Pyrimidopyridone derivatives and pteridone derivatives as GCN2 kinase inhibitors, their compositions and uses

Abstract

This application relates to pyrimidopyridone compounds and pteridone compounds of formula I, processes for preparing them, and compositions comprising them. More specifically, this application relates to compounds of formula I having activity as inhibitors of general control nonderepressible 2 (GCN2) kinase, and their use in the treatment of diseases, disorders, or conditions that can be treated by inhibiting GCN2 kinase, such as cancer and neuronal diseases. JPEG2026530208000163.jpg91131

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 pyrimidopyridone and pteridone 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 neurological 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

[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 this application to a subject in need.

[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, this 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 solvates thereof, the term "and / or" means that the compound of the present application exists as individual salts and individual hydrates, and also as a combination of, for example, a solvate of a salt of the compound of the present application.

[0024] As used in the present application, the singular forms "a", "an" and "the" include plural referents unless the content clearly dictates otherwise. For example, an embodiment comprising "a compound" should be understood as presenting specific aspects with one compound, or with two or more additional compounds.

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

[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 includes), or "containing" (and any form of containing, such as contain and contains) are inclusive or open-ended and do not exclude additional unlisted elements or process / method steps.

[0027] As used herein, the word "consisting" and its derivatives are intended to be closed-ended terms that specify the presence of the stated features, elements, components, groups, integers and / or steps, and exclude the presence of other unstated features, elements, components, groups, integers and / or steps.

[0028] As used herein, the term "consisting essentially of" is intended to specify the presence of the stated features, elements, components, groups, integers and / or steps, as well as those that do not substantially affect the basic and novel characteristics of these stated features, elements, components, groups, integers and / or steps.

[0029] As used herein, degree terms such as "substantially", "about" and "approximately" mean a reasonable amount of deviation from the modified term that does not significantly alter the final result. These degree terms should be construed to include at least ±5% deviation from the modified term, provided that such deviation does not negate the meaning of the word modified by the term.

[0030] As used herein, the term "suitable" means that while the selection of a particular compound or particular condition depends on the specific synthetic operation to be performed, the identity of the molecule to be converted and / or the specific use of the compound, such selection is well within the skill of a person skilled in the art. All process / method steps described herein are to be carried out under conditions sufficient to provide the stated product. Those skilled in the art will appreciate that all reaction conditions can be varied to optimize the yield of the desired product, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio, and whether the reaction should be carried out under an anhydrous or inert atmosphere, and that doing so is within the skill of those 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 in 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, C1~10 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", whether used alone or as part of another group, means a linear or branched unsaturated alkynyl group containing at least one triple bond. The number of possible carbon atoms in the mentioned alkyl group is indicated by the prefix "C n1~n2 ". For example, C 2~6 the term alkynyl means an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms.

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

[0052] As used herein, the term "heterocycloalkyl", whether used alone or as part of another group, refers to a cyclic group containing at least one non-aromatic ring containing 3 to 10 atoms, wherein one or more of said atoms is a hetero moiety selected from O, S, S(O), SO₂, N, NH and N(C 1~6 alkyl), and the remaining atoms are carbon. A heterocycloalkyl group is either saturated or unsaturated (i.e., contains one or more double bonds). When a heterocycloalkyl group includes the prefix C n1~n2 , this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, wherein one or more, suitably 1 to 5, of said ring atoms are replaced with a heteroatom as defined above. A heterocycloalkyl group may optionally be benzo-fused.

[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 "dppf" refers to 1,1'-bis(diphenylphosphino)ferrocene.

[0079] As used herein, the terms "RT" or "rt" refer to room temperature.

[0080] As used herein, the term "HPLC" refers to high-performance liquid chromatography.

[0081] As used herein, the terms "TEA" or "Et3N" refer to triethylamine.

[0082] As used herein, the term "EDTA" refers to ethylenediaminetetraacetic acid.

[0083] As used herein, the term "ATP" refers to adenosine triphosphate.

[0084] As used herein, the term "FBS" refers to fetal bovine serum.

[0085] As used herein, the term "MEM" refers to the minimum essential culture medium.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] As used herein, the terms “effective dose” or “therapeutic dose” mean the amount of the compound or one or more of the compounds of the Application that is effective in the dose and duration required to achieve the desired result.

[0090] The term "disease, disorder, or condition that can be treated by inhibiting GCN2" means that the disease, disorder, or condition being treated is affected by, modulated by, and / or has a biological basis that includes, in particular, increased GCN2 activity, directly or indirectly. These diseases respond favorably when the GCN2 activity associated with the disease, disorder, or condition is inhibited by one or more of the compounds or compositions of the Application.

[0091] As used herein, the expression "inhibiting GCN2" refers to inhibiting, blocking, and / or destroying the kinase activity or function of GCN2 in a cell. Such inhibition, blocking, and / or destruction causes a therapeutic effect in that cell.

[0092] "Inhibition, blockage, and / or destruction" means any detectable inhibition, blockage, and / or destruction in the presence of a compound, compared to conditions that are identical except for the absence of the compound.

[0093] As used herein, the term "GCN2" refers to General Control Nonderepressible 2, or any functional variant or analog thereof.

[0094] 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 compared to healthy cells under otherwise identical conditions.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] As used herein, the term "GLS1" refers to "renal-type" glutaminase, or any functional variant or analog thereof.

[0099] 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.

[0100] 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).

[0101] 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.

[0102] II. Compounds of the present invention We prepared pyrimidopyridone and pteridone compounds according to this application and found that they inhibit kinases and generalized uninhibited desuppression 2 (GCN2).

[0103] Accordingly, the present application encompasses a compound of formula I, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:

Chemical Formula

[0104] This application also includes compounds of formula I, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: [ka] 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. 8It may be arbitrarily replaced with; X 1 N and CR 9 Selected from; R 2 H, C 1~6 Alkyl and C 1~6 Selected from haloalkyl; X 2 N and CR 10 Selected from; R 3 , R 4 and R 5 H, Haro, CN, C 1~6 Alkyl and C 1~6 Independently selected from haloalkyl groups; X 3 N and CR 11 Selected from; R 6 and R 7 H, Haro, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, OC 1~6 Alkyl and OC 1~6 Independently selected from haloalkyl groups; Each R 8 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, where alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are all 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 10 and R 11 H, Halo, C 1~6Alkyl and C 1~6 Independently selected from haloalkyl groups; 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.

[0105] In some embodiments, 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 R 8 It may be optionally replaced with R. In some embodiments, 1 C 3~10 Cycloalkyl and C 3~10 Selected from heterocycloalkyl groups, each of which has one or two R groups. 8 It may be replaced as needed.

[0106] In some embodiments, R 1 H, C 1~6 Alkyl and C 1~6 Selected from haloalkyls. In some embodiments, R 1 H, C 1~4 Alkyl and C 1~4 Selected from haloalkyls. In some embodiments, R 1 H, C 1~4 Alkyl and C 1~4 Selected from fluoroalkyls. In some embodiments, R1 is selected from H, CH3, CF3, CHF2, CH2CH3, 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.

[0107] In some embodiments, R 1 is one or two R 8 C may be arbitrarily replaced. 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. 8 It may be optionally replaced with R. In some embodiments, 1 is one or two R 8 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. 8 It may be optionally replaced with R. In some embodiments, 1 The compounds are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which has one R 8 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 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. 8 It is replaced by R1 is one or two R 8 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 8 It is replaced by R 1 is one R 8 It is cyclobutyl substituted with R. In some embodiments, 1 is one R 8 It is a cyclohexyl substituted with [a specific compound].

[0108] 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. 8 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 8 It may be optionally substituted with. In one embodiment, spirocondensation C 6~10 Cycloalkyls have one or two R 8 Spiro[3.3]heptane may be optionally substituted with C. In some embodiments, spirocondensation C 5~10 Cycloalkyl is [ka] That is the case.

[0109] In some embodiments, R 1 is one or two R 8 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. 8 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 8 It may be optionally replaced with C. In some embodiments, crosslinked C 5~10 Cycloalkyls are [ka] Selected from.

[0110] In some embodiments, R 1 is one or two R 8 C may be arbitrarily replaced. 3~10 It is heterocycloalkyl. In some embodiments, R 1 is one R 8 C may be arbitrarily replaced. 3~10 It is heterocycloalkyl. In some embodiments, R 1 is one R 8 C may be arbitrarily replaced. 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 8 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 8 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 8 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 8 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.

[0111] In some embodiments, X 1 X is selected from N and CH. In some embodiments, X 1 In some embodiments, X 1 It is CH.

[0112] In some embodiments, R 2 H, C 1~4 Alkyl and C 1~4 Selected from haloalkyls. 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, 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, R2 R is selected from H, CH3, and CH(CH3)2. In some embodiments, R 2 This is selected from H and CH3.

[0113] 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.

[0114] 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 In some embodiments, R is independently selected from haloalkyl groups. 3 , R 4 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 4and 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 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 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 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, R4 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 4 is 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.

[0115] In some embodiments, X 3 X is selected from N and CH. In some embodiments, X 3 It is CH.

[0116] 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 OC1~4 It is independently selected from fluoroalkyls. In some embodiments, R 6 and R 7 R is independently selected from H, Cl, F, CN, CH3, CHF2, CF3, CH2CH3, OCH3, OCHF2, and OCF3. In some embodiments, R 6 and R 7 is independently selected from Cl, F, CH3, CF3, CHF2, CH2CH3, 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.

[0117] In some embodiments, each R 8 is OR 12 , C(O)NR 12 R 13 , C(O)OR 12 ,=O,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 8 is OR 12 , C(O)NR 12 R 13 , NR 12 R13 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 8 is OR 12 , C(O)NR 12 R 13 , C(O)OR 12 ,=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 They may be optionally substituted with one or more substituents selected from alkyl groups. In some embodiments, each R 8 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 3~6 Selected independently from heterocycloalkyls, all alkyl, cycloalkyl and heterocycloalkyls are Cl, Br, F, OR 14 , NR 14 R 15 and C 1~4They may be optionally substituted with one or more substituents selected from alkyl groups. In some embodiments, each R 8 is OR 12 , NR 12 R 13 , C(O)NR 12 R 13 , C(O)OR 12 ,=O,Cl,F,CH3,CHF2,CH3CH3 and CF3 are independently selected. In some embodiments, each R 8 is OR 12 , NR 12 R 13 , C(O)NR 12 R 13 , independently selected from Cl, F, CH3, CHF2, CH3CH3 and CF3. In some embodiments, each R 8 R is independently selected from Cl, F, CH3, CHF2, CH3CH3, and CF3. In some embodiments, each R 8 R is independently selected from CH3, CHF2, CH3CH3, and CF3. In some embodiments, each R 8 is OR 12 , NR 12 R 13 and C(O)NR 12 R 13 Selected independently from R. In some embodiments, each R 8 , NR 12 R 13 and C(O)NR 12 R 13 Selected independently from R. In some embodiments, each R 8 is =O and C(O)OR 12 Selected independently from R. In some embodiments, each R 8 is = O. In some embodiments, each R 8 is C(O)OR 12 In some embodiments, each R 8 However, OR 12 , C(O)NR 12 R 13 , C(O)OR 12 ,=O,NR 12 R13 , C 3~10 Cycloalkyl and C 3~10 When selected independently from heterocycloalkyls, R 1 is one R 8 It is replaced by only that.

[0118] In some embodiments, R 9 , 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 10 and R 11 R is independently selected from H, Cl, F, CH3, CF3, CHF2, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, and CH(CH3)3. In some embodiments, R 9 , R 10 and R 11 R is independently selected from H, Cl, F, CH3 and CF3. In some embodiments, R 9 , R 10 and R 11 is selected independently from H and F. In some embodiments, R 9 , R 10 and R 11 H is H.

[0119] 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 12 is selected from H, CH3, CF3, CHF2, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3 and CH(CH3)3. In some embodiments, R12 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.

[0120] 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, 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.

[0121] 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, 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.

[0122] 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] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] or its pharmaceutically acceptable salts, solvates, and / or prodrugs.

[0123] 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).

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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 compounds of the Application 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.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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).

[0142] 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.

[0143] 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.

[0144] 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.

[0145] IV. Method and Use of the Present Application The compound described in this application has been shown to inhibit or block the general unregulated, unrepressive 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.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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.

[0166] In one embodiment, diseases, disorders, or conditions that can be treated by inhibiting GCN2 include cancer and / or peripheral neuropathy.

[0167] In some embodiments, GCN2 is inhibited by the use and methods of the present application.

[0168] In one embodiment, "the subject requiring it" refers to the subject having the disease, disorder, or condition to be treated.

[0169] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0170] 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.

[0171] 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).

[0172] 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.

[0173] 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).

[0174] 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.

[0175] 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 to a subject in need, in combination with an effective amount of the said one or more cancer treatments to a subject in need.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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 dosing 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] Therefore, in some embodiments, the compound of formula I is prepared as shown in scheme 1. [ka]

[0193] Commercially available 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8h)-one (Hal=Br,X 1The compound of formula A) is oxidized to the sulfoxide intermediate compound of formula B with a suitable oxidizing agent, such as meta-chloroperoxybenzoic acid (m-CPBA). Next, the compound of formula B is coupled to a suitable amine of formula C or its protected form in a suitable solvent, such as iPrOH, MeCN, or DMF, in the presence of a suitable base, such as Cs2CO3 or DIPEA, to obtain the intermediate compound of formula D. Using suitable conditions such as the Suzuki-Miyaura coupling conditions, the compound of formula D is coupled to the boronic acid ester or boronic acid of formula G (wherein R is used in the formula). 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 treatment with a 4-6 member saturated or unsaturated ring (which may be optionally substituted with alkyl groups).

