GCN2 and PERK kinase modulators and methods of use thereof

Abstract

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

Description

Cross-references

[0001] This application claims priority to U.S. Provisional Application No. 63 / 504,801, filed May 30, 2023, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0002] Cancer cells require a constant supply of nutrients to sustain their abnormal growth and rapid division. Among these nutrients, amino acids are crucial for supporting the high metabolic demands of tumor cells.

[0003] General control nonderepressible protein 2 (GCN2) is a serine / threonine protein kinase and one of the eukaryotic initiation factor 2α (eIF2α) kinases, which is a major regulator of the integrated stress response (ISR). ISR is essential for maintaining cellular homeostasis under various stressors and is activated when cells adapt to stress conditions such as hypoxia and amino acid deprivation. ISR is regulated by phosphorylation and activation of eIF2α kinases, including GCN2, which act as early responders to disturbances in cellular homeostasis. Besides GCN2, three other families of eIF2α kinases exist: PKR-like ER kinase (PERK), double-stranded RNA-dependent protein kinase (PKR), and heme-regulated eIF2α kinase (HRI). All four eIF2α kinases share broad homology in their kinase catalytic domains but have distinct regulatory domains. Each IF2α kinase responds to different environmental and physiological stresses, reflecting its unique regulatory mechanism. PERK kinase is activated under stress conditions including ATP depletion and unfolded protein responses, and like GCN2, PERK kinase activation leads to the upregulation of the key ISR transcription factor ATF4.

[0004] Under conditions of essential amino acid restriction or other stressors (UV irradiation, redox stress, or proteasome inhibition), GCN2 phosphorylates eIF2α, which inhibits the formation of novel ternary complexes and thus suppresses mRNA translation initiation. While reducing overall mRNA translation, eIF2α phosphorylation also increases the translation of the ISR transcription factor ATF4 in tumor cells, which increases the expression of many stress-responsive genes, including those specifically supplying amino acids to tumor cells. Right now ATF4 is an amino acid synthase and a transporter that mediates the influx of amino acids into tumor cells. Overexpression of ATF4 in both solid and liquid tumors in humans suggests a crucial role in tumor progression.

[0005] Asparagine is an important amino acid involved in several biosynthetic pathways that can significantly influence carcinogenesis and tumor biology. All cells require asparagine for their protein synthesis and growth. Normal cells obtain most of their required asparagine through internal synthesis. Compared to normal cells, cancer cells require much higher levels of asparagine for growth and proliferation, cannot produce the necessary amount themselves, and must rely on circulating asparagine for survival. Asparagine synthase (ASNS) catalyzes the synthesis of asparagine from aspartate and glutamine. L-asparaginase (ASNase) removes circulating asparagine, thereby depriving cancer cells of a critical nutrient and causing their death. The use of L-asparaginase represents the first instance of anticancer therapy targeting specific metabolic features of tumors and is a well-established treatment for childhood acute lymphoblastic leukemia (ALL), although its toxicity limits its use outside this patient population. ASNS expression is particularly low in many ALL cell lines compared to normal cells, making asparagine depletion an effective treatment, attributed to the cells' aberrant dependence on circulating serum asparagine as an essential nutrient for growth. Adverse reactions to asparaginase are associated with an increased risk of recurrence. Other hematologic and solid cancers express low levels of ASNS and are therefore likely asparagine auxotrophs and asparaginase-sensitive. Conversely, in some cancer types, ASNS overexpression promotes cell proliferation, chemoresistance, and metastatic behavior. In the case of asparaginase-resistant cancers, the depletion of hematologic asparagine via L-asparaginase leads to significant ASNS overexpression as a compensatory mechanism, effectively negating the effects of chemotherapeutic drugs. Numerous studies have shown that ASNS is central to the cellular response to amino acid deprivation and other forms of cellular stress. Through transcriptional regulation, ASNS genes are targets of two signaling pathways designed to ensure cell survival. The first pathway, called the amino acid response (AAR), is activated by GCN2 kinase under conditions of amino acid availability imbalance. The second pathway, called the unfolded protein response (UPR), is activated by PERK kinase under conditions of increased endoplasmic reticulum stress. The AAR and UPR pathways converge on eIF2α phosphorylation, leading to a reduction in overall protein synthesis and simultaneously resulting in the preferential translation of a selected population of mRNAs, including the translation factor ATF4. ATF4 is the main factor in ASNS induction, and it functions as a trans-activator via an enhancer element bound to the ASNS promoter.

[0006] GCN2, both in vitro and in vivo, sensitizes cancer cells with low basal ASNS expression to the antileukemic drug L-asparaginase. Treatment with GCN2 inhibitors sensitizes acute lymphoblastic leukemia (ALL) cells to L-asparaginase by preventing ASNS induction. GCN2 inhibitors and L-asparaginase exhibit synergistic antiproliferative effects in ASN-deficient / low-grade cancers. Therefore, combination therapy with GCN2 inhibitors and L-asparaginase shows promise for improved outcomes in ALL and other cancer types. ALL, acute myeloid leukemia (AML), and pancreatic cancer cells are particularly sensitive to combination therapy with L-asparaginase and GCN2 inhibitors. Previous reports have demonstrated robust antitumor activity in ALL, AML, and pancreatic cancer cells compared to monotherapy with either L-asparaginase or GCN2 inhibitors. Therefore, GCN2 inhibitors can represent sensitizers for treating L-asparaginase in these tumors. In summary, GCN2 inhibition enhances sensitivity to L-asparaginase therapy by preventing ASNS induction in cancer cells with low basal ASNS expression.

[0007] GCN2 inhibition could also be an effective strategy for targeting the tumor microenvironment, including the immune system, such as tryptophan-dependent immune surveillance of tumor cells.

[0008] The tumor microenvironment [TME; a series of extracellular components and stromal cells surrounding tumor cells (endothelial cells, cancer-associated fibroblasts, tumor-associated macrophages, tumor-infiltrating T cells)] is characterized by a lack of oxygen and key nutrients (such as glucose and amino acids), resulting in an overall immunosuppressive environment.

[0009] Many tumors evolve to evade immune surveillance by utilizing their metabolic flexibility and redirecting nutrients for their own benefit. Stromal cells and bone marrow-derived suppressor cells (MDSCs) within tumors create a malnourished environment that suppresses immune function and supports tumor growth.

[0010] Increased tryptophan catabolism (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 cellularly driven by the tumor microenvironment, creating an immunosuppressive microenvironment in various cancer types. Local tryptophan depletion is considered a key T-cell immunosuppressive mechanism. In T cells, GCN2 kinase has been identified as a molecular sensor for tryptophan deprivation. Activation of GCN2 through tryptophan depletion 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.

[0011] The GCN2 pathway is not only important for tumor immune escape but also plays an active role in regulating other aspects of the tumor microenvironment. GCN2 attenuation has been shown to prevent amino acid deprivation (AAD)-induced expression of vascular endothelial growth factor (VEGF), which tumors utilize to enhance nutrient supply through increased angiogenesis. Therefore, activation of the GCN2 / ATF4 pathway promotes tumor growth and angiogenesis via AAD-mediated VEGF expression. Elimination of ATF4 or GCN2 expression significantly inhibits tumor growth in vivo.

[0012] Therefore, selective inhibition of GCN2 can increase immune system activity and reduce angiogenesis in the tumor microenvironment. The GCN2-eIF2α-ATF4 pathway is crucial for maintaining metabolic homeostasis of tumor cells under stress and for maintaining the immunosuppressive immune cell microenvironment. The PERK-ATF4 pathway is also crucial for maintaining tumor cell homeostasis under stress. It has been reported that both the GCN2 and PERK signaling pathways are subject to crosstalk regulation, allowing GCN2 inhibition to activate PERK as a compensatory mechanism. vice versa In other words, inhibiting PERK can activate GCN2 as a compensatory mechanism.

[0013] We need regulators of GCN2 and / or PERK that modulate the pro-tumorigenic aspects of GCN2 and / or PERK in both the tumor cell (tumor cell autonomous) and tumor immune cell microenvironment. Summary of the Invention

[0014] This article describes regulation ( For example Compounds that generally control (inhibit or activate) repressor protein 2 (GCN2) kinase and / or PKR-like ER kinase (PERK) kinase and their use in treating conditions, including GCN2 or PERK-related diseases.

[0015] In one embodiment, this document describes a compound represented by formula IA: Formula IA Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 and X 4 Each is independently selected from the following groups: CH and N; X 2 Selected from the following groups: C and N; X 3 Selected from the following group: CR 4 and NR 4 As long as X 1 X 2 X 3 and X 4 The number of elements in the range is no more than two, N; X5 Selected from the following group: CR 5 and N;R 1 and R 2 Each is independently selected from the following group: H, alkoxy, alkyl, cyano, haloalkoxy, haloalkyl, and halogen; R 3 Selected from the following groups: H, alkyl, alkoxy, cyano, and halogen; R 4 Selected from the following group: H, alkyl, alkenyl, alkenylalkyl, ynyl, ynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclic, heterocyclic, aryl, heteroaryl, and heteroarylalkyl; R 5 Selected from the following group: H, hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, aminoalkyl, aminocycloalkyl, aminocarbonyl, acylamino, acyloxyalkyl, hydroxyimino, alkoxyimino, alkylamino, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxycarbonyl, and heterocyclic alkyl; R 6 R 7 and R 8 Each is independently selected from the group consisting of: H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl; and R. 9 Selected from the group consisting of: H, halogens, and alkyl groups; provided that: i) X 2 When it is C, Not for , where R 6 Selected from the following group: halogens, alkoxy groups, and alkyl groups; R 8 Selected from the following group: H, halogens and alkyl groups; and R 10 Selected from the following group: H, alkyl, and acyl; ii) when X 2 For C and X 3 For NR 4 hour, Not for , where R 6 For H; R 7 Selected from the following groups: H, Cl, and OCH3; R 8 For H or Br; and R 9 For H; and iii) when X 2 For C and X 3 For NR 4 hour, Not for Where R 5 Selected from the following groups: H, F, Cl, CH3, OCH3, CF3, and CN; R 6 For H or F; R 7Selected from the following groups: H, F, Cl, Br, I, CH3, OCH3, OCH2CH3, OCH(CH3)2, CF3, OH, and OCF3; R 8 Selected from the following groups: H, F, Cl, CH3, OCH3, CF3, and CN; and R 9 It can be H or F.

[0016] In another embodiment, a pharmaceutical composition is described herein comprising the compounds described herein ( example like The compounds of formulas IA, IB, IC, ID, IE, IF and IG described herein, or their pharmaceutically acceptable salts, enantiomers, stereoisomers or tautomers, and pharmaceutically acceptable carriers or excipients.

[0017] In another embodiment, a method described herein for treating a patient with a condition resulting from an integrated stress response disorder is described, comprising administering to the patient a therapeutically effective amount of the compound described herein. For example The pharmaceutical composition described herein may be a compound of formula IA, IB, IC, ID, IE, IF, or IG, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0018] In another embodiment, a method described herein for treating a patient with a condition resulting from dysregulation of the integrated stress response and / or unfolded protein response is described, comprising administering to the patient a therapeutically effective amount of the compound described herein. For example The pharmaceutical composition described herein may be a compound of formula IA, IB, IC, ID, IE, IF, or IG, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0019] In another embodiment, a method for modulating the activity of GCN2 kinase in a patient with this need is described herein, comprising administering to the patient a therapeutically effective amount of the compound described herein. For example The pharmaceutical composition described herein may be a compound of formula IA, IB, IC, ID, IE, IF, or IG, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0020] In another embodiment, a method for activating GCN2 kinase in a patient requiring this function is described herein, comprising administering to the patient a therapeutically effective amount of the compound described herein. For example The pharmaceutical composition described herein may be a compound of formula IA, IB, IC, ID, IE, IF, or IG, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0021] In another embodiment, a method for modulating the activity of PERK kinase in a patient with this need is described herein, comprising administering to the patient a therapeutically effective amount of the compound described herein. For example The pharmaceutical composition described herein may be a compound of formula IA, IB, IC, ID, IE, IF, or IG, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0022] In another embodiment, a method for activating PERK kinase in a patient requiring this function is described herein, comprising administering to the patient a therapeutically effective amount of the compound described herein. For example The pharmaceutical composition described herein may be a compound of formula IA, IB, IC, ID, IE, IF, or IG, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0023] In another embodiment, this document describes a method for inhibiting GCN2 kinase in a patient with this need and a method for inhibiting PERK kinase in a patient with this need, comprising administering to the patient a therapeutically effective amount of the compound described herein. example like The pharmaceutical composition described herein may be a compound of formula IA, IB, IC, ID, IE, IF, or IG, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0024] In another embodiment, a method for inhibiting the activity of GCN2 kinase in a patient with this need is described herein, comprising administering to the patient a therapeutically effective amount of the compound described herein. For example The pharmaceutical composition described herein may be a compound of formula IA, IB, IC, ID, IE, IF, or IG, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0025] In another embodiment, a method for inhibiting the activity of PERK kinase in a patient with this need is described herein, comprising administering to the patient a therapeutically effective amount of the compound described herein. For example The pharmaceutical composition described herein may be a compound of formula IA, IB, IC, ID, IE, IF, or IG, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0026] In another embodiment, a method of treating a patient with a condition selected from GCN2-related diseases and PERK-related diseases is described herein, comprising administering to the patient a therapeutically effective amount of the compound described herein. example likeThe pharmaceutical composition described herein may be a compound of formula IA, IB, IC, ID, IE, IF, or IG, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0027] In another embodiment, a method of treating a patient with a condition selected from GCN2-related diseases and PERK-related diseases is described herein, comprising administering to the patient a therapeutically effective amount of the compound described herein. example like The compound of formula IA, IB, IC, ID, IE, IF and IG described herein) or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more therapeutic agents.

[0028] In another embodiment, a method of treating cancer in a patient with this need is described herein, comprising administering to the patient a therapeutically effective amount of the compound described herein. For example The pharmaceutical composition described herein may be a compound of formula IA, IB, IC, ID, IE, IF, or IG, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0029] In another embodiment, this document describes a method for treating a patient with a condition selected from the group consisting of: melanoma, fibrosarcoma, thyroid cancer, ovarian cancer, colorectal cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumors, solid tumors, hematogenous cancers, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and other cancers caused by activation of the GCN2 signaling pathway, comprising administering to the patient a therapeutically effective amount of the compound described herein. For example The pharmaceutical composition described herein may be a compound of formula IA, IB, IC, ID, IE, IF, or IG, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. Detailed Implementation

[0030] Features and other details of the invention are described more specifically below. Certain terms used in this specification, examples, and appended claims are collected herein. These definitions should be read in accordance with the remainder of this disclosure and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0031] definition The definitions set forth in this application are intended to clarify the terminology used throughout this application.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Unless otherwise stated, the following terms have the meanings assigned to facilitate understanding of this disclosure as used in the specification and appended claims.

[0033] When a bond to a substituent is shown to cross with a bond between two atoms in the connecting ring, such a substituent may bond to any atom in that ring. When the listed substituents do not indicate that such a substituent is bonded to atoms in the remainder of the compound of the specified chemical formula, such a substituent may bond via any atom of such a substituent. Such combinations are permitted when a combination of substituents, substituent positions, and / or variations results in a stable compound.

[0034] As used herein, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” include plural references.

[0035] As used herein, the term "this article" refers to the entire application.

[0036] As used herein, “deuteration” means that at least one hydrogen atom is substituted with deuterium. In any sample of a deuterated compound, some discrete molecules of the compound may have hydrogen instead of deuterium at a specified position. However, the percentage of molecules in a deuterated compound having deuterium at a specified position will be much greater than in naturally occurring compounds. Deuterium is enriched at the deuterated position.

[0037] As used herein, the terms “optionally” or “optionally” mean that the event or situation described below may or may not occur, and the description includes examples of the event or situation occurring and examples of its non-occurrence. For example, “optionally substituted alkyl” means both cases where the alkyl group is substituted and cases where the alkyl group is not substituted.

[0038] It should be understood that those skilled in the art can select the substituents and substitution modes of the disclosed compounds to produce chemically stable compounds that can be readily synthesized from readily available starting materials using techniques known in the art and the methods described below. If a substituent is itself substituted by more than one group, it should be understood that such multiple groups may be on the same carbon or on different carbons, as long as a stable structure is produced.

[0039] As used herein, the term "optionally substituted" means that one to six hydrogen atoms in a given structure are substituted with a specific substituent group, including but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, aryl, cycloalkyl, heterocyclic, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, and -OC(=O)-CH2-O alkyl. Preferably, "optionally substituted" means that one to four hydrogen atoms in a given structure are substituted with the substituents mentioned above. More preferably, one to three hydrogen atoms are substituted with the substituents mentioned above. It should be understood that the substituents may be further substituted.

[0040] As used herein, the term “substituted” refers to a portion of the main chain having a substituent with a hydrogen-substituted group on one or more carbons. It should be understood that “substituted” or “substituted” includes the implicit limitation that such substitution conforms to the permissible valence of the substituted atom and substituent, and that the substitution produces a stable compound, for example, one that does not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, or other reactions. As used herein, the term “substituted” is considered to include all permissible substituents in organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. For suitable organic compounds, permissible substituents may be one or more and may be the same or different. For the purposes of this application, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents in organic compounds that satisfy the heteroatom valence as described herein.

[0041] Substituents may include any substituents described herein, such as halogens, hydroxyl groups, carbonyl groups (such as carboxyl, alkoxycarbonyl, formyl, or acyl), alkoxy groups, amino groups, amide groups, imine groups, cyano groups, sulfonyl groups, heterocyclic groups, aralkyl groups, heteroaralkyl groups, or aromatic or heteroaromatic moieties, unless otherwise specified. Those skilled in the art will understand that substituents themselves may be substituted where appropriate. For example, substituents of substituted alkyl groups may include substituted and unsubstituted forms of amino, amide, sulfonyl groups, and ethers, carboxyl groups (including carboxylates and esters), -CF3, -CN, etc. Unless specifically stated as "unsubstituted," references to the chemical part herein should be understood to include substituted variants. For example, references to the "aryl" group or part thereof implicitly include substituted variants as well as unsubstituted variants.

[0042] As used herein, the term "alkyl" refers to a fully saturated straight-chain or branched non-aromatic hydrocarbon. Generally, unless otherwise defined, straight-chain or branched alkyl groups have 1 to about 20 carbon atoms, preferably 1 to about 10, and may be, for example, C1-C2. 10Alkyl groups, such as C1-C6 alkyl groups. Examples of straight-chain and branched alkyl groups include (but are not limited to) methyl, ethyl, 1-propyl (n-propyl), 2-propyl, n-butyl, secondary butyl, tertiary butyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl, etc. Furthermore, as used throughout the specification, examples, and claims, the term "alkyl" is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter referring to an alkyl portion having a substituent replacing hydrogen on one or more carbons of the hydrocarbon backbone. The "alkyl" group may optionally be substituted.

[0043] Term "C" x -C y "When used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, it is intended to include groups containing 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 x to y carbons in the chain, including straight-chain alkyl and branched-chain alkyl groups, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. CO alkyl indicates hydrogen when the group is at the end position, and a single bond when it is inside.

[0044] As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, straight-chain or branched groups having 2-6 or 3-4 carbon atoms, referred to herein as C2-C6 alkenyl and C3-C4 alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

[0045] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight-chain or branched groups having 2-6 or 3-6 carbon atoms, referred to herein as C2-C6 alkynyl and C3-C6 alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentyynyl, hexynyl, methylpropynyl, etc.

[0046] As used herein, the term "alkoxy group" refers to a straight-chain 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. Right now It can be a C1-C6 alkoxy group. Examples of alkoxy groups include (but are not limited to) methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 3-methylbutoxy, etc.

[0047] As used herein, the term "alkoxyalkyl" refers to an alkoxy-substituted alkyl group (as defined above) and may be represented by the general formula alkyl-O-alkyl. Examples of alkoxyalkyl groups include, but are not limited to, methyl-O-ethylene- and ethyl-O-ethylene-.

[0048] As used herein, the term "haloalkyl" refers to an alkyl group (as defined above) that has been substituted with one or more halogens. For example, a monohaloalkyl group may have chlorine, bromine, iodine, or fluorine atoms. Dihaloalkyl and polyhaloalkyl groups may have two or more identical or different halogen atoms. Examples of haloalkyl groups include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, etc.

[0049] As used herein, the term "haloalkoxy" refers to a group in which one or more hydrogen atoms of the alkoxy group are substituted with one or more halogens. Representative examples of "haloalkoxy" include, but are not limited to, difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3), or trifluoroethoxy (-OCH2CF3).

[0050] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups, wherein each atom in the ring is a carbon atom. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic aromatic groups having two or more rings, wherein the two or more carbons are shared by two adjacent rings (fused rings), at least one of which is aromatic, for example, the other ring may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. The term "fused" means attached to or forming a second ring by sharing two adjacent atoms with a first ring. The term "fused" is equivalent to the term "condensation." Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, phenol, aniline, indenyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, indololinyl, isoindololinyl, etc. Unless otherwise specified, the aryl groups described herein may optionally be substituted.

