Triazolopyridopyrimidine derivatives and dihydroimidazopyridopyrimidine derivatives as GCN2 kinase inhibitors, their compositions, and uses

Abstract

This application relates to triazolopyridopyrimidine compounds and dihydroimidazopyridopyrimidine compounds having activity as inhibitors of general-control nonderepressible (GCN2) kinase, processes for preparing them, compositions comprising them, and their use (e.g., in therapy). More specifically, this application relates to compounds useful for treating diseases, disorders, or conditions (e.g., cancer and neuronal diseases) that can be treated by inhibiting GCN2 kinase. JPEG2026530211000089.jpg100138

Description

[Technical Field]

[0001] This application claims priority under concurrently pending U.S. Provisional Patent Application No. 63 / 535,418, filed on 30 August 2023, the contents of which are incorporated herein by reference in their entirety.

[0002] This application relates to triazolopyridopyrimidine compounds and dihydroimidazopyridopyrimidine compounds having activity as inhibitors of general-control nonderepressible (GCN2) kinase, processes for preparing them, compositions comprising them, and their use (e.g., in therapy). More specifically, this application relates to compounds useful for treating diseases, disorders, or conditions (e.g., cancer and neuronal diseases) that can be treated by inhibiting GCN2 kinase. [Background technology]

[0003] Generalized unrepressive 2 (GCN2), a eukaryotic translation initiation factor 2α (eIF2α) kinase, drives cellular adaptation to amino acid restriction by activating the integrated stress response (ISR), which induces activating transcription factor 4 (ATF4). GCN2 kinase-mediated cellular adaptation to amino acid restriction occurs primarily through translational regulation of gene expression carried out by phosphorylation of eIF2α. Dokladal et al. recently demonstrated using quantitative phosphoproteomics that GCN2 targets physiologically relevant auxiliary effectors, including eIF2β and Gcn20, to fine-tune translational regulation in response to amino acid starvation (Molecular Cell 2021;81(9),P1879-1889.e6). In addition to phosphorylating the eIF2-α subunit, GCN2 also phosphorylates the β subunit of the trimer eIF2 G protein complex, thereby promoting its association with eIF5, which in turn contributes to the inhibition of translation initiation.

[0004] Cellular ISRs are activated under different stress conditions by four eukaryotic translation initiation factor 2α (eIF2α) kinases: GCN2, protein kinase-like endoplasmic reticulum kinase (PERK), double-stranded RNA-dependent kinase (PRK), and heme regulatory inhibitor (HRK) [Nat Rev Mol Cell Biol 2016,17:213-226]. These four eIF2α kinases generally phosphorylate S51 of eIF2α, thereby reducing general protein synthesis. However, certain mRNAs with upstream open reading frames, such as activating transcription factor 4 (ATF4), are selectively translated by delaying translation reinitiation through eIF2α phosphorylation. ATF4 is a key transcription factor for stress adaptation and subsequently drives the transcription of genes involved in processes such as protein folding, amino acid metabolism, and autophagy [Nat Rev Mol Cell Biol 2019,20:436-450].

[0005] Within tumors, cancer cells often suffer from amino acid deficiency, partly due to the increased need for amino acids to produce proteins, lipids, and nucleic acids caused by abnormal proliferation, and partly due to insufficient and disordered vascular formation leading to an insufficient supply of amino acids. Therefore, GCN2 may be important for cancer cell survival and tumor development. Furthermore, knockout of GCN2 or ATF4 has been shown to reduce tumor growth in vivo [EMBO.J.2010,29:2082-2096]. In addition, the GCN2 arm of ISR has been shown to protect cancer cells from endogenous stress induced by the c-Myc oncogene [Nat Cell Biol 2019,21:1413-1424;Nat Cell Biol 2019,21:889-899]. Inhibition of GCN2 in cancer cells expressing low levels of asparagine synthetase (ASNS) induces sensitization to the antitumor agent L-asparaginase (L-ASNase), suggesting that GCN2 may also be involved in resistance to cancer chemotherapy [Proc Natl Acad Sci USA 2018,115:E7776-E7785]. ASNS catalyzes the biosynthesis of asparagine (Asn) from aspartic acid and is highly responsive to cellular stress, particularly intracellular amino acid depletion. Intracellular depletion of Asn induces apoptosis, but ATF4 induces ASNS [J Biol Chem.2017;292(49):19952-19958], which in turn sustains Asn levels and suppresses apoptosis. Therefore, ASNS plays a role in maintaining cell viability during tumor cell accumulation and tumor progression. Elevated ASNS protein expression is also associated with resistance to asparaginase therapy [J Biol Chem. 2017;292(49):19952-19958]. Therefore, when combined with L-ASNase and GCN2 inhibition, ASNS-highly expressing tumors should be sensitive to inhibition of ASNS activity. This combination is a viable strategy for controlling, eliminating, or enhancing the sensitivity of cancer cells to existing chemotherapeutic or radiotherapy therapies, as well as controlling their growth, proliferation, and migration. The GCN2-mediated ISR pathway has been suggested as a promising target for cancer therapy.Therefore, disrupting this pro-oncogenic stress-inducing pathway by inhibiting GCN2 is an attractive therapeutic strategy.

[0006] Another important therapeutic area involving ISR activation is neuronal diseases or neuropathy [Science 2021, 373, 1161-1166]. Dominant mutations in the ubiquitously expressed transfer RNA (tRNA) synthetase gene cause axonal peripheral neuropathy, which is responsible for at least six forms of Charcot-Marie-Tooth (CMT) disease. Genetic evidence in mouse and Drosophila models suggests a gain-of-function mechanism. Mutant tRNA synthetase has been shown to activate the integrated stress response (ISR) via the sensor kinase GCN2 (Generally Regulated Unrepressive 2). Chronic activation of the ISR contributes to the pathophysiology, and gene deletion or pharmacological inhibition of GCN2 mitigated peripheral neuropathy. GCN2 activation suggests that abnormal activity of mutant tRNA synthetase is still associated with translation, and that inhibition of GCN2 or ISR may be a therapeutic strategy in CMT [Science 2021, 373, 1156-1161].

[0007] Recently, a small molecule inhibitor of GCN2 kinase has been described (WO2021165346, Black Belt TX LTD). [Overview of the project] [Problems that the invention aims to solve]

[0008] There is still a need for potent GCN2 kinase inhibitors to treat cancer and peripheral neuropathy. Furthermore, GCN2 kinase inhibitors that exhibit selectivity for other kinases are also required. [Means for solving the problem]

[0009] The applicant has developed a novel inhibitor of the general controlled unrepressive glycan 2 (GCN2) kinase.

[0010] Accordingly, the present invention encompasses a compound of formula I, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

[0011] This application also encompasses pharmaceutical compositions comprising one or more of the compounds of the present application and a pharmaceutically acceptable carrier.

[0012] This application further encompasses a method for inhibiting generalized unrepressive 2 (GCN2) in cells in a biological sample or in a patient, comprising administering an effective amount of one or more of the compounds of the application to cells.

[0013] This application also includes methods for treating diseases, disorders, or conditions that can be treated by inhibiting GCN2, which include administering one or more therapeutically effective doses of the compounds of the present application to a subject in need of such treatment.

[0014] This application also includes a method for treating a disease, disorder, or condition that can be treated by inhibiting GCN2, comprising administering to a subject in need one or more therapeutically effective amounts of one or more of the compounds of this application in combination with another known active agent useful for treating the disease, disorder, or condition that can be treated by inhibiting GCN2.

[0015] In some embodiments, the disease, disorder, or condition that can be treated by inhibiting GCN2 is cancer, and the one or more compounds of the present invention are administered or used in combination with one or more additional cancer treatments, such as radiotherapy, chemotherapy (e.g., cisplatin), targeted therapies (including anti-PD1 antibodies and / or anti-PD-L1 antibodies), and small molecule therapies, such as tyrosine kinase inhibitor therapy, glutaminase inhibitors (e.g., glutaminase-1 (GLS1) inhibitors), and asparagine synthase (ASNS) inhibitors, immunotherapy, hormone therapy, and anti-angiogenic therapy.

[0016] In some embodiments, diseases, disorders, or conditions that can be treated by inhibiting GCN2 include cancer and / or peripheral neuropathy, including Charcot-Marie-Tooth (CMT) peripheral neuropathy.

[0017] This application also includes a method for improving the effectiveness of one or more cancer treatments for treating cancer, which comprises administering an effective amount of one or more of the compounds of the present application in combination with an effective amount of the one or more cancer treatments.

[0018] Other features and advantages of this application will become apparent from the following detailed description. However, although the detailed description and specific examples illustrate embodiments of this application, they are merely illustrative, and the claims are not limited by these embodiments, and should be given the broadest interpretation consistent with the entire Spec. [Modes for carrying out the invention]

[0019] I. Definition Unless otherwise indicated, the definitions and embodiments set forth in this section and other sections are intended to be applicable to all embodiments and aspects of this application in which they are appropriate, as will be understood by those skilled in the art.

[0020] All features disclosed herein, including the claims, abstract, and drawings, and all steps of any methods or processes disclosed herein, may be combined in any combination except in any combination in which at least some of such features and / or steps are mutually exclusive. Each feature disclosed herein, including the claims, abstract, and drawings, may be replaced by alternative features that serve the same, equivalent, or similar purpose unless otherwise specified.

[0021] As used herein, terms such as “the compound of this application” or “the compound of this application” refer to the compound of formula I (including its pharmaceutically acceptable salts, solvates and / or prodrugs).

[0022] As used herein, terms such as “the composition of this application” or “the composition of this application” refer to a composition comprising one or more of the compounds of this application and at least one additional component.

[0023] As used herein, the term "and / or" means that the listed items exist or are used individually or in combination. In short, the term means that "at least one" or "one or more" of the listed items are used or exist. With respect to pharmaceutically acceptable salts and / or their solvates, the term "and / or" means that the compound of the Application exists as individual salts and individual hydrates, and as a combination such as, for example, a solvate of a salt of the compound of the Application.

[0024] When used in this application, the singular forms "a," "an," and "the" encompass multiple references unless the content clearly indicates otherwise. For example, an embodiment containing "a compound" should be understood to present a particular aspect of one compound or of two or more further compounds.

[0025] In embodiments including "additional" or "secondary" components, such as additional compounds or a second compound, the second component used herein is chemically different from the other components or the first component. The "third" component is different from the other components, the first component, and the second component, as are any further listed or "additional" components.

[0026] As used herein, the words “comprising” (and any form of comprising, such as comprise and comprises), “having” (and any form of having, such as have and has), “including” (and any form of including, such as include and includess), or “containing” (and any form of containing, such as contain and contains) are inclusive or open-ended and do not exclude any additional unlisted elements or process / method steps.

[0027] As used herein, the word "consisting" and its derivatives are intended to be closed-end terms that specify the existence of specified features, elements, components, bases, integers and / or steps, and exclude the existence of other unspecified features, elements, components, bases, integers and / or steps.

[0028] As used herein, the term “essentially derived from” is intended to specify the presence of the specified features, elements, components, bases, integers, and / or steps, as well as those that do not substantially affect the fundamental and novel features of these features, elements, components, bases, integers, and / or steps.

[0029] As used herein, terms indicating degree, such as “substantially,” “about,” and “approximately,” mean a reasonable amount of deviation from the modified term such that the final result does not change significantly. These terms indicating degree should be interpreted as including a deviation of at least ±5% from the modified term (where this deviation does not negate the meaning of the word the term modifies).

[0030] As used herein, the term “appropriate” means that the selection of a particular compound or conditions depends on the specific synthetic operation performed, the identity of the molecule being transformed, and / or the specific use of the compound, but that such selection is well within the scope of the skill of a person skilled in the art. All process / method steps described herein should be carried out under conditions sufficient to provide the indicated product. It will be understood by a person skilled in the art that all reaction conditions can be modified, including, for example, the reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio, and whether the reaction should be carried out under an anhydrous or inert atmosphere, in order to optimize the yield of the desired product, and that doing so is within the scope of the skill of a person skilled in the art.

[0031] This application refers to several chemical terms and abbreviations used by those skilled in the art. However, for clarity and consistency, definitions are provided for selected terms.

[0032] As used herein, terms such as “protecting group” or “PG” refer to a chemical part that protects or masks the reactive parts of a molecule while different parts of the molecule are being manipulated or reacted, thereby preventing side reactions in those reactive parts of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not decompose or reduce the rest of the molecule. Those skilled in the art can select an appropriate protecting group. In the art, many conventional protecting groups are known, for example, as described in “Protective Groups in Organic Chemistry” edited by McOmie, JFW, Plenum Press, 1973; “Protective Groups in Organic Synthesis” by Greene, TW and Wuts, PGM, John Wiley & Sons, 3rd edition, 1999; and “Protective Groups in Organic Synthesis” by Kocienski, P. Protecting Groups, 3rd edition, 2003, Georg Thieme Verlag (The Americas).

[0033] As used herein, the term “cell” refers to a single cell or a group of cells, and includes any cells in a cell culture or within a subject.

[0034] As used herein, the term “subject” encompasses all members of the animal kingdom, including mammals. Therefore, the methods and uses described herein are applicable to both human therapeutic and veterinary applications.

[0035] The term "pharmaceutically acceptable" means that it is suitable for the treatment in question.

[0036] The term "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, adjuvant, or other substance that is mixed with the active ingredient (e.g., one or more of the compounds of the present invention) to enable the formation of a pharmaceutical composition, i.e., a dosage form that can be administered to a subject.

[0037] The term "pharmaceutically acceptable salt" means either an acid addition salt or a base addition salt that is suitable for or compatible with the treatment in question.

[0038] An acid addition salt suitable for or compatible with the treatment in question is any non-toxic organic or inorganic acid addition salt of any basic compound.

[0039] A base addition salt suitable for or compatible with the treatment in question is any non-toxic organic or inorganic base addition salt of any acidic compound.

[0040] As used herein, the term "prodrug" means a compound or a salt and / or solvate of a compound that is converted into an active drug after administration.

[0041] As used herein, the term “solvate” means a compound or a salt or prodrug of a compound in which molecules of a suitable solvent are incorporated into the crystal lattice.

[0042] As used herein, the term “inert organic solvent” refers to a solvent that is generally considered not to react with functional groups present in compounds combined with each other in any given reaction, so as not to interfere with or inhibit the desired synthetic transformation. Organic solvents are typically nonpolar and dissolve compounds that are insoluble in aqueous solutions.

[0043] As used herein, the term “alkyl” means a linear or branched saturated alkyl group, whether used alone or as part of another group. The number of possible carbon atoms in the alkyl group mentioned is determined by the prefix “C n1~n2 This is shown by ". For example, C 1~10 The term alkyl refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0044] As used herein, the term "halo" or "halogen" refers to a halogen atom, whether used alone or as part of another group, and includes fluoro, chloro, bromo, and iodine atoms.

[0045] As used herein, the term “haloalkyl” refers to the alkyl group defined above in which one or more of the available hydrogen atoms are replaced by halogen atoms. For example, “C 1~6 A "haloalkyl" (or "C1-C6 haloalkyl") refers to a C1-C6 linear or branched alkyl group as defined above, having one or more halogen substituents.

[0046] As used herein, the term "fluoroalkyl" refers to the haloalkyl group defined above, in which the halogen atom is fluoro.

[0047] As used herein, the term "chloroalkyl" refers to the haloalkyl group defined above, in which the halogen atom is chloro.

[0048] The term "available" in phrases such as "available hydrogen atom" or "available atom" refers to an atom that is known to those skilled in the art to be replaceable by another atom or group.

[0049] As used herein, the term “alkenyl” means a linear or branched unsaturated alkyl group containing at least one double bond, whether used alone or as part of another group. The number of possible carbon atoms in the alkylene group mentioned is determined by the prefix “C n1~n2 This is shown by ". For example, C 2~6 The term alkenyl refers to an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms and at least one double bond.

[0050] As used herein, the term “alkynyl” means a linear or branched unsaturated alkynyl group containing at least one triple bond, whether used alone or as part of another group. The number of carbon atoms possible in the alkyl group mentioned is determined by the prefix “C n1~n2 This is shown by ". For example, C 2~6 The term alkynyl refers to an alkynyl group having 2, 3, 4, 5, or 6 carbon atoms.

[0051] As used herein, the term “cycloalkyl” means a saturated carbocyclic group containing 3 to 20 carbon atoms and one or more rings, whether used alone or as part of another group. The number of carbon atoms possible in the cycloalkyl group mentioned is indicated by the numeral prefix “C”. n1~n2 This is shown by ". For example, C 3~10 The term cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0052] As used herein, the term "heterocycloalkyl" refers to a cyclic group containing at least one non-aromatic ring containing 3 to 10 atoms, whether used alone or as part of another group, where one or more of those atoms are O, S, S(O), SO2, N, NH and N(C) 1~6 A heterocycloalkyl group is a heteromolecule selected from alkyl groups, with the remaining atoms being carbon (C). Heterocycloalkyl groups can be either saturated or unsaturated (i.e., they contain one or more double bonds). Heterocycloalkyl groups are prefixed with C. n1~n2 If present, this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, where one or more of those ring atoms, preferably 1 to 5, are replaced by heteroatoms as defined above. The heterocycloalkyl group may optionally be benzo-condensed.

[0053] All cyclic groups, including aryl groups, heteroaryl groups, heterocyclo groups, and cycloalkyl groups, contain either one ring (i.e., monocyclic) or two or more rings (i.e., polycyclic). If a cyclic group contains two or more rings, those rings may be condensed, cross-linked, or spiro-condensed.

[0054] As used herein, the term "benzo-condensation" refers to a polycyclic group in which a benzene ring is fused with another ring.

[0055] The statement that the first ring is "condensed" with the second ring means that the first and second rings share two adjacent atoms between them.

[0056] The first ring being "bridged" to the second ring means that the first and second rings share two non-adjacent atoms between them.

[0057] The statement that the first ring is "spiro-condensed" with the second ring means that the first and second rings share one atom between them.

[0058] As used herein, the term "optionally substituted" means that the group referred to is either unsubstituted or substituted.

[0059] As used herein, the term “substituted” means that the atom referred to contains at least one substituent other than a hydrogen atom.

[0060] When a group is substituted with one or more substituents, the selection of those substituents is understood to be independent of each other; that is, the one or more substituents may be the same or different.

[0061] symbol [ka] When drawn perpendicularly across a bond, this symbol indicates a covalent bond point of a chemical group.

[0062] As used herein, the term "LCMS" refers to liquid chromatography-mass spectrometry.

[0063] As used herein, the term "NMR" refers to nuclear magnetic resonance.

[0064] As used herein, the term "aq." refers to aqueous.

[0065] In this specification, the term "N" used, for example, in the form "4N," refers to the unit symbol for normality, indicating "equivalent / L."

[0066] In this specification, the term "M" used, for example, in the form "4M," refers to the unit symbol for volume molar concentration, which is "moles / L."

[0067] As used herein, the term "DIPEA" refers to N,N-diisopropylethylamine.

[0068] As used herein, the term "DMF" refers to dimethylformamide.

[0069] As used herein, the term "THF" refers to tetrahydrofuran.

[0070] As used herein, the term "DMSO" refers to dimethyl sulfoxide.

[0071] As used herein, the term "ethylacetate" refers to ethyl acetate.

[0072] As used herein, the term "MeOH" refers to methanol.

[0073] As used herein, the term "EtOH" refers to ethanol.

[0074] As used herein, the terms "MeCN" or "ACN" refer to acetonitrile.

[0075] As used herein, the term "HCl" refers to hydrochloric acid.

[0076] As used herein, the term "TFA" refers to trifluoroacetic acid.

[0077] As used herein, the term "Hex" refers to hexanes.

[0078] As used herein, the term "PBS" refers to a phosphate-based buffer.

[0079] As used herein, the term "IPA" refers to isopropyl alcohol.

[0080] As used herein, the term "dppf" refers to 1,1'-bis(diphenylphosphino)ferrocene.

[0081] As used herein, the terms "RT" or "rt" refer to room temperature.

[0082] As used herein, the term "HPLC" refers to high-performance liquid chromatography.

[0083] As used herein, the term "PPA" refers to polyphosphate.

[0084] As used herein, the terms "TEA" or "Et3N" refer to triethylamine.

[0085] As used herein, the term "EDTA" refers to ethylenediaminetetraacetic acid.

[0086] As used herein, the term "ATP" refers to adenosine triphosphate.

[0087] As used herein, the term "FBS" refers to fetal bovine serum.

[0088] As used herein, the term "MEM" refers to the Minimum Essential Medium.