[0194] The boronic acid ester or boronic acid of formula G is prepared by coupling an aryl sulfonyl compound of formula E, where Y' is a halogen such as Cl, with a boronic acid ester or aniline boronic acid compound of formula F in the presence of a suitable base such as pyridine. [ka]

[0195] In some embodiments, the compounds of formula I are prepared as shown in Scheme 2. Thus, the intermediate compound of formula D, in which Hal is a halogen such as Br, is coupled with the substituted 3-anilino-boronate compound of formula F (which is prepared from a commercially available or synthesized corresponding 3-halo-aniline compound under standard boronylation conditions such as Miyaura borylation conditions using (pinacolato)diborone with a suitable catalyst, e.g., PdCl2(dppf) ([1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride:CH2Cl2 complex) under basic conditions and under Suzuki-Miyaura coupling conditions to obtain the intermediate compound of formula J. The compound of formula I is obtained by sulfonylation of the compound of formula J using the sulfonyl halide-containing heterocyclic compound of formula E, in which Y' is a halogen, e.g., under basic conditions. [ka]

[0196] In some embodiments, the compound of formula I is prepared as shown in Scheme 3. Therefore, the compound of formula A is boronated under standard boration conditions, such as Miyaura boration conditions, in the presence of a suitable reagent such as bispinacolatodiborone, a base such as PdCl2dppf:CH2Cl2 complex and KOAc, in a suitable solvent such as dioxane, at a suitable temperature, for example, 100-110°C, to obtain the boronated compound of formula K (wherein R, 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. 1~3A 4-6 member saturated or unsaturated ring (which may be optionally substituted with alkyl) is obtained. Next, the compound of formula K is treated with various halo-sulfonamides of formula H in which Y'' is a halogen (prepared by coupling the corresponding sulfonyl halide compound of formula E in which Y' is a halogen with the aniline compound of formula M, for example, under appropriate coupling conditions) using appropriate conditions such as Suzuki-Miyaura coupling conditions to obtain the compound of formula L. The compound of formula L is oxidized to an intermediate sulfoxide with an appropriate oxidizing agent such as meta-chloroperoxybenzoic acid (m-CPBA), and then, under basic conditions, is coupled with various appropriate amine compounds of formula C to obtain the compound of formula I. [ka]

[0197] In some embodiments, the compounds of formula I are prepared as shown in Scheme 4. Therefore, the compound of formula N is coupled with a sulfonyl halide compound of formula E, in which Y' is a halogen, under appropriate coupling conditions, for example, in the presence of a base (e.g., pyridine), to obtain the compound of formula L. The compound of formula L is oxidized to an intermediate sulfoxide with a suitable oxidizing agent such as meta-chloroperoxybenzoic acid (m-CPBA), and then coupled with various suitable amine compounds of formula C under basic conditions to obtain the compound of formula I. [ka]

[0198] In some embodiments, the compound of formula I is prepared as shown in scheme 5. Therefore, the intermediate compound of formula D, in which Hal is a halogen such as Br, is coupled with the boronate compound of formula G under appropriate coupling conditions such as Suzuki-Miyaura coupling conditions to obtain the compound of formula I. [ka]

[0199] In some embodiments, R 2 The compound of formula I, where =H, is prepared as shown in scheme 6. Therefore, R 2 The intermediate compound of formula O, which has a suitable protecting group such as p-methoxybenzyl (PMB), is deprotected under acidic conditions, R 2 We obtain the compound of formula I, where =H. [ka]

[0200] In some embodiments, as shown in scheme 7, X 1 The compound of formula N (compound of formula N-1), which is equal to N, is prepared from readily available 2,4-dichloro-5-nitropyrimidine (compound of formula P). Under appropriate conditions, such as in the presence of Fe, it is nitro-reduced to the amine compound of formula Q, and then, under appropriate conditions, for example in the presence of a base such as DIPEA, a suitable amine (e.g., R) is prepared. 2 By substitution with NH2, the intermediate compound of formula R is obtained. The compound of formula R is cyclized with ethyl gloxalate and then substituted with sodium thiomethioxide to obtain the intermediate methylthio compound of formula T. By radical-mediated coupling with tert-butyl nitrite, the intermediate compound of formula V is obtained. Next, under appropriate conditions, for example, in the presence of diphenylmethaneimine, xanthophos, Pd(OAc)2 and Cs2CO3, the compound of formula NI is obtained by amination. [ka]

[0201] In some embodiments, as shown in Scheme 7, the intermediate boronic acid ester or boronic acid of formula F is prepared from the corresponding halo derivative compound of formula W (wherein Hal' is a halogen such as Br) under standard boration conditions, for example, under Miyaura boration conditions, in a suitable solvent such as dioxane, at a suitable temperature, for example, 100-110°C, in the presence of a suitable reagent, such as bispinacolatodiborone, PdCl2dppf:CH2Cl2 complex, and a base such as potassium acetate (KOAc). [ka]

[0202] In some embodiments, as shown in Scheme 9, an intermediate compound of formula D (compound of formula D-1) where Hal is Br is prepared by a reaction of a compound of formula Z where Hal'' is a halogen such as Cl with various suitable amino compounds of formula C under suitable conditions, for example, in the presence of a base, such as KOAc or DIPEA, to obtain a compound of formula AA. Next, the compound of formula AA is brominated with Br2 in a suitable solvent such as acetonitrile (MeCN) to obtain a compound of formula D-1.

[0203] Generally, the above reactions are carried out in a suitable inert organic solvent at a temperature and time optimized for 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 (DCM), chloroform, tetrahydrofuran (THF), and toluene.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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).

[0208] 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.

[0209] 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.

[0210] 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]

[0211] The following non-limiting examples are illustrative of this application. A. Synthesis and Characterization of Representative Compounds in this Application

[0212] 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.

[0213] 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, SiO2Biotage® cartridge, or 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 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.

[0214] 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 slowly allowed to reach room temperature, and stirring was continued overnight. The reaction mixture was then concentrated on Celite under reduced pressure or washed by extraction with H2O. The organic extract was concentrated under reduced pressure and deposited on a Biotage® sample or Celite, and then purified by flash chromatography on silica gel using one of the following cartridges: InnoFlash®, Biotage®, or RediSep® Rf.

[0215] General method MO (mCPBA-mediated oxidation) To a CH2Cl2 suspension of methylthioheteroaryl (1 equivalent), 3-chloroperbenzoic acid (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: N-(3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide [ka]

[0216] 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 2:**6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one [ka] Step 1: 6-Bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0217] To a 150 mL solution of cooled 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one (10 g, 37 mmol) in DMF (150 mL), K2CO3 (7.6 g, 55 mmol) was added under N2 at -5°C. The reaction mixture was stirred at -5°C for 10 minutes, then MeI (6.26 g, 44.1 mmol) was added at -5°C. The reaction was stirred for a further 45 minutes while cooling. The reaction mixture was then diluted with ice-cold H2O (150 mL), filtered, washed with hexane, and dried under vacuum to obtain 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one as an off-white solid (4 g, 38%). MS(ESI)m / z[M+H] + 286.0 / 288.0. Step 2.6-Bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0218] To a solution of cooled 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one (3 g, 10.5 mmol) in CH2Cl2 (45 mL), m-CPBA (7.3 g, 41.9 mmol) was gradually added at 0°C under N2. The reaction mixture was then stirred at room temperature for 16 hours, diluted with saturated NaHCO3 aqueous solution (150 mL), and extracted with CH2Cl2 (60 mL x 3). The combined organic layer was dried (anhydrous Na2SO4) and concentrated under reduced pressure. 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one was obtained as a light brown solid (2.4 g, 72%) by trituration with 20% siRNA in hexane. MS(ESI)m / z[M+H] + 318.0 / 320.0. 1 H NMR(400 MHz,DMSO-d6)δ 3.51(s,3H),3.74(s,3H),8.75(s,1H),9.29(s,1H). Intermediate: 3: 6-(5-amino-2-fluorophenyl)-8-methyl-2-(methylthio)pteridine-7(8H)-one [ka] Step 1. 2,4-Dichloropyrimidine-5-amine [ka]

[0219] To a 50 mL solution of 2,4-dichloro-5-nitropyrimidine (5 g, 26 mmol) in AcOH (50 mL), Fe powder (2.89 g, 51.5 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered through Celite, and the filter bed was rinsed with ELISA (300 mL). The filtrate was concentrated under reduced pressure. 2,4-dichloropyrimidine-5-amine was obtained as an orange solid (3 g, 71%) by trituration of the solid residue with hexane. MS(ESI)m / z[M+H] + 164.0. Step 2. 2-Chloro-N 4 -Methylpyrimidine-4,5-diamine [ka]

[0220] To a 30 mL solution of 2,4-dichloropyrimidine-5-amine (3 g, 18 mmol) in EtOH, DIPEA (6.3 mL, 36 mmol) was added at room temperature. The reaction mixture was then stirred for 10 minutes, after which MeNH2 (2 M solution in THF, 19 mL, 37 mmol) was added dropwise. The reaction mixture was then stirred at 80°C for 16 hours. The reaction mixture was then concentrated under reduced pressure. The crude product was triturated with methyl tert-butyl ether to obtain 2-chloro-N 4 Methylpyrimidine-4,5-diamine was obtained as a dark purple semi-solid (2.8 g, 96%). MS(ESI)m / z[M+H] + 159.04. Step 3. 2-Chloro-8-methylpteridine-7(8H)-one [ka]

[0221] Stirred 2-chloro-N 4 To a solution of methylpyrimidine-4,5-diamine (11 g, 70 mmol) in EtOH (110 mL), a PhMe solution of ethyl glyoxylate (30%, 7.07 mL, 69.6 mmol) was added dropwise, and the reaction mixture was stirred at 80°C for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. By trituration of the crude product with methyl tert-butyl ether, 2-chloro-8-methylpteridine-7(8H)-one was obtained as a white solid (4.5 g, 33%). MS(ESI)m / z[M+H] + 197.0. Step 4: 8-Methyl-2-(methylthio)pteridine-7(8H)-one [ka]

[0222] To a stirred solution of 2-chloro-8-methylpteridine-7(8H)-one (1.6 g, 8.1 mmol) in THF (16 mL), MeSNa (0.91 g, 13 mmol) was gradually added. The reaction mixture was stirred at 80 °C for 16 hours, then diluted with H₂O (100 mL) and extracted with SiO₂ (100 mL x 3). The combined organic layer was dried (anhydrous Na₂SO₄) and concentrated under reduced pressure. The crude product was purified by flash chromatography using SiO₂ in hexanes to obtain 8-methyl-2-(methylthio)pteridine-7(8H)-one as an off-white solid (0.9 g, 53%). 1 H NMR(400 MHz,DMSO-d6)δ 8.97(s,1H),8.22(s,1H),3.54(s,3H),2.63(s,3H). Step 5. 6-(5-bromo-2-fluorophenyl)-8-methyl-2-(methylthio)pteridine-7(8H)-one [ka]

[0223] To a 50 mL solution of 5-bromo-2-fluoroaniline (1.8 g, 9.5 mmol) in MeCN under N2 conditions, tert-butyl nitrite (1.48 g, 14.3 mmol) was added at 0°C. The resulting solution was stirred at 0°C for 30 minutes. Then, a 5 mL solution of 8-methyl-2-(methylthio)pteridine-7(8H)-one (0.5 g, 2.4 mmol) in MeCN was added at 0°C. Next, the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with H2O (100 mL) and extracted with CH2Cl2 (100 mL x 3). The combined organic layers were dried (anhydrous Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography using SiO in hexanes yielded 6-(5-bromo-2-fluorophenyl)-8-methyl-2-(methylthio)pteridine-7(8H)-one as an off-white solid (0.2 g, 22%). MS(ESI)m / z[M+H] + 381.1 / 383.1 Step 6. 6-(5-amino-2-fluorophenyl)-8-methyl-2-(methylthio)pteridine-7(8H)-one [ka]

[0224] To a solution of 6-(5-bromo-2-fluorophenyl)-8-methyl-2-(methylthio)pteridine-7(8H)-one (1.1 g, 2.9 mmol) in 1,4-dioxane (11 mL), diphenylmethanymine (0.57 g, 3.2 mmol), xanthophos (0.5 g, 0.86 mmol), Pd(OAc)2 (0.097 g, 0.43 mmol), and Cs2CO3 (2.8 g, 8.7 mmol) were added under N2. The reaction mixture was degassed under N2 for 10 minutes and stirred at 100°C for 3 hours. After completion, the reaction mixture was acidified with 2 M HCl aqueous solution (pH=2) and extracted with siRNA (100 mL x 3). The organic layer was discarded, and the aqueous layer was basicized with 2 M NaOH aqueous solution and extracted with siRNA (100 mL x 3). The combined organic layers were dried (anhydrous Na2SO4) and concentrated under reduced pressure. The crude material was purified by column chromatography using 60-120 silica and SiO in hexanes to obtain 6-(5-amino-2-fluorophenyl)-8-methyl-2-(methylthio)pteridine-7(8H)-one as an orange solid (0.8 g, 87%). MS(ESI)m / z[M+H] + 318.2. 1 H NMR(400 MHz,DMSO-d6)δ 9.00(s,1H),6.98(t,J=8.6 Hz,1H),6.60-6.85(m,2H),5.31(br.s.,2H),3.62(s,3H),2.65(s,3H). Intermediate 4: 6-bromo-2-((4-(dimethylamino)cyclohexyl)amino)-8-methylpteridine-7(8H)-one [ka] Step 1.2-((1R,4R4-(dimethylamino)cyclohexyl)amino)-8-methylpteridine-7(8H)-one [ka]

[0225] To a 17 mL solution of 2-chloro-8-methylpteridine-7(8H)-one (1.7 g, 88 mmol) in DMF (1.69 g, 95.4 mmol) and K2CO3 (3.5 g, 26 mmol) were added at room temperature. The mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with SiO (20 mL x 3). The combined organic layer was washed with brine (25 mL), dried (anhydrous Na2SO4), and concentrated under reduced pressure. The crude product was purified by column chromatography using MeOH in CH2Cl2 to obtain 2-((4-(dimethylamino)cyclohexyl)amino)-8-methylpteridine-7(8H)-one as a brown solid (0.83 g, 32%). MS(ESI)m / z[M+H] + 303.2. Step 2.6-Bromo-2-((4-(dimethylamino)cyclohexyl)amino)-8-methylpteridine-7(8H)-one*HBr [ka]

[0226] 0.5 g, 1.6 mmol of 2-((4-(dimethylamino)cyclohexyl)amino)-8-methylpteridine-7(8H)-one (0.5 g, 1.6 mmol) was added to a 5.0 ml solution of MeCN (5 ml) at 0°C. The reaction mixture was stirred at 0°C for 2 hours. After completion, the reaction mixture was directly injected into a silica column and purified by column chromatography using MeOH in CH2Cl2. 6-bromo-2-((4-(dimethylamino)cyclohexyl)amino)-8-methylpteridine-7(8H)-one*HBr was obtained as a brown solid (0.467 g, 73%) by trituration with n-pentane and Et2O. MS(ESI)m / z[M+H] + 381.3 / 383.2. 1H NMR(400 MHz,DMSO-d6)δ 9.64(br.s.,1H),8.50-8.80(m,1H),8.30-8.00(m,1H),3.70-3.40(m,3 H)3.30-3.05(m,2H),2.74(s,6H),2.25-1.85(m,4H),1.75-1.20(s,4H). Intermediate 5: 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]