[0051] As used herein, the terms "polycyclic group," "polycyclic," and "polycyclic" refer to two or more rings ( For example (cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic groups), wherein one or more atoms are shared by two adjacent rings. For example The ring is a "fused ring". Each ring in the polycyclic ring may be substituted or unsubstituted. In some embodiments, each ring in the polycyclic ring contains 3 to 10, preferably 5 to 7 atoms.

[0052] As used herein, the term "acyl" refers to the group -C(=O)-R. w , where Rw Optionally substituted alkyl groups. Examples of "acyl" include (but are not limited to) alkyl groups in which R w For C1-C 10 Alkyl (C1-C) 10 Acyl) or C1-C 6- Alkyl (C1-C6 acyl). In some embodiments, the optionally substituted substituents are selected independently from the group consisting of H, OH, alkoxy, cyano, F, and amino, each time they appear. Additional examples of "acyl" include -C(=O)-CH3, -C(=O)-CH2-CH3, -C(=O)-CH2-CH2-CH3, or -C(=O)-CH(CH3)2.

[0053] As used herein, the terms "amine" and "amino" refer to unsubstituted and substituted amines and their salts, such as portions that can be represented by the following formula: or Among them, each R z Independently representing a hydrogen or hydrocarbon group, or R z The group, together with the N atom it is attached to, completes a heterocycle with 4 to 8 atoms in the ring structure.

[0054] As used herein, the terms "amide" and "amide group" refer to groups represented by the following: Where R x R y and R z Each can independently represent a hydrogen or hydrocarbon group, or R y and R z Together with the N atom it is attached to, it completes a heterocyclic group with 4 to 8 atoms in the ring structure.

[0055] As used herein, the term "acylamino" refers to an amino group that has been substituted with an acyl group as defined above.

[0056] As used herein, the term "aminocarbonyl" refers to a carbonyl group that has been substituted with an amino group.

[0057] As used herein, the term "alkenylalkyl" refers to an alkyl group that has been substituted with an alkenyl group.

[0058] As used herein, the term "alkynyl alkyl" refers to an alkyl group that has been substituted with an alkynyl group.

[0059] As used herein, the term "alkylamino" refers to an amino group as defined above that has been substituted with at least one alkyl group.

[0060] As used herein, the term "aminoalkyl" refers to an alkyl group that has been substituted with an amino group.

[0061] As used herein, the term "amide-alkyl" refers to an alkyl group that has been substituted with an amide group.

[0062] As used herein, the term "cyanoalkyl" refers to an alkyl group that has been substituted with a cyano group.

[0063] As used herein, the term "cycloalkoxyalkyl" refers to an alkyl group substituted with a cycloalkoxy group (as defined above) and can be represented by the general formula cycloalkoxy-O-alkyl. Examples of cycloalkoxyalkyl groups include, but are not limited to, cyclopropyl-O-methylene and cyclopropyl-O-ethylene.

[0064] As used herein, the term "cycloalkylalkyl" refers to an alkyl group that has been substituted with a cycloalkyl group.

[0065] As used herein, the term “heteroaryl alkyl” refers to an alkyl group that has been substituted with a heteroaryl group.

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

[0067] As used herein, the term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group.

[0068] 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 hydrocarbons. Generally, unless otherwise defined, monocyclic cycloalkyl hydrocarbons have 3 to approximately 10 carbon atoms, more commonly 3 to 8 carbon atoms (e.g., C3-C4). 10 cycloalkyl or, for example, C 3- (C6 cycloalkyl). Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The second or third ring of a bicyclic or tricyclic cycloalkyl group may be self-saturated, unsaturated, or aromatic. Cycloalkyl groups include bicyclic and tricyclic molecules, wherein the two rings share one, two, three, or more atoms. Cycloalkyl groups may be further substituted with alkyl, alkenyl, alkoxy, aminoalkyl, carbonyl-substituted alkyl groups, -CF3, -CN, etc.

[0069] As used herein, the term "cycloalkylalkyl" refers to an alkyl group that has been substituted with a cycloalkyl group.

[0070] As used herein, the term "cyano" refers to the -CN group.

[0071] As used herein, the term "hydroxyl" or "hydroxyl" refers to the -OH group.

[0072] As used herein, the term “halogenated” or “halogen” alone or in combination with other terms means chlorine, fluorine, bromine, and iodine.

[0073] As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Exemplary heteroatoms include nitrogen (N), oxygen (O), sulfur (S), and silicon (Si).

[0074] As used herein, the terms “heterocyclic,” “heterocyclic alkyl,” “heterocycle,” and “heterocyclic” refer to a non-aromatic, saturated, or partially saturated, including monocyclic, polycyclic (e.g., bicyclic, tricyclic) bridged or fused 3- to 15-membered ring system having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2, NH, or C(O), with the remaining ring atoms independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. Examples of "heterocyclic alkyl" include, but are not limited to, azacyclobutyl, oxacyclobutyl, imidazolinyl, pyrrololinyl, oxazolinyl, thiazoalkyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxalyl, dioxothiomorpholinyl, oxapirazinyl, oxapiridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopheneyl, dihydropyranyl, dihydroindolyl, dihydroindolylmethyl, 2-azabicyclo[2.2.2]octyl, azooctyl, chromyl, xanthanyl, and their N-oxides. The connection of the heterocyclic alkyl substituent can occur via a carbon atom or via a heteroatom. The heterocyclic alkyl group may optionally be substituted by one or more of the aforementioned groups via one or more suitable groups. Preferably, "heterocyclic alkyl" refers to a 5- to 6-membered ring selected from the group consisting of: azirrobutyl, oxacyclobutyl, imidazolinyl, pyrrolinyl, oxazolinyl, thiazoalkyl, pyrrolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxane, and their N-oxides. More preferably, "heterocyclic alkyl" includes azirrobutyl, pyrrolinyl, morpholinyl, and piperidinyl. The heterocyclic alkyl group may optionally be substituted with one or more of the aforementioned groups.

[0075] As used herein, the term "heteroaryl" refers to a substituted or unsubstituted aromatic monocyclic structure, preferably a 5- to 7-membered ring, more preferably a 5- to 6-membered ring, whose ring structure includes at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The term "heteroaryl" also refers to a substituted or unsubstituted aromatic or partially aromatic ring system containing at least one heteroatom and having two or more cyclic rings (bicyclic, tricyclic, or polycyclic), containing 8 to 20 ring atoms, suitably 5 to 10 ring atoms, which may be covalently linked or fused, wherein two or more atoms are shared by two adjacent rings, wherein at least one of said rings is heteroaromatic; for example, the other cyclic ring may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. The ring may contain an N or S atom, wherein the N or S atom is optionally oxidized, or the N atom is 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: furanyl, thiophene, pyrrole, pyrazolyl, imidazolyl, oxazolyl, cenylyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazoleyl, oxadiazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, triazinyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzofuranyl, benzothiophene, benzotriazinyl, phthalazinyl, thiazolyl, dibenzofuranyl, dibenzothiaphene, benzoimidazolyl, indole, isoindole, indazole, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purine, pteridinyl, 9 H -Carbazole, α-carboline, indazinyl, benzoisothiazolyl, benzoxazolyl, pyrrolidinyl, furanylpyridinyl, purine, benzothiadiazole, benzoxadiazole, benzotriazole, benzothiadiazole, carbazole, benzotriazolyl, acridineyl, etc.

[0076] As used herein, the term "hydrocarbon group" refers to a group bonded via a carbon atom, which does not have a =O or =S substituent and typically has at least one carbon-hydrogen bond and a major carbon backbone, but may optionally include heteroatoms. Therefore, for the purposes of this application, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbon groups, but substituents such as acetyl (which has a =O substituent on its linking carbon) and ethoxy (which is linked via oxygen rather than carbon) are not. Hydrocarbon groups include, but are not limited to, aryl, heteroaryl, cycloalkyl, heterocyclic, alkyl, alkenyl, ynyl, and combinations thereof.

[0077] As used herein, the term "sulfonamide" is referred to as follows: or Where R z Each time it appears, it independently indicates hydrogen, alkyl, or cycloalkyl, or R.z The group, together with the N atom it is attached to, completes a heterocycle with 4 to 8 atoms in the ring structure.

[0078] As used herein, the term "acyloxy group" refers to a portion represented by the following: Where R z It indicates a hydrocarbon group.

[0079] As used herein, the term "sulfonyl" refers to the group -S(O)2-R. 6d , where R 6d Indicates alkyl or cycloalkyl.

[0080] "Combination therapy" includes administering it to patients in need. For example Treatment with two or more therapeutic agents of compounds of formula IA, IB, IC, ID, IE, IF or IG and the enzyme asparaginase (ASNase) or its derivatives.

[0081] The terms “disease,” “symptom,” and “condition” are used interchangeably in this article.

[0082] The terms "individual," "patient," or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred. The compounds described herein can be administered not only to mammals such as humans but also to other mammals, such as animals requiring veterinary treatment. For example livestock( For example Dogs, cats, etc.), livestock ( For example Cows, sheep, pigs, horses, etc.) and laboratory animals ( example like (Rat, mouse, guinea pig, etc.)

[0083] The compounds described herein can be used to treat GCN2-driven diseases (sometimes abbreviated as "GCN2-related diseases" in this invention), such as cancer. For example Colorectal cancer ( For example Colorectal cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors, and lung cancer. For example Non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer ( For example Pancreatic duct cancer, pancreatic endocrine tumors), pharyngeal cancer, laryngeal cancer, esophageal cancer, stomach cancer ( For example Papillary carcinoma, mucinous carcinoma, adenosquamous carcinoma), duodenal cancer, small bowel cancer, breast cancer ( For example Invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer), ovarian cancer ( For example Ovarian epithelial cancer, extragonadal germ cell tumors, ovarian germ cell tumors, low-grade malignant potential ovarian tumors), testicular tumors, prostate cancer ( For example Hormone-dependent prostate cancer, non-hormone-dependent prostate cancer, castration-resistant prostate cancer, and liver cancer ( For example Hepatocellular carcinoma, primary liver cancer, extrahepatic bile duct cancer, thyroid cancer ( For example Medullary thyroid carcinoma), renal cell carcinoma ( For example Renal cell carcinoma ( For example Clear cell renal cell carcinoma), transitional cell carcinoma of the renal pelvis and ureter), uterine cancer ( For example Cervical cancer, endometrial cancer, uterine sarcoma), gestational choriocarcinoma, brain tumors ( For example Medulloblastoma, glioma, pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, pituitary adenoma, retinoblastoma, skin cancer ( For example Basal cell carcinoma, malignant melanoma (melanoma), sarcoma ( For example Rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, spindle cell sarcoma, osteosarcoma), malignant bone tumors, bladder cancer, blood cancers ( For example Multiple myeloma, leukemia For example Acute myeloid leukemia, acute lymphoblastic leukemia (including the blast crisis of chronic leukemia), malignant lymphoma, Hodgkin's disease, chronic myeloproliferative disorders, carcinoma of unknown primary nucleus, cancer growth inhibitors, cancer metastasis inhibitors, apoptosis promoters, and agents for the prevention or treatment of precancerous lesions. For example Myelodysplastic syndrome).

[0084] The compounds described in this article, For example Compounds of formulas IA, IB, IC, ID, IE, IF, or IG as defined herein may be used in combination with one or more additional therapeutic agents to treat conditions described herein, such as 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, asparaginase enzymes (ASNase)).

[0085] "Pharmaceutical or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other undesirable reactions when administered to animals or humans, when appropriate. For human use, formulations should meet the sterility, pyrogenicity, and general safety and purity standards required by the FDA Office of Biologics Standards.

[0086] As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceuticalally acceptable excipient" refer to any and all solvents, dispersion media, coatings, isotonics, and absorption delay agents compatible with drug administration. The use of media and pharmaceuticals for pharmaceutically active substances is well known in the art. Compositions may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0087] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein, formulated together with one or more pharmaceutically acceptable carriers.

[0088] As used herein, the term "pharmaceutically acceptable salt" refers to a salt containing an acidic or basic group that may be present in the compound used in the composition. The compounds included in the compositions of this invention, which are inherently basic, are capable of forming a wide variety of salts with a wide range of inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts. Right now Salts containing pharmacologically acceptable anions, including but not limited to: malates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, isonicotinate, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrate, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucuronides, glycosides, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates. right Toluenesulfonate and pamoate ( Right now ,1,1'-methylene- pair-(2-hydroxy-3-naphthylcarbamate). The compounds included in the compositions of the present invention, which are inherently acidic, are capable of forming basic salts with a variety of pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, specifically calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. The compounds included in the compositions of the present invention, including basic or acidic portions, can also form pharmaceutically acceptable salts with a variety of amino acids. The compounds disclosed herein may contain acidic and basic groups; for example, an amino group and a carboxylic acid group. In such cases, the compounds may exist as acid addition salts, zwitterions, or basic salts.

[0089] The compounds disclosed herein may contain one or more chiral centers and therefore exist in stereoisomer form. The term "stereoisomer," as used herein, comprises all enantiomers or diastereomers. Depending on the configuration of the substituents surrounding the stereocentral carbon atom, these compounds may be represented by the symbol "". R "or" S The symbols “(±)” are used in the nomenclature, but those skilled in the art will recognize that the structure may implicitly represent the chiral center. These compounds may also be designated by “(+)” and “(-)” based on their optical rotational properties. The compounds described in this invention encompass a variety of stereoisomers of these compounds and mixtures thereof. Enantiomers or mixtures of diastereomers may be designated by the symbol “(±)” in the nomenclature, but those skilled in the art should recognize that the structure may implicitly represent the chiral center.

[0090] In this specification, the term "therapeutic effective dose" means the dose that researchers, veterinarians, physicians, or other clinicians are seeking to induce an effect in tissues, systems, or animals ( For example The amount of the compounds of the present invention that elicit a biological or medical response in mammals or humans. The compounds described herein are administered in therapeutically effective amounts to treat a condition.

[0091] "Treatment" includes any action that causes improvement in a condition, disease, symptom, etc., such as reducing, decreasing, regulating, or eliminating it.

[0092] This disclosure also covers isotopically labeled compounds consistent with those described herein, except that one or more atoms are substituted with atoms whose atomic masses or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32P, 35 S, 18 F and 36 Cl. For example, the compounds disclosed herein may have one or more deuterated H atoms.

[0093] Individual enantiomers and diastereomers of the disclosed compounds can be prepared synthetically from commercially available starting materials containing asymmetric or stereosymmetric centers, or by preparing racemic mixtures followed by resolution methods known to those skilled in the art. These resolution methods are exemplified by: (1) attaching a mixture of enantiomers to a chiral cofactor, separating the resulting mixture of diastereomers by recrystallization or chromatography and releasing an optically pure product from the cofactor; (2) forming a salt using an optically active resolving agent; (3) directly separating a mixture of optically enantiomers on a chiral liquid chromatography column; or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved to their component enantiomers by known methods such as chiral liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis of chemical or enzymatic reactions in which a single reactant forms a heterogeneous mixture of stereoisomers during the generation of a new stereocenter or during the transformation of a pre-existing stereocenter is known in the art. Stereoselective synthesis encompasses enantioselective and diastereoselective conversions and may involve the use of chiral auxiliary groups. See, for example, Carreira and Kvaerno. Classics in Stereoselective Synthesis Wiley-VCH: Weinheim, 2009.

[0094] compound In one embodiment, this document describes a compound represented by formula IA: Formula IA Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 and X 4 Each is independently selected from the following groups: CH and N; X 2 Selected from the following groups: C and N; X 3 Selected from the following group: CR 4 and N; As long as X 1 X 2 X 3 and X 4 The number of elements is no more than N; X 5 Selected from the following group: CR 5 and N; R 1 and R 2 Each is independently selected from the following group: H, alkoxy, alkyl, cyano, haloalkoxy, haloalkyl, and halogen; R 3 Selected from the following group: H, alkyl, alkoxy, cyano, and halogen; R 4 Selected from the following group: H, alkyl, alkenyl, alkenylalkyl, ynyl, ynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclic, heterocyclic, aryl, heteroaryl and heteroarylalkyl; R 5 Selected from the following group: H, hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, aminoalkyl, aminocycloalkyl, aminocarbonyl, acylamino, acyloxyalkyl, hydroxyimino, alkoxyimino, alkylamino, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxycarbonyl, and heterocyclic alkyl; R 6 R 7 and R 8 Each is independently selected from the group consisting of: H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl; and R 9 Selected from the following group: H, halogens, and alkyl groups; if only: When X 2 When it is C, Not for Where R 6 Selected from the following group: halogens, alkoxy groups, and alkyl groups; R 8 Selected from the following groups: H, halogens and alkyl groups; and R 10 Selected from the group consisting of H, alkyl, and acyl groups.

[0095] In one embodiment, this document describes a compound represented by formula IA: Formula IA Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 and X 4 Each is independently selected from the following groups: CH and N; X 2 Selected from the following groups: C and N; X 3 Selected from the following group: CR4 and NR 4 ; As long as X 1 X 2 X 3 and X 4 The number of elements is no more than N; X 5 Selected from the following group: CR 5 and N; R 1 and R 2 Each is independently selected from the following group: H, alkoxy, alkyl, cyano, haloalkoxy, haloalkyl, and halogen; R 3 Selected from the following group: H, alkyl, alkoxy, cyano, and halogen; R 4 Selected from the following group: H, alkyl, alkenyl, alkenylalkyl, ynyl, ynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclic, heterocyclic, aryl, heteroaryl and heteroarylalkyl; R 5 Selected from the following group: H, hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, aminoalkyl, aminocycloalkyl, aminocarbonyl, acylamino, acyloxyalkyl, hydroxyimino, alkoxyimino, alkylamino, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxycarbonyl, and heterocyclic alkyl; R 6 R 7 and R 8 Each is independently selected from the group consisting of: H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl; and R 9 Selected from the following group: H, halogens, and alkyl groups; if only: i) When X 2 When it is C, Not for Where R 6 Selected from the following group: halogens, alkoxy groups, and alkyl groups; R 8 Selected from the following groups: H, halogens and alkyl groups; and R 10 Selected from the group consisting of H, alkyl, and acyl groups; ii) When X 2 For C and X 3 For NR 4 hour, Not for Where R 6 For H; R 7 Selected from the following groups: H, Cl, and OCH3; R 8 For H or Br; and R 9 For H; and iii) When X 2 For C and X 3 For NR 4 hour, Not for Where R 5 Selected from the following groups: H, F, Cl, CH3, OCH3, CF3, and CN; R 6 For H or F; R 7 Selected from the following groups: H, F, Cl, Br, I, CH3, OCH3, OCH2CH3, OCH(CH3)2, CF3, OH and OCF3; R 8 Selected from the following groups: H, F, Cl, CH3, OCH3, CF3, and CN; and R 9 It can be H or F.

[0096] In some implementation schemes, R 1 R 2 and R 3 At least one of them is a halogen. In some embodiments, R 1 R 2 and R 3 At least one of them is fluorine. In some embodiments, R 1 It is fluorine.

[0097] In some implementation schemes, X 1 Let N be the number of elements in the array.

[0098] In some implementation schemes, X 2 Let N be the number of elements in the array.

[0099] In some implementation schemes, X 3 For NR 4 .

[0100] In some implementation schemes, X 3 For CR 4 .

[0101] In another embodiment, a compound represented by formula IB is described herein: Formula IB Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 5 Selected from the following group: CR 5 and N; R 1 and R 2 Each is independently selected from the following group: H, alkoxy, alkyl, cyano, haloalkoxy, haloalkyl, and halogen; R 3 Selected from the following group: H, alkyl, and halogen; R 4 Selected from the following group: H, alkyl, alkenyl, alkenylalkyl, ynyl, ynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclic, heterocyclic, aryl, heteroaryl and heteroarylalkyl; R 5 Selected from the following group: H, hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, aminoalkyl, aminocycloalkyl, aminocarbonyl, acylamino, acyloxyalkyl, hydroxyimino, alkoxyimino, alkylamino, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxycarbonyl, and heterocyclic alkyl; R 6 R 7 and R 8 Each is independently selected from the group consisting of: H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl; and R 9 Selected from the following group: H, halogens, and alkyl groups; if only: Not for Where R 6 Selected from the following group: halogens, alkoxy groups, and alkyl groups; R 8 Selected from the following groups: H, halogens and alkyl groups; and R 10 Selected from the group consisting of H, alkyl, and acyl groups.

[0102] In another embodiment, a compound represented by formula IB is described herein: Formula IB Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 5 Selected from the following group: CR 5 and N; R1 and R 2 Each is independently selected from the following group: H, alkoxy, alkyl, cyano, haloalkoxy, haloalkyl, and halogen; R 3 Selected from the following group: H, alkyl, and halogen; R 4 Selected from the following group: H, alkyl, alkenyl, alkenylalkyl, ynyl, ynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclic, heterocyclic, aryl, heteroaryl and heteroarylalkyl; R 5 Selected from the following group: H, hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, aminoalkyl, aminocycloalkyl, aminocarbonyl, acylamino, acyloxyalkyl, hydroxyimino, alkoxyimino, alkylamino, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxycarbonyl, and heterocyclic alkyl; R 6 R 7 and R 8 Each is independently selected from the group consisting of: H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl; and R 9 Selected from the following group: H, halogens, and alkyl groups; if only: i) Not for Where R 6 Selected from the following group: halogens, alkoxy groups, and alkyl groups; R 8 Selected from the following groups: H, halogens and alkyl groups; and R 10 Selected from the group consisting of H, alkyl, and acyl groups; ii) Not for Where R 6 For H; R 7 Selected from the following groups: H, Cl, and OCH3; R 8 For H or Br; and R 9 For H; and iii) Not for Where R 5 Selected from the following groups: H, F, Cl, CH3, OCH3, CF3, and CN; R 6 For H or F; R 7 Selected from the following groups: H, F, Cl, Br, I, CH3, OCH3, OCH2CH3, OCH(CH3)2, CF3, OH and OCF3; R 8 Selected from the following groups: H, F, Cl, CH3, OCH3, CF3, and CN; and R 9 It can be H or F.