[0089] As used herein and as well understood in the art, the terms “to treat” or “treatment” mean an approach to obtain beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes include, but are not limited to, the reduction or improvement of one or more symptoms or conditions, whether detectable or undetectable; a reduction in the degree of disease, disability or condition; a stabilized (i.e., non-worsening) state of disease, disability or condition; prevention of the progression of disease, disability or condition; delay or slowing of the progression of disease, disability or condition; improvement or mitigation of disease, disability or condition; a reduction in recurrence of disease, disability or condition; and remission (whether partial or complete remission). “To treat” and “treatment” may also mean extending survival compared to the survival expected without treatment. As used herein, “to treat” and “treatment” also include prophylactic treatment.

[0090] To “alleviate” a disease, disorder, or condition means that, compared to not treating the disease, disorder, or condition, the severity of the disease, disorder, or condition and / or the manifestation of undesirable clinical symptoms are reduced, and / or the time course of its progression is slowed or prolonged.

[0091] As used herein, “prevention” or “prevention” or their synonyms refer to the reduction of the risk or probability of an subject developing a disease, disorder or condition that can be treated by inhibition of GCN2, or the reduction of the risk or probability of developing symptoms associated with a disease, disorder or condition that can be treated by inhibition of GCN2.

[0092] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of the compound of the present application, or one or more compounds of the present application, that is effective in the dosage and duration required to achieve the desired result.

[0093] The term "a disease, disorder or condition that can be treated by inhibiting GCN2" means that the disease, disorder or condition to be treated is affected by any biological basis, direct or indirect, that involves GCN2 activity, particularly increased GCN2 activity, is regulated by said biological basis and / or has said biological basis. These diseases respond advantageously when GCN2 activity associated with the disease, disorder or condition is inhibited by one or more of the compound(s) of the present application or the composition(s) of the present application.

[0094] As used herein, the expression "inhibiting GCN2" refers to inhibiting, blocking and / or disrupting the kinase activity or function of GCN2 in a cell, wherein said inhibition, blocking and / or disruption produces a therapeutic effect in the cell.

[0095] "Inhibiting, blocking and / or disrupting" means any detectable inhibition, blocking and / or disruption in the presence of a compound compared to the same conditions otherwise in the absence of the compound.

[0096] As used herein, the term "GCN2" refers to General Control Nonderepressible 2, or any functional variant or isoform thereof.

[0097] As used herein, the expression "low asparagine synthetase (ASNS) expression" means any detectable decrease or reduction in the level of asparagine synthetase (ASNS) in cancer cells under otherwise identical conditions, as compared to the level in healthy cells.

[0098] As used herein, the expression “overexpression or dysregulation of asparagine synthetase (ASNS)” means any detectable increase in the level of asparagine synthetase (ASNS) in cancer cells compared to healthy cells under otherwise identical conditions.

[0099] As used herein, the expression “low glutaminase expression” means any detectable decrease or reduction in the level of glutaminase (e.g., GLS1) in cancer cells compared to healthy cells under otherwise identical conditions.

[0100] As used herein, the expression “glutaminase overexpression or dysregulation” means any detectable increase in the level of glutaminase (e.g., GLS1) in cancer cells compared to healthy cells under otherwise identical conditions.

[0101] As used herein, the term "GLS1" refers to "renal-type" glutaminase, or any functional variant or analog thereof.

[0102] As used herein, the term “administered” means the administration of a therapeutically effective amount of the compound, or one or more of the compounds or compositions, to a cell or subject.

[0103] As used herein, the term “neoplastic disorder” refers to a disease, disorder, or condition characterized by cells having the ability to grow or replicate autonomously, such as an abnormal condition or condition characterized by proliferative cell growth. As used herein, the term “neoplasm” refers to a tissue mass resulting from the abnormal growth and / or division of cells in an object having a neoplastic disorder. Neoplasms may be benign (e.g., uterine fibroids and pigmented nevi), potentially malignant (e.g., carcinoma in situ), or malignant (i.e., cancer).

[0104] As used herein, the term “fibrosis” refers to a disease, disorder, or condition characterized by thickening and scarring of connective tissue, usually as a result of injury.

[0105] II. Compounds of the Present Application Triazolopyridopyrimidine compounds and dihydroimidazopyridopyrimidine compounds of the present application have been prepared, and it has been found that they inhibit kinase, general control non-derepressible 2 (GCN2).

[0106] Accordingly, the present application encompasses a compound of formula I, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

[0107] In some embodiments, R 1 is selected from H, C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl and C 3~10 heterocycloalkyl, wherein the latter four groups are optionally substituted with one R 8a . In some embodiments, R 1 is selected from C 3~10 cycloalkyl and C 3~10 heterocycloalkyl, each of which is optionally substituted with one or two R 8a .

[0108] In some embodiments, R 1 is selected from H, C 1~6 alkyl and C 1~6 haloalkyl. In some embodiments, R 1 is selected from H, C 1~4 alkyl and C 1~4 haloalkyl. In some embodiments, R 1 is selected from H, C 1~4 alkyl and C 1~4 fluoroalkyl. In some embodiments, R 1is selected from H, CH3, CF3, CHF2, CH2CH3, CH2CH2F, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3 and CH(CH3)3. In some embodiments, R 1 The ion is selected from H, CH3, CH2CH3, and CH(CH3)2.

[0109] In some embodiments, R 1 is one or two R 8a C may be arbitrarily replaced with 3~10 It is cycloalkyl. In some embodiments, R 1 This is a single ring C 3~10 Cycloalkyl or bicyclic C 5~10 They are cycloalkyl groups, each of which has one or two R groups. 8a It may be optionally replaced with R. In some embodiments, 1 is one or two R 8a Monoring C may be arbitrarily substituted. 3~8 It is cycloalkyl. In some embodiments, R 1 The inner ring C 3~8 Cycloalkyls are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which has one or two R groups. 8a It may be optionally replaced with R. In some embodiments, 1 R is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which is unsubstituted. In some embodiments, R 1 It is cyclopropyl. In some embodiments, R 1 The compounds are selected from cyclobutyl, cyclopentyl, and cyclohexyl, each of which contains one or two R compounds. 8a It is replaced by R 1 The compounds are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which has one R 8a It may be optionally replaced with R. In some embodiments,1 is one or two R 8a It is a cyclohexyl substituted with R. In some embodiments, 1 The compounds are selected from cyclobutyl and cyclohexyl, each of which has one R 8a It is replaced by R 1 is one R 8a It is cyclobutyl substituted with R. In some embodiments, 1 is one R 8a It is a cyclohexyl substituted with [a specific compound].

[0110] In some embodiments, R 1 This is spirocondensation C 5~10 Cycloalkyl or crosslinked C 5~10 They are cycloalkyl groups, each of which has one or two R groups. 8a It may be optionally substituted with. In some embodiments, spirocondensation C 5~10 The cycloalkyls are selected from spiro[3.3]heptane, spiro[4.4]nonane, spiro[5.4]decane, spiro[4.5]octane, and spiro[5.2]octane, each of which has one or two R 8a It may be optionally substituted with. In one embodiment, spirocondensation C 6~10 Cycloalkyls have one or two R 8a Spiro[3.3]heptane may be optionally substituted with C. In some embodiments, spirocondensation C 5~10 Cycloalkyl is [ka] That is the case.

[0111] In some embodiments, R 1 is one or two R 8a Crosslinked C may be optionally substituted. 5~10 It is cycloalkyl. In some embodiments, crosslinked C 5~10The cycloalkyl group is selected from bicyclopentanyl, bicycloheptanyl, and bicyclooctanyl, each of which has one or two R groups. 8a It may be optionally replaced with C. In some embodiments, crosslinked C 5~10 The cycloalkyl group is selected from bicyclopentanyl, bicycloheptanyl, and bicyclooctanyl, each of which has one R 8a It may be optionally replaced with C. In some embodiments, crosslinked C 5~10 Cycloalkyls are [ka] Selected from.

[0112] In some embodiments, R 1 is one or two R 8a C may be arbitrarily replaced with 3~10 It is heterocycloalkyl. In some embodiments, R 1 is one R 8a C may be arbitrarily replaced with 3~10 It is heterocycloalkyl. In some embodiments, R 1 is one R 8a C may be arbitrarily replaced with 3~6 It is heterocycloalkyl. In some embodiments, R 1 These are selected from azilidinyl, oxiranil, thiranil, azetidinil, oxetanil, thietanil, diazetidinil, dioxetanil, dithietanil, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxalanil, dithiolanil, piperidinyl, tetrahydropyranil, diazinyl (e.g., piperazinyl), morpholinil, thiomorpholinil, dioxanil, dithianil, azepanil, oxepanil, and thiepanil, each of which contains one or two R 8a It may be optionally replaced with R. In some embodiments,1 The compounds are selected from thietanyl, oxetanyl, tetrahydrofuranil, tetrahydropyranil, thiomorpholinil, azilidinyl, azetidinil, pyrrolidinyl, morpholinil, piperazinyl, and piperidinil, each of which has one R 8a It may be optionally replaced with R. In some embodiments, 1 The compounds are selected from oxetanil, tetrahydrofuranil, tetrahydropyranil, pyrrolidinil, morpholinil, piperazinil, and piperidinil, each of which has one R 8a It may be optionally replaced with R. In some embodiments, 1 The compounds are selected from oxetanil, tetrahydrofuranil, and tetrahydropyranil, each of which has one R 8a It may be optionally replaced with R. In some embodiments, 1 The compounds are selected from oxetanil, tetrahydrofuranil, and tetrahydropyranil, each of which is unsubstituted.

[0113] In some embodiments, R 2 H, C 1~4 Alkyl and C 1~4 Selected from fluoroalkyls. In some embodiments, R 2 is selected from H, CH3, CF3, CHF2, CH2CH3, CH2CH2F, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3 and CH(CH3)3. In some embodiments, R 2 R is selected from H, CH3, CH2CH3 and CH(CH3)2. In some embodiments, R 2 is selected from H and CH3. In some embodiments, R 2 H is H.

[0114] In some embodiments, [ka] If X is a double bond, 1 CR9 Selected from N, [ka] If it is a single bond, X 1 CR 9 R 9a In some embodiments, [ka] If X is a double bond, 1 In some embodiments, [ka] If X is a double bond, 1 CR 9 In some embodiments, [ka] If it is a single bond, X 1 CR 9 R 9a That is the case.

[0115] In some embodiments, X 2 X is selected from N and CH. In some embodiments, X 1 In some embodiments, X 2 It is CH.

[0116] In some embodiments, R 3 , R 4 and R 5 Not all of them are H. In some embodiments, R 3 , R 4 and R 5 H, Haro, CN, C 1~4 Alkyl and C 1~4 Selected independently from haloalkyl. In some embodiments, R 3 , R4 and R 5 At least one of them is Halo, CN, and C 1~4 Selected from haloalkyls. In some embodiments, R 3 and R 5 At least one of them is Halo, CN, and C 1~4 Selected from haloalkyls. In some embodiments, R 3 , R 4 and R 5 At least one of these is selected from halo and CN. In some embodiments, R 3 and R 5 At least one of these is selected from halo and CN. In some embodiments, R 3 , R 4 and R 5 At least one of them is a halo. In some embodiments, R 3 and R 5 At least one of them is a halo. In some embodiments, R 3 , R 4 and R 5 H, Cl, F, Br, CN, C 1~4 Alkyl and C 1~4 It is independently selected from fluoroalkyls. In some embodiments, R 3 , R 4 and R 5 At least one of them is F, Cl, Br, CN, and C 1~4 Selected from fluoroalkyls. In some embodiments, R 3 and R 5 At least one of them is F, Cl, Br, CN, and C 1~4 Selected from fluoroalkyls. In some embodiments, R 3 , R 4 and R 5 is independently selected from H, Cl, F, CN, CH3 and CF3. In some embodiments, R 3 , R 4 and R 5 is selected independently from H, F, and CN. In some embodiments, R 3, R 4 and R 5 At least one of these is selected from Cl, F, CN, and CF3. In some embodiments, R 3 , R 4 and R 5 At least one of these is selected from Cl, F, and CN. In some embodiments, R 3 and R 5 At least one of these is selected from Cl, F, and CN. In some embodiments, R 3 , R 4 and R 5 At least one of these is selected from F and CN. In some embodiments, R 3 and R 5 At least one of these is selected from F and CN. In some embodiments, R 3 and R 5 At least one of them is selected from F and CN, and R 4 is H. In some embodiments, R 3 is CN, R 4 H is R 5 is H. In some embodiments, R 3 H is R 4 H is R 5 is CN. In some embodiments, R 3 and R 5 It is selected independently from H, F, and CN, and R 4 is H. In some embodiments, R 3 and R 5 R is selected independently from H and F, 4 is H. In some embodiments, R 3 and R 5 At least one of them is F. In some embodiments, R 3 and R 5 At least one of them is F, and R 4 is H. In some embodiments, R 3 and R 5 Both are F, and R 4is H. In some embodiments, R 3 F is R 4 H is R 5 is F. In some embodiments, R 3 F is R 4 H is R 5 is H. In some embodiments, R 3 H is R 4 H is R 5 It is F.

[0117] In some embodiments, X 3 X is selected from N and CH. In some embodiments, X 3 It is CH.

[0118] In some embodiments, R 6 and R 7 H, Cl, F, Br, CN, C 1~4 Alkyl, C 1~4 Fluoralkyl, OC 1~4 Alkyl and OC 1~4 It is independently selected from fluoroalkyls. In some embodiments, R 6 and R 7 is independently selected from H, Cl, F, CN, CH3, CHF2, CF3, CH2CH3, CH2CH2F, OCH3, OCHF2, and OCF3. In some embodiments, R 6 and R 7 is independently selected from Cl, F, CH3, CHF2, CF3, CH2CH3, CH2CH2F, OCH3, OCHF2, and OCF3. In some embodiments, R 6 It is selected from OCH3 and OCF3, R 7 R is selected from Cl, F, CH3, and CF3. In some embodiments, R 6 It is selected from OCH3 and OCF3, R 7 is Cl. In some embodiments, R 6 It is OCH3, and R 7 It is Cl.

[0119] In some embodiments, R 8 H, C 1~4 Alkyl and C 1~4 Selected from fluoroalkyls. In some embodiments, R 8 is selected from H, CH3, CF3, CHF2, CH2CH3, CH2CH2F, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3 and CH(CH3)3. In some embodiments, R 8 R is selected from H, CH3, CH2CH3 and CH(CH3)2. In some embodiments, R 8 is selected from H and CH3. In some embodiments, R 8 H is H.

[0120] In some embodiments, each R 8a is OR 12 , C(O)NR 12 R 13 , NR 12 R 13 Hello, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 3~10 Cycloalkyl and C 3~10 Selected independently from heterocycloalkyls, all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyls are halo, OR 14 , NR 14 R 15 and C 1~4 They may be optionally substituted with one or more substituents selected from alkyl groups. In some embodiments, each R 8a is OR 12 , C(O)NR 12 R 13 , NR 12 R 13 Cl, F, Br, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 3~6 Cycloalkyl and C 3~6Selected independently from heterocycloalkyls, all alkyl, cycloalkyl and heterocycloalkyls are Cl, Br, F, OR 14 , NR 14 R 15 and C 1~4 They may be optionally substituted with one or more substituents selected from alkyl groups. In some embodiments, each R 8a is OR 12 , NR 12 R 13 , C(O)NR 12 R 13 , independently selected from Cl, F, CHF2, CH3, CH3CH3 and CF3. In some embodiments, each R 8a R is independently selected from Cl, F, CH3, CHF2, CH3CH3, and CF3. In some embodiments, each R 8a R is independently selected from CH3, CHF2, CH3CH3, and CF3. In some embodiments, each R 8a is OR 12 , NR 12 R 13 and C(O)NR 12 R 13 Selected independently from. In some embodiments, each R 8a , NR 12 R 13 and C(O)NR 12 R 13 It is selected independently of others.

[0121] In some embodiments, R 9 , R 9a , R 10 and R 11 H, Cl, Br, F, C 1~4 Alkyl and C 1~4 It is independently selected from fluoroalkyls. In some embodiments, R 9 , R 9a , R 10 and R 11is independently selected from H, Cl, F, CH3, CF3, CHF2, CH2CH3, CH2CH2F, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, and CH(CH3)3. In some embodiments, R 9 , R 9a , R 10 and R 11 R is independently selected from H, Cl, F, CH3 and CF3. In some embodiments, R 9 , R 9a , R 10 and R 11 is selected independently from H and F. In some embodiments, R 9 , R 9a , R 10 and R 11 H is H.

[0122] In some embodiments, R 9b H, C 1~4 Alkyl and C 1~4 Selected from fluoroalkyls. In some embodiments, R 9b This is selected from HCH3, CF3, CHF2, CH2CH3, CH2CH2F, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, and CH(CH3)3. In some embodiments, R 9b R is selected from H, CH3 and CF3. In some embodiments, R 9b This is selected from H and CH3.

[0123] In some embodiments, R 12 H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 3~10 Cycloalkyl and C 3~10 Selected from heterocycloalkyl groups, the latter four groups may be optionally substituted with one or two substituents selected from Cl, F, Br, OH, OCH3, and OCF3. In some embodiments, R 12is selected from H, CH3, CF3, CHF2, CH2CH3, CH2CH2F, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3 and CH(CH3)3. In some embodiments, R 12 R is selected from H, CH3 and CF3. In some embodiments, R 12 is selected from H and CH3. In some embodiments, R 12 It is CH3.

[0124] In some embodiments, R 13 H, C 1~4 Alkyl and C 1~4 Selected from fluoroalkyls. In some embodiments, R 13 is selected from H, CH3, CF3, CHF2, CH2CH3, CH2CH2F, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3 and CH(CH3)3. In some embodiments, R 13 R is selected from H, CH3 and CF3. In some embodiments, R 13 This is selected from H and CH3.

[0125] In some embodiments, R 14 and R 15 H, C 1~4 Alkyl and C 1~4 It is independently selected from fluoroalkyls. In some embodiments, R 14 and R 15 is independently selected from H, CH3, CF3, CHF2, CH2CH3, CH2CH2F, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, and CH(CH3)3. In some embodiments, R 14 and R 15 R is independently selected from H, CH3 and CF3. In some embodiments, R 14 and R 15 It is selected independently from H and CH3.

[0126] In some embodiments, compounds of formula I are selected from the following: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] or its pharmaceutically acceptable salts, solvates, and / or prodrugs.

[0127] In some embodiments, the pharmaceutically acceptable salts are acid addition salts or base addition salts. Those skilled in the art can select a suitable salt (see, for example, SMBerge, et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19).

[0128] An acid addition salt suitable for or compatible with the treatment in question is any non-toxic organic or inorganic acid addition salt of any basic compound. Basic compounds that form acid addition salts include, for example, compounds containing an amine group. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acidic metal salts, such as sodium monohydrogen orthophosphate and potassium bisulfate. Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids. Examples of such organic acids include acetic acid, formic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. In some embodiments, monosodium or disodium salts are formed, and such salts exist in either hydrate, solvate, or substantially anhydrous forms. Generally, acid addition salts are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base forms. The criteria for selecting a suitable salt will be apparent to those skilled in the art. Other salts that are not pharmaceutically acceptable, such as oxalates, may also be used, for example, when isolating the compound for laboratory use or for subsequent conversion to a pharmaceutically acceptable acid addition salt. In some embodiments, the acid addition salt is a hydrochloric acid addition salt or a formic acid addition salt.

[0129] A suitable or appropriate base addition salt for the treatment in question is any non-toxic organic or inorganic base addition salt of any acidic compound. Examples of acidic compounds that form basic addition salts include compounds containing a carboxylic acid group. Examples of inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or barium hydroxide, and ammonia. Examples of organic bases that form suitable salts include aliphatic organic amines, alicyclic organic amines or aromatic organic amines, such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. Typical organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The selection of an appropriate salt can be useful, for example, to prevent hydrolysis if an ester functional group is present elsewhere in the compound. The criteria for selecting an appropriate salt will be apparent to those skilled in the art.

[0130] Examples of solvates of the compound in this application include those prepared with pharmaceutically acceptable solvents. Examples of such solvents include water (the resulting solvate is called a hydrate) and ethanol. A suitable solvent is physiologically acceptable at the administered dose.

[0131] In some embodiments of this application, the compounds described herein have at least one chiral center. If a compound has two or more chiral centers, they may exist as diastereomers. It should be understood that all such isomers and mixtures thereof in any ratio are encompassed within the scope of this application. The stereochemistry of the compounds may be as shown for any given compound listed herein, but it should be further understood that such compounds may contain a certain amount (e.g., less than 20%, preferably less than 10%, more preferably less than 5%) of the Application compounds having alternative stereochemistry. It is intended that any optical isomer be encompassed within the scope of this application as separated optical isomers, pure optical isomers, or partially purified optical isomers, or as racemic mixtures thereof.

[0132] The compounds of this application may exist in different tautomers, and the scope of this application is intended to encompass any tautomers formed by the compounds, as well as mixtures thereof.

