth and rapid division. As part of these nutrients, amino acids are critical to supporting the high metabolic demands of tumor cells.

GCN2 is a serine/threonine protein kinase, one of eukaryotic initiation factor 2 alpha (eif2α) kinases, which are major mediators of Integrated Stress Response (ISR). ISR is critical to maintaining cell homeostasis under various pressure sources, and is activated when cells are subjected to stress conditions such as hypoxia and amino acid deprivation. ISR is regulated by phosphorylation and activation of eif2α kinases (including GCN 2), which act as early responders to disturbances in cellular homeostasis. In addition to GCN2, there are three other families of eif2α kinases including PKR-like ER kinase (PERK), double-stranded RNA-dependent Protein Kinase (PKR), and heme-regulated eif2α kinase (HRI). All four eif2α kinases share extensive homology in their kinase catalytic domains, but have different regulatory domains. Each IF2 alpha kinase responds to different environmental and physiological stresses, reflecting its unique regulatory mechanism. PERK kinase is activated under pressure conditions including ATP depletion and unfolded protein response, and similar to GCN2, PERK kinase activation results in upregulation of the key ISR transcription factor ATF 4.

Under conditions of essential amino acid limitation or other pressure sources (UV irradiation, redox pressure or proteasome inhibition), GCN2 phosphorylates eif2α, which inhibits the formation of novel ternary complexes and thus mRNA translation initiation. While reducing overall mRNA translation, eif2α phosphorylation also increases translation of the ISR transcription factor ATF4 in tumor cells, which increases many stress response genes, including genes specifically providing amino acids to tumor cells: that is, the expression of amino acid synthetases and transporters that mediate the influx of amino acids into tumor cells. ATF4 is overexpressed in human solid and liquid tumors, suggesting an important function in tumor progression.

Asparagine is an important amino acid involved in a variety of biosynthetic pathways that can significantly affect carcinogenesis and tumor biology. All cells require asparagine for their protein synthesis and growth. Normal cells will obtain a large portion of their required asparagine via internal synthesis. Cancer cells require higher amounts of asparagine to grow and proliferate than normal cells, do not self-produce the required amounts, and must rely on circulating asparagine to survive. Asparagine synthetase (ASNS) catalyzes the synthesis of asparagine from aspartate and glutamine. L-asparaginase removes circulating asparagine, depriving cancer cells of critical nutrients and causing death. The use of L-asparaginase is the first example of an anti-cancer therapy targeting a specific metabolic profile of a tumor, a putative treatment for pediatric Acute Lymphoblastic Leukemia (ALL), but toxicity limits its use outside of this patient population. ASNS is expressed at particularly low levels in many ALL cell lines compared to normal cells, making asparagine depletion an effective treatment due to the abnormal dependence of cells on circulating serum asparagine as a necessary nutrient for growth. Adverse reactions to asparaginase are associated with an increased risk of relapse. Other blood and solid cancers express low levels of ASNS and therefore should also be auxotrophic for asparagine and asparaginase sensitive. In contrast, in certain cancer types, ASNS is overexpressed, promoting cell proliferation, chemoresistance, and metastatic behavior. In the case of asparaginase resistant cancers, the effect of depleting blood asparagine via L-asparaginase instead results in a significant oversurface to ASNS to compensate, effectively killing the effect of the chemotherapeutic agent. Numerous studies have shown that ASNS is centered in the response of cells to amino acid deprivation and other forms of cellular stress. Via transcriptional regulation, ASNS genes are two targets of signaling pathways aimed at ensuring cell survival. The first pathway, known as the Amino Acid Reaction (AAR), is activated by GCN2 kinase under conditions of unbalanced amino acid availability. The second pathway, called the Unfolded Protein Response (UPR), is activated by PERK kinase under conditions of increased endoplasmic reticulum pressure. The AAR and UPR pathways converge on eif2α phosphorylation, leading to a decrease in overall protein synthesis, while leading to preferential translation of a selected mRNA population including the translation factor ATF 4. ATF4 is the major factor in ASNS induction and acts as a transactivator via an enhancer component incorporated into the ASNS promoter.

GCN2 sensitizes cancer cells with low basal expression of ASNS to L-asparaginase, an anti-leukemia drug, in vitro and in vivo. Treatment with GCN2 inhibitors sensitizes acute lymphoblastic leukemia cells to L-asparaginase by preventing induction of ASNS. The GCN2 inhibitors and L-asparaginase exhibit synergistic antiproliferative effects in ASNS low/defective cancers. Thus, combination treatment of GCN2 inhibitors and L-asparaginase shows promise for improved results in acute lymphoblastic leukemia and other types of cancer. Acute lymphoblastic leukemia, acute myelogenous leukemia, and pancreatic cancer cells are particularly sensitive to combination therapy with an L-asparaginase and a GCN2 inhibitor. The previously reported studies demonstrate robust anti-tumor activity in acute lymphoblastic leukemia, acute myelogenous leukemia and pancreatic cancer cells for ASNase and GCN2 inhibitor combination therapy as compared to the results of L-asparaginase or GCN2 inhibitor monotherapy. Thus, GCN2 inhibitors may represent sensitizers for L-asparaginase for the treatment of these tumors. In summary, GCN2 inhibition increases sensitivity to L-asparaginase treatment by preventing ASNS induction in cancer cells with low basal levels of ASNS expression.

GCN2 inhibition can also be an effective strategy for targeting tumor microenvironments, including the immune system, including tryptophane dependent immune surveillance of tumor cells.

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

Many tumors evolve into escape immune surveillance by exploiting their metabolic flexibility and redirecting nutrients for their own benefit. Stromal cells and bone Marrow Derived Suppressor Cells (MDSCs) within a tumor create a malnutritional environment that inhibits immune function and supports tumor growth.

The increased catabolic resolution of tryptophan (one of the essential amino acids) driven by the overexpression of key enzymes in tryptophan metabolism [ indoleamine-2, 3-dioxygenase (IDO) and tryptophan-2, 3-dioxygenase (TDO) ] is driven by tumor microenvironment cells, creating an immunosuppressive microenvironment in a variety of cancer types. Local tryptophan depletion is considered a critical T cell immunosuppressive mechanism. In T cells, GCN2 kinase has been identified as a molecular sensor of tryptophan deprivation. Activation of GCN2 by tryptophan depletion induces apoptosis and reduces 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.

The GCN2 pathway is important not only for tumor immune escape, but also plays a positive role in regulating other aspects of the tumor microenvironment. GCN2 attenuation (knockdown) has been shown to prevent Amino Acid Deprivation (AAD) induced expression of Vascular Endothelial Growth Factor (VEGF), which tumors use to enhance nutrient supply via increased angiogenesis. Thus, activation of the GCN2/ATF4 pathway promotes tumor growth and angiogenesis via AAD-mediated VEGF expression. The elimination of ATF4 or GCN2 expression significantly inhibited tumor growth in vivo.

Thus, selective inhibition of GCN2 can increase immune system activity and reduce angiogenesis in the tumor microenvironment. The GCN2-eif2α -ATF4 pathway is critical for maintaining metabolic homeostasis of tumor cells under stress conditions and for maintaining an immunosuppressive immune cell microenvironment. The PERK-ATF4 pathway is also critical for maintaining tumor cell homeostasis under stress conditions. It is reported that there is cross-talk modulation of both GCN2 and PERK signaling pathways such that inhibition of GCN2 activates PERK as a compensation mechanism and vice versa, i.e., inhibition of PERK activates GCN2 as a compensation mechanism.

There is a need for inhibitors of GCN2 and/or PERK that block the pro-neoplastic aspects of GCN2 and/or PERK in both tumor cells (tumor cell autonomous) and tumor immune cell microenvironments.

Summary of The Invention

Described herein are compounds that exhibit inhibitory activity of GCN2 (generally control non-inhibiting 2) kinase and/or PERK (PKR-like ER kinase) kinase and methods of their use in treating disorders, including GCN2 or PERK related diseases.

In one embodiment, described herein is a compound represented by formula I:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein:

X ¹ selected from the group consisting of: CH and N; x is X ² And X ³ Each independently selected from the group consisting of: n, CH, C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² Provided that the limit is X ² Selected from the group consisting of: CH and N, and X ³ Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² The method comprises the steps of carrying out a first treatment on the surface of the With the proviso that X ² Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² And X is ³ Selected from the group consisting of: CH and N; x is X ⁴ Selected from the group consisting of: CR (computed radiography) ³ And N; x is X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ And R is ⁷ Each independently selected from the group consisting of: halogen, H and alkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxoA group, cyano, cyanoalkyl, and sulfonyl; a is selected from the group consisting of: substituted 5-membered heteroaryl, substituted 6-membered heteroaryl, pyridone and substituted aryl rings; l (L) ² Selected from the group consisting of: a direct bond and an alkyl group, wherein the alkyl group is optionally substituted with (E ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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; with the proviso that the compound is not:

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

In another embodiment, described herein is a method of treating a disease caused by a disorder of integrated stress in a patient in need thereof, 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.

In another embodiment, described herein is a method of treating a disease caused by dysregulation of integrated stress and/or unfolded protein response in a patient in need thereof, 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.

In another embodiment, described herein is a method of modulating GCN2 kinase activity in a patient in need thereof 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.

In another embodiment, described herein is a method of activating GCN2 kinase in a patient in need thereof, 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.

In another embodiment, described herein is a method of modulating PERK kinase activity in a patient in need thereof 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.

In another embodiment, described herein is a method of activating a PERK kinase in a patient in need thereof, 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.

In another embodiment, described herein is a method of inhibiting GCN2 kinase and inhibiting PERK kinase in a patient in need thereof, 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.

In another embodiment, described herein is a method of inhibiting PERK kinase activity in a patient in need thereof, 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.

In another embodiment, described herein is a method of treating a disease selected from GCN 2-related disease and PERK-related disease in a patient in need thereof, 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.

In another embodiment, described herein is a method of treating a disease selected from GCN 2-related disease and PERK-related disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of one or more therapeutic agents.

In another embodiment, described herein is a method of treating cancer in a patient in need thereof, 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 another embodiment, described herein is a method of treating a disorder selected from the group consisting of: melanoma, fibrosarcoma, thyroid cancer, ovarian cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumor, solid tumors, cancers of blood origin, acute Myelogenous Leukemia (AML), acute Lymphoblastic Leukemia (ALL), and other cancers caused by activation of the GCN2 signaling pathway, comprising administering to a 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.

Drawings

Figure 1 depicts a stimulation pattern of cellular ATF4 in H929 multiple myeloma cells induced by compound 16.

Figure 2 depicts a PERK oligomer stimulation pattern of compound 16 in HEK293T NanoBRET-based assays.

FIG. 3 depicts the stimulated PERK downstream signaling proteins ATF4 and CHOP with actin as an internal reference (loading control). The figure shows that compound 16 increases the expression of the PERK signaling pathway in H929 multiple myeloma cells as detected by western blot.

FIG. 4 depicts the fold increase in expression of PERK pathway target genes ATF4, CHOP, GADD34, GPT2 and VEGFA in H929 multiple myeloma cells using a QRT-PCR assay (compared to the DMSO control).

FIG. 5 illustrates the effect of compound 16 as a single agent on apoptotic pathway readings, including cleaved PARP, cleaved Caspase7 and cleaved Caspase3, in H929 multiple myeloma cells using Western blotting.

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

Figures 7A and 7B show the effect of compound 16 in combination with asparaginase on ATF4 content in an in vivo PK/PD model using western blot analysis to measure GCN2 activity. The corresponding plasma levels of compound 16 were determined at PD time points of 2, 6 and 10 hours post-administration. Fig. 7A shows a data plot of results obtained from PK/PD model studies, and fig. 7B graphically depicts the results.

FIG. 8 depicts a graph showing the effect of compound 16 in combination with asparaginase on tumor growth in a MV-4-11 xenograft model.

Detailed Description

Features and other details of the present invention are described in more detail below. Specific terms used in the specification, examples and claims are collected here. These definitions should be read in light of the remainder of the present invention and as understood by those skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

Definition of the definition

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

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter herein belongs. Unless indicated to the contrary, the following terms, as used in the specification and claims, have the meanings indicated to facilitate understanding of the invention.

When a bond to a substituent is shown to intersect a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. If the substituents listed do not indicate an atom that would bond such substituent to the remainder of the compound of the specified formula, such substituent may be bonded via any atom in such substituent. Such combinations may be allowed when the combination of substituents, substituent positions and/or variables results in a stable compound.

As used herein, the singular forms "a," "an," and "the" encompass plural referents, unless the context clearly dictates otherwise.

As used herein, the term "herein" refers to the entire application.

As used herein, "deuterated" refers to the replacement of at least one hydrogen atom with deuterium. In any sample of deuterated compound, some discrete molecules of the compound may have hydrogen instead of deuterium at the designated positions. However, the molecular percentage of deuterated compounds having deuterium at a given position will be much greater than naturally occurring compounds. Deuterium enrichment at deuterated sites.

As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" means that the alkyl group may be substituted as well as the alkyl group is unsubstituted.

It will be appreciated that the substituents and substitution patterns of the disclosed compounds can be selected by one of ordinary skill in the art to produce chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art and those methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure is created.

Such as the bookAs used herein, the term "optionally substituted" means that one to six hydrogen atoms in a given structure are replaced with groups of specified substituents including, but not limited to: hydroxy, hydroxyalkyl, alkoxy, halogen, alkyl, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OC (=o) -CH ₂ -O alkyl. Preferably, "optionally substituted" means that one to four hydrogen atoms in a given structure are replaced with substituents mentioned above. More preferably, one to three hydrogen atoms are replaced by substituents as mentioned above. It is understood that the substituents may be further substituted.

As used herein, the term "substituted" refers to a moiety having a substituent on one or more carbons of the backbone that displaces hydrogen. It is to be understood that "substitution" or "substituted" includes the implied limitation that such substitution is in accordance with the permissible valences of the substituted atoms and substituents, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo conversion (such as by recombination, cyclization, elimination, etc.). As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For suitable organic compounds, the permissible substituents can be one or more and the same or different. For the purposes of this application, a heteroatom such as nitrogen may have a hydrogen substituent and/or any permissible substituent of the organic compounds described herein which satisfy the valences of the heteroatoms.

Substituents may include any of the substituents described herein, for example, such substituents may include, if not otherwise specified, for example, halogen, hydroxy, carbonyl (such as carboxy, alkoxycarbonyl, formyl, or acyl), alkoxy, amino, amido, imine, cyano, sulfonyl, heterocyclyl, aralkyl, heteroaralkyl, or an aromatic or heteroaromatic moiety. It will be appreciated by those skilled in the art that the substitution bases may be substituted as appropriate. For example, substituents of substituted alkyl groups may include amino, amido,sulfonyl and ether, carboxyl (including carboxylates and esters), -CF ₃ -CN and the like. Unless specifically stated as "unsubstituted," references to chemical moieties herein are understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

As used herein, the term "alkyl" refers to a fully saturated straight or branched chain non-aromatic hydrocarbon. Typically, unless otherwise defined, straight or branched chain alkyl groups have from 1 to about 20 carbon atoms, preferably from 1 to about 10, and may be, for example, C ₁ -C ₁₀ Alkyl or e.g. C ₁ -C ₆ An alkyl group. Examples of straight 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 the like. 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 substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. "alkyl" groups may be optionally substituted.

The term "C _x -C _y "when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy is intended to include groups containing from x to y carbons in the chain. For example, the term "C _x -C _y "refers to a substituted or unsubstituted saturated hydrocarbon group containing from x to y carbons in the chain, including straight chain alkyl groups and branched chain alkyl groups, including haloalkyl groups such as trifluoromethyl and 2, 2-trifluoroethyl, and the like. C (C) ₀ Alkyl indicates hydrogen when the group is in the terminal position and indicates a chemical bond if it is in the interior.

As used herein, the term "alkoxy" refers to a straight or branched, saturated aliphatic (alkyl) hydrocarbon group bonded to an oxygen atom attached to a core structure. Preferably, the alkoxy group has one to six carbon atoms, i.e. it can be C ₁ -C ₆ An alkoxy group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 3-methylbutoxy, and the like.

As used herein, the term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy 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-ethylene-, ethyl-O-ethylene-.

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

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

As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups in which each atom on the ring is carbon. The ring is preferably a 5-to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are shared by two adjoining rings (fused rings), at least one of which is aromatic, e.g., the other ring may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl. The term "fused" refers to the attachment or formation of a second ring by sharing two adjacent atoms with the first ring. The term "fused" is equivalent to the term "condensed". Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, phenol, anilines, indanyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, indolinyl, isoindolinyl, and the like. Unless otherwise specified, aryl groups described herein may be optionally substituted.

As used herein, the terms "polycyclyl," polycyclic, "and" polycyclic "refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl) in which one or more atoms are shared by two adjoining rings, e.g., the rings are" fused rings. Each ring in the polycyclic may be substituted or unsubstituted. In certain embodiments, each ring in the polycyclic ring contains 3 to 10, preferably 5 to 7 atoms in the ring.

The term "acyl" as used herein refers to the group-C (=o) -R ^w Wherein R is ^w Is an optionally substituted alkyl group. Examples of "acyl" include, but are not limited to, wherein R ^w Is C ₁ -C ₁₀ Alkyl (C) ₁ -C ₁₀ Acyl) or C ₁ -C _6- Alkyl (C) ₁ -C ₆ Acyl). In some embodiments, the optionally substituted substituents are independently selected at each occurrence from the group consisting of: H. OH, alkoxy, cyano, F and amino. Other examples of "acyl" include-C (=o) -CH ₃ 、-C(＝O)-CH ₂ -CH ₃ 、-C(＝O)-CH ₂ -CH ₂ -CH ₃ or-C (=O) -CH (CH) ₃ ) ₂ 。

As used herein, the terms "amine" and "amino" refer to unsubstituted and substituted amines and salts thereof, such as moieties that may be represented by the following formula:

wherein R is ^6b Independently represents hydrogen, alkyl or cycloalkyl, or R ^6b The group together with the N atom to which it is attached completes a heterocyclic ring having 4 to 8 atoms in the ring structure.

As used herein, the terms "amide" and "amido" refer to groups represented by:

wherein R is ⁷ ”、R ⁸ "and R ¹⁰ "each independently represents hydrogen or hydrocarbyl, or R ⁸ "and R ¹⁰ "completes a heterocyclic group having 4 to 8 atoms in the ring structure with the N atom to which it is attached.

As used herein, the term "amido" refers to an amino group as defined above substituted with an acyl group.

As used herein, the term "aminocarbonyl" refers to an amino-substituted carbonyl.

As used herein, the term "alkylamino" refers to an amino group as defined above substituted with at least one alkyl group.

As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

As used herein, the term "acylaminoalkyl" refers to an alkyl group substituted with an acylamino group.

As used herein, the term "cyanoalkyl" refers to an alkyl group substituted with a cyano group.

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

As used herein, the term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group.

As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group.

As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

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. In generalUnless otherwise defined, monocyclic cycloalkyl groups have 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms (e.g., C ₃ -C ₁₀ Cycloalkyl or e.g. C _3- C ₆ Cycloalkyl). Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The second ring of the bicyclic cycloalkyl or the second ring or the third ring of the tricyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic and tricyclic molecules in which one, two, or three or more atoms are shared between the two rings. Cycloalkyl groups may be further alkyl, alkenyl, alkoxy, aminoalkyl, carbonyl-substituted alkyl, -CF ₃ -CN, etc.

As used herein, the term "cycloalkylalkyl" refers to cycloalkyl-substituted alkyl.

As used herein, the term "cyano" refers to a —cn group.

As used herein, the term "hydroxy" or "hydroxyl" refers to an-OH group.

As used herein, the term "halo" or "halogen", alone or in combination with other terms, refers to chloro, fluoro, bromo and iodo.

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

As used herein, the terms "heterocyclyl", "heterocycloalkyl", "heterocycle" and "heterocyclic" refer to a non-aromatic, saturated or partially saturated ring system comprising 3 to 15 members bridged or fused with a single ring, multiple rings (e.g., bicyclic, tricyclic), having at least one member selected from O, N, S, S (O), S (O) ₂ A heteroatom or a heteroatom of NH or C (O), the remaining ring atoms being independently selected from the group consisting of: carbon, oxygen, nitrogen and sulfur. Examples of "heterocycloalkyl" include, but are not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidine, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1, 4-dioxanyl, thiomorpholino, and thiomorpholino A group selected from the group consisting of a dioxazine group, an oxapiperidinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a tetrahydrothienyl group, a dihydropyranyl group, an indolinyl group, an indolinylmethyl group, and a 2-azabicyclo [ 2.2.2.2]Octyl, azepinyl, chromanyl, xanthenyl and N-oxides thereof. Attachment of the heterocycloalkyl substituent can occur via a carbon atom or via a heteroatom. The heterocycloalkyl group may be optionally substituted with one or more suitable groups through one or more of the foregoing groups. Preferably, "heterocycloalkyl" means a 5-to 6-membered ring selected from the group consisting of: azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, tetrahydrothiazolyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1, 4-dioxanyl and N-oxides thereof. More preferably, "heterocycloalkyl" includes azetidinyl, pyrrolidinyl, morpholinyl, and piperidinyl. Heterocycloalkyl optionally substituted with one or more of the foregoing groups.

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, the ring structure of which 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), which contains 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 adjoining rings, wherein at least one of these rings is heteroaromatic, e.g., another cyclic ring may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl. The rings may contain N or S atoms, wherein the N or S atoms are optionally oxidized, or the N atoms are optionally quaternized. All heteroaryl groups are optionally substituted. 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: furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, alpha-carboline, indolizinyl, benzisothiazolyl, benzoxazolyl, pyrrolopyridinyl, furanpyridyl, purinyl, benzothiadiazolyl, benzooxadiazolyl, benzotriazolyl, benzothiadiazolyl, carbazolyl, dibenzothiophenyl, benzacridyl, etc.

As used herein, the term "sulfonamide" is represented by:

wherein R is ^6c Each occurrence of R independently represents hydrogen, alkyl or cycloalkyl, or together with the N atom to which it is attached ^6c A group, completing a heterocyclic ring having 4 to 8 atoms in the ring structure.

As used herein, the term "sulfonyl" refers to the group-S (O) ₂ -R ^6d Wherein R is ^6d Represents alkyl or cycloalkyl.

A "combination therapy" is a treatment comprising administering to a patient in need thereof two or more therapeutic agents, e.g., a compound of formula I and an enzyme asparaginase (ASNase) or derivative thereof.

"disease," "disorder," and "condition" are used interchangeably herein.

"individual" 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, and most preferably humans. The compounds described herein may be administered not only to mammals such as humans, but also to other mammals such as animals in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats and the like), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

The compounds described herein are useful in treating diseases driven by GCN2 (sometimes abbreviated herein as "GCN 2-related diseases"), such as cancers [ e.g., colorectal cancer (e.g., colorectal cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor), lung cancer (e.g., non-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 adenocarcinomas), duodenum cancer, small intestine cancer, breast cancer (e.g., invasive breast duct cancer, in situ breast duct cancer, inflammatory breast cancer), ovarian cancer (e.g., ovarian epithelial cancer, extragonadal germ cell tumor, ovarian low malignant potential tumor), testicular tumor, prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone dependent prostate cancer, castration resistant prostate cancer), liver cancer (e.g., liver cancer, primary, extrahepatic carcinoma), thyroid cancer (e.g., astrocyte cancer), astrocyte carcinoma (e.g., astrocyte tumor), astrocyte carcinoma, carcinoma of the kidney (e.g., astrocyte tumor), astrocyte tumor, carcinoma of the uterus), astrocytes (e.g., carcinoma of the kidney, carcinoma of the brain, carcinoma, astrocytes (e.g., astroduct cancer of the brain, carcinoma), astrocytes (e.g., astrocytes, carcinoma of the brain cells, carcinoma) Pituitary adenoma), retinoblastoma, skin cancer (e.g., basal cell carcinoma, malignant melanoma (melanoma)), sarcomas (e.g., rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, clostridial cell sarcoma, osteosarcoma), malignant bone tumors, bladder cancer, hematological cancers (e.g., multiple myeloma, leukemia (e.g., acute myelogenous leukemia, acute lymphoblastic leukemia (including acute stage of chronic leukemia)), malignant lymphoma, hodgkin's disease, chronic myeloproliferative disease), cancer of the unknown primary nucleus, cancer growth inhibitors, cancer metastasis inhibitors, apoptosis promoters, and methods for preventing or treating pre-cancerous conditions (e.g., myelodysplastic syndrome).

The compounds described herein, e.g., a compound of formula I as defined herein, may be administered in combination with one or more additional therapeutic agents to treat the disorders 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, enzyme asparaginase (ASNase), and the like.

"pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered to an animal or human as appropriate. For human administration, the formulation should meet sterility, pyrogenicity, and general safety and purity standards as required by the FDA biological formulation standard office (FDAOffice of Biologics standards).

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of these media and medicaments for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic functions.

The term "pharmaceutical composition" as used herein refers to a composition comprising at least one compound as disclosed herein formulated with one or more pharmaceutically acceptable carriers.

The term "one or more pharmaceutically acceptable salts (pharmaceutically acceptable salt (s))" as used herein refers to salts having acidic or basic groups that may be present in the compounds used in the composition. The compounds included in the compositions of the present invention, which are basic in nature, are capable of forming a wide variety of salts with a wide variety of inorganic and organic acids. Acids that can be used to prepare the pharmaceutically acceptable acid addition salts of these basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, gluconate, formate, benzoate, glutamate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1' -methylene-bis- (2-hydroxy-3-naphthoate)). The compounds included in the compositions of the present invention, which are acidic in nature, are capable of forming base salts with a variety of pharmacologically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, in particular calcium, magnesium, sodium, lithium, zinc, potassium and iron salts. The compounds included in the compositions of the present invention, including basic or acidic moieties, may also form pharmaceutically acceptable salts with various amino acids. The compounds of the present invention may contain both acidic groups and basic groups; such as an amino group and a carboxylic acid group. In such cases, the compounds may exist in the form of acid addition salts, zwitterionic or basic salts.

The compounds of the invention may contain one or more chiral centers and thus exist as stereoisomers. The term "stereoisomers" as used herein consists of all enantiomers or diastereomers. Depending on the structure of the substituents around the sterically generated carbon atom, these compounds may be designated by the symbol "R" or "S", but those skilled in the art will recognize that the structure may implicitly represent a chiral center. These compounds may also be designated by "(+)" and "(-)" based on their optical rotation properties. The compounds described herein encompass the various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated by the symbol "(±)" in nomenclature, but those skilled in the art will recognize that the structure may implicitly represent a chiral center.

In this specification, the term "therapeutically effective amount" refers to the amount of a compound of the invention that elicits the biological or medicinal response in a tissue, system, or animal (e.g., mammalian or human) that is being sought by a researcher, veterinarian, medical doctor or other clinician. The compounds described herein are administered in a therapeutically effective amount to treat a disorder.

"treating" includes any effect that causes an improvement in a condition, disease, disorder, or the like, such as alleviation, reduction, modulation, or elimination.

Isotopically-labeled compounds consistent with those recited herein are also encompassed by the present invention, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually 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, respectively, such as ² H、 ³ H、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ O、 ¹⁷ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and F ³⁶ Cl. For example, the compounds of the invention may have one or more deuterium substituted H atoms.

The individual enantiomers and diastereomers of the disclosed compounds may be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers or by preparing racemic mixtures followed by analytical methods well known to those skilled in the art. These analytical methods are exemplified by: (1) attaching the mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography and releasing the optically pure product from the auxiliary, (2) forming a salt with an optically active resolving agent, (3) directly separating the mixture of optical enantiomers on a chiral liquid chromatography column, or (4) kinetic resolution using a stereoselective chemical or enzymatic reagent. The racemic mixture may also be resolved into its constituent enantiomers by known methods such as chiral phase liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis by chemical or enzymatic reactions that form unequal mixtures of stereoisomers as a single reactant during the creation of a new stereocenter or during the conversion of a pre-existing stereocenter is well known in the art. Stereoselective synthesis encompasses both enantioselective and diastereoselective transformations, and may involve the use of chiral auxiliary agents. See, for example, carreira and Kvaerno, classics in Stereoselective Synthesis, wiley-VCH: weinheim,2009.

Compounds of formula (I)

In one embodiment, described herein is a compound represented by formula I:

X ¹ selected from the group consisting of: CH and N; x is X ² And X ³ Each independently selected from the group consisting of: n, CH, C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² Provided that the limit is X ² Selected from the group consisting of: CH and N, and X ³ Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² The method comprises the steps of carrying out a first treatment on the surface of the With the proviso that X ² Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² And X is ³ Selected from the group consisting of: CH and N; x is X ⁴ Selected from the group consisting of: CR (computed radiography) ³ And N; x is X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, arylHeteroaryl and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ And R is ⁷ Each independently selected from the group consisting of: halogen, H and alkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; a is selected from the group consisting of: substituted 5-membered heteroaryl, substituted 6-membered heteroaryl, pyridone and substituted aryl rings; l (L) ² Selected from the group consisting of: a direct bond and an alkyl group, wherein the alkyl group is optionally substituted with (E ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, whereinThe heterocyclyl is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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; with the proviso that the compound is not:

in some embodiments, the compound is represented by formula I-a:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: x is X ³ Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ⁵ Selected from the group consisting of: CR (computed radiography) ⁸ And N; x is X ⁶ Selected from the group consisting of: CR (computed radiography) ⁹ And N; x is X ⁷ Selected from the group consisting of: CR (computed radiography) ¹⁰ And N; x is X ⁸ Selected from the group consisting of: CR (computed radiography) ¹¹ And N; x is X ⁹ Selected from the group consisting of: CR (computed radiography) ⁸ And N, provided that X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ And X ⁹ Not more than three of them are N; x is X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxyA group, an alkoxy group, a halogen, an amine, an amide, an acyl group, an alkoxyalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, a cyanoalkyl group, and a heterocyclic group, and wherein the heterocyclic group is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ And R is ⁷ Each independently selected from the group consisting of: halogen, H and alkyl; r is R ⁸ Selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxy and CN; r is R ⁹ 、R ¹⁰ And R is ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acylamino, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, haloalkyl, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; L ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In some embodiments, the compound is represented by formula I-B:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: x is X ³ Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ⁴ Selected from the group consisting of: CR (computed radiography) ³ And N; x is X ⁵ Selected from the group consisting of: CR (computed radiography) ⁸ And N; x is X ⁶ Selected from the group consisting of: CR (computed radiography) ⁹ And N; x is X ⁷ Selected from the group consisting of: CR (computed radiography) ¹⁰ And N; x is X ⁸ Selected from the group consisting of: CR (computed radiography) ¹¹ And N; x is X ⁹ Selected from the group consisting of: CR (computed radiography) ⁸ And N, provided that X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ And X ⁹ Not more than three of them are N; x is X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroarylAnd heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ And R is ⁷ Each independently selected from the group consisting of: halogen, H and alkyl; r is R ⁸ Selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxy and CN; r is R ⁹ 、R ¹⁰ And R is ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, haloalkyl, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy Alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In some embodiments, the compounds are represented by formula I-C:

X ² and X ³ Each independently selected from the group consisting of: n, CH, C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² Provided that the limit is X ² Selected from the group consisting of: CH and N, and X ³ Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² The method comprises the steps of carrying out a first treatment on the surface of the With the proviso that X ² Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² And X is ³ Selected from the group consisting of: CH and N; x is X ⁴ Selected from the group consisting of: CR (computed radiography) ³ And N; x is X ⁵ Selected from the group consisting of: CR (computed radiography) ⁸ And N; x is X ⁶ Selected from the group consisting of: CR (computed radiography) ⁹ And N; x is X ⁷ Selected from the group consisting of: CR (computed radiography) ¹⁰ And N; x is X ⁸ Selected from the group consisting of: CR (computed radiography) ¹¹ And N; x is X ⁹ Selected from the group consisting of: CR (computed radiography) ⁸ And N, provided that X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ And X ⁹ Not more than three of them are N; x is X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ And R is ⁷ Each independently selected from the group consisting of: halogen, H and alkyl; r is R ⁸ Selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxy and CN; r is R ⁹ 、R ¹⁰ And R is ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy,Cycloalkylamino, haloalkyl, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In some embodiments, the compounds are represented by formula I-D:

X ² and X ³ Each independently selected from the group consisting of: n, CH, C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² Provided that the limit is X ² Selected from the group consisting of: CH and N, and X ³ Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² The method comprises the steps of carrying out a first treatment on the surface of the With the proviso that X ² Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² And X is ³ Selected from the group consisting of: CH and N; x is X ⁴ Selected from the group consisting of: CR (computed radiography) ³ And N; x is X ⁵ Selected from the group consisting of: CR (computed radiography) ⁸ And N; x is X ⁶ Selected from the group consisting of: CR (computed radiography) ⁹ And N; x is X ⁷ Selected from the group consisting of: CR (computed radiography) ¹⁰ And N; x is X ⁸ Selected from the group consisting of: CR (computed radiography) ¹¹ And N; x is X ⁹ Selected from the group consisting of: CR (computed radiography) ⁸ And N, provided that X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ And X ⁹ Not more than three of them are N; x is X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxyGroup, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ And R is ⁷ Each independently selected from the group consisting of: halogen, H and alkyl; r is R ⁸ Selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxy and CN; r is R ⁹ 、R ¹⁰ And R is ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, acylamino, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, haloalkyl, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;E ²¹ independently at each occurrence 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.