[0227] 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 6: (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid [ka]

[0228] 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 7: 6-bromo-8-methyl-2-(methylamino)pteridine-7(8H)-one [ka] Step 1: 8-Methyl-2-(methylamino)pteridine-7(8H)-one [ka]

[0229] A solution of 2-chloro-8-methylpteridine-7(8H)-one (0.9 g, 4.57 mmol) in EtOH (9 mL) and DIPEA (1.1 g, 8.5 mmol) was stirred at room temperature for 15 minutes, and then MeNH2 (2 M in THF, 2.5 mL, 5.0 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 16 hours, then filtered, rinsed with ethyl acetate, and dried under vacuum to obtain 8-methyl-2-(methylamino)pteridine-7(8H)-one as an off-white solid (0.4 g, 46%). MS(ESI)m / z[M+H] + 192.19. Step 2: 6-Bromo-8-methyl-2-(methylamino)pteridine-7(8H)-one

[0230] Br2 (4 g, 25.1 mmol) was added dropwise at 0°C to a stirred solution of 8-methyl-2-(methylamino)pteridine-7(8H)-one (0.8 g, 4.2 mmol) in MeCN (16 mL). Stirring was continued at that temperature for 2 hours. After completion, the reaction mixture was diluted with H2O (30 mL) and extracted with siRNA (30 mL x 3). The combined organic layer was dried (anhydrous Na2SO4) and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain 6-bromo-8-methyl-2-(methylamino)pteridine-7(8H)-one as a pale yellow solid (0.15 g, 13%). 1 H NMR(400 MHz,DMSO-d6)δ 8.75-8.58(m,1H),8.15-7.95(m,1H),3.62-3.45(m,3H),2.89(d,J=4.8 Hz,3H).MS(ESI)m / z [M+H] + 270.2 / 272.2. Intermediate 8: 2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [ka]

[0231] 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 (Hex) 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). 1H 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). Representative compound of the present invention Example 1: N-(3-(2-amino-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide(I-1) [ka] Step 1: 6-Bromo-8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0232] A lidded, dry microwave vial containing 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one (0.5 g, 1.8 mmol) and NaH (60% in mineral oil, 0.110 g, 2.8 mmol) was evacuated and packed with Ar. Anhydrous DMF (10 mL) was added, and the mixture was stirred at room temperature for 10 minutes, after which the reaction mixture was heated at 50 °C for 30 minutes. i-PrI (0.276 mL, 2.76 mmol) was added all at once at room temperature. After stirring briefly at room temperature, the reaction mixture was placed in an oil bath at 40 °C for 1.5 hours, and then aged at room temperature for 3 days and 18 hours. DMF was removed under reduced pressure, and the substance was suspended in EtOH. H2O was added, and the solid was collected by filtration. The filtered cake was rinsed with H2O and dried under vacuum to obtain 6-bromo-8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one as an off-white solid (565 mg, yield 75% based on purity 77%). MS(ESI)m / z[M+H] + 314.05 / 316.01 Step 2. (8-Isopropyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)boronic acid [ka]

[0233] A solution was prepared by the general MB method using 6-bromo-8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one (200 mg, 0.49 mmol, purity 77%), B2pin2 (162 mg, 0.64 mmol), KOAc (168 mg, 1.72 mmol), and PdCl2dppf·CH2Cl2 (40.0 mg, 0.049 mmol) in anhydrous 1,4-dioxane (12 mL), sealed and heated in an oil bath at 100°C for 2 hours. The reaction was then left at room temperature overnight. Subsequently, the sealed reaction was heated in an oil bath at 120°C for 3.5 hours. The crude mixture was used directly in the next step. MS(ESI)m / z[M+H] + 280.28 Step 3. 5-Chloro-N-(2,4-difluoro-3-(8-isopropyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [ka]

[0234] The reaction mixture was prepared by conventional SMC by using Cs2CO3 (177 mg, 0.543 mmol), N-(3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (100 mg, 0.242 mmol), (8-isopropyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)boronic acid (137 mg, 0.152 mmol) (31% in 12 mL of dioxane), PdCl2dppf·CH2Cl2 (14.79 mg, 0.018 mmol), and H2O (6 mL), sealing the mixture, and heating it in a microwave reactor at 90°C for 2 hours. The reaction mixture was concentrated under reduced pressure, attached to Celite, and subjected to preparative HPLC (C). 18Purification by column chromatography (using MeCN in H2O + 0.1% HCO2H) yielded 5-chloro-N-(2,4-difluoro-3-(8-isopropyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a yellow solid (63.0 mg, yield 40% based on 55% purity). MS(ESI)m / z[M+H] + 568.25. Step 4. N-(3-(2-amino-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide(I-1)

[0235] A solution was prepared by conventional MO method using 5-chloro-N-(2,4-difluoro-3-(8-isopropyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (63 mg, 0.061 mmol, 55%) and mCPBA (26 mg, 0.13 mmol) in CH2Cl2 (6 mL), followed by an additional 3-chloroperbenzoic acid (8.2 mg, 0.043 mmol). After the reaction was complete, saturated NaHCO3 aqueous solution (5 mL) was added. After stirring, the layers were separated, the organic phase was concentrated under reduced pressure, and the crude substance obtained as an orange solid was dried under high vacuum. This crude substance was placed in i-PrOH (9 mL), sonicated, and then NH4OH aqueous solution (28-30%, 0.32 mL, 2.4 mmol) was added dropwise at room temperature for 30 minutes. NH4OH aqueous solution (28-30%, 0.32 mL, 2.4 mmol) was added at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, attached to Celite, and subjected to preparative HPLC (C). 18The compound N-(3-(2-amino-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide was obtained as an off-white solid (8.0 mg, 24% based on 97% purity) by purification with MeCN in H2O + 0.1% HCO2H, filtration through a Waters PoraPak CX column, rinsing with MeOH, and elution with 2M NH3 in MeOH. + 537.25. 1 H NMR(500 MHz,CD3OD)δ ppm 8.53(s,1 H),8.32(d,J=2.32 Hz,1 H),8.02-8.07(m,1 H),7.67(s,1 H),7.47(td,J=8.74,5.87 Hz,1 H),7.01(t,J=8.80 Hz,1 H),5.86(br.s.,1 H),4.01(s,3 H),1.56(d,J=6.85 Hz,6 H). Example 2 trans-5-chloro-N-(3-(2-(4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide (trans I-2) [ka] Step 1: 6-Bromo-8-ethyl-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0236] A lidded, dry microwave vial containing 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one (0.5 g, 1.8 mmol) and NaH (60% in mineral oil, 0.110 g, 2.8 mmol) was evacuated and filled with Ar. Anhydrous DMF (10 mL) was added. After stirring at room temperature for 10 minutes, the reaction mixture was heated in an oil bath at 50°C for 30 minutes, and then EtBr (0.21 mL, 2.8 mmol) was added all at once at room temperature. After stirring briefly at room temperature, the reaction was stirred in an oil bath at 40°C for 1.5 hours. After leaving it at room temperature overnight, the DMF was removed under reduced pressure, and the substance was suspended in EtOH. H2O was added, and the mixture was concentrated until EtOH was removed. The substance was filtered, and the filter cake was rinsed with an excess amount of H2O to obtain 6-bromo-8-ethyl-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one as a yellowish-brown solid (543.0 mg, yield 65% based on purity 66%). MS(ESI)m / z[M+H] + 300.13 / 302.09 Step 2: trans-6-bromo-2-((4-(dimethylamino)cyclohexyl)amino)-8-ethylpyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0237] 6-bromo-8-ethyl-2-(methylthio)pyridin[2,3-d]pyrimidine-7(8H)-one (200 mg, 0.44 mmol, 66%) in CH2Cl2 (6 mL) and mCPBA (93 mg, 0.48 mmol) in CH2Cl2 (approximately 1 mL) were used at 0°C to prepare a reaction by conventional MO method. After 1.5 hours, the reaction was cooled again to 0°C, and mCPBA (45 mg, 0.26 mmol) was added as a slurry in CH2Cl2 (1 mL). The reaction was warmed to room temperature. After completion, saturated NaHCO3 aqueous solution (5 mL) was added. The layers were separated, the organic layer was concentrated, and dried under high vacuum. The solid residue was suspended in i-PrOH (9 mL) using sonication. trans-N1,N1-dimethylcyclohexane-1,4-diamine*2HCl (284 mg, 1.3 mmol) was added, followed by DIPEA (0.77 mL, 4.4 mmol) at room temperature. After sonication to remove any solid clumps, the reaction was stirred overnight at room temperature. The reaction mixture was then concentrated under reduced pressure, attached to Celite, and subjected to preparative HPLC (C). 18 By purification with MeCN + 0.1% HCO2H in H2O, trans-6-bromo-2-((4-(dimethylamino)cyclohexyl)amino)-8-ethylpyrido[2,3-d]pyrimidine-7(8H)-one was obtained as a pale yellow solid (198 mg, quantitative). MS(ESI)m / z[M+H] + 394.25 / 396.32 Step 3. trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide(trans I-2)

[0238] Cs2CO3 (147 mg, 0.452 mmol), 5-chloro-N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methoxypyridine-3-sulfonamide (5.6 mL, 0.23 mmol, crude product, 0.04 M in dioxane), 6-bromo-2-((4-(dimethylamino)cyclohexyl)amino)-8-ethylpyrido[2,3-d]pyrimidine-7(8H)-one (89 mg, 0.23 mmol), and PdCl2dppf·CH2Cl2 (18 mg, 0.023 mmol) were used in H2O (2 mL), sealed and heated in a microwave reactor at 90°C for 1.5 hours by the general method of SMC. The reaction mixture was concentrated under reduced pressure, deposited on Celite, and purified by flash chromatography using MeOH in CH2Cl2. The isolated substance was filtered through a Waters PoraPak CX column to obtain trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide as an off-white solid (66 mg, 46% yield). 1 H NMR(500 MHz,DMSO-d6)δ ppm 8.59-8.68(m,1 H),8.37(d,J=2.45 Hz,1 H),8.03(d,J=2.45 Hz,1 H),7.88(d,J=7.46 Hz,1 H),7.65-7.76(m,2 H),7.19(t,J=7.34 Hz,1 H),6.94-7.05(m,2 H),4.23-4.34(m,2 H),3.86(s,3 H),3.71(br.s.,1 H),2.41(s,6 H),2.09(d,J=9.90 Hz,1 H),1.81-2.01(m,3 H),1.30-1.45(m,4 H),1.15-1.26(m,4 H).MS(ESI)m / z [M+H] + 630.24. Example 3: trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide (trans I-3) [ka]

[0239] Cs2CO3 (147 mg, 0.452 mmol), 5-chloro-N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methoxypyridine-3-sulfonamide (3.6 mL, 0.23 mmol, 0.063 M in 1,4-dioxane), 6-bromo-2-((4-(dimethylamino)cyclohexyl)amino)-8-ethylpyrido[2,3-d]pyrimidine-7(8H)-one (89 mg, 0.23 mmol), and PdCl2dppf·CH2Cl2 (18 mg, 0.023 mmol) were used in H2O (3 mL) and DME (5.4 mL) and prepared by the general method of SMC by heating in an oil bath at 110-90°C for 2.8 hours. The reaction mixture was concentrated under reduced pressure, deposited on Celite, and purified by flash chromatography with SiO2 using MeOH in CH2Cl2. The collected material was then filtered through a Waters PoraPak CX column to obtain 5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide as a beige solid (63 mg, 42% yield based on 95% purity). 1H NMR(500 MHz,DMSO-d6)δ ppm 8.61-8.70(m,1 H),8.44-8.52(m,1 H),8.22(s,1 H),8.16(d,J=2.45 Hz,1 H),7.93(d,J=7.34 Hz,1 H),7.70-7.79(m,1 H),7.20(d,J=4.40 Hz,1 H),7.12-7.17(m,1 H),7.03-7.10(m,1 H),4.23-4.38(m,2 H),3.96(s,3 H),2.38(d,J=11.37 Hz,1 H),2.32(s,6 H),1.82-2.12(m,4 H),1.30-1.43(m,4 H),1.13-1.28(m,4 H).MS(ESI)m / z [M+H] + 630.24. Example 4: trans-5-chloro-N-(3-(2-(4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (trans I-4) [ka] Step 1. (8-Methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)boronic acid [ka]

[0240] A crude mixture was prepared using the general MB method by heating 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one (100 mg, 0.35 mmol), B2pin2 (266 mg, 1.0 mmol), KOAc (120 mg, 1.2 mmol), and PdCl2dppf·CH2Cl2 (28 mg, 0.035 mmol) in an anhydrous 1,4-dioxane (10 mL) at 100°C for 3 days and 20 hours. The crude mixture was directly used in the following Suzuki-Miyaura coupling step: MS(ESI)m / z[M+H] +252.13 Step 2. 5-Chloro-N-(2,4-difluoro-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [ka]

[0241] (8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)boronic acid (88 mg, 0.35 mmol, crude product in 1,4-dioxane, 10 mL), Cs2CO3 (229 mg, 0.70 mmol), N-(3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (145 mg, 0.35 mmol), PdCl2dppf·CH2Cl2 (28.7 mg, 0.035 mmol), and H2O (5 mL) were used, and the mixture was heated in an oil bath at 90°C to 100°C for 4 hours in a sealed container by the general method of SMC preparation. The reaction mixture was then cooled to room temperature, and N-(3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (116 mg, 0.28 mmol) and PdCl2dppf·CH2Cl2 (18 mg, 0.025 mmol) were added. After degassing, heating was continued in an oil bath at 90-100°C for a total of 1 day and 19 hours. The reaction mixture was concentrated under reduced pressure, deposited on Celite, and purified by flash chromatography (using MeOH in SiO2, CH2Cl2), followed by further purification by flash chromatography (using siRNA in SiO2, CH2Cl2) to obtain 5-chloro-N-(2,4-difluoro-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as an off-white solid (29 mg, 14% based on 90% purity). Step 3. trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide(trans I-4)