[0133] The compounds of this application may also exist in various polymorphic forms, and it is assumed that the scope of this application encompasses any polymorphs or mixtures thereof that may be formed.

[0134] The compounds of this application may be further radiolabeled, and therefore all radiolabeled forms of the compounds of this application are included in the scope of this application. The compounds of this application also include those in which one or more radioactive atoms are incorporated into their structure.

[0135] III. Composition of the present invention The compounds of this application are appropriately formulated using one or more carriers in a conventional manner. Therefore, this application also encompasses compositions comprising one or more of the compounds of this application and carriers. The compounds of this application are appropriately formulated into pharmaceutical compositions for administration to a subject in a biocompatible form suitable for in vivo administration. Therefore, this application further encompasses pharmaceutical compositions comprising one or more of the compounds of this application and pharmaceutically acceptable carriers. In embodiments of this application, the pharmaceutical compositions are used to treat any of the diseases, disorders, or conditions described herein.

[0136] As will be understood by those skilled in the art, the compound of this application is administered to the target in various forms depending on the selected route of administration. For example, the compound of this application is administered by oral administration, inhalation, parenteral administration, buccal administration, sublingual administration, nasal administration, rectal administration, vaginal administration, transdermal administration, pump administration, minipump administration, topical administration, or transdermal administration, in a appropriately formulated pharmaceutical composition. In some embodiments, administration is carried out using a pump for periodic or continuous delivery. Conventional procedures and components for the selection and preparation of appropriate compositions are described, for example, in Remington's Pharmaceutical Sciences (2000, 20th edition) and the United States Pharmacopeia: National Composition of Drugs (USP 24 NF19), published in 1999.

[0137] Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract, such as intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (e.g., by aerosol), intrathecal, rectal, and topical administration (including the use of patches or other transdermal delivery devices). Parenteral administration may be performed by continuous infusion over a selected period.

[0138] In some embodiments, the compounds of the present invention are administered orally, or encapsulated in hard or soft gelatin capsules, or compressed into tablets, or directly incorporated into food, for example, with an inert diluent or an assimilated food carrier. In some embodiments, the compounds are incorporated into excipients and used in the form of orally ingestible tablets, buccal tablets, lozenges, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions, and aqueous suspensions. In the case of tablets, carriers used include salts of lactose, corn starch, sodium citrate, and phosphoric acid. Pharmaceutically acceptable excipients include binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). In embodiments, tablets are coated by methods well known in the art. For tablets, capsules, caplets, pellets, or granules for oral administration, pH-sensitive enteric coatings, such as Eudragit®, designed to control the release of the active ingredient, are optionally used. Oral dosage forms also include controlled-release formulations, such as immediate-release formulations and time-controlled formulations. Examples of controlled-release formulations include sustained-release (SR), extended-release (ER, XR, or XL), time-release or time-controlled formulations, controlled-release (CR), or continuous-release (CR or Contin) formulations, used in the form of coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, aggregated particles, such as molecular sieve-type particles, or fine hollow permeable fiber bundles, or hollow permeable fiber-cut hollow fibers that are aggregated or held within fibrous packets. Time-controlled formulations are formulated, for example, as liposomes, or in which the active compound is protected by a selectively degradable coating, such as microencapsulation or multiple coatings.Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles, and multilayer vesicles. In some embodiments, liposomes are formed from various phospholipids such as cholesterol, stearylamine, or phosphatidylcholine. For oral administration in capsule form, lactose and dried corn starch are useful carriers or diluents.

[0139] In some embodiments, liquid preparations for oral administration are appropriately presented, for example, in the form of solutions, syrups, or suspensions, or as dry products to be composed of with water or other suitable vehicles before use. When aqueous suspensions and / or aqueous emulsions are administered orally, the compounds of the present invention are appropriately suspended or dissolved in an oil phase combined with emulsifiers and / or suspending agents. Certain sweeteners and / or flavoring agents and / or coloring agents are added, if desired. Such liquid preparations for oral administration are prepared by conventional means using pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fat); emulsifiers (e.g., lecithin or gum arabic); non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycol.

[0140] The compound of this invention can also be freeze-dried, and the resulting freeze-dried product can be used, for example, in the preparation of injectable products.

[0141] In some embodiments, the compound is administered parenterally. For example, a solution of the compound is prepared in water appropriately mixed with a surfactant such as hydroxypropylcellulose. In some embodiments, the dispersion is prepared with or without alcohol in glycerol, liquid polyethylene glycol, DMSO and mixtures thereof, or in oil. Under normal storage and use conditions, these preparations contain preservatives to prevent microbial growth. Methods for preparing suitable formulations will be apparent to those skilled in the art. For parenteral administration, a sterile solution of the compound is usually prepared, with the pH of the solution appropriately adjusted and buffered. For intravenous use, the total concentration of the solute should be controlled to make the preparation isotonic. For ophthalmic administration, an ointment or droppable liquid is delivered by an ophthalmic delivery system known in the art, such as an applicator or eyedropper. In one embodiment, such a composition comprises a mucus-mimicking substance such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose, or polyvinyl alcohol, a preservative such as sorbic acid, EDTA, or benzyl chromium chloride, and a typical amount of diluent or carrier. For intrapulmonary administration, the diluent or carrier is selected to be suitable for enabling aerosol formation.

[0142] In some embodiments, the compounds of the present invention are formulated for parenteral administration by injection, including the use of conventional catheterization or infusion methods. The injectable formulations are presented, for example, in unit dosage forms with added preservatives, such as ampoules or multi-dose containers. In some embodiments, the compositions take the form of a sterile suspension, sterile solution or sterile emulsion in an oily or aqueous vehicle and contain formulation agents such as suspending agents, stabilizers and / or dispersants. In all cases, the dosage forms must be sterile and fluid enough to allow for good needle permeability. Alternatively, the compounds of the present invention may take the form of a sterile powder for reconstitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0143] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, gels, and powders. For intranasal or inhalation administration, the compounds are conveniently delivered in the form of solutions, dry powder formulations, or suspensions from a pump-spray container squeezed or pumped by the patient, or as aerosol spray presentations from a pressurized container or nebulizer. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in sterile single or multiple doses in a sealed container, typically in the form of a cartridge or refill for use with a spray device. Alternatively, the sealed container is an integrated dispensing device, such as a single-dose nasal inhaler or an aerosol dispensing device with a metering valve, intended for disposal after use. If the dosage form includes an aerosol dispensing device, it contains a propellant, such as a compressed gas, such as compressed air, or an organic propellant, such as a fluorochloro hydrocarbon. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkane, carbon dioxide, or other suitable gases. In the case of pressurized aerosols, the dosage unit is appropriately determined by providing a valve for delivering a measured amount. In some embodiments, the pressurized vessel or nebulizer contains a solution or suspension of the active compound. Capsules and cartridges (e.g., made of gelatin) for use in inhalers or injectors are formulated to contain, for example, a suitable powder mixture of the compound of the present invention and a suitable powder base, such as lactose or starch. The aerosol dosage form may also take the form of a pump sprayer.

[0144] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastils, in which the compound of the present invention is formulated with a carrier such as sugar, gum arabic, tragacanth, or gelatin and glycerin. Compositions for rectal administration are conveniently available in the form of suppositories containing conventional suppository bases such as cocoa butter.

[0145] The suppository formulation of the present compound is useful for vaginal, urethral, ​​and rectal administration. Such suppositories are generally constructed from a mixture of substances that are solid at room temperature but melt at body temperature. Substances commonly used to prepare such vehicles include, but are not limited to, theobroma oil (also known as cocoa butter), glycerin gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol. For further information on suppository formulations, see, for example, pages 1530–1533 of Remington's Pharmaceutical Sciences (16th edition, Mack Publishing, Easton, Pennsylvania, 1980).

[0146] In some embodiments, the compounds of the present invention are coupled with soluble polymers as targetable drug carriers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxy-ethyl aspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, the compounds of the present invention are coupled with a class of biodegradable polymers that help achieve controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked copolymers or amphiphilic block copolymers of hydrogels.

[0147] In some embodiments, the compounds of the present invention may be coupled with a viral vector, a non-viral vector, or other vector. Viral vectors may include retroviruses, lentiviruses, adenoviruses, herpesviruses, poxviruses, alphaviruses, vaccinia viruses, or adeno-associated viruses. Non-viral vectors may include nanoparticles, cationic lipids, cationic polymers, metal nanoparticles, nanorods, liposomes, micelles, microbubbles, cell-permeable peptides, or lipospheres. Nanoparticles may include silica, lipids, carbohydrates, or other pharmaceutically acceptable polymers.

[0148] The compound of the present invention, including its pharmaceutically acceptable salts and / or solvates, can be appropriately used alone, but is generally administered in the form of a pharmaceutical composition in which one or more compounds of the present invention (active ingredients) are combined with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition contains about 0.05% to about 99% by weight or about 0.10% to about 70% by weight of the active ingredient and about 1% to about 99.95% by weight or about 30% to about 99.90% by weight of a pharmaceutically acceptable carrier. Here, all weight percentages are based on the entire composition.

[0149] IV. Method and Use of the Present Application The compound described in this application has been shown to inhibit or block general unregulated derepressive 2 (GCN2) kinase, thereby attenuating the transcriptional function of ATF4 target gene expression. Therefore, the compound described in this application is useful for inhibiting GCN2.

[0150] Accordingly, this application encompasses a method for inhibiting generalized unrepressive 2 (GCN2) in cells in a biological sample or in a patient, comprising administering an effective amount of one or more of the compounds of the application to cells.

[0151] This application also includes the use of one or more of the compounds for inhibiting GCN2 in cells, and the use of one or more of the compounds for preparing a pharmacopoeia for inhibiting GCN2 in cells. This application further includes one or more of the compounds for use in inhibiting GCN2 in cells.

[0152] Since the compound of this application has been shown to inhibit the activity of the GCN2 protein, it is useful for treating diseases, disorders, or pathological conditions by inhibiting GCN2. Therefore, the compound of this application is useful as a pharmaceutical. Accordingly, this application encompasses the compound of this application for use as a pharmaceutical.

[0153] Therefore, this application also includes methods for treating diseases, disorders, or conditions that can be treated by inhibiting GCN2, which include administering one or more therapeutically effective amounts of the compounds of the application to a subject in need.

[0154] This application also includes the use of one or more of the compounds of the present invention for treating diseases, disorders, or conditions that can be treated by inhibiting GCN2, and the use of one or more of the compounds of the present invention for preparing pharmaceuticals for treating diseases, disorders, or conditions that can be treated by inhibiting GCN2. This application further includes one or more of the compounds of the present invention for use in treating diseases, disorders, or conditions that can be treated by inhibiting GCN2.

[0155] GCN2 is a protein kinase belonging to the eukaryotic translation initiation factor 2α (eIF2α) kinase family. In some embodiments, this serine / threonine protein kinase is an enzyme encoded in humans by GCN2 or EIF2AK4 (Gene ID: 851877), which includes the amino acid sequence disclosed in Mol. Cell. Biol. 1995, 15(8): 4497-506.

[0156] In some embodiments, the diseases, disorders, or conditions that can be treated by inhibiting GCN2 are neoplasms. Accordingly, the application also includes methods for treating neoplasms, comprising administering one or more therapeutically effective amounts of the compounds of the Application to a subject in need thereof. The application also includes the use of one or more of the compounds of the Application for treating neoplasms, and the use of one or more of the compounds of the Application for preparing a pharmacopoeia for treating neoplasms. The application further includes one or more of the compounds of the Application for use in treating neoplasms. In some embodiments, the treatment is performed in an amount effective in improving at least one symptom of the neoplasm in a subject in need of such treatment, for example, in particular, a reduction in cell proliferation, a reduction in tumor mass.

[0157] Neoplasms can be benign (e.g., uterine fibroids and pigmented nevi), potentially malignant (e.g., carcinoma in situ), or malignant (i.e., cancer). Typical neoplasms include, but are not limited to, so-called solid tumors and humoral tumors, including cancer, sarcoma, metastatic disorders (e.g., tumors arising from the prostate), hematopoietic neoplasms (e.g., leukemia, lymphoma, myeloma, and other malignant plasmacytoplasms), metastatic tumors, and other cancers. Common cancers include breast cancer, prostate cancer, colorectal cancer, lung cancer, liver cancer, brain cancer, ovarian cancer, and pancreatic cancer.

[0158] The compound of this invention has been demonstrated to inhibit the growth of cancer cells. In some embodiments, the disease, disorder, or condition that can be treated by inhibiting GCN2 is cancer.

[0159] Accordingly, this application also encompasses a method for treating cancer, comprising administering a therapeutically effective dose of one or more of the compounds to a subject in need thereof. This application also encompasses the use of one or more of the compounds for treating cancer, and the use of one or more of the compounds for preparing a pharmacopoeia for treating cancer. This application further encompasses one or more of the compounds for use in treating cancer. In one embodiment, the compounds are administered to prevent cancer in subjects such as mammals predisposed to cancer.

[0160] In some embodiments, cancer is defined as acute lymphoblastic leukemia, adult; acute lymphoblastic leukemia, pediatric; acute myeloid leukemia, adult; adrenocortical carcinoma; adrenocortical carcinoma, pediatric; AIDS-associated lymphoma; AIDS-associated malignant disease; anal cancer; astrocytoma, pediatric cerebellar; astrocytoma, pediatric cerebral; cholangiocarcinoma, extrahepatic; bladder cancer; bladder cancer, pediatric; bone cancer, osteosarcoma / malignant fibrous histiocytoma; brainstem glioma, pediatric; brain tumor, adult; brain tumor, brainstem glioma, pediatric; brain tumor, cerebellar astrocytoma, pediatric; brain tumor, cerebral astrocytoma / malignant glioma, pediatric; brain tumor, ventricle ependymoma, pediatric; brain tumor, cerebrospinal Blastoma, pediatric; brain tumor, supratentorial primitive neuroectodermal tumor, pediatric; brain tumor, glioma of the visual pathway and hypothalamus, pediatric; brain tumor, pediatric (other); breast cancer; breast cancer and pregnancy; breast cancer, pediatric; breast cancer, male; bronchial adenoma / carcinoid, pediatric; carcinoid tumor, pediatric; carcinoid tumor, gastrointestinal; cancer, adrenal cortex; cancer, islet cell; cancer of unknown primary origin; central nervous system lymphoma, primary; cerebellar astrocytoma, pediatric; cerebral astrocytoma / malignant glioma, pediatric; cervical cancer; childhood cancer; chronic lymphocytic leukemia; chronic myeloid leukemia; chronic myeloproliferative disorder; clear cell sarcoma of the tendon sheath; colorectal cancer; rectal rectum Intestinal cancer, pediatric; cutaneous T-cell lymphoma; endometrial cancer; ventriculependymoma, pediatric; epithelial cancer, ovarian; esophageal cancer; esophageal cancer, pediatric; Ewing family tumors; extracranial germ cell tumors, pediatric; extragonadal germ cell tumors; extrahepatic bile duct cancer; eye cancer, intraocular melanoma; eye cancer, retinoblastoma; gallbladder cancer; gastric (stomach) cancer; gastric (stomach) cancer, pediatric; gastrointestinal carcinoid tumors; germ cell tumors, extracranial, pediatric; germ cell tumors, extragonadal; germ cell tumors, ovarian; gestational trophoblastic neoplasm; glioma, pediatric brainstem; glioma, pediatric visual tract and hypothalamus; hair cell leukemia; head and neck cancer; hepatocellular carcinoma (liver cancer), Adult (primary); hepatocellular (liver) cancer, pediatric (primary); Hodgkin lymphoma, adult; Hodgkin lymphoma, pediatric; Hodgkin lymphoma during pregnancy; hypopharyngeal cancer; glioma of the hypothalamus and visual pathway, pediatric; intraocular melanoma; islet cell carcinoma (pancreatic endocrine part); Kaposi's sarcoma; renal cancer; laryngeal cancer; laryngeal cancer, pediatric; leukemia, acute lymphoblastic, adult; leukemia, acute lymphoblastic, pediatric; leukemia, acute myeloid, adult; leukemia, acute myeloid, pediatric; leukemia, chronic lymphocytic; leukemia, chronic myeloid; hair cell; lip and oral cancer; liver cancer, adult (primary); liver cancer, pediatric (primary);Lung cancer, non-small cell; lung cancer, small cell; lymphoblastic leukemia, adult acute; lymphoblastic leukemia, pediatric acute; lymphocytic leukemia, chronic; lymphoma, AIDS-related; lymphoma, central nervous system (primary); lymphoma, cutaneous T cell; lymphoma, Hodgkin, adult; lymphoma, Hodgkin, pediatric; lymphoma, gestational Hodgkin; lymphoma, non-Hodgkin, adult; lymphoma, non-Hodgkin, pediatric; lymphoma, gestational non-Hodgkin; lymphoma, primary central nervous system; macroglobulinemia, Waldenström; male breast cancer; malignant mesothelioma, adult; malignant mesothelioma, pediatric; malignant thymoma; medulloblastoma, Pediatric; melanoma; intraocular melanoma; Merkel cell carcinoma; malignant mesothelioma; metastatic squamous cell carcinoma of unknown primary origin; multiple endocrine neoplasia syndrome, pediatric; multiple myeloma / plasmacytic neoplasm; mycosis fungoides; myelodysplastic syndrome; chronic myeloid leukemia; acute myeloid leukemia, pediatric; multiple myeloma; chronic myeloproliferative disorder; nasal and paranasal sinus cancer; nasopharyngeal cancer; pediatric nasopharyngeal cancer; neuroblastoma; adult non-Hodgkin lymphoma; pediatric non-Hodgkin lymphoma; pregnancy-related non-Hodgkin lymphoma; non-small cell lung cancer; pediatric oral cancer; oral and lip cancer; oropharyngeal cancer; osteosarcoma / malignant fibrous histiocytoma of bone; oocyte Focal cancer, pediatric; ovarian epithelial carcinoma; ovarian germ cell tumor; low-grade ovarian tumor; pancreatic cancer; pancreatic cancer, pediatric; pancreatic cancer, islet cell; paranasal sinus / nasal cavity cancer; parathyroid cancer; penile cancer; pheochromocytoma; pineal and supratentorial primitive neuroectodermal tumors, pediatric; pituitary tumor; plasma cell neoplasms / multiple myeloma; pleuropulmonary blastoma; pregnancy and breast cancer; pregnancy and Hodgkin lymphoma; pregnancy and non-Hodgkin lymphoma; primary central nervous system lymphoma; primary liver cancer, adult; primary liver cancer, pediatric; prostate cancer; rectal cancer; renal cell (kidney) carcinoma; renal cell carcinoma, pediatric; renal pelvis and ureteral transition cell carcinoma; retinoblastoma; rhabdomyoblastoma Myosarcoma, pediatric; salivary gland cancer; salivary gland cancer, pediatric; sarcoma, Ewing family tumor; sarcoma, Kaposi's sarcoma; sarcoma (osteosarcoma) / malignant fibrous histiocytoma of bone; sarcoma, rhabdomyosarcoma, pediatric; sarcoma, soft tissue, adult; sarcoma, soft tissue, pediatric; Sézary syndrome; skin cancer; skin cancer, pediatric; skin cancer (melanoma); skin cancer, Merkel cells; small cell lung cancer; small intestine cancer; soft tissue sarcoma, adult; soft tissue sarcoma, pediatric; squamous cell carcinoma of unknown primary origin, metastatic; gastric (stomach) cancer; gastric (stomach) cancer, pediatric; supratentorial primitive neuroectodermal tumor, pediatric; T-cell lymphoma, skin; testicular cancer; thymoma, pediatric;Selected from, but not limited to, thymoma, malignant; thyroid cancer; thyroid cancer, pediatric; transitional cell carcinoma of the renal pelvis and ureter; gestational trophoblastic neoplasm; cancer of unknown primary site, pediatric; rare cancers in children; transitional cell carcinoma of the ureter and renal pelvis; urethral cancer; uterine sarcoma; vaginal cancer; glioma of the visual pathway and hypothalamus, pediatric; vulvar cancer; Waldenström macroglobulinemia; and Wilms' tumor. Metastases of the aforementioned cancers can also be treated according to the methods described herein.

[0161] In some embodiments, cancer is any cancer in which cells exhibit increased expression of the gene encoding GCN2 or activation of GCN2 under stress conditions. "Increased expression" means any increase in the expression of the gene encoding GCN2 in the cell compared to the expression of the gene encoding GCN2 in the corresponding normal or healthy cell.

[0162] In some embodiments, the cancer is selected from one or more of the following: solid tumors, breast cancer, colorectal cancer, bladder cancer, skin cancer, head and neck cancer, liver cancer, lung cancer, pancreatic cancer, ovarian cancer, prostate cancer, bone cancer, and glioblastoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is glioblastoma. In some embodiments, the bone cancer is osteosarcoma.