In some embodiments, the compounds are represented by formulas I-E:

X ² selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ⁵ Selected from the group consisting of: CR (computed radiography) ⁸ And N; x is X ⁶ Selected from the group consisting of: CR (computed radiography) ⁹ And N; x is X ⁷ Selected from the group consisting of: CR (computed radiography) ¹⁰ And N; x is X ⁸ Selected from the group consisting of: CR (computed radiography) ¹¹ And N; x is X ⁹ Selected from the group consisting of: CR (computed radiography) ⁸ And N, provided that X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ And X ⁹ Not more than three of them are N; x is X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ And R is ⁷ Each independently selected from the group consisting of: halogen, H and alkyl; r is R ⁸ Selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxy and CN; r is R ⁹ 、R ¹⁰ And R is ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, haloalkyl, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally independently selected from the group consisting of one or more occurrences of heterocyclylSubstituent substitution: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In some embodiments, the compounds are represented by formulas I-F:

X ² selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ⁴ Selected from the group consisting of: CR (computed radiography) ³ And N; x is X ⁵ Selected from the group consisting of: CR (computed radiography) ⁸ And N; x is X ⁶ Selected from the group consisting of: CR (computed radiography) ⁹ And N; x is X ⁷ Selected from the group consisting of: CR (computed radiography) ¹⁰ And N; x is X ⁸ Selected from the group consisting of: CR (computed radiography) ¹¹ And N; x is X ⁹ Selected from the group consisting of: CR (computed radiography) ⁸ And N, provided that X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ And X ⁹ Not more than three of them are N; x is X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein heterocyclyl is optionally taken independently selected from the group consisting of one or more occurrences of taken atSubstitution of substituents: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ And R is ⁷ Each independently selected from the group consisting of: halogen, H and alkyl; r is R ⁸ Selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxy and CN; r is R ⁹ 、R ¹⁰ And R is ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, haloalkyl, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxyAn alkoxyalkyl group, a cyano group, a halogen, a sulfonyl group, an H, an alkyl group, an amine, an amide, an acyl group, a haloalkoxy group, a haloalkyl group, and a heterocyclic group, wherein the heterocyclic group is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In some embodiments, the compounds are represented by formulas I-G:

X ³ selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ And R is ⁷ Each independently selected from the group consisting of: halogen, H and alkyl; r is R ¹² Individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, haloalkyl, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; b 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 optionally substituted at each substitutable position by R ¹² Substitution; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl,Haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In some embodiments, the compounds are represented by formulas I-H:

X ³ selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ⁴ Selected from the group consisting of: CR (computed radiography) ³ And N; x is X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl andCN；R ⁶ and R is ⁷ Each independently selected from the group consisting of: halogen, H and alkyl; r is R ¹² Individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, haloalkyl, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; b 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 optionally substituted at each substitutable position by R ¹² Substitution; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence selected from the group consisting of: H. alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkaneOxy, haloalkyl, hydroxy, hydroxyalkyl and halogen; and each p is independently 0, 1 or 2.

In some embodiments, the compounds are represented by formulas I-J:

X ² and X ³ Each independently selected from the group consisting of: n, CH, C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² Provided that the limit is X ² Selected from the group consisting of: CH and N, and X ³ Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² The method comprises the steps of carrying out a first treatment on the surface of the With the proviso that X ² Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² And X is ³ Selected from the group consisting of: CH and N; x is X ⁴ Selected from the group consisting of: CR (computed radiography) ³ And N; x is X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ And R is ⁷ Each independently selected from the group consisting of: halogen, H and alkyl; r is R ¹² Individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, haloalkyl, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, heterocyclyl and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; b 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 optionally substituted at each substitutable position by R ¹² Substitution; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkaneA group, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In some embodiments, the compounds are represented by formulas I-K:

X ² and X ³ Each independently selected from the group consisting of: n, CH, C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² Provided that the limit is X ² Selected from the group consisting of: CH and N, and X ³ Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² The method comprises the steps of carrying out a first treatment on the surface of the With the proviso that X ² Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² And X is ³ Selected from the group consisting of: CH and N; x is X ⁴ Selected from the group consisting of: CR (computed radiography) ³ And N; x is X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein heterocyclyl is optionally independently selected from the group consisting of one or more occurrences of heterocyclylSubstituent substitution: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ And R is ⁷ Each independently selected from the group consisting of: halogen, H and alkyl; r is R ¹² Individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, haloalkyl, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; b 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 optionally substituted at each substitutable position by R ¹² Substitution; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl,Amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In some embodiments, the compounds are represented by formulas I-L:

X ² selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ And R is ⁷ Each independently selected from the group consisting of: halogen, H and alkyl; r is R ¹² Individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, haloalkyl, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, heterocyclyl and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; b 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 optionally substituted at each substitutable position by R ¹² Substitution; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxygenSubstituents, cyano and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In some embodiments, the compounds are represented by formula I-M:

X ² selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ⁴ Selected from the group consisting of: CR (computed radiography) ³ And N; x is X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ And R is ⁷ Each independently selected from the group consisting of: halogen-free foodPlain, H and alkyl; r is R ¹² Individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, haloalkyl, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; b 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 optionally substituted at each substitutable position by R ¹² Substitution; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence selected from the group consisting of: H. alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl and halogen; and each p is independentGround is 0, 1 or 2.

In some embodiments, the compounds are represented by formulas I-N:

X ³ selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen, H and alkyl; r is R ⁷ Selected from the group consisting of: h and F; r is R ⁸ Selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy and CN; r is R ¹⁰ And R is ¹¹ Each independently ofThe site is selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In some embodiments, the compound is represented by formula I-O:

X ³ selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen, H and alkyl; r is R ⁷ Selected from the group consisting of: h and F; r is R ⁸ Selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy and CN; r is R ¹⁰ And R is ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylAmino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In some embodiments, the compound is represented by formula I-P:

or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereofAn isomer or tautomer, wherein: x is X ³ Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen, H and alkyl; r is R ⁷ Selected from the group consisting of: h and F; r is R ⁸ Selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy and CN; r is R ⁹ 、R ¹⁰ And R is ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, haloalkyl, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl,A cycloalkyloxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In some embodiments, the compounds are represented by formulas I-Q:

X ³ selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen, H and alkyl; r is R ⁷ Selected from the group consisting of: h and F; r is R ⁸ Selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy and CN; r is R ⁹ ,R ¹⁰ And R is ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, haloalkyl, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally independently represented by one or more occurrences Substitution with a substituent selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In some embodiments, the compound is represented by formula I:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: x is X ¹ Selected from the group consisting of: CH and N; x is X ² And X ³ Each independently selected from the group consisting of: n, CH, C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² Provided that the limit is X ² Selected from the group consisting of: CH and N, and X ³ Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² The method comprises the steps of carrying out a first treatment on the surface of the With the proviso that X ² Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² And X is ³ Selected from the group consisting of: CH and N; x is X ⁴ Selected from the group consisting of: CR (computed radiography) ³ And N; x is X ⁴ Selected from the group consisting of: CR (computed radiography) ³ And N; x is X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ An alkoxyalkyl group, a cycloalkoxyalkyl group, an aminoalkyl group, a heterocyclylalkyl group, an aryl group, a heteroaryl group, and a heteroarylalkyl group, wherein each of the aryl group and the heteroaryl group is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ And R is ⁷ Each independently selected from the group consisting of: halogen, H and alkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein heterocyclyl is optionally independently selected from the group consisting of one or more occurrences of heterocyclylIs substituted by a substituent of (a): alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; a is selected from the group consisting of: substituted 5-membered heteroaryl, substituted 6-membered heteroaryl, pyridone and substituted aryl rings; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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; with the proviso that the compound is not:

in some embodiments, the compound is represented by formula I:

X ¹ selected from the group consisting of: CH and N; x is X ² Selected from the group consisting of: n, CH, C-O-L ² -E ² And C-L ² -E ² ；X ³ Is C-N (R) ² )-L ² -E ² ；X ⁴ Selected from the group consisting of: CR (computed radiography) ³ And N; x is X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ And R is ⁷ Each independently selected from the group consisting of: halogen, H and alkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; a is selected from the group consisting of: substituted 5-membered heteroaryl, substituted 6-membered heteroaryl, pyridone and substituted aryl rings; l (L) ² Selected from the group consisting of: direct bondAnd C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In one embodiment, described herein is a compound represented by formula I:

X ¹ CH; x is X ² And X ³ Each independently selected from the group consisting of: n, CH, C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² Provided that the limit is X ² Selected from the group consisting of: CH and N, and X ³ Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² The method comprises the steps of carrying out a first treatment on the surface of the With the proviso that X ² Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² And X is ³ Selected from the group consisting of: CH and N; x is X ⁴ Selected from the group consisting of: CR (computed radiography) ³ And N; x is X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ And R is ⁷ Each independently selected from the group consisting of: halogen, H and alkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; a is selected from the group consisting of: substituted 5-membered heteroaryl, substituted 6-membered heteroaryl, pyridone and substituted aryl rings; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of:hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In some embodiments, L ² Is a direct bond. In some embodiments, L ² Is alkyl. In some embodiments, L ² Is C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p And (3) substitution.

In some embodiments, X ² Is N and X ³ Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² 。

In some embodiments, X ² Is CH and X ³ Selected from the group consisting of: n, C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² 。

In some embodiments, X ² Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² And X is ³ Is N.

In some embodiments, X ² Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² And X is ³ CH.

In some embodiments, X ² Selected from the group consisting of: n and CH, and X ³ Is C-N (R) ² )-L ² -E ² 。

In one placeIn some embodiments, X ² Is N and X ³ Is C-N (R) ² )-L ² -E ² 。

In some embodiments, X ² Is CH and X ³ Is C-N (R) ² )-L ² -E ² 。

In some embodiments, X ² Is C-O-L ² -E ² And X is ³ Is C-N (R) ² )-L ² -E ² 。

In some embodiments, X ² Is C-L ² -E ² And X is ³ Is C-N (R) ² )-L ² -E ² 。

In some embodiments, X ³ Is C-N (R) ² )-L ² -E ² 。

In some embodiments, X ² Is N and X ³ For CCH ₃ 。

In some embodiments, X ² Is N and X ³ Is CN (H) CH ₃ 。

In some embodiments, X ² Is CH and X ³ Is N.

In some embodiments, X ³ Selected from the group consisting of:

wherein R is ¹⁴ Independently selected from the group consisting of: H. alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl and cyanoalkyl.

In some embodiments, R ¹ H.

In some embodiments, R ¹ Is methyl.

In some embodiments, R ¹ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl and heterocyclylalkyl.

In some embodiments, R ¹ Selected from the group consisting of:

wherein R is ¹⁴ Independently at each occurrence selected from the group consisting of: H. alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl and cyanoalkyl.

In some embodiments, R ¹ Selected from the group consisting of: aryl and heteroaryl, wherein each of the aryl and heteroaryl groups is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxyl, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl.

In some embodiments, R ¹ Selected from the group consisting of:

in some embodiments, R ¹ Selected from the group consisting of: (c=o) R ¹³ Wherein R is ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl.

In some embodiments, R ¹ Selected from the group consisting of:

In some embodiments, X ¹ Is N.

In some embodiments, X ¹ CH.

In some embodiments, X ² Selected from the group consisting of:

In some embodiments, X ³ Selected from the group consisting of:

In some embodiments, X ⁴ Selected from the group consisting of: n and CR ³ 。

In some embodiments, X ¹⁰ Selected from the group consisting of: n and CR ⁵ 。

In some embodiments, X ¹¹ Selected from the group consisting of: n and CR ⁷ 。

In some embodiments, R ³ Selected from the group consisting of: H. alkyl and halogen.

In some embodiments, R ³ Selected from the group consisting of: H. c (C) ₁ -C ₃ Alkyl and halogen. In some embodiments, R ³ Is C ₁ -C ₃ An alkyl group.

In some embodiments, R ³ Selected from the group consisting of: H. methyl and F. In some embodiments, R ³ H. In some embodiments, R ³ F. In some embodiments, R ³ Is Cl. In some embodiments, R ³ Is methyl.

In some embodiments, X ⁴ CH.

In some embodiments, R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl and CN.

In some embodiments, R ⁴ Is F and R ⁵ 、R ⁶ And R is ⁷ Each is H.

In some embodiments, R ⁶ Is F and R ⁴ 、R ⁵ And R is ⁷ Each is H.

In some embodiments, R ⁴ And R is ⁵ Each is F, and R ⁶ And R is ⁷ Each is H.

In some embodiments, R ⁵ And R is ⁶ Each is F, and R ⁴ And R is ⁷ Each is H.

In some embodiments, R ⁴ And R is ⁶ Each is F, and R ⁵ And R is ⁷ Each is H.

In some embodiments, R ⁴ And R is ⁶ Each is H, and R ⁵ And R is ⁷ Each is F.

In some embodiments, a or B is selected from the group consisting of:

in some embodiments, a or B is selected from the group consisting of:

in some embodiments, a is selected from the group consisting of:

In some embodiments, a or B is selected from the group consisting of:

in some embodiments, a is optionally substituted pyridone.

In some embodiments, a is selected from the group consisting of:

in some embodiments of the present invention, in some embodiments,is->Wherein X is ³ Selected from the group consisting of: CH. C-L ² -E ² 、C-O-L ² -E ² And C-N (R) ² )-L ² -E ² 。

In some embodiments of the present invention, in some embodiments,is->Wherein X is ³ Selected from the group consisting of: CH. C-L ² -E ² 、C-O-L ² -E ² And C-N (R) ² )-L ² -E ² Wherein X is ⁴ Is N or CR ³ 。

In some embodiments of the present invention, in some embodiments, Is->Wherein X is ² Selected from the group consisting of: CH. C-L ² -E ² 、C-O-L ² -E ² And C-N (R) ² )-L ² -E ² Wherein X is ⁴ Is N or CR ³ 。

In some embodiments of the present invention, in some embodiments,is->Wherein X is ² Selected from the group consisting of: CH. C-L ² -E ² 、C-O-L ² -E ² And C-N (R) ² )-L ² -E ² 。

In some embodiments of the present invention, in some embodiments,is->Wherein X is ² Is CH, C-L ² -E ² 、C-O-L ² -E ² And C-N (R) ² )-L ² -E ² Wherein E is ² And is not F.

In some embodiments of the present invention, in some embodiments,is->Wherein X is ³ Is CH, C-L ² -E ² 、C-O-L ² -E ² And C-N (R) ² )-L ² -E ² Wherein E is ² And is not F.

In some embodiments of the present invention, in some embodiments,is->Wherein X is ³ Is CH, C-L ² -E ² 、C-O-L ² -E ² And C-N (R) ² )-L ² -E ² 。

In some embodiments of the present invention, in some embodiments,is->Wherein X is ² Is CH,C-L ² -E ² 、C-O-L ² -E ² And C-N (R) ² )-L ² -E ² 。

In one embodiment, described herein is a compound represented by formula I-R:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: x is X ¹ Selected from the group consisting of: CH and N; x is X ³ Selected from the group consisting of: C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen, H and alkyl; r is R ⁷ Selected from the group consisting of: h and F; r is R ¹⁰ And R is ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino,Aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ¹⁵ Selected from the group consisting of: alkyl, cycloalkyl, and heterocyclyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In one embodiment, described herein is a compound represented by the formula I-S:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: x is X ¹ Selected from the group consisting of: CH and N; x is X ³ Selected from the group consisting of: C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; r is R ¹ Selected from the group consisting of: alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen, H and alkyl; r is R ⁷ Selected from the group consisting of: h and F; r is R ¹⁰ And R is ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, arylA group, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ¹⁵ Selected from the group consisting of: alkyl, cycloalkyl, and heterocyclyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In one embodiment, described herein is a compound represented by formula I-T:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: x is X ¹ Selected from the group consisting of: CH and N; x is X ³ Selected from the group consisting of: C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；R ¹ Selected from the group consisting of: alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen, H and alkyl; r is R ⁷ Selected from the group consisting of: h and F; r is R ¹⁰ And R is ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy Alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ¹⁵ Selected from the group consisting of: alkyl, cycloalkyl, and heterocyclyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In one embodiment, described herein is a compound represented by formula I-U:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: x is X ¹ Selected from the group consisting of: CH and N; x is X ³ Selected from the group consisting of: C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more times with a substituent independently selected from the group consisting ofSubstitution: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁵ Selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen, H and alkyl; r is R ⁷ Selected from the group consisting of: h and F; r is R ¹¹ Selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ¹⁵ Selected from the group consisting of: alkyl, cycloalkyl, and heterocyclyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution of；E ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In one embodiment, described herein is a compound represented by formulas I-V:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: x is X ¹ Selected from the group consisting of: CH and N; x is X ³ Selected from the group consisting of: C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; r is R ¹ Selected from the group consisting of: alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl and A sulfonyl group; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁵ Selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen, H and alkyl; r is R ⁷ Selected from the group consisting of: h and F; r is R ¹¹ Selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ¹⁵ Selected from the group consisting of: alkyl, cycloalkyl, and heterocyclyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ At each time go outThe current 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.

In one embodiment, described herein is a compound represented by formula I-W:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: x is X ¹ Selected from the group consisting of: CH and N; x is X ³ Selected from the group consisting of: C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁵ Selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen, H and alkyl; r is R ⁷ Selected from the group consisting of: h and F; r is R ¹¹ Selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl Amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ¹⁵ Selected from the group consisting of: alkyl, cycloalkyl, and heterocyclyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In one embodiment, described herein is a compound represented by formula I-X:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: x is X ¹ Selected from the group consisting of: CH and N; x is X ³ Selected from the group consisting of: C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；R ¹ Selected from the group consisting of: alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁵ Independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen, H and alkyl; r is R ⁷ Selected from the group consisting of: h and F; r is R ¹¹ Selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more times with a substituent independently selected from the group consisting ofSubstitution: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ¹⁵ Selected from the group consisting of: alkyl, cycloalkyl, and heterocyclyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In one embodiment, described herein is a compound represented by the formula I-Y:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: x is X ¹ Selected from the group consisting of: CH and N; x is X ³ Selected from the group consisting of: C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；R ¹ Selected from the group consisting of: alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocycle A group, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁵ Independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen, H and alkyl; r is R ¹¹ Selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ¹⁵ Selected from the group consisting of: alkyl, cycloalkyl, and heterocyclyl; l (L) ² Selected from the group consisting ofThe following groups: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In one embodiment, described herein is a compound represented by formulas I-Z:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: x is X ¹ Selected from the group consisting of: CH and N; x is X ³ Selected from the group consisting of: C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein heterocyclyl is optionally taken independently selected from the group consisting of one or more occurrences of taken atSubstitution of substituents: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen, H and alkyl; r is R ⁷ Selected from the group consisting of: h and F; r is R ⁸ Selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy and CN; r is R ¹⁰ And R is ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy group,Alkoxy, alkoxyalkyl, cyano, halo, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In one embodiment, described herein is a compound represented by formula I-AA:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: x is X ¹ Selected from the group consisting of: CH and N; x is X ³ Selected from the group consisting of: C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; r is R ¹ Selected from the group consisting of: alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of:h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen, H and alkyl; r is R ⁷ Selected from the group consisting of: h and F; r is R ⁸ Selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy and CN; r is R ¹⁰ And R is ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halo, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In one embodiment, described herein is a compound represented by formula I-AB:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: x is X ¹ Selected from the group consisting of: CH and N; x is X ³ Selected from the group consisting of: C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁴ And R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen-free foodPlain, H and alkyl; r is R ⁷ Selected from the group consisting of: h and F; r is R ⁸ Selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy and CN; r is R ¹¹ Selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In one embodiment, described herein is a compound represented by formula I-AC:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: x is X ¹ Selected from the group consisting of: CH and N; x is X ³ Selected from the group consisting of: C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; x is X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁵ Selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen, H and alkyl; r is R ⁷ Selected from the group consisting of: h and F; r is R ⁸ Selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkylA group, a hydroxyl group, and CN; r is R ¹¹ Selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In one embodiment, described herein is a compound represented by formula I-AD:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: x is X ¹ Selected from the group consisting of: CH and N; x is X ³ Selected from the group consisting of: C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ¹⁰ Selected from the group consisting of: CR (computed radiography) ⁵ And N; r is R ¹ Selected from the group consisting of: alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁵ Selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen, H and alkyl; r is R ⁷ Selected from the group consisting of: h and F; r is R ⁸ Selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy and CN; r is R ¹¹ Selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkyloxyA group, cycloalkylamino group, heterocyclic group, alkoxycarbonyl group, and heterocyclylalkyl group; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In one embodiment, described herein is a compound represented by formula I-AE:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: x is X ¹ Selected from the group consisting of: CH and N; x is X ³ Selected from the group consisting of: C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N; r is R ¹ Selected from the group consisting of: alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁵ Selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen, H and alkyl; r is R ⁷ Selected from the group consisting of: h and F; r is R ⁸ Selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy and CN; r is R ¹¹ Selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of aryl and heteroaryl is optionally substituted with one or more alkyl groupsSubstituted with one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In one embodiment, described herein is a compound represented by formula I-AF:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: x is X ¹ Selected from the group consisting of: CH and N; x is X ³ Selected from the group consisting of: C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；R ¹ Selected from the group consisting of: alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkylA group, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁵ Selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen, H and alkyl; r is R ⁷ Selected from the group consisting of: h and F; r is R ⁸ Selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy and CN; r is R ¹¹ Selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy Alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In one embodiment, described herein is a compound represented by formula I-AG:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: x is X ¹ Selected from the group consisting of: CH and N; x is X ³ Selected from the group consisting of: C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；R ¹ Selected from the group consisting of: alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl and heteroA cyclic group, and wherein the heterocyclic group is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; r is R ² Selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen; r is R ⁵ Selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN; r is R ⁶ Selected from the group consisting of: halogen, H and alkyl; r is R ⁸ Selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy and CN; r is R ¹¹ Selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl, wherein each of the aryl and heteroaryl groups is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and wherein the heterocyclyl is optionally substituted one or more occurrences of substituents independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; l (L) ² Selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution; e (E) ² Selected from the group consisting of: hydroxy, alkoxyAn alkoxyalkyl group, a cyano group, a halogen, a sulfonyl group, an H, an alkyl group, an amine, an amide, an acyl group, a haloalkoxy group, a haloalkyl group, and a heterocyclic group, wherein the heterocyclic group is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; e (E) ²¹ Independently at each occurrence 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.

In some embodiments, R ¹ Selected from the group consisting of:

in some embodiments, R ¹ Selected from the group consisting of: H.

in some embodiments, R ¹ Selected from the group consisting of:

/>

In some embodiments, X ¹ Is N. In some embodiments, X ¹ CH. In some embodiments, X ³ Is C-N (R) ² )-L ² -E ² . In some embodiments, X ³ Is CN (H) CH ₃ . In some embodiments, X ³ For CCH ₃ 。

In some embodiments, X ³ Selected from the group consisting of:

In some embodiments, X ¹⁰ Is N and X ¹¹ Is CR (CR) ⁷ . In some embodiments, X ¹⁰ And X ¹¹ Is N. In some embodiments, X ¹⁰ Is CR (CR) ⁵ And X is ¹¹ Is N. In some embodiments, R ³ H, C of a shape of H, C ₁ -C ₆ Alkyl and halogen. In some embodiments, R ³ H. In some embodiments, R ³ Me. In some embodiments, R ³ F. In some embodiments, R ³ Is Cl. In some casesIn embodiments, R ⁴ Selected from the group consisting of: H. f, cl, me, OMe, CF ₃ And CN. In some embodiments, R ⁵ Selected from the group consisting of: H. f, cl, me, OMe, CF ₃ And CN. In some embodiments, R ⁶ And R is ⁷ Each independently selected from the group consisting of: H. f, cl, me. In some embodiments, R ⁴ ，R ⁵ 、R ⁶ And R is ⁷ Each independently is H or F, and R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ At least one of which is F. In some embodiments, R ⁶ F is the same as F; and R is ⁴ 、R ⁵ And R is ⁷ Each is H. In some embodiments, R ⁴ F is the same as F; and R is ⁵ 、R ⁶ And R is ⁷ Each is H. In some embodiments, R ⁴ And R is ⁶ Each is F; and R is ⁵ And R is ⁷ Each is H. In some embodiments, R ⁴ And R is ⁵ Each is F; and R is ⁶ And R is ⁷ Each is H. In some embodiments, R ⁵ And R is ⁶ Each is F; and R is ⁴ And R is ⁷ Each is H. In some embodiments, R ¹⁵ Selected from the group consisting of: c (C) ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl and C ₃ -C ₆ A heterocyclic group. In some embodiments, R ¹⁵ Is cyclopropyl. In some embodiments, R ¹⁵ Me. In some embodiments, R ¹⁵ Is an oxetanyl group. In some embodiments, R ¹⁵ Is oxetan-2-yl. In some embodiments, R ¹⁵ Is oxetan-3-yl.

In some embodiments, the compound is selected from the group consisting of:

/>

and pharmaceutically acceptable salts, enantiomers, stereoisomers and tautomers thereof.

Therapeutic method

The compounds described herein, e.g., a compound of formula I as defined herein, may act as therapeutic agents for diseases driven by GCN2 or PERK kinase, and are useful in treating diseases and disorders, such as cancer, in patients in need thereof. Exemplary cancers include, but are not limited to, colorectal cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor, lung cancer (e.g., non-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 adenocarcinomas, adenosquamous carcinoma), duodenal cancer, small intestine cancer, breast cancer (e.g., invasive breast duct cancer, in situ breast duct cancer, inflammatory breast cancer), ovarian cancer (e.g., ovarian epithelium cancer, extragonadal germ cell tumor, ovarian low malignant potential tumor), testicular tumor, prostate cancer (e.g., hormone-dependent prostate cancer) hormone-independent 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 cancer), 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, uterine body cancer, uterine sarcoma), gestational choriocarcinoma, brain tumor (e.g., medulloblastoma, glioma, pineal astrocytoma, hairy astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, pituitary adenoma), retinoblastoma, skin cancer (e.g., basal cell carcinoma, malignant melanoma, melanoma), sarcoma (e.g., rhabdomyosarcoma, uterine sarcoma), gestational choriocarcinoma, diffuse astrocytoma, pituitary adenoma, and the like, leiomyosarcoma, soft tissue sarcoma, clostridial cell sarcoma, osteosarcoma), fibrosarcoma, malignant bone tumor, bladder cancer, hematological cancer (e.g., multiple myeloma, leukemia, acute Myelogenous Leukemia (AML), acute Lymphoblastic Leukemia (ALL), including acute stage of chronic leukemia), malignant lymphoma, hodgkin's disease, chronic myeloproliferative disease), cancer of unknown primary nuclei, cancer growth inhibitor, cancer metastasis inhibitor, apoptosis promoter, and methods for preventing or treating precancerous lesions (e.g., myelodysplastic syndrome).

In one embodiment, also described herein is a method of treating a disease caused by a disorder of integrated stress response in a patient in need thereof, 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 deregulation of the integrated stress response and/or the unfolded protein response is caused by GCN2 kinase. In some embodiments, the deregulation of the integrated stress response and/or the unfolded protein response is caused by a PERK kinase. In some embodiments, the deregulation of the integrated stress response is caused by GCN2 kinase. In some embodiments, the deregulation of the unfolded protein response is caused by a PERK kinase. In some embodiments, the imbalance of the integrated stress response is caused by activation of a kinase selected from the group consisting of: PERK kinase and GCN2 kinase. In some embodiments, the deregulation of the integrated stress response is caused by activation of GCN2 kinase. In some embodiments, the deregulation of the integrated stress response is caused by activation of a PERK kinase.

In another embodiment, also described herein is a method of treating a disease caused by dysregulation of integrated stress and/or unfolded protein response in a patient in need thereof, 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 deregulation of the integrated 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, the deregulation of the integrated stress response is caused by activation of GCN2 kinase. In some embodiments, the deregulation of the unfolded protein response is caused by activation of PERK kinase.

In another embodiment, described herein is a method of treating cancer in a patient in need thereof, 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, gastric cancer, duodenal cancer, small intestine cancer, breast cancer, ovarian cancer, testicular tumor, prostate cancer, liver cancer, thyroid cancer, renal cancer, uterine cancer, pregnancy choriocarcinoma, brain tumor, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumor, bladder cancer, blood cancer, leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, and malignant lymphoma. 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 cancer, duodenum cancer, small intestine 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, hematological cancer, leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocyte lymphoma, fahrenheit macroglobulinemia (waldenstrom macroglobulinemia), and malignant lymphoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is acute myelogenous 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 a B cell lymphoma. In some embodiments, the cancer is a T cell lymphoma.

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

In another embodiment, described herein is a method of treating a disease selected from GCN 2-related disease and PERK-related disease in a patient in need thereof, 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 GCN 2-associated 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 cancer, duodenal cancer, small intestine cancer, breast cancer, ovarian cancer, testicular tumor, prostate cancer, liver cancer, thyroid cancer, renal cancer, uterine cancer, pregnancy choriocarcinoma, brain tumor, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumor, bladder cancer, blood cancer, leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, and malignant lymphoma. 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, duodenal cancer, small intestine cancer, breast cancer, ovarian cancer, testicular tumor, prostate cancer, liver cancer, thyroid cancer, renal cancer, uterine cancer, gestational choriocarcinoma, brain tumor, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumor, bladder cancer, hematological cancer, leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocyte lymphoma, megaloblastic, and malignant lymphoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is acute myelogenous 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 a B cell lymphoma. In some embodiments, the cancer is a T cell lymphoma. In some embodiments, the disease is an amyloidosis. In some embodiments, the disease is light chain amyloidosis.

In another embodiment, described herein is a method of treating a disease selected from GCN 2-related disease and PERK-related disease in a patient in need thereof, 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 GCN 2-associated 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 cancer, duodenal cancer, small intestine cancer, breast cancer, ovarian cancer, testicular tumor, prostate cancer, liver cancer, thyroid cancer, renal cancer, uterine cancer, pregnancy choriocarcinoma, brain tumor, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumor, bladder cancer, blood cancer, leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, and malignant lymphoma. 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 cancer, duodenum cancer, small intestine cancer, breast cancer, ovarian cancer, testicular tumor, prostate cancer, liver cancer, thyroid cancer, renal cancer, uterine cancer, gestational choriocarcinoma, brain tumor, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumor, bladder cancer, hematological cancer, leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocyte lymphoma, megaloblastic, and malignant lymphoma. In some embodiments, the cancer is leukemia. In some embodiments, the leukemia is acute myelogenous 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 a B cell lymphoma. In some embodiments, the cancer is a T cell lymphoma. In some embodiments, the disease is an 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: l-asparaginase, pegylated asparaginase, 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: an IMiD agent, proteasome inhibitor, steroid, anti-CD 38 agent, anti-CD 20 agent, bcl-2 inhibitor, PI3K inhibitor, bispecific antibody, nucleoside analog, BTK inhibitor, DNA alkylating agent, EZH2 inhibitor, anthracycline, topoisomerase inhibitor, platinum, tyrosine kinase inhibitor, HDAC inhibitor, nuclear export inhibitor, anti-microtubule agent, L-asparaginase, pegylated asparaginase, 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, pegasporarase (pegasporagase), pego-karman-mknl (calaspargase pegol-mnkl), bortezomib (bortezomib), carfilzomib (carfilzomib), etiquette Sha Zuo meter (ixazomib), thalidomide (thalidomide), pomalidomide (pomalidomide), lenalidomide (lenalidomide), dexamethasone (dexamethasol), prednisone (prednisone), darumab (daratumumab)/hyaluronidase, ai Satuo ximab (isatuximab), rituximab (rituximab), atozumab (obinutuzumab), vinneturab (velocide), iderilis (idellab), ku (copalib), corydalib (copalib), du Weili, pandura (32) and other substances erlotinib, gemcitabine, cytarabine, ibrutinib, acarbosin, ibrutinib, dacarbatinib, imatinib, nilutatinib, pontemustine, cyclophosphamide, tazemetostat, doxorubicin, daunomycin, daunorubicin, etoposide, oxaliplatin, carboplatin, cisplatin Su Tini, dasatinib, imatinib, nilotinib, ponatinib, panobinostat, visualon, vincristaline, and vincristaline, JZP-458, erythrocyte-encapsulated L-asparaginase (eryaspase), PF745 (JZP-341), asparaginase E.chrysanthemi (Erwinia chrysanthemi) (Cristaase), E.coli (Escherichia coli) asparaginase (clapase), anti-PD 1 agents, anti-PDL 1 agents and anti-CTLA 4 agents.