[0103] In some implementation schemes, R 2 For H and R 3 For H.

[0104] In some implementation schemes, R 1 For F, R 2 For H and R 3 For H.

[0105] In some implementation schemes, R 2 For F and R 3 For H.

[0106] In some implementation schemes, R 2 For H and R 3 It is F.

[0107] In another embodiment, a compound represented by formula IC is described herein: IC Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 and X 4 Each is independently selected from the following groups: CH and N; X 2 Selected from the following groups: C and N; X 3 Selected from the following group: CR 4 and N; As long as X 1 X 2 X 3 and X 4 The number of elements is no more than N; R 1 and R 2 Each is independently selected from the following group: H, alkoxy, alkyl, cyano, haloalkoxy, haloalkyl, and halogen; R 3 Selected from the following group: H, alkyl, and halogen; R 4Selected from the following group: H, alkyl, alkenyl, alkenylalkyl, ynyl, ynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclic, heterocyclic, aryl, heteroaryl and heteroarylalkyl; R 6 R 7 and R 8 Each is independently selected from the group consisting of: H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl; and R 9 Selected from the following group: H, halogens, and alkyl groups.

[0108] In another embodiment, a compound represented by formula IC is described herein: IC Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 and X 4 Each is independently selected from the following groups: CH and N; X 2 Selected from the following groups: C and N; X 3 Selected from the following group: CR 4 and NR 4 ; As long as X 1 X 2 X 3 and X 4 The number of elements is no more than N; R 1 and R 2 Each is independently selected from the following group: H, alkoxy, alkyl, cyano, haloalkoxy, haloalkyl, and halogen; R 3 Selected from the following group: H, alkyl, and halogen; R 4 Selected from the following group: H, alkyl, alkenyl, alkenylalkyl, ynyl, ynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclic, heterocyclic, aryl, heteroaryl and heteroarylalkyl; R 6 R 7 and R 8 Each is independently selected from the group consisting of: H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl; and R 9Selected from the following group: H, halogens, and alkyl groups.

[0109] if only When X 2 Let C, X 3 For NR 4 R 6 For H, R 8 It is H or Br and R 9 When it is H, R 7 It is not H, Cl or OCH3.

[0110] In some implementation schemes, R 2 For H and R 3 For H.

[0111] In some implementation schemes, R 1 For F, R 2 For H and R 3 For H.

[0112] In some implementation schemes, R 2 For F and R 3 For H.

[0113] In some implementation schemes, R 2 For H and R 3 It is F.

[0114] In some implementation schemes, X 1 Let N be the number of elements in the array.

[0115] In some implementation schemes, X 2 Let N be the number of elements in the array.

[0116] In some implementation schemes, X 3 For NR 4 .

[0117] In some implementation schemes, X 3 For CR 4 .

[0118] In another embodiment, a compound represented by formula ID is described herein: Formula ID Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 and X 4 Each is independently selected from the following groups: CH and N; X 3 Selected from the following group: CR 4 and N; As long as X 1 X 3 and X4 N is a subset of N; X 5 Selected from the following group: CR 5 and N; R 1 and R 2 Each is independently selected from the following group: H, alkoxy, alkyl, cyano, haloalkoxy, haloalkyl, and halogen; R 3 Selected from the following group: H, alkyl, and halogen; R 4 Selected from the following group: H, alkyl, alkenyl, alkenylalkyl, ynyl, ynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclic, heterocyclic, aryl, heteroaryl and heteroarylalkyl; R 5 Selected from the following group: H, hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, aminoalkyl, aminocycloalkyl, aminocarbonyl, acylamino, acyloxyalkyl, hydroxyimino, alkoxyimino, alkylamino, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxycarbonyl, and heterocyclic alkyl; R 6 R 7 and R 8 Each is independently selected from the group consisting of: H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl; and R 9 Selected from the following group: H, halogens, and alkyl groups.

[0119] In another embodiment, a compound represented by formula ID is described herein: Formula ID Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 and X 4 Each is independently selected from the following groups: CH and N; X 3 Selected from the following group: CR 4 and NR 4 ; As long as X 1 X 3 and X 4 N is a subset of N; X 5 Selected from the following group: CR 5 and N; R 1and R 2 Each is independently selected from the following group: H, alkoxy, alkyl, cyano, haloalkoxy, haloalkyl, and halogen; R 3 Selected from the following group: H, alkyl, and halogen; R 4 Selected from the following group: H, alkyl, alkenyl, alkenylalkyl, ynyl, ynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclic, heterocyclic, aryl, heteroaryl and heteroarylalkyl; R 5 Selected from the following group: H, hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, aminoalkyl, aminocycloalkyl, aminocarbonyl, acylamino, acyloxyalkyl, hydroxyimino, alkoxyimino, alkylamino, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxycarbonyl, and heterocyclic alkyl; R 6 R 7 and R 8 Each is independently selected from the group consisting of: H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl; and R 9 Selected from the following group: H, halogens, and alkyl groups.

[0120] In some implementation schemes, R 2 For H and R 3 For H.

[0121] In some implementation schemes, R 1 For F, R 2 For H and R 3 For H.

[0122] In some implementation schemes, R 2 For F and R 3 For H.

[0123] In some implementation schemes, R 2 For H and R 3 It is F.

[0124] In some implementation schemes, X 1 For CH, X 3 For CR 4 and X 4 Let N be the number of elements in the array.

[0125] In another embodiment, a compound represented by formula IE is described herein: IE Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 5 Selected from the following group: CR 5 and N; R 1 and R 2 Each is independently selected from the following group: H, alkoxy, alkyl, cyano, haloalkoxy, haloalkyl, and halogen; R 3 Selected from the following group: H, alkyl, and halogen; R 4 Selected from the following group: H, alkyl, alkenyl, alkenylalkyl, ynyl, ynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclic, heterocyclic, aryl, heteroaryl and heteroarylalkyl; R 5 Selected from the following group: H, hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, aminoalkyl, aminocycloalkyl, aminocarbonyl, acylamino, acyloxyalkyl, hydroxyimino, alkoxyimino, alkylamino, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxycarbonyl, and heterocyclic alkyl; R 6 R 7 and R 8 Each is independently selected from the group consisting of: H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl; and R 9 Selected from the following group: H, halogens, and alkyl groups.

[0126] In some implementation schemes, R 2 For H and R 3 For H.

[0127] In some implementation schemes, R 1 For F, R 2 For H and R 3 For H.

[0128] In some implementation schemes, R 2 For F and R 3 For H.

[0129] In some implementation schemes, R 2 For H and R 3 It is F.

[0130] In another embodiment, a compound represented by the formula IF is described herein: Formula IF Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: R 1 and R 2 Each is independently selected from the following group: H, alkoxy, alkyl, cyano, haloalkoxy, haloalkyl, and halogen; R 3 Selected from the following group: H, alkyl, and halogen; R 4 Selected from the following group: H, alkyl, alkenyl, alkenylalkyl, ynyl, ynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclic, heterocyclic, aryl, heteroaryl and heteroarylalkyl; R 6 R 7 and R 8 Each is independently selected from the following group: H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl; R 9 Selected from the following groups: H, halogens and alkyl groups; and R 11 Selected from the following group: H and acyl group.

[0131] In some implementation schemes, R 2 For H and R 3 For H.

[0132] In some implementation schemes, R 1 For F, R 2 For H and R 3 For H.

[0133] In some implementation schemes, R 2 For F and R 3 For H.

[0134] In some implementation schemes, R 2 For H and R 3 It is F.

[0135] In another embodiment, a compound represented by the formula IG is described herein: IG Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: R 1 and R 2 Each is independently selected from the following group: H, alkoxy, alkyl, cyano, haloalkoxy, haloalkyl, and halogen; R 3Selected from the following group: H, alkyl, and halogen; R 4 Selected from the following group: H, alkyl, alkenyl, alkenylalkyl, ynyl, ynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclic, heterocyclic, aryl, heteroaryl and heteroarylalkyl; R 6 R 7 and R 8 Each is independently selected from the group consisting of: H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl; and R 9 Selected from the following group: H, halogens, and alkyl groups.

[0136] In some implementation schemes, R 2 For H and R 3 For H.

[0137] In some implementation schemes, R 1 For F, R 2 For H and R 3 For H.

[0138] In some implementation schemes, R 2 For F and R 3 For H.

[0139] In some implementation schemes, R 2 For H and R 3 It is F.

[0140] In some implementation schemes, R 4 Selected from the group consisting of: H, alkyl, (C2-C8)alkenyl, (C2-C8)alkenyl-(C1-C4)alkyl, (C2-C8)ynyl, (C2-C8)ynyl-(C1-C4)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl-(C1-C4)alkyl, alkoxy-(C1-C4)alkyl, (C3-C8)cycloalkenyl, (C3-C8)cycloalkenyl-(C1-C4)alkyl, alkylamino, amide, thio-(C1-C4)alkyl, heterocyclic, heterocyclic-(C1-C4)alkyl, aryl, heteroaryl, and heteroaryl-(C1-C4)alkyl, wherein the alkyl component of the alkylamino group is optionally substituted with an alkoxy group. In some embodiments, R 4 Selected from the group consisting of: H, alkyl, (C3-C8)cycloalkyl, alkylamino, amide, thio-(C1-C4)alkyl, heterocyclic, and heteroaryl, wherein the alkyl component of the alkylamino group is optionally substituted with a (C1-C6)alkoxy group. In some embodiments, R 4 Selected from the following group: H, In some implementation schemes, R 5 Selected from the group consisting of: H, alkyl, (C3-C8)cycloalkyl, alkylamino, hydroxy-(C1-C4)alkyl, hydroxy-(C3-C8)cycloalkyl, alkoxy-(C1-C4)alkyl, alkoxy-(C3-C8)cycloalkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, amino-(C1-C4)alkyl, amino-(C3-C8)cycloalkyl, aminocarbonyl, amide, amide-(C1-C4)alkyl, hydroxyimino, alkoxyimino, cyano-(C1-C4)alkyl, heterocyclic, (C3-C8)cycloalkylamino, (C1-C4)alkoxycarbonyl, and heterocyclic-(C1-C4)alkyl. In some embodiments, R 5 Selected from the group consisting of: H, alkyl, alkylamino, hydroxy-(C1-C4)alkyl, alkoxy-(C1-C4)alkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, amino-(C1-C4)alkyl, acyloxy-(C1-C4)alkyl, hydroxyimino, alkoxyimino, cyano-(C1-C4)alkyl, heterocyclic, and alkoxycarbonyl. In some embodiments, R 5 Selected from the following group: H, fluorine, chlorine, bromine, CF3, In some implementation schemes, R 6 R 7 and R 8 Each is independently selected from the group consisting of: H, alkyl, alkoxy, hydroxy, cyano, halogen, haloalkyl, alkylamino, (C3-C8)cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxy-(C1-C4)alkyl. In some embodiments, R 6 R 7 and R 8 Each is independently selected from the following group: H, alkyl, alkoxy, hydroxy, halogen and hydroxy-(C1-C4)alkyl.

[0141] In some implementation schemes, R 6 Selected from the following group: H, methyl, methoxy, fluorine, and chlorine.

[0142] In some implementation schemes, R 7 Selected from the following group: H, methoxy, fluorine, bromine and .

[0143] In some implementation schemes, R 9 Selected from the group consisting of H, halogens, and alkyl groups. In some embodiments, R... 9 Selected from the following group: H and fluorine.

[0144] In some implementation schemes, R 11Selected from the following group: H, In some implementation schemes, R 11 Selected from the following groups: H, fluorine, and chlorine.

[0145] In one embodiment, a compound is described herein selected from the group consisting of:

[0146] And its pharmaceutically acceptable salts, enantiomers, stereoisomers and tautomers.

[0147] Treatment The compounds described in this article, For example Compounds of formulas IA, IB, IC, ID, IE, IF, and IG as defined herein can function as therapeutic agents for diseases driven by GCN2 or PERK kinases and are intended to treat diseases and conditions in patients with such needs, such as cancer. Exemplary cancers include (but are not limited to) colorectal cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors, and lung cancer. For example Non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer ( For example Pancreatic duct cancer, pancreatic endocrine tumors), pharyngeal cancer, laryngeal cancer, esophageal cancer, stomach cancer ( For example Papillary carcinoma, mucinous carcinoma, adenosquamous carcinoma), duodenal cancer, small bowel cancer, breast cancer ( For example Invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer), ovarian cancer ( For example Ovarian epithelial cancer, extragonadal germ cell tumors, ovarian germ cell tumors, low-grade malignant potential ovarian tumors), testicular tumors, prostate cancer ( For example Hormone-dependent prostate cancer, non-hormone-dependent prostate cancer, castration-resistant prostate cancer, and liver cancer ( For example Hepatocellular carcinoma, primary liver cancer, extrahepatic bile duct cancer, thyroid cancer ( For example Medullary thyroid carcinoma), renal cell carcinoma ( For example Renal cell carcinoma ( For example Clear cell renal cell carcinoma), transitional cell carcinoma of the renal pelvis and ureter), uterine cancer ( For example Cervical cancer, endometrial cancer, uterine sarcoma), gestational choriocarcinoma, brain tumors ( For example Medulloblastoma, glioma, pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, pituitary adenoma, retinoblastoma, skin cancer ( For exampleBasal cell carcinoma, malignant melanoma, melanoma, sarcoma ( For example Rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, spindle cell sarcoma, osteosarcoma, fibrosarcoma, malignant bone tumors, bladder cancer, blood cancers ( For example Multiple myeloma, leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), including the blast crisis of chronic leukemia, malignant lymphoma, Hodgkin's disease, chronic myeloproliferative disorders, carcinoma of unknown primary nucleus, cancer growth inhibitors, cancer metastasis inhibitors, apoptosis promoters, and agents for the prevention or treatment of precancerous lesions. For example Myelodysplastic syndrome).

[0148] In one embodiment, a method for treating a disease caused by dysregulation of integrated stress response and / or unfolded protein response in a patient with this need is also described herein, comprising administering to the patient a therapeutically effective amount of the compound described herein. For example The pharmaceutical composition described herein may be a compound of formula IA, IB, IC, ID, IE, IF, or IG, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, dysregulation of the integrated stress response and / or unfolded protein response is caused by GCN2 kinase. In some embodiments, dysregulation of the integrated stress response and / or unfolded protein response is caused by PERK kinase. In some embodiments, dysregulation of the integrated stress response is caused by GCN2 kinase. In some embodiments, dysregulation of the unfolded protein response is caused by PERK kinase. In some embodiments, dysregulation of the integrated stress response is caused by activation of a kinase selected from the group consisting of PERK kinase and GCN2 kinase. In some embodiments, dysregulation of the integrated stress response is caused by activation of GCN2 kinase. In some embodiments, dysregulation of the integrated stress response is caused by activation of PERK kinase.

[0149] In one embodiment, a method for treating a disease caused by dysregulation of integrated stress response and / or unfolded protein response in a patient with this need is also described herein, comprising administering to the patient a therapeutically effective amount of the compound described herein. For example The pharmaceutical composition described herein may be a compound of formula IA, IB, IC, ID, IE, IF, or IG, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, dysregulation of the integrated stress response and / or unfolded protein response is caused by activation of kinases selected from the group consisting of PERK kinase and GCN2 kinase. In some embodiments, dysregulation of the integrated stress response is caused by activation of GCN2 kinase. In some embodiments, dysregulation of the unfolded protein response is caused by activation of PERK kinase.

[0150] In another embodiment, this document describes a method for modulating the GCN2 kinase activity of a patient in need, comprising administering to the patient a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0151] In another embodiment, a method for activating GCN2 kinase in a patient in need is described herein, comprising administering to the patient a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0152] In another embodiment, this document describes a method for modulating the PERK kinase activity of a patient in need, comprising administering to the patient a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0153] In another embodiment, a method for activating PERK kinase in a patient in need is described herein, comprising administering to the patient a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0154] In another embodiment, this document describes a method for inhibiting GCN2 kinase and PERK kinase in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0155] In another embodiment, a method for inhibiting the activity of GCN2 kinase in a patient with this need is described herein, comprising administering to the patient a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0156] In another embodiment, this document describes a method for inhibiting the activity of PERK kinase in a patient in need, comprising administering to the patient a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0157] In another embodiment, a method of treating cancer in a patient with this need is described herein, comprising administering to the patient a therapeutically effective amount of the compound described herein. For exampleThe cancer described herein is a compound of formula IA, IB, IC, ID, IE, IF, and IG, 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 bowel cancer, breast cancer, ovarian cancer, testicular tumor, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumor, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumor, bladder cancer, hematologic malignancies, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and malignant lymphoma. In some implementations, the cancer is selected from the following group: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumors, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumors, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumors, bladder cancer, hematologic malignancies, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocytic lymphoma, Waldenstrom macroglobulinemia, and malignant lymphoma. In some implementations, the cancer is leukemia. In some embodiments, the cancer is acute myeloid leukemia. In some embodiments, the cancer is acute lymphoblastic leukemia. In some embodiments, the cancer is fibrosarcoma. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is B-cell lymphoma. In some embodiments, the cancer is T-cell lymphoma.

[0158] In one embodiment, this document describes a method for treating amyloidosis in a patient with this need, comprising administering to the patient a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In another embodiment, this document describes a method for treating light chain amyloidosis in a patient with this need, comprising administering to the patient a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0159] In some embodiments, the method described herein further comprises administering a therapeutically effective amount of one or more therapeutic agents to the patient. In some embodiments, the one or more therapeutic agents are selected from the group consisting of: L-asparaginase, pegylated asparaginase, PERK inhibitors, mTOR inhibitors, immunomodulators, MAPK pathway inhibitors, MEK inhibitors, ERK inhibitors, and Ras inhibitors. In some embodiments, the one or more therapeutic agents are selected from the group consisting of: IMiD agents, proteasome inhibitors, steroids, anti-CD38 agents, anti-CD20 agents, Bcl-2 inhibitors, PI3K inhibitors, bispecific antibodies, nucleoside analogs, BTK inhibitors, DNA alkylating agents, EZH2 inhibitors, anthracycline, topoisomerase inhibitors, platinum, tyrosine kinase inhibitors, HDAC inhibitors, nuclear export inhibitors, antimicrotubule agents, L-asparaginase, pegylated asparaginase, PERK inhibitors, mTOR inhibitors, immunomodulators, MAPK pathway inhibitors, MEK inhibitors, ERK inhibitors, and Ras inhibitors.In some embodiments, the one or more therapeutic agents are selected from the group consisting of: L-asparaginase, pegaspargase, calaspargase pegol-mnkl, bortezomib, carfilzomib, ixazomib, thalidomide, pomalidomide, lenalidomide, dexamethasone, prednisone. Prednisone, daratumumab, daratumumab / hyaluronidase, isatuximab, rituximab, obinutuzumab, venetoclax, idelalisib, copanlisib, duvelisib, umbralisib, gemcitabine bine, cytarabine, ibrutinib, acalabtinib, zanubrutinib, bendamustine, cyclophosphamide, tazemetostat, doxorubicin, daunorubicin, etoposide, oxaloplatin, carboplatin ), cisplatinbosutinib, dasatinib, imatinib, nilotinib, ponatinib, panobinostat, selinexor, vincristine, JZP-458, erythrocyte-encapsulated asparaginase, PF745 (JZP-341), asparaginase Erwinia chrysanthemi (crisantaspase), Escherichia coli asparaginase (colaspase), anti-PD1 agents, anti-PDL1 agents, and anti-CTLA4 agents.

[0160] In another embodiment, a method of treating a patient with a condition selected from GCN2-related diseases and PERK-related diseases is described herein, comprising administering to the patient a therapeutically effective amount of the compound described herein. example like The disease is a compound of formula IA, IB, IC, ID, IE, IF, and IG described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the disease is a GCN2-related disease. In some embodiments, the disease is a PERK-related disease. In some embodiments, the disease is cancer. In some embodiments, the cancer is selected from the group consisting of: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumor, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumor, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumor, bladder cancer, hematologic malignancy, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and malignant lymphoma. In some implementations, the cancer is selected from the following group: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumors, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumors, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumors, bladder cancer, hematologic malignancies, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocytic lymphoma, Waldenstrom macroglobulinemia, and malignant lymphoma. In some implementations, the cancer is leukemia. In some embodiments, the cancer is acute myeloid leukemia. In some embodiments, the cancer is acute lymphoblastic leukemia. In some embodiments, the cancer is fibrosarcoma. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is B-cell lymphoma. In some embodiments, the cancer is T-cell lymphoma. In some embodiments, the disease is amyloidosis. In some embodiments, the disease is light chain amyloidosis.