[0163] In some embodiments, the diseases, disorders, or conditions that can be treated by inhibiting GCN2 are diseases, disorders, or conditions associated with uncontrolled and / or abnormal cellular activity that is directly or indirectly affected by inhibiting GCN2. In another embodiment, the uncontrolled and / or abnormal cellular activity that is directly or indirectly affected by inhibiting GCN2 is proliferative activity in cells.

[0164] Accordingly, this application also includes a method for inhibiting proliferative activity in cells, comprising administering an effective amount of one or more of the compounds of the application to cells. This application also includes the use of one or more of the compounds of the application for inhibiting proliferative activity in cells, and the use of one or more of the compounds of the application for preparing a pharmacopoeia for inhibiting proliferative activity in cells. This application further includes one or more of the compounds of the application for use in inhibiting proliferative activity in cells.

[0165] This application also includes methods for inhibiting uncontrolled and / or abnormal cellular activity directly or indirectly affected by inhibiting GCN2 in any cell in a biological sample or subject, comprising administering an effective amount of one or more of the compounds of the Application to cells. This application also includes the use of one or more of the compounds of the Application for inhibiting uncontrolled and / or abnormal cellular activity directly or indirectly affected by inhibiting GCN2 in cells, and the use of one or more of the compounds of the Application for preparing a pharmacopoeia for inhibiting uncontrolled and / or abnormal cellular activity directly or indirectly affected by inhibiting GCN2 in cells. This application further includes one or more of the compounds of the Application for use in inhibiting uncontrolled and / or abnormal cellular activity directly or indirectly affected by inhibiting GCN2 in cells.

[0166] In some embodiments, the disease, disorder, or condition that can be treated by inhibiting GCN2 is peripheral neuropathy. Therefore, the application also encompasses a method for treating peripheral neuropathy, comprising administering a therapeutically effective amount of one or more of the compounds to a subject in need thereof. The application also encompasses the use of one or more of the compounds for treating peripheral neuropathy, and the use of one or more of the compounds for preparing a pharmacopoeia for treating peripheral neuropathy. The application further encompasses one or more of the compounds for use in treating peripheral neuropathy.

[0167] In some embodiments, peripheral neuropathy is Charcot-Marie-Tooth (CMT) peripheral neuropathy. Heterozygous mutations in six genes encoding cytoplasmic aminoacyl-tRNA synthetase (AARS) cause axonal and intermediate forms of CMT peripheral neuropathy. AARS is a ubiquitously expressed enzyme that covalently attaches amino acids to their homologous tRNAs (tRNA aminoacylation). Aminoacylated tRNAs are used by ribosomes for mRNA translation. In Charcot-Marie-Tooth (CMT) peripheral neuropathy, mutant tRNA synthetases activate the integrated stress response (ISR) via the sensor kinase GCN2. Chronic activation of ISR contributes to the pathophysiology, and gene deletion or pharmacological inhibition of GCN2 has mitigated peripheral neuropathy. Therefore, in some embodiments, a disease, disorder, or condition that can be treated by inhibiting GCN2 is Charcot-Marie-Tooth (CMT) peripheral neuropathy.

[0168] Accordingly, this application also encompasses a method for treating Charcot-Marie-Tooth (CMT) peripheral neuropathy, comprising administering one or more therapeutically effective doses of the compounds of the Application to a subject in need thereof. This application also encompasses the use of one or more of the compounds of the Application for treating Charcot-Marie-Tooth (CMT) peripheral neuropathy, and the use of one or more of the compounds of the Application for preparing a medicament for treating Charcot-Marie-Tooth (CMT) peripheral neuropathy. This application further encompasses one or more of the compounds of the Application for use in treating Charcot-Marie-Tooth (CMT) peripheral neuropathy.

[0169] This application also includes a method for treating a disease, disorder, or condition that can be treated by inhibiting GCN2, comprising administering to a subject in need one or more therapeutically effective amounts of one or more of the compounds of the Application in combination with another known active agent useful for treating the disease, disorder, or condition that can be treated by inhibiting GCN2. This application also includes the use of one or more of the compounds of the Application in combination with another known active agent useful for treating a disease, disorder, or condition that can be treated by inhibiting GCN2, and the use of one or more of the compounds of the Application in combination with another known active agent useful for treating a disease, disorder, or condition that can be treated by inhibiting GCN2 for the preparation of a pharmacopoeia for treating a disease, disorder, or condition that can be treated by inhibiting GCN2. This application further includes one or more of the compounds of the Application in combination with another known active agent useful for treating a disease, disorder, or condition that can be treated by inhibiting GCN2, for use in treating a disease, disorder, or condition that can be treated by inhibiting GCN2.

[0170] In one embodiment, diseases, disorders, or conditions that can be treated by inhibiting GCN2 include cancer and / or peripheral neuropathy.

[0171] In some embodiments, GCN2 is inhibited by the use and methods of the present application.

[0172] In one embodiment, "the subject requiring it" refers to the subject having the disease, disorder, or condition to be treated.

[0173] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0174] In some embodiments, the disease, disorder, or condition that can be treated by inhibiting GCN2 is cancer, and the one or more compounds of the present invention are administered or used in combination with one or more additional cancer treatments. In another embodiment, the one or more additional cancer treatments are selected from one or more targeted therapies such as radiotherapy, chemotherapy, antibody therapy (including anti-PD1 antibodies and / or anti-PD-L1 antibodies), as well as small molecule therapies, such as tyrosine kinase inhibitor therapy, glutaminase inhibitors (e.g., glutaminase-1 (GLS1) inhibitors), and asparagine synthase (ASNS) inhibitors, immunotherapy, hormone therapy, and anti-angiogenic therapy.

[0175] In some embodiments, the chemotherapy is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is cisplatin. Therefore, in some embodiments, the disease, disorder, or condition that can be treated by inhibiting GCN2 is cancer, and one or more of the compounds of the present invention are administered or used in combination with cisplatin. In some embodiments, the chemotherapeutic agent is L-asparaginase (L-ASNase). Therefore, in some embodiments, the disease, disorder, or condition that can be treated by inhibiting GCN2 is cancer, and one or more of the compounds of the present invention are administered or used in combination with L-asparaginase (L-ASNase).

[0176] In some embodiments, the small molecule therapy is a glutaminase (e.g., glutaminase-1, (GLS1)) inhibitor or an asparagine synthase (ASNS) inhibitor. Therefore, in some embodiments, the disease, disorder or condition that can be treated by inhibiting GCN2 is cancer, and the one or more compounds of the present invention are administered or used in combination with one or more glutaminase inhibitors (e.g., GLS1 inhibitors) and / or asparagine synthase (ASNS) inhibitors.

[0177] In some embodiments, the disease, disorder, or condition that can be treated by inhibiting GCN2 is cancer, and the one or more compounds of the present invention are administered or used in combination with one or more glutaminase inhibitors (e.g., GLS1 inhibitors) and / or asparagine synthase (ASNS) inhibitors and / or L-asparaginase (L-ASNase).

[0178] Asparagine deficiency mediated by L-asparaginase (L-ASNase) is an effective therapeutic strategy in cancer, but resistance arises due to the upregulation of asparagine synthetase (ASNS), the only human enzyme that synthesizes asparagine (Annu. Rev. Biochem. 2006, 75(1), 629-654). The effectiveness of L-asparaginase in solid tumors is limited by dose-related toxicity (OncoTargets and Therapy 2017, pp 1413-1422). Large-scale loss-of-function gene in vitro screening identified ASNS as cancer-dependent in several solid malignancies (Cell 2017, 170(3), 564-576.e16.Cell 2017, 170(3), 577-592.e10). Genome-wide CRISPR screening revealed that cancer cell resistance mechanisms are induced by the GCN2-ATF4 axis, which aims to restore amino acid levels to promote survival. Therefore, pharmacological inhibition of GCN2 synergistically interacts with L-asparaginase-mediated asparagine deficiency in ASNS-deficient cells, suggesting a potential novel therapeutic combination in cancer treatment.

[0179] Therefore, in some embodiments, the present application also includes a method for improving the effectiveness of one or more cancer treatments for treating cancer, which involves administering an effective amount of one or more of the compounds of the present application in combination with an effective amount of the said one or more cancer treatments to a subject in need thereof.

[0180] This application also includes the use of one or more compounds of the present invention in combination with one or more cancer treatments for treating cancer, to improve the effectiveness of one or more cancer treatments for treating cancer, and the use of one or more compounds of the present invention in combination with one or more cancer treatments for improving the effectiveness of one or more cancer treatments for treating cancer. This application further includes one or more compounds of the present invention in combination with one or more cancer treatments for use in improving the effectiveness of one or more cancer treatments for treating cancer.

[0181] In some embodiments, the one or more cancer treatments are selected from one or more targeted therapies such as radiotherapy, chemotherapy, antibody therapy (including anti-PD1 antibodies and / or anti-PD-L1 antibodies), as well as small molecule therapies, such as tyrosine kinase inhibitor therapy, glutaminase inhibitors (e.g., GLS1 inhibitors), and / or asparagine synthase (ASNS) inhibitors, immunotherapy, hormone therapy, and anti-angiogenic therapy.

[0182] In some embodiments, the chemotherapy is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is cisplatin. Therefore, in some embodiments, one or more compounds of the present invention are administered or used in combination with cisplatin to enhance the efficacy of cisplatin for treating cancer.

[0183] In some embodiments, the chemotherapeutic agent is L-asparaginase (L-ASNase). Therefore, in some embodiments, one or more compounds of the present invention are administered or used in combination with L-asparaginase (L-ASNase) to enhance the efficacy of L-ASNase for treating cancer.

[0184] In some embodiments, the small molecule therapy is a glutaminase inhibitor (e.g., a GLS1 inhibitor) or an asparagine synthase (ASNS) inhibitor. Therefore, in some embodiments, one or more compounds of the present invention are administered or used in combination with one or more glutaminase inhibitors (e.g., GLS1 inhibitors) and / or one or more ASNS inhibitors to enhance the efficacy of said glutaminase inhibitors (e.g., GLS1 inhibitors) or one or more ASNS inhibitors for treating cancer.

[0185] In some embodiments, cancer is associated with low asparagine synthase (ASNS) expression. In some embodiments, cancer is associated with low asparagine synthase (ASNS) expression, and the chemotherapeutic agent is L-asparaginase (L-ASNase). Therefore, in some embodiments, one or more compounds of the present invention are administered or used in combination with L-asparaginase (L-ASNase) to enhance the efficacy of L-ASNase for treating cancer associated with low asparagine synthase (ASNS) expression.

[0186] In some embodiments, cancer is associated with the overexpression or dysregulation of asparagine synthase (ASNS). In some embodiments, cancer is associated with the overexpression or dysregulation of asparagine synthase (ASNS), and the chemotherapeutic agent is one or more asparagine synthase (ASNS) inhibitors and / or L-asparaginase. Therefore, in some embodiments, one or more compounds of the present invention are administered or used in combination with one or more asparagine synthase (ASNS) inhibitors and / or L-asparaginase to treat cancer associated with the overexpression or dysregulation of asparagine synthase (ASNS). In some embodiments, the chemotherapeutic agent is one or more asparagine synthase (ASNS) inhibitors and L-asparaginase.

[0187] In some embodiments, cancer is associated with low asparagine synthase (ASNS) expression and low glutaminase (e.g., GLS1) expression. In some embodiments, cancer is associated with low asparagine synthase (ASNS) expression and low glutaminase (e.g., GLS1) expression, and the chemotherapeutic agent is L-asparaginase (L-ASNase) and / or one or more glutaminase inhibitors. Therefore, in some embodiments, one or more compounds of the present invention are administered or used in combination with L-asparaginase (L-ASNase) and / or one or more glutaminase inhibitors to improve the efficacy of L-ASNase and / or one or more glutaminase inhibitors for treating cancer associated with low asparagine synthase (ASNS) expression and low glutaminase (e.g., GLS1) expression. In some embodiments, the glutaminase inhibitor is a GLS1 inhibitor. In some embodiments, the chemotherapeutic agent is L-asparaginase (L-ASNase) and one or more glutaminase inhibitors.

[0188] In some embodiments, cancer is associated with overexpression or dysregulation of asparagine synthase (ASNS) and glutaminase (e.g., GLS1). In some embodiments, cancer is associated with overexpression or dysregulation of asparagine synthase (ASNS) and glutaminase (e.g., GLS1), and the chemotherapeutic agent is L-asparaginase (L-ASNase), one or more glutaminase inhibitors, and / or one or more asparagine synthase (ASNS) inhibitors. Therefore, in some embodiments, one or more compounds of the present invention are administered or used in combination with L-asparaginase (L-ASNase) and / or one or more glutaminase inhibitors and / or one or more asparagine synthase (ASNS) inhibitors to improve the efficacy of L-ASNase and / or the one or more glutaminase inhibitors and / or the one or more asparagine synthase (ASNS) inhibitors for treating cancers associated with overexpression or dysregulation of asparagine synthase (ASNS) and glutaminase (e.g., GLS1). In some embodiments, the glutaminase inhibitor is a GLS1 inhibitor. In some embodiments, the chemotherapeutic agents are L-asparaginase (L-ASNase), one or more glutaminase inhibitors and one or more asparagine synthase (ASNS) inhibitors.

[0189] The compounds of this application are used alone or in combination with other known active agents useful for treating diseases, disorders, or conditions that can be treated by inhibiting GCN2. When used in combination with other active agents useful for treating diseases, disorders, or conditions that can be treated by inhibiting GCN2, administering the compounds of this application concurrently with those active agents is one embodiment. As used herein, “contemporary administration” of two substances to a subject means that each of the two substances is given such that they are both simultaneously biologically active in that organism. The exact details of the administration depend on the pharmacokinetics of the two substances in the presence of each other and may include administering the two substances within a few hours of each other, or, if the pharmacokinetics are appropriate, administering one substance within 24 hours of the administration of the other. Designing appropriate administration regimens is commonplace for those skilled in the art. In certain embodiments, the two substances are administered substantially simultaneously, i.e., within a few minutes of each other, or as a single composition containing both substances. The non-contemporary administration of combinations of active agents to a subject is a further embodiment of this application. In some embodiments, the compounds of the present application are administered together with other therapeutic agents, either simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form. Accordingly, the present application provides a single unit dosage form comprising one or more of the compounds of the present application (e.g., compounds of formula I), an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0190] The treatment method comprises administering one or more therapeutically effective doses of the compound of the present invention to a subject, optionally consisting of a single dose or a series of doses, and optionally including the simultaneous administration or use of one or more other therapeutic agents. For example, in some embodiments, the compound of the present invention is administered at least once a week. In some embodiments, the compound is administered to the subject for a given treatment, ranging from about once every two or three weeks, or about once a week, to about once a day. In other embodiments, the compound is administered two, three, four, five, or six times a day. The length of the treatment period depends on various factors, including the severity of the disease, disorder, or condition, the age of the subject, the concentration and / or activity of the compound of the present invention, and / or combinations thereof. The effective dose of the compound used in treatment may be increased or decreased during the course of a particular treatment regimen. Changes in dosage may be made and revealed by standard diagnostic assays known in the art. In some cases, chronic administration may be necessary. For example, the compound is administered to the subject in an amount and for a period sufficient to treat the subject. In some embodiments, the treatment includes prophylactic treatment. For example, subjects with early-stage cancer can be treated to prevent progression, or subjects in remission can be treated with the compound or composition of the present invention to prevent recurrence.

[0191] The dosage of the compound in this application varies depending on many factors, including the pharmacodynamic properties of the compound, the mode of administration, the patient's age, health status and weight, the nature and severity of symptoms, the frequency and type of concomitant treatments, if any, and the clearance rate of the compound in the treated area. Those skilled in the art can determine an appropriate dosage based on the above factors. The compound in this application may be administered first at an appropriate dosage, which may be adjusted as needed based on the clinical response. The dosage is generally selected to maintain serum levels of the compound in this application at approximately 0.01 μg / cc to approximately 1000 μg / cc, or approximately 0.1 μg / cc to approximately 100 μg / cc. As a typical example, the oral dosage of one or more compounds in this application for adults is in the range of approximately 0.05 mg / day to approximately 1000 mg / day, preferably approximately 0.1 mg / day to approximately 500 mg / day, and more preferably approximately 1 mg / day to approximately 200 mg / day. For parenteral administration, typical doses are approximately 0.001 mg / kg to 10 mg / kg, approximately 0.01 mg / kg to 10 mg / kg, approximately 0.01 mg / kg to 1 mg / kg, or approximately 0.1 mg / kg to 1 mg / kg. For oral administration, typical doses are approximately 0.001 mg / kg to 10 mg / kg, approximately 0.1 mg / kg to 10 mg / kg, approximately 0.01 mg / kg to 1 mg / kg, or approximately 0.1 mg / kg to 1 mg / kg. For administration in suppository form, typical doses are approximately 0.1 mg / kg to 10 mg / kg or approximately 0.1 mg / kg to 1 mg / kg. The compound of this application may be administered once daily, once weekly, or once monthly, or the total daily dose may be divided into two, three, or four doses per day.

[0192] In one embodiment, the effective dose varies depending on factors such as the disease state of the subject, age, sex, and / or weight. In a further embodiment, the amount of one or more given compounds that constitutes an effective dose varies depending on factors such as the one or more given drugs or compounds, pharmaceutical formulations, routes of administration, pathological conditions, types of diseases or disorders, and the identity of the subject being treated, but a person skilled in the art can still determine this routinely.

[0193] For the sake of clarity, in the above, "a compound" includes embodiments that refer to one or more compounds. Similarly, "compounds of the application" also includes embodiments that refer to only one compound.

[0194] V. Method for preparing the compound of this invention The compounds of this invention can be prepared by a variety of synthetic processes. The selection of specific structural features and / or substituents may influence the preference for one process over another. The choice of a particular process for preparing a compound of formula I is within the understanding of those skilled in the art. Some starting materials for preparing the compounds of this invention are available from commercial chemical suppliers. Other starting materials, such as those described below, can be readily prepared from available precursors using straightforward transformations well known in the art.

[0195] Compounds of formula I can generally be prepared according to the process illustrated in the following scheme. In the structural formulas shown below, the variable part is as defined in formula I unless otherwise specified. Those skilled in the art will understand that many of the reactions shown in the following scheme are sensitive to oxygen and water, and that the reactions should be carried out in an anhydrous, inert atmosphere as necessary. The reaction temperatures and reaction times are given for illustrative purposes only and may be modified to optimize the yield, as will be understood by those skilled in the art.