In one embodiment, described herein is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in treating a disease caused by dysregulation of integrated stress response and/or unfolded protein response in a patient in need thereof. In some embodiments, the deregulation of the integrated 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, the deregulation of the integrated stress response and/or the unfolded protein response is caused by GCN2 kinase. In some embodiments, the deregulation of the integrated stress response and/or the unfolded protein response is caused by a PERK kinase. In some embodiments, the deregulation of the integrated stress response is caused by GCN2 kinase. In some embodiments, the deregulation of the unfolded protein response is caused by a PERK kinase. In some embodiments, the imbalance of the integrated stress response is caused by activation of a kinase selected from the group consisting of: PERK kinase and GCN2 kinase. In some embodiments, the deregulation of the integrated stress response is caused by activation of GCN2 kinase. In some embodiments, the deregulation of the integrated stress response is caused by activation of a PERK kinase. In one embodiment, described herein is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in modulating GCN2 kinase activity in a patient in need thereof. In one embodiment, described herein is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in activating GCN2 kinase in a patient in need thereof. In one embodiment, described herein is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in modulating the activity of a PERK kinase in a patient in need thereof. In one embodiment, described herein is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in activating PERK kinase in a patient in need thereof.

In one embodiment, described herein is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in inhibiting GCN2 kinase and inhibiting PERK kinase in a patient in need thereof. In one embodiment, described herein is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in modulating GCN2 kinase activity in a patient in need thereof. In one embodiment, described herein is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in inhibiting the activity of PERK kinase in a patient in need thereof.

In one embodiment, described herein is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in treating cancer in a patient in need thereof. 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 cancer, duodenum cancer, small intestine 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, hematological cancer, leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocyte lymphoma, fahrenheit macroglobulinemia, and malignant lymphoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is acute myelogenous 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 a B cell lymphoma. In some embodiments, the cancer is a T cell lymphoma.

In one embodiment, described herein is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in treating an amyloidosis in a patient in need thereof. In one embodiment, described herein is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in treating light chain amyloidosis in a patient in need thereof.

In one embodiment, described herein is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in treating a disease selected from GCN 2-related disease and PERK-related disease in a patient in need thereof. In some embodiments, the disease is a GCN 2-associated 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 cancer, duodenum cancer, small intestine 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, hematological cancer, leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocyte lymphoma, fahrenheit macroglobulinemia, and malignant lymphoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is acute myelogenous 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 a B cell lymphoma. In some embodiments, the cancer is a T cell lymphoma. In some embodiments, the disease is an amyloidosis. In some embodiments, the disease is light chain amyloidosis.

In one embodiment, described herein is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in treating a disease selected from GCN 2-related disease and PERK-related disease in a patient in need thereof. In some embodiments, the disease is a GCN 2-associated 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 cancer, duodenum cancer, small intestine 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, hematological cancer, leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocyte lymphoma, fahrenheit macroglobulinemia, and malignant lymphoma. In some embodiments, the cancer is leukemia. In some embodiments, the leukemia is acute myelogenous 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 a B cell lymphoma. In some embodiments, the cancer is a T cell lymphoma. In some embodiments, the disease is an 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: an IMiD agent, proteasome inhibitor, steroid, anti-CD 38 agent, anti-CD 20 agent, bcl-2 inhibitor, PI3K inhibitor, bispecific antibody, nucleoside analog, BTK inhibitor, DNA alkylating agent, EZH2 inhibitor, anthracycline, topoisomerase inhibitor, platinum, tyrosine kinase inhibitor, HDAC inhibitor, nuclear export inhibitor, anti-microtubule agent, L-asparaginase, pegylated asparaginase, 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: bortezomib, carfilzomib, ibrutin Sha Zuomi, thalidomide, pomalidomide, lenalidomide, dexamethasone, prednisone, darimab/hyaluronidase, ai Satuo ximab, rituximab, atozumab, valinamide, idarubiris, coppernix, du Weili sibutramine, erbitux, gemcitabine, cytarabine, ibrutinib, acartinib, zebutinib, bendamustine, cyclophosphamide, taziestat, doxorubicin, daunorubicin etoposide, oxaliplatin, carboplatin, cisplatin-Bo Su Tini, dasatinib, imatinib, nilotinib, plaitinib, panorastat, celecoxib Li Nisuo, vincristine, L-asparaginase, peganase, pego-karst-mknl, JZP-458, erythrocyte-encapsulated L-asparaginase, PF745 (JZP-341), asparaginase E.chrysanthemi (Creatase), E.coli asparaginase (Clapatase), anti-PD 1, anti-PDL 1 and anti-CTLA 4.

The compounds provided herein can be administered to patients (animals and humans) in need of such treatment in dosages that provide optimal pharmaceutical efficacy. It will be appreciated that the dosage required to be used in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, the concurrent medication or the particular diet the patient follows later on, and other factors that will be appreciated by those skilled in the art, with the appropriate dosage ultimately being determined by the attending physician. For the treatment of the above-mentioned clinical conditions and diseases, the compounds provided herein may be administered orally, subcutaneously, topically, parenterally, by inhalation spray, or rectally in the form of dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration may include subcutaneous injections, intravenous or intramuscular injection or infusion techniques.

The treatment may last for a long period of time or for a short period of time as desired. The composition may be administered on a regimen of, for example, one to four or more times per day. Suitable treatment periods may be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about 1 year, or an indefinite period of time. The treatment period may be terminated when the desired result is achieved.

Combination therapy

The compounds described herein, e.g., a compound of formula I as defined herein, may be administered in combination with one or more additional therapeutic agents to treat the disorders described herein, such as the cancers described herein. For example, the present invention provides pharmaceutical compositions comprising a compound described herein (e.g., a compound 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 may be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, a compound of formula I as defined herein and an additional therapeutic agent may be formulated and administered separately. Combination therapy may also be achieved by administering two or more therapeutic agents in a single formulation, e.g., a pharmaceutical composition comprising a compound of formula I as one therapeutic agent and one or more additional therapeutic agents, such as chemotherapeutic agents. For example, a compound of formula I and an additional therapeutic agent as defined herein may be administered in a single formulation. Combination therapies also encompass other combinations. Although two or more agents in combination therapy may be administered simultaneously, they need not be. For example, the administration of a first agent (or combination of agents) may be minutes, hours, days, or weeks prior to the administration of a second agent (or combination of agents). Thus, administration of two or more agents may be within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9 weeks, or weeks of each other. In some cases, even longer intervals are possible. While in many cases, two or more agents used in combination therapy need to be present in the patient at the same time, this is not necessarily the case.

Combination therapy may also include two or more administrations of one or more agents used in combination in different orders of use of the component agents. For example, if agent X and agent Y are used in combination, they may be administered sequentially in any combination, e.g., one or more times in the order of X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc.

Combination therapy may also include two or more administrations of one or more agents used in combination using different routes of administration. Each of the one or more medicaments may be administered independently in a dosage unit formulation containing a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and vehicle, orally, subcutaneously, topically, parenterally, by inhalation spray or rectally. Parenteral administration may include subcutaneous injections, intravenous or intramuscular injection or infusion techniques.

In some embodiments, a 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 chrysanthemi and is referred to as a kriging enzyme or asparaginase erwinia chrysanthemi. E.chrysanthemi strain with asparaginase and trademark Or->To be sold. In some embodiments, the asparaginase is obtained from escherichia coli and is referred to as clapase. Claapase is under the trademark-> Or->(recombinant E.coli asparaginase). Polyethylene glycol of clapraseThe derivative is shown by the trademark->Periplase sold under the trademark +.>Pergol's winterse-mknl is sold. Other asparaginase products currently in preclinical or clinical development include JZP-458 (recombinant E.erwinia asparaginase), PF745 (JZP-341), erythrocyte-encapsulated L-asparaginase->And xoncan.

In some embodiments, the compounds of formula I as defined herein are combined with an immunomodulatory agent. In some embodiments, immunomodulation enhances adaptive immune responses. In some embodiments, immunomodulation enhances the activity of antigen presenting cells. In some embodiments, the immunomodulator enhances the anti-tumor activity of bone marrow cells including macrophages. In some embodiments, immunomodulation enhances the anti-tumor activity of natural killer cells. In some embodiments, the immunomodulator enhances the activity of effector T cells (including cytotoxic T cells).

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

Exemplary MEK inhibitors include, but are not limited to, trametinib (trametinib), semetinib (selumetinib), cobimetinib (cobimetinib), bimetinib (binemetinib), and pharmaceutically acceptable salts thereof. Exemplary ERK inhibitors include, but are not limited to: ulitinib (ulixertiinib), SCH772984, LY3214996, lavoxertiinib (ravoxertiinib), VX-11e, ASN-007, GDC-0994, MK-8353, ASTX-029, LTT462, KO-947, and pharmaceutically acceptable salts thereof. Exemplary Ras inhibitors include, but are not limited to, AMG-510, MRTX849, ARS-1620, ARS-3248, LY3499446 and pharmaceutically acceptable salts thereof.

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 (pembrolizumab), nivolumab (nivolumab), pimelizumab (pimelizumab), cimip Li Shan anti (cemiplimab), atuzumab (atezolizumab), devaluzumab (durvalumab), BMS-936559, or avermectin (avelumab). In some embodiments, the additional therapeutic agent may be an anti-TIM 3 (anti-HAVcr 2) therapeutic agent, including but not limited to TSR-022 or MBG453; anti-LAG 3 therapeutic agents, including but not limited to, rilatlimab Li Shan (rellatlimab), LAG525, or TSR-033; anti-4-1 BB (anti-CD 37, anti-TNFRSF 9); CD40 agonist therapeutic agents, including but not limited to SGN-40, CP-870,893 or RO7009789; anti-CD 47 therapeutic agents including, but not limited to, hu5F9-G4; an anti-CD 20 therapeutic agent; an anti-CD 38 therapeutic agent; STING agonists, including but not limited to ADU-S100, MK-1454, ASA404, or amidobenzimidazole. In some embodiments, the additional therapeutic agent may be an anti-CTLA 4 agent comprising ipilimumab (ipilimumab), tremelimumab (tremelimumab). In some embodiments, the additional therapeutic agent may be a hypomethylation agent including, but not limited to, azacytidine or decitabine, and other immunomodulatory therapeutic agents including, but not limited to, epidermal growth factor inhibitors, statins, metformin (metformin), angiotensin receptor blockers, thalidomide, lenalidomide, pomalidomide, prednisone, or dexamethasone. In some embodiments, the additional therapeutic agent can be an immunotherapeutic agent, including targeted therapeutic agents, cancer vaccines, and CAR-T cell therapies.

The compounds of formula I as described herein may be administered in combination with other therapeutic agents known to treat cancer. Such other therapeutic agents include radiation therapy, anti-tubulin agents, DNA alkylating agents, DNA synthesis inhibitors, DNA intercalating agents, antiestrogens, 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-HER 2 agents, anti-angiogenic agents, proteasome inhibitors, PARP (poly ADP ribose polymerase) inhibitors, cell cycle regulating kinase inhibitors, thalidomide, lenalidomide, pomalidomide, bortezomib, carfilzomib, ezetimibe Sha Zuomi, darymumab/hyaluronidase, ai Satuo ximab, dexamethasone, and antibody-drug conjugates (ADCs).

In one embodiment, the additional therapeutic agent may be a chemotherapeutic agent, including but not limited to, an anti-tubulin agent (e.g., paclitaxel protein binding particles for injectable suspensions, including albumin-bound paclitaxel (nab-paclitaxel), eribulin (e.g., epothilin), docetaxel (docetaxel), ixabepilone (ixabepilone), vincristine, auristatin (auristatin) or maytansinoids), vinorelbine (vinorelbine), a DNA alkylating agent (including cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide), temozolomide (temozolomide), a DNA intercalating agent or a DNA topoisomerase inhibitor (including anthracyclines (e.g., doxorubicin), pegylated liposomal doxorubicin, daunorubicin, dactinomycin (idamycin), tolteroxine (e) or pseudomycin (e.g., thioxaprin), or 5-azamycin), or a derivative (e.g., thioxaprop-5-azamycin), or a derivative (e.g., thioflavin), a derivative (e.g., fluxaprop-5-azatabine), and a derivative (e.g., fluxaprop-5-azatabine).

In some embodiments, the additional therapeutic agent may be a kinase inhibitor, including but not limited to erlotinib, gefitinib, lenatinib, afatinib, oantinib, lapatinib, crizotinib, briatinib, ceritinib, aletinib, loratinib, everatinib, temsirolimus, abelmatinib, LEE011 Pa Bai Xili (palbociclib), caboztinib (cabozantinib), liptinib (rilatinib), sunitinib (sunitinib), pazopanib (pazopanib), sorafenib (sorafenib), regorafenib (regorafenib), sunitinib, axitinib (axitinib), dasatinib (dasatinib), imatinib (imatinib), nilotinib (nilotinib), ibrutinib-667, loxo 292, lartinib (laruretinib) and quinatinib.

In some embodiments, these additional therapeutic agents may be antiestrogens, including, but not limited to, tamoxifen (tamoxifen), fulvestrant (fulvestrant), anastrozole (anastrozole), letrozole (letrozole), and exemestane (exemestane); anti-androgens including, but not limited to, abiraterone acetate (abiraterone acetate), enzalutamide (enzalutamide), nilutamide (nilutamide), bicalutamide (bicalutamide), flutamide, cyproterone acetate (cyproterone acetate); steroid agents including, but not limited to, prednisone and dexamethasone; PARP inhibitors including, but not limited to, nilaparib (nerapanib), olaparib (olaparib), tazopanib (tazopanib), and Lu Kapa ni (rucaparib); topoisomerase I inhibitors including, but not limited to, irinotecan, camptothecin, irinotecan, and topotecan; topoisomerase II inhibitors including, but not limited to, anthracyclines, etoposide phosphate and mitoxantrone; histone Deacetylase (HDAC) inhibitors, including but not limited to vorinostat (vorinostat), romidepsin (romidepsin), panobinostat (panobinostat), valproic acid (valproic acid), and belinostat (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; biological agents, including but not limited to trastuzumab (trastuzumab), ado-trastuzumab (pertuzumab), cetuximab (cetuximab), and panitumumab (panitumumab).

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

In some embodiments, the additional therapeutic agent may be an antibody-drug-conjugate (ADC) including DM1, DM4, MMAE, MMAF or camptothecin payload, rituximab Shan Kangwei statin (brentuximab vedotin) and trastuzumab Shan Kangen statin (emtansine), radiation therapy, therapeutic vaccines including but not limited to sipuleucel-T.

In some embodiments, the additional therapeutic agent may be an autophagy inhibitor comprising a ULK inhibitor, a VPS34 inhibitor, a PIKfyve inhibitor, a PPT1 inhibitor, or a lysosomal blocking agent. In some embodiments, the additional therapeutic agent may be DCC-3116, SAR405, SB02024, hydroxychloroquine, chloroquine, apilimod, MRT403, and LYS05.

In some embodiments, the additional therapeutic agent is selected from Luteinizing Hormone Releasing Hormone (LHRH) analogs including goserelin (goserelin) and leuprolide (leuprolide).

In some embodiments, the additional therapeutic agent is selected from the group consisting of: everolimus (everolimus), trabectedin, abamectin (abaxane), TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib (vanretanib), ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, pemetrexed (pemetrexed), erlotinib, dasatinib, nilotinib, decartinib (decatanib), panitumomab, amrubicin (amrubicin) ago Fu Shan antibody (orevomab), lep-etu, nolatrexed (nolatexed), AZD 2171, batabulin, ofatumumab, zanolimumab, ai Teka forest (edotecarin), tetrandrine (tetrandrine), lu Biti kang (rubecan), ti Mi Lifen (tesilifene), olanemerson (obimersen), tiximab (ticilimumab), irimumab (ipilimumab), gossypol (gossypol), bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide (cilengitide), ji Ma Tikang (gimatecan), IL13-PE38QQR INO 1001, IPdR ₁ KRX-0402, thioxanthone (lucanthone), LY 317615, neopradib, viterspan (Viterspan), rta 744, alranosin (alanosine) (Sdx), talampanel, atrasentan (atastenan), XR 311, romidepsin (romidepsin), ADS-100380, sunitinib, 5Fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, lipid doxorubicin, 5' -deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, plug Li Xibu (seliciclib); PD0325901, AZD-6244, capecitabine, L-glutamic acid, N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2,3-d ]]Pyrimidin-5-yl) -ethyl]Benzoyl group]Disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate (toremifene citrate), anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258, 3- [5- (methylsulfonylpiperidinomethyl) -indol-quinolinone, vatalanib, AG-013136, AVE-0005, [ D-Ser (tBu) 6, azgly 10]Is (pyro-Glu-His-Trp-Ser-Tyr-D-Ser (tBu) -Leu-Arg-Pro-Azgly-NH) ₂ Acetate [ C ] ₅₉ H ₈₄ N ₁₈ O ₁₄ -(C ₂ H ₄ O ₂ ) _x Wherein x=1 to 2.4]Goserelin acetate (goserelin acetate), leuprolide acetate (leuprolide acetate), triptorelin pamoate (triptorelin pamoate), medroxyprogesterone acetate, medroxyprogesterone caproate (hydroxyprogesterone caproate), megestrol acetate (megestrol acetate), raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, ai Bituo (erbitux), EKB-569, PKI-166, GW-572016, sinafanib (ionofarnib), BMS-214662, tipifanib (tipifanib); amifostine (amifostine), NVP-LAQ824, suberoylaniline (suberoylanilide) hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, assamiline (arnacirine), anagrelide, L-asparaginase, BCG, bleomycin (bleomycin), buserelin (buserelin), buserellin (busulfan), carboplatin, dichloroethylnitrourea (carmustine), chlorpyribezene (chlorpyril), cisplatin (cisplatin), cladribine (clariton), clodrone (clodrone) Acid salts (clodronate), cyproterone (cyproterone), cytarabine (cytarabine), dacarbazine (dacarbazine), actinomycin (dacarbazine), daunorubicin, diethylstilbestrol, epirubicin (epirubicin), fludarabine (fludarabine), flucorosone (fludrocortisone), fluorohydroxymethyltestosterone (fluoxysterone), flutamide (flutamide), gemcitabine, gliclazide (gleevac), hydroxyurea, idamycin (idarubicin), ifosfamide, imatinib, leuprolide, levamisole (levamisole), lomustine (lomustine), methyldi (chloroethyl) amine (mechlorethane), melphalan, 6-mercaptopurine, mesna), methotrexate, mitomycin mitotane (mitotane), mitoxantrone, nilamide, octreotide (octreotide), oxaliplatin, pamidronate, penstatin (pentastatin), plicamycin (plicamycin), porphin (porfimer), procarbazine (procarbazine), raltitrexed (raltitrexed), rituximab, streptozotocin (streptozocin), teniposide (teniposide), testosterone, thalidomide, thioguanine, thiotepa (thiotepa), retinoic acid (tretin), vindesine, 13-cis-retinoic acid, chlorambucil, uracil nitrogen mustard, estramustine (estramustine), altretamine (altretamine), fluorouridine, 5-deoxyuridine (dexyuridine), cytosine arabinoside), 6-mercaptopurine (6-mecaptoprene), deoxyauxiliary mycin (deoxyoformycin), calcitriol, valrubicin (valrubicin), mithramycin (mithramycin), vinblastine (vinblastine), vinorelbine, topotecan, lazoxin (razoxin), marimastat (marimastat), COL-3, squalane (neovastat), BMS-2791, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin vitamin E, qu Luoxi E, idoxifene, spironolactone, finasteride, cimetidine, trastuzumab, dimetidine (denileukin diftitox), gefitinib, bortezomib, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab and Ai Bituo (erbitux), g Lei Mofo-free paclitaxel (cremophor-free paclitaxel), epothilone The pharmaceutical composition comprises the following components of mycin B, BMS-247550, BMS-310705, qu Luoxi, 4-hydroxy tamoxifen, perpenxifene (pipendxifene), ERA-923, arzoxifene, fulvestrant, acolbifene (acolbifene), lasofoxifene (lasofoxifene), idoxifene (idoxifene), TSE-424, HMR-3339, ZK186619, PTK787/ZK 222584, VX-745, PD 184352, rapamycin (rapamycin), 40-O- (2-hydroxyethyl) -rapamycin, temsirolimus (temsirolimus), AP-23573, RAD001, ABT-578, BC-210, LY294002, 292223, 292696, 293684, LY293646, wortmannin (wotmannin), ZM336372, L-779450, PEG-fefilstin (Betadalastin), and (Beetdamascin) erythropoietin, granulocyte colony stimulating factor, zepinol (zoledronate), prednisone, cetuximab, granulocyte macrophage colony stimulating factor, histamine relin (histrelin), pegylated interferon alpha-2 a, pegylated interferon alpha-2 b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans-retinoic acid (all-transretinoic acid), ketoconazole (ketoconazole), interleukin-2, megestrol, immunoglobulins, nitrogen mustard, methylprednisolone Lai Su Ibritgulomab tazitane (tiuxetan), androgens, decitabine, altretamine, bexarotene (bexarotene), tositumomab (tositumomab), arsenic trioxide, cortisone (coristolone), etidronate (etidronate), mitotane (mitotane), cyclosporine (cycloporine), lipodaunomycin, edwin-asparaginase, strontium 89, casopitane (casopitane), netupitant, NK-1 receptor antagonists, palonosetron (palonosetron) Alpidan (aprepatan), diphenhydramine (diphenhydramine), hydroxyzine (hydroxyzine), methoclopramide (metalopramide), lorazepam (lorazepam), alprazolam (alprazolam), haloperidol (haloperidol), haloperidol (droperidol), dronabinol (dronabinol), dexamethasone, methylprednisolone, prochlorperazine (prochlorperazine), granisetron (granisetron), ondansetron (dolasetron), terbisetron (tropisetron) Pefeiginestine (pegfilgrastim), erythropoietin, alfazoparetin (epoetin alfa) and alfazoparetin (darbepoetin alfa), yi Pushan anti (ipilumumab) and mixtures thereof.

Pharmaceutical composition and kit

Another aspect of the invention provides a pharmaceutical composition comprising a compound as disclosed herein formulated with a pharmaceutically acceptable carrier. In particular, the invention provides pharmaceutical compositions comprising a compound as disclosed herein formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although 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 being used. For example, the disclosed compositions may be formulated in unit dosage form and/or may be formulated for oral or subcutaneous administration.

Exemplary pharmaceutical compositions may be used in the form of pharmaceutical formulations, for example in solid, semi-solid or liquid form, containing as active ingredient a mixture of one or more of the compounds described herein with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral administration. The active ingredient may be compounded, for example, with conventional non-toxic, pharmaceutically acceptable carriers for tablets, pills, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable use form. 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.

For preparing solid compositions such as tablets, the primary active ingredient may be mixed with a pharmaceutical carrier, e.g., a conventional tableting ingredient (such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums), and other pharmaceutical diluents, e.g., water, to form a solid pre-formulated composition containing a homogeneous mixture of the compounds provided herein or non-toxic, pharmaceutically acceptable salts thereof. When referring to these pre-formulated compositions as homogeneous pre-formulated compositions, it is meant that the active ingredient is uniformly dispersed throughout the composition such that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

In solid dosage forms (capsules, tablets, pills, dragees, powders, granules, etc.) for oral administration, the compositions of the invention are mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and/or any of the following: (1) Fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) Binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and/or acacia; (3) humectants, such as glycerin; (4) Disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, specific silicates and sodium carbonate; (5) solution retarders such as paraffin; (6) absorption enhancers such as quaternary ammonium compounds; (7) Humectants, such as acetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite; (9) Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and (10) a colorant. In the case of capsules, lozenges and pills, the composition may also comprise buffering agents. Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose/mill sucer and high molecular weight polyethylene glycols and the like.

Tablets may be manufactured by compression or molding, optionally together with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g. gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g. sodium starch glycolate or croscarmellose sodium), surfactants or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the composition of the invention moistened with an inert liquid diluent. Tablets and other solid dosage forms such as sugar-coated pills, capsules, pills, and granules may optionally be scored or otherwise prepared with coatings and shells, such as enteric and other coatings well known in the pharmaceutical compounding arts.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the compositions of the present invention, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizing agents and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

In addition to the compositions of the present invention, the suspensions may also contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as suppositories which may be prepared by mixing the compositions of the present invention with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycols, a suppository wax or a salicylate and which are solid at room temperature but liquid at body temperature and therefore will melt in the body cavity and release the active agent.

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

In addition to the compositions of the present invention, ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

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 silicates and polyamide powder or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

The compositions and compounds of the present invention may alternatively be administered by aerosol. This is achieved by preparing an aqueous aerosol, a liposome formulation or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellant) suspensions may be used. Sonic sprayers may be used because they minimize exposure of the agent to shear forces that may lead to degradation of the compounds contained in the compositions of the present invention. Generally, aqueous mists are produced by formulating an aqueous solution or suspension of the composition of the invention with conventional pharmaceutically acceptable carriers and stabilizers. The carrier and stabilizer will vary with the needs of a particular present composition, but typically include a nonionic surfactant (Tween, pluronic or polyethylene glycol); harmless proteins such as serum albumin; sorbitan esters; oleic acid; lecithin; amino acids such as glycine; a buffering agent; a salt; sugar or sugar alcohol. Foggers are generally prepared from isotonic solutions.

Pharmaceutical compositions of the invention suitable for parenteral administration comprise a composition of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which sterile powders may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous 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. Proper fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

In another embodiment, an enteral pharmaceutical formulation is provided comprising the disclosed compounds and an enteric material; and pharmaceutically acceptable carriers or excipients thereof. Enteric materials refer to polymers that are substantially insoluble in gastric acid environments and are primarily soluble in intestinal fluids at a particular pH. The small intestine is a part of the gastrointestinal tract (the intestine) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the terminal ileum is about 7.5.

Thus, the enteric material is insoluble, for example, until the pH is 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. Exemplary enteric materials include Cellulose Acetate Phthalate (CAP); hydroxypropyl methylcellulose phthalate (HPMCP); polyvinyl acetate phthalate (PVAP); hydroxypropyl methylcellulose succinate acetate (HPMCAS); cellulose acetate trimellitate; hydroxypropyl methylcellulose succinate; cellulose acetate succinate; cellulose acetate hexahydrophthalate; cellulose propionate phthalate; cellulose acetate maleate; cellulose acetate butyrate; cellulose acetate propionate; copolymers of methacrylic acid and methyl methacrylate; copolymers of methyl acrylate, methyl methacrylate and methacrylic acid; copolymers of methyl vinyl ether with maleic anhydride (Gantrez ES series); ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer; natural resins such as zein, shellac, and cabazitaxel (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 Aquaterec). The solubility of each of the above materials is known or can be readily determined in vitro. The foregoing materials are a list of possible materials, but those skilled in the art having the benefit of this disclosure will recognize that they are not comprehensive and that there are other enteric materials that meet the objectives described herein.

Advantageously, provided herein are kits for use, for example, by consumers in need of treatment for cancer. Such kits include suitable dosage forms such as those described above; and instructions describing a method of using the dosage form to mediate, reduce or prevent inflammation. The instructions will direct the consumer or medical personnel to administer the dosage form according to a mode of administration known to those skilled in the art. These kits may advantageously be packaged and sold in single or multiple kit-of-parts units. An example of such a kit is a so-called plastic mold package. Encapsulation by molding is well known in the encapsulation industry and is widely used for encapsulating pharmaceutical unit dosage forms (tablets, capsules, etc.). The molded package is typically composed of a sheet of relatively rigid material covered with a foil of a preferably transparent plastic material. During the encapsulation process, a recess is formed in the plastic foil. The recess has the size and shape of the tablet or capsule to be encapsulated. Next, a tablet or capsule is placed in the groove and the sheet of relatively rigid material is sealed against the plastic foil at the foil face opposite the direction in which the groove is formed. As a result, the tablet or capsule is sealed in the groove between the plastic foil and the sheet. Preferably, the sheet strength is such that the tablet or capsule can be removed from the die package by manually applying pressure on the groove, thereby forming an opening in the sheet at the groove location. Subsequently, the tablet or capsule may be removed through the opening.

It may be desirable to provide memory assistance on the kit, for example in the form of a number immediately adjacent to the tablet or capsule, whereby the number corresponds to the number of days in the regimen that the tablet or capsule so prescribed should be ingested. Another example of such memory assistance is a calendar printed on a card, such as the following "first week, monday, tuesday, …, etc.; second week, monday, tuesday, …, etc.). Other variations of memory assistance are apparent. A "daily dose" may be a single tablet or capsule or several pills or capsules to be taken on a specified date. Furthermore, a daily dose of a first compound may consist of one tablet or capsule, while a daily dose of a second compound may consist of several tablets or capsules, and vice versa. The memory assistance should reflect this.

Examples

The compounds described herein may be prepared in a variety of ways based on the teachings contained herein and the disclosure of synthetic procedures in the art. In the description of the synthetic methods described below, it should be understood that all proposed reaction conditions, including solvent selection, reaction atmosphere, reaction temperature, experimental duration, and treatment procedure, can be selected as condition criteria for that reaction unless indicated otherwise. Those skilled in the art of organic synthesis will appreciate that the functional groups present on the various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents that are not compatible with the reaction conditions will be apparent to those skilled in the art and thus indicate alternative methods. The starting materials for the examples are commercially available or are readily prepared from known materials by standard methods.