[0161] In another embodiment, a method of treating a patient with a condition selected from GCN2-related diseases and PERK-related diseases is described herein, comprising administering to the patient a therapeutically effective amount of the compound described herein. example likeThe disease is a compound of formula IA, IB, IC, ID, IE, IF, and IG described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more therapeutic agents. In some embodiments, the disease is a GCN2-related disease. In some embodiments, the disease is a PERK-related disease. In some embodiments, the disease is cancer. In some embodiments, the cancer is selected from the group consisting of: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumor, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumor, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumor, bladder cancer, hematologic malignancy, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and malignant lymphoma. In some implementations, the cancer is selected from the following group: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumors, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumors, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumors, bladder cancer, hematologic malignancies, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocytic lymphoma, Waldenstrom macroglobulinemia, and malignant lymphoma. In some implementations, the cancer is leukemia. In some embodiments, the leukemia is acute myeloid leukemia. In some embodiments, the leukemia is acute lymphoblastic leukemia. In some embodiments, the cancer is fibrosarcoma. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is B-cell lymphoma. In some embodiments, the cancer is T-cell lymphoma. In some embodiments, the disease is amyloidosis. In some embodiments, the disease is light chain amyloidosis. In some embodiments, one or more therapeutic agents are selected from the group consisting of: L-asparaginase, pegylated asparaginase, PERK inhibitors, mTOR inhibitors, immunomodulators, MAPK pathway inhibitors, MEK inhibitors, ERK inhibitors, and Ras inhibitors.In some embodiments, the one or more therapeutic agents are selected from the group consisting of: IMiD agents, proteasome inhibitors, steroids, antiCD38 agents, antiCD20 agents, Bcl-2 inhibitors, PI3K inhibitors, bispecific antibodies, nucleoside analogs, BTK inhibitors, DNA alkylating agents, EZH2 inhibitors, anthracycline, topoisomerase inhibitors, platinum, tyrosine kinase inhibitors, HDAC inhibitors, nuclear export inhibitors, antimicrotubule agents, L-asparaginase, pegylated asparaginase, PERK inhibitors, mTOR inhibitors, immunomodulators, MAPK pathway inhibitors, MEK inhibitors, ERK inhibitors, and Ras inhibitors.In some embodiments, the one or more therapeutic agents are selected from the group consisting of: L-asparaginase, pegaspargase, calaspargase pegol-mnkl, bortezomib, carfilzomib, ixazomib, thalidomide, pomalidomide, lenalidomide, dexamethasone, prednisone. Prednisone, daratumumab, daratumumab / hyaluronidase, isatuximab, rituximab, obinutuzumab, venetoclax, idelalisib, copanlisib, duvelisib, umbralisib, gemcitabine bine, cytarabine, ibrutinib, acalabtinib, zanubrutinib, bendamustine, cyclophosphamide, tazemetostat, doxorubicin, daunorubicin, etoposide, oxaloplatin, carboplatin ), cisplatinbosutinib, dasatinib, imatinib, nilotinib, ponatinib, panobinostat, selinexor, vincristine, JZP-458, erythrocyte-encapsulated asparaginase, PF745 (JZP-341), asparaginase Erwinia chrysanthemi (crisantaspase), Escherichia coli asparaginase (colaspase), anti-PD1 agents, anti-PDL1 agents, and anti-CTLA4 agents.

[0162] In one embodiment, this document describes the use of a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein for therapeutic purposes.

[0163] In one embodiment, this document describes the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for the treatment of a patient in need of a condition caused by dysregulation of the integrated stress response and / or the unfolded protein response. In some embodiments, the dysregulation 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 dysregulation of the integrated stress response and / or the unfolded protein response is caused by GCN2 kinase. In some embodiments, the dysregulation of the integrated stress response and / or the unfolded protein response is caused by PERK kinase. In some embodiments, the dysregulation of the integrated stress response is caused by GCN2 kinase. In some embodiments, the dysregulation of the unfolded protein response is caused by PERK kinase. In some embodiments, the dysregulation 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 dysregulation of the integrated stress response is caused by activation of GCN2 kinase. In some embodiments, the dysregulation of the integrated stress response is caused by activation of PERK kinase.

[0164] In one embodiment, this document describes the use of a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein for modulating the activity of GCN2 kinase in a patient in need.

[0165] In one embodiment, this document describes the use of a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein for activating GCN2 kinase in a patient who requires it.

[0166] In one embodiment, this document describes the use of a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein for modulating the activity of PERK kinase in a patient in need.

[0167] In one embodiment, this document describes the use of a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein for activating PERK kinase in a patient who requires it.

[0168] In one embodiment, this document describes the use of a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein for inhibiting GCN2 kinase in a patient with this need and for inhibiting PERK kinase in a patient with this need.

[0169] In one embodiment, this document describes the use of a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein for inhibiting the activity of GCN2 kinase in a patient with this need.

[0170] In one embodiment, this document describes the use of a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein for inhibiting the activity of PERK kinase in a patient with this need.

[0171] In one embodiment, this document describes the use of a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein for the treatment of cancer in a patient in need. In some implementations, the cancer is selected from the following group: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumors, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumors, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumors, bladder cancer, hematologic malignancies, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocytic lymphoma, Waldenstrom macroglobulinemia, and malignant lymphoma. In some implementations, the cancer is leukemia. In some embodiments, the cancer is acute myeloid leukemia. In some embodiments, the cancer is acute lymphoblastic leukemia. In some embodiments, the cancer is fibrosarcoma. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is B-cell lymphoma. In some embodiments, the cancer is T-cell lymphoma.

[0172] In one embodiment, this document describes the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for the treatment of amyloidosis in a patient with this need. In another embodiment, this document describes the use of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for the treatment of light chain amyloidosis in a patient with this need.

[0173] In some embodiments, the compounds or compositions used herein further comprise the use of one or more therapeutic agents. In some embodiments, the one or more therapeutic agents are selected from the group consisting of: L-asparaginase, pegylated asparaginase, PERK inhibitors, mTOR inhibitors, immunomodulators, MAPK pathway inhibitors, MEK inhibitors, ERK inhibitors, and Ras inhibitors. In some embodiments, the one or more therapeutic agents are selected from the group consisting of: IMiD agents, proteasome inhibitors, steroids, anti-CD38 agents, anti-CD20 agents, Bcl-2 inhibitors, PI3K inhibitors, bispecific antibodies, nucleoside analogs, BTK inhibitors, DNA alkylating agents, EZH2 inhibitors, anthracycline, topoisomerase inhibitors, platinum, tyrosine kinase inhibitors, HDAC inhibitors, nuclear export inhibitors, antimicrotubule agents, L-asparaginase, pegylated asparaginase, PERK inhibitors, mTOR inhibitors, immunomodulators, MAPK pathway inhibitors, MEK inhibitors, ERK inhibitors, and Ras inhibitors.In some embodiments, the one or more therapeutic agents are selected from the group consisting of: L-asparaginase, pegaspargase, calaspargase pegol-mnkl, bortezomib, carfilzomib, ixazomib, thalidomide, pomalidomide, lenalidomide, dexamethasone, prednisone. Prednisone, daratumumab, daratumumab / hyaluronidase, isatuximab, rituximab, obinutuzumab, venetoclax, idelalisib, copanlisib, duvelisib, umbralisib, gemcitabine bine, cytarabine, ibrutinib, acalabtinib, zanubrutinib, bendamustine, cyclophosphamide, tazemetostat, doxorubicin, daunorubicin, etoposide, oxaloplatin, carboplatin ), cisplatinbosutinib, dasatinib, imatinib, nilotinib, ponatinib, panobinostat, selinexor, vincristine, JZP-458, erythrocyte-encapsulated asparaginase, PF745 (JZP-341), asparaginase Erwinia chrysanthemi (crisantaspase), Escherichia coli asparaginase (colaspase), anti-PD1 agents, anti-PDL1 agents, and anti-CTLA4 agents.

[0174] In one embodiment, this document describes a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for the treatment of a patient in need of a disease selected from GCN2-related diseases and PERK-related diseases. In some embodiments, the disease is a GCN2-related disease. In some embodiments, the disease is a PERK-related disease. In some embodiments, the disease is cancer. In some implementations, the cancer is selected from the following group: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumors, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumors, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumors, bladder cancer, hematologic malignancies, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocytic lymphoma, Waldenstrom macroglobulinemia, and malignant lymphoma. In some implementations, the cancer is leukemia. In some embodiments, the cancer is acute myeloid leukemia. In some embodiments, the cancer is acute lymphoblastic leukemia. In some embodiments, the cancer is fibrosarcoma. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is B-cell lymphoma. In some embodiments, the cancer is T-cell lymphoma. In some embodiments, the disease is amyloidosis. In some embodiments, the disease is light chain amyloidosis.

[0175] In one embodiment, this document describes a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for the treatment of a patient in need of a disease selected from GCN2-related diseases and PERK-related diseases. In some embodiments, the disease is cancer. In some implementations, the cancer is selected from the following group: colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumors, prostate cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumors, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumors, bladder cancer, blood cancers, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocytic lymphoma, Waldenstrom macroglobulinemia, and malignant lymphoma. In some implementations, the cancer is leukemia. In some embodiments, the leukemia is acute myeloid leukemia. In some embodiments, the leukemia is acute lymphoblastic leukemia. In some embodiments, the cancer is fibrosarcoma. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is B-cell lymphoma. In some embodiments, the cancer is T-cell lymphoma. In some embodiments, the disease is amyloidosis. In some embodiments, the disease is light chain amyloidosis. In some embodiments, the one or more therapeutic agents are selected from the group consisting of: IMiD agents, proteasome inhibitors, steroids, antiCD38 agents, antiCD20 agents, Bcl-2 inhibitors, PI3K inhibitors, bispecific antibodies, nucleoside analogs, BTK inhibitors, DNA alkylating agents, EZH2 inhibitors, anthracycline, topoisomerase inhibitors, platinum, tyrosine kinase inhibitors, HDAC inhibitors, nuclear export inhibitors, antimicrotubule agents, L-asparaginase, pegylated asparaginase, PERK inhibitors, mTOR inhibitors, immunomodulators, MAPK pathway inhibitors, MEK inhibitors, ERK inhibitors, and Ras inhibitors.In some implementations, the one or more therapeutic agents are selected from the group consisting of: bortezomib, carfilzomib, ixazomib, thalidomide, pomalidomide, lenalidomide, dexamethasone, prednisone, daratumumab, or daratumumab / hyaluronic acid. Enzymes, isatuximab, rituximab, obinutuzumab, venetoclax, idelalisib, copanlisib, duvelisib, umbralisib, gemcitabine, cytarabine, ibrutinib, acalabtinib Labrutinib, Zanubrutinib, Bendamustine, Cyclophosphamide, Tazemetostat, Doxorubicin, Daunorubicin, Etoposide, Oxaloplatin, Carboplatin, Cisplatin-Bosutinib, Dasatinib Imatinib, nilotinib, ponatinib, panobinostat, selinexor, vincristine, L-asparaginase, pegol-mnkl, calaspargase, JZP-458, erythrocyte-encapsulated asparaginase, PF745 (JZP-341), asparaginase from Erwinia chrysanthemi (crisantaspase), asparaginase from Escherichia coli (colaspase), anti-PD1 agents, anti-PDL1 agents, and anti-CTLA4 agents.

[0176] The compounds described herein can provide doses of optimal pharmaceutical efficacy to patients (animals and humans) requiring this treatment. It should be understood that the dose required for any particular application will vary from patient to patient, not only with the specific compound or composition chosen, but also with the route of administration, the nature of the condition being treated, the patient's age and condition, concurrent drug therapy, any special diet followed by the patient, and other factors that will be recognized by those skilled in the art, with the appropriate dose ultimately determined by the attending physician. For the treatment of the clinical conditions and diseases mentioned above, the compounds described herein can be administered orally, subcutaneously, topically, parenterally, by inhalation spray, or rectally in the form of dosage units containing conventional, non-toxic, pharmaceutically acceptable carriers, adjuvants, and solvents. Parenterally administration may include subcutaneous injection, intravenous or intramuscular injection, or infusion techniques.

[0177] Treatment can be continued for a long or short period of time as needed. The composition can be administered, for example, once to four or more times daily. Appropriate 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 one year, or indefinite. Treatment may be terminated when the desired results are achieved.

[0178] Combination therapy The compounds described in this article, For example Compounds of formulas IA, IB, IC, ID, IE, IF, and IG as defined herein may be administered in combination with one or more additional therapeutic agents to treat conditions described herein, such as cancers described herein. For example, this disclosure provides a pharmaceutical composition comprising compounds described herein. For exampleCompounds of formulas IA, IB, IC, ID, IE, IF, and IG as defined herein, one or more additional therapeutic agents, and pharmaceutically acceptable excipients. In some embodiments, a compound of formulas IA, IB, IC, ID, IE, IF, and IG as defined herein and another therapeutic agent are administered. In some embodiments, a compound of formulas IA, IB, IC, ID, IE, IF, and IG as defined herein and two additional therapeutic agents are administered. In some embodiments, a compound of formulas IA, IB, IC, ID, IE, IF, and IG as defined herein and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is separately formulated and administered. For example, a compound of formulas IA, IB, IC, ID, IE, IF, and IG as defined herein and an additional therapeutic agent can be separately formulated and administered. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, such as a pharmaceutical composition comprising a compound of formulas IA, IB, IC, ID, IE, IF, and IG as a therapeutic agent and one or more additional therapeutic agents, such as a chemotherapeutic agent. For example, compounds and additional therapeutic agents of formulas IA, IB, IC, ID, IE, IF, and IG as defined herein can be administered in single formulations. Combination therapy also encompasses other combinations. Although two or more agents in a combination therapy may be administered simultaneously, this is not always the case. For example, the administration of the first agent (or combination of agents) may precede the administration of the second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the administration of two or more agents may occur 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, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 9 weeks of each other. In some cases, even longer time intervals are possible. While in many cases it is necessary for two or more agents used in a combination therapy to be present in the patient simultaneously, this is not always the case.

[0179] Combination therapy may also include two or more administrations of one or more drugs used in the combination, using different sequences of the component drugs. For example, if drug X and drug Y are used in combination, they can be administered one or more times in any combination, such as in the order of XYX, XXY, YXY, YYX, XXYY, etc.

[0180] Combination therapy may also include two or more administrations of one or more agents used in the combination, using different routes of administration. Each of the one or more agents may be administered independently in dose units containing conventional, non-toxic, pharmaceutically acceptable carriers, adjuvants, and solvents via oral, subcutaneous, topical, parenteral, inhalation spray, or rectal administration. Parenteral administration may include subcutaneous injection, intravenous or intramuscular injection, or infusion techniques.

[0181] In some embodiments, compounds of formulas IA, IB, IC, ID, IE, IF, and IG described herein are combined with asparaginase (ASNase, L-asparaginase) or a derivative thereof. In some embodiments, the asparaginase is obtained from *Erwinia* spp. and is referred to as *Erwinia* asparaginase or *Erwinia* asparaginase. *Erwinia* asparaginase is marketed under the trademarks Erwinaze® or Erwinase®. In some embodiments, the asparaginase is obtained from *Escherichia coli* and is referred to as clappaase. Clappaase is marketed under the trademarks Elspar®, Leunase®, Kidrolase®, or Spectrila® (recombinant *Escherichia coli* asparaginase). Polyethylene glycol derivatives of clappaase include pegol-mnkl, marketed under the trademark Oncaspar®, and pegol-mnkl, marketed under the trademark Asparlas®. Other asparaginase products currently in preclinical or clinical development include JZP-458 (recombinant Erwinia asparaginase), PF745 (JZP-341), erythrocyte-encapsulated asparaginase (GRASPA®), and Xoncane.

[0182] In some embodiments, compounds of formulas IA, IB, IC, ID, IE, IF, and IG as defined herein are combined with immunomodulators. In some embodiments, immunomodulation enhances adaptive immune responses. In some embodiments, immunomodulation enhances the activity of antigen-presenting cells. In some embodiments, immunomodulators enhance the antitumor activity of myeloid cells, including macrophages. In some embodiments, immunomodulation enhances the antitumor activity of natural killer cells. In some embodiments, immunomodulators enhance the activity of effector T cells, including cytotoxic T cells.

[0183] In some embodiments, one or more additional therapeutic agents that can 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.

[0184] Exemplary MEK inhibitors include, but are not limited to, trametinib, selumetinib, cobimetinib, binimetinib, and their pharmaceutically acceptable salts. Exemplary ERK inhibitors include, but are not limited to, ulixertinib, SCH772984, LY3214996, ravoxertinib, VX-11e, ASN-007, GDC-0994, MK-8353, ASTX-029, LTT462, KO-947, and their pharmaceutically acceptable salts. Exemplary Ras inhibitors include, but are not limited to, AMG-510, MRTX849, ARS-1620, ARS-3248, LY3499446, and their pharmaceutically acceptable salts.

[0185] In some implementations, the additional therapeutic agent may be an immunomodulatory agent, including but not limited to anti-PD-1 or anti-PDL-1 therapeutic agents, such as pembrolizumab, nivolumab, pidilizumab, cemiplimab, atezolizumab, durvalumab, BMS-936559, or avelumab. In some implementations, the additional therapeutic agent may be an anti-TIM3 (anti-HAVcr2) agent, including but not limited to TSR-022 or MBG453; an anti-LAG3 agent, including but not limited to relatlimab, LAG525, or TSR-033; an anti-4-1BB (anti-CD37, anti-TNFRSF9) agent; a CD40 agonist therapy, including but not limited to SGN-40, CP-870, 893, or RO7009789; an anti-CD47 agent, including but not limited to Hu5F9-G4; an anti-CD20 agent; an anti-CD38 agent; or a STING agonist, including but not limited to ADU-S100, MK-1454, ASA404, or amide benzimidazole. In some implementations, the additional therapeutic agent may be an anti-CTLA4 agent, including ipilimumab or tremelimumab. In some implementations, the additional therapeutic agent may be a hypomethylating agent, including but not limited to azacitidine or decitabine, or other immunomodulatory agents, including but not limited to epidermal growth factor inhibitors, statins, metformin, angiotensin receptor blockers, thalidomide, lenalidomide, pomalidomide, prednisone, or dexamethasone. In some implementations, the additional therapeutic agent may be an immunotherapeutic agent, including targeted therapies, cancer vaccines, and CAR-T cell therapy.

[0186] The compounds of formulas IA, IB, IC, ID, IE, IF, and IG described herein can be administered in combination with other known cancer treatments. Such other treatments include radiation therapy, anti-microtubule agents, DNA alkylating agents, DNA synthesis inhibitors, DNA intercalating agents, anti-estrogens, anti-androgens, steroids, anti-EGFR agents, kinase inhibitors, mTOR inhibitors, PI3 kinase inhibitors, cyclin-dependent kinase inhibitors, CD4 / CD6 kinase inhibitors, topoisomerase inhibitors, histone deacetylase (HDAC) inhibitors, DNA methylation inhibitors, anti-HER2 agents, anti-angiogenic agents, proteasome inhibitors, PARP (poly-ADP-ribose polymerase) inhibitors, cell cycle regulatory kinase inhibitors, thalidomide, lenalidomide, pomalidomide, bortezomib, carfilzomib, ixazomib, daratumumab, daratumumab / hyaluronidase, esatuximab, dexamethasone, and antibody-drug conjugates (ADCs).

[0187] In one embodiment, the additional therapeutic agent may be a chemotherapeutic agent, including but not limited to anti-microtubule agents (e.g., paclitaxel, paclitaxel protein-bound particles for injectable suspensions, including nab-paclitaxel, eribulin, docetaxel, ixabepilone, vincristine, auristatins, or maytansinoids), vinorelbine, DNA alkylating agents (including cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide), and temozolomide. e) DNA intercalation agents or DNA topoisomerase inhibitors (including anthracyclines such as doxorubicin, PEGylated lipid doxorubicin, donomycin, idarubicin, mitoxantrone, or epirubicin), camptothecin such as topotecan, irinotecan, or exatecan), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytadine, gemcitabine, and methotrexate).

[0188] In some implementations, the additional treatment agent may be a kinase inhibitor, including but not limited to erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatinib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, and temsirolimus. mus), abemaciclib, LEE011, palbociclib, cabozantinib, ripretinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, nilotinib, ederaris, ibrutinib, BLU-667, Loxo 292, larotrectinib, and quizartinib.

[0189] In some embodiments, the additional therapeutic agent may be an anti-estrogenic agent, including but not limited to tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane; or an anti-androgenic agent, including but not limited to abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, and cyproterone acetate. Acetate); steroid medications, including but not limited to prednisone and dexamethasone; PARP inhibitors, including but not limited to neraparib, olaparib, talazoparib, and rucaparib; topoisomerase I inhibitors, including but not limited to irinotecan, camptothecin, eczemab, and topotecan; topoisomerase II inhibitors, including but not limited to anthracycline, etoposide, etoposide phosphate, and mitoxantrone; histone deacetylase (HDAC) inhibitors, including but not limited to vorinostat. Romidesin, panobinostat, valproic acid, and belinostat; DNA methylation inhibitors, including but not limited to DZNep and 5-aza-2'-deoxycytidine; proteasome inhibitors, including but not limited to bortezomib and carfilzomib; and biologics, including but not limited to trastuzumab, ado-trastuzumab, pertuzumab, cetuximab, and panitumumab.