[0242] To a suspension of 5-chloro-N-(2,4-difluoro-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (29 mg, 0.054 mmol, 90%) in CH2Cl2 (10 mL), mCPBA (15.5 mg, 0.081 mmol) was added in CH2Cl2 (1 mL) at 0°C. The mixture was stirred and slowly warmed to room temperature over a total of 1.9 hours. A saturated aqueous solution of NaHCO3 (5 mL) was added. After stirring, the layers were separated. The organic layer was filtered through a plug of anhydrous Na2SO4, concentrated, and dried under high vacuum. The resulting crude substances, trans--N1,N1-dimethylcyclohexane-1,4-diamine*2HCl (34.7 mg, 0.16 mmol) and DIPEA (0.094 mL, 0.54 mmol), were suspended in i-PrOH (8 mL) by sonication. The suspension was stirred at room temperature for 6 days. Subsequently, the reaction mixture was concentrated on Celite and subjected to preparative HPLC (C). 18 By purification using MeCN in H2O + 0.1% HCO2H, trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide formate was obtained as a white solid (15.8 mg, yield 43%). 1H NMR(500 MHz,DMSO-d6)δ 8.59-8.69(m,1H),8.34(s,1H),8.17(br.s.,1H),8.01(d,J=1.59 Hz,1H),7.96(d,J=7.34 Hz,1H),7.81(d,J=8.19 Hz,1H),7.78(s,1H),7.13-7.25(m,1H),6.93(t,J=8.80 Hz,1H),3.85(s,3H),3.77(d,J=6.48 Hz,1H),3.50-3.59(m,3H),2.64(br.s.,1H),2.45(br.s.,6H),1.84-2.16(m,4H),1.30-1.50(m,4H).MS(ESI)m / z [M+H] + 634.23. Example 5: N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide(I-5) [ka]

[0243] To a suspension of 5-chloro-N-(2,4-difluoro-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (40 mg, 0.074 mmol)) in CH2Cl2 (10 mL), mCPBA (19 mg, 0.078 mmol) in CH2Cl2 (2 mL) was added at 0°C. The mixture was slowly warmed to room temperature over a total of 2 hours while continuing to stir with cooling. The reaction was then aged overnight at -20°C. After warming to room temperature, saturated aqueous NaHCO3 (5 mL) was added. After stirring at room temperature, the organic layer was separated, filtered through an anhydrous Na2SO4 plug, concentrated, and dried under vacuum. The residue was briefly sonicated in i-PrOH (8 mL), and NH4OH aqueous solution (0.96 mL, 7.4 mmol) was added dropwise at room temperature. The reaction was vigorously stirred at room temperature for 1.5 hours, then concentrated on Celite and analyzed by preparative HPLC (C). 18By purification using MeCN in H2O + 0.1% HCO2H, N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide*formic acid was obtained as a white solid (10 mg, yield 24%). MS(ESI)m / z[M+H] + 509.18. 1 H NMR(500 MHz,DMSO-d6)δ 9.94-11.07(br m,1H),8.57-8.70(m,1H),8.40(br.s.,1H),8.03(d,J=2.32 Hz,1H),7.75-7.86(m,1H),7.42(s,2H),7.24(d,J=5.75 Hz,1H),7.01(br.s.,1H),3.87(s,3H),3.53(s,3H). Example 6: 5-Chloro-N-(2,4-difluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-6) [ka]

[0244] To a cold (-78°C) solution of 5-chloro-N-(2,4-difluoro-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (42 mg, 0.078 mmol) in 10 mL of CH2Cl2, mCPBA (20 mg, 0.082 mmol) in 2 mL of CH2Cl2 was added. The mixture was stirred and allowed to slowly warm to room temperature for a total of 1.5 hours. Then, saturated aqueous NaHCO3 solution was added, and after stirring briefly, the organic layer was separated and concentrated to remove CH2Cl2. The recovered solid was vigorously stirred in i-PrOH (8 mL) and MeNH2 (2.0 M in THF, 0.97 mL, 1.9 mmol) at room temperature for 19.5 hours. Next, the reaction mixture is concentrated on Celite and subjected to preparative HPLC (C 18By purification using MeCN in H2O + 0.1% HCO2H, 5-chloro-N-(2,4-difluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide*formic acid was obtained as a white solid (10 mg, 23%). MS(ESI)m / z[M+H] + 523.25. 1 H NMR(500 MHz,DMSO-d6)δ 8.56-8.78(m,1H),8.39(br.s.,1H),8.03(d,J=1.96 Hz,1H),7.92(d,J=3.30 Hz,1H),7.80(s,1H),7.23(d,J=5.87 Hz,1H),7.00(br.s.,1H),6.53(br.s.,1H),3.86(s,3H),3.50-3.63(m,3H),2.92(d,J=4.40 Hz,3H). Example 7: trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide(trans I-7) [ka] Step 1. trans-6-bromo-2-((4-(dimethylamino)cyclohexyl)amino)-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0245] Solid trans-N1,N1-dimethylcyclohexane-1,4-diamine*2HCl (101 mg, 0.47 mmol), CsF (95 mg, 0.63 mmol), and 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (100 mg, 0.31 mmol) were placed in DMSO (5 mL). DIPEA (0.55 mL, 3.1 mmol) was added, and the reaction mixture was heated at 50°C for 2 days and 19 hours. The reaction was then partitioned into H2O and ethyl acetate. The aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were concentrated under reduced pressure, attached to Celite, and purified by flash chromatography (using SiO2, MeOH in CH2Cl2, 0 → 85%, then 2M NH3-MeOH in CH2Cl2) to obtain trans-6-bromo-2-((4-(dimethylamino)cyclohexyl)amino)-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one as a pale orange thin film (55 mg, yield 45% based on 98% purity). MS(ESI)m / z[M+H] + 380.28 / 382.29 Step 2. trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide(trans I-7)

[0246] It was prepared by the general method of SMC by using 5-chloro-N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methoxypyridine-3-sulfonamide (2.3 mL, 0.14 mmol in 1,4-dioxane), trans-6-bromo-2-((4-(dimethylamino)cyclohexyl)amino)-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one (55 mg, 0.14 mmol), Cs2CO3 (141 mg, 0.43 mmol), PdCl2dppf·CH2Cl2 (11.8 mg, 0.014 mmol), DME (5.6 mL), and H2O (4 mL), and heating in an oil bath at 80°C for 2.5 days in a sealed container. Next, the reaction mixture is concentrated under reduced pressure, attached to Celite, purified by flash chromatography (using MeOH in SiO2, CH2Cl2), and then subjected to preparative HPLC (C 18 By purification using MeCN in H2O + 0.1% HCO2H, trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide, formic acid was obtained as a white powder (20 mg, yield 21% based on 98% purity). MS(ESI)m / z[M+H] + 616.36. 1 H NMR(500 MHz,DMSO-d6)δ 8.59-8.69(m,1H),8.43(d,J=2.20 Hz,1H),8.25(br.s.,1H),8.13(d,J=2.45 Hz,1H),7.90(d,J=7.58 Hz,1H),7.68-7.79(m,2H),7.15(d,J=4.40 Hz,1H),7.07-7.12(m,1H),7.03(br.s.,1H),3.93(s,3H),3.71-3.86(m,2H) ,3.51-3.60(m,3H),2.23(br.s.,6H),1.80-2.11(m,4H),1.26-1.37(m,4H). Example 8: 5-Chloro-N-(4-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-8) [ka] Step 1: 5-Chloro-N-(4-fluoro-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [ka]

[0247] 6-(5-amino-2-fluorophenyl)-8-methyl-2-(methylthio)pteridine-7(8H)-one (200 mg, 0.62 mmol, 98%) and 5-chloro-2-methoxypyridine-3-sulfonyl chloride (164 mg, 0.68 mmol) were cooled to -10°C, and then CH2Cl2 (20 mL) was added. After further cooling (10 minutes), pyridine (0.25 mL, 3.1 mmol) was added, the vial was removed from the cooling bath, and the mixture was warmed to room temperature while stirring. The reaction was stirred at room temperature for 4 days, then concentrated under reduced pressure, deposited on Celite, and purified by flash chromatography (using SiO2, CH2Cl2) to obtain 5-chloro-N-(4-fluoro-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a pale orange solid (259 mg, yield 80%). MS(ESI)m / z[M+H] + 523.25. Step 2. 5-Chloro-N-(4-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-8)

[0248] 5-Chloro-N-(4-fluoro-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (60 mg, 0.11 mmol) was added to a cold (-10°C) CH2Cl2 (10 mL) solution, to which mCPBA (30 mg, 0.12 mmol) was added in CH2Cl2 (2 mL). The reaction was warmed to room temperature and stirred at room temperature for a total of 18 hours. CH2Cl2 was removed under reduced pressure. i-PrOH (8 mL) was added, followed by MeNH2 (40 wt% in H2O, 0.50 mL, 5.7 mmol). After stirring at room temperature for 1.5 hours, the substance was allowed to adhere to Celite and subjected to preparative HPLC (C 18 By purification using MeCN in H2O + 0.1% HCO2H, 5-chloro-N-(4-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide*formic acid was obtained as a pale yellow solid (25 mg, 39% based on 99% purity). MS(ESI)m / z[M+H] + 506.25. 1 H NMR(500 MHz,DMSO-d6)δ 10.64(br.s.,1H),8.63-8.78(m,1H),8.47(d,J=2.45 Hz,1H),7.93-8.23(m,2H),7.30(d,J=5.87 Hz,1H),7.18(d,J=7.21 Hz,2H),3.95(s,3H),3.46-3.61(m,3H),2.93(d,J=4.65 Hz,3H). Example 9: trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropteridine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide (trans I-9) [ka]

[0249] 5-Chloro-N-(4-fluoro-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (70 mg, 0.134 mmol) was added to a cold (-78°C) CH2Cl2 (10 mL) solution, to which mCPBA (35 mg, 0.14 mmol) was added in CH2Cl2 (2 mL). The reaction was then slowly warmed to room temperature and stirred at room temperature for a total of 18 hours. CH2Cl2 was removed under reduced pressure. trans-N1,N1-dimethylcyclohexane-1,4-diamine*2HCl (89 mg, 0.41 mmol) was added. The entire substance was suspended in i-PrOH (8 mL), sonicated, and then DIPEA (0.23 mL, 1.3 mmol) was added. The mixture was vigorously stirred at room temperature for 2.5 hours. Subsequently, i-PrOH (8 mL) was added, and after brief sonication, stirring was continued overnight at room temperature. Then, the reaction was heated in an oil bath at 50°C for 3 hours. Next, the reaction mixture was concentrated under reduced pressure, attached to Celite, and subjected to preparative HPLC (C). 18 By purification using MeCN in H2O + 0.1% HCO2H, 5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropteridine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide was obtained as a pale yellow solid (16.5 mg, yield 18% based on 98% purity). MS(ESI)m / z[M+H] + 617.30. 1 H NMR(500 MHz,DMSO-d6)δ 8.55-8.69(m,1H),8.38(d,J=2.57 Hz,1H),8.16(br.s.,1H),7.87-8.07(m,2H),7.20(d,J=5.38 Hz,1H),7.09(d,J=7.70 Hz,2H),3.87(s,3H),3.64-3.82(m,1H),3.42-3.47(m,3H),2.27-2.37(m,1H),2.22(s,6H),1.76-2.04(m,4H),1.21-1.38(m,4H). Example 10: trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide (trans I-10) [ka]

[0250] PdCl2dppf·CH2Cl2 (15.0 mg, 0.018 mmol), Cs2CO3 (180 mg, 0.55 mmol), trans-6-bromo-2-((4-(dimethylamino)cyclohexyl)amino)-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one (70 mg, 0.18 mmol), H2O (1.8 mL), and (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (3.5 mL, 0.18 mmol, 0.052 M crude product in 1,4-dioxane) were used, sealed, and heated in a microwave reactor at 90°C for 100 minutes by conventional SMC method. The solution was purified by flash chromatography (using MeOH in SiO2 and CH2Cl2), and then HPLC (C) was used for preparative HPLC (C) chromatography. 18 By purification using MeCN in H2O + 0.1% HCO2H, trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide, formic acid was obtained as a white solid (23 mg, yield 17% based on 99% purity). MS(ESI)m / z[M+H] + 616.43. 1H NMR(500 MHz,DMSO-d6)δ 8.57-8.68(m,1H),8.33-8.40(m,1H),8.18(d,J=10.39 Hz,1H),8.03(d,J=2.57 Hz,1H),7.82-7.91(m,1H),7.67-7.75(m,1H),7.19(t,J=7.64 Hz,1H),6.98-7.03(m,1H),6.94(br.s.,1H),3.82-3.90(m,3H),3.75(br.s.,1 H),3.50-3.58(m,3H),2.41(br.s.,6H),1.85-2.14(m,4H),1.27-1.49(m,4H). Example 11: trans-5-chloro-N-(2-cyano-3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (trans I-11) [ka] Step 1. N-(3-bromo-2-cyanophenyl)-5-chloro-N-((5-chloro-2-methoxypyridine-3-yl)sulfonyl)-2-methoxypyridine-3-sulfonamide [ka]

[0251] Solid 5-chloro-2-methoxypyridine-3-sulfonyl chloride (307 mg, 1.27 mmol) and 2-amino-6-bromobenzonitrile (250 mg, 1.27 mmol) were cooled to -78°C, and then CH2Cl2 (10 mL) and pyridine (0.51 mL, 6.3 mmol) were added. Next, the reaction mixture was removed from the cooling bath and stirred at room temperature for 2 days. Then, 5-chloro-2-methoxypyridine-3-sulfonyl chloride (307 mg, 1.27 mmol) was added at room temperature, and stirring was continued for 3 days. The reaction mixture was concentrated under reduced pressure, deposited on Celite, and purified by flash chromatography (using SiO2 and  in hexane) to obtain N-(3-bromo-2-cyanophenyl)-5-chloro-N-((5-chloro-2-methoxypyridine-3-yl)sulfonyl)-2-methoxypyridine-3-sulfonamide as a white powder (333 mg, 43%). MS(ESI)m / z[M+H] + 606.99 / 609.1. Step 2. (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-cyanophenyl)boronic acid [ka]