[0196] Therefore, in some embodiments, the compound of formula I is prepared as shown in scheme 1. [ka]

[0197] In some embodiments shown in Scheme 1, the compound of formula I is prepared by oxidizing the compound of formula A to the corresponding sulfoxide with a suitable oxidizing agent such as meta-chloroperoxybenzoic acid (m-CPBA), and then substituting it with various suitable amine compounds of formula B to obtain the bromo intermediate of formula C. Subsequently, the compound of formula C is substituted with a suitable boronate of formula D (wherein R a and R b C is independent 1~6 It is alkyl, or linked together, with the B and O atoms between them, and as a whole, one or two C atoms. 1~3 The compound of formula I is obtained by coupling a 4-6 member saturated or unsaturated ring (which may be optionally substituted with alkyl groups) with a compound of formula I under appropriate coupling conditions, for example, under Suzuki-Miyaura coupling conditions. [ka]

[0198] In some embodiments, the compound of formula I is prepared as shown in Scheme 2. Therefore, the intermediate compound of formula A is coupled with the boronate compound of formula D under appropriate coupling conditions, for example, under Suzuki-Miyaura coupling conditions, to obtain the intermediate compound of formula E. The compound of formula E is oxidized to the corresponding sulfoxide with an appropriate oxidizing agent such as meta-chloroperoxybenzoic acid (m-CPBA), and then substituted with various appropriate amines of formula B to obtain the compound of formula I. [ka]

[0199] In some embodiments, the compound of formula I is prepared as shown in scheme 3. Therefore, the compound of formula A is prepared with a suitable boronate of formula F (wherein R c and R d C is independent 1~6 It is alkyl, or linked together, with the B and O atoms between them, and as a whole, one or two C atoms. 1~3Compound G is obtained by coupling a 4-6 member saturated or unsaturated ring (which may be optionally substituted with alkyl groups) under appropriate coupling conditions, for example, under Suzuki-Miyaura coupling conditions. Subsequently, compound E is obtained by sulfonyling compound G with an appropriate aryl sulfonyl chloride of formula H. Compound E is oxidized to the corresponding sulfoxide with an appropriate oxidizing agent such as meta-chloroperoxybenzoic acid (m-CPBA), and then substituted with various appropriate amine compounds of formula B to obtain compound I. [ka]

[0200] In some embodiments, as shown in Scheme 4, X 1 The compound of formula A (compound of formula A-1), where =C, is prepared from the intermediate compound of formula J. The compound of formula J is treated with a suitable amino alcohol (e.g., aminoethanol), and then, under a suitable base such as triethylamine (Et3N), methanesulfonyl chloride is added to obtain the compound of formula A-1. [ka]

[0201] In some embodiments shown in Scheme 5, X 1 Compound A (compound A-2), where =N, is prepared from commercially available 4-amino-2-(methylthio)-5-pyrimidinecarboxaldehyde (compound K). K is condensed with a substituted triethylphosphonoacetate under basic conditions to obtain the intermediate compound L. The intermediate compound M is obtained by base-mediated cyclization of the compound L. The compound N is obtained by selective bromination of the compound M, and then the intermediate compound O is obtained by chlorination with a suitable chlorinating agent such as POCl3. The hydrazide compound P is obtained by treating the compound O with a suitable hydrazine in a suitable solvent such as ethanol, and then the tricyclic intermediate compound A-2 is obtained by subjecting it to a cyclization reaction, such as in the presence of formic acid (Z=H). [ka]

[0202] In some embodiments, as shown in Scheme 6, a compound of formula C (wherein R a and R b C is independent 1~6 It is alkyl, or linked together, with the B and O atoms between them, and as a whole, one or two C atoms. 1~3 The compounds (which may optionally be substituted with alkyl groups to form a 4-6 member saturated or unsaturated ring) are prepared by coupling the arylsulfonyl compound of formula Q with the aniline compound of formula R (wherein Y' and Y'' are each independently halogens, e.g., Cl or Br) in the presence of a suitable base such as pyridine. Subsequently, the compound of formula R is borated under basic conditions under standard boration conditions such as the Miyaura boration conditions using (pinacolato)diborone together with a suitable catalyst, e.g., PdCl2(dppf)(([1,1'bis(diphenylphosphino)ferrocene]palladium(II) dichloride)) to obtain the compound of formula C. [ka]

[0203] In some embodiments, as shown in Scheme 7, a compound of formula C (wherein R a and R b C is independent 1~6 It is alkyl, or linked together, with the B and O atoms between them, and as a whole, one or two C atoms. 1~3Compounds of formula C (forming a 4-6 member saturated or unsaturated ring which may be optionally substituted with alkyl) are prepared by coupling an aryl sulfonyl compound of formula Q with an anilinoboronic acid ester or anilinoboronic acid compound of formula T in the presence of a suitable base such as pyridine. Compounds of formula T are prepared by borylation of a compound of formula U under basic conditions and borylation conditions such as the Miyaura borylation conditions using (pinacolato)diborone with a suitable catalyst such as PdCl2(dppf).

[0204] Generally, the above reactions are carried out in a suitable inert organic solvent at a temperature and time that optimizes the yield of the desired compound. Examples of suitable inert organic solvents include, but are not limited to, 2-propanol, dimethylformamide (DMF), 1,4-dioxane, methylene chloride, chloroform, tetrahydrofuran (THF), and toluene.

[0205] Salts of the compounds of this invention are generally formed by dissolving a neutral compound in an inert organic solvent, adding a desired acid or base, and isolating the resulting salt by filtration or any other known means.

[0206] The formation of the desired compound salt is achieved using standard techniques. For example, a neutral compound is treated with an acid or base in a suitable solvent, and the resulting salt is isolated by filtration, extraction, or any other suitable method.

[0207] The formation of solvates varies depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in a suitable solvent and isolating the solvate by cooling or using a poor solvent. Solvates are typically dried or azeotropically decomposed under ambient conditions. Those skilled in the art can select appropriate conditions for forming a particular solvate. Examples of suitable solvents include ethanol and water. When water is the solvent, the molecule is called a "hydrate." The formation of solvates of the compounds of this application varies depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in a suitable solvent and isolating the solvate by cooling or using a poor solvent. Solvates are typically dried or azeotropically decomposed under ambient conditions. Those skilled in the art can select appropriate conditions for forming a particular solvate.

[0208] The prodrug of the compound of this application may be, for example, a conventional ester formed with available hydroxyl, thiol, amino, or carboxyl groups. For example, the available hydroxyl or amino groups may be acylated in an inert solvent, optionally in the presence of a base, using an activated acid (e.g., an acid chloride in pyridine).

[0209] Throughout the processes described herein, it is understood that, where appropriate, suitable protecting groups are added to various reactants and intermediates and subsequently removed from them, in a manner readily understood by those skilled in the art. Conventional procedures for using such protecting groups, and examples of suitable protecting groups, are described, for example, in *Protective Groups in Organic Synthesis*, TW Green, PGMWuts, Wiley-Interscience, New York (1999). The conversion of one group or substituent to another by chemical operation can be performed on any intermediate or final product in the synthetic pathway toward the final product, and it is understood that the types of possible conversions are limited only by the inherent incompatibility of other functional groups supported by the molecule at that stage to the conditions or reagents used for the conversion. Such inherent incompatibility, and methods for avoiding them by performing appropriate conversion and synthesis steps in the appropriate order, are readily understood by those skilled in the art. Examples of conversions are described herein, but it should be understood that the conversions described are not limited to the general groups or substituents exemplified. References and descriptions of other suitable transformations are given in *Comprehensive Organic Transformations—A Guide to Functional Group Preparations*, RCLarrock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are found in organic chemistry textbooks, such as *Advanced Organic Chemistry*, March, 4th edition, McGraw Hill (1992) or *Organic Synthesis*, Smith, McGraw Hill (1994). Purification techniques for intermediates and final products include, for example, normal-phase and reverse-phase chromatography on columns or rotating plates, recrystallization, distillation, and liquid-liquid or solid-liquid extraction, which are readily understood by those skilled in the art.

[0210] The products of the process of this application may be isolated according to known methods, for example, the compounds may be isolated by evaporation of the solvent, filtration, centrifugation, chromatography or other suitable method.

[0211] Those skilled in the art will see that if the reaction steps of this application are carried out in various solvents or solvent systems, the reaction steps may be carried out in a mixture of those appropriate solvents or solvent systems. [Examples]

[0212] The following non-limiting examples are illustrative of this application. A. Synthesis and Characterization of Representative Compounds in this Application

[0213] General method General method MB (Miyaura boration) A degassed 1,4-dioxane mixture consisting of aryl halide (1.0 equivalent), B2pin2 (1.3 equivalents), KOAc (3.5 equivalents), and typically PdCl2(dppf)*CH2Cl2 or PdCl2(dppf) (0.1 equivalent) was heated in a microwave reactor (typically 90-100°C) or oil bath (typically 100-110°C) under argon in a sealed state. The crude mixture was then used directly in the subsequent Suzuki-Miyaura cross-coupling step, in most cases without further purification.

[0214] General method SMC (Suzuki-Miyaura cross coupling) In a vial equipped with a stirring bar and filled with Ar or N2, arylboronic acid or arylboronic ester (typically 1-1.5 equivalents; in most cases, arylboronic ester was used as a crude mixture in 1,4-dioxane), a base (Cs2CO3, typically 3 equivalents), an aryl halide (typically 1 equivalent), and a catalyst / ligand (in most cases one of PdCl2(dppf)*CH2Cl2 or PdCl2(dppf); typically 0.1 equivalents) were added. The vial was sealed and H2O and an organic solvent or mixture of organic solvents (DME or 1,4-dioxane) were added. The reaction mixture was degassed with Ar or N2 by repeated exhaustion and refilling with inert gas, and then heated in a microwave reactor or oil bath in a sealed state for a specified time. After the reaction is deemed complete by LC-MS analysis, the mixture is concentrated under reduced pressure and deposited on a Celite® plug or SiO2 samplelet for flash chromatography (typically using an SiO2InnoFlash® cartridge, an SiO2Biotage® cartridge, or an SiO2RediSep® Rf cartridge with an aqueous solution of CH2Cl2-MeOH, CH2Cl2-MeOH-NH3, or CH2Cl2-MeOH-concentrated NH3 in hexane-siRNA or CH2Cl2) or preparative HPLC (typically using a Biotage® SNAP KP-C 18 -HS cartridge or RedisSep(registered trademark)Rf C 18 The solution was purified using either MeOH in H2O + 0.05% TFA or MeCN in H2O + 0.1% formic acid, and optionally subsequently filtered using a Waters PoraPak™ CX column or an Isolute™ CSX-2 column, rinsed with MeOH, and the desired substance was eluted with 2M NH3 in MeOH.

[0215] General method NS (N-sulfonylation) A CH2Cl2 solution (typically 0.06–0.19 M) of substituted 3-bromoaniline (1 equivalent) and anhydrous pyridine (typically 1.5–2.0 equivalents) was treated in one step at 0°C with solid aryl sulfonyl chloride (typically 1 equivalent). The reaction was allowed to slowly reach room temperature and stirred overnight. The reaction mixture was then concentrated under reduced pressure on Celite® or washed by extraction with H2O. The organic extract was concentrated under reduced pressure and deposited on a Biotage® samplelet or Celite®, after which it was purified by flash chromatography on silica gel using one of the following cartridges: InnoFlash®, Biotage®, or RediSep® Rf.

[0216] General method MO (mCPBA-mediated oxidation) To a CH2Cl2 suspension of methylthioheteroaryl (1 equivalent), mCPBA (mCPBA) (typically 1.1–2.2 equivalents, industrial grade, <77%) was added as a solid or in small amounts in CH2Cl2 at 0°C. The reaction was then slowly warmed to room temperature and stirred at room temperature until the reaction was complete. The resulting mixture of sulfoxide and sulfone intermediates was washed by extraction with a saturated aqueous NaHCO3 solution, and the organic layer was concentrated, or simply concentrated under reduced pressure, and used without workup or further purification. intermediate Intermediate 1,6-bromo-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine [ka] Step 1. 6-Bromo-7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine [ka]

[0217] 6-Bromo-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one (5 g, 18.4 mmol) was mixed with POCl3 (100 mL), and the mixture was heated overnight at 110 °C. After completion, the reaction mixture was concentrated to 5 mL and carefully poured into ice-cold H2O. After stirring for 15 minutes, the formed solid was filtered, washed with distilled H2O, and dried under vacuum to obtain 6-bromo-7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine as a white solid (4 g, 75%). MS(ESI)m / z[M+H] + 289.0 / 292.0. Step 2.6-bromo-7-hydrazinyl-2-(methylthio)pyrido[2,3-d]pyrimidine. [ka]

[0218] To a suspension of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one (4.0 g, 13.8 mmol) in EtOH (40 mL), hydrazine hydrate (20 mL) was added, and the reaction mixture was stirred at 80°C for 2 hours. After completion, the reaction mixture was cooled and precipitated. The solid was filtered, washed with EtOH, and dried under reduced pressure to obtain 6-bromo-7-hydrazinyl-2-(methylthio)pyrido[2,3-d]pyrimidine as a white solid (3.0 g, 74%). 1 ¹H NMR (400 MHz, DMSO-d6): δ 9.22 (br.s., 1H), 8.82 (s, 1H), 8.34 (s, 1H), 4.89 (br.s., 2H). The signal corresponding to the Me group is expected to be buried in the solvent peak. Step 3.6-Bromo-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine

[0219] 6-Bromo-7-hydrazinyl-2-(methylthio)pyrido[2,3-d]pyrimidine (3.0 g, 10 mmol) was mixed with HCO2H (30 mL), and the reaction mixture was stirred at 100°C for 3 hours. After completion, the reaction mixture was poured onto crushed ice, the resulting solid was filtered, washed with H2O, and dried under reduced pressure to obtain 6-bromo-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine as a grayish-white solid (1.4 g, 45%). MS(ESI)m / z[M+H] + 296.1 / 298.0. 1 H NMR (400 MHz, DMSO-d6): δ 10.00(s,1H),9.23(s,1H),8.24(s,1H),2.70(s,3H). Intermediate 2: N-(3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide [ka]

[0220] To a stirred solution of 5-chloro-2-methoxypyridine-3-sulfonyl chloride (20 g, 83 mmol) in pyridine (200 mL), 3-bromo-2,4-difluoroaniline (15.5 g, 74.3 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was quenched with 2 M aqueous HCl (500 mL) and extracted with RINKAN (300 mL x 3). The combined organic layer was washed with brine (300 mL x 3), dried (Na2SO4), and concentrated under reduced pressure. The crude substance was triturated with 2% RINKAN in hexane to obtain N-(3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide as a white solid (17 g, 50%). MS(ESI)m / z[M+H] + 412.8 / 414.8. 1 H NMR(400 MHz,DMSO-d6)δ 10.54(s,1H),8.53(d,J=2.4 Hz,1H),8.07(d,J=2.6 Hz,1H),7.37-7.24(m,2H),3.92(s,3H). Intermediate 3: 5-Chloro-N-(4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methoxypyridine-3-sulfonamide and (5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid [ka]

[0221] To a 40 mL solution of pyridine containing 4.0 g of 5-chloro-2-methoxypyridine-3-sulfonyl chloride (4.0 g, 17 mmol), 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (4.0 g, 17 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was directly loaded onto silica gel and purified by column chromatography using MeOH in CH2Cl2. Tritulation with CH2Cl2 and Et2O yielded a mixture of 5-chloro-N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methoxypyridine-3-sulfonamide and (5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid as a white solid (1.7 g, 23%). MS(ESI)m / z[M+H] + 361.2. Intermediate 4: (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid [ka]

[0222] To a 30 mL solution of cooled 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.5 g, 10.5 mmol) in anhydrous pyridine, 5-chloro-2-methoxypyridine-3-sulfonyl chloride (2.5 g, 10.3 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was directly loaded onto a silica gel column and purified using MeOH in CH2Cl2 to obtain (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid as a brown solid (2.8 g, 74%). MS(ESI)m / z[MH] - 359.3. Intermediate 5: 2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [ka]

[0223] A solution of 3-bromo-2,4-difluoroaniline (15 g, 72.1 mmol), Pd(dppf)Cl2 (5.27 g, 7.21 mmol), B2pin2 (27.4 g, 108.1 mmol), and KOAc (21.2 g, 216.3 mmol) in 1,4-dioxane (275 mL) was stirred at 100 °C for 16 hours under N2 conditions. After completion, the solid was removed by filtration and rinsed with CH2Cl2 (150 mL). The filtrate was concentrated under reduced pressure and purified by column chromatography using SiO2 in hexane to obtain 2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as a white solid (10 g, 54%). MS(ESI)m / z[M+H] + 256.2 and 174.0 (corresponding boronic acid). 1 H NMR(400 MHz,DMSO-d6)δ 6.83-6.79(m,1H),6.71(t,J=8.6 Hz,1H),4.91(s,2H),1.29(s,12H). Intermediate 6,6-bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine [ka]

[0224] 6-Bromo-7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine (4.0 g, 14 mmol) was mixed with 2-aminoethane-1-ol (4.2 g, 69 mmol), and the reaction mixture was stirred at 70°C for 4 hours. The reaction mixture was then cooled and cold H2O was added. The solid was filtered and washed to obtain 2-((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidine-7-yl)amino)ethane-1-ol as a white solid (3.0 g, 69%). MS(ESI)m / z[M+H] + 315.0 / 316.9. To a solution of 2-((6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidine-7-yl)amino)ethane-1-ol (3.0 g, 9.5 mmol) in dichloromethane (72 mL), triethylamine (4.0 mL, 29 mmol) and MeSO2Cl (1.47 mL, 19.0 mmol) were added at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. Next, the reaction mixture was poured onto crushed ice. The solid was filtered, washed with H2O, tritulated with MeOH, CH2Cl2, and dried under vacuum to obtain 6-bromo-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine as a pale green solid (0.75 g, 26%). 1 H NMR(400 MHz,DMSO)δ 9.06(s,1H),8.80(s,1H),4.73-4.66(m,2H),4.20-4.13(m,2H),2.64(s,3H).MS(ESI)m / z [M+H] + 296.9 / 299.0. Intermediate 7,6-bromo-9-methyl-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine. [ka]

[0225] A mixture of 6-bromo-7-hydrazinyl-2-(methylthio)pyrido[2,3-d]pyrimidine (2.5 g, 8.7 mmol) and CH3CO2H (10 mL) was stirred at 100°C for 3 hours. The reaction mixture was then poured onto crushed ice. The solid was filtered, washed with H2O, dried, and purified by column chromatography using neutral aluminum oxide and 5% MeOH in DCM to obtain 6-bromo-9-methyl-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine as an orange solid (1.2 g, 44%). MS(ESI)m / z[M+H] + 310.0 / 312.0. 1 H NMR(400 MHz,DMSO)δ 9.17(s,1H),8.16(s,1H),3.10(s,3H),2.69(s,3H). Representative compound of the present invention Example 1: 5-Chloro-N-(4-fluoro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-1) [ka] Step 1: 6-Bromo-2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine [ka]

[0226] 6-Bromo-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (200 mg, 0.67 mmol) was added as a solid to a cold (0°C) CH2Cl2 (60 mL) suspension and slowly warmed to room temperature for a total of 19.6 hours. The resulting pale yellow suspension was concentrated to dryness and used crudely in the next step. MS(ESI)m / z[M+H] + 312.07|314.20 Step 2: 6-Bromo-N-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-amine

[0227] At room temperature, 6-bromo-2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (70 mg, 0.23 mmol) was suspended in i-PrOH (12 mL) and treated with MeNH2 (40 wt% in H2O, 1.2 mL, 13.5 mmol). After stirring at room temperature for 1 day and 21 hours, the solution was concentrated under reduced pressure, attached to Celite®, and purified by flash chromatography (using MeOH in SiO2, CH2Cl2) to obtain 6-bromo-N-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-amine as a white solid. MS(ESI)m / z[M+H] + 279.15 / 281.22 Step 3: 5-Chloro-N-(4-fluoro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-1)

[0228] Following the general SMC method, the entire substance from the previous step (6-bromo-N-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-amine), Cs2CO3 (220 mg, 0.67 mmol), Pd(dppf)Cl2*CH2Cl2 (18.20 mg, 0.022 mmol), crude 5-chloro-N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methoxypyridine-3-sulfonamide (4.6 mL, 0.24 mmol, 0.053 M in 1,4-dioxane) and H2O (2.3 mL) were heated at 100°C for 2 hours. The mixture was purified by flash chromatography (using MeOH in SiO2 and CH2Cl2), and then by preparative HPLC (C 18 By purifying with MeCN in H2O + 0.1% HCO2H, 5-chloro-N-(4-fluoro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide was obtained as a beige solid after lyophilization (20 mg, yield 16%). MS(ESI)m / z[M+H] + 515.35.1H NMR(500MHz,DMSO-d6)δ=10.61(br.S.,1H),9.73(s,1H),9.45(s,0.5 H),9.10(s,1H),9.01(s,0.5 H),8.46(d,J=2.4 Hz,1H),8.24(d,J=4.5 Hz,1H),8.19-8.10(m,1H),7.79-7.66(m,2H),7.32-7.24(m,1H),7.21-7.13(m,1H),3.99(s,3H),3.06-2.94(m,3H). Example 2: trans-5-chloro-N-(3-(2((-4-(dimethylamino)cyclohexyl)amino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide(trans I-2.HCO2H) [ka] Step 1: trans-N1-(6-bromo-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)-N4,N4-dimethylcyclohexane-1,4-diamine [ka]

[0229] trans-N1,N1-dimethylcyclohexane-1,4-diamine,2HCl (72 mg, 0.34 mmol), 6-bromo-2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (70 mg, 0.224 mmol), and K2CO3 (124 mg, 0.90 mmol) were suspended in DMF (6 mL) using sonication. The reaction mixture was stirred at room temperature for 1 day and 22 hours. The reaction mixture was then concentrated under reduced pressure, deposited on Celite®, and purified by flash chromatography (using MeOH in SiO2, CH2Cl2) to obtain trans-N1-(6-bromo-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)-N4,N4-dimethylcyclohexane-1,4-diamine as a beige solid (88 mg, 67% purity based on 67%). MS(ESI)m / z[M+H] + 390.37|392.38 Step 2: trans-5-chloro-N-(3-(2-((-4-(dimethylamino)cyclohexyl)amino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide(trans I-2.HCO2H)