[0190] In some implementations, the additional therapeutic agent may be an anti-angiogenic agent, including bevacizumab, aflibercept, and AMG386.

[0191] In some implementations, the additional therapeutic agent may be an antibody-drug conjugate (ADC), including DM1, DM4, MMAE, MMAF or camptothecin payload, brentuximab vedotin and emtansine, radiation therapy, or a therapeutic vaccine, including but not limited to sipuleucel-T.

[0192] In some embodiments, the additional therapeutic agent may be an autophagy inhibitor, including ULK inhibitors, VPS34 inhibitors, PIKfyve inhibitors, PPT1 inhibitors, or lysosomal blockers. In some embodiments, the additional therapeutic agent may be DCC-3116, SAR405, SB02024, hydroxychloroquine, chloroquine, apimod, MRT403, and LYS05.

[0193] In some implementations, the additional treatment agent is a luteinizing hormone-releasing hormone (LHRH) analogue selected from goserelin and leuprolide.

[0194] In some implementations, the additional treatment agent is selected from the following group: everolimus, trabectedin, abraxane, 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, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, Pemetrexed, Erlotinib, Dasatinib, Nilotinib, Decatanib, Panitumumab, Amrubicin, Oregomab, Lep-etu, Nolatrexed, AZD 2171, Batabulin, Atumtunab, Zanolimumab, Eotecarin, Tetrandrine, Rubitecan, Tesmilifene, Oblimersen, Ticilimumab, Ipilimumab, Gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Cilengitide, Gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, Lucanthone, LY 317615, Neuradiab, Vitespan, Rta 744, alanosine (Sdx102), talampanel, atrasentan, XR 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, lipid doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, 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]-disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258, 3-[5-(methanesulfonylpiperidinylmethyl)-indolyl-j-quinolinone, vatalanib, AG-013736, AVE-0005, [D-Ser(tBu) 6, Azgly

[10] Acetate (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu-Arg-Pro-Azgly-NH2 acetate (SEQ ID NO: 3) [C; 59 H 84 N 18 O 14 -(C2H4O2) xWhere x = 1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate Acetate), raloxifene, bicalutamide, flutanide, nilumethoxazole, medroxyprogesterone acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid valproic acid, trichostocin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, BCG, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone e) Cytarabine, dacarbazine, dactinomycin, donomycin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevac, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprorelin, levamisole, lomustine, mechlorethamine, melphalan.6-Mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilumethicone, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vinorelbine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, fluorouracil, deooxyuridine, cytosine Arabinoglycoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, toponotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endothelial somatostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin Diftitox, Gefitinib, Bortezomib, Irinotecan, Topotecan, Doxorubicin, Docetaxel, Vinorelbine, Bevacizumab (monoclonal antibody), Erbitux, Paclitaxel without Cremophor, Epothilone B, BMS-247550, BMS-310705, Droloxifen, 4-Hydroxytamoxifen, Pipenoxifene, ERA-923, Arzoxifene, Fulvestrant, Acolbifene, Lasofoxifene, Idoxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK222584, VX-745.PD 184352, Rapamycin, 40-O-(2-hydroxyethyl)-Rapamycin, Temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wortmannin, ZM336372, L-779450, PEG-Figrastim, Dabepoetin, Erythropoietin, Granulocyte Colony-Stimulating Factor, Zolendronate, Prednisone, Cetuximab Anti-, granulocyte-macrophage colony-stimulating factor, histamine, pegylated interferon α-2a, interferon α-2a, pegylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, medroxyprogesterone acetate, immunoglobulin, nitrogen mustard, methylprednisolone, ibritgumomab Tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, lipodinomycin, Edwina-asparaginase, strontium-89, caspopitant, netupitant, NK-1 receptor antagonists, palonosetron (The following are listed as unrelated to the preceding text and appear to be separate entries:) aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron.Dolastron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, ipilimumab, and mixtures thereof.

[0195] Pharmaceutical Compositions and Kits Another aspect of the invention provides pharmaceutical compositions comprising compounds as disclosed herein formulated with pharmaceutically acceptable carriers. Specifically, this disclosure provides pharmaceutical compositions comprising compounds 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 nebulized administration, but in any given case, the most suitable form of administration will depend on the extent and severity of the condition being treated and on the nature of the particular compound used. For example, the disclosed compositions may be formulated in unit dose form and / or may be formulated for oral or subcutaneous administration.

[0196] Exemplary pharmaceutical compositions may be used in pharmaceutical formulations, such as solid, semi-solid, or liquid forms, comprising one or more of the compounds described herein as active ingredients, mixed with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral application. The active ingredient may be formulated, for example, with a commonly used, non-toxic, pharmaceutically acceptable carrier for tablets, pills, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable form of use. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the course or condition of a disease.

[0197] For the preparation of solid compositions such as tablets, the major active ingredient may be mixed with a pharmaceutical carrier, such as a conventional tableting component (e.g., corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum), and other pharmaceutical diluents such as water, to form a solid preformed composition containing a homogeneous mixture of the compounds described herein or their non-toxic, pharmaceutically acceptable salts. When these preformed compositions are referred to as homogeneous preformed compositions, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily reclassified into equivalent dosage forms such as tablets, pills, and capsules.

[0198] In solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) for oral administration, the compositions of the present 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 silica; (2) binders, such as, for example, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) moisturizers. (3) Disintegrants, such as glycerin; (4) Disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates and sodium carbonate; (5) Solution blockers, such as paraffin; (6) Absorption enhancers, such as quaternary ammonium compounds; (7) Wetting agents, such as acetyl alcohol and glyceryl monostearate; (8) Absorbents, such as kaolin and bentonite; (9) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) Colorants. In the case of capsules, tablets and pills, the composition may also contain a buffer. Similar types of solid compositions may also be used as fillers in soft-filled and hard-filled gelatin capsules, using excipients such as lactose and high molecular weight polyethylene glycol.

[0199] Tablets can be manufactured by compression or molding, optionally together with one or more adjunct ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium glycolate starch or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be manufactured by molding a mixture of the compositions of the invention moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms such as sugar-coated pills, capsules, pellets, and granules can optionally be scored or prepared with coatings and shells such as enteric coatings and other coatings known in the field of pharmaceutical formulation.

[0200] Compositions for inhalation or inhalation 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, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuran methanol, fatty acid esters of polyethylene glycol and sorbitan, cyclodextrins, and mixtures thereof.

[0201] In addition to the compositions of the present invention, the suspension may contain, for example, ethoxylated isostearyl alcohol, polyethylene oxide sorbitol and sorbitan ester, microcrystalline cellulose, aluminum hydroxide, bentonite, agar-agar and tragacanth gum and mixtures thereof as suspending agents.

[0202] Formulations for rectal or vaginal administration may be presented in suppository form, which may be prepared by mixing the composition of the present invention with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, suppository wax or salicylates, and are solid at room temperature but liquid at body temperature and thus will melt in the body cavity and release the active agent.

[0203] Dosage forms for transdermal application of the compositions of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants that may be required.

[0204] 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, paraffin waxes, starches, tragacanth gums, cellulose derivatives, polyethylene glycols, polysiloxanes, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0205] In addition to the compositions of the present invention, powders and aerosols may contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders or mixtures thereof. Aerosols may also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane and propane).

[0206] The compositions and compounds disclosed herein can alternatively be administered via nebulizers. This is achieved by preparing aqueous nebulizers, liposome formulations, or solid particles containing the compounds. Non-aqueous suspensions (e.g., fluorocarbon propellants) can be used. Sonic nebulizers can be used because they minimize the exposure of the agent to shear forces that can lead to degradation of the compounds contained in the compositions of the invention. Generally, aqueous nebulizers are manufactured by formulating an aqueous solution or suspension of the compositions of the invention with conventionally pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary depending on the specific requirements of the compositions of the invention, but generally include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol); harmless proteins such as serum albumin; sorbitan esters; oleic acid; lecithin; amino acids such as glycine; buffers; salts; sugars or sugar alcohols. Nebulizers are generally prepared from isotonic solutions.

[0207] The pharmaceutical compositions of this disclosure suitable for parenteral administration comprise the compositions of the invention and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions just before use, said sterile powders may contain antioxidants, buffers, antibacterial agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

[0208] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions provided herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate), and cyclodextrins. Appropriate flowability can be maintained, for example, by using coating materials such as lecithin, by maintaining the desired particle size in the case of a dispersion, and by using surfactants.

[0209] In another embodiment, an enteric pharmaceutical preparation is provided, comprising the disclosed compound and an enteric-coating material, and a pharmaceutically acceptable carrier or excipient thereof. The enteric-coating material refers to a polymer that is substantially insoluble in the acidic environment of the stomach and is primarily soluble in intestinal fluid at a specific pH. The small intestine is part of the gastrointestinal tract (intestine) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is approximately 5.5, the pH of the jejunum is approximately 6.5, and the pH of the terminal ileum is approximately 7.5.

[0210] Therefore, the enteric material is insoluble, for example up to a pH of about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP); hydroxypropyl methylcellulose phthalate (HPMCP); polyvinyl acetate phthalate (PVAP); hydroxypropyl methylcellulose succinate (HPMCAS); cellulose acetate benzotriglyceride; hydroxypropyl methylcellulose succinate; cellulose succinate; cellulose hexahydrophthalate; cellulose propionate; cellulose maleate acetate; cellulose acetate butyrate; cellulose acetate propionate; copolymers of methyl methacrylate and methyl methacrylate; methyl acrylate, methyl methacrylate and methacrylate copolymers; copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series); ethyl methacrylate-methyl methacrylate-ethyl chlorotrimethylammonium acrylate copolymers; natural resins such as corn gluten, shellac and copal colophorium; and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit...). FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric. The solubility of each of the above materials is known or can be readily determined in vitro. The foregoing is a list of possible materials, but those skilled in the art who benefit from this disclosure will recognize that it is incomplete and that other enteric-coated materials exist that satisfy the objectives described herein.

[0211] Advantageously, this document provides a kit for use by consumers, for example, who require treatment for cancer. Such a kit includes a suitable dosage form, such as the dosage form described above; and instructions describing methods of using such a dosage form to mediate, reduce, or prevent inflammation. The instructions will guide the consumer or medical professional to administer the dosage form according to administration methods known to those skilled in the art. Such kits can advantageously be packaged and sold as single or multiple kit units. An example of such a kit is the so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging drug unit dosage forms (tablets, capsules, etc.). Blister packs typically consist of a relatively rigid material sheet covered with a foil of a preferred transparent plastic material. During the packaging process, a groove is formed in the plastic foil. The groove has the size and shape of the tablet or capsule to be packaged. The tablet or capsule is then placed in the groove, and the relatively rigid material sheet is sealed against the plastic foil at the foil side opposite to 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 is strong enough that pressure can be manually applied to the groove, thereby creating an opening in the sheet at the groove location for removal of tablets or capsules from the blister pack. The tablets or capsules can then be removed through this opening.

[0212] Memory aids may need to be provided on the kit, for example, in the form of numbers immediately preceding the tablets or capsules, corresponding to the number of days in the regimen for which the prescribed tablets or capsules should be taken. Another example of such a memory aid is a calendar printed on a card, such as "Week 1, Monday, Tuesday, ..., etc.; Week 2, Monday, Tuesday, ..., etc." Other variations of memory aids are self-evident. A "daily dose" can be a single tablet or capsule, or several tablets or capsules, taken on a given day. Furthermore, the first compound in a daily dose may consist of one tablet or capsule, while the second compound in a daily dose may consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

[0213] Example The compounds described herein can be prepared in various ways based on the teachings contained herein and the disclosure of synthetic procedures in the art. In the description of the synthetic methods below, it should be understood that, unless otherwise stated, all reaction conditions (including solvent selection, reaction atmosphere, reaction temperature, experimental duration, and processing procedures) presented are standard conditions for the reaction. Those skilled in the art of organic chemistry will understand that... The synthesis demonstrates that functionality present at multiple parts of the molecule should be compatible with the proposed reagents and reactants. Substituents incompatible with the reaction conditions will be apparent to those skilled in the art, and therefore alternative methods are indicated. The starting materials in the examples are commercially available or readily prepared from known materials using standard methods.

[0214] The following abbreviations are used in this disclosure and have the following definitions: "CH3CN" is acetonitrile, "ADP" is adenosine diphosphate, "ASNase" is asparaginase, and "Boc" is carbonic acid. Uncle -Butyl ester, "BSA" is bovine serum albumin, "CuCl" is copper chloride (I), "DCC" is N,N'-dicyclohexylcarbodiimide, "DCM" is dichloromethane, "DIEA" is... N , N -Diisopropylethylamine, "DMF" is N , N - Dimethylformamide, "dppf" for 1,1'-bis(diphenylphosphine)ferrocene, "DMSO" for dimethyl sulfoxide, "EDTA" for ethylenediaminetetraacetic acid, "ESI" for electrospray ionization, "EtOAc" for ethyl acetate, "EtOH" for ethanol, "GST" for glutathione S-transferase, "h" for one or more hours, "HATU" for 1-[bis(dimethylamino)methylene]-1 H -1,2,3-Triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, "HBTU" is (2-( 1H (-benzotriazole-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate, "H2" represents hydrogen, "HCl" represents hydrochloric acid, "IPA" represents isopropanol, "H2O" represents water, "HOBt" represents hydroxybenzotriazole, "IC 50 "K2CO3" represents potassium carbonate, "KOAc" represents potassium acetate, "K2PO4" represents dipotassium phosphate, "LAH" represents lithium aluminum hydride, "MeCN" represents acetonitrile, "MeOH" represents methanol, "MnO2" represents manganese dioxide, "MgSO4" represents magnesium sulfate, "MHz" represents megahertz, "min" represents one minute or more minutes, "MS" represents mass spectrometry, "NADH" represents nicotinamide adenine dinucleotide, "Na2CO3" represents sodium carbonate, "NaHCO3" represents sodium bicarbonate, "NaNO2" represents sodium nitrite, "NaOH" represents sodium hydroxide, "NaOMe" represents sodium methoxide, "NaSMe" represents sodium methanethiol, "Na2SO4" represents sodium sulfate, and "NBS" represents... N - Bromosuccinimide, "NCS" is N -Chlorosuccinimide, "NIS" is N- Iodosuccinimide, "NH4Cl" is ammonium chloride, "NMR" is nuclear magnetic resonance, "PBS" is phosphate buffered saline, "Pd / C" is palladium / carbon, "Pd2(dba)3" is tris(diphenylmethyleneacetone)dipalladium(0), "Pd(dppf)Cl2" is 1,1-bis(diphenylphosphine)ferrocene-palladium(II) chloride, "Pd(PPh3)4" is tetra(triphenylphosphine)palladium, "POCl3" is phosphorus oxychloride, "rt" is room temperature, also known as "ambient temperature", which should be understood as the normal laboratory temperature range of 15-25℃, "sat'd." is saturation, "NaBH4" is sodium borohydride, "SM" is starting material, "SOCl2" is thionyl chloride, "TEA" is triethylamine, "THF" is tetrahydrofuran, and "Xantphos" is 4,5-bis(diphenylphosphine)-9,9-dimethyldibenzoxanthracene.

[0215] General chemical reactions The exemplary compounds described herein can be obtained by the general synthetic methods illustrated in the following schemes, intermediate preparations and accompanying examples.

[0216] Option 1 Example 1 illustrates an exemplary preparation of sulfonyl chloride 1.3. Bromide 1.1a (commercially available or synthesized by those skilled in the art) is converted to sulfide 1.2a via a Pd-catalyzed coupling reaction (e.g., using Pd2(dba)3, XantPhos, phenylmethanethiol, in the presence of a base such as DIEA, in a solvent such as toluene, and at high temperature). Sulfide 1.2a is then subjected to steady oxidation (…). For example The corresponding sulfonyl chloride 1.3 was obtained by reacting NCS with dilute HCl (a combination of 1,3-dichloro-5,5-dimethylhydantoin), which is based on... Synthesis ,2006, 24 , 4131-4134 and Bioorg. Med. Chem ,2017, 25 The general reaction conditions reported in 3447-3460. Alternatively, sulfonyl chloride 1.3 can be prepared by diazotization of amine 1.1b (commercially available or synthesized by those skilled in the art), followed by Cu-mediated chlorination of the resulting intermediate (according to...). Org. Proc. Res. Dev ,2009, 5 (The general reaction conditions reported in 875-879).

[0217] Option 2 Example 2 illustrates an exemplary preparation of sulfonyl chloride 2.5. Bromide 2.1a (commercially available or synthesized by those skilled in the art) is converted to thioether 2.2 via a Pd-catalyzed coupling reaction (e.g., using Pd2(dba)3, XantPhos, phenylmethanethiol, in the presence of a base such as DIEA, in a solvent such as toluene, and at high temperature). Alternatively, compound 2.2 can be prepared from aniline 2.1b (commercially available or synthesized by those skilled in the art) by diazotization in CH3CN at high temperature using dibenzyl disulfide and pentyl nitrite. Reduction of ester 2.2 with LAH yields primary alcohol 2.3. Acyl chloride R is then used in the presence of a base such as DIEA. 5a -COCl acylation of alcohol 2.3 yields 2.4. Finally, 2.4(R) is obtained by combining NCS with dilute HCl or acetic acid. 5 = CH2OCOR 5a The steady oxidation to the corresponding sulfonyl chloride 2.5 was carried out under the general reaction conditions reported below: Synthesis ,2006, 24 , 4131-4134 and Bioorg. Med. Chem ,2017, 25 ,3447-3460. In another embodiment, 2.5b(R 5 = COOMe) can be prepared from thioether 2.2 by a combination of NCS and dilute HCl or acetic acid.

[0218] Option 3 Scheme 3 illustrates an exemplary preparation of borate esters 3.4a and 3.4b. Compound 3.1 (commercially available, synthesized as described in WO2013134298, or synthesized by a person skilled in the art) is reacted with bis(pinacolyl)diboron via a borylation reaction known to a person skilled in the art (a palladium-mediated reaction using a palladium catalyst such as Pd(dppf)Cl2, a suitable base such as KOAc, and at high temperature in a suitable solvent such as 1,4-dioxane) to give compound 3.2, which is then reacted with sulfonyl chlorides 1.3 and 2.5, respectively, to give compounds 3.4a and 3.4b. Alternatively, compound 3.1 is reacted with sulfonyl chlorides 1.3 and 2.5 to give sulfonamides 3.3a and 3.3b, which are converted to borate esters 3.4a and 3.4b, respectively, under borylation reaction conditions known to a person skilled in the art.

[0219] Option 4 Example 4 illustrates an exemplary preparation of intermediate 4.3. Commercially available 7-bromopyrrolo[2,1-f][1,2,4]triazine-4-amine 4.1 is converted to 4.2 by several different methods: (1) with Zn(R 4 The Pd-catalyzed coupling reaction of 2, (2) with R 4 -H-mediated Pd(II) / Cu(I) coupling reaction of sage, and (3) with R 4 The Suzuki reaction of -B(OR)2. If compound 4.2 contains a double or triple bond, it can be reduced in a hydrogen atmosphere in the presence of a catalyst such as Pd-C. Finally, bromination (or iodination) of 4.2 with NBS (or NIS) yields intermediate 4.3.

[0220] Option 5 Example 5 illustrates an exemplary preparation of intermediate 5.3. Those skilled in the art can use acyl chloride (R) under appropriate conditions... 4 -COCl) or trimethyl orthoformate (R 4 = H) to form an amide from (3-chloropyrazin-2-yl)methylamine 5.1, yielding amide 5.2a. Under triphosgene conditions, an amine (R) was used for amide formation. 4a -NH2) undergoes urea formation at 5.1 to yield urea 5.2b (R 4 = NHR 4a 5.1 was reacted with methyl 2-chloro-2-oxoacetate to give methyl 2-(((3-chloropyrazin-2-yl)methyl)amino)-2-oxoacetate 5.2c. Acetamides 5.2a, 5.2b, and 5.2c were cyclized with POCl3 at high temperature in an inert solvent such as CH3CN to give 3-substituted -8-chloroimidazolo[1,5-a]pyrazine 5.3.

[0221] Option 6 Example 6 illustrates the exemplary preparation of intermediates 6.3, 6.5, 6.6, and 6.8. 8-Clonimidazolo[1,5-a]pyrazine (5.3:R) is prepared. 4 = H) was brominated in DMF (2 equivalents) to give 1,3-dibromo-8-chloroimidazolo[1,5-a]pyrazine (6.1). Substitution of 6.1 with ammonia in a protic solvent such as CH3CN at high temperature in a sealed tube gave 1,3-dibromoimidazolo[1,5-a]pyrazine-8-amine (6.2). Using NaSR 4b Substitution of 6.2 yields thioether 6.3. Under Suzuki conditions, boronic acid ester R was used. 4-B(OR)2 undergoes a Pd-catalyzed coupling reaction to give intermediate 6.5. In another embodiment, compound 5.3 is brominated (or iodinated) with NBS (or NIS) in DCM to give compound 6.4. 6.4 is then substituted with ammonia in a protic solvent such as IPA at high temperature in a sealed tube to give intermediate 6.5 (from Cl to NH2). Methyl 1-bromo-8-chloroimidazolo[1,5-a]pyrazine-3-carboxylate (6.4:R) is then substituted with ammonia in a sealed tube at high temperature. 4 = COOMe) reacts with ammonia in CH3CN to give 8-amino-1-bromoimidazolo[1,5-a]pyrazin-3-carboxamide (6.6). 6.4 (R) is hydrolyzed with LiOH. 4 = COOMe) to give 1-bromo-8-chloroimidazolo[1,5-a]pyrazin-3-carboxylic acid (6,7). The substitution reaction of 6,7 with ammonia in a protic solvent at high temperature in a sealed tube yields 8-amino-1-bromoimidazolo[1,5-a]pyrazin-3-carboxylic acid, which can react with amine R 4a -NH2 reacts with amide coupling reactions known to those skilled in the art to give amide 6.8.