The following abbreviations are used in the present invention and have the following definitions: "AcOH" is acetic acid, "ADP" is adenosine diphosphate, "AgNO ₃ "silver nitrate," ASNase "asparaginase," Boc "t-butyl carbonate," CDI "carbonyl diimidazole," cont "concentrated," Cs ₂ CO ₃ "cesium carbonate," CuI "copper (I) iodide," DBU "1, 8-diazabicyclo [5.4.0]Undec-7-ene, "DCC" is N, N '-dicyclohexylcarbodiimide, "DCE" is dichloroethane, "DCM" is dichloromethane, "DIAD" is diisopropyl azodicarboxylate, "DIEA" is N, N-diisopropylethylamine, "DMA" is N, N-dimethylacetamide, "DMAP" is 4- (dimethylamino) pyridine, "DMF" is N, N-dimethylformamide, "dppf" is 1,1' -bis (diphenylphosphino) ferrocene, "DMSO" is dimethyl sulfoxide, "EDTA" is ethylenediamine tetraacetic acid, "ESI" is electrospray ionization, "EtOAc" is ethyl acetate, "EtOH" is ethanol, "GST" is Gu Gantai S-transThe transferase, "H" is H, "HBTU" is (2- (1H-benzotriazol-1-yl) -1, 3-tetramethyluronium hexafluorophosphate, "H ₂ "hydrogen," HCl "hydrochloric acid," Hex "hexane," H ₂ O "is water," HOBt "is hydroxybenzotriazole," IC ₅₀ "half maximum inhibitory concentration," K ₂ CO ₃ "Potassium carbonate", "KOAc" potassium acetate "," K ₃ PO ₄ "Potassium phosphate", "NaBH ₄ "sodium borohydride," LAH "is lithium aluminum hydride," LiOH "is lithium hydroxide," MeCN "is acetonitrile," MeOH "is methanol," Me ₄ tBuXPhos "is di-tert-butyl (2 ',4',6 '-triisopropyl-3, 4,5, 6-tetramethyl- [1,1' -biphenyl)]-2-yl) phosphine, "MgSO ₄ "magnesium sulfate," MHz "is megahertz," min "is minutes," MnO ₂ "manganese (IV) oxide," MS "mass spectrometry," NADH "nicotinamide adenine dinucleotide," Na "sodium," NaH "sodium hydride," NaHCO ₃ "sodium bicarbonate", "NaNO ₂ "sodium nitrite," NaOMe "sodium methoxide," Na ₂ SO ₄ "sodium sulfate," NBS "is N-bromosuccinimide," NCS "is N-chlorosuccinimide," NH ₄ Cl "is ammonium chloride," NH ₂ OH "hydroxylamine," NMP "N-methyl-2-pyrrolidone," NMR "nuclear magnetic resonance," PBS "phosphate buffered saline," Pd/C "palladium/carbon," Pd ₂ (dba) ₃ "is tris (dibenzylideneacetone) dipalladium (0)," Pd (OAc) ₂ "palladium (II) acetate" Pd (PPh) ₃ ) ₄ "tetrakis (triphenylphosphine) palladium (0)," Pd (dppf) Cl ₂ "1, 1-bis (diphenylphosphino) ferrocene-palladium (II) dichloride," preparative HPLC "is preparative high performance liquid chromatography," PCl ₃ "phosphorus trichloride", "Ph ₃ P 'is triphenylphosphine,' PhPOCl ₂ "being phenylphosphine dichloride," PMB "being p-methoxyphenylmethyl," POCl ₃ "phosphorus oxychloride," PyBOP "is benzotriazol-1-yl-oxy-tripyrrolidinyl hexafluorophosphate," rt "is room temperature, also referred to as" ambient temperature, "which will be understood to consist of normal laboratory temperatures in the range of 15 to 25 ℃, and" satd. "is shown to be the case where the phosphorus oxychloride is the phosphorus oxychloride.Saturated, "SDS" is sodium dodecyl sulfate, "SFC" is supercritical fluid chromatography, "S _N Ar "is a nucleophilic aromatic substitution," SOCl ₂ "is thionyl chloride", "T ₃ P "is n-propane phosphoric anhydride," TEA "is triethylamine," TFA "is trifluoroacetic acid," THF "is tetrahydrofuran," Xantphos "is 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene," X-Phos "is 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl and" ZnCl "is used as the solvent ₂ "is zinc chloride.

In the following examples and corresponding figures, "compound 16" refers to the compound depicted as example 16 in table I below.

General chemical reaction

The exemplary compounds described herein can be obtained by the general synthetic methods illustrated in the schemes, intermediate preparations, and accompanying examples below.

Synthetic scheme

Scheme 1

Scheme 1 illustrates an exemplary preparation of borate 1.4. Compound 1.1 (commercially available, synthesized as described in WO2013134298 or synthesized by one skilled in the art) is reacted with bis (pinacolato) diboron by a boration reaction known to one skilled in the art (using a catalyst such as Pd (dppf) Cl at elevated temperature ₂ Palladium mediated reaction of a suitable base such as KOAc in a suitable solvent such as 1, 4-dioxane) to give compound 1.2, which is reacted with sulfonyl chloride 2.3 (see scheme 2) to give compound 1.4. Alternatively, the reaction of compound 1.1 with sulfonyl chloride 2.3 gives sulfonamide 1.3, which is converted to boronate 1.4 under boronation reaction conditions known to those skilled in the art.

Scheme 2

Scheme 2 illustrates an exemplary preparation of sulfonyl chloride 2.3. By Pd-catalyzed coupling reactions (e.g., using Pd ₂ (dba) ₃ XantPhos, phenyl methyl mercaptan in the presence of a base such as DIEA, in a solvent such as toluene, and at elevated temperature) to convert bromide 2.1a (ring A: substituted aryl, five-or six-membered heteroaryl, commercially available or synthesized by one skilled in the art) to thioether 2.2a. According to the general reaction conditions reported in Synthesis,2006,24,4131-4134 and biorg. Med. Chem.,2017,25,3447-3460, smooth oxidation of thioether 2.2a (e.g., by combination of NCS with dilute HCl,1, 3-dichloro-5, 5-dimethylhydantoin) gives the corresponding sulfonyl chloride 2.3. Alternatively, sulfonyl chloride 2.3 may be prepared by diazotisation starting from amine 2.1b (ring a: substituted aryl, five-or six-membered heteroaryl, commercially available or synthesized by one skilled in the art), followed by Cu-mediated chlorination of the resulting intermediate (according to the general reaction conditions reported in org. Proc. Res. Dev.,2009,5,875-879).

Scheme 3

Scheme 3 illustrates intermediate 3.9 (X ²¹ ＝O、NR ² ) Is described. Compound 3.1 (commercially available or synthesized by one skilled in the art) is reacted with ethyl 2-bromoacetate in the presence of a base such as piperidine to give pyridopyrimidinone 3.2. Reacting compound 3.2 with an amine R in a polar aprotic solvent such as NMP in the presence of a base such as DIEA at elevated temperature ¹ NHP (p=protecting group or H) reaction gave 3.3. Compound 3.3 and POCl ₃ Reaction gives 3.4 by reaction with alkoxide (E ² -L ² -OH/Na) or an amine (E ² -L ² -NHR ² ) Is converted to intermediate 3.9 (X) ²¹ ＝O、NR ² ). In another embodiment, pyridopyrimidinone 3.2 is used in combination with POCl ₃ Reaction, followed by reaction of the resulting intermediate with an amine (R ¹ NH ₂ ) Substitution reaction was carried out to give intermediate 3.9 (X) ²¹ -L ² -E ² ＝NHR ¹ ). Alternatively, intermediate 3.9 may be prepared starting from compound 3.5 according to the general reaction conditions reported in WO2018153373, CN105481858 and CN 105968108. Bromination of 3.5 with bromine in AcOH gives bromide 3.6, which is passed through POCl ₃ The treatment converts to chloride 3.7. Followed by reaction with alkoxide (E) ² -L ² -OH/Na) or an amine (E ² -L ² -NHR ² ) The reaction converts intermediate 3.7 to compound 3.8 (X ²¹ ＝O、NR ² ). The conversion of compound 3.8 to intermediate 3.9 is performed in a two-step process comprising: (i) Thioether oxidation at rt in the presence of an oxidizing agent such as mCPBA in a suitable solvent such as DCM to obtain the corresponding sulfoxide and (ii) sulfoxide and amine R ¹ NHP (p=protecting group or H) condensation.

Scheme 4

Scheme 4 illustrates an exemplary preparation of a compound of formula I. In a catalyst such as Pd (PPh) ₃ ) ₄ Or Pd (dppf) Cl ₂ In the presence of Pd catalyst, intermediate 3.9 (prepared as described in scheme 3, X ²¹ ＝O、NR ² ) Condensation with borate 1.4 affords compounds of formula I. Alternatively, 3.9 is reacted with bis (pinacolato) diboron under palladium mediated boronation reaction conditions to afford the boronate intermediate 4.1. The borate ester 4.1 is reacted with bromide 1.3 by Suzuki reaction known to the person skilled in the art to give the compound of formula I. In another embodiment, 3.9 is reacted with borate 1.2 under Pd catalyzed coupling conditions (suzuki reaction) to afford compound 4.2. Reacting aniline compound 4.2 with sulfonyl chloride 2.3 in the presence of a base such as pyridine gives a compound of formula I. Where the compound of formula I contains a nitrogen protecting group P such as Boc or PMB, the protecting group may be removed under acidic conditions (TFA or HCl in 1, 4-dioxane) to give the corresponding amine (compound of formula I).

Scheme 5

Scheme 5 illustrates an exemplary preparation of a compound of formula I. In a catalyst such as Pd (PPh) ₃ ) ₄ Or Pd (dppf) Cl ₂ In the presence of a Pd catalyst of 5.1 (y=oso ₂ CF ₃ ，X ²¹ Direct bond as described in WO2013134243, WO2013029084 and j.med.chem.,2015,58,4165-4179) with boronate 1.2 to give anilines 5.5. In a similar manner, compound 5.1 (y=oso ₂ CF ₃ ，X ²¹ =direct bond) with borate 1.4 (suzuki reaction), providing compound 5.6. Alternatively, 5.6 can be prepared by sulfonamide coupling reaction of aniline compound 5.5 with sulfonyl chloride 2.3. The conversion of compound 5.6 to a compound of formula I is carried out in a two-step process comprising: (i) Thioether oxidation at rt in the presence of an oxidizing agent such as mCPBA in a suitable solvent such as DCM to obtain the corresponding sulfoxide and (ii) sulfoxide and amine R ¹ NH ₂ Condensation. Alternatively, the compound of formula I may be reacted with an amine R via 5.6 ¹ NH ₂ Obtained by direct substitution at high temperature.

In another embodiment, compound 5.1 (y=h, X) is oxidized with mCPBA ²¹ =direct bond, commercially available or synthesized as described in WO2013134243, WO2013029084 and j.med.chem.,2015,58,4165-4179), followed by the resulting intermediate with amine R ¹ NH ₂ The substitution reaction is generally carried out in an aprotic solvent at a temperature of from rt to 150 ℃ to give compound 5.2. Bromination of 5.2 (e.g., with NBS or Br) is carried out according to the general reaction conditions reported in WO2013134243, WO2013029084 and J.Med.chem.,2015,58,4165-4179 ₂ HOAc) to give bromide 5.3 (X ²¹ =direct bond). Compound 5.3 and boronate 1.2 in a catalyst such as Pd (PPh) ₃ ) ₄ Or Pd (dppf) Cl ₂ Pd in the presence of Pd catalyst (Suzuki reaction) to give compound 5.4, which is reacted with sulfonyl chloride 2.3 to give the corresponding sulfonamide (compound of formula I). Alternatively, the compound of formula I may be prepared directly from 5.3 and boronate 1.4 by suzuki reaction.

Scheme 6

Scheme 6 illustrates an exemplary preparation of intermediate 6.5. Compound 6.1 (commercially available or synthesized by one skilled in the art) was reacted with 3- (triphenyl-l 5-phosphoranylidene) propionitrile (3- (triphenyl-l 5-phosphazene) procyanide) under Wittig reaction (Wittig reaction) conditions known to one skilled in the art to give compound 6.2. DBU-promoted cyclization of compound 6.2 under microwave irradiation at high temperature gives 1, 6-naphthyridin-2-amine 6.3. Bromination of 6.3 with NBS gives intermediate 6.4 by reaction with amine R ¹ Substitution reaction of NHP at high temperature converts to compound 6.5.

Scheme 7

Scheme 7 illustrates intermediate 7.6 (X ²¹ = O, NH). Compound 7.1 (commercially available or synthesized by one skilled in the art) is reacted with phenylacetonitrile 7.2 (commercially available or synthesized by one skilled in the art) at elevated temperature in the presence of a suitable base such as sodium alkoxide and in a protic solvent such as 2-ethoxyethanol to give 7.4a (r=nh ₂ ). Intermediate 7.4a (r=nh ₂ ) Reaction with DMF-dimethyl acetal followed by NaBH ₄ Reduction to give 7.5a (X ²¹ =nh). Reduction of the nitro substituent of compound 7.5a with ammonium chloride under mild reducing conditions (such as zinc or iron metal) gives aniline derivative 7.6. In another embodiment, compound 7.1 is reacted with ester 7.3 (commercially available or synthesized by one skilled in the art) in a protic solvent such as EtOH in the presence of a base such as piperidine at elevated temperature to give 7.4b (r=oh). Under standard light-casting conditions (e.g., at Ph ₃ Performed in the presence of P and DIAD) intermediate 7.4b with an alcohol (E) ² -L ² -OH) reaction to provide ethers7.5b(X ²¹ =o), which is converted to compound 7.6 via reduction of the nitro function of 7.5b to the corresponding amine with ammonium chloride in the presence of zinc or iron.

Scheme 8

Scheme 8 illustrates an exemplary preparation of a compound of formula I. From triflate 8.1 (X) according to the general reaction conditions reported in WO2013134298 and WO2018229629 ²¹ =direct bond) starts to prepare aniline compound 8.3 in 2 steps. The triflate 8.1 (synthesized as described in j.med.chem.,2015,58,4165-4179) reacted with suzuki of borate 1.2 to give 8.2. Contacting chloride 8.2 with R at elevated temperature in the presence of a base such as DIEA ¹ NHP (p=protecting group) to give compound 8.3, which is converted to sulfonamide 8.5 by reaction with sulfonyl chloride 2.3. In another embodiment, compound 8.5 is prepared by a suzuki coupling reaction of bromide 6.5 (see preparation of intermediate 6.5 described in scheme 6) with borate 1.4. Alternatively, aniline compound 7.6 (X ²¹ = O, NH, see preparation of intermediate 7.6 described in scheme 7) with sulfonyl chloride 2.3 to give sulfonamide 8.4 by reaction on a catalyst such as Pd ₂ (dba) ₃ Or Pd (OAc) ₂ In the presence of a palladium catalyst such as Xantphos or t-butylxphos in the presence of a metal ligand such as Cs ₂ CO ₃ In the presence of a base such as 1, 4-dioxane with an amine R ¹ NHP (p=protecting group) reaction converts sulfonamide 8.4 to compound 8.5, thus yielding intermediate 8.5. Removal of the protecting group of 8.5 provides the compound of formula I. In the case of compounds containing a nitrogen protecting group P such as Boc or PMB, the protecting group may be removed under acidic conditions (TFA or HCl in 1, 4-dioxane) to give the corresponding amine (compound of formula I).

Scheme 9

Scheme 9 illustrates an exemplary preparation of a compound of formula I. Aldehyde 9.1a (commercially available or synthesized by one skilled in the art, X ²¹ =direct bond, O, NH) with guanidine carbonate to give 6-bromoquinazolin-2-amine 9.2a. The sandmeyer reaction conditions known to those skilled in the art (e.g., x=i: isoamyl nitrite, cuI and CH ₂ I ₂ ) Compound 9.2a was converted to 9.3a (x=cl, I). 9.3a (x=cl or I) with an amine R ¹ NH ₂ S at high temperature _N Ar reaction gave 9.4a (X) ¹ N, general reaction conditions reported in accordance with WO2018046739, WO 2006039518 US20090197862 and j.med.chem.,2006,49,5671-5686). In another embodiment, primary amine 9.1b (commercially available or synthesized by one skilled in the art, X ²¹ =direct bond, O, NH) with ethyl 2, 2-dimethoxyacetate, followed by acid-mediated cyclization and trifluoride with trifluoromethanesulfonic anhydride to give triflate 9.2b. When R is ³ In the case of H, any of the resulting positional isomers of 9.2b may be separated by suitable methods such as SFC purification, crystallization or chromatography. According to the general reaction conditions reported in ACS Med. Chem. Lett,2015,6,31-36, the reaction is carried out at elevated temperature via S _N Ar reaction of triflate 9.2b with amine R ¹ NH ₂ Reaction gave 9.4b (X) ¹ =ch). Commercially available 9.2c (X) ¹ ＝N，X ³ =ch and R ³ =h: 6-bromoquinazolin-2-amine and X ¹ ＝CH，X ³ =ch and R ³ =h: 7-bromoisoquinolin-3-amine) and anhydride ((R) ¹³ (CO)) ₂ O) at high temperature to give acetamide 9.4 (X) ¹ =n or CH; r is R ¹ ＝(CO)R ¹³ ). Palladium catalyzed coupling of 9.4a, 9.4b and 9.4c with boronates 1.2 under suzuki reaction conditions gave intermediates 9.5a, 9.5b and 9.5c, respectively. Coupling of 9.5a, 9.5b and 9.5c with sulfonyl chloride 2.3 under reaction conditions known to those skilled in the art gives compounds of formula I. Alternatively, the compounds of formula I can be prepared from 9.2c, 9.4a, 9.4b and 9.4c with boronates 1.4 by palladium catalyzed coupling (Suzuki reaction).

Flow 10

The compounds of formula I may be prepared as described in scheme 10. Commercially available 2, 6-dichloropyrido [3,2-d ] is reacted in the presence of a base such as DIEA]Pyrimidine (10.1) and amine R ¹ NH ₂ (commercially available or synthesized by one skilled in the art) to afford intermediate 10.2. The palladium catalytic coupling reaction (suzuki reaction) of the chloride 10.2 and the borate 1.2 yields the aniline compound 10.3. The aniline compound 10.3 is reacted with sulfonyl chloride 2.3 to provide the compound of formula I. Alternatively, the compound of formula I may be prepared directly from chloride 10.2 and borate 1.4 under Suzuki reaction conditions.

Scheme 11

The compounds of formula I can be prepared as described in scheme 11. Reacting an amine 11.1 (commercially available or synthesized by one skilled in the art) with a borate 1.4 under palladium-mediated suzuki coupling conditions to give a compound of formula I (R ¹ =h). In another embodiment, amine 11.1 is reacted with carboxylic acid R under amide coupling conditions (e.g., HATU and DMAP in the presence of DIEA) ¹³ COOH reaction, or with acid chloride R in the presence of a base such as pyridine ¹³ COCl reaction gave 11.2. Intermediate 11.2 was reacted with boronate ester 1.2 under suzuki reaction conditions to give compound 11.3, which was converted to the compound of formula I via reaction with sulfonyl chloride 2.3. Alternatively, the compound of formula I may be prepared directly from 11.2 with the boronate 1.4 under suzuki reaction conditions.

Process 12

The intermediate of formula 12.5 can be prepared as described in scheme 12. Gashira in Pd/Cu-catalysisUnder head (Sonogashira) cross-coupling reaction conditions (e.g., under conditions such as Pd (PPh) ₃ ) ₂ Cl ₂ In the presence of a palladium 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 in the range of rt to 120℃) to give acetylene 12.3. Intermediate 12.3 is reacted with hydroxylamine hydrochloride in the presence of a suitable base such as NaOAc to give oxime 12.4. N-oxide 12.5 according to the synthetic procedure reported in US20190270742 by using AgNO ₃ Electrophilic metal catalyzed cyclization 12.4.

Flow 13

The compounds of formula I may be prepared as described in scheme 13. Copper-catalyzed direct amination of N-oxide 12.5 (see preparation of 12.5 illustrated in scheme 12) with amine E in an aprotic solvent such as toluene in the presence of a catalyst such as CuI at elevated temperature ² -L ² -NHR ² The reaction (according to the general reaction conditions reported in J.org.chem.,2017,82,8933-8942) gave 13.1 (X) ²¹ ＝NR ² ). According to the synthetic procedure reported in US20190270742, in PCl ₃ N-oxide 13.1 is converted to compound 13.2 in the presence of. Nitroreduction of 13.2 (reaction with ammonium chloride in the presence of metals such as zinc or iron) under mild reducing conditions gives anilines 13.3 which are converted to the corresponding sulfonamides 13.4 by reaction with sulfonyl chloride 2.3. Finally, 13.4 and R ¹ NH ₂ Pd catalyzed coupling reactions (Buchwald) known to those skilled in the art are carried out to give compounds of formula I.

Flow 14

The intermediate of formula 14.6 can be prepared as described in scheme 14. Commercial methyl 5-bromo-2- (methylthio) pyrimidine-4-carboxylate (14.1) was reacted with 3-nitrophenylacetylene 12.2 (commercially available or synthesized by one skilled in the art) under Pd/Cu-catalytic conditions known to one skilled in the art (sonotrodon reaction) to afford 14.2. Hydrolysis of ester 14.2 with LiOH (aqueous solution) gives the corresponding acid 14.3. Acid-promoted intramolecular cyclization of acid 14.3 gave 14.4 according to the general reaction conditions reported in org. Intermediate 14.4 in NH in glacial acetic acid at elevated temperature ₄ Conversion to 14.5 under OAc. Compound 14.5 was reacted with PhPOCl according to the general reaction conditions reported in WO2018113584 ₂ The reaction gave intermediate 14.6.

Flow 15

The compounds of formula I may be prepared as described in scheme 15. According to the general reaction conditions reported in WO2018113584, in Ag ₂ CO ₃ In the presence of alkylating agent E ² L ² O-alkylation of 14.5 (see preparation of 14.5 illustrated in scheme 14) gives 15.1a (X ²¹ =o). Alternatively, according to the general reaction conditions reported in WO2014037750, chloride 14.6 is reacted with an alcohol (E by substitution reaction in a polar aprotic solvent such as NMP at elevated temperature in the presence of a base such as DIEA ² -L ² -OH) or an amine (E ² -L ² -NHR ² ) Reaction gives 15.1b (X) ²¹ ＝O、NR ² ). Alternatively, chloride 14.6 (prepared in scheme 14) is reacted with boric acid or a borate E under Pd catalyzed coupling conditions ² -L ² -B(OR) ₂ (commercially available or synthesized by one skilled in the art) reaction (Suzuki reaction) to give 15.1c (X) ²¹ =direct bond). The nitroreduction of 15.1a, 15.1b and 15.1c under palladium-catalyzed hydrogenation or mild reduction conditions (zinc or iron metal with ammonium chloride) gives anilines 15.2. When 15.1c is at L ² -E ² Where double or triple bonds are present, these moietiesTogether with the nitro group, can be completely reduced under palladium-catalyzed hydrogenation conditions, giving 15.2. The aniline compound 15.2 is reacted with sulfonyl chloride 2.3 under sulfonamide coupling conditions known to those skilled in the art to give sulfonamide 15.3. Finally, the compound of formula I can be prepared by oxidation with mCPBA 15.3 followed by amine R ¹ NH ₂ S is carried out on the obtained intermediate _N Ar reaction.

Flow 16

The intermediate of formula 16.6 can be prepared as described in scheme 16. Commercially available 5-amino-2-chloroisonicotinamide (16.1) was reacted with 3-nitro-aldehyde 16.2 (commercially available or synthesized by one skilled in the art) to give 16.3. According to the general reaction conditions reported in WO2018113584, using, for example, mnO ₂ Is oxidized by the oxidizing agent of 16.3 to obtain 16.4. Intermediate 16.4 with amine R ¹ NH ₂ The reaction under Pd-catalyzed coupling (Buch-Ward reaction) known to those skilled in the art gives 16.5, which can be reacted with POCl ₃ The reaction yielded intermediate chloride 16.6.

Scheme 17

The compounds of formula I may be prepared as described in scheme 17. Chloride 16.6 (prepared as described in scheme 16) was reacted with alcohol (E ² -L ² -OH) or an amine (E ² -L ² -NHR ² ) Reaction gave 17.1a (X) ²¹ =o) or 17.B (X ²¹ ＝NR ² ). Alternatively, 17.1c (X ²¹ =direct bond) can be obtained from 16.6 by reacting with boric acid or boric acid ester (E ² -L ² -B(OR) ₂ ) Is prepared by Pd-coupling reaction (Suzuki reaction). The nitroreduction of 17.1a, 17.1b and 17.1c is carried out via palladium-catalyzed hydrogenation or mild reduction conditions (zinc or iron metal with ammonium chloride) to give the anilines 17.2. When 17.1c is at L ² -E ² Where double or triple bonds are present, these moieties together with the nitro group may be fully reduced under palladium-catalysed hydrogenation conditions to give 17.2. Finally, reacting the aniline compound 17.2 with sulfonyl chloride 2.3 under the condition of sulfonamide coupling to obtain the compound shown in the formula I. In another embodiment, commercially available 2-chloro-5-iodoisonicotinal (17.3) is reacted with various benzamidines 17.4 (commercially available or synthesized by one skilled in the art) to afford Ullmann (Ullmann) with no ligand copper catalysis, according to the general reaction conditions reported in Tetrahedron lett, 2010,51,785-760, to afford 17.5 (X) ²¹ -L ² -E ² =h). Pyridopyrimidine 17.5 and amine R are reacted by Pd catalyzed coupling reactions known to those skilled in the art ¹ NH ₂ The reaction gave 17.6. The nitro reduction of 17.6 was carried out via palladium catalyzed hydrogenation or mild reduction conditions (zinc or iron metal with ammonium chloride) to give aniline 17.7. The aniline compound 17.7 and the sulfonamide of sulfonyl chloride 2.3 are subjected to coupling reaction to obtain the compound shown in the formula I.

Preparation of intermediates and final compounds.

The following compounds were made using the synthetic procedures and methods described herein and methods known to those skilled in the art:

general procedure a: boration reaction

Example A1: 2-fluoro-4-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline

A mixture of potassium acetate (14.4 g,147 mmol), 5-bromo-2-fluoro-4-methylaniline (10.0 g,49 mmol) and 4,4', 5' -octamethyl-2, 2' -bis (1, 3, 2-dioxaborolan) (17.4 g,69 mmol) in 1, 4-dioxane (150 mL) was degassed with Ar for 10 min. Adding PdCl ₂ (dppf) (1.79 g,2.5 mmol) and the reaction mixture was heated at 110℃for 6 hours. The reaction was cooled to rt and filtered through a pad of celite. The filtrate was removed under reduced pressure and the residue was purified by silica gel column chromatography (0 to 50% EtOAc/hexanes and 1% EtOAc/DCM) to give a brown solid 2-fluoro-4-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (6.2 g,50% yield). ¹ H NMR(500MHz,DMSO-d ₆ ):δ7.12(d,J＝10.4Hz,1H),6.78(d,J＝12.8Hz,1H),4.86(s,2H),2.29(s,3H),1.26(s,12H)；MS(ESI)m/z:252.2(M+H ⁺ )。

The following intermediates of table a were prepared using general procedure a above.

Table a.

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General procedure B: condensation

Example B1: 7-methyl-2- (methylthio) pyrido [2,3-d ] pyrimidine

Using K ₂ CO ₃ (3.1 g,22 mmol) A solution of 4-amino-2- (methylthio) pyrimidine-5-carbaldehyde (3.0 g,18 mmol) in acetone (50 mL) was treated. The reaction was heated to 65 ℃ overnight. The reaction was filtered off while hot, 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 ] as a yellow solid]Pyrimidine (3.1 g,93% yield). ¹ H NMR(400MHz,DMSO-d ₆ ):δ9.40(s,1H),8.42(d,J＝8.2Hz,1H),7.55(d,J＝8.2Hz,1H),2.71(s,3H),2.63(s,3H).

General procedure C: substitution of

Example B2: n, 7-dimethylpyrido [2,3-d ] pyrimidin-2-amines

Heating 7-methyl-2- (methylthio) pyrido [2,3-d ] in a sealed tube at 80 DEG C]A solution of pyrimidine (B1, 1.00g,0.52 mmol) in N-methylamine (33% in ethanol, 8 mL) was used overnight. The reaction was cooled to rt and then concentrated under reduced pressure to give N, 7-dimethylpyrido [2,3-d ] as an orange solid]Pyrimidin-2-amine (0.62 g,68% yield). This material was used in the next reaction without further purification. MS (ESI) M/z 175.2 (M+H) ⁺ )。

General procedure D: halogenation (Br or I)

Example B3: 6-bromo-N, 7-dimethylpyrido [2,3-d ] pyrimidin-2-amine

At rt toward N, 7-dimethylpyrido [2,3-d ]]A solution of pyrimidine-2-amine (B2, 0.62g,0.36 mmol) in DCM (7.5 mL) was added NBS (0.67 g,0.38 mmol) in portions. The reaction mixture was stirred at rt overnight. The reaction mixture was cooled to 0 ℃ and stirred for 15 minutes. The solid was filtered off and washed with cold DCM (15 mL) to give 6-bromo-N, 7-dimethylpyrido [2,3-d ]]Pyrimidin-2-amine (0.48 g,53% yield). ¹ H NMR(500MHz,DMSO-d ₆ ):δ9.07(s,1H),8.47(s,1H),7.84(s,1H),2.90(d,J＝4.7Hz,3H),2.68(s,3H)；MS(ESI)m/z:253.0(M+H ⁺ ) And 255.0.

General procedure E: condensation

Example B4: 7-methyl-2- (methylthio) pyrido [2,3-d ] pyrimidin-6-ol

A suspension of 4-amino-2- (methylthio) pyrimidine-5-carbaldehyde (45 g,266 mmol) in water (600 mL) was treated with NaOH (21 g,530 mmol). 1-hydroxy-propan-2-one (23 g,319 mmol) was added followed by heating the reaction mixture to 55℃for maintenance4 hours. The reaction was cooled to 0 ℃ and concentrated HCl was added drop wise to a pH of about 3-4 under the same conditions. The reaction was stirred at 0deg.C for 30min, followed by filtering the solid to obtain 7-methyl-2- (methylthio) pyrido [2,3-d ] as a yellow solid]Pyrimidin-6-ol (51 g,93% yield). ¹ H NMR(500MHz,DMSO-d ₆ ):δ10.8(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 procedure F: activation of

Example B5: 7-methyl-2- (methylthio) pyrido [2,3-d ] pyrimidin-6-yl triflate

Stirring 7-methyl-2- (methylthio) pyrido [2,3-d ] at 0 DEG C]A suspension of pyrimidin-6-ol (B4, 20g,97 mmol) and DIEA (37 g,290 mmol) in DCM (500 mL). A solution of 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 warmed to rt over 3 hours. With saturated NaHCO ₃ (aqueous, 500 mL) the reaction mixture was quenched and the solution was then filtered through a pad of celite. The filtrate was extracted with DCM (3X 100 mL) and the combined organics were washed with water (2X 20 mL), over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude product was suspended in hexane and the solid was filtered off to give 7-methyl-2- (methylthio) pyrido [2,3-d ] as a yellowish-brown solid]Pyrimidin-6-yl triflate (23 g,70% yield). ¹ H NMR(500MHz,DMSO-d ₆ ):δ9.55(s,1H),8.77(s,1H),2.75(s,3H),2.65(s,3H)；MS(ESI)m/z:340.0(M+H ⁺ ).

General procedure G: oxidation and substitution

Example B6: 7-methyl-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrido [2,3-d ] pyrimidin-6-yl triflate

7-methyl-2- (methylthio) pyrido [2,3-d]A solution of pyrimidin-6-yl triflate (B5, 1.0g,2.9 mmol) in THF (50 mL) was cooled to 0deg.C. mCPBA (0.51 g,2.9 mmol) was added in portions and the reaction mixture was stirred under the same conditions for 1h. 1-methyl-1H-pyrazol-4-amine (0.29 g,2.9 mmol) and DIEA (1.0 mL,5.9 mmol) were added and the reaction mixture was stirred at rt overnight. The reaction was quenched with water (50 mL) and extracted with DCM (3X 50 mL). The combined organic extracts were washed with saturated NaHCO ₃ (2X 50 mL), brine (2X 50 mL), followed by anhydrous Na ₂ SO ₄ Dried and concentrated under reduced pressure to give 7-methyl-2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrido [2,3-d ] as a brown solid]Pyrimidin-6-yl triflate (0.81 g,71% yield). NMR (500 MHz, DMSO-d) ₆ ):δ10.3(s,1H),9.33(s,1H),8.49(s,1H),8.20(s,1H),7.64(s,1H),3.88(s,3H),2.67(s,3H)；MS(ESI)m/z:389.0(M+H ⁺ ).

General procedure H: condensation under tris (((trifluoromethyl) sulfonyl) oxy) ytterbium as catalyst

Example B7: 3-bromo-7-chloro-1, 6-naphthyridine

A mixture of 4-amino-6-chloronicotinaldehyde (2.2 g,14 mmol) and 2-bromo-1, 1-dimethoxyethane (3.3 mL,28 mmol) in DCE (50 mL) was treated with tris (((trifluoromethyl) sulfonyl) oxy) ytterbium (0.55 g,0.89 mmol). The reaction mixture was heated at 100 ℃ for 12 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 100% EtOAc/hexanes) to give 3-bromo-7-chloro-1, 6-naphthyridine (2.7 g,79% yield) as a yellow solid. MS (ESI) M/z 243.0 (M+H) ⁺ ) And 245.0.