[0230] The entire solid from the previous step, trans-N1-(6-bromo-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)-N4,N4-dimethylcyclohexane-1,4-diamine (88 mg), Pd(dppf)Cl2*CH2Cl2 (13 mg, 0.016 mmol), Cs2CO3 (146 mg, 0.45 mmol), H2O (1.7 mL), and crude 5-chloro-N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methoxypyridine-3-sulfonamide (3.4 mL, 0.18 mmol, in dioxane, 0.053 M) were used and prepared according to the general method of SMC by heating at 95°C for 3 hours. The solution was purified by flash chromatography (using MeOH in SiO2 and CH2Cl2), and then separated by preparative HPLC (C 18 By purification with MeCN + 0.1% HCO2H in H2O, and after lyophilization, 5-chloro-N-(3-(2-((trans-4-(dimethylamino)cyclohexyl)amino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide*HCO2H was obtained as an off-white solid (25.0 mg, yield 23 based on 95% purity). MS(ESI)m / z[M+H] + 626.58.1H NMR(500 MHz,DMSO-d6)δ ppm 9.72-9.78(m,0.54 H),9.44(s,0.34 H),9.06(s,0.38 H),8.98-9.03(m,0.61 H),8.44(d,J=2.45 Hz,1 H),8-18-8.40(m,2 H),8.14-8.19(m,1 H),7.70-7.72(m,1 H),7.65-7.69(m,1 H),7.24-7.29(m,1 H),7.15-7.20(m,1 H),3.98(s,3 H),2.41-2.47(m,6 H),1.88-2.14(m,4 H), 1.31-1.59 (m, 4 H). Example 3: N-(3-(2-amino-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide(I-3) [ka] Step 1: 6-Bromo-[1,2,4]Triazolo[4',3':1,6]Pyrido[2,3-d]Pyrimidine-2-amine [ka]

[0231] A suspension of 6-bromo-2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (70 mg, 0.224 mmol) in i-PrOH (12 mL) was treated with NH4OH aqueous solution (0.618 mL, 4.93 mmol) at room temperature for 1 day and 21.5 hours. The reaction mixture was stirred at room temperature for 2 days, then concentrated under reduced pressure and deposited on Celite®. Purification by flash chromatography (using MeOH in SiO, CH2Cl2) yielded 6-bromo-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-amine as a pale yellow solid (79 mg, yield 84% based on purity 63%). MS(ESI)m / z[M+H] + 265.23 | 267.18 Step 2: N-(3-(2-amino-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide(I-3)

[0232] All the solids from the previous step (6-bromo-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-amine, 79 mg, 0.19 mmol), Pd(dppf)Cl2*CH2Cl2 (13 mg, 0.016 mmol), Cs2CO3 (146 mg, 0.45 mmol), H2O (1.7 mL), and crude 5-chloro-N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methoxypyridine-3-sulfonamide (3.4 mL, 0.18 mmol, 0.053 M in 1,4-dioxane) were used to prepare the mixture according to the general method of SMC. The mixture was degassed, then sealed and heated at 95°C for 3 hours. The solution was purified by flash chromatography (using MeOH in SiO2 and CH2Cl2), and then separated by preparative HPLC (C 18 The fraction was eluted from MeCN + 0.1% HCO2H in H2O, pooled, filtered through an SCX-2 500 mg column, rinsed with MeOH, and eluted with 2M NH3 in MeOH to obtain N-(3-(2-amino-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide as a white solid (1 mg, 1% based on 97% purity). MS(ESI)m / z[M+H] + 501.36.1H NMR(500 MHz,DMSO-d6)δ ppm 9.49(s,1 H),9.01(s,1 H),8.41(d,J=2.45 Hz,1 H),8.14(d,J=2.45 Hz,1 H),7.66-7.76(m,3 H),7.62(br.S.,1 H),7.20-7.29(m,1 H),7.09-7.18(m,1 H),3.96(s,3 H). Example 4: 5-Chloro-N-(4-fluoro-3-(2-(isopropylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-4) [ka] Step 1: 6-Bromo-N-isopropyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-amine [ka]

[0233] At room temperature, 6-bromo-2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (105 mg, 0.34 mmol) was suspended in i-PrOH (12 mL) and treated with i-PtNH2 (0.87 mL, 10 mmol). The suspension was stirred at room temperature for 2 days and 21 hours. By collecting the solid matter by filtration, 6-bromo-N-isopropyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-amine was obtained as a pale pink solid (105.0 mg, quantitative). MS(ESI)m / z[M+H] + 307.24|309.25 Step 2: 5-Chloro-N-(4-fluoro-3-(2-(isopropylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-4)

[0234] The solution was prepared according to the general SMC method by heating 6-bromo-N-isopropyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-amine (50 mg, 0.16 mmol), Pd(dppf)Cl2*CH2Cl2 (13 mg, 0.016 mmol), Cs2CO3 (133 mg, 0.41 mmol), H2O (1.88 mL), and crude 5-chloro-N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methoxypyridine-3-sulfonamide (in 1,4-dioxane, 3.8 mL, 0.19 mmol) at 90°C for 2 hours. It was purified by flash chromatography (using MeOH in SiO2, CH2Cl2) and then purified by preparative HPLC (C18 By purification with MeCN in H2O + 0.1% HCO2H, 5-chloro-N-(4-fluoro-3-(2-(isopropylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide was obtained as a beige solid (20.0 mg, yield 23% based on 97% purity). MS(ESI)m / z[M+H] + 543.49.1H NMR(500 MHz,DMSO-d6)δ ppm 9.69(s,0.6 H),9.46(br.S.,0.3 H),8.92-9.13(m,1 H),8.46(d,J=2.57 Hz,1 H),8.05-8.23(m,2 H),7.65-7.74(m,2 H),7.26-7.32(m,1 H),7.15-7.23(m,1 H),4.22-4.39(m,1 H),3.99(s,3 H),1.17-1.29(m,6 H). Example 5: 5-Chloro-N-(2-fluoro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-5) [ka]

[0235] The solution was prepared by conventional SMC by using 6-bromo-N-methyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-amine (60 mg, 0.21 mmol), Pd(dppf)Cl2*CH2Cl2 (18 mg, 0.021 mmol), Cs2CO3 (175 mg, 0.54 mmol), and crude 5-chloro-N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methoxypyridine-3-sulfonamide (0.052 M in 1,4-dioxane, 4.1 mL, 0.25 mmol), sealing the solution, and heating it in an oil bath at 90°C for 2 hours. Purified by flash chromatography (using MeOH in SiO2 and CH2Cl2), and then subjected to preparative HPLC (C 18 By re-purifying with MeCN in H2O + 0.1% HCO2H, 5-chloro-N-(2-fluoro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide was obtained as a white solid (34.5 mg, yield 31%). MS(ESI)m / z[M+H] + 515.42.1H NMR(500 MHz,DMSO-d6)δ ppm 10.17-10.97(m,1 H),9.71(s,0.7 H),9.48(s,0.3 H),8.92-9.14(m,1 H),8.46(d,J=2.45 Hz,1 H),8.19(d,J=4.77 Hz,1 H),8.09(d,J=2.57 Hz,1 H),7.65(s,1 H),7.59(br.S.,1 H),7.33-7.39(m,1 H),7.23-7.30(m,1 H),3.89(s,3 H),2.94-3.04(m,3 H). Example 6: 5-Chloro-N-(2,4-difluoro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-6) [ka] Step 1: 2,4-difluoro-3-(2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)aniline [ka]

[0236] 2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (323 mg, 1.266 mmol), 6-bromo-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (150 mg, 0.51 mmol), in H2O (1 mL) and 1,4-dioxane (10 mL). Chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (40 mg, 0.051 mmol) and K3PO4 (376 mg, 1.8 mmol) were used and the mixture was heated at 70°C for 4 days in a sealed vial using the standard SMC method. The reaction mixture was cooled to room temperature, and K3PO4 (376 mg, 1.8 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (40 mg, 0.051 mmol), and 2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (323 mg, 1.3 mmol) were added again. The mixture was degassed with Ar and heated in an MW reactor at 65°C for 6 hours. Purification by flash chromatography (using MeOH in SiO2, CH2Cl2) yielded 2,4-difluoro-3-(2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)aniline as an orange solid (128.0 mg, yield 71%). MS(ESI)m / z[M+H] + 345.30. Step 2: 5-Chloro-N-(2,4-difluoro-3-(2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [ka]

[0237] The following preparations were made using a standard NS method with 2,4-difluoro-3-(2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)aniline (128 mg, 0.37 mmol), 5-chloro-2-methoxypyridine-3-sulfonyl chloride (99 mg, 0.41 mmol), and pyridine (0.15 mL, 1.9 mmol) in CH2Cl2 (18 mL). Purification by flash chromatography (using MeOH in SiO2, CH2Cl2) yielded 5-chloro-N-(2,4-difluoro-3-(2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a pale yellow solid (151.0 mg, yield 74%). MS(ESI)m / z[M+H] + 550.40. Step 3: 5-Chloro-N-(2,4-difluoro-3-(2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [ka]

[0238] To a cold (0°C) CH2Cl2 (12 mL) suspension of 5-chloro-N-(2,4-difluoro-3-(2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (151 mg, 0.27 mmol), mCPBA (71 mg, 0.29 mmol, >70%) was added as a solid, and the reaction was allowed to proceed for 1.5 hours, slowly warming to room temperature.

[0239] Assuming complete conversion, a 5:1 mixture of the substance, 5-chloro-N-(2,4-difluoro-3-(2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide, was concentrated to dryness and used directly in the next step. MS(ESI)m / z[M+H] + 566.32 and 582.29 (corresponding sulfones). Step 4.5-Chloro-N-(2,4-difluoro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-6)

[0240] 5-Chloro-N-(2,4-difluoro-3-(2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (51.6 mg, 0.091 mmol) was suspended in i-PrOH (10 mL) and treated with MetNH2 (40 wt% in H2O, 0.32 mL, 3.6 mmol) at room temperature. The suspension was stirred at room temperature for 3 days and 21 hours. The reaction mixture was concentrated under reduced pressure, attached to Celite®, and purified by flash chromatography (using 89 / 10 / 1 aqueous solution of NH4OH in SiO2, CH2Cl2) to obtain 5-chloro-N-(2,4-difluoro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as an off-white solid (21.0 mg, yield 43%). 1H NMR(500 MHz,DMSO-d6)δ ppm 10.26-10.71(m,1 H),9.71(s,0.7 H),9.48(s,0.3 H),8.95-9.11(m,1 H),8.46(d,J=2.32 Hz,1 H),8.12-8.30(m,1 H),8.07(d,J=2.57 Hz,1 H),7.70(s,1 H),7.38-7.50(m,1 H),7.11-7.30(m,1 H),3.89(s,3 H),2.91-3.05(m,3 H). LC-MS calculated value [C 21 H 15 [CLF2N8O3S+H] + As 533.06; measured value MS(ESI)m / z[M+H] + 533.35 Example 7: 5-Chloro-N-(3-(2-(ethylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide(I-7) [ka]

[0241] 5-Chloro-N-(2,4-difluoro-3-(2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (52 mg, 0.091 mmol) was suspended in i-PrOH (10 mL) and treated with EtNH2 (66-72% in H2O, 0.29 mL, 3.6 mmol) at room temperature. The suspension was stirred at room temperature for 3 days and 21 hours, then concentrated under reduced pressure and attached to Celite®. Purification by flash chromatography (using 89 / 10 / 1 aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in SiO2, CH2Cl2) yielded 5-chloro-N-(3-(2-(ethylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide as an off-white solid (26 mg, yield 52%). MS(ESI)m / z[M+H] + 547.33.1H NMR(500 MHz,DMSO-d6)δ ppm 10.47(br.S.,1 H),9.43-9.71(m,1 H),8.96-9.07(m,1 H),8.47(d,J=2.57 Hz,1 H),8.18-8.36(m,1 H),8.07(d,J=2.57 Hz,1 H),7.68(s,1 H),7.37-7.49(m,1 H),7.25(t,J=8.80 Hz,1 H),3.90(s,3 H),3.40-3.47(m,2 H),1.14-1.27(m,3 H). Example 8: 5-Chloro-N-(2,4-difluoro-3-(2-(isopropylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-8) [ka]

[0242] 5-Chloro-N-(2,4-difluoro-3-(2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (52 mg, 0.091 mmol) was suspended in i-PrOH (10 mL) and treated with isopropylamine (0.31 mL, 3.6 mmol) for 3 days and 21 days. The reaction mixture was concentrated under reduced pressure, deposited on Celite®, and purified by flash chromatography (using an aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in SiO2, CH2Cl2 89 / 10 / 1) to obtain 5-chloro-N-(2,4-difluoro-3-(2-(isopropylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as an off-white solid (20 mg, yield 39%). MS(ESI)m / z[M+H] + 561.43.1H NMR(500 MHz,DMSO-d6)δ ppm 10.24-10.67(m,1 H),9.67(s,0.7 H),9.44(s,0.3 H),8.96-9.09(m,1 H),8.46(d,J=2.45 Hz,1 H),8.16-8.31(m,1 H),8.07(d,J=2.57 Hz,1 H),7.68(s,1 H),7.38-7.47(m,1 H),7.24(t,J=8.68 Hz,1 H),4.20-4.39(m,1 H),3.87-3.92(m,3 H),1.17-1.29(m,6 H) Example 9: 5-Chloro-N-(3-(2-(ethylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide(I-9) [ka] Step 1. 5-Chloro-N-(4-fluoro-3-(2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [ka]

[0243] A reaction mixture was prepared according to the general SMC method by using (5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (670 mg, 1.86 mmol), 6-bromo-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (500 mg, 1.69 mmol), Cs2CO3 (1375 mg, 4.22 mmol), and Pd(dppf)Cl2*CH2Cl2 (138 mg, 0.17 mmol) in H2O (20 mL) and 1,4-dioxane (40 mL), and heating overnight at 100 °C. The reaction mixture was diluted with H2O (100 mL) and acidified to approximately pH 1 with 1 M aqueous HCl (8 mL). The solid product was collected by filtration, rinsed with H2O, and then triturated with Et2O (using sonication) to obtain 5-chloro-N-(4-fluoro-3-(2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a yellowish-brown solid (871 mg, yield 88% based on purity 91%). MS(ESI)m / z[M+H] + 532.20. Step 2: 5-Chloro-N-(4-fluoro-3-(2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide and 5-Chloro-N-(4-fluoro-3-(2-(methylsulfonyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [ka]

[0244] 5-Chloro-N-(4-fluoro-3-(2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (871 mg, 1.5 mmol, 91%) was added all at once as a solid to a cold (0°C) CH2Cl2 (70 mL) suspension of mCPBA (386 mg, 1.6 mmol, >75%). After 2.5 hours, mCPBA (538 mg, 2.339 mmol) was added all at once as a solid at room temperature. After stirring for 3.5 hours, the reaction was aged at 0°C for 16.5 hours, and stirring was resumed at room temperature for 2 days. mCPBA (514 mg, 2.235 mmol) was added all at once as a solid again at room temperature. Stirring was continued at room temperature for 19.5 hours. At this point, the reaction appeared to be complete, and it was used as a mixture of 5-chloro-N-(4-fluoro-3-(2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide and 5-chloro-N-(4-fluoro-3-(2-(methylsulfonyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide. This crude mixture was concentrated to dryness and used in the next step without purification. MS(ESI)m / z[M+H] + 548.23 and 564.18. Step 3.5-Chloro-N-(3-(2-(ethylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide(I-9)

[0245] Crude 5-chloro-N-(4-fluoro-3-(2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (104 mg, 0.190 mmol, mixture with the corresponding sulfone) was shaken in i-PrOH (12 mL) with EtNH2 (66-72% in H2O, 0.58 mL, 7.6 mmol) at room temperature for 2 hours and 45 minutes. The reaction mixture was concentrated under reduced pressure, attached to Celite®, and purified by flash chromatography (using an aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in SiO2, CH2Cl2 89 / 10 / 1) to obtain 5-chloro-N-(3-(2-(ethylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide as a pale yellow solid (22 mg, yield 21% based on 98% purity). MS(ESI)m / z[M+H] + 529.34.1H NMR(500 MHz,DMSO-d6)δ ppm 10.34-10.81(m,1 H),9.64-9.74(m,0.6 H),9.38-9.55(m,0.3 H),8.93-9.09(m,1 H),8.40-8.49(m,1 H),8.24-8.31(m,0.7 H),8.18-8.23(m,0.3 H),8.13-8.18(m,1 H),7.65-7.73(m,2 H),7.24-7.32(m,1 H),7.13-7.22(m,1 H),3.98(s,3 H),3.50-3.75(m,2H),1.09-1.26(m,3H). Example 10: 5-Chloro-N-(3-(2-(cyclopropylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide(I-10) [ka]

[0246] Crude 5-chloro-N-(4-fluoro-3-(2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (104 mg, 0.190 mmol, mixture with the corresponding sulfone) was shaken in i-PrOH (12 mL) with c-PrNH2 (0.523 mL, 7.59 mmol) at room temperature for 2.7 hours. The reaction mixture was concentrated under reduced pressure, deposited on Celite®, and purified by flash chromatography (using an aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in SiO2.CH2Cl2, 89 / 10 / 1) to obtain 5-chloro-N-(3-(2-(cyclopropylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide as a pale yellow solid (31.0 mg, yield 29% based on 96% purity). MS(ESI)m / z[M+H] + 541.31.1H NMR 1H NMR(500 MHz,DMSO-d6)δ ppm 10.36-10.77(brs,1 H)9.35-9.77(m,1 H)8.91-9.17(m,1 H)8.45(d,J=2.57 Hz,2 H)8.17(d,J=2.57 Hz,1 H)7.58-7.75(m,2 H)7.25-7.32(m,1 H)7.16-7.22(m,1 H)3.94(s,3 H)2.84-3.10(m,1 H)0.47-0.89(m,4 H). Example 11: 5-Chloro-N-(4-fluoro-3-(2-(oxetane-3-ylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-11) [ka]

[0247] Crude 5-chloro-N-(4-fluoro-3-(2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (104 mg, 0.190 mmol, mixture with the corresponding sulfone) was shaken in i-PrOH (12 mL) with 3-oxetanamine (0.53 mL, 7.6 mmol) at room temperature for 1.1 hours. The reaction mixture was concentrated under reduced pressure, deposited on Celite®, and purified by flash chromatography (using an aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in SiO2, CH2Cl2 89 / 10 / 1) to obtain 5-chloro-N-(4-fluoro-3-(2-(oxetane-3-ylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a pale yellow solid (20.0 mg, yield 18% based on 97% purity). MS(ESI)m / z[M+H] + 557.33.1H NMR(500 MHz,DMSO-d6)δ ppm 9.72-9.81(m,0.7 H),9.51(br.S.,0.3 H),9.07(s,1 H),8.93-9.03(m,1 H),8.39-8.51(m,1 H),8.13-8.21(m,1 H),7.73(s,1 H),7.69(dd,J=6.48,2.69 Hz,1 H),7.25-7.32(m,1 H),7.11-7.22(m,1 H),5.03-5.20(m,1 H),4.93(t,J=6.66 Hz,1 H),4.79-4.88(m,1 H),4.58-4.66(m,2 H), 3.98 (s, 3 H). Example 12: 5-Chloro-N-(3-(2-(ethylamino)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide(I-12) [ka] Step 1. 5-Chloro-N-(4-fluoro-3-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [ka]

[0248] (5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (194 mg, 0.54 mmol), 6-bromo-2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (152 mg, 0.51 mmol), Cs2CO3 (417 mg, 1.3 mmol), and Pd(dppf)Cl2*CH2Cl2 (42 mg, 0.051 mmol) were used in H2O (5 mL) and 1,4-dioxane (10 mL), and the mixture was heated in a sealed MW reactor at 90°C for 1.5 hours to prepare the mixture according to the general SMC method. Purification by flash chromatography (using an aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in SiO2, CH2Cl2, 89 / 10 / 1) yielded 5-chloro-N-(4-fluoro-3-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as an orange solid (191.0 mg, yield 66% based on 95% purity). MS(ESI)m / z[M+H] + 533.26. Step 2: A mixture of 5-chloro-N-(4-fluoro-3-(2-(methylsulfinyl)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide, 5-chloro-N-(4-fluoro-3-(2-(methylsulfonyl)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide and 5-chloro-N-(4-fluoro-3-(2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [ka] Step 3. Mixture 5-chloro-N-(4-fluoro-3-(2-(methylsulfinyl)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide, 5-chloro-N-(4-fluoro-3-(2-(methylsulfonyl)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide, and 5-chloro-N-(4-fluoro-3-(2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [ka]

[0249] 5-Chloro-N-(4-fluoro-3-(2-(methylthio)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (191 mg, 0.340 mmol) was added as a solid to a cold (0°C) CH2Cl2 (20 mL) suspension, and mCPBA (88 mg, 0.36 mmol, >70%) was added as a solid and stirred while cooling for a total of 3 hours, slowly warming to room temperature. The reaction was then aged at 0°C for 3 days and 19 hours. Stirring was resumed at room temperature for 2.5 hours, after which mCPBA (123 mg, 0.53 mmol, 75%) was added as a solid at room temperature. After stirring for 1 hour, the reaction was aged at -20°C for 1 day and 17 hours.