[0222] Option 7 Example 7 illustrates an exemplary preparation of Formula I. Bromine (or iodide) 4.3, 6.3, 6.5, 6.6, 6.7, and 6.8 are reacted with borate ester 3.2 in the presence of a Pd catalyst (Suzuki conditions) to give aniline 7.1. Aniline 7.1 is then coupled with sulfonyl chlorides 1.3 and 2.5 via a sulfonamide coupling reaction to give Formula I (7.2). Alternatively, Formula I (7.2) can be prepared by reacting bromides (or iodides) 4.3, 6.3, 6.5, 6.6, 6.7, and 6.8 with borate esters 3.4a and 3.4b under Suzuki conditions. When X 5 C-CH2OCOR 5a When K2CO3 is used to hydrolyze (deacetylate) formula I (7.2), the free hydroxyl compound of I (7.3) is obtained.

[0223] Option 8 Scheme 8 illustrates an exemplary preparation of formulas I (8.2, 8.3, and 8.5). The compound of formula I (7.3) reacts with POCl3 to give chloride 8.1. The nucleophile NaOR is then used... 5b NH3 / MeOH or R 5b-NH2 substituted chloride 8.1 to give formulas I (8.2, 8.3). In another embodiment, formula I (7.3) was oxidized with an oxidizing agent such as MnO2 to give the corresponding aldehyde 8.4. Aldehyde 8.4 can be converted into a substituted oxime of formula I (8.5).

[0224] Preparation of intermediates and final compounds The following compounds were prepared using the synthetic procedures and methods described herein and methods known to those skilled in the art: Pd-boronization Preparation Example A1: 2-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)aniline A solution of 3-bromo-2-fluoroaniline (2.5 g, 13 mmol), pinacol diborane (4.3 g, 17 mmol), and KOAc (9.9 g, 101 mmol) in 1,4-dioxane (45 mL) was degassed with Ar for 10 min. PdCl2 (dppf) (0.48 g, 0.66 mmol) was added, and the reaction mixture was degassed again with Ar for 5 min. The reaction mixture was heated to 100 °C for 1 h. The reaction mixture was filtered through a diatomaceous earth filter and washed with 1,4-dioxane. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (0 to 100% EtOAc / hexane) to give 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)aniline (2.5 g, 80%) as a brown oil. 1 H NMR (400 MHz, DMSO-d6): δ 6.86 (m, 2H), 6.76 (d,J = 6.8 Hz, 1H), 5.02 (s, 2H), 1.28 (s, 12H); MS(ESI)m / z: 238.2(M+H) + ).

[0225] The following compounds are basically prepared by the method for preparing A1.

[0226] Formation of sulfides Preparation Example B1: Ethyl 3-(benzylthio)-2,5-dichlorobenzoate A solution of ethyl 3-amino-2,5-dichlorobenzoate (12.0 g, 51 mmol) in CH3CN (250 mL) was treated with amyl nitrite (9.6 mL, 81 mmol). Dibenzyl disulfide (12.6 g, 51 mmol) was added at room temperature, and the reaction mixture was heated at 70 °C for 3 h. The reaction mixture was quenched with ice water (100 mL) and extracted with EtOAc (3×). The combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (10 to 20% EtOAc / hexane) to give ethyl 3-(benzylthio)-2,5-dichlorobenzoate (10.0 g, 58%) as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.63 (d, J = 2.8 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.44 (d, J = 7.2 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H) 7.28 (d, J = 7.2 Hz, 1H), 4.42 (s, 2H), 4.33 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 6.8 Hz, 3H).

[0227] The following compounds are basically prepared by the same method used to prepare B1.

[0228] Formation of sulfides Preparation Example B6: Methyl 3-(benzylthio)-5-chloro-2-methoxybenzoate A solution of methyl 3-bromo-5-chloro-2-methoxybenzoate (1.0 g, 3.6 mmol) and phenylmethanethiol (0.50 g, 4.3 mmol) in toluene (10 mL) was treated with DIEA (1.3 mL, 7.2 mmol). The mixture was purged with Ar for 5 min, followed by the addition of XantPhos (0.18 g, 0.32 mmol) and Pd2(dba)3 (0.16 g, 0.17 mmol). The mixture was again purged with Ar for 5 min and heated to 90 °C overnight. The reaction mixture was cooled to room temperature and filtered through a silica gel pad, washed with EtOAc:hexane (1:1). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0 to 100% EtOAc / hexane) to give methyl 3-(benzylthio)-5-chloro-2-methoxybenzoate (0.81 g, 74%) as an orange oil. 1H NMR (400MHz, DMSO-d6): δ 7.55 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.41 (m,2H), 7.33 (m, 2H), 7.24 (m, 1H), 4.14 (s, 2H), 3.90 (s, 3H), 3.70 (s, 3H).

[0229] The following compounds are basically prepared by the same method used to prepare B6.

[0230] Ester reduction Preparation Example C1: (3-(benzylthio)-2,5-dichlorophenyl)methanol A mixture of CaCl2 (0.45 g, 0.92 mmol) and NaBH4 (6.2 g, 37 mmol) in EtOH (200 mL) was stirred at 0 °C. A cold solution of ethyl 3-(benzylthio)-2,5-dichlorobenzoate (B1, 14 g, 9.2 mmol) in THF (200 mL) was added dropwise at 0 °C. The reaction mixture was slowly heated to room temperature and then heated at 60 °C for 5 hours. The reaction mixture was cooled to room temperature, quenched with saturated NH4Cl solution (50 mL), and then extracted with EtOAc (3×). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0 to 10% EtOAc / hexane) to give 8.0 g, 66% methanol (3-(benzylthio)-2,5-dichlorophenyl) as a brown solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.44 (m, 2H), 7.35 (m, 3H), 7.25-7.32(m, 2H), 5.57 (t, J = 5.6 Hz, 1H), 4.51 (d, J = 6.0 Hz, 2H), 4.36 (s, 2H).

[0231] The following compounds are basically prepared by methods for preparing C1.

[0232] acylation Preparation Example D1: 3-(benzylthio)-2,5-dichlorobenzyl acetate A solution of (3-(benzylthio)-2,5-dichlorophenyl)methanol (Cl, 0.82 g, 2.7 mmol) in THF (10 mL) was treated with acetic anhydride (0.31 mL, 3.3 mmol) at room temperature. The mixture was stirred at 50 °C under Ar for 2 hours and then diluted with water. The solution was extracted with EtOAc (3×), and the combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 3-(benzylthio)-2,5-dichlorobenzyl acetate (0.92 g, 98%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.51 (m, 3H), 7.41 (m, 3H), 7.35 (m, 1H), 5.16 (s, 2H), 4.45 (s, 2H), 2.16 (s, 3H).

[0233] The following compounds are basically prepared by the method for preparing D1.

[0234] Oxidation of sulfides Preparation Example E1: 2,5-Dichloro-3-(chlorosulfonyl)benzyl acetate A solution of 3-(benzylthio)-2,5-dichlorobenzyl acetate (D1, 0.92 g, 2.7 mmol) and 1-chloropyrrolidone-2,5-dione (1.8 g, 13 mmol) in THF:H2O (1:1, 3 mL) was treated with acetic acid (7 mL) at 0 °C. The reaction mixture was slowly heated to room temperature and then stirred at room temperature for 6 hours. The reaction mixture was quenched with saturated NaHCO3 solution (100 mL) and extracted with EtOAc (3×). The combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (0 to 100% EtOAc / hexane) to give 2,5-dichloro-3-(chlorosulfonyl)benzyl acetate (0.45 g, 53%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.84 (d, J = 2.8 Hz, 1H), 7.52 (d, J = 2.8 Hz, 1H), 5.13 (s, 2H), 2.11 (s, 3H).

[0235] The following compounds are basically prepared by methods for preparing E1.

[0236] sulfonation Preparation Example E13: 5-chloro-2-fluoro-4-methoxybenzenesulfonyl chloride A solution of 1-chloro-4-fluoro-2-methoxybenzene (10.0 g, 62 mmol) in DCM (625 mL) was cooled to 0 °C. Chlorosulfonic acid (17 mL, 250 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with water and extracted with DCM (2x). The combined organic matter was washed with water, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 5-chloro-2-fluoro-4-methoxybenzenesulfonyl chloride (11.0 g, 68%) as a white crystalline solid. 1 H NMR (400MHz, DMSO-d6): δ 7.60 (d, J = 7.4 Hz, 1H), 7.04 (d, J = 11.3 Hz, 1H), 3.87 (s, 3H).

[0237] sulfonation Preparation Example E14: Methyl 2,5-dichloro-3-(chlorosulfonyl)benzoate 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 c-HCl (18 mL) at -15 °C. The solution was stirred for 30 min under the same conditions) was added dropwise to solution B (preparation: thionyl chloride (2.8 mL, 39 mmol) was added dropwise to water (17 mL) in acetone / ice bath. The mixture was stirred at room temperature for 16 h. Copper(I) (10 mg, 1 mmol) was added at room temperature, and the mixture was then cooled to -15 °C and stirred for 30 min). The reaction mixture was stirred for 2 h under the same conditions and then diluted with DCM (100 mL). The aqueous layer was extracted with DCM (3×). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (0 to 50% EtOAc / hexane) to obtain methyl 2,5-dichloro-3-(chlorosulfonyl)benzoate (2.1 g, 76%), which was a yellow viscous liquid. 1HNMR (400 MHz, DMSO-d6): δ 8.00 (d, J = 2.7 Hz, 1H), 7.72 (d, J = 2.7 Hz, 1H), 3.86 (s, 3H).

[0238] Formation of sulfonamides Preparation Example G1: 2,5-Dichloro-3-( N Methyl 2-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)aminesulfonyl)benzoate A solution of 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)aniline (Al, 2.2 g, 9.3 mmol) in DCM (30 mL) was treated with pyridine (2.2 mL, 28 mmol). The reaction mixture was cooled to 0 °C, and methyl 2,5-dichloro-3-(chlorosulfonyl)benzoate (E14 2.8 g, 9.3 mmol) was added dropwise to a solution of DCM (10 mL). The reaction mixture was slowly heated to room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was dissolved in DCM (50 mL). The solution was washed with 1.0 M HCl aqueous solution (2×), NaHCO3 aqueous solution (3×), and brine (1×). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was suspended in hexane and the solid was collected by vacuum filtration to obtain a brown solid, 2,5-dichloro-3-( N methyl benzoate (4.2 g, 90%) of 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)aminesulfonyl)benzoate. 1 H NMR (400 MHz, DMSO-d6): δ10.71 (s, 1H), 8.13 (d, J = 2.6 Hz, 1H), 8.02 (d, J = 2.6 Hz, 1H), 7.46 (m,1H), 7.38 (dt, J = 1.8, 7.9 Hz, 1H), 7.16 (t, J = 7.7 Hz, 1H), 3.91 (s, 3H),1.28 (s, 12H); MS(ESI)m / z 526.0 (M+Na+H + ).

[0239] The following compounds are basically prepared by the method for preparing G1.

[0240] Ester reduction Preparation Example G18: 2,5-Dichloro- N -(2-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)phenyl)-3-(hydroxymethyl)benzenesulfonamide 2,5-Dichloro-3-( N A solution of methyl 2,5-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)aminesulfonyl)benzoate (G1, 0.5 g, 0.99 mmol) in THF (5 mL) was fractionally treated with LAH (0.11 g, 30 mmol) and then stirred at 0 °C for 1 h. The reaction mixture was diluted with diethyl ether and then quenched with water (0.2 mL), 15% NaOH aqueous solution (0.2 mL), and water (0.4 mL). The mixture was stirred for 4 h and then filtered through a diatomaceous earth mat. The filtrate was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2,5-dichloro- N -(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)-3-(hydroxymethyl)benzenesulfonamide (0.26 g, 55%), which was used in the next reaction without further purification. MS (ESI) m / z 498.0 (M+Na+H) + ).

[0241] acylation Preparation Example H1: N -((3-chloropyrazin-2-yl)methyl)acetamide A solution of (3-chloropyrazin-2-yl)methylamine hydrochloride (5.0 g, 28 mmol) in DCM (100 mL) was cooled to 0 °C. DIEA (12 mL, 69 mmol) and acetic anhydride (2.6 mL, 28 mmol) were added, and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into water (100 mL) and extracted with DCM (2x). The combined organic matter was dried over anhydrous Mg2SO4, filtered, and concentrated under reduced pressure. The crude material was filtered through a silica gel pad and washed with DCM. The filtrate was concentrated under reduced pressure, and the residue was treated with EtOAc / hexane. The material was cooled in an ice bath, and the solid was collected by vacuum filtration to give a brown crystalline solid. N -((3-chloropyrazine-2-yl)methyl)acetamide (3.5 g, 68%).1 H NMR (400 MHz, DMSO-d6): δ 8.64 (d,J = 2.5 Hz, 1H), 8.38-8.47 (m, 2H), 4.50 (d,J = 5.6 Hz, 2H), 1.90 (s, 3H).

[0242] The following compounds are basically prepared by the method for preparing H1.

[0243] Urea formation Preparation Example H8: 3-((3-chloropyrazin-2-yl)methyl)-1-(4-methoxybenzyl)-1-methylurea A solution of (3-chloropyrazin-2-yl)methylamine hydrochloride (4.0 g, 22 mmol) and 1-(4-methoxyphenyl)-N-methylmethylamine (5.6 g, 22 mmol) in DCM (160 mL) was cooled to 0 °C. Et3N (20 mL, 155 mmol) was added, and the reaction mixture was stirred at 0 °C for another 5 min. Triphosgene (9.9 g, 33 mmol) was added fractionally under the same conditions. The reaction mixture was heated to room temperature and stirred for 16 h. The reaction mixture was quenched with water (100 mL) and subsequently extracted with DCM (2×). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (0 to 10% MeOH / DCM) to obtain 2.5 g, 35% grayish-white solid 3-((3-chloropyrazin-2-yl)methyl)-1-(4-methoxybenzyl)-1-methylurea. 1 H NMR (400 MHz, DMSO-d6): δ 8.66 (d, J = 2.4 Hz, 1H), 8.41 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 6.98 (t, J = 5.6 Hz, 1H), 6.90 (d, J = 8.4 Hz, 2H), 4.48 (d, J = 5.2 Hz, 2H), 4.36 (s, 2H), 3.73 (s,3H), 2.75 (s, 3H); MS(ESI)m / z: 320.9(M+H) + ).

[0244] The following compounds are basically prepared by the method for preparing H8.

[0245] cyclization Preparation Example I1: 8-chloro-3-methylimidazo[1,5-a]pyrazine Will N A solution of 3-((3-chloropyrazin-2-yl)methyl)acetamide (H1, 3.5 g, 19 mmol) in CH3CN (40 mL) was treated with POCl3 (8.8 mL, 94 mmol). The reaction mixture was heated to 80 °C over a period of time. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was dissolved in DCM and the solution was slowly added to ice water (100 mL) to quench residual POCl3. The aqueous layer was extracted with DCM (3×) and the combined organic matter was washed with saturated NaHCO3, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude material was recrystallized from MeOH / EtOAc. The crystals were collected by vacuum filtration to give 1.2 g, 38% brown crystalline solid 8-chloro-3-methylimidazo[1,5-a]pyrazine. 1 H NMR (400 MHz, DMSO-d6): δ8.22 (dd, J = 1.0, 4.9 Hz, 1H), 7.78 (d, J = 1.1 Hz, 1H), 7.39 (d, J = 5.0Hz, 1H), 2.65 (s, 3H); MS(ESI)m / z: 168.2(M+H + ).

[0246] The following compounds are basically prepared by methods for preparing I1.

[0247] Zinc-mediated Pd-catalyzed coupling reactions Preparation Example J1: 7-Methylpyrrolo[2,1-f][1,2,4]triazine-4-amine A solution of 7-bromopyrrolo[2,1-f][1,2,4]triazine-4-amine (1.2 g, 5.7 mmol) in THF (36 mL) was treated with toluene (2.8 mL, 5.7 mmol) containing 2.0 M dimethylzinc at room temperature under an Ar atmosphere. The reaction mixture was bubbled with Ar for 10 min, followed by the addition of Pd(PPh3)4 (0.65 g, 0.57 mmol). The resulting reaction mixture was heated at 60 °C for 4 h and then cooled to room temperature. The mixture was filtered through a diatomaceous earth mat and washed with THF. The filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with water (2×). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 7-methylpyrrolo[2,1-f][1,2,4]triazine-4-amine (0.45 g, 64%) as a grayish-white solid. 1 HNMR (400 MHz, DMSO-d6): δ 7.80 (s, 1H), 7.48 (br s, 2H), 6.79 (d, J = 4.4 Hz, 1H), 6.41 (d, J = 4.0 Hz, 1H), 2.39 (s, 3H).

[0248] Iodination (bromination) Preparation Example K1: 8-chloro-1-iodo-3-methylimidazo[1,5-a]pyrazine A solution of 8-chloro-3-methylimidazo[1,5-a]pyrazine (I1, 1.3 g, 0.78 mmol) in DMF (15.5 mL) was treated with 1-iodopyrrolidine-2,5-dione (2.6 g, 12 mmol). The reaction mixture was heated to 60 °C overnight. The reaction mixture was poured into DCM (200 mL) and the solution was subsequently washed with water (2×). The combined organic compounds were concentrated under reduced pressure, and the residue was subsequently treated with water. The precipitate was filtered, washed with hexane, and dried under high vacuum to give 8-chloro-1-iodo-3-methylimidazo[1,5-a]pyrazine (2.3 g, 101%) as an orange solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.26 (d, J = 5.0 Hz, 1H), 7.37 (d, J = 5.0 Hz, 1H), 2.61 (s, 3H); MS (ESI) m / z: 294.0 (M+H + ).

[0249] The following compounds are basically prepared by the method used to prepare K1.

[0250] hydrolysis Preparation Example L1: 1-Bromo-8-chloroimidozano[1,5-a]pyrazine-3-carboxylic acid A solution of methyl 1-bromo-8-chloroimidazolo[1,5-a]pyrazin-3-carboxylic acid (K7, 3.5 g, 12 mmol) in a mixture of THF and H₂O (2:1, 40 mL) was treated with LiOH monohydrate (0.99 g, 24 mmol). The reaction mixture was stirred at room temperature for another 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude material was acidified with 1.0 N HCl. The precipitated solid was filtered, washed with water (5 mL), and dried under high vacuum to give 1-bromo-8-chloroimidazolo[1,5-a]pyrazin-3-carboxylic acid (3.0 g, 97%) as a grayish-white solid. 1 ¹H NMR (400 MHz, DMSO-d⁶): δ 9.07 (d, J = 4.8 Hz, 1H), 7.74 (d, J = 4.8 Hz, 1H), proton missing; MS (ESI) m / z: 275.9 (M+H) + ).

[0251] Aromatic substitution reaction Preparation Example M1: 1-Iodo-3-methylimidazo[1,5-a]pyrazine-8-amine A solution of 8-chloro-1-iodo-3-methylimidazo[1,5-a]pyrazine (K1, 2.3 g, 7.8 mmol) in THF (8 mL) was treated with ammonia (2.0 M in IPA, 78 mL, 157 mmol). The container was sealed and heated to 110 °C for 24 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give 1-iodo-3-methylimidazo[1,5-a]pyrazine-8-amine (2.1 g, 98%) as a brown solid. 1 H NMR(400 MHz, DMSO-d6): δ 7.59 (d, J = 5.2 Hz,1H), 7.31 (br s, 2H), 7.01 (d, J = 5.2 Hz, 1H), 2.52 (s, 3H); MS(ESI)m / z: 275.0(M+H) + ).

[0252] The following compounds were prepared primarily by the method used to prepare M1.

[0253] amide coupling reaction Preparation Example M13: 8-amino-1-bromo-N-methylimidazo[1,5-a]pyrazine-3-carboxamide A suspension of 8-amino-1-bromoimidazolo[1,5-a]pyrazin-3-carboxylic acid (M12, 0.1 g, 0.39 mmol) in DMF (4 mL) was treated with DIEA (0.6 mL, 3.9 mmol). HATU (0.50 g, 0.97 mmol) was added, and the resulting mixture was stirred at room temperature for 10 min. A solution of DMF (2 mL) containing methylamine hydrochloride (0.13 g, 1.95 mmol) was added, and the reaction mixture was then stirred at room temperature for 3 h. The mixture was quenched with ice-cold water (5 mL), and the aqueous layer was extracted with 10% MeOH / DCM (3x). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 8-amino-1-bromo-N-methylimidazolo[1,5-a]pyrazin-3-carboxamide (0.08 g, 76%) as a pale brown solid, which was used in the next step without further purification. MS(ESI) m / z: 270.0 (M+H) + ) and 272.0.