General procedure I: wittig reaction and cyclization

Example B8: 7-chloro-1, 6-naphthyridin-2-amine

A solution of 4-amino-6-chloronicotinaldehyde (0.5 g,3.2 mmol) and (triphenylphosphine) acetonitrile (0.97 g,3.2 mmol) in THF (5 mL) was stirred at rt overnight. The reaction mixture was concentrated and the solid residue was suspended in EtOAc (5 mL). The solid was filtered off to obtain (E) -3- (4-amino-6-chloropyridin-3-yl) acrylonitrile (0.51 g,89% yield). A mixture of (E) -3- (4-amino-6-chloropyridin-3-yl) acrylonitrile (0.51 g,2.9 mmol) and DBU (0.85 mL,5.7 mmol) was heated in a microwave to 170℃for 5 hours. The reaction mixture was cooled to rt and taken up with saturated NaHCO ₃ (aqueous, 10 mL) quenching. The solution was extracted with EtOAc (3X 10 mL). The combined organics were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give 7-chloro-1, 6-naphthyridin-2-amine (0.24 g,47% yield). MS (ESI) M/z 180.0 (M+H) ⁺ )。

General procedure J: amide coupling

Example B9: n- (6-bromoquinazolin-2-yl) acetamides

A solution of 6-bromoquinazolin-2-amine (0.20 g,0.89 mmol) in acetic anhydride (5 mL) was heated to 140℃for 45 min. The reaction mixture was cooled to rt and the solid was filtered off, washed with water, and dried overnight under vacuum to give N- (6-bromoquinazolin-2-yl) acetamide (0.09 g,38% yield). MS (ESI) M/z 266.0 (M+H) ⁺ ) And 268.0.

General procedure K: with POCl ₃ Reaction

Example B12: 6-bromo-2-chloropyrido [2,3-d ] pyrimidines

6-bromopyrido [2,3-d ]]Pyrimidin-2-ol (B11, 5.0g,22 mmol) with POCl ₃ (31 mL) was worked up and the reaction was heated to 100deg.C overnight. Cooling the reactionBut to rt and concentrated under reduced pressure. Ice (about 200-300 g) was added to the remaining residue and the solution extracted with EtOAc (3×250 mL). The combined organics were treated with saturated NaHCO ₃ (aqueous solution, 100 mL) washing. The organic layer was treated with anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure to obtain 6-bromo-2-chloropyrido [2,3-d ] as yellow solid ]Pyrimidine (4.5 g,83% yield). MS (ESI) M/z 244.0 (M+H) ⁺ ) And 246.0.

The following intermediates of Table B were prepared using general procedure B-K above.

Table B.

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The following intermediates of table C were prepared using general procedure a above.

Table C.

General procedure L: suzuki reaction

Example D1:2, 4-difluoro-5- (isoquinolin-7-yl) aniline

7-chloro-2-methyl-1, 6-naphthyridin-3-yl triflate (B27, 3.0g,9.2 mmol), 2-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan) -2-yl) aniline (A6, 2.2g,9.2 mmol) and K were reacted with Ar ₂ CO ₃ (3.81 g,28 mmol) in 1, 4-dioxane (15 mL) and water (2.5 mL) was degassed for 5 min. Adding PdCl ₂ (dppf) (0.34 g,0.46 mmol) and the reaction mixture was heated at 80℃for 1 h. The reaction mixture was cooled to rt and the solution was then filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the crude product purified by silica gel column chromatography (0 to 100% EtOAc/hexanes) to give 3- (7-chloro-2-methyl-1, 6-naphthyridin-3-yl) -2-fluoroaniline (2.0 g,76% yield) as a brown solid. ¹ H NMR(500MHz,DMSO-d ₆ ):δ9.27(s,1H),8.45(s,1H),8.02(s,1H),7.03(t,J＝7.7Hz,1H),6.90(t,J＝8.3Hz,1H),6.56(t,J＝6.9Hz,1H),5.35(s,2H)；MS(ESI)m/z:288.0(M+H ⁺ ).

The following intermediates of table D were prepared using general procedure L above.

Table D.

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General procedure M: substitution reaction

Example E1:3- (5-amino-2, 4-difluorophenyl) -N- (4-methoxyphenylmethyl) -N, 2-dimethyl-1, 6-naphthyridin-7-amine

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A solution of 5- (7-chloro-2-methyl-1, 6-naphthyridin-3-yl) -2, 4-difluoroaniline (D8, 0.60g,2.0 mmol) and 4-methoxy-N-methylbenzylamine (1.2 g,8.0 mmol) in NMP (7 mL) was treated with DIEA (1.4 mL,8.0 mmol). The pressure tube was capped and the mixture was heated to 185 ℃ for 3 days. The mixture was cooled to rt and saturated NaHCO ₃ (aqueous, 20 mL) dilution. The solution was extracted with EtOAc (4×20 mL) and the combined organics were washed with 5% LiCl (aq), followed by brine. The organic layer was dried over anhydrous MgSO ₄ Dried and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (5 to 50% EtOAc/hexanes) to give 3- (5-amino-2, 4-difluorophenyl) -N- (4-methoxybenzyl) -N, 2-dimethyl-1, 6-naphthyridin-7-amine (0.77 g,94% yield). MS (ESI) M/z 421.2 (M+H) ⁺ )。

The following intermediates of table E were prepared using general procedure M above.

Table E.

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Example E11 was prepared by Pd-catalyzed reaction: n- (3- (3-amino-2-fluorophenyl) -2-methyl-1, 6-naphthyridin-7-yl) acetamide

3- (7-chloro-2-methyl-1, 6-naphthyridin-3-yl) -2-fluoroaniline (D1, 0.29g,1.0 mmol), acetamide (0.48 g,8.1 mol) and K were reacted with Ar ₃ PO ₄ (0.86 g,4.0 mmol) in 1, 4-dioxane (10 mL) was degassed for 5 min. Pd addition ₂ (dba) ₃ (0.046 g,0.05 mmol) and 5- (di-tert-butylphosphino) -1',3',5' -triphenyl-1 ' H-1,4' -bipyrazole (0.026 g,0.05 mmol) and the reaction mixture was degassed with Ar for an additional 5 minutes. The reaction mixture was stirred at 80℃for 2 hours. The reaction mixture was filtered through a pad of celite and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 100% EtOAc/hexanes) to give N- (3- (3-amino-2-fluorophenyl) -2-methyl-1, 6-naphthyridin-7-yl) acetamide (0.15 g,48% yield) as a brown solid. ¹ H NMR(500MHz,DMSO-d ₆ ):δ10.8(s,1H),9.16(s,1H),8.52(s,1H),8.27(s,1H),7.01(m,1H),6.88(m,1H),6.53(m,1H),5.31(s,2H),2.52(s,3H),2.18(s,3H)；MS(ESI)m/z:311.0(M+H ⁺ ).

General procedure N: preparation of sulfonyl chloride

Example F1: 5-chloro-2-methoxypyridine-3-sulfonyl chloride

A mixture of 3-bromo-5-chloro-2-methoxypyridine (50 g,225 mmol), benzyl mercaptan (29 mL,247 mmol), DIEA (79 mL,450 mol), and XantPhos (13 g,22 mmol) in toluene (500 mL) was rinsed with Ar for 5 min. Pd addition ₂ (dba) ₃ (10 g,11 mmol) the reaction was sealed under Ar and heated to 90℃for 3 hours. The reaction was cooled to rt and concentrated under reduced pressure. The residue was treated with EtOAc (500 mL). The solution was filtered through a pad of silica gel and washed with EtOAc (500 ml). The filtrate was concentrated under reduced pressure,3- (phenylmethylsulfanyl) -5-chloro-2-methoxypyridine (60 g,100% yield) was obtained as an orange solid. ¹ H NMR(500MHz,DMSO-d ₆ ):δ7.94(d,J＝2.4Hz,1H),7.65(d,J＝2.6Hz,1H),7.41(d,J＝7.9Hz,2H),7.32(t,J＝7.6Hz,2H),7.26(d,J＝8.3Hz,1H),4.27(s,2H),3.89(s,3H)。

A solution of 3- (benzylthio) -5-chloro-2-methoxypyridine (19.3 g,73 mol) in acetonitrile (200 mL) was cooled to 0deg.C. Acetic acid (42 mL, 720 mmol) and distilled water (10 mL) were added followed by 1, 3-dichloro-5, 5-dimethylimidazolidine-2, 4-dione (68% chlorine was obtained) (41 g,141 mol). The resulting solution was stirred at rt for 1 hour. The reaction mixture was diluted with EtOAc (200 mL) followed by washing the solution with water (2X 100 mL). The organic extract is treated with anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (5% EtOAc/hexanes) to give 5-chloro-2-methoxypyridine-3-sulfonyl chloride (10 g,57% yield) as a white crystalline solid. ¹ H NMR(500MHz,DMSO-d ₆ ):δ8.18(d,J＝2.7Hz,1H),7.93(d,J＝2.7Hz,1H),3.87(s,3H).

The following intermediates of table F were prepared using general procedure N above.

Table F.

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Preparation example F12:2, 5-dichloro-3- (chlorosulfonyl) benzoic acid methyl ester

A solution of thionyl chloride (12 mL,164 mmol) in MeOH (45 mL) was stirred at 0deg.C for 15 min. 3-amino-2, 5-dichlorobenzoic acid (7.5 g,36 mmol) was added under the same conditions. The reaction mixture was warmed to rt and stirred for 1 hour, followed by addition ofHeat to reflux for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAC. The solution was treated with 1N Na ₂ CO ₃ The solution (aqueous, 200 mL) was washed and the organic layer was washed with brine (50 mL). The organic layer was treated with anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated under reduced pressure to give crude methyl 3-amino-2, 5-dichlorobenzoate (7.0 g,87% yield), which was carried forward to the next step without further purification. ¹ H NMR(500MHz,DMSO-d ₆ ):δ6.98(d,J＝2.5Hz,1H),6.88(d,J＝2.5Hz,1H),5.97(s,2H),3.83(s,3H)；MS(ESI)m/z:220.0(M+H ⁺ ).

Solution A (preparation: a solution of sodium nitrite (0.68 g,9.8 mmol) in water (5.4 mL) was treated with a solution of methyl 3-amino-2, 5-dichlorobenzoate (2.0 g,9.1 mmol) in HCl (18 mL) at-15 ℃ C. The solution was stirred under the same conditions for 30 minutes) was added dropwise to solution B (preparation: thionyl chloride (2.8 mL,39 mmol) was added dropwise to water (17 mL) under acetone and ice bath.) the mixture was stirred at rt for 16 hours. Copper (I) chloride (10 mg,1 mmol) was added at rt, then the mixture was cooled to-15 ℃ C. And stirred for 30 minutes) and the reaction mixture was stirred under the same conditions for 2 hours. Once the reaction was complete, the mixture was diluted with DCM (100 mL). The aqueous phase was extracted with DCM (3X 50 mL). The combined organic extracts were dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 50% EtOAc/hexanes) to give methyl 2, 5-dichloro-3- (chlorosulfonyl) benzoate (F12, 2.1g,76% yield) as a yellow viscous liquid. ¹ H NMR(500MHz,DMSO-d ₆ ):δ8.00(d,J＝2.7Hz,1H),7.72(d,J＝2.7Hz,1H),3.86(s,3H).

Preparation example F13:2, 5-dichloro-3- ((4-methoxybenzyl) carbamoyl) benzenesulfonyl chloride

4-Methoxybenzylamine (2.09 mL,16 mmol) was added to a solution of 3-amino-2, 5-dichlorobenzoic acid (3.00 g,15 mmol) in DMF (10 mL). DIEA (5)34mL,31 mmol) and HATU (5.81 g,15 mmol) followed by stirring the reaction at rt overnight. The reaction mixture was poured into water and extracted with EtOAc (3×). The combined organic layers were washed with saturated NaHCO ₃ Aqueous solution (2×), brine wash, over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The residue was washed with hexane to give 3-amino-2, 5-dichloro-N- (4-methoxybenzyl) benzamide (2.40 g,51% yield) as a beige solid. ¹ H NMR(500MHz,DMSO-d ₆ ):δ8.86(t,J＝6.0Hz,1H),7.26(d,J＝8.4Hz,2H),6.91(d,J＝8.4Hz,2H),6.85(d,J＝2.5Hz,1H),6.55(d,J＝2.5Hz,1H),5.83(s,2H),4.34(d,J＝6.0Hz,2H),3.74(s,3H).

Pan (pot) a: water (13.7 mL,760 mmol) was cooled to-15 ℃. Then drop wise add SOCl ₂ (2.32 mL,32 mmol) and the mixture was stirred at rt for 16 h. Copper (I) chloride (0.008 g,0.08 mmol) was added at rt, the mixture was cooled to-15℃and stirred for 30 min.

Pan B: sodium nitrite (0.55 g,7.9 mmol) was added to H at-15 ℃ ₂ A solution of O (4.4 mL,244 mmol) and 1, 4-dioxane (4 mL) was added dropwise to a solution of 3-amino-2, 5-dichloro-N- (4-methoxybenzyl) benzamide (2.40 g,7.4 mmol) in HCl (14.8 mL,487 mmol) and stirred with maintaining temperature for 30 min.

Pot B was then added drop wise to pot a at-15 ℃, slowly warmed to rt and rapidly stirred for 1.5 hours. (Pan B reuse 4mL H ₂ O is rinsed and added to pan a). The solid was filtered and the crude product purified by silica gel column chromatography (5-100% EtOAc/hexanes plus 0.5% acetic acid modifier) to give 2, 5-dichloro-3- ((4-methoxybenzyl) carbamoyl) benzenesulfonyl chloride (F13, 1.5g,50% yield) as a pale orange solid.

Preparation example F14:2- (2, 5-dichloro-3- (chlorosulfonyl) phenyl) propan-2-yl acetate

A solution of 3-amino-2, 5-dichlorobenzoic acid (14.0 g,68.0 mmol) in EtOH (120 mL) was cooledBut to 0 ℃ and thionyl chloride (20.0 ml,169 mmol) was added dropwise. The reaction mixture was heated at 85 ℃ for an additional 16 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude product was triturated with n-pentane to give ethyl 3-amino-2, 5-dichlorobenzoate (14.0 g,83% yield) as a brown solid. ¹ H NMR(500MHz,DMSO-d ₆ ):δ6.96(d,J＝2.4Hz,1H),6.85(d,J＝2.4Hz,1H),5.96(brs,2H),4.29(q,J＝7.2Hz,2H),1.29(t,J＝6.8Hz,3H).

Treatment of ethyl 3-amino-2, 5-dichlorobenzoate (12.0 g,51.0 mmol) with amyl nitrite (9.64 mL,81.0 mmol) on CH ₃ Solutions in CN (250 mL). Benzhydryl disulfide (12.6 g,51.0 mmol) was added at rt and the reaction mixture was heated at 70 ℃ for 3 hours. The reaction mixture was quenched with ice water (100 mL) and extracted with EtOAc (3×). The combined organics were purified over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (10 to 20% EtOAc/hexanes) to give ethyl 3- (phenylmethylsulfanyl) -2, 5-dichlorobenzoate (10.0 g,58% yield) as an off-white solid. ¹ H NMR(500MHz,DMSO-d ₆ ):δ7.63(d,J＝2.8Hz,1H),7.56(d,J＝2.4Hz,1H),7.44(d,J＝7.2Hz,2H),7.35(t,J＝7.6Hz,2H)7.28(d,J＝7.2Hz,1H),4.42(s,2H),4.33(q,J＝7.2Hz,2H),1.29(t,J＝6.8Hz,3H).

A solution of ethyl 3- (phenylthio) -2, 5-dichlorobenzoate (10.0 g,29.32 mmol) in diethyl ether (20 mL) was stirred at 0deg.C under Ar. Methyl magnesium bromide (9.0 g,76.24 mmol) was added under the same conditions, followed by stirring the mixture at rt for 6 hours. The reaction mixture was quenched with ice water (50 mL) and extracted with EtOAc (3×). The combined organics were purified over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (5 to 10% EtOAc/hexanes) to give 2- (3- (phenylthio) -2, 5-dichlorophenyl) propan-2-ol as an off-white solid (6.0 g,62% yield). ¹ H NMR(500MHz,DMSO-d ₆ ):δ7.59(s,1H),7.43(d,J＝7.2Hz,2H),7.35(m,3H),7.28(m,1H),5.49(s,1H),4.33(s,2H),1.58(s,6H).

2- (3- (phenylthio) -2, 5-dichlorophenyl) propan-2-ol (3.0 g,9.2 mmol) acetic anhydride (2.81)g,27.6mmol,3.0 eq), triethylamine (4.0 mL,27.6mmol,3.0 eq) and dimethylaminopyridine (2.24 g,18.4mmol,2.0 eq) in THF (60 mL) were heated for 24 hours. The reaction mixture was cooled to rt and quenched with water (100 mL). The mixture was extracted with EtOAc (3×) and the combined organics were dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (1 to 2% MeOH/DCM) to give 2- (3- (phenylmethylsulfanyl) -2, 5-dichlorophenyl) propan-2-yl acetate (2.20 g,65% yield) as a brown solid. ¹ H NMR(500MHz,DMSO-d ₆ ):δ7.42(d,J＝7.6Hz,2H),7.35(m,3H),7.28(d,J＝7.2Hz,1H),7.25(s,1H),4.33(s,2H),1.98(s,3H),1.72(s,6H).

2- (3- (Benzenothio) -2, 5-dichlorophenyl) propan-2-ylacetate (3.0 g,9.2 mmol) and 1, 3-dichloro-5, 5-dimethylimidazolidine-2, 4-dione (2.35 g,11.9 mmol) were treated with acetic acid (3.6 g,59.7 mmol) and water (2.0 mL) on CH ₃ Solutions in CN (60 mL). The reaction mixture was stirred at rt for 16 h and saturated NaHCO ₃ The solution (100 mL) was quenched. The mixture was extracted with EtOAc (3×), and the combined organics were dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure to give 2- (2, 5-dichloro-3- (chlorosulfonyl) phenyl) propan-2-yl acetate (F14, 1.5g, crude) as a white solid, which was used for the next reaction without further purification.

Preparation example F15: 5-chloro-2, 4-dimethoxy benzenesulfonyl chloride

1-chloro-2, 4-dimethoxybenzene (1.0 g,5.8 mmol) was reacted with CHCl under Ar ₃ The solution in (15 mL) was cooled to 0deg.C. Chlorosulfonic acid (1.5 mL,12.9 mmol) was added dropwise at 0deg.C and the mixture was stirred at rt for an additional 3 h. The mixture was quenched with ice water (50 mL) and extracted with EtOAc (2×). The combined organics were purified over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude product was further triturated with n-pentane to give the desired 5-chloro-2, 4-dimethoxybenzenesulfonyl chloride as an off-white solid(F15, 0.9g,51% yield). ¹ H NMR(500MHz,DMSO-d ₆ ):δ7.60(s,1H),6.70(s,1H),3.88(s,3H),3.80(s,3H)。

Preparation example F16:2, 5-dichloro-3- (methylcarbamoyl) benzenesulfonyl chloride

2, 5-dichloro-3- (methylcarbamoyl) benzenesulfonyl chloride was prepared from methyl 3-bromo-2, 5-dichlorobenzoate using general methods J and N. ¹ H NMR(500MHz,DMSO-d ₆ ):δ8.46(brm,1H),7.86(d,J＝2.8Hz,1H),7.41(d,J＝2.8Hz,1H),2.73(d,J＝4.4Hz,3H)；MS(ESI)m/z:302.1(M+H ⁺ )。

Preparation example F17: acetic acid 2, 5-dichloro-3- (chlorosulfonyl) benzyl ester

A solution of ethyl 3-amino-2, 5-dichlorobenzoate (14.0 g,51.0 mmol) in acetonitrile (250 mL) was treated with amyl nitrite (9.64 mL,81.0 mmol) and benzhydryl disulfide (12.6 g,51.0 mmol). The reaction was heated at 70℃for 3 hours, then quenched with ice-cold water (100 mL). The aqueous layer was extracted with EtOAc (3×). The combined organics were purified over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (1% to 10% EtOAc/hexanes) to give ethyl 3- (phenylmethylthio) -2, 5-dichlorobenzoate (14.0 g,58% yield) as an off-white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.65(d,J＝2.8Hz,1H),7.56(d,J＝2.4Hz,1H),7.43-7.45(m,2H),7.33-7.37(m,2H),7.28(m,1H),4.42(s,2H),4.33(q,J＝7.2Hz,2H),1.31(t,J＝6.8Hz,3H).

By CaCl ₂ (0.45 g,0.92 mmol) A solution of ethyl 3- (phenylmethylsulfanyl) -2, 5-dichlorobenzoate (14.0 g,9.2 mmol) in THF/EtOH (1:1, 400 mL) was treated. Adding NaBH at 0 DEG C ₄ (6.20 g,36.8mmol,4.0 eq.) and the reaction mixture was heated at 60℃for a further 5 hours.The reaction was cooled to rt and quenched with NH ₄ Cl solution (50 mL) was quenched. The solution was extracted with EtOAc (3×), and the combined organics were dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (1 to 10% etoac/hexanes) to give (3- (phenylthio) -2, 5-dichlorophenyl) methanol (8.0 g,66% yield) as a brown solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.42-7.45(m,2H),7.33-7.36(m,3H),7.25-7.32(m,2H),5.57(t,J＝5.6Hz,1H),4.51(d,J＝6.0Hz,2H),4.36(s,2H).

A solution of (3- (phenylthio) -2, 5-dichlorophenyl) methanol (8.0 g,2.60 mmol) in THF (60 mL) was treated with acetic anhydride (8.32 g,8.08 mmol), triethylamine (13.6 g,67.1 mmol) and dimethylaminopyridine (0.90 g,0.26 mmol). The reaction mixture was heated at 80 ℃ for 3 hours and then cooled to rt. The reaction mixture was quenched with water (300 mL) and extracted with EtOAc (3×). The combined organics were purified over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (10 to 20% EtOAc/hexanes) to give 3- (phenylmethylthio) -2, 5-dichlorobenzyl acetate (8.0 g,88% yield) as an off-white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.44-7.46(m,2H),7.43(s,1H),7.36(s,1H),7.33-7.35(m,2H),7.27(m,1H),5.10(s,2H),4.39(s,2H),2.09(s,3H)。

A solution of 3- (phenylmethylthio) -2, 5-dichlorobenzyl acetate (8.0 g,2.3 mmol) in AcOH/THF/water (8:1:1, 400.0 mL) was treated with N-chlorosuccinimide (12.0 g,4.8 mmol). The reaction mixture was stirred at rt for 2 h, then quenched with water (100 mL). The mixture was extracted with EtOAc (3×) and the combined organics were dried over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (10 to 20% EtOAc/hexanes) to give 2, 5-dichloro-3- (chlorosulfonyl) benzyl acetate (F17, 4.2g,88% yield) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.84(d,J＝2.8Hz,1H),7.52(d,J＝2.8Hz,1H),5.13(s,2H),2.11(s,3H).

General procedure O: sulfonamide coupling

Example G1: n- (6-bromoquinazolin-2-yl) acetamides

A solution of 2-fluoro-4-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (A1, 0.2g,0.80 mmol) in DCM (3 mL) was cooled to 0deg.C. Pyridine-3-sulfonyl chloride (0.14 g,0.80 mmol) was added in portions and the reaction mixture was slowly warmed to rt overnight.

The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (0 to 10% DCM/MeOH) to give N- (2-fluoro-4-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyridine-3-sulfonamide (0.30 g,98% yield) as a white solid. ¹ H NMR(500MHz,DMSO-d ₆ ):δ10.2(s,1H),8.80(m,2H),8.03(d,J＝8.2Hz,1H),7.62(m,1H),7.39(d,J＝9.0Hz,1H),7.03(d,J＝11.6Hz,1H),2.41(s,3H),1.29(s,12H)；MS(ESI)m/z:393.2(M+H ⁺ ).

The following intermediates of table G were prepared using general procedure O above.

Table G.

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The following intermediates of table H were prepared using general procedure O above.

Table H.

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Preparation example H8: n- (3-bromo-2-fluorophenyl) -2, 5-dichloro-3- (2-hydroxypropan-2-yl) benzenesulfonamide

A solution of methyl 3- (N- (3-bromo-2-fluorophenyl) sulfamoyl) -2, 5-dichlorobenzoate (H2, 0.85g,1.9 mmol) in THF (10 mL) was stirred at-78deg.C. Methyl magnesium bromide (3.2M in THF, 3.8mL,12 mmol) was added dropwise at-78deg.C. The reaction mixture was slowly warmed up to rt overnight. With saturated NH ₄ The reaction was quenched with Cl (aq, 20 mL) and the solution extracted with EtOAc (3X 30 mL). The combined organics were purified over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (1% etoac/DCM) to give N- (3-bromo-2-fluorophenyl) -2, 5-dichloro-3- (2-hydroxypropan-2-yl) benzenesulfonamide (0.4 g,47% yield).

General procedure P: suzuki reaction

Example 1: n- (2-fluoro-4-methyl-5- (7-methyl-2- (methylamino) pyrido [2,3-d ] pyrimidin-6-yl) phenyl) pyridine-3-sulfonamide

N- (2-fluoro-4-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyridine-3-sulfonamide (G1, 0.20G,0.51 mmol), 6-bromo-N, 7-dimethylpyrido [2, 3-d) was reacted with Ar ]Pyrimidin-2-amine (B3)0.13g,0.51 mmol) and K ₂ CO ₃ (0.21 g,1.5 mmol) in 1, 4-dioxane (2 mL) and water (0.5 mL) for 10 min. Pd (PPh) was added ₃ ) ₄ (0.059 g,0.05 mmol) and reacted under microwave heating at 80℃for 3 hours. The reaction was cooled to rt and filtered through a pad of celite. The filtrate was concentrated under reduced pressure, followed by purification of the residue by silica gel column chromatography (0% to 10% MeOH/DCM) to give N- (2-fluoro-4-methyl-5- (7-methyl-2- (methylamino) pyrido [2, 3-d) as an orange solid]Pyrimidin-6-yl) phenyl) pyridine-3-sulfonamide (0.11 g,48% yield). ¹ H NMR(500MHz,DMSO-d ₆ ) δ10.4 (s, 1H), 9.08 (s, 1H), 8.82 (m, 2H), 8.10 (m, 1H), 7.89 (s, 1H), 7.72 (s, 1H), 7.65 (dd, j=4.9 and 8.1hz, 1H), 7.23 (d, j=11.2 hz, 1H), 6.99 (d, j=8.0 hz, 1H), 2.93 (d, j=4.7 hz, 3H), 2.20 (s, 3H), 1.99 (s, 3H); MS (ESI) M/z 439.2 (M+H) ⁺ ).

General procedure Q: sulfonamide coupling

Example 2: 5-chloro-N- (2-fluoro-3- (7-methyl-2- (methylthio) pyrido [2,3-d ] pyrimidin-6-yl) phenyl) -2-methoxypyridine-3-sulfonamide

2-fluoro-3- (7-methyl-2- (methylthio) pyrido [2,3-d ] at 0 DEG C]A solution of pyrimidin-6-yl) aniline (D3, 0.50g,1.7 mmol) in pyridine (2 mL) was added to a solution of 5-chloro-2-methoxypyridine-3-sulfonyl chloride (F1, 0.44g,1.8 mmol) in pyridine (2 mL). The reaction mixture was warmed to rt and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 100% EtOAc/hexanes) to give 5-chloro-N- (2-fluoro-3- (7-methyl-2- (methylthio) pyrido [2, 3-d) as a yellow solid ]Pyrimidin-6-yl) phenyl) -2-methoxypyridine-3-sulfonamide (0.60 g,71% yield). MS (ESI) M/z 506.0 (M+H) ⁺ )。

General procedure R: oxidation and substitution

Example 3: 5-chloro-N- (2-fluoro-3- (7-methyl-2- (methylamino) pyrido [2,3-d ] pyrimidin-6-yl) phenyl) -2-methoxypyridine-3-sulfonamide

Treatment of 5-chloro-N- (2-fluoro-3- (7-methyl-2- (methylthio) pyrido [2, 3-d) at 0℃with mCPBA (0.12 g,0.54 mmol)]A solution of pyrimidin-6-yl) phenyl) -2-methoxypyridine-3-sulfonamide (2, 0.26g,0.52 mmol) in DCM (2 mL). The reaction was stirred for 60 minutes. The solid was filtered off and rinsed with cold DCM (25 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in THF (2 mL), followed by DIEA (0.17 mL,0.97 mmol) was added. Methylamine (33% in EtOH, 0.65ml,5.2 mmol) was added and the reaction mixture was slowly warmed to rt over 1 hour. With saturated NaHCO ₃ (aqueous, 30 mL) quench the reaction mixture and extract the solution with DCM (2X 25 mL). The combined organics were purified over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. By reverse phase column chromatography (0% to 100% (0.4% FA) water/CH ₃ CN) to obtain 5-chloro-N- (2-fluoro-3- (7-methyl-2- (methylamino) pyrido [2, 3-d)]Pyrimidin-6-yl) phenyl) -2-methoxypyridine-3-sulfonamide (0.13 g,53% yield). ¹ H NMR(500MHz,DMSO-d ₆ ):δ10.4(brs,1H),9.09(s,1H),8.34(s,1H),8.00(m,3H),7.72(s,1H),7.30(s,1H),7.06(m,1H),3.88(s,3H),2.92(d,J＝4.8Hz,3H),2.27(s,3H)；MS(ESI)m/z:489.0(M+H ⁺ ).

General procedure S: by LiAlH ₄ Reduction of

Example 4:2, 5-dichloro-N- (2-fluoro-3- (7- (methylamino) -1, 6-naphthyridin-3-yl) phenyl) -3- (hydroxymethyl) benzenesulfonamide

General procedure Q preparation of 2, 5-dichloro-3- (N- (2-fluoro-3- (7- (methylamino) -1, 6-naphthyridin-3-yl) phenyl) sulfamoyl) benzoic acid methyl ester (G17, 0.42G,0.84 mmol) from 3-bromo-N-methyl-1, 6-naphthyridin-7-amine (B26, 0.20G,0.84 mmol) and 2, 5-dichloro-3- (N- (2-fluoro-3- (4, 5-tetramethyl-1, 3-dioxaborolan-2-yl) phenyl) sulfamoyl) benzoic acid methyl ester (G17, 0.42G,0.84 mmol)47% yield). MS (ESI) M/z 535.0 (M+H) ⁺ )。

By LiAlH under Ar ₄ (0.021 g,0.56 mmol) A solution of methyl 2, 5-dichloro-3- (N- (2-fluoro-3- (7- (methylamino) -1, 6-naphthyridin-3-yl) phenyl) sulfamoyl) benzoate (0.10 g,0.19 mmol) in THF (2 mL) was treated. The reaction mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was quenched with EtOAc (1 mL) and MeOH (1 mL) at 0deg.C. The reaction mixture was warmed to rt and stirred for 2 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. By reverse phase column chromatography (0% to 100% (0.4% FA) water/CH ₃ CN) to give 2, 5-dichloro-N- (2-fluoro-3- (7- (methylamino) -1, 6-naphthyridin-3-yl) phenyl) -3- (hydroxymethyl) benzenesulfonamide (0.02 g,21% yield) as a yellow solid. ¹ H NMR(500MHz,DMSO-d ₆ ):δ10.8(s,1H),8.98(s,1H),8.82(s,1H),8.30(s,1H),7.83(m,2H),7.51(t,J＝5.6Hz,1H),7.28(m,2H),6.99(m,1H),6.60(s,1H),5.75(m,1H),4.63(d,J＝5.4Hz,2H),2.87(d,J＝4.9Hz,3H)；MS(ESI)m/z:507.0(M+H ⁺ ).

General procedure T: removal of protecting groups with TFA

Example 5: 5-chloro-N- (2, 4-difluoro-5- (2-methyl-7- (methylamino) -1, 6-naphthyridin-3-yl) phenyl) -2-methoxypyridine-3-sulfonamide

5-chloro-N- (2, 4-difluoro-5- (7- ((4-methoxybenzyl) (methyl) amino) -2-methyl-1, 6-naphthyridin-3-yl) phenyl) -2-methoxypyridine-3-sulfonamide (0.14 g,93% yield) was prepared by reacting 3- (5-amino-2, 4-difluorophenyl) -N- (4-methoxybenzyl) -N, 2-dimethyl-1, 6-naphthyridin-7-amine (E7, 0.10g,0.24 mmol) with 5-chloro-2-methoxypyridine-3-sulfonyl chloride (F1, 0.07g,0.29 mmol). MS (ESI) M/z 626.2 (M+H) ⁺ )。

A solution of 5-chloro-N- (2, 4-difluoro-5- (7- ((4-methoxybenzyl) (methyl) amino) -2-methyl-1, 6-naphthyridin-3-yl) phenyl) -2-methoxypyridine-3-sulfonamide (0.10 g,0.16 mmol) in TFA (1.0 mL) was stirred at rt for 1 h. Concentrating under reduced pressureThe crude product should be purified by flash column chromatography (0 to 100% EtOAc/hexanes) to give 5-chloro-N- (2, 4-difluoro-5- (2-methyl-7- (methylamino) -1, 6-naphthyridin-3-yl) phenyl) -2-methoxypyridine-3-sulfonamide (0.070 g,84% yield) as a yellow solid. ¹ H NMR(500MHz,DMSO-d ₆ ):δ10.5(s,1H,),8.88(s,1H),8.53(d,J＝2.6Hz,1H),8.08(d,J＝2.6Hz,1H),7.99(s,1H),7.47(t,J＝9.8Hz,1H),7.32(t,J＝8.3Hz,1H),6.89(d,J＝5.7Hz,1H),6.54(s,1H),3.96(s,3H),2.86(d,J＝4.9Hz,3H),2.32(s,3H)；MS(ESI)m/z:506.0(M+H ⁺ ).