[0250] After stirring at room temperature for 6.5 hours, mCPBA (117 mg, 0.51 mmol, 75%) was added all at once as a solid at room temperature. Stirring was continued for 19 hours. At this point, the starting materials are consumed, and the reaction mixture consists of 5-chloro-N-(4-fluoro-3-(2-(methylsulfinyl)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(MS(ESI)m / z[M+H]+547.3) and 5-chloro-N-(4-fluoro-3-(2-(methylsulfonyl)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(MS(ESI)m / z[M+H]) in a ratio of approximately 1:1:0.5, as determined by UV-DAD. + 563.2) and 5-chloro-N-(4-fluoro-3-(2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(MS(ESI)m / z[M+H] + 565.3) was the result.

[0251] This substance, containing three different products, was concentrated under reduced pressure and used crudely in the next step. Step 5.5-Chloro-N-(3-(2-(ethylamino)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide(I-12)

[0252] 5-Chloro-N-(4-Fluoro-3-(2-(methylsulfinyl)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide from the mCPBA oxidation step, 5-Chloro-N-(4-Fluoro-3-(2-(methylsulfonyl)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine Fifty percent of a crude mixture of -3-sulfonamide and 5-chloro-N-(4-fluoro-3-(2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide was shaken in i-PrOH (10 mL) with EtNH2 (66-72% in H2O, 0.11 mL, 1.4 mmol) at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, deposited on Celite®, and purified by flash chromatography (immersion, using CH2Cl2 / MeOH / concentrated NH4OH aqueous solution 89 / 10 / 1 in CH2Cl2) to isolate two distinct substances: (1) an off-white solid corresponding to m / z 528 and (2) a pale yellow solid corresponding to m / z 530.

[0253] The off-white solid (1) (m / z 528) was re-purified by flash chromatography (using an aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in SiO2, CH2Cl2 89 / 10 / 1) to obtain 5-chloro-N-(3-(2-(ethylamino)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide as a white solid (9.0 mg, two starting materials). Based on an estimated combined yield of 5-chloro-N-(4-fluoro-3-(2-(methylsulfinyl)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide and 5-chloro-N-(4-fluoro-3-(2-(methylsulfonyl)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide, yield was 17%. MS(ESI)m / z[M+H] + 528.22.1H NMR(500 MHz,DMSO-d6)δ=10.78-10.20(br.s.,1H),9.07-8.94(m,1H),8.47(d,J=2.4 Hz,1H),8.34(s,0.7H),8.22(br s,0.3H),8.18-8.13(m,1H),8.12-8.05(m,0.7H),8.04-7.97(m,0.3H),7.62-7.59(m,1H),7.57(br s,2H), 7.27-7.21(m,1H), 7.17-7.10(m,1H), 3.97(s,3H), 1.27-1.11(m,3H). The CH2 signal is hidden by the solvent peak. Example 13: 5-Chloro-N-(3-(2-(ethylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide(I-13) [ka]

[0254] The pale yellow solid (m / z 530) isolated from the first column chromatography described in the final step of the synthesis of 5-chloro-N-(3-(2-(ethylamino)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide was re-purified by flash chromatography (using CH2Cl2 / MeOH / concentrated NH4OH aqueous solution 89 / 10 / 1 in SiO2, CH2Cl2) to obtain 5-chloro-N-(3-(2-(Ethylamino)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide. (Tylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide is a pale yellow solid (6.6 mg, based on the estimated amount of the corresponding sulfone in the crude starting material: 5-chloro-N-(4-fluoro-3-(2-(methylsulfonyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide), 22%). MS(ESI)m / z[M+H] + 530.25.1H NMR (500MHz, methanol-d4)δ=8.30(d,J=2.6Hz,1H),8.27-8.23(m,1H),8.11(d,J=2.6Hz,1H),7.31-7.22(m,2H),7.17-7.12(m,1H) ,7.05(t,J=9.2Hz,1H),4.59(brs,1H),4.30-4.13(m,2H),4.07(s,3H),4.03-3.95(m,2H),3.53-3.41(m,2H),1.26-1.20(m,3H). Example 14: 5-Chloro-N-(2-fluoro-3-(2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-14) [ka] Step 1. 5-Chloro-N-(2-fluoro-3-(2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [ka]

[0255] A saturated phosphate mixture (SMC) was prepared according to the general method by heating 6-bromo-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (200 mg, 0.67 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (243 mg, 0.67 mmol), Cs2CO3 (550 mg, 1.7 mmol), and Pd(dppf)Cl2 (49 mg, 0.068 mmol) in H2O (7 mL) and 1,4-dioxane (14 mL) at 100 °C for 3.5 days. The reaction mixture was cooled to room temperature, diluted to 100 mL with H2O, and acidified to approximately pH 1 with 1 M aqueous HCl (3 mL). The newly formed precipitate was collected by filtration. The filtered cake was rinsed with H2O. Purification by flash chromatography (using MeOH in SiO2 and SiO2) yielded 5-chloro-N-(2-fluoro-3-(2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a pale yellow solid (58.0 mg, 16% based on 96% purity). MS(ESI)m / z[M+H] + 532.20.1H NMR(500 MHz,DMSO-d6)δ=10.61-10.42(m,1H,NH),9.95(s,1H),9.36(s,1H),8.50(d,J=2.6 Hz,1H),8.12(d,J=2.6 Hz,1H),7.85(s,1H),7.66(br t,J=6.6 Hz,1H),7.49-7.22(m,2H),3.90(s,3H),2.73(s,3H). Step 2.5-Chloro-N-(2-fluoro-3-(2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [ka]

[0256] 5-chloro-N-(2-fluoro-3-(2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (54 mg, 0.10 mmol) in CH2Cl2 (10 mL) was treated by adding mCPBA (32.5 mg, 0.13 mmol, 70%) as a suspension in CH2Cl2 (1 mL) at 0°C. After brief stirring, the cooling bath was removed and stirring was continued at room temperature for 50 minutes. The reaction mixture was aged at -20°C for 2 days. The reaction mixture was concentrated and CH2Cl2 was removed, leaving 5-chloro-N-(2-fluoro-3-(2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a pale yellow solid, which was used crudely in the next step. MS(ESI)m / z[M+H] + 548.20 Step 3. N-(3-(2-amino-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide(I-14)

[0257] The entirety of 5-chloro-N-(2-fluoro-3-(2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide from the previous step was suspended in i-PrOH (10 mL) and treated by adding concentrated NH3 aqueous solution (28-30%, 0.30 mL, 4.3 mmol) all at once at room temperature. The reaction was shaken at room temperature for 2 hours, then concentrated under reduced pressure and deposited on Celite®. Purification by flash chromatography (using 89 / 10 / 1 aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in SiO2, CH2Cl2) yielded N-(3-(2-amino-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide as a white solid (11.0 mg, yield 22%). MS(ESI)m / z[M+H] + 501.18.1H NMR(500 MHz,DMSO-d6)δ=10.48(s,1H),9.51-9.31(m,1H),9.03(s,1H),8.49(d,J=1.7 Hz,1H),8.10(d,J=2.4 Hz,1H),7.81-7.68(m,2H),7.67-7.64(m,1H),7.64-7.57(m,1H),7.41-7.34(m,1H),7.33-7.23(m,1H),3.90(s,3H). Example 15: 5-Chloro-N-(4-fluoro-3-(9-methyl-2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-15) [ka] Step 1: 6-Bromo-N,9-dimethyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-amine [ka]

[0258] 6-bromo-9-methyl-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (300 mg, 0.97 mmol) in 10 mL of CH2Cl2 was treated by adding mCPBA (310 mg, 1.26 mmol, 70%) as a CH2Cl2 suspension (1 mL) at 0°C. After brief stirring, the cooling bath was removed and stirring was continued at room temperature for 1.4 hours. The reaction mixture was stored overnight at -20°C. This reaction mixture is complete at this point and consists of 6-bromo-9-methyl-2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine and 6-bromo-9-methyl-2-(methylsulfonyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (in a 1.5:1 ratio under UV). MS(ESI)m / z[M+H] + 326.04|328.15 and MS(ESI)m / z[M+H] + 342.06 | 344.09.

[0259] The entire substance was concentrated and CH2Cl2 was removed, leaving a pale yellow-orange solid. This solid was suspended in i-PrOH (10 mL) and treated by adding MetNH2 (40 wt% in H2O, 1.0 mL, 12 mmol) all at once at room temperature. The reaction was shaken for 1.8 hours. The suspension was then diluted with H2O and filtered. By rinsing the collected solid with H2O, 6-bromo-N,9-dimethyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-amine was obtained as a pale pink solid (249.0 mg, yield 83% based on 95% purity). MS(ESI)m / z[M+H] + 293.09 | 295.12 Step 2.5-Chloro-N-(4-fluoro-3-(9-methyl-2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-15)

[0260] (5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (106 mg, 0.29 mmol), Cs2CO3 (185 mg, 0.57 mmol), 6-bromo-N,9-dimethyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-amine (70 mg, 0.23 mmol), and Pd(dppf)Cl2 (17 mg, 0.023 mmol) were used in 1,4-dioxane (4 mL) and H2O (2 mL), and the mixture was heated in an MW reactor at 100°C for 2 hours to prepare the mixture according to the general SMC method. Purification by flash chromatography (using an aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in SiO2, CH2Cl2, 89 / 10 / 1) yielded 5-chloro-N-(4-fluoro-3-(9-methyl-2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a white solid (82.0 mg, yield 68%). MS(ESI)m / z[M+H] + 529.11.1H NMR(500 MHz,DMSO-d6)δ=10.4(s,1H),9.02-8.88(m,1H),8.47(d,J=2.6 Hz,1H),8.17(d,J=2.6 Hz,1H),8.15-8.11(m,0.8H),8.01-7.95(m,0.2H),7.67-7.62(m,1H),7.59(s,1H) ),7.31-7.24(m,1H),7.22-7.13(m,1H),3.99(s,3H),3.19-3.04(m,3H),2.98(br d,J=4.6 Hz,3H). Example 16: 5-Chloro-N-(2-fluoro-3-(9-methyl-2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-16) [ka]

[0261] Using 1,4-dioxane (4 mL) and H2O (82 mg, 0.23 mmol) (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (in 2 mL), Cs2CO3 (185 mg, 0.57 mmol), 6-bromo-N,9-dimethyl-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-amine (70 mg, 0.23 mmol) and Pd(dppf)Cl2 (17 mg, 0.023 mmol), the mixture was heated in an MW reactor at 100°C for 2 hours. The solution was prepared according to the general method of SMC. Purification by flash chromatography (using CH2Cl2 / MeOH / concentrated NH4OH aqueous solution 89 / 10 / 1 in SiO2, CH2Cl2) yielded 5-chloro-N-(2-fluoro-3-(9-methyl-2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a pale orange solid (24.5 mg, yield 20% based on 97% purity). MS(ESI)m / z[M+H] + 529.16.1H NMR(500 MHz,DMSO-d6)δ=10.50-10.39(m,1H),9.03-8.87(m,1H),8.49(d,J=2.4 Hz,1H),8.17-8.11(m,0.7H),8.11-8.08(m,1H),8.00-7.94(m,0.2H),7.60-7.54(m,1H),7.54-7.49( m,1H),7.38-7.33(m,1H),7.30-7.24(m,1H),3.92-3.88(m,3H),3.15-3.03(m,3H),3.01-2.94(m,3H) Example 17: trans-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide (trans I-17) [ka] Step 1. (1R,4R)-4-((6-bromo-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide [ka]

[0262] Crude 6-bromo-2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (105.5 mg, 0.34 mmol), (1R,4R)-4-amino-N-methylcyclohexane-1-carboxamide TFA (137 mg, 0.51 mmol), and K2CO3 (173 mg, 1.2 mmol) in NMP (4 mL) were shaken at room temperature for 3.1 hours. The reaction was diluted with H2O (10 mL). After standing overnight at room temperature, trans-4-((6-bromo-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide was obtained as an off-white solid (89 mg, 65% yield in 2 steps). MS(ESI)m / z[M+H] + 404.28 / 406.23 Step 2. trans-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide(I-17)

[0263] (5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (51.6 mg, 0.143 mmol), Cs2CO3 (90 mg, 0.275 mmol), (1R,4R)-4-((6-bromo-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide (44.5 mg, 0.110 mmol), and Pd(dppf)Cl2 (8.0 mg, 0.011 mmol) were used in 1,4-dioxane (8 mL) and H2O (4 mL), and the mixture was heated at 100°C for 2.1 hours to prepare the solution according to the general SMC method. Trans-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide was obtained as a beige solid (36 mg, yield 50% based on 97% purity). MS(ESI)m / z[M+H] + 640.29.1H NMR(500 MHz,DMSO-d6)δ=10.58(m,1H),9.79(s,0.6H),9.40(s,0.4H),9.11-9.05(m,0.4H),9.03-8.96(m,0.6H),8.47(d,J=2.3 Hz,1H),8.24(br d,J=8.1 Hz,0.6H),8.18(d,J=2.6 Hz,1.4H),7.77-7.63(m,3H),7.32-7.24(m,1H),7.23-7.13(m,1H),4.00(s,3H),3.95-3.85(m,1H),2.61-2 .54(m,3H),2.17-1.92(m,3H),1.83-1.75(m,2H),1.69-1.54(m,1H),1.52-1.41(m,1H),1.41-1.28(m,2H). Example 18: trans-4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide (trans-I-18) [ka]

[0264] (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (51.6 mg, 0.143 mmol), Cs2CO3 (90 mg, 0.27 mmol), trans-4-((6-bromo-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide (44.5 mg, 0.11 mmol), and Pd(dppf)Cl2 (8.0 mg, 0.011 mmol) were used in 1,4-dioxane (4 mL) and H2O (2 mL), and the mixture was heated in an MW reactor at 100°C for 2 hours, according to the general SMC method. By purification using flash chromatography (using an aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in SiO2, CH2Cl2 89 / 10 / 1), trans-4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide was obtained as a white solid (29 mg, yield 41%). MS(ESI)m / z[M+H] +640.37.1H NMR(500 MHz,DMSO-d6)δ ppm 10.48(br.s.,1 H),9.79(s,0.7 H),9.40(s,0.3 H),8.95-9.13(m,1 H),8.48(d,J=2.69 Hz,1 H),8.13-8.30(m,1 H),8.10(d,J=2.57 Hz,1 H),7.67-7.78(m,1 H),7.63(s,2 H),7.32-7.43(m,1 H),7.17-7.31(m,1 H),3.96-4.07(m,1 H),3.90(s,3H),2.55-2.61(m,3 H),1.93-2.16(m,3 H),1.75-1.83(m,2 H),1.57-1.71(m,1.5 H),1.43-1.53(m,0.8 H),1.27-1.40(m,2 H). Example 19. trans-4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide (trans I-19) [ka] Step 1. trans-4-((6-bromo-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide [ka]

[0265] Crude 6-bromo-2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (105.5 mg, 0.39 mmol), trans-4-aminocyclohexane-1-carboxamide hydrochloride (91 mg, 0.51 mmol), and K2CO3 (173 mg, 1.2 mmol) were shaken in NMP (4 mL) at room temperature for 3.1 hours. The reaction was diluted with H2O (10 mL), then concentrated to dryness under reduced pressure, attached to Celite®, and purified by flash chromatography (using an aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in SiO2, CH2Cl2 89 / 10 / 1) to obtain trans-4-((6-bromo-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide as a beige solid (48.0 mg, 36% yield in 2 steps). MS(ESI)m / z[M+H] + 390.15 | 390.18. Step 2. trans-4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide

[0266] The solution was prepared according to the general SMC method by heating 1,4-dioxane (4 mL) and H2O (2 mL) with 3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (58 mg, 0.16 mmol), Cs2CO3 (100 mg, 0.31 mmol), trans-4-((6-bromo-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide (48 mg, 0.12 mmol) and Pd(dppf)Cl2 (9.0 mg, 0.012 mmol) at 100°C for 2 hours. It was then purified by flash chromatography (using an aqueous solution 89 / 10 / 1 of CH2Cl2 / MeOH / concentrated NH4OH in SiO2, CH2Cl2). The collected fraction was concentrated to 5-10 mL under reduced pressure to form a white precipitate. After standing overnight at room temperature, the white solid was collected by filtration and, after rinsing with MeOH, trans-4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide was obtained as a white solid (40 mg, 52%). MS(ESI)m / z[M+H] + 626.60.1H NMR(500 MHz,DMSO)δ 10.47(s,1H),9.76(s,0.6H),9.41(s,0.4H),9.07(s,0.4H),9.00(s,0.6H),8.48(s,1H),8.23(d,J=8.1 Hz,0.6H),8.18(d,J=8.1 Hz,0.4H),8.10(s,1H),7.63(s,2H),7.37(t,J=7.5 Hz,1H),7.31-7.20(m,2H),6.71(s,1H),3.98(d,J=8.1 Hz,1H),3.90(s,3H),2.15-1.95(m,3H),1.82(d,J=12.4 Hz,2H),1.60(q,J=12.3 Hz,1H),1.50-1.30(m,3H). Example 20. ((5-chloro-2-methoxypyridine-3-yl)sulfonyl)(4-fluoro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)amide, potassium (I-1 K) [ka]

[0267] A suspension of 5-chloro-N-(4-fluoro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (352.7 mg, 0.66 mmol) in EtOH (60 mL) was sonicated for approximately 2 minutes and treated with aqueous KOH solution (0.5 M, 1.32 mL, 0.66 mmol) at room temperature. H2O (60 mL) was added to obtain a clear pale yellowish-brown solution. Excess EtOH was removed under reduced pressure. By freeze-drying the aqueous solution, ((5-chloro-2-methoxypyridine-3-yl)sulfonyl)(4-fluoro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)amide, potassium was obtained as a beige powder (341.0 mg, 91%). MS(ESI)m / z[M+H] + 515.32.1H NMR(500 MHz,DMSO-d6)δ 9.69(s,0.6H),9.45(s,0.4H),9.08(s,0.3H),8.99(s,0.7H),8.15(s,1.6H),8.04(s,0.4H),7.96(s,1H),7.56(s,1H),7.15(d,J=6.1 Hz,1H),6.92(t,J=9.5 Hz,1H),6.87-6.80(m,1H),3.79(s,3H),3.03-2.93(m,3H).19F NMR(471 MHz,DMSO-d6)δ-128.49. Example 21. 5-Chloro-N-(3-(2-(ethylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide(I-20) [ka]

[0268] 5-chloro-N-(2-fluoro-3-(2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (60 mg, 0.11 mmol) in i-PrOH (5 mL) was treated with EtNH2 (66-72% in H2O, 0.27 mL, 3.3 mmol), shaken at room temperature for 1.2 hours, and then stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, attached to Celite, and purified by flash chromatography (SiO2, CH2Cl2 with siRNA) to obtain 5-chloro-N-(3-(2-(ethylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide as a white solid (32.0 mg, yield 54% based on 98% purity).

[0269] MS(ESI)m / z[M+H] + 529.16.1H NMR(500 MHz,DMSO-d6)δ 10.48(s,1H),9.70(s,0.6H),9.43(s,0.4H),9.09(s,0.4H),9.02(s,0.6H),8.49(d,J=2.4 Hz,1H),8.33(t,J=5.3 Hz,0.6H),8.27-8.21(m,0.4H),8.11(d,J=2.5 Hz,1H),7.65(s,1H),7.63-7.59(m,1H),7.38(t,J=7.0 Hz,1H),7.29(t,J=7.9 Hz,1H),3.90(s,3H),3.58-3.40(m,2H),1.29-1.15(m,3H). Example 22. 5-Chloro-N-(3-(2-(cyclopropylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide(I-21) [ka]

[0270] 5-chloro-N-(2-fluoro-3-(2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (60 mg, 0.11 mmol) in i-PrOH (5 mL) was treated with c-PrNH2 (0.27 mL, 3.8 mmol), shaken at room temperature for 1.2 hours, and then stirred overnight at room temperature.

[0271] The reaction mixture was concentrated under reduced pressure, deposited on Celite, and purified by flash chromatography (MeOH in SiO2, CH2Cl2) to obtain 5-chloro-N-(3-(2-(cyclopropylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide as a pale yellow solid (42 mg, yield 69% based on 97% purity). MS(ESI)m / z[M+H] + 541.20.1H NMR(500 MHz,DMSO-d6)δ 10.47(s,1H),9.67(s,0.6H),9.39(s,0.4H),9.13(s,0.4H),9.02(s,0.6H),8.54-8.33(m,2H),8.10(d,J=2.5 Hz,1H),7.71-7.54(m,2H),7.37(t,J=7.2 Hz,1H),7.28(t,J=7.8 Hz,1H),3.90(s,3H),3.12-2.90(m,1H),0.92-0.69(m,2H),0.68-0.47(m,2H). Example 23. 5-Chloro-N-(2-fluoro-3-(2-(isopropylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-22) [ka]

[0272] 5-chloro-N-(2-fluoro-3-(2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (60 mg, 0.11 mmol) in i-PrOH (5 mL) was treated with i-PrNH2 (0.25 mL, 3.0 mmol), shaken at room temperature for 1.2 hours, and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, deposited on Celite, and purified by flash chromatography (SiO2, CH2Cl2 with siRNA) to obtain 5-chloro-N-(2-fluoro-3-(2-(isopropylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as an off-white solid (37 mg, 60% yield based on 97% purity).