[0254] Aromatic substitution reaction Preparation Example M14: 1-Bromo-3-(methylthio)imidazo[1,5-a]pyrazine-8-amine A solution of 1,3-dibromoimidazolo[1,5-a]pyrazin-8-amine (L8, 0.5 g, 1.73 mmol) in DMF (5 mL) was treated with NaSMe (0.2 g, 3.46 mmol) at room temperature. The reaction mixture was heated at 70 °C for 16 h and then cooled to room temperature. The mixture was quenched with ice-cold water (20 mL). The resulting precipitate was filtered, washed with water (20 mL), and dried under high vacuum to give 1-bromo-3-(methylthio)imidazolo[1,5-a]pyrazin-8-amine (0.3 g, 68%) as a grayish-white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.47 (d, J = 5.2 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 6.74 (br s, 2H), 2.57 (s, 3H); MS(ESI)m / z: 258.8(M+H) + ).

[0255] Suzuki reaction Preparation Example M15: 1-bromo-3-(1 H -pyrazol-4-yl)imidazo[1,5-a]pyrazin-8-amine A solution of 1,3-dibromoimidazolo[1,5-a]pyrazin-8-amine (L8, 0.50 g, 1.7 mmol) in a mixture of 1,4-dioxane:water (3:1, 10 mL) was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1H-pyrazole (0.39 g, 2.1 mmol) and Na₂CO₃ (0.54 g, 5.2 mmol). The reaction mixture was degassed with Ar for 10 min. Pd(dppf)Cl₂•DCM (0.14 g, 0.17 mmol) was added and the reaction mixture was heated at 110 °C for 4 h. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth mat, and thoroughly washed with 10% MeOH / DCM. The filtrate was washed with water, and the organic layer was dried over anhydrous Na₂SO₄. The mixture was filtered and concentrated under reduced pressure to give crude material (0.50 g), which was used in the next step without further purification. MS (ESI) m / z: 278.9 (M+H) + ).

[0256] The following compounds were prepared primarily using the method for preparing M15.

[0257] Suzuki reaction Preparation Example N1: 5-(3-amino-2-fluorophenyl)-7-methyl-7 H -pyrrolo[2,3-d]pyrimidin-4-amine 5-Iodo-7-methyl-7 H A solution of pyrrolo[2,3-d]pyrimidin-4-amine (0.4 g, 1.45 mmol) in dioxane and water (3:1, 10 mL) was prepared with (2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)phenyl)carbamic acid. Uncle DingThe mixture was treated with ester (0.59 g, 1.75 mmol) and cesium carbonate (1.42 g, 4.37 mmol). The reaction mixture was degassed with N2 gas for 5 min and then Pd(dppf)Cl2•DCM (0.12 g, 0.14 mmol) was added. The reaction mixture was heated at 90 °C for 16 h and cooled to room temperature. The reaction mixture was filtered through a diatomaceous earth mat and washed with EtOAc (10 mL). The filtrate was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue. The crude substance was purified by silica gel column chromatography to give (3-(4-amino-7-methyl-7-) H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)carbamic acid Uncle Ding Ester (0.36 g, 69%). LC-MS (ESI) m / z: 358.4 (M+H) + ).

[0258] At room temperature, (3-(4-amino-7-methyl-7-) H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)carbamic acid Uncle Ding A solution of the ester (0.36 g, 1.0 mmol) in DCM (5 mL) was treated with 1,4-dioxane (1.0 mL, 4.0 mmol) containing 4.0 N HCl. The reaction mixture was stirred for 3 h and the solution was concentrated under reduced pressure to give 5-(3-amino-2-fluorophenyl)-7-methyl-7 H -Pyrrolo[2,3-d]pyrimidine-4-amine HCl salt (0.32 g, crude material). LC-MS (ESI) m / z: 257.9 (M+H) + ).

[0259] Suzuki reaction Preparation Example 1: Acetic acid 3-( N -(3-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)aminosulfonyl)-2,5-dichlorobenzyl ester A solution of 1-iodo-3-methylimidazo[1,5-a]pyrazin-8-amine (L1, 3.0 g, 11 mmol) in a mixture of 1,4-dioxane:water (8:1, 67.5 mL) was prepared at room temperature with 2,5-dichloro-3-( N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)aminesulfonyl)benzyl ester (G13, 6.8 g, 13 mmol) and K2CO3 (4.5 g, 33 mmol). The reaction mixture was degassed with Ar for 20 min, followed by the addition of Pd(dppf)Cl2•DCM (0.89 g, 1.1 mmol). The resulting mixture was heated at 90 °C for 12 h. The reaction mixture was cooled to room temperature and filtered through a diatomaceous earth mat, and thoroughly washed with EtOAc (500 mL). The filtrate was washed with saturated NaHCO3 (2x) and water. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by reversed-phase column chromatography (0 to 100% CH3CN / water (0.1% FA)) to give 3-( ) acetic acid as a light brown solid. N -(3-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)aminesulfonyl)-2,5-dichlorobenzyl ester (5.9 g, 35%). 1 H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 7.88 (d, J = 2.6 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.43 (d, J = 5.0 Hz, 1H), 7.22 (m, 2H), 7.16 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 4.9 Hz, 1H), 5.84 (s,2H), 5.13 (s, 2H), 2.48 (s, 3H), 2.02 (s, 3H).

[0260] hydrolysis Preparation Example 2: N -(3-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2,5-dichloro-3-(hydroxymethyl)benzenesulfonamide Acetic acid 3-( NA solution of 1,05-(3-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)aminesulfonyl)-2,5-dichlorobenzyl ester (1, 0.53 g, 0.98 mmol) in MeOH (5 mL) was treated with K₂CO₃ (0.40 g, 2.9 mmol). The suspension was stirred at room temperature for 1 h, and the reaction mixture was concentrated directly under reduced pressure. The crude material was acidified with 10% citric acid solution (approximately 50 mL, pH approximately 5), and a solid began to precipitate. The solid was filtered, washed with water, and dried under high vacuum to obtain N -(3-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2,5-dichloro-3-(hydroxymethyl)benzenesulfonamide (0.12 g, 25%). 1 H NMR (400 MHz, DMSO-d6): δ 10.77 (br m, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.75 (br s, 1H), 7.50 (d, J = 4.8 Hz, 1H), 7.27 (m,1H), 7.20 (m, 2H), 7.04 (d, J = 4.8 Hz, 1H), 5.84 (br s, 2H), 5.70 (t, J =6.0 Hz, 1H), 4.60 (d, J = 5.6, 2H), 2.54 (s, 3H); MS(ESI)m / z: 496.3(M+H) + ).

[0261] The following compounds were prepared essentially by the methods described in Examples 1 and 2.

[0262] The following compounds were prepared essentially by the method described in Example 1.

[0263] Formation of sulfonamides Preparation Example 45: N-(3-(4-amino-7-methyl-7) H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide 5-(3-amino-2-fluorophenyl)-7-methyl-7 H A solution of pyrrolo[2,3-d]pyrimidine-4-amine HCl salt (N1, 0.06 g, 0.20 mmol) in pyridine (3 mL) was treated with 5-chloro-2-methoxypyridine-3-sulfonyl chloride (E12, 0.06 g, 0.24 mmol). The reaction mixture was stirred at room temperature for 16 h and then diluted with EtOAc (20 mL). The solution was washed with saturated NaHCO3, and the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude substance. The crude substance was further ground with Et2O and the solid was filtered to give a pure, grayish-white solid. N -(3-(4-amino-7-methyl-7) H -Pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (0.025 g, 27%). 1 H NMR (400 MHz, DMSO-d6): δ 10.39 (br s, 1H), 8.49 (d, J = 2.4Hz, 1H), 8.15 (s, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.26 (s, 1H), 7.22 (m, 3H), 5.99 (br s, 2H), 3.91 (s, 3H), 3.73 (s, 3H). LC-MS(ESI)m / z: 463.2(M+H + ).

[0264] Nucleophilic substitution reaction Preparation Example 46: N -(3-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2,5-dichloro-3-(chloromethyl)benzenesulfonamide At room temperature under a nitrogen atmosphere NA solution of 3-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2,5-dichloro-3-(hydroxymethyl)benzenesulfonamide (2, 0.20 g, 0.404 mmol) in 1,2-dichloroethane (7 mL) was treated with POCl3 (0.11 mL, 1.21 mmol). The reaction mixture was stirred at room temperature for 6 hours, and then the mixture was slowly quenched with ice-cold water (20 mL). The aqueous layer was neutralized with saturated NaHCO3 solution, and then extracted with 10% MeOH / DCM (3x). The combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a light brown solid. N -(3-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2,5-dichloro-3-(chloromethyl)benzenesulfonamide (0.2 g, 62%). MS (ESI) m / z: 514.0 (M+H) + ).

[0265] The following compounds were prepared essentially by the method described in Example 46.

[0266] Nucleophilic substitution reaction Preparation Example 48: N -(3-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2,5-dichloro-3-(methoxymethyl)benzenesulfonamide At room temperature N A solution of 3-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2,5-dichloro-3-(chloromethyl)benzenesulfonamide (46, 0.20 g, 0.39 mmol) in MeOH (5 mL) was treated with MeOH (5 mL) containing 25% NaOMe. The reaction mixture was stirred at room temperature for 16 h, and then the mixture was slowly quenched with ice-cold water (20 mL). The aqueous layer was extracted with 10% MeOH / DCM (3x), and the combined organic matter was dried over anhydrous Ns2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0 to 10% MeOH / DCM) to obtain the desired product as a grayish-white solid. N -(3-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2,5-dichloro-3-(methoxymethyl)benzenesulfonamide (0.045 g, 11%). 1H NMR (400 MHz, DMSO-d6): δ 10.76 (br s, 1H), 7.88 (d, J= 2.8 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 4.8 Hz, 1H), 7.20-7.31(m, 3H), 7.05 (d, J = 4.8 Hz, 1H), 5.88 (br s, 2H), 4.55 (s, 2H), 3.37 (s,3H), 2.55 (s, 3H); MS(ESI)m / z: 510.0(M+H) + ).

[0267] The following compounds were prepared essentially by the method described in Example 48.

[0268] Oxidation Preparation Example 51: N -(3-(4-amino-7-methyl-7) H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-2,5-dichloro-3-carboxybenzenesulfonamide Will N -(3-(4-amino-7-methyl-7) H A solution of pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-2,5-dichloro-3-(hydroxymethyl)benzenesulfonamide (synthesized by those skilled in the art, 0.5 g, 1.0 mmol) in THF (20 mL) was treated with MnO2 (1.3 g, 15 mmol). The reaction mixture was stirred at room temperature for 3 days. The reactants were diluted with EtOAc and filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure to give N -(3-(4-amino-7-methyl-7) H -Pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-2,5-dichloro-3-carboxybenzenesulfonamide (crude, 100%). MS (ESI) m / z: 494.0 (M+H) + ).

[0269] Oxime formation Preparation Example 52: ( Z )- N -(3-(4-amino-7-methyl-7) H -pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-2,5-dichloro-3-((hydroxyimino)methyl)benzenesulfonamide 11597 coarse material N -(3-(4-amino-7-methyl-7) H A solution of pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-2,5-dichloro-3-carboxybenzenesulfonamide (51, 0.49 g, 1.0 mmol) in EtOH (20 mL) was treated with NH₂OH HCl (0.35 g, 5.0 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the residue was subsequently purified by reversed-phase column chromatography (10-100% MeCN (0.1% TFA) / water). The fractions containing the product were combined and neutralized with saturated NaHCO₃ solution. The solution was extracted with 5% MeOH / DCM. The organic layer was dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure to give a pale yellow solid ( Z )- N -(3-(4-amino-7-methyl-7) H -Pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-2,5-dichloro-3-((hydroxyimino)methyl)benzenesulfonamide (0.12 g, 21%). 1 H NMR (400 MHz, DMSO-d6): δ 12.11 (s, 1H), 10.76 (br s, 1H), 8.43 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.26 (d, J = 5.4 Hz, 1H), 7.14-7.22 (m, 4H), 6.00 (br s, 2H), 3.73(s, 3H); MS(ESI)m / z: 509.0(M+H + ).

[0270] The following compounds were prepared essentially by the method described in Preparation Example 52.

[0271] Biochemical analysis of GCN2 The activity of GCN2 kinase was determined using TR-FRET kinase activity assay. For example , Analytical Biochemistry ,2006, 356 The determination was made using 108-116. The assay volume was 13 µL in a 384-well plate using 2 nM GCN2 (CarnaBiosciences), 130 nM GFP-EIf2α (Invitrogen), and 0.2 mg / mL. E. coliThe assay was performed using kinase buffer (Invitrogen) containing tRNA (Sigma) and 1 mM ATP. GCN2 inhibition was measured by adding serially diluted test compounds (final assay concentration 0.5% DMSO) followed by incubation for 3 hours. Tb-peIF2a (pSer52) antibody (Invitrogen) (2 nM final assay concentration) was added to kinase buffer containing ETDA (final assay concentration 20 mM). After incubation at room temperature for 60 minutes, TR-FRET was monitored using an excitation wavelength of 340 nm and emission wavelengths of 490 nm and 520 nm. A control was used (…). Right now (The reaction of the test compound was not observed, and the reaction was observed with known inhibitors). The emission ratio (520 / 490) of the compound at various concentrations was converted into the inhibition percentage, and the IC was calculated by fitting a four-parameter sigmoid curve to the data using Prism (GraphPad software). 50 value.

[0272] SEQ ID NO: 1-GCN2 protein sequence (residues 1-1649; G556E with an N-terminal GST tag) Biochemical analysis of PERK PERK kinase activity was determined spectroscopically using a pyruvate kinase / lactate dehydrogenase-coupled assay that continuously monitors ATP-dependent NADH oxidation. Science ,2000, 289 , 1938–1942). Assays were performed in 384-well plates (100 μL final volume) using an assay buffer (100 mM Tris pH 7.5, 15 mM MgCl2, 0.5 mM DTT, 0.004% (w / v) BSA, and 0.004% Triton X-100) containing 10 nM PERK (from Beryllium), 0.25 mg / mL myelin basic protein substrate, 1.5 units of pyruvate kinase, 2.1 units of lactate dehydrogenase, 1 mM pyruvate phosphoenol, 0.28 mM NADH, and 1 mM ATP). PERK inhibition was measured by adding serially diluted test compounds (final analytical concentration 1% DMSO). The decrease in absorbance at 340 nm was continuously monitored for up to 6 hours at 30°C using a multimodal microplate reader (BioTek). Reaction rates were calculated using 2–3 h time intervals. A control was used ( Right now (Reactions without test compounds and reactions with known inhibitors) convert the reaction rates at various concentrations of the compound into percentage inhibition, and calculate the IC using software routines in Prism (GraphPad software). 50 value.

[0273] SEQ ID NO: 2 - PERK protein sequence (residues 563-1115; sequence ID: NM 004836) MSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLK SSKYIAWPLQGWQATFGGGDHPPKSDLVPRGSKYDSVSGEANDSSWNDIKNSGYISRYLTDFEPIQCLGRGGFGVVFEAKNKVDDCNYAIKRIRLPNRELAREKVMREVKALAKLEHPGIVRYFNAWLEAPPEKWQEKMDEIWLKDESTDWPLSSPSPMDAPSVKIRRMDPFSTKEHIEIIAPSPQRSRSFSVGI SCDQTSSSESQFSPLEFSGMDHEDISESVDAAYNLQDSCLTDCDVEDGTMDGNDEGHSFELCPSEASPYVRSRERTSSSIVFEDSGCDNASSKEEPKTNRLHIGNHCANKLTAFKPTSSKSSSEATLSISPPRPTTLSLDLTKNTTEKLQPSSPKVYLYIQMQLCRKENLKDWMNGRCTIEERERSVCLHIFLQI AEAVEFLHSKGLMHRDLKPSNIFFTMDDVVKVGDFGLVTAMDQDEEEQTVLTPMPAYARHTGQVGTKLYMSPEQIHGNSYSHKVDIFSLGLILFELLYPFSTQMERVRTLTDVRNLKFPPLFTQKYPCEYVMVQDMLSPSPMERPEAINIIENAVFEDLDFPGKTVLRQRSRSLSSSGTKHSRQSNNSHSPLPSN Table 1. Inhibition of the biochemical activity of GCN2 and PERK kinases by exemplary compounds.

[0274] For Table 1, "+" indicates IC values ​​less than or equal to 100 nM. 50 "++" refers to an IC with a value greater than 100 nM and less than or equal to 500 nM. 50"++" refers to an IC with a capacity greater than 500 nM and less than or equal to 1000 nM. 50 Furthermore, "++++" refers to an IC that is greater than 1000 nM and less than or equal to 10000 nM. 50 .

[0275] CCRF-CEM ASNase cell proliferation assay, a phenotypic assay for cell inhibition of GCN2.

[0276] CCRF-CEM leukemia cells (catalog number CCL-116) were obtained from the American Type Culture Collector (ATCC, Manassas, VA). Cells were grown at 37°C, 5% CO2, 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 to one million cells / mL, at which point they were passaged or collected for assays. Ten thousand cells per well were dispensed from 200 µL RPMI-1640 medium supplemented with 10% heat-inactivated fetal bovine serum and 1% penicillin / streptomycin into 96-well black clear plates. Serially diluted test compounds and 1 mU / mL ASNase were added in triplicate, and the plates were incubated at 37°C, 5% CO2, and 95% humidity for 72 hours. At the end of incubation, 40 µL of a 440 mM solution of resazurin (Sigma, St. Louis, MO) in PBS was added to each well of the plate, and the plate was incubated for another 6 hours at 37°C, 5% CO2, and 95% humidity. The plate was then read using a Synergy2 reader or equivalent reader (Biotek, Winooski VT) with 540 nM excitation and 600 nM emission. The data were analyzed using GraphPad Prism software (GraphPad Software, San Diego, CA) to calculate the IC50. 50 value.

[0277] CCRF-CEM TG ATF4 ELISA, a phenotypic analysis for cell inhibition of PERK pre-activated by carotenoid (TG). CCRF-CEM leukemia cells (catalog number CCL-116) were obtained from the American Type Culture Collection (ATCC, Manassas, VA). In short, cells were grown at 37°C, 5% CO2, 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 to one million cells / mL, at which point they were passaged or collected for assays. 1.5 million cells / well of 1 mL of complete growth medium were aliquoted into 12-well plates and incubated overnight. Serially diluted test compounds were added, and cells were incubated at 37°C, 5% CO2, and 95% humidity for three hours, followed by the addition of 1 µM beta-carotene and incubation at 37°C, 5% CO2, and 95% humidity for one hour. Cells were lysed, and ATF4 levels were then measured using an ELISA assay (Proteintech, Rosemont, IL). Uptake was measured at 450 nM and 544 nM using a Synergy2 or equivalent reader (Biotek, Winooski VT). Data were analyzed using PRISM software (GraphPad, San Diego, CA) to calculate IC50. 50 value.

[0278] Table 2. Inhibition of proliferation of exemplary compounds in ASNase-treated CCRF-CEM cells and ATF4 in CCRF-CEM cells stimulated by carotenoids.

[0279] For Table 2, "+" indicates IC values ​​less than or equal to 100 nM. 50 "++" refers to an IC with a value greater than 100 nM and less than or equal to 500 nM. 50 "++" refers to an IC with a capacity greater than 500 nM and less than or equal to 1000 nM. 50 Furthermore, "++++" refers to an IC that is greater than 1000 nM and less than or equal to 10000 nM. 50 .

[0280] H929 ATF4 ELISA assay H929 multiple myeloma cells (catalog number CRL-9068) were obtained from the American Type Culture Collection (ATCC, Manassas, VA). In short, cells were grown at 37°C, 5% CO2, and 95% humidity in RPMI-1640 medium supplemented with 20% heat-inactivated fetal bovine serum (catalog number A3840002, ThermoFisher Scientific, Waltham, MA), 1% penicillin / streptomycin / L-glutamine (catalog number 10378016, ThermoFisher Scientific, Waltham, MA), and 0.05 mM 2-mercaptoethanol (catalog number 21985-023, ThermoFisher Scientific, Waltham, MA) until a cell density of 1.5 million cells / mL was reached. At this point, cells were passaged or collected for assays. 1.5 million cells / well from 1 mL of complete growth medium were aliquoted into 12-well plates and incubated overnight. Serially diluted test compounds were added, and cells were incubated at 37°C, 5% CO2, and 95% HCl for four hours. Cells were lysed, and ATF4 levels were measured using ELISA (Proteintech, Rosemont, IL). Uptake was measured at 450 nM and 544 nM using Synergy2 or an equivalent reader (Biotek, Winooski VT). Data were analyzed using PRISM software (Graphpad, San Diego, CA) to calculate the fold stimulation of cellular ATF4 relative to solvent-treated controls.

[0281] Table 3. ATF4 in H929 multiple myeloma cells stimulated by exemplary compounds.

[0282] For Table 3, "+" means a stimulus of 5 times or less than or equal to 5 times the ATF4 stimulus; "++" means a stimulus of 5 times or less than or equal to 10 times the ATF4 stimulus; "+++" means a stimulus of 10 times or less than or equal to 20 times the ATF4 stimulus; and "++++" means a stimulus of 20 times or more the ATF4 stimulus.