[0252] A solution was prepared by the general MB method using 1,4-dioxane (5 mL) containing N-(3-bromo-2-cyanophenyl)-5-chloro-N-((5-chloro-2-methoxypyridine-3-yl)sulfonyl)-2-methoxypyridine-3-sulfonamide (100 mg, 0.16 mmol), B2pin2 (63 mg, 0.25 mmol), KOAc (48 mg, 0.49 mmol), and PdCl2dppf·CH2Cl2 (13 mg, 0.016 mmol). The solution was sealed and heated in a microwave reactor at 100°C for 2 hours, followed by heating in an oil bath at 100°C for 1 day and 19 hours. The entire crude product was used in the next step. MS ESI[M+H] + 368.18. Step 3. trans-5-chloro-N-(2-cyano-3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(trans I-11)

[0253] (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-cyanophenyl)boronic acid (4.9 mL, 0.16 mmol, 5.0 mL, 0.033 M crude product in 1,4-dioxane), PdCl2dppf·CH2Cl2 (13 mg, 0.016 mmol), Cs2CO3 (266 mg, 0.81 mmol), trans-6-bromo-2-((4-(dimethylamino)cyclohexyl)amino)-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one (62 mg, 0.16 mmol), and H2O (2.5 mL) were used, and the mixture was sealed and heated in a microwave reactor at 90°C for 2 hours by conventional SMC method. It was purified by flash chromatography (using MeOH in CH2Cl2) and then purified by preparative HPLC (C 18 By re-purifying with MeCN in H2O + 0.1% HCO2H, trans-5-chloro-N-(2-cyano-3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide was obtained as a white solid (38 mg, 33%). MS(ESI)m / z[M+H] + 623.43. 1H NMR(500 MHz,DMSO-d6)δ 10.83(br.s.,0.3H),9.33(d,J=8.44 Hz,0.6H),8.64-8.75(m,1H),8.39(br.s.,1H),8.12-8.19(m,1H),7.99-8.07(m,1H),7.92(d,J=2.69 Hz,1H),7.78-7.90(m,1H),7.47(br.s.,1H),7.25(d,J=8.07 Hz,1H),3.84-3.86(m,4H),3.53-3.63(m,3H),3.09-3.25(m,1H),2.72-2.79(m,6H),1.98-2.20(m,4H),1.31-1.69(m,4H). Example 12: 5-Chloro-N-(2-fluoro-3-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-12) [ka] Step 1.6-Bromo-2-(methylamino)pyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0254] A suspension of 6-bromo-2-(methylsulfinyl)pyrido[2,3-d]pyrimidine-7(8H)-one (600 mg, 2.082 mmol) and MeNH2 (40% by weight in H2O, 3.6 mL, 42 mmol) in i-PrOH (20 mL) was prepared by standard NS method. The reaction was shaken at room temperature for 10 minutes, then stirred at room temperature for 19 hours. After that, the reaction was shaken again at room temperature for 2 hours. Filtration and rinsing with EtOH yielded 6-bromo-2-(methylamino)pyrido[2,3-d]pyrimidine-7(8H)-one as a white solid (414 mg, yield 78%). MS(ESI)m / z[M+H] + 255.10 | 257.20. Step 2.5-Chloro-N-(2-fluoro-3-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-12)

[0255] A conventional SMC (Small Mixture Cell) was prepared using H2O (5 mL) and 1,4-dioxane (10 mL) containing Cs2CO3 (644 mg, 1.98 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (261 mg, 0.72 mmol), 6-bromo-2-(methylamino)pyrido[2,3-d]pyrimidine-7(8H)-one (168 mg, 0.66 mmol), and PdCl2dppf·CH2Cl2 (54 mg, 0.066 mmol). The mixture was sealed and heated in an oil bath at 95°C for 22 hours. The crude mixture was then cooled to room temperature and partitioned into H2O and CH2Cl2. The aqueous layer was extracted twice with 2% v / v MeOH in CH2Cl2. The combined organic layers were concentrated under reduced pressure, attached to Celite, and purified by flash chromatography to obtain 5-chloro-N-(2-fluoro-3-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a white solid (62.0 mg, yield 19%). MS(ESI)m / z[M+H] + 491.27. 1 H NMR(500 MHz,DMSO-d6)δ ppm 11.82-12.11(m,1 H),10.37(br.s.,1 H),8.53-8.70(m,1 H),8.46(d,J=2.32 Hz,1 H),8.05(d,J=2.45 Hz,1 H),7.65-7.81(m,1.6 H),7.45-7.57(m,0.4 H),7.25(dt,J=14.09,6.95 Hz,2 H),7.12-7.19(m,1 H),3.89(s,3 H),2.86(d,J=4.65 Hz,3 H) Example 13: 5-Chloro-N-(4-fluoro-3-(2-(isopropylamino)-8-methyl-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-13) [ka]

[0256] To a cold (0°C) CH2Cl2 (20 mL) solution of 5-chloro-N-(4-fluoro-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (129 mg, 0.25 mmol), mCPBA (64 mg, 0.26 mmol) in CH2Cl2 (1-2 mL) was added, and the mixture was stirred for a total of 4 hours while slowly warming to room temperature. 50% of the crude mixture was concentrated to remove the CH2Cl2. The solid residue was suspended in i-PrOH (6 mL) and treated with i-PrNH2 (0.32 mL, 3.7 mmol) at room temperature. The suspension was stirred at room temperature for 1 day and 19 hours, then concentrated on Celite and subjected to preparative HPLC (C 18 By purification with MeCN in H2O + 0.1% HCO2H, 5-chloro-N-(4-fluoro-3-(2-(isopropylamino)-8-methyl-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide was obtained as an off-white solid (28 mg, 40% yield based on 94% purity). MS(ESI)m / z[M+H] + 534.53. 1 ¹H NMR (500 MHz, DMSO-d6) δ ppm 8.62-8.75 (m, 1 H), 8.46 (d, J=2.32 Hz, 1 H), 8.13 (d, J=2.45 Hz, 1 H), 7.88-8.08 (m, 1 H), 7.29 (d, J=5.75 Hz, 1 H), 7.12-7.22 (m, 2 H), 4.09-4.26 (m, 1 H), 3.95 (s, 3 H), 1.15-1.27 (m, 6 H). The N-Me signal is thought to be masked by the "H2O" peak. Example 14: 5-Chloro-N-(3-(2-(ethylamino)-8-methyl-7-oxo-7,8-dihydropteridine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide(I-14) [ka]

[0257] Using EtNH2 (66-72% in H2O), 5-chloro-N-(3-(2-(ethylamino)-8-methyl-7-oxo-7,8-dihydropteridine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide was prepared according to the same method as for 5-chloro-N-(3-(2-(ethylamino)-8-methyl-7-oxo-7,8-dihydropteridine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide was obtained as a pale yellow solid (25.0 mg, yield 40%). MS(ESI)m / z[MH] - 518.31. 1 ¹H NMR (500 MHz, DMSO-d6) δ ppm 10.55 (br.s., 1 H), 8.61-8.78 (m, 1 H), 8.47 (d, J=2.45 Hz, 1 H), 8.14 (d, J=2.57 Hz, 2 H), 7.96-8.06 (m, 1 H), 7.30 (d, J=5.99 Hz, 1 H), 7.11-7.24 (m, 2 H), 3.96 (s, 3 H), 1.06-1.29 (m, 3 H). The N-Me signal is thought to be masked by the "H2O" peak. Example 15: 5-Chloro-N-(2,4-difluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-15) [ka] Step 1. 6-(3-amino-2,6-difluorophenyl)-8-methyl-2-(methylamino)pteridine-7(8H)-one [ka]

[0258] A mixture of 2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (153 mg, 0.60 mmol), 6-bromo-8-methyl-2-(methylamino)pteridine-7(8H)-one (67.5 mg, 0.25 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (29.5 mg, 0.037 mmol), and K3PO4 (186 mg, 0.875 mmol) was suspended in 1,4-dioxane (5 mL), and then H2O (0.5 mL) was added. The vial was sealed and degassed. Next, the mixture was sealed in a microwave reactor and heated at 65°C for 5 hours. The reaction mixture was concentrated under reduced pressure, deposited on Celite, and purified by flash chromatography (using MeOH in CH2Cl2) to obtain 6-(3-amino-2,6-difluorophenyl)-8-methyl-2-(methylamino)pteridine-7(8H)-one as a pale yellow solid (67 mg, yield 84%). MS(ESI)m / z[M+H] + 319.41. Step 2.5-Chloro-N-(2,4-difluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-15)

[0259] The mixture was prepared using a standard NS method with CH2Cl2 (11 mL), 6-(3-amino-2,6-difluorophenyl)-8-methyl-2-(methylamino)pteridine-7(8H)-one (67 mg, 0.211 mmol), 5-chloro-2-methoxypyridine-3-sulfonyl chloride (56 mg, 0.23 mmol), and pyridine (0.093 mL, 1.2 mmol). After completion, the reaction mixture was concentrated under reduced pressure, attached to Celite, purified by flash chromatography (using MeOH in CH2Cl2), and then purified by preparative HPLC (C). 18 By purification with MeCN in H2O + 0.1% HCO2H, 5-chloro-N-(2,4-difluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide was obtained as a very slightly yellowish white solid (43 mg, yield 39% based on 97% purity). MS(ESI)m / z[M+H] + 524.39. 1 ¹H NMR (500 MHz, DMSO-d6) δ ppm 8.76 (s, 0.3 H), 8.68 (s, 0.7 H), 8.43-8.50 (m, 1 H), 8.16 (d, J=4.77 Hz, 1 H), 8.05 (d, J=2.57 Hz, 1 H), 7.34-7.45 (m, 1 H), 7.15 (t, J=8.80 Hz, 1 H), 3.89 (s, 3 H), 2.88-2.99 (m, 3 H). One of the N-Me signals is hidden by the solvent peak. Example 16: 5-Chloro-N-(3-(2-(ethylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide(I-16) [ka] Step 1: 6-Bromo-2-(ethylamino)-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0260] A mixture of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (300 mg, 0.94 mmol), i-PrOH (10 mL), and EtNH2 (66-72% in H2O, 1.5 mL, 19 mmol) was stirred at room temperature for 1 day. The solid was collected by filtration and rinsed with EtOH to obtain 6-bromo-2-(ethylamino)-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one as a white solid (227 mg, yield 85%). MS(ESI)m / z[M+H] + 282.94 | 284.97. Step 2.6-(3-amino-2,6-difluorophenyl)-2-(ethylamino)-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0261] The solution was prepared by conventional SMC by using 1,4-dioxane (5 mL) and H2O (0.5 mL) containing 2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (130 mg, 0.51 mmol), 6-bromo-2-(ethylamino)-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one (60 mg, 0.21 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (25 mg, 0.032 mmol) and K3PO4 (157 mg, 0.74 mmol), sealing the mixture, and heating it in a microwave reactor at 65°C for 10 hours. The reaction mixture was concentrated under reduced pressure, deposited on Celite, and purified by flash chromatography (using MeOH in CH2Cl2) to obtain 6-(3-amino-2,6-difluorophenyl)-2-(ethylamino)-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one as a pale yellowish-brown solid (83 mg, quantitative yield). MS(ESI)m / z[M+H] + 332.20 Step 3.5-Chloro-N-(3-(2-(ethylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide(I-16)

[0262] The mixture was prepared by standard NS method using CH2Cl2 (11 mL), 6-(3-amino-2,6-difluorophenyl)-2-(ethylamino)-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one (70 mg, 0.21 mmol), 5-chloro-2-methoxypyridine-3-sulfonyl chloride (56 mg, 0.23 mmol), and pyridine (0.094 mL, 1.2 mmol) at 0°C. After stirring at room temperature for 1 day and 18 hours, the reaction mixture was concentrated under reduced pressure, attached to Celite, and subjected to preparative HPLC (C). 18The solution was purified by MeCN in H2O (0.1% HCO2H) and then re-purified twice by flash chromatography (using CH2Cl2 / MeOH / concentrated NH4OH aqueous solution 89 / 10 / 1 in CH2Cl2) to obtain 5-chloro-N-(3-(2-(ethylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide as a white solid (9.0 mg, yield 8%). MS(ESI)m / z[M+H] + 537.42. 1 H NMR(500 MHz,CD3OD)δ ppm 8.40-8.50(m,1 H),8.16-8.23(m,1 H),7.95(d,J=2.57 Hz,1 H),7.62(s,1 H),7.37(td,J=8.86,5.75 Hz,1 H),6.91(td,J=8.89,1.41 Hz,1 H),3.86-3.92(m,3 H),3.51-3.66(m,3 H),3.43(d,J=6.72 Hz,2 H),1.10-1.24(m,3 H). Example 17: 5-Chloro-N-(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide(I-17) [ka] Step 1: 6-Bromo-2-(methylsulfinyl)pyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0263] A cold (0°C) CH2Cl2 (100 mL) suspension of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one (500 mg, 1.8 mmol) and mCPBA (476 mg, 1.9 mmol) was slowly warmed to room temperature and stirred for a total of 1 day and 19 hours. The product was isolated by filtration and rinsed with CH2Cl2 to obtain 6-bromo-2-(methylsulfinyl)pyrido[2,3-d]pyrimidine-7(8H)-one as a white solid (490 mg, 93%). MS(ESI)m / z[M+H] + 288.24 | 290.25 Step 2.6-Bromo-2-(ethylamino)pyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0264] 6-bromo-2-(methylsulfinyl)pyrido[2,3-d]pyrimidine-7(8H)-one (100 mg, 0.35 mmol) was added in a single dose to an i-PrOH (10 mL) suspension with EtNH2 (66-72% in H2O, 0.55 mL, 6.9 mmol). After stirring at room temperature for 21 hours, the product was collected by filtration and rinsed with EtOH to obtain 6-bromo-2-(ethylamino)pyrido[2,3-d]pyrimidine-7(8H)-one as a white solid (70 mg, yield 75%). MS(ESI)m / z[M+H] + 269.25 | 271.25. Step 3. 5-Chloro-N-(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide(I-17)