General procedure U: conversion from SMe to Cl

Example 109A: 5-chloro-N- (3- (2-chloro-7- (methylamino) pyrido [2,3-d ] pyrimidin-6-yl) -2-fluorophenyl) -2-methoxypyridine-3-sulfonamide

5-chloro-N- (2-fluoro-3- (7- (methylamino) -2- (methylsulfanyl) pyrido [2, 3-d)]Pyrimidin-6-yl) phenyl) -2-methoxypyridine-3-sulfonamide (0.88 g,1.7 mmol) on CH ₃ The solution in CN (8.5 mL) was cooled to 0deg.C for 10 minutes. A solution of sulfuryl chloride (1.37 mL,17 mmol) in DCM (8.5 mL) was then added dropwise and the reaction warmed to rt over 1 hour. The reaction mixture was saturated with NaHCO ₃ (aqueous) quench followed by pouring into 10% AcOH (aqueous) (25 mL). The solution was extracted with DCM (3×). The combined organics were purified over anhydrous Na ₂ SO ₄ Drying, filtering and concentrating under reduced pressure to obtain 5-chloro-N- (3- (2-chloro-7- (methylamino) pyrido [2, 3-d)) as an orange solid]Pyrimidin-6-yl) -2-fluorophenyl) -2-methoxypyridine-3-sulfonamide (0.36 g,41% yield). MS (ESI) M/z 509.0 (M+H) ⁺ )。

General procedure V: substitution of

Example 109: n- (3- (2-amino-7- (methylamino) pyrido [2,3-d ] pyrimidin-6-yl) -2-fluorophenyl) -5-chloro-2-methoxypyridine-3-sulfonamide

5-chloro-N- (3- (2-chloro-7- (methylamino) pyrido [2, 3-d)]Pyrimidine-6-yl) -2-fluorophenyl) -2-methoxypyridine-3-sulfonamide (109A, 0.25g,0.49 mmol) on NH ₄ The mixture in OH (30%, 1.27mL,9.8 mmol) was sealed and heated to 100deg.C overnight. The reaction mixture was cooled to rt and dissolved in a small amount of DMSO, purified by reverse phase column chromatography (10 to 100% (0.4% FA) water/CH ₃ CN) purification. With saturated NaHCO ₃ The residue was neutralized (aqueous solution) and the solution was extracted with DCM (3×). The combined organics were purified over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give N- (3- (2-amino-7- (methylamino) pyrido [2, 3-d) as a pale yellow solid]Pyrimidin-6-yl) -2-fluorophenyl) -5-chloro-2-methoxypyridine-3-sulfonamide (0.14 g,60% yield). ¹ H NMR(500MHz,DMSO-d ⁶ ):δ10.3(brs,1H),8.55(s,1H),8.42(d,J＝2.6Hz,1H),8.02(d,J＝2.6Hz,1H),7.41(s,1H),7.31(td,J＝1.8and 7.7Hz,1H),7.16(t,J＝7.7Hz,1H),7.11(m,1H),6.62(s,2H),6.39(q,J＝4.5Hz,1H),3.84(s,3H),2.71(d J＝4.5Hz,3H)；MS(ESI)m/z:490.0(M+H ⁺ ).

Preparation example 121A: 5-chloro-N- (2-chloro-3- (7-chloro-2-methyl-1, 6-naphthyridin-3-yl) phenyl) -2-methoxypyridine-3-sulfonamide

Using general procedure P, 5-chloro-N- (2-chloro-3- (7-chloro-2-methyl-1, 6-naphthyridin-3-yl) phenyl) -2-methoxypyridine-3-sulfonamide (1.5G, 96% yield) was prepared from 7-chloro-2-methyl-1, 6-naphthyridin-3-yl triflate (B23) and 5-chloro-N- (2-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -2-methoxypyridine-3-sulfonamide (G21). ¹ H NMR(500MHz,DMSO-d ⁶ ):δ9.24(s,1H),8.31(s,1H),8.20(s,1H),8.01(d,J＝6.6Hz,2H),7.33(d,J＝8.3Hz,1H),7.05(t,J＝7.8Hz,1H),6.57(d,J＝7.3Hz,1H),3.82(s,3H),2.46(s,3H).

General procedure W: buch-Var reaction

Example 121B: (3- (2-chloro-3- ((5-chloro-2-methoxypyridine) -3-sulfonylamino) phenyl) -2-methyl-1, 6-Pyridin-7-yl) carbamic acid tert-butyl ester

5-chloro-N- (2-chloro-3- (7-chloro-2-methyl-1, 6-naphthyridin-3-yl) phenyl) -2-methoxypyridine-3-sulfonamide (121A, 0.50g,0.98 mmol), cs, was reacted with Ar ₂ CO ₃ A mixture of (0.96 g,2.9 mmol) and tert-butyl carbamate (0.17 g,1.5 mmol) in 1, 4-dioxane (5 mL) was degassed for 3 min. tBuBrettPhos Pd G3 (0.042 g,0.05 mmol) was added and the mixture was degassed with Ar for 2 min. The reaction mixture was stirred at 100℃for 12 hours. The reaction mixture was cooled to rt and diluted with EtOAc (20 mL). The mixture was filtered through a pad of celite and washed with EtOAc (10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0 to 50% MeOH/DCM) to give tert-butyl (3- (2-chloro-3- ((5-chloro-2-methoxypyridine) -3-sulfonylamino) phenyl) -2-methyl-1, 6-naphthyridin-7-yl) carbamate (0.54 g,93% yield) as a brown solid. MS (ESI) M/z 590.2 (M+H) ⁺ )。

General procedure X: by K ₂ CO ₃ Removing protecting groups

3-N- (3- (2-amino-7-methoxyquinazolin-6-yl) -2-fluorophenyl) sulfamoyl-2, 5-dichlorobenzyl acetate (0.16G, 29% yield) was prepared by reacting 2, 5-dichloro-3- (N- (2-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) sulfamoyl) benzyl acetate (G24, 0.65G,0.012 mmol) with 6-bromo-7-methoxyquinazolin-2-amine (B41, 0.25G,0.098 mmol). ¹ H NMR(400MHz,DMSO-d ₆ )δ10.68(s,1H),8.92(s,1H),7.88(m,2H),7.56(s,1H),7.17-7.28(m,3H),6.86(s,1H),6.80(s,2H),5.20(s,2H),3.75(s,3H),2.06(s,3H)；MS(ESI)m/z:565.0(M+H ⁺ ).

By K ₂ CO ₃ (0.16 g,0.11 mmol) A solution of acetic acid 3- (N- (3- (2-amino-7-methoxyquinazolin-6-yl) -2-fluorophenyl) sulfamoyl) -2, 5-dichlorobenzyl ester (0.16 g,0.028 mmol) in MeOH (5.0 mL) was treated. The reaction mixture was stirred at rt for 4 hours, then concentrated under reduced pressure. The crude product was acidified with citric acid (pH 4-5) to give a solid precipitate. The solid was filtered, followed by filtration over CH ₃ Grinding in CN gave N- (3- (2-amino-7-methoxyquinazolin-6-yl) -2-fluorophenyl) -2, 5-dichloro-3- (hydroxymethyl) benzenesulfonamide (0.075 g,57% yield) as an off-white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.6(s,1H),8.92(s,1H),7.8(brs,1H),7.80(d,J＝2.4Hz 1H),7.78(brs,1H),7.56(s,1H),7.25-7.23(m,1H),7.18(brs,1H),6.85(s,1H),6.79(s,2H),5.73(t,J＝5.6Hz,1H),4.60(d,J＝5.6Hz,2H),3.75(s,3H)；LCMS(ES)m/z 523.23(M+H ⁺ ).

Using the general methods P to X described above, the compounds (examples) of table I below were prepared.

Table I.

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Example 180 biochemical assay of GCN2

The activity of GCN2 kinase is determined using a TR-FRET kinase activity assay (e.g., riddle et al Analytical Biochemistry (2006) 356 (1) 108-116). The assay was performed in 384 well plates (13 μl assay volume) using kinase buffer (Invitrogen) containing 2nM GCN2 (Carna Biosciences), 130nM GFP-EIf2α (Invitrogen), 0.2mg/mL escherichia coli tRNA (sigma) and 1mM ATP. By adding serial dilutions of the test compound (final assay concentration Degree of 0.5% dmso) followed by incubation for 3 hours to measure inhibition of GCN 2. Tb-peIF2a (pSer 52) antibody (Invitrogen) (2 nM final assay concentration) was added to a kinase buffer containing ETDA (final assay concentration of 20 mM). After incubation for 60 minutes at room temperature, TR-FRET was monitored using an excitation wavelength of 340nm and emission wavelengths of 490nm and 520 nm. Using a control (i.e., a reaction without test compound and a reaction with known inhibitor), the emission ratio (520/490) at each concentration of compound was converted to percent inhibition and IC was calculated by fitting the data to a four parameter sigmoid curve using Prism (GraphPad software) ₅₀ Values.

SEQ ID NO. 1-GCN2 protein sequence (residues 1-1649; G556E with N-terminal GST tag)

MAPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDLEVLFQGPLGAMGSGIQRPTSTSSLVMAGGRGAPGRGRDEPPESYPQRQDHELQALEAIYGADFQDLRPDACGPVKEPPEINLVLYPQGLTGEEVYVKVDLRVKCPPTYPDVVPEIELKNAKGLSNESVNLLKSRLEELAKKHCGEVMIFELAYHVQSFLSEHNKPPPKSFHEEMLERRAQEEQQRLLEAKRKEEQEQREILHEIQRRKEEIKEEKKRKEMAKQERLEIASLSNQDHTSKKDPGGHRTAAILHGGSPDFVGNGKHRANSSGRSRRERQYSVCNSEDSPGSCEILYFNMGSPDQLMVHKGKCIGDEQLGKLVYNALETATGGFVLLYEWVLQWQKKMGPFLTSQEKEKIDKCKKQIQGTETEFNSLVKLSHPNVVRYLAMNLKEQDDSIVVDILVEHISGVSLAAHLSHSGPIPVHQLRRYTAQLLSGLDYLHSNSVVHKVLSASNVLVDAEGTVKITDYSISKRLADICKEDVFEQTRVRFSDNALPYKTGKKGDVWRLGLLLLSLSQGQECGEYPVTIPSDLPADFQDFLKKCVCLDDKERWSPQQLLKHSFINPQPKMPLVEQSPEDSGGQDYVETVIPSNRLPSAAFFSETQRQFSRYFIEFEELQLLGKGAFGAVIKVQNKLDGCCYAVKRIPINPASRQFRRIKGEVTLLSRLHHENIVRYYNAWIERHERPAGPGTPPPDSGPLAKDDRAARGQPASDTDGLDSVEAAAPPPILSSSVEWSTSGERSASARFPATGPGSSDDEDDDEDEHGGVFSQSFLPASDSESDIIFDNEDENSKSQNQDEDCNEKNGCHESEPSVTTEAVHYLYIQMEYCEKSTLRDTIDQGLYRDTVRLWRLFREILDGLAYIHEKGMIHRDLKPVNIFLDSDDHVKIGDFGLATDHLAFSADSKQDDQTGDLIKSDPSGHLTGMVGTALYVSPEVQGSTKSAYNQKVDLFSLGIIFFEMSYHPMVTASERIFVLNQLRDPTSPKFPEDFDDGEHAKQKSVISWLLNHDPAKRPTATELLKSELLPPPQMEESELHEVLHHTLTNVDGKAYRTMMAQIFSQRISPAIDYTYDSDILKGNFSIRTAKMQQHVCETIIRIFKRHGAVQLCTPLLLPRNRQIYEHNEAALFMDHSGMLVMLPFDLRIPFARYVARNNILNLKRYCIERVFRPRKLDRFHPKELLECAFDIVTSTTNSFLPTAEIIYTIYEIIQEFPALQERNYSIYLNHTMLLKAILLHCGIPEDKLSQVYIILYDAVTEKLTRREVEAKFCNLSLSSNSLCRLYKFIEQKGDLQDLMPTINSLIKQKTGIAQLVKYGLKDLEEVVGLLKKLGIKLQVLINLGLVYKVQQHNGIIFQFVAFIKRRQRAVPEILAAGGRYDLLIPQFRGPQALGPVPTAIGVSIAIDKISAAVLNMEESVTISSCDLLVVSVGQMSMSRAINLTQKLWTAGITAEIMYDWSQSQEELQEYCRHHEITYVALVSDKEGSHVKVKSFEKERQTEKRVLETELVDHVLQKLRTKVTDERNGREASDNLAVQNLKGSFSNASGLFEIHGATVVPIVSVLAPEKLSASTRRRYETQVQTRLQTSLANLHQKSSEIEILAVDLPKETILQFLSLEWDADEQAFNTTVKQLLSRLPKQRYLKLVCDEIYNIKVEKKVSVLFLYSYRDDYYRILF

Example 181 biochemical assay of PERK

The activity of PERK kinase is determined spectroscopically using an ATP hydrolysis dependent oxidative coupled pyruvate kinase/lactate dehydrogenase assay that continuously monitors NADH (e.g., schindler et al Science (2000) 289: 1938-1942). Assay buffers (100 mM Tris, pH 7.5, 15mM MgCl) containing 10nM PERK (from Berylelium), 0.25mg/mL myelin basic protein substrate, 1.5 units of pyruvate kinase, 2.1 units of lactate dehydrogenase, 1mM phosphoenolpyruvate, 0.28mM NADH and 1mM ATP were used in 384 well plates (100. Mu.L final volume) ₂ Analysis was performed with 0.5mM DTT, 0.004% (w/v) BSA and 0.004% Triton X-100). Inhibition of PERK was measured by addition of serially diluted test compounds (final assay concentration 1% DMSO). The absorbance decrease at 340nm was continuously monitored on a multi-mode microplate reader (BioTek) at 30 ℃ for up to 6 hours. The reaction rate was calculated using a period of 2-3 h. The reaction rate at each concentration of compound was converted to percent inhibition using a control (i.e., reaction without test compound and reaction with known inhibitor), and IC was calculated using a software routine in Prism (GraphPad software) ₅₀ Values.

SEQ ID NO. 2-PERK protein sequence (residues 563-1115; sequence ID: NM 004836)

MSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDLVPRGSKYDSVSGEANDSSWNDIKNSGYISRYLTDFEPIQCLGRGGFGVVFEAKNKVDDCNYAIKRIRLPNRELAREKVMREVKALAKLEHPGIVRYFNAWLEAPPEKWQEKMDEIWLKDESTDWPLSSPSPMDAPSVKIRRMDPFSTKEHIEIIAPSPQRSRSFSVGISCDQTSSSESQFSPLEFSGMDHEDISESVDAAYNLQDSCLTDCDVEDGTMDGNDEGHSFELCPSEASPYVRSRERTSSSIVFEDSGCDNASSKEEPKTNRLHIGNHCANKLTAFKPTSSKSSSEATLSISPPRPTTLSLDLTKNTTEKLQPSSPKVYLYIQMQLCRKENLKDWMNGRCTIEERERSVCLHIFLQIAEAVEFLHSKGLMHRDLKPSNIFFTMDDVVKVGDFGLVTAMDQDEEEQTVLTPMPAYARHTGQVGTKLYMSPEQIHGNSYSHKVDIFSLGLILFELLYPFSTQMERVRTLTDVRNLKFPPLFTQKYPCEYVMVQDMLSPSPMERPEAINIIENAVFEDLDFPGKTVLRQRSRSLSSSGTKHSRQSNNSHSPLPSN

Table 1. Inhibition of biochemical activity of GCN2 and PERK kinase by exemplary compounds.

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For Table 1, "+" refers to an IC of less than or equal to 100nM ₅₀ The method comprises the steps of carrying out a first treatment on the surface of the "++" is big finger at 100nM and IC of 500nM or less ₅₀ The method comprises the steps of carrying out a first treatment on the surface of the "+++". Refers to greater than 500nM and IC of less than or equal to 1000nM ₅₀ The method comprises the steps of carrying out a first treatment on the surface of the And "+) ++" is refers to greater than 1000nM and less than or equal to 10000nM ₅₀ 。

Example 182 CCRF-CEM ASNase cell proliferation assay, a phenotypic assay for cell inhibition of GCN 2.

CCRF-CEM leukemia cells (catalog number CCL-116) were obtained from the American type culture Collection (American Type Culture Collect, ATCC, manassas, va.). Cells were incubated at 37℃with 5% CO ₂ And 95% humidity in RPMI-1640 medium supplemented with 10% heat-inactivated fetal bovine serum (Invitrogen, carlsbad, calif.) and 1% penicillin/streptomycin/L-glutamine. Cells were expanded until one million cells/ml was reached, at which point they were subcultured or harvested for assay use. Ten thousand cells/well in 200 μl RPMI-1640 supplemented with 10% heat-inactivated fetal bovine serum and 1% penicillin/streptomycin were dispensed into 96-well black transparent bottom plates. Serial dilutions of test compound and 1mU/mL ASNase were added in triplicate and the plates were incubated at 37℃with 5% CO ₂ And incubated at 95% humidity for 72 hours. At the end of incubation, 40 μl of 440mM solution of resazurin (Sigma, st.louis, MO) in PBS was added to each well of the plate and the plate was incubated at 37 ℃, 5% CO ₂ And further incubation at 95% humidity for 6 hours. Plates were read on a Synergy2 or equivalent reader (Biotek, winooski VT) using 540nM excitation and 600nM emission. Data were analyzed using GraphPad Prism software (GraphPad, san Diego, CA) to calculate IC ₅₀ Values.

Example 183 HCT116 amino acid starvation (-AA) phospho-GCN2 (phospho-GCN 2) and ATF4 assay

HCT116 colorectal cancer cells (catalog number CCL-247) were obtained from the American type culture Collection (ATCC, manassas, va.). Briefly, cells were incubated at 37℃with 5% CO ₂ And 95% humidity in RPMI 1640 medium supplemented with 10% heat-inactivated fetal bovine serum (Invitrogen, carlsbad, CA) and 1% penicillin/streptomycin/L-glutamine. Cells were expanded until 70-95% confluence was reached, at which point they were subcultured or harvested for assay use. Cells were seeded in 12-well plates at 1mL of complete growth medium in half-million cells/well and 5% CO at 37 °c ₂ And incubated overnight at 95% humidity. The next day, each well was treated with 1mL of Er Balanced salt solution (Earle's Balanced Salt Solution, EBSS, I) supplemented with 10% dialyzed fetal bovine serum, 5.5mM glucose, 1% penicillin/streptomycin and 1% vitamin solution (Thermo # 11120052)nvitrogen, carlsbad, CA). Serial dilutions of test compounds were dispensed into wells. Culture plates were incubated at 37℃with 5% CO ₂ And incubated at 95% humidity for 4 hours. At the end of incubation, cells were washed with PBS supplemented with 1 XHalt protease inhibitor, 1 XHalt phosphatase inhibitor, 1 XSigma phosphatase inhibitor cocktail 2 and 1 XEDTA, followed by lysis with M-PER mammalian protein extraction reagent supplemented with 3 Xinhibitor cocktail as described above. Cell lysates were sonicated with a water bath sonicator (Qsonica, newtown, CT) and supernatants were boiled with SDS buffer and reducing agent. Western blotting was performed on each lysate to quantify phospho-GCN 2 (Thr 899), total GCN2, ATF4 and beta-actin. The membrane was imaged using an LI-COR Odyssey CLx imaging system (LI-COR, lincoln, NE). Data were analyzed using GraphPad Prism software (GraphPad, san Diego, CA) to calculate IC ₅₀ Values.

EXAMPLE 184 CCRF-CEM TG ATF4 assay, a phenotypic assay for cytostatic PERK preactivated by Thapsigargin (TG)

CCRF-CEM leukemia cells (catalog number CCL-116) were obtained from the American type culture Collection (ATCC, manassas, va.). Briefly, cells were incubated at 37℃with 5% CO ₂ And 95% humidity in RPMI-1640 medium supplemented with 10% heat-inactivated fetal bovine serum (Invitrogen, carlsbad, calif.) and 1% penicillin/streptomycin/L-glutamine. Cells were expanded until one million cells/ml was reached, at which point they were subcultured or harvested for analysis. One hundred million cells/well in 1mL of complete growth medium were dispensed into 12 well plates and incubated overnight. Serial dilutions of test compound were added and the cells were incubated at 37 ℃ with 5% CO ₂ And 95% for three hours, followed by the addition of 1. Mu.M thapsigargin and the cells were incubated at 37℃with 5% CO ₂ And an additional one hour incubation at 95%. Cells were lysed and the ATF4 content was then measured using ELISA assay (Rosemont, IL). Absorbance was measured using a Synergy2 or equivalent reader (Biotek, winooski VT) at 450nM and 544 nM. Analysis of data using PRISM software (GraphPad, san Diego, calif.) to calculate IC ₅₀ Values.

Table 2. Proliferation of phospho-GCN 2 and ATF4 in amino acid starved HCT116, and thapsigargin stimulated CCRF-CEM cells was inhibited by exemplary compounds.

/>

For Table 2, "+" refers to an IC of less than or equal to 100nM ₅₀ The method comprises the steps of carrying out a first treatment on the surface of the "++" is big finger at 100nM and IC of 500nM or less ₅₀ The method comprises the steps of carrying out a first treatment on the surface of the "+++". Refers to greater than 500nM and IC of less than or equal to 1000nM ₅₀ The method comprises the steps of carrying out a first treatment on the surface of the And "+) ++" is refers to greater than 1000nM and less than or equal to 10000nM ₅₀ 。

Example 185.H929 ATF4 ELISA assay

H929 multiple myeloma cells (catalog number CRL-9068) were obtained from the American type culture Collection (ATCC, manassas, va.). Briefly, at 37℃5% CO ₂ And 95% humidity, cells were grown in RPMI-1640 medium supplemented with 20% heat-inactivated fetal bovine serum (catalog No. a3840002, thermoFisher Scientific, waltham, MA), 1% penicillin/streptomycin/L-glutamine (catalog No. 10378016,ThermoFisher Scientific,Waltham,MA) and 0.05mm 2-mercaptoethanol (catalog No. 21985-023,ThermoFisher Scientific,Waltham,MA), and the cells were expanded until one hundred and a hundred million cells/ml were reached, at which time they were subcultured or harvested for analysis. One hundred million cells/well in 1mL of complete growth medium were dispensed into 12 well plates and incubated overnight. Serial dilutions of test compound were added and the cells were incubated at 37℃with 5% CO ₂ And incubation at 95% for 4 hours. Lysing cells followed by ELISA assay(protein, rosemont, IL) the ATF4 content was measured. Absorbance was measured using a Synergy2 or equivalent reader (Biotek, winooski VT) at 450nM and 544 nM. The data were analyzed using PRISM software (Graphpad, san Diego, CA) to calculate fold-stimulation (fold-stimulation) of cell ATF4 relative to vehicle-treated controls.

Table 3. ATF4 in H929 multiple myeloma cells was stimulated by exemplary compounds.

Example numbering	H929 NS ATF4 assay
		16	+++
25	++
		31	++
49	+
		79	+++
86	+++
		109	+++
110	++
		128	+++
151	++
		174	+++
175	+++
		179	+++

For table 3, "+" refers to less than or equal to 5-fold ATF4 stimulation; "++" is big finger at 5 times and less than or ATF4 stimulation equal to 10-fold; "+++". Refers to big at 10 times and small ATF4 stimulation at or equal to 20 fold.

Compound 16 unexpectedly showed ATF4 stimulation in H929 multiple myeloma cells (in the absence of thapsigargin) at a concentration ranging from 123nM to 10 μm. Shown in fig. 1 is a stimulus pattern of cellular ATF4 in H929 multiple myeloma cells induced by compound 16.

EXAMPLE 186 detection of PERK oligomerization Using nanoBRET

BRET construction System uses nanoBRET ^TM PPI Starter System (Promega, madison, wis.). Full length PERK ORF was obtained from Genscript (Piscataway, NJ). HEK-293 cells (catalog number CRL-1573) were obtained from the American type culture Collection (ATCC, manassas, va.). The cells were incubated at 37℃with 5% CO ₂ And 95% humidity in MEM medium supplemented with 10% heat-inactivated fetal bovine serum (Invitrogen, carlsbad, CA) and 1% penicillin/streptomycin/L-glutamine.For the BRET assay, cells were seeded in 6-well plates at a density of 40,000 cells/ml in medium and allowed to attach and recover. Cells were transfected with C-terminal-labeled PERK-NLuc and C-terminal-labeled PERK-Halo using Lipofectamine LTX (Thermo, waltham, mass.) and allowed to reach 37℃at 5% CO ₂ And expressing the protein at 95% humidity overnight. Cells were then isolated from the dishes using 0.05% trypsin-EDTA, collected and diluted to 22,000 cells/mL in assay medium consisting of a medium supplemented with 4% FBS (Thermo)I reducing serum culture medium. Cells were distributed into 96-well cell culture plates and +.>NanoBRET ^TM 618 ligand (Promega) to a final concentration of 100nM. Compounds or DMSO are added to cells and the plates are incubated at 37deg.C, 5% CO ₂ And incubation at 95% humidity for 4 to 24 hours. nanoBRET ^TM />Substrate was added to the cells and the cells were shaken for 30 seconds. Donor (460 nM) and recipient (618) emissions were measured on a Synergy Neo2 multimode reader (BioTek, winooski, VT) within 10 minutes of substrate addition. Data are reported as BRET ratio (recipient/donor).

Compound 16 unexpectedly showed stimulation of PERK oligomer formation, wherein EC ₅₀ 270nM. A graph of stimulated PERK oligomers induced by compound 16 is shown in fig. 2.

Example 187 stimulation of multiple myeloma UPR/ISR signaling pathway proteins ATF4 and CHOP

H929 multiple myeloma cells (catalog number CRL-9068) were obtained from the American type culture Collection (ATTC, manassas, va.) at 37deg.C, 5% CO ₂ And grown at 95% humidity supplemented with 20% heat-inactivated fetal bovine serum (Invitrogen, carlsbad, calif.), 1% penicillin/streptavidinIn RPMI 1640 with plain/L-glutamine and 0.05mM 2-mercaptoethanol, and maintained at 1-2 million cells/ml. Cells were seeded in 6-well plates in 4 million cells/well in 2mL complete growth medium and 5% CO at 37 °c ₂ And a treatment with serial dilutions of the test compound at 95% humidity for 4 hours. At the end of incubation, cells were washed with PBS supplemented with 1 XHalt protease inhibitor, 1 XHalt phosphatase inhibitor, 1 XSigma phosphatase inhibitor cocktail 2 and 1 XEDTA, followed by lysis with M-PER mammalian protein extraction reagent supplemented with 3 Xinhibitor cocktail as described above. Cell lysates were sonicated with a water bath sonicator (Qsonica, newtown, CT) and supernatants were boiled with SDS buffer and reducing agent. Western blotting was performed to quantify ATF4, CHOP and beta-actin (Cell Signaling Technology, danvers, mass.). The membrane was imaged using an LI-COR Odyssey CLx imaging system (LI-COR, lincoln, NE).

Compound 16 unexpectedly showed stimulation of the PERK pathway in H929 multiple myeloma cells. FIG. 3 is a graph showing stimulation of PERK downstream signaling proteins ATF4 and CHOP (actin as an internal reference). ATF4 was stimulated at a concentration ranging from 123nM to 10. Mu.M. CHOP was stimulated in a concentration range of 1.1 to 10 μm.

EXAMPLE 188 stimulation of multiple myeloma UPR/ISR target genes Using quantitative RT-PCR

H929 multiple myeloma cells (catalog number CRL-9068) were obtained from the American type culture Collection (ATCC, manassas, va.). At 37℃with 5% CO ₂ And 95% humidity, cells were grown in RPMI-1640 medium supplemented with 20% heat-inactivated fetal bovine serum (catalog No. a3840002, thermoFisher Scientific, waltham, MA), 1% penicillin/streptomycin/L-glutamine (catalog No. 10378016,ThermoFisher Scientific,Waltham,MA) and 0.05mm 2-mercaptoethanol (catalog nos. 21985-023,ThermoFisher Scientific,Waltham,MA). Cells were expanded until 70-95% confluence was reached, at which point they were subcultured or harvested for assay use. Cells were grown in 2mL of complete growth medium at 3.0X10 ⁶ Individual cells/well were inoculated in 6-well plates and incubated at 37℃with 5% CO ₂ And 95% humidityThe indicated concentrations of compound 16 were incubated together for 4 hours or 24 hours. At the end of incubation, cells were washed with PBS (Sigma) and usedRNA was extracted using Plus kit (Qiagen, germanown, MD). cDNA was synthesized using a high capacity cDNA reverse transcription kit (Applied Biosciences, beverly Hills, calif.) and quantitative PCR was performed on Quantum studio 3 (Applied Biosciences) using TaqMan assay (Table A, thermo) and TaqMan Fast Advanced reaction mixture (Thermo) according to manufacturer's instructions.

Compound 16 unexpectedly induces the expression of the PERK UPR/ISR target gene in H929 multiple myeloma cells. Shown in fig. 4 is a graph illustrating fold increases in ATF4, CHOP, GADD34, GPT2, and VEGFA (compared to DMSO control). The target gene increased in the concentration range of 100nM to 10. Mu.M.

EXAMPLE 189 stimulation of apoptosis signaling pathways in multiple myeloma cells

H929 multiple myeloma cells (catalog number CRL-9068) were obtained from the American type culture Collection (ATTC, manassas, va.) at 37deg.C, 5% CO ₂ And 95% humidity in RPMI 1640 supplemented with 20% heat-inactivated fetal bovine serum (Invitrogen, carlsbad, CA), 1% penicillin/streptomycin/L-glutamine and 0.05mm 2-mercaptoethanol, and maintained at 1-2 million cells/ml. RPMI8226 (catalog number CCL-155) was obtained from the American type culture Collection (ATTC, manassas, va.) at 37℃with 5% CO ₂ And 95% humidity in RPMI 1640 supplemented with 10% heat-inactivated fetal bovine serum (Invitrogen, carlsbad, CA) and 1% penicillin/streptomycin/L-glutamine, and maintained at 0.1-1 million cells/ml. Cells were seeded in 6-well plates at 4 million cells/well in 2mL of complete growth medium and 5% co at 37 °c ₂ And serial dilutions of the assay with 100nM dexamethasone (Selleckchem, houston, TX) or equivalent volumes of DMSO at 95% humidityThe test compound was treated for 24 hours. At the end of incubation, cells were washed with PBS supplemented with 1 XHalt protease inhibitor, 1 XHalt phosphatase inhibitor, 1 XSigma phosphatase inhibitor cocktail 2 and 1 XEDTA, followed by lysis with M-PER mammalian protein extraction reagent supplemented with 3 Xinhibitor cocktail as described above. Cell lysates were sonicated with a water bath sonicator (Qsonica, newtown, CT) and supernatants were boiled with SDS buffer and reducing agent. Western blotting was performed to quantify cleaved Caspase3, cleaved Caspase7, PARP and beta-actin (Cell Signaling Technology, danvers, mass.). Imaging was performed using an LI-COR Odyssey CLx imaging system (LI-COR, lincoln, NE).

Compound 16 unexpectedly induced expression of pro-apoptotic proteins in H929 multiple myeloma cells. A diagram illustrating cleaved PARP, cleaved Caspase7 and cleaved Caspase3 is shown in FIG. 5. The apoptotic proteins increased in the concentration range of 123nM to 10. Mu.M.