[0273] MS(ESI)m / z[M+H] + 543.23.1H NMR(500 MHz,DMSO-d6)δ 10.54(s,1H),9.75(s,0.6H),9.46(s,0.4H),9.15(s,0.4H),9.09(s,0.6H),8.56(d,J=2.4 Hz,1H),8.32(d,J=7.9 Hz,0.6H),8.23(d,J=7.1 Hz,0.4H),8.17(t,J=5.2 Hz,1H),7.75-7.65(m,2H),7.44(t,J=7.0 Hz,1H),7.35(t,J=7.8 Hz,1H),4.46-4.29(m,1H),3.97(s,3H),1.31(m,6H). Example 24. 5-Chloro-N-(3-(2-(cyclopropylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide(I-23) [ka]

[0274] 5-chloro-N-(2,4-difluoro-3-(2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (75 mg, 0.13 mmol) in i-PrOH (10 mL) was treated with c-PrNH2 (0.32 mL, 4.6 mmol), shaken at room temperature for 20 minutes, and then stirred at room temperature for 1.8 hours. The reaction mixture was concentrated under reduced pressure, deposited on Celite, and purified by flash chromatography (MeOH in SiO2, CH2Cl2) to obtain 5-chloro-N-(3-(2-(cyclopropylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide as a white solid (13 mg, 18%). MS(ESI)m / z[M+H] + 559.18.

[0275] 1H NMR(500 MHz,CD3OD)δ 9.70-9.52(m,1H),9.10-8.83(m,1H),8.32(d,J=2.5 Hz,1H),8.09(d,J=2.5 Hz,1H),7.68(s,1H),7.62(td,J=8.9,5.8 Hz,1H),7.14(t,J=8.9 Hz,1H),4.00(s,3H),3.07-2.84(m,1H),0.92(br s,2H),0.60(br s,2H). Example 25. N-(3-(2-amino-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide(I-24) [ka] 5-chloro-N-(2,4-difluoro-3-(2-(methylsulfinyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (75 mg, 0.13 mmol) in i-PrOH (10 mL) was treated with NH3 (7 M in MeOH, 0.76 mL, 5.3 mmol), shaken at room temperature for 20 minutes, and then stirred at room temperature for 1.8 hours. The reaction mixture was concentrated under reduced pressure, deposited on Celite, and purified by flash chromatography (MeOH in SiO2, CH2Cl2) to obtain N-(3-(2-amino-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide as a white solid (21 mg, yield 30%). MS(ESI)m / z[M+H] + 519.16.1H NMR(500 MHz,DMSO-d6)δ 10.47(s,1H),9.46(s,1H),9.02(s,1H),8.49(d,J=2.1 Hz,1H),8.09(d,J=2.5 Hz,1H),7.81(s,2H),7.70(s,1H),7.47-7.40(m,1H),7.25(t,J=8.6 Hz,1H),3.91(s,3H).

[0276] B. Biological assays GCN2 enzyme assay To identify small molecule GCN2 inhibitors, a biochemical GCN2 enzyme assay was outsourced to Eurofins. This assay was performed using radiometric methods with full-length GST-tagged GCN2 (E556G) produced in insect cells. The kinase concentration was 18.5 nM in Tris buffer containing 300 μM of optimized peptide substrate (RSRSRSRSRSRSRSR), 70 μM ATP (Km=77 μM), and [g-33P]-ATP. The reaction was initiated by adding a Mg / ATP mix. After incubation at room temperature for 40 minutes, the reaction was stopped by adding phosphate to a concentration of 0.5%. Next, 10 μL of the reaction mixture was spotted onto a P30 filter mat and washed four times in 0.425% phosphate for 4 minutes each, followed by one wash in methanol, drying, and scintillation counting. The results are shown in Table 1. Here, IC50 is calculated. 50 The following ranges have been reported for the compound of formula (I): A: 0.1~100 nM; B: 100~1000 nM; C: 1000~10000 nM; D: >10000 nM. [Table 2]

[0277] Cell-based phospho-eIF2α assay: To confirm targeted engagement in cells, the AlphaLISA assay (Perkin Elmer#TGREIR2S10K) was optimized to monitor eIF2α phosphorylation at serine-51. This event is specifically catalyzed by GCN2 induced by halofudinone (a glutamyl-prolyl tRNA synthetase inhibitor), boreridine (a threonyl-tRNA synthetase inhibitor), or L-asparaginase, which activate GCN2 kinase activity by triggering an amino acid starvation response. SKOV3 or U2OS cells (seeded at 40,000 cells per well) were pretreated with representative GCN2 inhibitor compounds of this application (1 nM to 1 μM) for 1 hour, stimulated with boreridine (10 μM) for 1 hour, then lysed and analyzed using the AlphaScreen SureFire kit, which quantitatively detects phospho-eIF2α in HTS format using an antibody-based method.

[0278] Tumor cell growth inhibition assay: SKOV3 / OVACR8 cells were seeded at a rate of 1,000 cells / well in 50 μl of medium (alpha-MEM containing 10% FBS, 100 mg / ml normocin (Invivogen), and 50 mg / ml gentamicin (Invitrogen)) in a 384-well plate. The plate was then incubated overnight to allow cell adhesion. Using an HP D300 digital dispenser, ASNase, DMSO, or the test compound was administered to the cells across 16 concentration ranges (from a high dose of 10 μM to a low dose of 5 nM). The plate was incubated at 37°C in a humidified 5% CO2 incubator. After 3–5 days, the plate was removed from the incubator and equilibrated to room temperature. Equal volumes of ATPlite assay reagent were then added to each well, and the samples were processed according to the manufacturer's instructions (Perkin Elmer). The luminescence signal was then measured using an Envision plate reader equipped with a US emission detector.

[0279] While this application is described with reference to what is considered a preferred example at present, it should be understood that this application is not limited to the disclosed example. Rather, this application is intended to cover a variety of modifications and equivalent configurations that fall within the spirit and scope of the appended claims.

[0280] All publications, patents, and patent applications are incorporated herein by reference to the same extent that each individual publication, patent, or patent application is specifically and individually indicated to be incorporated by reference in its entirety. If it is found that a different definition of a term in this application is given in a document incorporated herein by reference, the definition given herein shall be the definition of that term.

Claims

1. Compounds of formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: 【Chemistry 1】 During the ceremony, R １ H, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１０ Cycloalkyl and C ３～１０ Selected from heterocycloalkyl groups, the latter four groups have one or two R groups. ８ａ It may be arbitrarily replaced with; 【Chemistry 2】 It is either a single bond or a double bond; 【Transformation 3】 If X is a double bond, １ CR ９ Selected from N, 【Chemistry 4】 when is a single bond, X １ is CR ９ R ９ａ and NR ９ｂ is selected from; R ２ H, C １～４ Alkyl and C １～４ Selected from haloalkyls; X ２ N and CR １０ Selected from; R ３ , R ４ and R ５ H, Halo, CN, C １～６ Alkyl and C １～６ Selected independently from haloalkyl groups; X ３ N and CR １１ Selected from; R ６ and R ７ H, Halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, OC １～６ Alkyl and OC １～６ Selected independently from haloalkyl groups; R ８ H, C １～４ Alkyl and C １～４ Selected from haloalkyls; Each R ８ａ is OR １２ , NR １２ R １３ , C(O)NR １２ R １３ Hello, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１０ Cycloalkyl and C ３～１０ Selected independently from heterocycloalkyls, all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyls are halo, OR １４ , NR １４ R １５ and C １～６ They may be optionally substituted with one or more substituents selected from alkyl groups; R ９ , R ９ａ , R １０ and R １１ H, Halo, C １～６ Alkyl and C １～６ Selected independently from haloalkyl groups; R ９ｂ H, C １～６ Alkyl and C １～６ Selected from haloalkyls; R １２ H, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１０ Cycloalkyl and C ３～１０ Selected from heterocycloalkyl groups, the latter four groups are halo, OH, and OC. １～４ Alkyl and OC １～４ It may be optionally substituted with one or two substituents selected from fluoroalkyl groups; R １３ , R １４ and R １５ H, C １～６ Alkyl and C １～６ It is independently selected from haloalkyl groups.

2. R １ However, C ３～１０ Cycloalkyl and C ３～１０ Selected from heterocycloalkyl groups, each of which has one or two R groups. ８ａ The compound according to claim 1, which may be optionally substituted with.

3. R １ However, H, C １～４ Alkyl and C １～４ A compound according to claim 1, selected from fluoroalkyl groups.

4. R １ is selected from H, CH ３ , CF ３ , CHF ２ , CH ２ CH ３ , CH ２ CH ２ F, CH ２ CH ２ CH ３ , CH(CH ３ ) ２ , CH(CH ３ )CH ２ CH ３ and CH(CH ３ ) ３ , the compound according to claim 3.

5. R １ is, one or two R ８ａ C which may be optionally substituted with ３～１０ The compound according to claim 1, which is cycloalkyl.

6. R １ However, one or two R ８ａ Monocyclic C which may be arbitrarily substituted ３～８ The compound according to claim 5, wherein it is a cycloalkyl compound.

7. R １ However, these are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which has one or two R ８ａ The compound according to claim 6, which may be optionally substituted with.

8. R １ However, these are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which has one R ８ａ The compound according to claim 7, which may be optionally substituted with.

9. R １ However, it is selected from cyclobutyl and cyclohexyl, each of which has one R ８ａ The compound according to claim 8, which is substituted with

10. R １ However, one or two R ８ａ C may be arbitrarily replaced with ３～１０ The compound according to claim 1, wherein it is a heterocycloalkyl compound.

11. R １ However, each of these is selected from azilidinyl, oxylanil, thiranil, azetidinil, oxetanil, thietanil, diazetidinil, dioxetanil, dithietanil, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxalanil, dithiolanil, piperidinyl, tetrahydropyranil, diazinanil (e.g., piperazinyl), morpholinil, thiomorpholinil, dioxanil, dithianil, azepanil, oxepanil and thiepanil, each of which contains one or two R ８ａ The compound according to claim 10, which may be optionally substituted with.

12. R １ However, these are selected from thietanyl, oxetanyl, tetrahydrofuranil, tetrahydropyranil, thiomorpholinil, azilidinyl, azetidinil, pyrrolidinyl, morpholinil, piperazinyl, and piperidinil, each of which has one R ８ａ The compound according to claim 11, which may be optionally substituted with.

13. R １ However, these are selected from oxetanil, tetrahydrofuranil, tetrahydropyranil, pyrrolidinil, morpholinil, piperazinil, and piperidinil, each of which has one R ８ａ The compound according to claim 12, which may be optionally substituted with.

14. R １ However, these are selected from oxetanil, tetrahydrofuranil, and tetrahydropyranil, each of which has one R ８ａ The compound according to claim 13, which may be optionally substituted with.

15. R １ The compound according to claim 14, wherein the compound is selected from oxetanyl, tetrahydrofuranil, and tetrahydropyranil, each of which is unsubstituted. 【Request Item 16】 【Chemistry 5】 If it is a double bond, then X １ CR ９ Selected from N, 【Transformation 6】 If it is a single bond, X １ CR ９ R ９ａ The compound according to any one of claims 1 to 15.

17. R ２ The compound according to any one of claims 1 to 16, wherein is H.

18. X ２ The compound according to any one of claims 1 to 17, wherein N and CH are selected.

19. R ３ , R ４ and R ５ However, H, Cl, F, Br, CN, C １～４ Alkyl and C １～４ A compound according to any one of claims 1 to 18, independently selected from fluoroalkyls.

20. R ３ , R ４ and R ５ However, H, Cl, F, CN, CH ３ and CF ３ A compound according to claim 19, independently selected from the above.

21. R ３ and R ５ The compound according to any one of claims 1 to 18, wherein at least one of is selected from halo and CN.

22. X ３ The compound according to any one of claims 1 to 21, wherein the compound is selected from N and CH.

23. R ６ and R ７ However, H, Cl, F, Br, CN, C １～４ Alkyl, C １～４ Fluoroalkyl, OC １～４ Alkyl and OC １～４ A compound according to any one of claims 1 to 22, independently selected from fluoroalkyls.

24. R ６ and R ７ However, H, Cl, F, CN, CH ３ CHF ２ CF ３ ,CH ２ CH ３ ,CH ２ CH ２ F, OCH ３ , OCHF ２ and OCF ３ A compound according to claim 23, independently selected from the above.

25. R ６ ga OCH ３ and OCF ３ Selected from, R ７ Cl, F, CH ３ , and CF ３ A compound according to claim 24, selected from the above.

26. R ６ ga OCH ３ and OCF ３ Selected from, R ７ The compound according to claim 25, wherein is Cl.

27. R ８ H and CH ３ A compound according to any one of claims 1 to 26, selected from the above.

28. Each R ８ａ However, OR １２ , NR １２ R １３ , C(O)NR １２ R １３ , Cl, F, Br, C １～４ Alkyl, C １～４ Fluoroalkyl, C ３～６ Cycloalkyl and C ３～６ Selected independently from heterocycloalkyls, all alkyl, cycloalkyl and heterocycloalkyls are Cl, Br, F, OR １４ , NR １４ R １５ and C １～４ The compound according to any one of claims 1 to 27, which may be substituted with one or more substituents selected from alkyl groups.

29. Each R ８ａ However, OR １２ , NR １２ R １３ Cl, F, CH ３ CHF ２ ,CH ３ CH ３ and CF ３ A compound according to claim 28, independently selected from the above.

30. Each R ８ａ However, CH ３ CHF ２ ,CH ３ CH ３ and CF ３ A compound according to claim 29, independently selected from the above.

31. Each R ８ａ However, NR １２ R １３ and C(O)NR １２ R １３ A compound according to claim 29, independently selected from the above.

32. R ９ , R ９ａ , R １０ and R １１ However, H, Cl, Br, F, C １～４ Alkyl and C １～４ Selected independently from fluoroalkyls, R ９ｂ However, H, C １～４ Alkyl and C １～４ A compound according to any one of claims 1 to 16, selected from fluoroalkyls.

33. R ９ , R ９ａ , R １０ and R １１ H is R ９ｂ H and CH ３ A compound according to claim 32, selected from the above.

34. R １２ However, H, C １～４ Alkyl, C １～４ Fluoroalkyl, C ３～１０ Cycloalkyl and C ３～１０ Selected from heterocycloalkyl groups, the latter four groups are Cl, F, Br, OH, and OCH. ３ and OCF ３ The compound according to any one of claims 1 to 33, which may be optionally substituted with one or two substituents selected from the following.

35. R １２ However, H, CH ３ and CF ３ A compound according to claim 34, selected from the above.

36. R １２ However, H and CH ３ A compound according to claim 35, selected from the above.

37. R １３ However, H, C １～４ Alkyl and C １～４ A compound according to any one of claims 1 to 36, selected from fluoroalkyls.

38. R １３ However, H and CH ３ A compound according to claim 37, selected from the above.

39. R １４ and R １５ However, H, CH ３ and CF ３ A compound according to any one of claims 1 to 38, independently selected from the above.

40. R １４ and R １５ However, H and CH ３ A compound according to claim 39, independently selected from the above.

41. 5-Chloro-N-(4-fluoro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; trans-5-chloro-N-(3-(2-(((1R,4R)-4-(dimethylamino)cyclohexyl)amino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide formate; N-(3-(2-amino-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(4-fluoro-3-(2-(isopropylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(2-fluoro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(2,4-difluoro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(ethylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(2,4-difluoro-3-(2-(isopropylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(ethylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(cyclopropylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(4-fluoro-3-(2-(oxetanylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(ethylamino)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(ethylamino)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(2-fluoro-3-(2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(4-fluoro-3-(9-methyl-2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(2-fluoro-3-(9-methyl-2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; trans trans-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide; trans-4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide; trans-4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide; ((5-chloro-2-methoxypyridine-3-yl)sulfonyl)(4-fluoro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)amide, potassium; 5-Chloro-N-(3-(2-(ethylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(cyclopropylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(2-Fluoro-3-(2-(isopropylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(cyclopropylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide; and N-(3-(2-amino-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide, The compound according to claim 1, or selected from a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

42. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 41, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, and a pharmaceutically acceptable carrier.

43. A method for inhibiting general control nonderepressible 2 (GCN2) in any cells in a biological sample or in a patient, comprising administering to the cells an effective amount of one or more of the compounds described in any one of claims 1 to 41, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

44. A method for treating a disease, disorder, or condition that can be treated by inhibiting GCN2, comprising administering to a subject in need one or more therapeutically effective amounts of one or more compounds according to any one of claims 1 to 41, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

45. The method according to claim 44, wherein the disease, disorder, or condition that can be treated by inhibiting GCN2 is a neoplasm.

46. The method according to claim 44, wherein the disease, disorder, or condition that can be treated by inhibiting GCN2 is cancer.

47. The method according to claim 46, wherein the cancer is selected from one or more of solid tumors, breast cancer, colorectal cancer, bladder cancer, skin cancer, head and neck cancer, liver cancer, lung cancer, pancreatic cancer, ovarian cancer, prostate cancer, bone cancer, and glioblastoma.

48. The method according to claim 44, wherein the disease, disorder, or condition that can be treated by inhibiting GCN2 is peripheral neuropathy.

49. The method according to claim 48, wherein the peripheral neuropathy is Charcot-Marie-Tooth (CMT) peripheral neuropathy.

50. A method for treating a disease, disorder, or condition that can be treated by inhibiting GCN2, comprising administering to a subject in need of such treatment, in a therapeutically effective amount, one or more of the compounds described in any one of claims 1 to 41, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, in combination with another known active substance useful for treating the disease, disorder, or condition that can be treated by inhibiting GCN2.

51. The method according to claim 50, wherein the disease, disorder, or condition that can be treated by inhibiting GCN2 is cancer and / or peripheral neuropathy.

52. The method according to claim 50, wherein the disease, disorder or condition that can be treated by inhibiting GCN2 is cancer, and the one or more compounds of the present invention are administered or used in combination with one or more additional cancer treatments.

53. The method according to claim 52, wherein the one or more additional cancer treatments are chemotherapeutic agents, and the chemotherapeutic agent is cisplatin.

54. The method according to claim 52, wherein the one or more additional cancer treatments are chemotherapeutic agents, and the chemotherapeutic agent is L-asparaginase (L-ASNase).

55. The method according to claim 52, wherein the one or more additional cancer treatments are small molecule therapies, and the small molecule therapy is a glutaminase inhibitor or an asparagine synthase (ASNS) inhibitor.

56. A method for improving the effectiveness of one or more cancer treatments for treating cancer, comprising administering an effective amount of one or more of the compounds described in any one of claims 1 to 41, or pharmaceutically acceptable salts, prodrugs and / or solvates thereof, in combination with an effective amount of the one or more cancer treatments.

57. The method according to claim 56, wherein the one or more cancer treatments are chemotherapeutic agents, and the chemotherapeutic agent is cisplatin.

58. The method according to claim 56, wherein the one or more cancer treatments are chemotherapeutic agents, and the chemotherapeutic agent is L-asparaginase (L-ASNase).

59. The method according to claim 56, wherein the one or more cancer treatments are small molecule therapies, and the small molecule therapy is a glutaminase inhibitor or an asparagine synthase (ASNS) inhibitor.

60. The method according to claim 56, wherein the cancer is associated with low asparagine synthase (ASNS) expression, and the one or more additional cancer treatments are L-asparaginase (L-ASNase).

61. The method according to claim 56, wherein the cancer is associated with overexpression or dysregulation of asparagine synthase (ASNS), and the one or more additional cancer treatments are one or more asparagine synthase (ASNS) inhibitors and / or L-asparaginases.

62. The method according to claim 56, wherein the cancer is associated with low asparagine synthase (ASNS) expression and low glutaminase expression, and the one or more additional cancer treatments are L-asparaginase (L-ASNase) and / or one or more glutaminase inhibitors.

63. The method according to claim 56, wherein the cancer is associated with overexpression or dysregulation of asparagine synthase (ASNS) and overexpression or dysregulation of glutaminase, and the one or more additional cancer treatments are L-asparaginase (L-ASNase), one or more glutaminase inhibitors and / or one or more asparagine synthase (ASNS) inhibitors.

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