[0265] 6-Bromo-2-(ethylamino)pyrido[2,3-d]pyrimidine-7(8H)-one (60 mg, 0.22 mmol), PdCl2dppf·CH2Cl2 (21.24 mg, 0.026 mmol), Cs2CO3 (212 mg, 0.650 mmol), (5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (113 mg, 0.31 mmol), H2O (2 mL), and 1,4-dioxane (4 mL) were used, and the mixture was sealed and heated in a microwave reactor at 100°C for 2.5 hours to prepare a solution by conventional SMC method. It was purified by flash chromatography (using MeOH in CH2Cl2), and then purified by preparative HPLC (C 18 By purification with MeCN in H2O + 0.1% HCO2H, 5-chloro-N-(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide was obtained as a white solid (20.0 mg, yield 18%). MS(ESI)m / z[M+H] + 505.33. 1 ¹H NMR (500 MHz, DMSO-d6) δ ppm 11.97 (br.s., 1 H), 8.54-8.68 (m, 1 H), 8.44 (d, J=1.59 Hz, 1 H), 8.13 (d, J=1.83 Hz, 1 H), 7.76 (br.s., 0.5 H), 7.70 (s, 1 H), 7.58 (br.s., 0.5 H), 7.19 (d, J=4.28 Hz, 1 H), 7.09-7.16 (m, 1 H), 7.07 (br.s., 1 H), 3.95 (s, 3 H), 1.03-1.25 (m, 3 H). (The CH2 signal is masked by the "solvent / H2O" peak.) Example 18: 5-Chloro-N-(4-fluoro-3-(2-(isopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-18) [ka] Step 1.6-Bromo-2-(isopropylamino)pyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0266] 6-bromo-2-(methylsulfinyl)pyrido[2,3-d]pyrimidine-7(8H)-one (100 mg, 0.35 mmol) was added in a single dose of i-PrNH2 (0.60 mL, 6.9 mmol) to a suspension of i-PrOH (10 mL). After stirring at room temperature for 3 days, the product was collected by filtration and rinsed with EtOH to obtain 6-bromo-2-(isopropylamino)pyrido[2,3-d]pyrimidine-7(8H)-one as a white solid (84.0 mg, yield 85%). MS(ESI)m / z[M+H] + 283.24|285.27 Step 2.5-Chloro-N-(4-fluoro-3-(2-(isopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-18)

[0267] 6-Bromo-2-(isopropylamino)pyrido[2,3-d]pyrimidine-7(8H)-one (73 mg, 0.26 mmol), PdCl2dppf·CH2Cl2 (21 mg, 0.026 mmol), Cs2CO3 (210 mg, 0.64 mmol), and (5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (112 mg, 0.31 mmol), H2O (2 mL), and 1,4-dioxane (4 mL) were used, and the mixture was sealed and heated in a microwave reactor at 100°C for 2.5 hours by the general method of SMC. It was purified by flash chromatography (using MeOH in CH2Cl2), and then purified by preparative HPLC (C 18The compound was purified with MeCN in H2O (0.1% HCO2H) and then tritulated with MeCN to obtain 5-chloro-N-(4-fluoro-3-(2-(isopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a white solid (12.0 mg, yield 9% based on 95% purity). MS(ESI)m / z[M+H] + 519.31. 1 H NMR(500 MHz,DMSO-d6)δ ppm 11.94(br.s.,1 H),8.52-8.69(m,1 H),8.43(d,J=1.83 Hz,1 H),8.12(d,J=1.96 Hz,1 H),7.60-7.76(m,1.7 H),7.41-7.53(m,0.3 H),7.18(d,J=4.16 Hz,1 H),7.08-7.15(m,1 H),7.07(br.s.,1 H),4.14(br.s.,1 H),3.95(s,3 H),1.17(d,J=6.24 Hz,6 H). Example 19: 5-Chloro-N-(4-fluoro-3-(2-(isopropylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-19) [ka] Step 1: 6-Bromo-2-(isopropylamino)-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one

[0268] 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (300 mg, 0.94 mmol) was suspended in i-PrOH (10 mL) and i-PrNH2 (2.43 mL, 28 d mmol) was added dropwise. After stirring at room temperature for 1 day and 3 hours, the product was collected by filtration and rinsed with EtOH to obtain 6-bromo-2-(isopropylamino)-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one as a white solid (110.0 mg, yield 39%). MS(ESI)m / z[M+H] + 296.93 / 298.96. Step 2: 5-Chloro-N-(4-fluoro-3-(2-(isopropylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-19)

[0269] The solution was prepared by conventional SMC by heating at 90°C for 1.5 hours using H2O (2 mL) and 1,4-dioxane (4 mL) with 6-bromo-2-(isopropylamino)-8-methylpyridin[2,3-d]pyrimidine-7(8H)-one (77 mg, 0.26 mmol), PdCl2dppf·CH2Cl2 (21 mg, 0.026 mmol), Cs2CO3 (211 mg, 0.65 mmol), and (5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (112 mg, 0.31 mmol) in a microwave reactor. It was purified by flash chromatography (using MeOH in CH2Cl2) and then separated by preparative HPLC (C 18 By purification with MeCN in H2O + 0.1% HCO2H, 5-chloro-N-(4-fluoro-3-(2-(isopropylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide was obtained as an off-white powder (73.0 mg, yield 53%). 1¹H NMR (500 MHz, DMSO-d6) δ ppm 8.58-8.70 (m, 1 H), 8.45 (d, J=2.45 Hz, 1 H), 8.14 (d, J=2.57 Hz, 1 H), 7.83 (d, J=7.34 Hz, 0.5 H), 7.64-7.76 (m, 1.5 H), 7.20 (dd, J=6.36, 2.69 Hz, 1 H), 7.11-7.17 (m, 1 H), 7.05-7.10 (m, 1 H), 4.09-4.30 (m, 1 H), 3.86-3.98 (m, 3 H), 1.07-1.44 (m, 6 H). (CH3 signal is hidden). MS(ESI) m / z[M+H] + 533.48. Example 20: 5-Chloro-N-(2-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-20) [ka]

[0270] It was prepared by the general method of SMC by using 6-bromo-8-methyl-2-(methylamino)pteridine-7(8H)-one (67.5 mg, 0.25 mmol), Cs2CO3 (293 mg, 0.90 mmol), PdCl2dppf·CH2Cl2 (20 mg, 0.025 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (108 mg, 0.30 mmol), 1,4-dioxane (4.8 mL), and H2O (2.4 mL), sealing the mixture, and heating it in a microwave reactor at 90°C for 1.5 hours. Purification by flash chromatography (using an aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in CH2Cl2, 89 / 10 / 1) yielded 5-chloro-N-(2-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a pale yellow solid (18.0 mg, yield 14%). MS(ESI)m / z[M+H] + 506.41. 1¹H NMR (500 MHz, DMSO-d6) δ ppm 10.43 (br.s., 1 H), 8.73 (s, 0.3 H), 8.65 (s, 0.7 H), 8.46 (d, J=2.45 Hz, 1 H), 8.01-8.09 (m, 1.7 H), 7.93 (d, J=4.28 Hz, 0.3 H), 7.29-7.41 (m, 2 H), 7.14-7.27 (m, 1 H), 3.89 (s, 3 H), 2.93 (d, J=4.77 Hz, 3 H). One "Me" signal is buried in the solvent peak. Example 21: 5-Chloro-N-(3-(2-(cyclopropylamino)-8-methyl-7-oxo-7,8-dihydropteridine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide(I-21) [ka]

[0271] To a stirred suspension of 5-chloro-N-(4-fluoro-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (350 mg, 0.67 mmol) in a cold (0°C) CH2Cl2 (20 mL) solution, mCPBA (173 mg, 0.70 mmol) was added as a solid, and the mCPBA was completely transferred using CH2Cl2 (1 mL). The reaction was then stirred and slowly warmed to room temperature, and then stirred overnight at room temperature. The conversion was complete at this point, and the reaction mixture consisted of 5-chloro-N-(4-fluoro-3-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide and 5-chloro-N-(4-fluoro-3-(8-methyl-2-(methylsulfonyl)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide. The reaction mixture was divided into 6 equal parts by volume, each concentrated under reduced pressure, and without further purification, the next S N Used for Ar stepping. MS(ESI)m / z[M+H] +539.30 and 555.29.

[0272] One-sixth of the solid obtained in the mCPBA oxidation step was suspended in i-PrOH (10 mL), treated with c-PrNH2 (0.23 mL, 3.3 mmol), and then shaken at room temperature for 3 days and 22 hours. The solid was collected by filtration and rinsed with EtOH to obtain 5-chloro-N-(3-(2-(cyclopropylamino)-8-methyl-7-oxo-7,8-dihydropteridine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide as a pale yellow solid (49.3, yield 83%). MS(ESI)m / z[M+H] + 532.28. 1 1H NMR (500 MHz, DMSO-d6) δ ppm 9.99-10.94 (m, 1H), 8.62-8.80 (m, 1H), 8.41-8.50 (m, 1H), 8.17-8.33 (m, 1H), 8.02-8.15 (m, 1H), 7.29 (d, J=6.36 Hz, 1H), 7.12-7.22 (m, 2H), 3.95 (s, 3H), 2.89 (br.s., 1H), 0.76 (br.s., 2H), 0.56 (br.s., 2H). The signal corresponding to N-Me is masked by the solvent peak. Example 22: (R)-5-chloro-N-(4-fluoro-3-(8-methyl-7-oxo-2-((tetrahydrofuran-3-yl)amino)-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide((R)-I-22) [ka]

[0273] Similar to the synthesis of 5-chloro-N-(3-(2-(cyclopropylamino)-8-methyl-7-oxo-7,8-dihydropteridine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide, 1 / 6 of the mCPBA oxidation product derived from 5-chloro-N-(4-fluoro-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (350 mg, 0.669 mmol) was suspended in i-PrOH (10 mL), treated with (R)-3-aminotetrahydrofuran (0.29 mL, 3.3 mmol), and shaken at room temperature for 3 days and 22 hours. The solid was collected by filtration and rinsed with EtOH to obtain (R)-5-chloro-N-(4-fluoro-3-(8-methyl-7-oxo-2-((tetrahydrofuran-3-yl)amino)-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a pale yellow solid (46 mg, yield 73% based on 99% purity). MS(ESI)m / z[M+H] + 562.37. 1 H NMR(500 MHz,DMSO-d6)δ ppm 8.66-8.75(m,1 H),8.44(d,J=2.57 Hz,1 H),8.39(d,J=5.87 Hz,0.7 H),8.25(d,J=5.01 Hz,0.3 H),8.12(d,J=2.57 Hz,1 H),7.28(d,J=5.99 Hz,1 H),7.17(d,J=7.58 Hz,2 H),4.43-4.56(m,2 H),3.97-4.01(m,1 H),3.95(s,3 H),3.82-3.91(m,2 H),3.71-3.79(m,2 H),2.16-2.29(m,1 H), 1.88-2.03 (m, 1 H). Example 23: 5-Chloro-N-(4-fluoro-3-(8-methyl-2-(oxetane-3-ylamino)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-23) [ka]

[0274] Similar to the synthesis of 5-chloro-N-(3-(2-(cyclopropylamino)-8-methyl-7-oxo-7,8-dihydropteridine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide, 1 / 6 of the mCPBA oxidation product derived from 5-chloro-N-(4-fluoro-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (350 mg, 0.669 mmol) was suspended in i-PrOH (10 mL) and treated with 3-oxetanamine (269 mg, 3.7 mmol). The reaction mixture was shaken at room temperature for 3 days and 22 hours. The solid was collected by filtration and rinsed with EtOH to obtain 5-chloro-N-(4-fluoro-3-(8-methyl-2-(oxetane-3-ylamino)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a pale yellow solid (30.3 mg, yield 47% based on 95% purity). MS(ESI)m / z[M+H] + 548.38. 1 ¹H NMR (500 MHz, DMSO-d6) δ ppm 10.27 (br.s, 1 H), 8.73-8.85 (m, 1 H), 8.71 (s, 1 H), 8.45 (d, J=2.57 Hz, 1 H), 8.13 (d, J=2.57 Hz, 1 H), 7.29 (d, J=6.24 Hz, 1 H), 7.09-7.23 (m, 2 H), 4.94-5.12 (m, 1 H), 4.73-4.88 (m, 2 H), 4.46-4.66 (m, 2 H), 3.95 (s, 3 H). The N-Me signal is masked by the solvent peak. Example 24: 5-Chloro-N-(4-fluoro-3-(8-methyl-7-oxo-2-((tetrahydro-2H-pyran-4-yl)amino)-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-24) [ka]

[0275] Similar to the synthesis of 5-chloro-N-(3-(2-(cyclopropylamino)-8-methyl-7-oxo-7,8-dihydropteridine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide, 1 / 6 of the mCPBA oxidation product derived from 5-chloro-N-(4-fluoro-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (350 mg, 0.67 mmol) was suspended in i-PrOH (10 mL) and treated with tetrahydropyran-4-ylamine (113 mg, 1.1 mmol). The reaction mixture was shaken at room temperature for 3 days and 22 hours. The solid was collected by filtration and rinsed with EtOH to obtain 5-chloro-N-(4-fluoro-3-(8-methyl-7-oxo-2-((tetrahydro-2H-pyran-4-yl)amino)-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a pale yellow solid (39.4 mg, yield 61% based on 99% purity). MS(ESI)m / z[MH] - 574.34. 1 H NMR(500 MHz,DMSO-d6)δ ppm 9.79-10.91(m,1 H),8.62-8.77(m,1 H),8.46(d,J=2.45 Hz,1 H),8.17(d,J=7.34 Hz,0.7 H),8.13(d,J=2.57 Hz,1 H),8.05(d,J=7.83 Hz,0.3 H),7.29(d,J=5.6 Hz,1H),7.18(d,J=7.58 Hz,2 H),3.99-4.18(m,1 H),3.95(s,3 H),3.83-3.93(m,3 H),1.76-1.97(m,2 H),1.43-1.66(m,2 The H)CH and N-Me signals are masked by solvent peaks. Example 25: 5-Chloro-N-(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide(I-25) [ka] Step 1; 6-bromo-2-(ethylamino)pyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0276] 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one (800 mg, 2.9 mmol) was added as a solid to a cold (0°C) CH2Cl2 (200 mL) suspension with mCPBA (761 mg, 3.1 mmol). The reaction mixture was then stirred while slowly warming to room temperature for a total of 1 day and 19 hours. The substance was collected by filtration, and after rinsing with CH2Cl2, 6-bromo-2-(methylsulfinyl)pyrido[2,3-d]pyrimidine-7(8H)-one was obtained as a white solid (759.0 mg, yield 86% based on 96% purity). MS(ESI)m / z[M+H] + 288.13 | 290.16.