Example 190 inhibition of multiple myeloma and B-cell lymphoma cell proliferation

H929, RPMI8226, GA-10 and DoHH-2 cells (catalog number CRL-9068) were obtained from the American type culture Collection (ATCC, manassas, va.). H929 cells were maintained in RPMI-1640 medium supplemented with 20% heat-inactivated fetal bovine serum (catalog No. A3840002, thermoFisher Scientific, waltham, mass.), 1% penicillin/streptomycin/L-glutamine (catalog No. 10378016,ThermoFisher Scientific,Waltham,MA) and 0.05mM 2-mercaptoethanol (catalog No. 21985-023,ThermoFisher Scientific,Waltham,MA). RPMI8226, GA-10, doHH-2 were maintained in RPMI-1640 medium supplemented with 10% heat-inactivated fetal bovine serum (catalog No. A3840002, thermoFisher Scientific, waltham, mass.) and 1% penicillin/streptomycin/L-glutamine (catalog No. 10378016,ThermoFisher Scientific,Waltham,MA). All cells were incubated at 37℃with 5% CO ₂ And growth at 95% humidity. Cells were expanded until one hundred and hundred thousand cells/ml were reached, at which point they were subcultured or harvested for assay use.

For cell proliferation assays, each well was inoculated with 200. Mu.L of the appropriate mediumThe number of cells (H929 was forty-thousand cells; RPMI8226 and GA-10 was twenty-thousand cells; doHH-2 was eight thousand cells) was distributed into 96-well black transparent plates. Serial dilutions of test compounds were added in triplicate and the plates were incubated at 37 ℃, 5% CO ₂ And incubated at 95% humidity for 72 or 120 hours. Several standard care agents for treating multiple myeloma clinically were used in combination studies (lenalidomide (catalog number S1029, seleckchem, houston, TX), bortezomib (catalog number S1013, seleckchem, houston, TX), dexamethasone (catalog number S1322, seleckchem, houston, TX), ibrutinib (pharmic, senyveromyces, CA)). At the end of incubation with H929, RPMI8226 and GA-10, 40. Mu.L of 440mM solution of resazurin (Sigma, st. Louis, MO) in PBS was added to each well of the plate and the plate was incubated at 37℃with 5% CO ₂ And an additional 7 hours incubation at 95% humidity. Plates were read on a Synergy2 or equivalent reader (Biotek, winooski VT) using 540nM excitation and 600nM emission. At the end of DoHH-2 incubation, use Cell viability was determined by the assay (Promega, madison, wis.). Luminescence was measured using a EnVision Multilabel reader (PerkinElmer, waltham, MA). Data was analyzed using GraphPad Prism software (GraphPad, san Diego, CA) to calculate IC ₅₀ Values.

Compound 16 exhibits additivity or synergy for inhibiting cell proliferation in combination with standard of care (SOC) agents for treating multiple myeloma or B-cell lymphoma. A representative diagram is shown in fig. 6.

Example 191 CCRF-CEM xenograft pharmacokinetic/pharmacodynamic (PK/PD) model

The CCRF-CEM xenograft model was performed in accordance with all laws, regulations and guidelines of the national institutes of health (National Institutes of Health, NIH) and received the animal Care and use Committee of Labcorp (Ann Arbor, MI) (approval of AAALAC approved agency, food and water ad libitum. All mice were observed for clinical signs at least once daily using a 27 gauge needle and syringe for female Envigo immediately below the right high armpitB-17SCID (6-7 weeks old) was inoculated subcutaneously with ten million cells in Dulbecco's Phosphate Buffered Saline. When the tumor burden reaches 200mm on the 22 nd balance ³ At that time, mice were randomly assigned to groups such that the average tumor burden for all groups was within 10% of the overall average tumor burden for the study population. On days 23 to 24, each group was treated as follows: on day 23, vehicle control (oral and IP dosing to the simulated combination group) (n=9); ASNase (Abcam, cambridge, UK) was administered at 1000U/kg/day (n=9) IP. On day 24, vehicle controls (oral and IP dosing to the simulated combination group) (n=9); compound 16 (n=10) was orally administered at 50mg/kg, and ASNase (Abcam, cambridge, UK) was administered at 1000U/kg (n=9) IP 2 hours prior to sample collection; compound 16 was orally administered at 25mg/kg (n=10), and ASNase (Abcam, cambridge, UK) was administered at 1000U/kg (n=9) IP 2 hours before sample collection 2, 6, and 10 hours after compound 16 administration. Blood samples were collected in K2EDTA tubes and processed into plasma, snap frozen in liquid nitrogen, and then stored at-80 ℃. Pharmacokinetic analysis was performed on plasma samples using liquid chromatography in combination with tandem mass spectrometry (Cayman Chemical, ann Arbor, MI). Tumor and pancreatic tissue were harvested and powdered by liquid nitrogen in covaris bags and stored at-80 ℃. Frozen (Fr) tissue samples were processed, approximately 30mg of tumor or pancreatic tissue was dissolved in mPER lysis buffer (Thermo Fisher Scientific, waltham, MA) supplemented with 3 xhat protease inhibitor, 3 xhat phosphatase inhibitor cocktail 2 and 3 x EDTA on ice, and then homogenized using load rupter 96 (Omni, kennesaw, GA). The sample was then centrifuged at 21,000g for 10 minutes at 4 ℃. The clarified lysate was then transferred to a frozen conical bottom 96-well plate, sealed, and then stored at-80 ℃. The next day, the samples were thawed on ice and subsequently centrifuged at 3739g for 10 minutes at 4 ℃. The clarified lysate was then transferred to a frozen round bottom 96-well plate. Protein concentration was determined using BCA protein assay kit (Thermo Fisher Scientific, waltham, MA). Lysates were standardized to 10. Mu.g/μl and then boiled in 4 XSDS-sample buffer and reducing agent. Analysis of samples Using SDS-PAGE followed by Analysis was performed using western blotting to quantify phospho-GCN 2 (Thr 899) (Abcam, cambridge, UK), total GCN2, ATF4, and β -actin (Cell Signaling Technology, danvers, MA). The membrane was imaged using an LI-COR Odyssey CLx imaging system (LI-COR, lincoln, NE). Data were analyzed using GraphPad Prism software (GraphPad, san Diego, CA) to calculate% inhibition.

Compound 16 in combination with ASNase inhibited GCN 2-mediated ATF4 levels in a CCRF-CEM leukemia xenograft model. As shown in fig. 7, compound 16 inhibited ATF4 content by 81 to 98% compared to vehicle control when administered orally at 50mg/kg and by 69 to 92% compared to vehicle control when administered orally at 25 mg/kg. The corresponding plasma levels of compound 16 were determined at PD time points of 2, 6 and 10 hours post-administration.

Example 192 MV-4-11 xenograft efficacy model

The implementation of the MV-4-11 acute myeloid leukemia xenograft model complies with all laws, regulations and guidelines of the National Institutes of Health (NIH), and was approved by the animal care and use committee (AAALAC approved agency) of the coronal organism (tai chi, china). Food and water were provided ad libitum. All mice were observed for clinical signs at least once daily. Five million cells in Du's phosphate buffered saline: matrigel (1:1) were inoculated subcutaneously in the right anterior abdominal (flank) area with a 27 gauge needle and syringe on female NOD/SCID (6-9 weeks old; vetong Liwa laboratory research model and service (Beijing, china)). When tumor burden reached 150mm on average on day 7 ³ At that time, mice were randomly assigned to groups such that the average tumor burden for all groups was within 10% of the overall average tumor burden for the study population. On days 7 to 21, each group was treated as follows: vehicle control (oral and IP administration to mock combination group (n=10), compound 16 administered orally at 25 mg/kg/day (n=10), leunase (Kyowa Kirin, japan) administered at 1000U/kg/day (n=10) and compound 16 administered orally at 25 mg/kg/day (n=10.) tumor volume and body weight were measured three times per week tumor load (mg) was estimated from calliper measurements by(mg＝mm ³ ) = (length x width ² )/2。

Compound 16 in combination with ASNase inhibited MV-4-11 tumor growth when administered orally. As shown in fig. 8, compound 16 induced tumor regression when administered at 25 mg/kg/day in combination with Leunase administered at 1000U/kg for 14 days.

Equivalent(s)

Although specific implementations have been discussed, the above description is illustrative and not limiting. Many variations on the embodiments will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure and its equivalents, and the full scope of the specification and variations thereof, should be determined by reference to the claims.

Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and claims are approximations that may vary depending upon the desired properties sought to be obtained.

Sequence listing

<110> Dexifei drawing medicine Co., ltd

<120> GCN2 and PERK kinase inhibitors and methods of use thereof

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<150> 63/185,846

<151> 2021-05-07

<150> 63/115,496

<151> 2020-11-18

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<170> patent In version 3.5

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<211> 1894

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Met Ala Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro

1 5 10 15

Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu

20 25 30

Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu

35 40 45

Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys

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Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn

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Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu

85 90 95

Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser

100 105 110

Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu

115 120 125

Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn

130 135 140

Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp

145 150 155 160

Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu

165 170 175

Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr

180 185 190

Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala

195 200 205

Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu Glu Val Leu

210 215 220

Phe Gln Gly Pro Leu Gly Ala Met Gly Ser Gly Ile Gln Arg Pro Thr

225 230 235 240

Ser Thr Ser Ser Leu Val Met Ala Gly Gly Arg Gly Ala Pro Gly Arg

245 250 255

Gly Arg Asp Glu Pro Pro Glu Ser Tyr Pro Gln Arg Gln Asp His Glu

260 265 270

Leu Gln Ala Leu Glu Ala Ile Tyr Gly Ala Asp Phe Gln Asp Leu Arg

275 280 285

Pro Asp Ala Cys Gly Pro Val Lys Glu Pro Pro Glu Ile Asn Leu Val

290 295 300

Leu Tyr Pro Gln Gly Leu Thr Gly Glu Glu Val Tyr Val Lys Val Asp

305 310 315 320

Leu Arg Val Lys Cys Pro Pro Thr Tyr Pro Asp Val Val Pro Glu Ile

325 330 335

Glu Leu Lys Asn Ala Lys Gly Leu Ser Asn Glu Ser Val Asn Leu Leu

340 345 350

Lys Ser Arg Leu Glu Glu Leu Ala Lys Lys His Cys Gly Glu Val Met

355 360 365

Ile Phe Glu Leu Ala Tyr His Val Gln Ser Phe Leu Ser Glu His Asn

370 375 380

Lys Pro Pro Pro Lys Ser Phe His Glu Glu Met Leu Glu Arg Arg Ala

385 390 395 400

Gln Glu Glu Gln Gln Arg Leu Leu Glu Ala Lys Arg Lys Glu Glu Gln

405 410 415

Glu Gln Arg Glu Ile Leu His Glu Ile Gln Arg Arg Lys Glu Glu Ile

420 425 430

Lys Glu Glu Lys Lys Arg Lys Glu Met Ala Lys Gln Glu Arg Leu Glu

435 440 445

Ile Ala Ser Leu Ser Asn Gln Asp His Thr Ser Lys Lys Asp Pro Gly

450 455 460

Gly His Arg Thr Ala Ala Ile Leu His Gly Gly Ser Pro Asp Phe Val

465 470 475 480

Gly Asn Gly Lys His Arg Ala Asn Ser Ser Gly Arg Ser Arg Arg Glu

485 490 495

Arg Gln Tyr Ser Val Cys Asn Ser Glu Asp Ser Pro Gly Ser Cys Glu

500 505 510

Ile Leu Tyr Phe Asn Met Gly Ser Pro Asp Gln Leu Met Val His Lys

515 520 525

Gly Lys Cys Ile Gly Asp Glu Gln Leu Gly Lys Leu Val Tyr Asn Ala

530 535 540

Leu Glu Thr Ala Thr Gly Gly Phe Val Leu Leu Tyr Glu Trp Val Leu

545 550 555 560

Gln Trp Gln Lys Lys Met Gly Pro Phe Leu Thr Ser Gln Glu Lys Glu

565 570 575

Lys Ile Asp Lys Cys Lys Lys Gln Ile Gln Gly Thr Glu Thr Glu Phe

580 585 590

Asn Ser Leu Val Lys Leu Ser His Pro Asn Val Val Arg Tyr Leu Ala

595 600 605

Met Asn Leu Lys Glu Gln Asp Asp Ser Ile Val Val Asp Ile Leu Val

610 615 620

Glu His Ile Ser Gly Val Ser Leu Ala Ala His Leu Ser His Ser Gly

625 630 635 640

Pro Ile Pro Val His Gln Leu Arg Arg Tyr Thr Ala Gln Leu Leu Ser

645 650 655

Gly Leu Asp Tyr Leu His Ser Asn Ser Val Val His Lys Val Leu Ser

660 665 670

Ala Ser Asn Val Leu Val Asp Ala Glu Gly Thr Val Lys Ile Thr Asp

675 680 685

Tyr Ser Ile Ser Lys Arg Leu Ala Asp Ile Cys Lys Glu Asp Val Phe

690 695 700

Glu Gln Thr Arg Val Arg Phe Ser Asp Asn Ala Leu Pro Tyr Lys Thr

705 710 715 720

Gly Lys Lys Gly Asp Val Trp Arg Leu Gly Leu Leu Leu Leu Ser Leu

725 730 735

Ser Gln Gly Gln Glu Cys Gly Glu Tyr Pro Val Thr Ile Pro Ser Asp

740 745 750

Leu Pro Ala Asp Phe Gln Asp Phe Leu Lys Lys Cys Val Cys Leu Asp

755 760 765

Asp Lys Glu Arg Trp Ser Pro Gln Gln Leu Leu Lys His Ser Phe Ile

770 775 780

Asn Pro Gln Pro Lys Met Pro Leu Val Glu Gln Ser Pro Glu Asp Ser

785 790 795 800

Gly Gly Gln Asp Tyr Val Glu Thr Val Ile Pro Ser Asn Arg Leu Pro

805 810 815

Ser Ala Ala Phe Phe Ser Glu Thr Gln Arg Gln Phe Ser Arg Tyr Phe

820 825 830

Ile Glu Phe Glu Glu Leu Gln Leu Leu Gly Lys Gly Ala Phe Gly Ala

835 840 845

Val Ile Lys Val Gln Asn Lys Leu Asp Gly Cys Cys Tyr Ala Val Lys

850 855 860

Arg Ile Pro Ile Asn Pro Ala Ser Arg Gln Phe Arg Arg Ile Lys Gly

865 870 875 880

Glu Val Thr Leu Leu Ser Arg Leu His His Glu Asn Ile Val Arg Tyr

885 890 895

Tyr Asn Ala Trp Ile Glu Arg His Glu Arg Pro Ala Gly Pro Gly Thr

900 905 910

Pro Pro Pro Asp Ser Gly Pro Leu Ala Lys Asp Asp Arg Ala Ala Arg

915 920 925

Gly Gln Pro Ala Ser Asp Thr Asp Gly Leu Asp Ser Val Glu Ala Ala

930 935 940

Ala Pro Pro Pro Ile Leu Ser Ser Ser Val Glu Trp Ser Thr Ser Gly

945 950 955 960

Glu Arg Ser Ala Ser Ala Arg Phe Pro Ala Thr Gly Pro Gly Ser Ser

965 970 975

Asp Asp Glu Asp Asp Asp Glu Asp Glu His Gly Gly Val Phe Ser Gln

980 985 990

Ser Phe Leu Pro Ala Ser Asp Ser Glu Ser Asp Ile Ile Phe Asp Asn

995 1000 1005

Glu Asp Glu Asn Ser Lys Ser Gln Asn Gln Asp Glu Asp Cys Asn

1010 1015 1020

Glu Lys Asn Gly Cys His Glu Ser Glu Pro Ser Val Thr Thr Glu

1025 1030 1035

Ala Val His Tyr Leu Tyr Ile Gln Met Glu Tyr Cys Glu Lys Ser

1040 1045 1050

Thr Leu Arg Asp Thr Ile Asp Gln Gly Leu Tyr Arg Asp Thr Val

1055 1060 1065

Arg Leu Trp Arg Leu Phe Arg Glu Ile Leu Asp Gly Leu Ala Tyr

1070 1075 1080

Ile His Glu Lys Gly Met Ile His Arg Asp Leu Lys Pro Val Asn

1085 1090 1095

Ile Phe Leu Asp Ser Asp Asp His Val Lys Ile Gly Asp Phe Gly

1100 1105 1110

Leu Ala Thr Asp His Leu Ala Phe Ser Ala Asp Ser Lys Gln Asp

1115 1120 1125

Asp Gln Thr Gly Asp Leu Ile Lys Ser Asp Pro Ser Gly His Leu

1130 1135 1140

Thr Gly Met Val Gly Thr Ala Leu Tyr Val Ser Pro Glu Val Gln

1145 1150 1155

Gly Ser Thr Lys Ser Ala Tyr Asn Gln Lys Val Asp Leu Phe Ser

1160 1165 1170

Leu Gly Ile Ile Phe Phe Glu Met Ser Tyr His Pro Met Val Thr

1175 1180 1185

Ala Ser Glu Arg Ile Phe Val Leu Asn Gln Leu Arg Asp Pro Thr

1190 1195 1200

Ser Pro Lys Phe Pro Glu Asp Phe Asp Asp Gly Glu His Ala Lys

1205 1210 1215

Gln Lys Ser Val Ile Ser Trp Leu Leu Asn His Asp Pro Ala Lys

1220 1225 1230

Arg Pro Thr Ala Thr Glu Leu Leu Lys Ser Glu Leu Leu Pro Pro

1235 1240 1245

Pro Gln Met Glu Glu Ser Glu Leu His Glu Val Leu His His Thr

1250 1255 1260

Leu Thr Asn Val Asp Gly Lys Ala Tyr Arg Thr Met Met Ala Gln

1265 1270 1275

Ile Phe Ser Gln Arg Ile Ser Pro Ala Ile Asp Tyr Thr Tyr Asp

1280 1285 1290

Ser Asp Ile Leu Lys Gly Asn Phe Ser Ile Arg Thr Ala Lys Met

1295 1300 1305

Gln Gln His Val Cys Glu Thr Ile Ile Arg Ile Phe Lys Arg His

1310 1315 1320

Gly Ala Val Gln Leu Cys Thr Pro Leu Leu Leu Pro Arg Asn Arg

1325 1330 1335

Gln Ile Tyr Glu His Asn Glu Ala Ala Leu Phe Met Asp His Ser

1340 1345 1350

Gly Met Leu Val Met Leu Pro Phe Asp Leu Arg Ile Pro Phe Ala

1355 1360 1365

Arg Tyr Val Ala Arg Asn Asn Ile Leu Asn Leu Lys Arg Tyr Cys

1370 1375 1380

Ile Glu Arg Val Phe Arg Pro Arg Lys Leu Asp Arg Phe His Pro

1385 1390 1395

Lys Glu Leu Leu Glu Cys Ala Phe Asp Ile Val Thr Ser Thr Thr

1400 1405 1410

Asn Ser Phe Leu Pro Thr Ala Glu Ile Ile Tyr Thr Ile Tyr Glu

1415 1420 1425

Ile Ile Gln Glu Phe Pro Ala Leu Gln Glu Arg Asn Tyr Ser Ile

1430 1435 1440

Tyr Leu Asn His Thr Met Leu Leu Lys Ala Ile Leu Leu His Cys

1445 1450 1455

Gly Ile Pro Glu Asp Lys Leu Ser Gln Val Tyr Ile Ile Leu Tyr

1460 1465 1470

Asp Ala Val Thr Glu Lys Leu Thr Arg Arg Glu Val Glu Ala Lys

1475 1480 1485

Phe Cys Asn Leu Ser Leu Ser Ser Asn Ser Leu Cys Arg Leu Tyr

1490 1495 1500

Lys Phe Ile Glu Gln Lys Gly Asp Leu Gln Asp Leu Met Pro Thr

1505 1510 1515

Ile Asn Ser Leu Ile Lys Gln Lys Thr Gly Ile Ala Gln Leu Val

1520 1525 1530

Lys Tyr Gly Leu Lys Asp Leu Glu Glu Val Val Gly Leu Leu Lys

1535 1540 1545

Lys Leu Gly Ile Lys Leu Gln Val Leu Ile Asn Leu Gly Leu Val

1550 1555 1560

Tyr Lys Val Gln Gln His Asn Gly Ile Ile Phe Gln Phe Val Ala

1565 1570 1575

Phe Ile Lys Arg Arg Gln Arg Ala Val Pro Glu Ile Leu Ala Ala

1580 1585 1590

Gly Gly Arg Tyr Asp Leu Leu Ile Pro Gln Phe Arg Gly Pro Gln

1595 1600 1605

Ala Leu Gly Pro Val Pro Thr Ala Ile Gly Val Ser Ile Ala Ile

1610 1615 1620

Asp Lys Ile Ser Ala Ala Val Leu Asn Met Glu Glu Ser Val Thr

1625 1630 1635

Ile Ser Ser Cys Asp Leu Leu Val Val Ser Val Gly Gln Met Ser

1640 1645 1650

Met Ser Arg Ala Ile Asn Leu Thr Gln Lys Leu Trp Thr Ala Gly

1655 1660 1665

Ile Thr Ala Glu Ile Met Tyr Asp Trp Ser Gln Ser Gln Glu Glu

1670 1675 1680

Leu Gln Glu Tyr Cys Arg His His Glu Ile Thr Tyr Val Ala Leu

1685 1690 1695

Val Ser Asp Lys Glu Gly Ser His Val Lys Val Lys Ser Phe Glu

1700 1705 1710

Lys Glu Arg Gln Thr Glu Lys Arg Val Leu Glu Thr Glu Leu Val

1715 1720 1725

Asp His Val Leu Gln Lys Leu Arg Thr Lys Val Thr Asp Glu Arg

1730 1735 1740

Asn Gly Arg Glu Ala Ser Asp Asn Leu Ala Val Gln Asn Leu Lys

1745 1750 1755

Gly Ser Phe Ser Asn Ala Ser Gly Leu Phe Glu Ile His Gly Ala

1760 1765 1770

Thr Val Val Pro Ile Val Ser Val Leu Ala Pro Glu Lys Leu Ser

1775 1780 1785

Ala Ser Thr Arg Arg Arg Tyr Glu Thr Gln Val Gln Thr Arg Leu

1790 1795 1800

Gln Thr Ser Leu Ala Asn Leu His Gln Lys Ser Ser Glu Ile Glu

1805 1810 1815

Ile Leu Ala Val Asp Leu Pro Lys Glu Thr Ile Leu Gln Phe Leu

1820 1825 1830

Ser Leu Glu Trp Asp Ala Asp Glu Gln Ala Phe Asn Thr Thr Val

1835 1840 1845

Lys Gln Leu Leu Ser Arg Leu Pro Lys Gln Arg Tyr Leu Lys Leu

1850 1855 1860

Val Cys Asp Glu Ile Tyr Asn Ile Lys Val Glu Lys Lys Val Ser

1865 1870 1875

Val Leu Phe Leu Tyr Ser Tyr Arg Asp Asp Tyr Tyr Arg Ile Leu

1880 1885 1890

Phe

<210> 2

<211> 779

<212> PRT

<213> Chile person

<400> 2

Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro

1 5 10 15

Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu

20 25 30

Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu

35 40 45

Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys

50 55 60

Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn

65 70 75 80

Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu

85 90 95

Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser

100 105 110

Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu

115 120 125

Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn

130 135 140

Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp

145 150 155 160

Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu

165 170 175

Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr

180 185 190

Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala

195 200 205

Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu Val Pro Arg

210 215 220

Gly Ser Lys Tyr Asp Ser Val Ser Gly Glu Ala Asn Asp Ser Ser Trp

225 230 235 240

Asn Asp Ile Lys Asn Ser Gly Tyr Ile Ser Arg Tyr Leu Thr Asp Phe

245 250 255

Glu Pro Ile Gln Cys Leu Gly Arg Gly Gly Phe Gly Val Val Phe Glu

260 265 270

Ala Lys Asn Lys Val Asp Asp Cys Asn Tyr Ala Ile Lys Arg Ile Arg

275 280 285

Leu Pro Asn Arg Glu Leu Ala Arg Glu Lys Val Met Arg Glu Val Lys

290 295 300

Ala Leu Ala Lys Leu Glu His Pro Gly Ile Val Arg Tyr Phe Asn Ala

305 310 315 320

Trp Leu Glu Ala Pro Pro Glu Lys Trp Gln Glu Lys Met Asp Glu Ile

325 330 335

Trp Leu Lys Asp Glu Ser Thr Asp Trp Pro Leu Ser Ser Pro Ser Pro

340 345 350

Met Asp Ala Pro Ser Val Lys Ile Arg Arg Met Asp Pro Phe Ser Thr

355 360 365

Lys Glu His Ile Glu Ile Ile Ala Pro Ser Pro Gln Arg Ser Arg Ser

370 375 380

Phe Ser Val Gly Ile Ser Cys Asp Gln Thr Ser Ser Ser Glu Ser Gln

385 390 395 400

Phe Ser Pro Leu Glu Phe Ser Gly Met Asp His Glu Asp Ile Ser Glu

405 410 415

Ser Val Asp Ala Ala Tyr Asn Leu Gln Asp Ser Cys Leu Thr Asp Cys

420 425 430

Asp Val Glu Asp Gly Thr Met Asp Gly Asn Asp Glu Gly His Ser Phe

435 440 445

Glu Leu Cys Pro Ser Glu Ala Ser Pro Tyr Val Arg Ser Arg Glu Arg

450 455 460

Thr Ser Ser Ser Ile Val Phe Glu Asp Ser Gly Cys Asp Asn Ala Ser

465 470 475 480

Ser Lys Glu Glu Pro Lys Thr Asn Arg Leu His Ile Gly Asn His Cys

485 490 495

Ala Asn Lys Leu Thr Ala Phe Lys Pro Thr Ser Ser Lys Ser Ser Ser

500 505 510

Glu Ala Thr Leu Ser Ile Ser Pro Pro Arg Pro Thr Thr Leu Ser Leu

515 520 525

Asp Leu Thr Lys Asn Thr Thr Glu Lys Leu Gln Pro Ser Ser Pro Lys

530 535 540

Val Tyr Leu Tyr Ile Gln Met Gln Leu Cys Arg Lys Glu Asn Leu Lys

545 550 555 560

Asp Trp Met Asn Gly Arg Cys Thr Ile Glu Glu Arg Glu Arg Ser Val

565 570 575

Cys Leu His Ile Phe Leu Gln Ile Ala Glu Ala Val Glu Phe Leu His

580 585 590

Ser Lys Gly Leu Met His Arg Asp Leu Lys Pro Ser Asn Ile Phe Phe

595 600 605

Thr Met Asp Asp Val Val Lys Val Gly Asp Phe Gly Leu Val Thr Ala

610 615 620

Met Asp Gln Asp Glu Glu Glu Gln Thr Val Leu Thr Pro Met Pro Ala

625 630 635 640

Tyr Ala Arg His Thr Gly Gln Val Gly Thr Lys Leu Tyr Met Ser Pro

645 650 655

Glu Gln Ile His Gly Asn Ser Tyr Ser His Lys Val Asp Ile Phe Ser

660 665 670

Leu Gly Leu Ile Leu Phe Glu Leu Leu Tyr Pro Phe Ser Thr Gln Met

675 680 685

Glu Arg Val Arg Thr Leu Thr Asp Val Arg Asn Leu Lys Phe Pro Pro

690 695 700

Leu Phe Thr Gln Lys Tyr Pro Cys Glu Tyr Val Met Val Gln Asp Met

705 710 715 720

Leu Ser Pro Ser Pro Met Glu Arg Pro Glu Ala Ile Asn Ile Ile Glu

725 730 735

Asn Ala Val Phe Glu Asp Leu Asp Phe Pro Gly Lys Thr Val Leu Arg

740 745 750

Gln Arg Ser Arg Ser Leu Ser Ser Ser Gly Thr Lys His Ser Arg Gln

755 760 765

Ser Asn Asn Ser His Ser Pro Leu Pro Ser Asn

770 775

Claims

1. A compound represented by formula I:

X ¹ selected from the group consisting of: CH and N;

X ² and X ³ Each independently selected from the group consisting of: n, CH, C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ，

With the proviso that X ² Selected from the group consisting of: CH and N, and X ³ Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；

With the proviso that X ² Selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² And X is ³ Selected from the group consisting of: CH and N;

X ⁴ selected from the group consisting of: CR (computed radiography) ³ And N;

X ¹⁰ selected from the group consisting of: CR (computed radiography) ⁵ And N;

X ¹¹ Selected from the group consisting of: CR (computed radiography) ⁷ And N;

R ¹ selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl,Heterocyclyl, heterocyclylalkyl, aryl, heteroaryl and heteroarylalkyl,

wherein each of the aryl and heteroaryl groups is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of: haloalkyl, alkyl, haloalkoxy, alkoxy, halogen, amine, amide, acyl, alkoxyalkyl, hydroxyl, hydroxyalkyl, cyano, cyanoalkyl and heterocyclyl, and

wherein the heterocyclyl is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl;

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁴ and R is ⁵ Each independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN;

R ⁶ and R is ⁷ Each independently selected from the group consisting of: halogen, H and alkyl;

R ¹³ selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl and heteroarylalkyl,

a is selected from the group consisting of: substituted 5-membered heteroaryl, substituted 6-membered heteroaryl, pyridone and substituted aryl rings;

L ² selected from the group consisting of: a direct bond and an alkyl group, wherein the alkyl group is optionally substituted with (E ²¹ ) _p Substitution;

E ² selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl and heterocyclyl,

wherein the heterocyclyl is optionally substituted one or more occurrences of a substituent independently selected from the group consisting of: alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl;

E ²¹ Independently at each occurrence selected from the group consisting of: H. alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl and halogen; and is also provided with

Each p is independently 0, 1 or 2; with the proviso that the compound is not:

2. a compound represented by formula I-a:

X ³ selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；

X ⁵ Selected from the group consisting of: CR (computed radiography) ⁸ And N;

X ⁶ selected from the group consisting of: CR (computed radiography) ⁹ And N;

X ⁷ selected from the group consisting of: CR (computed radiography) ¹⁰ And N;

X ⁸ selected from the group consisting of: CR (computed radiography) ¹¹ And N;

X ⁹ selected from the group consisting of: CR (computed radiography) ⁸ And N, and the number of the groups,

with the proviso that X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ And X ⁹ Not more than three of them are N;

R ¹ selected from the group consisting of: H. alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl and heteroarylalkyl,

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁸ selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy,Haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxy and CN;

R ⁹ 、R ¹⁰ and R is ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl;

L ² selected from the group consisting of: direct bond and C ₁ -C ₆ Alkyl, wherein C ₁ -C ₆ Alkyl is optionally covered (E) ²¹ ) _p Substitution;

Each p is independently 0, 1 or 2.

3. A compound represented by formula I-B:

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁸ selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxy and CN;

Each p is independently 0, 1 or 2.

4. A compound represented by the formula I-C:

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

Each p is independently 0, 1 or 2.

5. A compound represented by the formula I-D:

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁴ and R is ⁵ Each independently selected from the group consisting of: halogen (halogen)H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN;

E ² selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen sulfonyl, H, alkyl, amine, amide, acyl,Haloalkoxy, haloalkyl and heterocyclyl,

Each p is independently 0, 1 or 2.

6. A compound represented by formulas I-E:

X ² selected from the group consisting of: CH. C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；

R ¹ selected from the group consisting of: H. alkyl (C)Radical, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl and heteroarylalkyl,

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl,Heterocyclylalkyl, aryl, heteroaryl and heteroarylalkyl,

Each p is independently 0, 1 or 2.

7. A compound represented by the formula I-F:

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

Each p is independently 0, 1 or 2.

8. A compound represented by formulas I-G:

R ² Selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ¹² individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, haloalkyl, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl and heterocyclylalkyl;

B is selected from the group consisting of: five membered heteroaryl, six membered heteroaryl and pyridone, wherein the five membered heteroaryl or six membered heteroaryl ring or the pyridone is optionally substituted at each substitutable position by R ¹² Substitution;

E ²¹ independently at each occurrence 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.

9. A compound represented by the formula I-H:

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

Each p is independently 0, 1 or 2.

10. A compound represented by the formula I-J:

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

E ² selected from the group consisting of: hydroxy, alkoxyGroups, alkoxyalkyl groups, cyano groups, halogens, sulfonyl groups, H, alkyl groups, amines, amides, acyl groups, haloalkoxy groups, haloalkyl groups, and heterocyclic groups,

Each p is independently 0, 1 or 2.

11. A compound represented by the formula I-K:

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

Each p is independently 0, 1 or 2.