[0283] equivalent Although specific embodiments have been described, the above description is illustrative and not restrictive. Many variations of the embodiments will be apparent to those skilled in the art upon review of this specification. The full scope of the disclosure and its equivalents, as well as the full scope of this specification and the variations thereof, should be determined with reference to the claims.

[0284] Unless otherwise specified, all figures representing amounts of components, reaction conditions, etc., as used in this specification and claims should be understood in all cases to be modified by the term "about". Therefore, unless otherwise indicated, the numerical parameters described in this specification and the appended claims are approximate values ​​that may vary depending on the desired properties being sought.

Claims

1. A compound represented by formula IA: Formula IA Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 and X 4 Each is independently selected from the following groups: CH and N; X 2 Selected from the following groups: C and N; X 3 Selected from the following group: CR 4 and NR 4 ; As long as X 1 X 2 X 3 and X 4 No more than two of them are N; X 5 Selected from the following group: CR 5 and N; R 1 and R 2 Each is independently selected from the following group: H, alkoxy, alkyl, cyano, haloalkoxy, haloalkyl, and halogen; R 3 Selected from the following group: H, alkyl, alkoxy, cyano, and halogen; R 4 Selected from the following group: H, alkyl, alkenyl, alkenylalkyl, ynyl, ynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclic, heterocyclic, aryl, heteroaryl and heteroarylalkyl; R 5 Selected from the following group: H, hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, aminoalkyl, aminocycloalkyl, aminocarbonyl, acylamino, acyloxyalkyl, hydroxyimino, alkoxyimino, alkylamino, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxycarbonyl, and heterocyclic alkyl; R 6 R 7 and R 8 Each is independently selected from the group consisting of: H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl; and R 9 Selected from the following group: H, halogens, and alkyl groups; if only: i) When X 2 When it is C, Not for , Where R 6 Selected from the following group: halogens, alkoxy groups, and alkyl groups; R 8 Selected from the following groups: H, halogens and alkyl groups; and R 10 Selected from the group consisting of H, alkyl, and acyl groups; ii) When X 2 For C and X 3 For NR 4 hour, Not for , Where R 6 For H; R 7 Selected from the following groups: H, Cl, and OCH3; R 8 For H or Br; and R 9 For H; and iii) When X 2 For C and X 3 For NR 4 hour, Not for , Where R 5 Selected from the following groups: H, F, Cl, CH3, OCH3, CF3, and CN; R 6 For H or F; R 7 Selected from the following groups: H, F, Cl, Br, I, CH3, OCH3, OCH2CH3, OCH(CH3)2, CF3, OH and OCF3; R 8 Selected from the following groups: H, F, Cl, CH3, OCH3, CF3, and CN; and R 9 It can be H or F.

2. The compound of claim 1, wherein R 1 R 2 and R 3 At least one of them is a halogen.

3. The compound of claim 1 or 2, wherein R 1 R 2 and R 3 At least one of them is fluorine.

4. The compound according to any one of claims 1 to 3, wherein R 1 It is fluorine.

5. The compound according to any one of claims 1 to 4, wherein X 1 Let N be the number of elements in the array.

6. The compound according to any one of claims 1 to 4, wherein X 2 Let N be the number of elements in the array.

7. A compound represented by formula IB: Formula IB Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 5 Selected from the following group: CR 5 and N; R 1 and R 2 Each is independently selected from the following group: H, alkoxy, alkyl, cyano, haloalkoxy, haloalkyl, and halogen; R 3 Selected from the following group: H, alkyl, and halogen; R 4 Selected from the following group: H, alkyl, alkenyl, alkenylalkyl, ynyl, ynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclic, heterocyclic, aryl, heteroaryl and heteroarylalkyl; R 5 Selected from the following group: H, hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, aminoalkyl, aminocycloalkyl, aminocarbonyl, acylamino, acyloxyalkyl, hydroxyimino, alkoxyimino, alkylamino, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxycarbonyl, and heterocyclic alkyl; R 6 R 7 and R 8 Each is independently selected from the group consisting of: H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl; and R 9 Selected from the following group: H, halogens, and alkyl groups; if only: i) Not for , Where R 6 Selected from the following group: halogens, alkoxy groups, and alkyl groups; R 8 Selected from the following groups: H, halogens and alkyl groups; and R 10 Selected from the group consisting of H, alkyl, and acyl groups; ii) Not for , Where R 6 For H; R 7 Selected from the following groups: H, Cl, and OCH3; R 8 For H or Br; and R 9 For H; and iii) Not for , Where R 5 Selected from the following groups: H, F, Cl, CH3, OCH3, CF3, and CN; R 6 For H or F; R 7 Selected from the following groups: H, F, Cl, Br, I, CH3, OCH3, OCH2CH3, OCH(CH3)2, CF3, OH and OCF3; R 8 Selected from the following groups: H, F, Cl, CH3, OCH3, CF3, and CN; and R 9 It can be H or F.

8. A compound represented by the formula IC: IC Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 and X 4 Each is independently selected from the following groups: CH and N; X 2 Selected from the following groups: C and N; X 3 Selected from the following group: CR 4 and NR 4 ; As long as X 1 X 2 X 3 and X 4 The number of elements is no more than two, and N is the maximum number of elements. R 1 and R 2 Each is independently selected from the following group: H, alkoxy, alkyl, cyano, haloalkoxy, haloalkyl, and halogen; R 3 Selected from the following group: H, alkyl, and halogen; R 4 Selected from the following group: H, alkyl, alkenyl, alkenylalkyl, ynyl, ynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclic, heterocyclic, aryl, heteroaryl and heteroarylalkyl; R 6 R 7 and R 8 Each is independently selected from the group consisting of: H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl; and R 9 Selected from the following group: H, halogens, and alkyl groups. if only When X 2 Let C, X 3 For NR 4 R 6 For H, R 8 It is H or Br, and R 9 When it is H, R 7 It is not H, Cl or OCH3.

9. The compound of claim 8, wherein X 1 Let N be the number of elements in the array.

10. The compound of claim 8, wherein X 2 Let N be the number of elements in the array.

11. A compound represented by formula ID: Formula ID Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 1 and X 4 Each is independently selected from the following groups: CH and N; X 3 Selected from the following group: CR 4 and NR 4 ; As long as X 1 X 3 and X 4 The number of elements is no more than one, which is N; X 5 Selected from the following group: CR 5 and N; R 1 and R 2 Each is independently selected from the following group: H, alkoxy, alkyl, cyano, haloalkoxy, haloalkyl, and halogen; R 3 Selected from the following group: H, alkyl, and halogen; R 4 Selected from the following group: H, alkyl, alkenyl, alkenylalkyl, ynyl, ynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclic, heterocyclic, aryl, heteroaryl and heteroarylalkyl; R 5 Selected from the following group: H, hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, aminoalkyl, aminocycloalkyl, aminocarbonyl, acylamino, acyloxyalkyl, hydroxyimino, alkoxyimino, alkylamino, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxycarbonyl, and heterocyclic alkyl; R 6 R 7 and R 8 Each is independently selected from the group consisting of: H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl; and R 9 Selected from the following group: H, halogens, and alkyl groups.

12. The compound of claim 11, wherein X 1 For CH, X 3 For CR 4 And X 4 Let N be the number of elements in the array.

13. A compound represented by the formula IE: Formula IE Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: X 5 Selected from the following group: CR 5 and N; R 1 and R 2 Each is independently selected from the following group: H, alkoxy, alkyl, cyano, haloalkoxy, haloalkyl, and halogen; R 3 Selected from the following group: H, alkyl, and halogen; R 4 Selected from the following group: H, alkyl, alkenyl, alkenylalkyl, ynyl, ynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclic, heterocyclic, aryl, heteroaryl and heteroarylalkyl; R 5 Selected from the following group: H, hydroxyalkyl, hydroxycycloalkyl, alkoxyalkyl, alkoxycycloalkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, aminoalkyl, aminocycloalkyl, aminocarbonyl, acylamino, acyloxyalkyl, hydroxyimino, alkoxyimino, alkylamino, cyanoalkyl, alkyl, cycloalkyl, cycloalkoxy, cycloalkylamino, alkoxycarbonyl, and heterocyclic alkyl; R 6 R 7 and R 8 Each is independently selected from the group consisting of: H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl; and R 9 Selected from the following group: H, halogens, and alkyl groups.

14. A compound represented by the formula IF: Formula IF Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: R 1 and R 2 Each is independently selected from the following group: H, alkoxy, alkyl, cyano, haloalkoxy, haloalkyl, and halogen; R 3 Selected from the following group: H, alkyl, and halogen; R 4 Selected from the following group: H, alkyl, alkenyl, alkenylalkyl, ynyl, ynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, alkylamino, amide, thioalkyl, heterocyclic, heterocyclic, aryl, heteroaryl and heteroarylalkyl; R 6 R 7 and R 8 Each is independently selected from the following group: H, alkyl, alkoxy, hydroxy, cyano, halogen, alkylamino, cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl, and hydroxyalkyl; R 9 Selected from the following groups: H, halogens and alkyl groups; and R 11 Selected from the following group: H and acyl group.

15. The compound of any one of claims 7 to 14, wherein R 2 For H and R 3 For H.

16. The compound of any one of claims 7 to 14, wherein R 1 For F, R 2 For H and R 3 For H.

17. The compound of any one of claims 7 to 14, wherein R 2 For F and R 3 For H.

18. The compound of any one of claims 7 to 14, wherein R 2 For H and R 3 It is F.

19. The compound of any one of claims 1 to 18, wherein R 4 Selected from the group consisting of: H, alkyl, (C2-C8)alkenyl, (C2-C8)alkenyl-(C1-C4)alkyl, (C2-C8)ynyl, (C2-C8)ynyl-(C1-C4)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl-(C1-C4)alkyl, alkoxy-(C1-C4)alkyl, (C3-C8)cycloalkenyl, (C3-C8)cycloalkenyl-(C1-C4)alkyl, alkylamino, amide, thio-(C1-C4)alkyl, heterocyclic, heterocyclic-(C1-C4)alkyl, aryl, heteroaryl and heteroaryl-(C1-C4)alkyl, wherein the alkyl component of the alkylamino is optionally substituted with an alkoxy group.

20. The compound of any one of claims 1 to 19, wherein R 4 Selected from the group consisting of: H, alkyl, (C3-C8)cycloalkyl, alkylamino, amide, thio-(C1-C4)alkyl, heterocyclic and heteroaryl, wherein the alkyl component of the alkylamino is optionally substituted with a (C1-C6)alkoxy group.

21. The compound according to any one of claims 1 to 20, wherein R 4 Selected from the following group: H, 。 22. The compound according to any one of claims 1 to 7, 11 to 13 and 15 to 21, wherein R 5 Selected from the following group: H, alkyl, (C3-C8)cycloalkyl, alkylamino, hydroxy-(C1-C4)alkyl, hydroxy-(C3-C8)cycloalkyl, alkoxy-(C1-C4)alkyl, alkoxy-(C3-C8)cycloalkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, amino-(C1-C4)alkyl, amino-(C3-C8)cycloalkyl, aminocarbonyl, acylamino, acyloxy-(C1-C4)alkyl, hydroxyimino, alkoxyimino, cyano-(C1-C4)alkyl, heterocyclic, (C3-C8)cycloalkylamino, (C1-C4)alkoxycarbonyl and heterocyclic-(C1-C4)alkyl.

23. The compound according to any one of claims 1 to 7, 11 to 13 and 15 to 22, wherein R 5 Selected from the following group: H, alkyl, alkylamino, hydroxy-(C1-C4)alkyl, alkoxy-(C1-C4)alkyl, halogen, fluoroalkyl, cyano, alkoxy, amine, amino-(C1-C4)alkyl, acyloxy-(C1-C4)alkyl, hydroxyimino, alkoxyimino, cyano-(C1-C4)alkyl, heterocyclic and alkoxycarbonyl.

24. The compound according to any one of claims 1 to 7, 11 to 13 and 15 to 23, wherein R 5 Selected from the following group: H, fluorine, chlorine, bromine, CF3, 。 25. The compound of any one of claims 1 to 24, wherein R 6 R 7 and R 8 Each is independently selected from the following group: H, alkyl, alkoxy, hydroxy, cyano, halogen, haloalkyl, alkylamino, (C3-C8)cycloalkoxy, amine, halogen, haloalkoxy, haloalkyl, amide, alkoxycarbonyl and hydroxy-(C1-C4)alkyl.

26. The compound of any one of claims 1 to 25, wherein R 6 R 7 and R 8 Each is independently selected from the following group: H, alkyl, alkoxy, hydroxy, halogen and hydroxy-(C1-C4)alkyl.

27. The compound of any one of claims 1 to 26, wherein R 6 Selected from the following group: H, methyl, methoxy, fluorine, and chlorine.

28. The compound of any one of claims 1 to 27, wherein R 7 Selected from the following group: H, methoxy, fluorine, bromine and .

29. The compound of any one of claims 1 to 28, wherein R 9 Selected from the following group: H, halogens, and alkyl groups.

30. The compound of any one of claims 1 to 29, wherein R 9 Selected from the following group: H and fluorine.

31. The compound of claim 14, wherein R 11 Selected from the following group: H, 。 32. The compound of claim 14, wherein R 11 Selected from the following groups: H, fluorine, and chlorine.

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

34. A pharmaceutical composition comprising a compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

35. A method of treating a patient with a condition caused by dysregulation of integrated stress response and / or unfolded protein response, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 34.

36. The method of claim 35, wherein the dysregulation of the integrated stress response and / or unfolded protein response is caused by a kinase selected from the group consisting of PKR-like ER kinase (PERK) kinase and generalized regulatory repressor protein 2 (GCN2) kinase.

37. The method of claim 35 or 36, wherein the dysregulation of the integrated stress response and / or unfolded protein response is caused by GCN2 kinase.

38. The method of claim 35 or 36, wherein the dysregulation of the integrated stress response and / or unfolded protein response is caused by PERK kinase.

39. A method of modulating the activity of GCN2 kinase in a patient with such need, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 34.

40. A method of modulating the activity of PERK kinase in a patient with such need, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 34.

41. A method of treating cancer in a patient with this need, comprising administering to the patient a therapeutically effective amount of a compound as claimed in any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 34.

42. The method of claim 41, 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, duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumor, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumor, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumor, bladder cancer, hematologic malignancy, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocytic lymphoma, Waldenstrom macroglobulinemia, light chain amyloidosis, and malignant lymphoma.

43. A method of treating amyloidosis in a patient with such need, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 34.

44. A method of treating light chain amyloidosis in a patient with this need, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 34.

45. The method of any one of claims 35 to 44, further comprising administering a therapeutically effective amount of one or more therapeutic agents to the patient.

46. ​​The method of claim 45, wherein the one or more therapeutic agents are selected from the group consisting of: IMiD agents, proteasome inhibitors, steroids, anti-CD38 agents, anti-CD20 agents, Bcl-2 inhibitors, PI3K inhibitors, bispecific antibodies, nucleoside analogs, BTK inhibitors, DNA alkylating agents, EZH2 inhibitors, anthracycline, topoisomerase inhibitors, platinum, tyrosine kinase inhibitors, HDAC inhibitors, nuclear export inhibitors, antimicrotubule agents, L-asparaginase, pegylated asparaginase, PERK inhibitors, mTOR inhibitors, immunomodulators, anti-angiogenic agents, EGFR inhibitors, MAPK pathway inhibitors, MEK inhibitors, ERK inhibitors, and Ras inhibitors.

47. The method of claim 45, wherein the one or more therapeutic agents are selected from the group consisting of: L-asparaginase, pegaspargase, calaspargase pegol-mnkl, bortezomib, carfilzomib, ixazomib, thalidomide, pomalidomide, lenalidomide, dexamethasone, and prednisone. nisone, daratumumab, daratumumab / hyaluronidase, isatuximab, rituximab, obinutuzumab, venetoclax, idelalisib, copanlisib, duvelisib, umbralisib, gemcitab ne), cytarabine, ibrutinib, acalabtinib, zanubrutinib, bendamustine, cyclophosphamide, tazemetostat, doxorubicin, daunorubicin, etoposide, oxaloplatin, carboplatin atin), cisplatin, bosutinib, dasatinib, imatinib, nilotinib, ponatinib, panobinostat, selinexor, vincristine, JZP-458, erythrocyte-encapsulated asparaginase, PF745 (JZP-341), Erwinia chrysanthemi asparaginase (crisantaspase), Escherichia coli asparaginaseAsparaginase (clavapase), erlotinib, gefitinib, osimertinib, afatanib, cetuximab, bevacizumab, axitinib, sunitinib, sorafenib, cabozantinib, pazopanib, lenvatinib, vandetanib, regorafenib, nintedanib, apatinib, anti-PD-1 agents, anti-PD-L1 agents, and anti-CTLA4 agents.

48. A compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 34, for treating a patient in need of treatment for a disease caused by dysregulation of integrated stress response and / or unfolded protein response.

49. The compound or composition of claim 48, wherein the dysregulation 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.

50. The compound or composition of claim 48 or 49, wherein the dysregulation of the integrated stress response and / or unfolded protein response is caused by GCN2 kinase.

51. The compound or composition of claim 48 or 49, wherein the dysregulation of the integrated stress response and / or unfolded protein response is caused by PERK kinase.

52. The compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 34, for modulating the activity of GCN2 kinase in a patient in need of doing so.

53. The compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 34, for modulating the activity of PERK kinase in a patient in need of doing so.

54. The compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 34, used in a therapeutic manner.

55. The compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 34, for treating cancer in a patient in need of such treatment.

56. The compound or composition of claim 55, 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, duodenal cancer, small bowel cancer, breast cancer, ovarian cancer, testicular tumor, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, gestational choriocarcinoma, brain tumor, retinoblastoma, skin cancer, melanoma, sarcoma, fibrosarcoma, malignant bone tumor, bladder cancer, hematologic malignancies, leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, T-cell lymphoma, erythroleukemia, histiocytic lymphoma, Waldenström macroglobulinemia, and malignant lymphoma.

57. The compound or composition of claim 55 or 56, wherein the cancer is leukemia.

58. The compound or composition of claim 55 or 56, wherein the cancer is acute myeloid leukemia.

59. The compound or composition of claim 55 or 56, wherein the cancer is acute lymphoblastic leukemia.

60. The compound or composition of claim 55 or 56, wherein the cancer is fibrosarcoma.

61. The compound or composition of claim 55 or 56, wherein the cancer is multiple myeloma.

62. The compound or composition of claim 55 or 56, wherein the cancer is lymphoma.

63. The compound or composition of claim 55 or 56, wherein the cancer is B-cell lymphoma.

64. The compound or composition of claim 55 or 56, wherein the cancer is T-cell lymphoma.

65. The compound or composition of claim 55 or 56, wherein the cancer is kidney cancer.

66. The compound or composition of claim 55 or 56, wherein the cancer is lung cancer.

67. The compound or composition of claim 55 or 56, wherein the cancer is colorectal cancer.

68. A compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 34, for the treatment of amyloidosis in patients with such need.

69. A compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 34, for treating light chain amyloidosis in patients with such need.

70. The compound or composition for use as claimed in any one of claims 48 to 69, further comprising the use of one or more therapeutic agents.

71. The compound or composition of claim 70, wherein the one or more therapeutic agents are selected from the group consisting of: IMiD agents, proteasome inhibitors, steroids, antiCD38 agents, antiCD20 agents, Bcl-2 inhibitors, PI3K inhibitors, bispecific antibodies, nucleoside analogs, BTK inhibitors, DNA alkylating agents, EZH2 inhibitors, anthracycline, topoisomerase inhibitors, platinum, tyrosine kinase inhibitors, HDAC inhibitors, nuclear export inhibitors, antimicrotubule agents, L-asparaginase, pegylated asparaginase, PERK inhibitors, mTOR inhibitors, immunomodulators, antiangiogenic agents, EGFR inhibitors, MAPK pathway inhibitors, MEK inhibitors, ERK inhibitors, and Ras inhibitors.

72. The compound or composition of claim 70, wherein the one or more therapeutic agents are selected from the group consisting of: L-asparaginase, pegol-mnkl, karasase, bortezomib, carfilzomib, ixazomib, thalidomide, pomalidomide, lenalidomide, dexamethasone, prednisone, daratumumab, daratumumab / hyaluronidase, esartanuximab, rituximab, atorciizumab, venatura, ederaris, cupanix, duveliximab, irblisse, gemcitabine, cytarabine, ibrutinib, acalabutinib, zanubrutinib, bendamustine, cyclophosphamide, tazestat, doxorubicin, doxorubicin, daunomycin, etoposide Oxaliplatin, carboplatin, cisplatin, besutinib, dasatinib, imatinib, nilotinib, ponatinib, pabistat, selinexol, vincristine, JZP-458, erythrocyte-encapsulated asparaginase, PF745 (JZP-341), Erwinia chrysogena asparaginase (crinase), Escherichia coli asparaginase (clapala), erlotinib, gefitinib, osimertinib, afatinib, cetuximab, bevacizumab, axitinib, sunitinib, sorafenib, cabozantinib, pazopanib, lenvatinib, vandetanib, regorafenib, nintedanib, apatinib, anti-PD-1 agents, anti-PD-L1 agents, and anti-CTLA4 agents.

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