[0277] 6-Bromo-2-(methylsulfinyl)pyrido[2,3-d]pyrimidine-7(8H)-one (159 mg, 0.22 mmol) was suspended in i-PrOH (10 mL) and treated by adding EtNH2 (66-72% in H2O, 0.93 mL, 11 mmol) all at once at room temperature. The reaction mixture was stirred at room temperature for 19 hours. The precipitate was collected by filtration and rinsed with EtOH to obtain 6-bromo-2-(ethylamino)pyrido[2,3-d]pyrimidine-7(8H)-one as a white solid (128 mg, yield 86%). MS(ESI)m / z[M+H] + 269.17|271.20 Step 2: 5-Chloro-N-(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide(I-25)

[0278] A conventional SMC (Small Molten Metal) was prepared using H2O (5 mL) and 1,4-dioxane (10 mL) containing Cs2CO3 (465 mg, 1.427 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (171 mg, 0.48 mmol), 6-bromo-2-(ethylamino)pyrido[2,3-d]pyrimidine-7(8H)-one (128 mg, 0.48 mmol), and PdCl2dppf·CH2Cl2 (39 mg, 0.048 mmol). The mixture was sealed and heated in an oil bath at 95°C for 23 hours. The reaction mixture was cooled to room temperature and partitioned into H2O and CH2Cl2. The aqueous layer was extracted twice with CH2Cl2 containing a small amount of MeOH. The combined organic layers were concentrated under reduced pressure, attached to Celite, and purified by flash chromatography (using MeOH|CH2Cl2|concentrated NH4OH aqueous solution 89:10:1) to obtain 5-chloro-N-(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide as a white solid (60.0 mg, yield 25%). MS(ESI)m / z[M+H] + 505.29. 1 H NMR(500 MHz,DMSO-d6)δ ppm 1.07-1.17(m,3 H)3.35(br d,J=5.50 Hz,2 H)3.88(s,3 H)7.11-7.18(m,1 H)7.19-7.29(m,2 H)7.51-7.63(m,0.3 H)7.69(s,1 H)7.73-7.85(m,1 H)7.98-8.15(m,0.7 H)8.46(d,J=2.45 Hz,1 H)8.51-8.70(m,1 H)10.25-10.47(m,1 H)11.82-12.05(m,1 H). Example 26: 5-Chloro-N-(4-fluoro-3-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-26) [ka]

[0279] A conventional SMC (Surface Mixture) was prepared by heating a sealed microwave reactor at 100°C for 4 hours using 6-bromo-2-(methylamino)pyrido[2,3-d]pyrimidine-7(8H)-one (120 mg, 0.47 mmol), PdCl2dppf·CH2Cl2 (38 mg, 0.047 mmol), Cs2CO3 (383 mg, 1.2 mmol), and (5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (204 mg, 0.56 mmol). The reaction mixture was partitioned into H2O and CH2Cl2. The aqueous layer was extracted twice with CH2Cl2 containing a small amount of MeOH. The combined organic layers were concentrated under reduced pressure, attached to Celite, and purified by flash chromatography (using MeOH|CH2Cl2|concentrated NH4OH aqueous solution 89:10:1) to obtain 5-chloro-N-(4-fluoro-3-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a white solid (129.0 mg, yield 56%). MS(ESI)m / z[M+H] + 491.35. 1 H NMR(500 MHz,DMSO-d6)δ ppm 11.78-12.17(m,1 H),10.23-10.72(m,1 H),8.53-8.68(m,1 H),8.45(d,J=2.4 Hz),8.14(d,J=2.4 Hz,1 H),7.66-7.75(m,1.7 H),7.50(br s,0.3 H),7.20(dd,J=6.24,2.32 Hz,1 H),7.11-7.16(m,1 H),7.05-7.10(m,1 H),3.96(s,3 H),2.83-2.88(m,3 H). Example 27: 5-Chloro-N-(4-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-27) [ka] Step 1: 6-Bromo-8-methyl-2-(methylamino)pyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0280] 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (500 mg, 1.57 mmol) was suspended in i-PrOH (17 mL), to which MeNH2 (40 wt% in H2O, 3.4 mL, 39 mmol) was added at room temperature. The reaction mixture was shaken at room temperature for 6 days and 23 hours. The precipitate was collected by filtration and rinsed with i-PrOH to obtain 6-bromo-8-methyl-2-(methylamino)pyrido[2,3-d]pyrimidine-7(8H)-one as a white solid (345.0 mg, yield 82%). MS(ESI)m / z[M+H] + 269.24 | 271.20. Step 2: 5-Chloro-N-(4-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-27)

[0281] A conventional SMC (Small Molten Metal) was prepared by heating a sealed microwave reactor at 90°C for 3 hours using 1,4-dioxane (4 mL) and H2O (2 mL) containing 6-bromo-8-methyl-2-(methylamino)pyrido[2,3-d]pyrimidine-7(8H)-one (100 mg, 0.37 mmol), (5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (147 mg, 0.41 mmol), Cs2CO3 (303 mg, 0.93 mmol), and PdCl2dppf·CH2Cl2 (15 mg, 0.019 mmol). The reaction mixture was cooled to room temperature, diluted with H2O (30 mL), and treated with 1 M aqueous HCl (1 mL). The solid was collected by filtration, and the filtration cake was rinsed with H2O. The beige precipitate was dissolved in CH2Cl2 / MeOH, dried on Celite, and purified by flash chromatography (using CH2Cl2 / MeOH / concentrated NH4OH aqueous solution 89 / 10 / 1 in CH2Cl2) to obtain 5-chloro-N-(4-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as an off-white solid (75.0 mg, 40%). MS(ESI)m / z[M+H] + 505.34. 1 ¹H NMR (500 MHz, DMSO-d6) δ ppm 10.10-10.81 (m, 1 H), 8.57-8.72 (m, 1 H), 8.46 (d, J=2.45 Hz, 1 H), 8.15 (d, J=2.45 Hz, 1 H), 7.84 (d, J=4.40 Hz, 0.7 H), 7.70-7.78 (m, 1.3 H), 7.21 (d, J=4.03 Hz, 1 H), 7.13-7.18 (m, 1 H), 7.05-7.11 (m, 1 H), 3.96 (s, 3 H), 2.92 (d, J=4.52 Hz, 3 H). One of the signals corresponding to Me is masked by a solvent peak. Example 28: 5-Chloro-N-(2-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-28) [ka]

[0282] A conventional SMC (Surface Molten Metal) was prepared by heating 1,4-dioxane (4 mL) and H2O (2 mL) with 6-bromo-8-methyl-2-(methylamino)pyrido[2,3-d]pyrimidine-7(8H)-one (100 mg, 0.37 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (134 mg, 0.37 mmol), Cs2CO3 (303 mg, 0.93 mmol), and PdCl2dppf·CH2Cl2 (15 mg, 0.019 mmol) in a microwave reactor at 90°C for 3 hours. The reaction mixture was diluted with H2O (30 mL) and treated with 1 M aqueous HCl (1 mL). The solid was collected by filtration, and the filtration cake was rinsed with H2O. The beige precipitate was redissolved in CH2Cl2 / MeOH, dried on Celite, and purified by flash chromatography (using CH2Cl2 / MeOH / concentrated NH4OH aqueous solution 89 / 10 / 1 in CH2Cl2) to obtain 5-chloro-N-(2-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a white solid (70.0 mg, 37%). MS(ESI)m / z[M+H] + 505.34. 1¹H NMR (500 MHz, DMSO-d6) δ ppm 10.25-10.49 (m, 1 H), 8.56-8.76 (m, 1 H), 8.46 (d, J=2.32 Hz, 1 H), 8.06 (d, J=2.57 Hz, 1 H), 7.83 (d, J=4.28 Hz, 0.7 H), 7.68-7.77 (m, 1.3 H), 7.19-7.30 (m, 2 H), 7.13-7.19 (m, 1 H), 3.89 (s, 3 H), 2.92 (d, J=4.40 Hz, 3 H). One of the Me signals is masked by a solvent peak. Example 29: N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide(I-29) [ka] Step 1: 2-amino-6-bromo-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one

[0283] 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (511 mg, 1.61 mmol) was suspended in i-PrOH (15 mL) and NH3 (7N in MeOH, 4.6 mL, 32 mmol) was added at room temperature. The mixture was stirred at room temperature for 1.2 hours. The reaction mixture was diluted with 1 M KOH aqueous solution (10 mL, 10 mmol), shaken for several minutes, and left at room temperature overnight. The yellow precipitate was collected by filtration and rinsed with H2O to obtain 2-amino-6-bromo-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one as a yellow solid (189.0 mg, 44%). MS(ESI)m / z[M+H] + 255.10 | 257.13. Step 2: N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide(I-29)

[0284] (5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (85 mg, 0.23 mmol), 2-amino-6-bromo-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one (60 mg, 0.23 mmol), Cs2CO3 (192 mg, 0.59 mmol), and PdCl2dppf (17 mg, 0.024 mmol) were used in H2O (2 mL) and 1,4-dioxane (4 mL), and the mixture was heated in a microwave reactor at 90°C for 2 hours using the general method of SMC. 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 CH2Cl2 (89 / 10 / 1) to obtain N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide as a white solid (48 mg, yield 42%). MS(ESI)m / z[M+H] + 491.20. 1 ¹H NMR (500 MHz, DMSO-d6) δ ppm 10.38 (br.s, 1 H), 8.62 (s, 1 H), 8.45 (d, J=2.57 Hz, 1 H), 8.14 (d, J=2.57 Hz, 1 H), 7.74 (s, 1 H), 7.35 (s, 2 H), 7.19 (dd, J=6.36, 2.57 Hz, 1 H), 7.10-7.17 (m, 1 H), 7.04-7.10 (m, 1 H), 3.95 (s, 3 H). The signal corresponding to "N-Me" appears to be obscured by the "DMSO" peak. Example 30: N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide(I-30) [ka]

[0285] A conventional SMC (Surface Microwave Concentrate) was prepared by heating in a microwave reactor at 90°C for 2 hours in a sealed container using 2 mL of H2O and 4 mL of 1,4-dioxane, containing 2-amino-6-bromo-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one (60 mg, 0.23 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (85 mg, 0.23 mmol), Cs2CO3 (192 mg, 0.59 mmol), and PdCl2dppf (17 mg, 0.024 mmol). The reaction mixture was concentrated under reduced pressure, deposited on Celite, and purified by flash chromatography (using a 12 g SiO2RediSep GOLD® cartridge with CH2Cl2 / MeOH / concentrated NH4OH aqueous solution 89 / 10 / 1 in CH2Cl2). Subsequently, the collected solid was dissolved in MeOH, filtered through Waters PoraPak CX, rinsed with MeOH, and eluted with 1.4 M NH3 in MeOH to obtain N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide as a white solid (33.4 mg, yield 29%). MS(ESI)m / z[M+H] + 491.20. 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.35(br.s.,1 H),8.62(s,1 H),8.48(d,J=1.83 Hz,1 H),8.06(d,J=2.57 Hz,1 H),7.66-7.80(m,1 H),7.38(s,2 H),7.05-7.30(m,3 H),3.82-3.98(m,3 H),3.49-3.58(m,3 H). Example 31: 5-Chloro-N-(5-fluoro-4-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)pyridine-2-yl)-2-methoxypyridine-3-sulfonamide (I-31) [ka] Step 1: 5-Chloro-N-(5-fluoro-4-iodopyridine-2-yl)-2-methoxypyridine-3-sulfonamide [ka]

[0286] 5-Fluoro-4-iodopyridine-2-amine (0.70 g, 2.9 mmol) was added to anhydrous pyridine (7 mL) at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. Then, 5-chloro-2-methoxypyridine-3-sulfonyl chloride (0.70 g, 2.9 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. A single dose of 5-chloro-2-methoxypyridine-3-sulfonyl chloride (1 equivalent) was added at 0°C, and stirring was continued at room temperature for 16 hours. Next, the reaction mixture was diluted with 10% citric acid solution (40 mL) and extracted with siRNA (50 mL x 3). The combined organic layer was dried (anhydrous Na2SO4) and concentrated under reduced pressure. Purification by column chromatography using siRNA in hexane yielded 5-chloro-N-(5-fluoro-4-iodopyridine-2-yl)-2-methoxypyridine-3-sulfonamide as a white solid (0.70 g, 55%). 1 H NMR(400 MHz,DMSO-d6)δ 11.47(s,1H),8.49(d,J=2.0 Hz,1H),8.25(d,J=2.0 Hz,1H),8.07(s,1H),7.49(d,J=3.6 Hz,1H),3.88(s,3H).MS(ESI)m / z [M+H] + 443.9. Step 2: (8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)boronic acid [ka]

[0287] The reaction was prepared by the standard MB method using 6-bromo-8-methyl-2-(methylamino)pyrido[2,3-d]pyrimidine-7(8H)-one (140 mg, 0.52 mmol), B2pin2 (396 mg, 1.56 mmol), KOAc (179 mg, 1.82 mmol), and PdCl2dppf (38 mg, 0.052 mmol) in anhydrous 1,4-dioxane (10 mL), and heated in an oil bath at 100°C for 4 hours. The crude reaction mixture (0.052 M) was used directly in the next step. MS(ESI)m / z[M+H] + 235.23. Step 3: 5-Chloro-N-(5-fluoro-4-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)pyridine-2-yl)-2-methoxypyridine-3-sulfonamide(I-31)

[0288] 5-chloro-N-(5-fluoro-4-iodopyridine-2-yl)-2-methoxypyridine-3-sulfonamide (80 mg, 0.18 mmol), PdCl2dppf (13.2 mg, 0.018 mmol), and Cs2CO3 (176 mg, 0.54 mmol) in H2O (2.1 mL), along with crude (8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)boronic acid (4.2 mL, 0.22 mmol, 0.052 M in 1,4-dioxane), were used, sealed, and heated in a microwave reactor at 65°C for 3 hours, followed by heating at 90°C for 3 hours, to prepare the solution using the standard SMC method. 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 (89 / 10 / 1) in CH2Cl2. The resulting solid was triturated with Et2O to obtain 5-chloro-N-(5-fluoro-4-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)pyridine-2-yl)-2-methoxypyridine-3-sulfonamide as an off-white solid (13.4 mg, yield 15%). MS(ESI)m / z[M+H] + 506.17.1 H NMR(500 MHz,DMSO-d6)δ ppm 11.37(br.s.,1 H),8.59-8.80(m,1 H),8.50(d,J=2.32 Hz,1 H),8.28(d,J=2.57 Hz,1 H),8.19(s,1 H),8.02(d,J=4.77 Hz,0.65 H),7.99(s,1 H),7.91(d,J=4.52 Hz,0.35 H),7.24(br.s.,1 H),3.90(s,3 H),3.61(s,2 H),3.53(s,1 H),2.86-2.96(m,3 H). Example 32: 5-Chloro-N-(3-fluoro-4-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)pyridine-2-yl)-2-methoxypyridine-3-sulfonamide(I-32) [ka] Step 1: 5-Chloro-N-(3-fluoro-4-iodopyridine-2-yl)-2-methoxypyridine-3-sulfonamide [ka]