12. A compound represented by the formula I-L:

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ¹² Individually and independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, haloalkylAlkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl and heterocyclylalkyl;

E ²¹ independently at each occurrence selected from the group consisting of: H. alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, halogenAlkyl, hydroxy, hydroxyalkyl, and halogen; and is also provided with

Each p is independently 0, 1 or 2.

13. A compound represented by the formula I-M:

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

E ² selected from the group consisting of: hydroxy, alkoxy, alkoxyalkyl, cyano, halogen, sulfonyl, HAlkyl, amine, amide, acyl, haloalkoxy, haloalkyl and heterocyclyl,

Each p is independently 0, 1 or 2.

14. A compound represented by the formula I-N:

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁶ selected from the group consisting of: halogen, H and alkyl;

R ⁷ selected from the group consisting of: h and F; r is R ⁸ Selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy and CN;

R ¹⁰ And R is ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl and heteroarylalkyl,

Each p is independently 0, 1 or 2.

15. The compound of claim 14, wherein X ¹¹ Is CR (CR) ⁷ 。

16. The compound of claim 14, wherein X ¹¹ Is N.

17. A compound represented by the formula I-O:

R ² selected from the group consisting of: h and alkyl; r is R ³ Selected from the group consisting of: H. alkyl and halogen;

R ⁶ selected from the group consisting of: halogen, H and alkyl;

R ⁷ selected from the group consisting of: h and F;

R ⁸ selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl, hydroxy and CN;

R ¹⁰ and R is ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl; r is R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl,Cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl and heteroarylalkyl,

Each p is independently 0, 1 or 2.

18. The compound of claim 17, wherein X ¹¹ Is CR (CR) ⁷ 。

19. The compound of claim 17, wherein X ¹¹ Is N.

20. A compound represented by formula I-P:

R ² Selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁶ selected from the group consisting of: halogen, H and alkyl;

R ⁷ selected from the group consisting of: h and F;

R ⁹ 、R ¹⁰ and R ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl;

Each p is independently 0, 1 or 2.

21. The compound of claim 20, wherein X ¹¹ Is CR (CR) ⁷ 。

22. The compound of claim 20, wherein X ¹¹ Is N.

23. A compound represented by the formula I-Q:

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁶ selected from the group consisting of: halogen, H and alkyl;

R ⁷ selected from the group consisting of: h and F;

Each p is independently 0, 1 or 2.

24. The compound of claim 23, wherein X ¹¹ Is CR (CR) ⁷ 。

25. The compound of claim 23, wherein X ¹¹ Is N.

26. A compound represented by formula I:

X ¹ selected from the group consisting of: CH and N；

R ¹ selected from the group consisting of: H. alkyl, (c=o) R ¹³ Alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclylalkyl, aryl, heteroaryl and heteroarylalkyl,

R ² Selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁴ and R is ⁵ Each independently selected from the group consisting of: halogen, halogen,H. Alkoxy, alkylamino, amino, alkyl, haloalkyl and CN;

E ²¹ independently at each occurrence selected from the group consisting of: H. alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkylBase and halogen; and is also provided with

Each p is independently 0, 1 or 2; with the proviso that the compound is not:

27. a compound represented by formula I:

X ¹ selected from the group consisting of: CH and N;

X ² selected from the group consisting of: n, CH, C-O-L ² -E ² And C-L ² -E ² ；

X ³ Is C-N (R) ² )-L ² -E ² ；

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

Each p is independently 0, 1 or 2.

28. A compound represented by formula I:

X ¹ CH;

X ² and X ³ Each independently selected from the group consisting of: n, CH, C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；

R ¹ selected from the group consisting of: H. alkyl group,(C＝O)R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl and heteroarylalkyl,

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

Each p is independently 0, 1 or 2.

29. A compound according to any one of claims 1 to 28, wherein R ¹ Selected from the group consisting of:

is->

30. A compound according to any one of claims 1 to 28, wherein R ¹ Selected from the group consisting of:

is->/>

31. A compound according to any one of claims 1 to 28, wherein R ¹ Selected from the group consisting of: H.

is->

32. A compound according to any one of claims 1 to 28, wherein R ¹ Selected from the group consisting of:

is->

33. A compound according to any one of claims 1 to 28, wherein R ¹ Selected from the group consisting of:

is->

34. The compound of any one of claims 1, 26 or 27, wherein X ¹ Is N.

35. The compound of any one of claims 1, 26 or 27, wherein X ¹ CH.

36. The compound of any one of claims 1 to 5, 8 to 11, or 14 to 20, wherein:

X ² selected from the group consisting of: n and CH; and is also provided with

X ³ Is C-N (R) ² )-L ² -E ² 。

37. The compound of any one of claims 1 to 5, 8 to 11, 14 to 28, or 36, wherein X ³ Is C-N (R) ² )-L ² -E ² 。

38. The compound of claim 37, wherein X ³ Is CN (H) CH ₃ 。

39. The compound of any one of claims 1 to 5, 8 to 11, or 14 to 28, wherein X ² Is N and X ³ For CCH ₃ 。

40. The compound of any one of claims 1, 4 to 7, 10 to 13, or 26 to 28, wherein X ² CH and X ³ Is N.

41. The compound of any one of claims 1, 4 to 7, 10 to 13, 26 to 35, wherein X ² Selected from the group consisting of:

is->

42. The compound according to any one of claims 1 to 5, 8 to 11, 14 to 35, wherein X ³ Selected from the group consisting of:

is->

43. The compound according to any one of claims 1 to 5, 8 to 11, 14 to 37, wherein X ³ Selected from the group consisting of:

is->

44. A compound according to any one of claims 1 to 43, wherein X ⁴ Is CR (CR) ³ 。

45. A compound according to any one of claims 1 to 44, wherein X ¹⁰ Is CR (CR) ⁵ And X is ¹¹ Is CR (CR) ⁷ 。

46. A compound according to any one of claims 1 to 44, wherein X ¹⁰ And X ¹¹ Is N.

47. A compound according to any one of claims 1 to 44, wherein X ¹⁰ Is CR (CR) ⁵ And X is ¹¹ Is N.

48. The compound of claim 44, wherein R ³ Selected from the group consisting of: H. methyl and F.

49. A compound according to any one of claims 1 to 48, wherein R ⁴ And R is ⁵ Each independently selected from the group consisting of: H. f, cl, me, OMe, CF ₃ And CN.

50. A compound according to any one of claims 1 to 49, wherein R ⁶ And R is ⁷ Each independently selected from the group consisting of: H. f, cl, me.

51. A compound according to any one of claims 1 to 49, wherein R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently is H or F, and wherein R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ At least one of which is F.

52. The compound of any one of claims 1 to 51, wherein:

R ⁶ f is the same as F; and is also provided with

R ⁴ 、R ⁵ And R is ⁷ Each is H.

53. The compound of any one of claims 1 to 51, wherein:

R ⁴ f is the same as F; and is also provided with

R ⁵ 、R ⁶ And R is ⁷ Each is H.

54. The compound of any one of claims 1 to 51, wherein:

R ⁴ and R is ⁶ Each is F; and is also provided with

R ⁵ And R is ⁷ Each is H.

55. The compound of any one of claims 1 to 51, wherein:

R ⁴ and R is ⁵ Each is F; and is also provided with

R ⁶ And R is ⁷ Each is H.

56. The compound of any one of claims 1 to 51, wherein:

R ⁵ and R is ⁶ Each is F; and is also provided with

R ⁴ And R is ⁷ Each is H.

57. The compound of any one of claims 1, 8 to 13, or 26 to 56, wherein a or B is selected from the group consisting of:

is->

58. The compound of any one of claims 1, 8 to 13, or 26 to 56, wherein a or B is selected from the group consisting of:

is->

59. The compound of any one of claims 1, or 26 to 56, wherein a is selected from the group consisting of:

60. The compound of any one of claims 1, or 26 to 56, wherein a is selected from the group consisting of:

is->

61. The compound of any one of claims 1, 8 to 13 or 26 to 56, wherein a or B is selected from the group consisting of:

is->

62. The compound of any one of claims 1, 8 to 13, or 26 to 56, wherein a or B is selected from the group consisting of:is->

63. A compound represented by the formula I-R:

X ¹ selected from the group consisting of: CH and N;

X ³ selected from the group consisting of: C-O-L ² -E ² 、C-L ² -E ² And C-N (R) ² )-L ² -E ² ；

R ¹ selected from the group consisting of: alkyl, (c=o) R ¹³ Cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl and heteroarylalkyl,

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁶ selected from the group consisting of: halogen, H and alkyl;

R ⁷ selected from the group consisting of: h and F;

R ¹⁰ and R is ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkylAlkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl;

R ¹⁵ selected from the group consisting of: alkyl, cycloalkyl, and heterocyclyl;

E ²¹ Independently at each occurrence 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.

64. A compound represented by the formula I-S:

X ¹ selected from the group consisting of: CH and N;

R ² Selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁴ and R is ⁵ Each independently selected from the group consisting of: halogen, H,Alkoxy, alkylamino, amino, alkyl, haloalkyl and CN;

R ⁶ selected from the group consisting of: halogen, H and alkyl;

R ⁷ selected from the group consisting of: h and F;

R ¹⁰ and R is ¹¹ Each independently selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl;

each p is independently 0, 1 or 2.

65. A compound represented by the formula I-T:

X ¹ selected from the group consisting of: CH and N;

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁶ Selected from the group consisting of: halogen, H and alkyl;

R ⁷ selected from the group consisting of: h and F;

each p is independently 0, 1 or 2.

66. A compound represented by the formula I-U:

X ¹ selected from the group consisting of: CH and N;

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁵ selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN;

R ⁶ selected from the group consisting of: halogen, H and alkyl;

R ⁷ selected from the group consisting of: h and F;

R ¹¹ selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl;

each p is independently 0, 1 or 2.

67. A compound represented by the formula I-V:

X ¹ selected from the group consisting of: CH and N;

R ¹ selected from the group consisting of: alkyl, (c=o) R ¹³ Cycloalkyl radicalsAlkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl and heteroarylalkyl,

R ² Selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁶ selected from the group consisting of: halogen, H and alkyl;

R ⁷ selected from the group consisting of: h and F;

each p is independently 0, 1 or 2.

68. A compound represented by the formula I-W:

X ¹ selected from the group consisting of: CH and N;

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁶ selected from the group consisting of: halogen, H and alkyl;

R ⁷ selected from the group consisting of: h and F;

R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkyl, heterocyclyl, heterocycloAminoalkyl, aryl, heteroaryl and heteroarylalkyl,

each p is independently 0, 1 or 2.

69. A compound represented by formula I-X:

X ¹ selected from the group consisting of: CH and N;

R ² Selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁵ independently selected from the group consisting of: halogen, H, alkoxy, alkylamino, amino, alkyl, haloalkyl and CN;

R ⁶ selected from the group consisting of: halogen, H and alkyl;

R ⁷ selected from the group consisting of: h and F;

R ¹¹ selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkyl, aminocycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkyloxyA group, cycloalkylamino group, heterocyclic group, alkoxycarbonyl group, and heterocyclylalkyl group;

each p is independently 0, 1 or 2.

70. A compound represented by the formula I-Y:

X ¹ selected from the group consisting of: CH and N;

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁶ selected from the group consisting of: halogen, H and alkyl;

R ¹¹ selected from the group consisting of: hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, amino, aminoalkylAmino cycloalkyl, aminocarbonyl, amido, halogen, cyano, alkoxy, alkylamino, H, cyanoalkyl, alkyl, cycloalkyl, haloalkyl, cycloalkoxy, cycloalkylamino, heterocyclyl, alkoxycarbonyl, and heterocyclylalkyl;

E ²¹ Independently at each occurrence selected from the group consisting of: H. alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkylAnd halogen, and

each p is independently 0, 1 or 2.

71. A compound represented by the formula I-Z:

X ¹ selected from the group consisting of: CH and N;

R ² Selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁶ selected from the group consisting of: halogen, H and alkyl;

R ⁷ selected from the group consisting of: h and F;

E ² selected from the group consisting of: hydroxy, alkoxyAlkyl, cyano, halogen, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl,

each p is independently 0, 1 or 2.

72. A compound represented by formula I-AA:

/>

X ¹ Selected from the group consisting of: CH and N;

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁶ selected from the group consisting of: halogen, H and alkyl;

R ⁷ Selected from the group consisting of: h and F;

each p is independently 0, 1 or 2.

73. A compound represented by the formula I-AB:

X ¹ selected from the group consisting of: CH and N;

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁶ selected from the group consisting of: halogen, H and alkyl;

R ⁷ selected from the group consisting of: h and F;

R ¹³ Selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkyl, cycloalkoxyalkyl, aminoalkylHeterocyclyl, heterocyclylalkyl, aryl, heteroaryl and heteroarylalkyl,

each p is independently 0, 1 or 2.

74. A compound represented by formula I-AC:

X ¹ selected from the group consisting of: CH and N;

R ² Selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁶ selected from the group consisting of: halogen, H and alkyl;

R ⁷ selected from the group consisting of: h and F;

R ⁸ selected from the group consisting of: alkoxy, alkylamino, cycloalkoxy, cycloalkylamino, halogen, H, alkyl, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, hydroxyalkyl, hydroxycycloalkyl,Hydroxyl and CN;

E ²¹ independently at each occurrence selected from the group consisting of: H. alkyl, cycloalkyl, alkoxy, cyanoGroup, cyanoalkyl group, haloalkoxy group, haloalkyl group, hydroxyl group, hydroxyalkyl group, and halogen, and

each p is independently 0, 1 or 2.

75. A compound represented by the formula I-AD:

X ¹ Selected from the group consisting of: CH and N;

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁵ selected from the group consisting of: halogen, H, alkylOxy, alkylamino, amino, alkyl, haloalkyl and CN;

R ⁶ selected from the group consisting of: halogen, H and alkyl;

R ⁷ selected from the group consisting of: h and F;

each p is independently 0, 1 or 2.

76. A compound represented by formula I-AE:

X ¹ selected from the group consisting of: CH and N;

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁶ selected from the group consisting of: halogen, H and alkyl;

R ⁷ selected from the group consisting of: h and F;

each p is independently 0, 1 or 2.

77. A compound represented by the formula I-AF:

X ¹ selected from the group consisting of: CH and N;

R ² Selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁶ selected from the group consisting of: halogen, H and alkyl;

R ⁷ selected from the group consisting of: h and F;

each p is independently 0, 1 or 2.

78. A compound represented by the formula I-AG:

X ¹ Selected from the group consisting of: CH and N;

R ² selected from the group consisting of: h and alkyl;

R ³ selected from the group consisting of: H. alkyl and halogen;

R ⁶ selected from the group consisting of: halogen, H and alkyl;

R ¹³ selected from the group consisting of: H. alkyl, cycloalkyl, alkoxyalkylA cycloalkoxyalkyl group, an aminoalkyl group, a heterocyclyl group, a heterocyclylalkyl group, an aryl group, a heteroaryl group and a heteroarylalkyl group,

each p is independently 0, 1 or 2.

79. The compound of any one of claims 63 to 78, wherein R ¹ Selected from the group consisting of:

is->

80. The compound of any one of claims 63 to 78, wherein R ¹ Selected from the group consisting of:

is->

81. The compound of any one of claims 63 to 78, wherein R ¹ Selected from the group consisting of: H.

is->

82. The compound of any one of claims 63 to 78, wherein R ¹ Selected from the group consisting of:

is->/>

83. The compound of any one of claims 63 to 78, wherein R ¹ Selected from the group consisting of:

is->

84. The compound of any one of claims 63 to 83, wherein X ¹ Is N.

85. The compound of any one of claims 63 to 83, wherein X ¹ CH.

86. The compound of any one of claims 63 to 85, wherein X ³ Is C-N (R) ² )-L ² -E ² 。

87. The compound of claim 86, wherein X ³ Is CN (H) CH ₃ 。

88. The compound of any one of claims 63 to 85An object, wherein X ³ For CCH ₃ 。

89. The compound of any one of claims 63 to 85, wherein X ³ Selected from the group consisting of:

is->

90. The compound of any one of claims 63 to 85, wherein X ³ Selected from the group consisting of:

/>

is->

91. The compound of any one of claims 63 to 68 and 71 to 76, wherein X ¹⁰ Is N and X ¹¹ Is CR (CR) ⁷ 。

92. The compound of any one of claims 63 to 68 and 71 to 76, wherein X ¹⁰ And X ¹¹ Is N.

93. The compound of any one of claims 63 to 68 and 71 to 76, wherein X ¹⁰ Is CR (CR) ⁵ And X is ¹¹ Is N.

94. The compound of any one of claims 63, 68 and 71 to 76, wherein R ³ H, C of a shape of H, C ₁ -C ₆ Alkyl and halogen.

95. The compound of any one of claims 63, 68, 71 to 76 and 94, wherein R ³ H.

96. The compound of any one of claims 63, 68, 71 to 76 and 94, wherein R ³ Me.

97. The compound of any one of claims 63, 68, 71 to 76 and 94, wherein R ³ F.

98. The compound of any one of claims 63, 68, 71 to 76 and 94, wherein R ³ Is Cl.

99. The compound of any one of claims 63 to 65, 71 to 73, and 79 to 98, wherein R ⁴ Selected from the group consisting of: H. f, cl, me, OMe, CF ₃ And CN.

100. The compound of any one of claims 63 to 99, wherein R ⁵ Selected from the group consisting of: H. f, cl, me, OMe, CF ₃ And CN.

101. The compound of any one of claims 63 to 100, wherein R ₆ And R is ₇ Each of which is a single pieceIndependently selected from the group consisting of: H. f, cl, me.

102. The compound of any one of claims 63 to 101, wherein R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ Each independently is H or F, and wherein R ⁴ 、R ⁵ 、R ⁶ And R is ⁷ At least one of which is F.

103. The compound of any one of claims 63 to 65, 71 to 73, and 79 to 102, wherein:

R ⁶ f is the same as F; and is also provided with

R ⁴ 、R ⁵ And R is ⁷ Each is H.

104. The compound of any one of claims 63 to 102, wherein:

R ⁴ f is the same as F; and is also provided with

R ⁵ 、R ⁶ And R is ⁷ Each is H.

105. The compound of any one of claims 63 to 102, wherein:

R ⁴ and R is ⁶ Each is F; and is also provided with

R ⁵ And R is ⁷ Each is H.

106. The compound of any one of claims 63 to 102, wherein:

R ⁴ and R is ⁵ Each is F; and is also provided with

R ⁶ And R is ⁷ Each is H.

107. The compound of any one of claims 63 to 65, 71 to 73, and 79 to 102, wherein:

R ⁵ and R is ⁶ Each is F; and is also provided with

R ⁴ And R is ⁷ Each is H.

108. Such as weightThe compound of any one of claims 63 to 107, wherein R ¹⁵ Selected from the group consisting of: c (C) ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl and C ₃ -C ₆ A heterocyclic group.

109. The compound of any one of claims 63 to 108, wherein R ¹⁵ Is cyclopropyl.

110. The compound of any one of claims 63 to 108, wherein R ¹⁵ Me.

111. The compound of any one of claims 63 to 108, wherein R ¹⁵ Is an oxetanyl group.

112. The compound of any one of claims 63 to 108, wherein R ¹⁵ Is oxetan-2-yl.

113. The compound of any one of claims 63 to 108, wherein R ¹⁵ Is oxetan-3-yl.

114. A compound selected from the group consisting of:

/>

115. A pharmaceutical composition comprising a compound of any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

116. A method of treating a disease caused by dysregulation of integrated stress and/or unfolded protein responses in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 115.

117. The method of claim 116, wherein the deregulation of the integrated stress response and/or unfolded protein response is caused by a kinase selected from the group consisting of: PERK kinase and GCN2 kinase.

118. The method of claim 116 or 117, wherein the deregulation of the integrated stress response and/or the unfolded protein response is caused by GCN2 kinase.

119. The method of claim 116 or 117, wherein the deregulation of the integrated stress response and/or the unfolded protein response is caused by a PERK kinase.

120. A method of modulating GCN2 kinase activity in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 115.

121. A method of activating GCN2 kinase in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 115.

122. A method of modulating PERK kinase activity in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 115.

123. A method of activating a PERK kinase in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 115.

124. A method of inhibiting GCN2 kinase in a patient in need thereof and inhibiting PERK kinase in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 115.

125. A method of inhibiting GCN2 kinase activity in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-114, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 115.

126. A method of inhibiting PERK kinase activity in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 115.

127. A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 115.

128. The method of claim 126, wherein the cancer is selected from the group consisting of: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenum cancer, small intestine 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, hematological cancer, leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocyte lymphoma, fahrenheit macroglobulinemia, light chain amyloidosis and malignant lymphoma.

129. The method of claim 127 or 128, wherein the cancer is leukemia.

130. The method of claim 127 or 128, wherein the cancer is acute myelogenous leukemia.

131. The method of claim 127 or 128, wherein the cancer is acute lymphoblastic leukemia.

132. The method of claim 127 or 128, wherein the cancer is fibrosarcoma.

133. The method of claim 127 or 128, wherein the cancer is multiple myeloma.

134. The method of claim 127 or 128, wherein the cancer is lymphoma.

135. The method of claim 127 or 128, wherein the cancer is a B-cell lymphoma.

136. The method of claim 127 or 128, wherein the cancer is a T cell lymphoma.

137. A method of treating an amyloidosis in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 115.

138. A method of treating light chain amyloidosis in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 115.

139. A method of treating a disease selected from a GCN 2-related disease and a PERK-related disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 115.

140. The method of claim 139, wherein the disorder is a GCN 2-associated disorder.

141. The method of claim 139, wherein the disorder is a PERK-related disorder.

142. The method of any one of claims 139-141, wherein the disease is cancer.

143. The method of claim 142, wherein the cancer is selected from the group consisting of: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenum cancer, small intestine 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, hematological cancer, leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocyte lymphoma, fahrenheit macroglobulinemia, and malignant lymphoma.

144. The method of claim 142 or 143, wherein the cancer is leukemia.

145. The method of claim 142 or 143, wherein the cancer is acute myelogenous leukemia.

146. The method of claim 142 or 143, wherein the cancer is acute lymphoblastic leukemia.

147. The method of claim 142 or 143, wherein the cancer is fibrosarcoma.

148. The method of claim 142 or 143, wherein the cancer is multiple myeloma.

149. The method of claim 142 or 143, wherein the cancer is lymphoma.

150. The method of claim 142 or 143, wherein the cancer is a B-cell lymphoma.

151. The method of claim 142 or 143, wherein the cancer is a T cell lymphoma.

152. The method of claim 139, wherein the disease is an amyloidosis.

153. The method of claim 139, wherein the disease is light chain amyloidosis.

154. A method of treating a disease selected from a GCN 2-related disease and a PERK-related disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more therapeutic agents.

155. The method of claim 154, wherein the disease is a GCN2 associated disease.

156. The method of claim 154, wherein the disorder is a PERK-related disorder.

157. The method of any one of claims 154-156, wherein the disease is cancer.

158. The method of claim 157, wherein the cancer is selected from the group consisting of: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenum cancer, small intestine 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, hematological cancer, leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocyte lymphoma, fahrenheit macroglobulinemia, light chain amyloidosis and malignant lymphoma.

159. The method of claim 157 or 158, wherein the cancer is leukemia.

160. The method of claim 157 or 158, wherein the leukemia is acute myelogenous leukemia.

161. The method of claim 157 or 158, wherein the leukemia is acute lymphoblastic leukemia.

162. The method of claim 157 or 158, wherein the cancer is fibrosarcoma.

163. The method of claim 157 or 158, wherein the cancer is multiple myeloma.

164. The method of claim 157 or 158, wherein the cancer is lymphoma.

165. The method of claim 157 or 158, wherein the cancer is a B-cell lymphoma.

166. The method of claim 157 or 158, wherein the cancer is a T cell lymphoma.

167. The method of claim 154, wherein the disease is an amyloidosis.

168. The method of claim 154, wherein the disease is light chain amyloidosis.

169. The method of any one of claims 154-168, wherein the one or more therapeutic agents are selected from the group consisting of: an IMiD agent, proteasome inhibitor, steroid, anti-CD 38 agent, anti-CD 20 agent, bcl-2 inhibitor, PI3K inhibitor, bispecific antibody, nucleoside analog, BTK inhibitor, DNA alkylating agent, EZH2 inhibitor, anthracycline, topoisomerase inhibitor, platinum, tyrosine kinase inhibitor, HDAC inhibitor, nuclear export inhibitor, anti-microtubule agent, L-asparaginase, pegylated asparaginase, PERK inhibitor, mTOR inhibitor, immunomodulator, MAPK pathway inhibitor, MEK inhibitor, ERK inhibitor, and Ras inhibitor.

170. The method of any one of claims 154-168, wherein the one or more therapeutic agents are selected from the group consisting of: l-asparaginase, pergolase, pego-karman-mknl, bortezomib, carfilzomib, E Sha Zuomi, thalidomide, pomalidomide, lenalidomide, dexamethasone, prednisone, darumab, darimab hyaluronidase, ai Satuo ximab, rituximab, atozumab, valinab, etalaro, idola, kubane, du Weili sibirica, erbutin, gemcitabine, cytarabine, ibrutinib, acartinib, zebutin, bendamustine, cyclophosphamide, tazizanol, doxorubicin, daunomycin, etoposide, oxaliplatin, carboplatin, cisplatin Su Tini, dasatinib, imatinib, platinib, panoramide, li Nisuo, neomycin, JZP-458, erythrocyte-encapsulated L-asparaginase, CTLE, and PDE (PDE), anti-PDE, E, and anti-PDK 1, anti-HIV agents (PDF, PDF 1).

171. A compound according to any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 115, for use in the treatment of a disease caused by dysregulation of an integrated stress response and/or an unfolded protein response in a patient in need thereof.

172. The use of claim 171, wherein said disorder of said integrated stress response and/or unfolded protein response is caused by a kinase selected from the group consisting of: PERK kinase and GCN2 kinase.

173. The use of claim 171 or 172, wherein said disorder of said integrated stress response and/or said unfolded protein response is caused by GCN2 kinase.

174. The use of claim 171 or 172, wherein the deregulation of the integrated stress response and/or the unfolded protein response is caused by a PERK kinase.

175. A compound according to any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 115, for use in modulating GCN2 kinase activity in a patient in need thereof.

176. A compound according to any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 115, for use in activating GCN2 kinase in a patient in need thereof.

177. A compound according to any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 115, for use in modulating the activity of PERK kinase in a patient in need thereof.

178. A compound according to any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 115, for use in activating PERK kinase in a patient in need thereof.

179. The compound of any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 115, for use in inhibiting GCN2 kinase and inhibiting PERK kinase in a patient in need thereof.

180. A compound according to any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 115, for use in modulating GCN2 kinase activity in a patient in need thereof.

181. A compound according to any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 115, for use in inhibiting the activity of PERK kinase in a patient in need thereof.

182. A compound according to any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 115, for use in the treatment of cancer in a patient in need thereof.

183. The use of claim 182, wherein the cancer is selected from the group consisting of: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenum cancer, small intestine 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, hematological cancer, leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocyte lymphoma, fahrenheit macroglobulinemia, and malignant lymphoma.

184. The use of claim 182 or 183, wherein the cancer is leukemia.

185. The use of claim 182 or 183, wherein the cancer is acute myelogenous leukemia.

186. The use of claim 182 or 183, wherein the cancer is acute lymphoblastic leukemia.

187. The use of claim 182 or 183, wherein the cancer is fibrosarcoma.

188. The use of claim 182 or 183, wherein the cancer is multiple myeloma.

189. The use of claim 182 or 183, wherein the cancer is lymphoma.

190. The use of claim 182 or 183, wherein the cancer is a B-cell lymphoma.

191. The use of claim 182 or 183, wherein the cancer is a T cell lymphoma.

192. A compound according to any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 115, for use in the treatment of amyloidosis in a patient in need thereof.

193. A compound according to any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 115, for use in the treatment of light chain amyloidosis in a patient in need thereof.

194. A compound according to any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 115, for use in the treatment of a disease selected from GCN 2-related disease and PERK-related disease in a patient in need thereof.

195. The use of claim 194, wherein the disease is a GCN 2-associated disease.

196. The use of claim 194, wherein the disorder is a PERK-related disorder.

197. The use of any one of claims 194-196, wherein the disease is cancer.

198. The use of claim 197, wherein the cancer is selected from the group consisting of: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenum cancer, small intestine 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, hematological cancer, leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocyte lymphoma, fahrenheit macroglobulinemia, and malignant lymphoma.

199. The use of claim 197 or 198, wherein the cancer is leukemia.

200. The use of claim 197 or 198, wherein the cancer is acute myelogenous leukemia.

201. The use of claim 197 or 198, wherein the cancer is acute lymphoblastic leukemia.

202. The use of claim 197 or 198, wherein the cancer is fibrosarcoma.

203. The method of claim 197 or 198, wherein the cancer is multiple myeloma.

204. The method of claim 197 or 198, wherein the cancer is lymphoma.

205. The method of claim 197 or 198, wherein the cancer is a B-cell lymphoma.

206. The method of claim 197 or 198, wherein the cancer is a T cell lymphoma.

207. The use of claim 194, wherein the disease is an amyloidosis.

208. The use of claim 194, wherein the disease is light chain amyloidosis.

209. A compound according to any one of claims 1 to 114, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 115, for use in the treatment of a disease selected from GCN 2-related disease and PERK-related disease in a patient in need thereof.

210. The use of claim 209, wherein the disease is a GCN 2-associated disease.

211. The use of claim 209, wherein the disease is a PERK-related disease.

212. The use of any one of claims 209 to 211, wherein the disease is cancer.

213. The use of claim 212, wherein the cancer is selected from the group consisting of: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenum cancer, small intestine 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, hematological cancer, leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocyte lymphoma, fahrenheit macroglobulinemia, and malignant lymphoma.

214. The use of claim 212 or 213, wherein the cancer is leukemia.

215. The use of claim 212 or 213, wherein the leukemia is acute myelogenous leukemia.

216. The use of claim 212 or 213, wherein the leukemia is acute lymphoblastic leukemia.

217. The use of claim 212 or 213, wherein the cancer is fibrosarcoma.

218. The method of claim 212 or 213, wherein the cancer is multiple myeloma.

219. The method of claim 212 or 213, wherein the cancer is lymphoma.

220. The method of claim 212 or 213, wherein the cancer is a B-cell lymphoma.

221. The method of claim 212 or 213, wherein the cancer is a T cell lymphoma.

222. The use of claim 209, wherein the disease is an amyloidosis.

223. The method of claim 209, wherein the disease is light chain amyloidosis.

224. The use of any one of claims 209 to 223, wherein the one or more therapeutic agents are selected from the group consisting of: an IMiD agent, proteasome inhibitor, steroid, anti-CD 38 agent, anti-CD 20 agent, bcl-2 inhibitor, PI3K inhibitor, bispecific antibody, nucleoside analog, BTK inhibitor, DNA alkylating agent, EZH2 inhibitor, anthracycline, topoisomerase inhibitor, platinum, tyrosine kinase inhibitor, HDAC inhibitor, nuclear export inhibitor, anti-microtubule agent, L-asparaginase, pegylated asparaginase, PERK inhibitor, mTOR inhibitor, immunomodulator, MAPK pathway inhibitor, MEK inhibitor, ERK inhibitor, and Ras inhibitor.

225. The use of any one of claims 209 to 223, wherein the one or more therapeutic agents are selected from the group consisting of: l-asparaginase, peganase, pego-karhunen-mknl, bortezomib, carfilzomib, E Sha Zuomi, thalidomide, pomalidomide, lenalidomide, dexamethasone, prednisone, darifenacin/hyaluronidase, ai Satuo ximab, rituximab, atorvastatin, valvulgare, edalargil, idola, copanex, du Weili sibutriclib, erbitux, gemcitabine, cytarabine, ibrutinib, acartinib, bustinib, bendamustine, cyclophosphamide, tazistat, doxorubicin, daunorubicin, etoposide, oxaliplatin, carboplatin, cisplatin-bo Su Tini, dasatinib, imatinib, nilotinib, plaitinib, panobinostat, plug Li Nisuo, vincristine, JZP-458, erythrocyte-encapsulated L-asparaginase, PF745 (JZP-341), asparaginase erwinia chrysanthemi (kretase), escherichia coli asparaginase (clapase), anti-PD 1 agents, anti-PDL 1 agents and anti-CTLA 4 agents.