[0289] To a cooled solution of t-BuOK (0.7 g, 6.3 mmol) in THF (5 mL), 3-fluoro-4-iodopyridine-2-amine (0.50 g, 2.1 mmol) was added at 0°C. After stirring at room temperature for 1 hour, 5-chloro-2-methoxypyridine-3-sulfonyl chloride (0.51 g, 2.1 mmol) was added at 0°C. After stirring at room temperature for 4 hours, the reaction mixture was diluted with H2O (5 mL) and extracted with siRNA (10 mL x 3). The combined organic layer was dried (anhydrous Na2SO4) and concentrated under reduced pressure. Purification by column chromatography using hexanes and siRNA yielded 5-chloro-N-(3-fluoro-4-iodopyridine-2-yl)-2-methoxypyridine-3-sulfonamide as a white solid (0.3 g, 33%). 1H NMR(400 MHz,DMSO-d6)δ 11.58(br.s.,1H),8.48(s,1H),8.22(s,1H),7.60(s,1H),7.48(br.s.,1H),3.86(s,3H).MS(ESI)m / z [M+H] + 444.1. Step 2: (2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)boronic acid [ka]

[0290] A crude mixture was prepared by the standard MB method using 6-bromo-2-(methylamino)pyrido[2,3-d]pyrimidine-7(8H)-one (150 mg, 0.59 mmol), B2pin2 (224 mg, 0.88 mmol), KOAc (202 mg, 2.06 mmol), and PdCl2dppf (55.9 mg, 0.076 mmol) in an anhydrous 1,4-dioxane (24 mL), by heating in an oil bath at 105°C for 1 day and 19 hours. The crude mixture was estimated to be 84% (2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)boronic acid. The reaction mixture was used as is in the next step. MS(ESI)m / z[M+H] + 221.24. Step 3: 5-Chloro-N-(3-fluoro-4-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)pyridine-2-yl)-2-methoxypyridine-3-sulfonamide(I-32)

[0291] 5-chloro-N-(3-fluoro-4-iodopyridine-2-yl)-2-methoxypyridine-3-sulfonamide (80 mg, 0.18 mmol), PdCl2dppf (13 mg, 0.018 mmol), and Cs2CO3 (176 mg, 0.54 mmol) in H2O (4.3 mL), along with crude (2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)boronic acid (8.7 mL, 0.22 mmol) in 1,4-dioxane, were sealed and heated in a microwave reactor at 60°C for 2.5 hours, followed by heating at 100°C for 2 hours, to prepare the product by the general method of SMC. A brown solid obtained by purifying an aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in CH2Cl2 from 0 to 100% using flash chromatography with MeOH in CH2Cl2 was triturated with Et2O, and then triturated multiple times with MeCN until 5-chloro-N-(3-fluoro-4-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)pyridine-2-yl)-2-methoxypyridine-3-sulfonamide was obtained as a gray solid (30.0 mg, 33% based on 97% purity). MS(ESI)m / z[M+H] + 492.22. 1 H NMR(500 MHz,DMSO-d6)δ ppm 11.97-12.32(m,1 H),8.54-8.76(m,1 H),8.45(br.s.,1 H),8.22(br.s.,1 H),7.96(br.s.,1 H),7.87(br.s.,1.5 H),7.56-7.72(m,0.5 H),6.84-7.30(m,2 H),3.74-4.03(br.s.,3 H),2.81-2.96(m,3 H). Example 33: (trans-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide (trans I-33) [ka] Step 1: trans-4-aminocyclohexane-1-carboxamide*trifluoroacetic acid [ka]

[0292] A mixture of TBTU (693 mg, 2.2 mmol), trans-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (500 mg, 2.0 mmol), and DIPEA (1.1 mL, 6.2 mmol) in DMF (3 mL) was stirred at room temperature for 30 minutes, after which NH4Cl (220 mg, 4.1 mmol) was added as a solid. The reaction was mixed overnight at room temperature, then diluted with Et2O and washed with 0.1 M aqueous HCl. The organic layer was separated and concentrated under reduced pressure to obtain a white solid (100 mg). An additional crop of this white solid was collected by filtration of the aqueous layer. The filtered cake was rinsed with an excess of H2O. The two crops were combined to obtain tert-butyl(trans-4-carbamoylcyclohexyl)carbamate (476.0 mg, 96%). The entire substance was stirred in CH2Cl2 (5 mL) and TFA (0.16 mL, 2.0 mmol) at room temperature for 1 day and 18 hours. The reaction mixture was then concentrated under reduced pressure and dried under vacuum to obtain trans 4-aminocyclohexane-1-carboxamide*trifluoroacetic acid as a pale yellow gum (505 mg, 96%), which was used directly in the next step. Step 2: trans 4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide [ka]

[0293] A mixture of trans-4-aminocyclohexane-1-carboxamide*trifluoroacetic acid (168 mg, 0.66 mmol) and K2CO3 (453 mg, 3.3 mmol) in DMF (4 mL) was stirred at room temperature for 0.2 hours. 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (217 mg, 0.68 mmol) was added all at once, and stirring was continued at room temperature for 2.5 hours before H2O (4 mL) was added. The solvent was removed under reduced pressure, the residue was redissolved in MeOH, and attached to Celite. Purification was performed by flash chromatography using an aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in CH2Cl2 (89 / 10 / 1) followed by MeOH in CH2Cl2, yielding trans-4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide as an off-white solid (216 mg, purity 77%). MS(ESI)m / z[M+H] + 380.20 | 382.16 Step 3: trans-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide(trans I-33)

[0294] (5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (80 mg, 0.22 mmol), Cs2CO3 (180 mg, 0.55 mmol), trans-4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide (109 mg, 0.22 mmol, 77%) and PdCl2dppf (16 mg, 0.022 mmol) in 1,4-dioxane (4 ml) and H2O (2 ml) were prepared by the general method of SMC by heating in a microwave reactor at 90°C for 2 hours in a sealed container. Trans-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide was obtained as an off-white solid (38.0 mg, yield 28% based on 99.7% purity). MS(ESI)m / z[M+H] + 616.21. 1 H NMR(500 MHz,DMSO-d6)δ=10.58-10.36(m,1H),8.70-8.59(m,1H),8.47(d,J=2.4 Hz,1H),8.16(d,J=2.4 Hz,1H),7.91(br d,J=7.7 Hz,1H),7.79-7.71(m,1H),7.25-7.18(m,2H),7.18-7.12(m,1H),7.11-7.05(m,1H),6.72-6.64( m,1H),,3.96(s,3H),3.90-3.73(m,1H),3.60-3.51(m,3H),2.14-1.74(m,5H),1.54-1.21(m,4H). Example 34: cis-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide (cis I-33) [ka] Step 1: cis-4-aminocyclohexane-1-carboxamide*TFA [ka]

[0295] A mixture of TBTU (693 mg, 2.2 mmol) and cis-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (500 mg, 2.0 mmol) in DMF (3 mL) was treated with DIPEA (1.1 mL, 6.2 mmol). After stirring at room temperature for 30 minutes, NH4Cl (220 mg, 4.1 mmol) was added as a solid. The reaction was mixed overnight at room temperature, then diluted with Et2O and washed with 0.1 M aqueous HCl. The organic layer was concentrated under reduced pressure to obtain an off-white solid, which was then dissolved in CH2Cl2 (5 mL) and TFA (0.79 mL, 10 mmol) at room temperature and stirred for 1 day and 18 hours. The reaction mixture was concentrated under reduced pressure and dried under vacuum to obtain cis-4-aminocyclohexane-1-carboxamide,trifluoroacetic acid as an off-white solid (318 mg, 60%). Step 2: cis-4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide [ka]

[0296] A mixture of cis-4-aminocyclohexane-1-carboxamide*TFA (175 mg, 0.68 mmol) and K2CO3 (472 mg, 3.4 mmol) in DMF (3 mL) was shaken at room temperature for 0.2 hours, after which 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (120 mg, 0.38 mmol) was added all at once. Stirring was continued at room temperature for 2.5 hours. The mixture was then diluted with H2O and filtered to obtain cis-4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide as a white solid (109 mg, 41% based on 54% purity). MS(ESI)m / z[M+H] + 380.20 | 382.16. Step 3: cis-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide (cis I-33)

[0297] (5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (114 mg, 0.31 mmol), Cs2CO3 (233 mg, 0.72 mmol), cis-4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide (109 mg, 0.15 mmol, 54%) and PdCl2dppf (21 mg, 0.029 mmol) in 1,4-dioxane (6 mL) and H2O (3 mL) were prepared by heating at 100°C for 2.5 hours using the general method of SMC. By using flash chromatography with an aqueous CH2Cl2 / MeOH / concentrated NH4OH solution (89 / 10 / 1) in CH2Cl2, cis-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide was obtained as a beige solid (42.0 mg, yield 42% based on 97% purity). MS(ESI)m / z[M+H] + 616.29. 1 H NMR(500 MHz,DMSO-d6)δ=10.64-10.34(m,1H),8.69-8.62(m,1H),8.48(d,J=2.4 Hz,1H),8.19-8.14(m,1H),7.91-7.84(m,1H),7.75(br s,1H),7.24-7.12(m,3H),7.11-7.04(m,1H),6.76-6.64(m,1H),4.08-3.9 8(m,1H),3.96(s,3H),3.56(s,3H),,2.26-2.17(m,1H),1.98-1.46(m,8H). Example 35: trans-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide (trans I-34) [ka] Step 1: trans-4-amino-N-methylcyclohexane-1-carboxamide, trifluoroacetic acid [ka]

[0298] A suspension of TBTU (693 mg, 2.2 mmol) and trans-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (500 mg, 2.0 mmol) in DMF (3 mL) was treated with DIPEA (1.074 mL, 6.17 mmol). After stirring at room temperature for 10 minutes, MeNH2*HCl (166 mg, 2.5 mmol) was added as a solid. The reaction was shaken for 30 minutes, then stirred at room temperature for 2 days. The reaction was then diluted with Et2O and washed with 0.1 M aqueous HCl. The organic layer was concentrated under reduced pressure. The off-white solid of the additional crop was collected by filtration of the aqueous layer. The filtered solid was rinsed with an excess of H2O and dried together with the substance obtained from the Et2O layer to obtain tert-butyltrans-4-(methylcarbamoyl)cyclohexyl)carbamate as a white solid (417 mg, 79% yield). MS(ESI)m / z[M+H] + 257.36. The entire substance was stirred at room temperature for 2 days in CH2Cl2 (5 mL) and TFA (0.71 mL, 9.2 mmol) . The reaction was concentrated under reduced pressure. The substance was sonicated with Et2O (5 mL), allowed to stand overnight at room temperature, and then filtered. Trans-4-amino-N-methylcyclohexane-1-carboxamide,trifluoroacetic acid was obtained as a white solid (370.0 mg, 67%) by rinsing the filtered cake with an excess amount of Et2O. MS(ESI)m / z[M+H] + 157.33. Step 2: trans-4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide [ka]

[0299] A mixture of trans-4-amino-N-methylcyclohexane-1-carboxamide, trifluoroacetic acid (0.102 g, 0.38 mmol) and K2CO3 (0.217 g, 1.6 mmol) in DMF (5 mL) was shaken at room temperature for 30 minutes, after which 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (0.100 g, 0.31 mmol) was added all at once. The reaction mixture was then shaken for 2 hours, and then stirred at room temperature for 5 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 CH2Cl2 (89 / 10 / 1) to obtain trans-4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide as a white solid (39.0 mg, yield 32%). MS(ESI)m / z[M+H] + 394.20 | 396.23. Step 3: trans-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide (trans I-34)

[0300] (5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (46.4 mg, 0.13 mmol), Cs2CO3 (81 mg, 0.25 mmol), trans-4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide (39 mg, 0.099 mmol), and PdCl2dppf (7 mg, 0.010 mmol) were degassed with an Ar stream in 1,4-dioxane (6 mL) and H2O (3 mL). The reaction was then heated at 100 °C for 2.1 hours. The reaction mixture was concentrated under reduced pressure, deposited on Celite, and purified by flash chromatography using u CH2Cl2 / MeOH / concentrated NH4OH aqueous solution 89 / 10 / 1 in CH2Cl2 to obtain trans-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide (29 mg, yield 46% based on 98% purity) as a white solid. MS(ESI)m / z[M+H] + 630.28. 1 H NMR(500 MHz,DMSO-d6)δ=10.62-10.37(m,1H),8.70-8.61(m,1H),8.48(d,J=2.4 Hz,1H),8.16(d,J=2.6 Hz,1H),7.91(br d,J=7.6 Hz,1H),7.79-7.72(m,1H),7.68(br s,1H),,7.25-7.19(m,1H),7.18-7.12(m,1H),7.11-7.04(m,1H),3.96(s,3H),3.90-3.72(m,1H),3.63-3.50(m,3H),2.57(br d,J=4.3 Hz,3H),2.14-1.88(m,3H),1.86-1.72(m,2H),1.58-1.40(m,2H),1.38-1.22(m,2H). Example 36: (cis-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide (cis I-34) [ka] Step 1: cis-4-amino-N-methylcyclohexane-1-carboxamide, trifluoroacetic acid [ka]

[0301] A suspension of TBTU (693 mg, 2.2 mmol) and cis-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (500 mg, 2.0 mmol) in DMF (3 mL) was treated with DIPEA (1.1 mL, 6.2 mmol). After stirring at room temperature for 10 minutes, MeNH2*HCl (166 mg, 2.5 mmol) was added as a solid. The reaction mixture was shaken at room temperature for 30 minutes, then stirred overnight at room temperature, diluted with Et2O, and subsequently washed with 0.1 M aqueous HCl. The organic layer was concentrated under reduced pressure to obtain tert-butyl(cis-4-(methylcarbamoyl)cyclohexyl)carbamate as a pale yellow oil (640.0 mg). The entire substance was stirred overnight at room temperature in CH2Cl2 (5 mL) and TFA (0.71 mL, 9.2 mmol). The reaction solution was concentrated under reduced pressure, and the resulting white solid was dried for a short time under high vacuum. The solid was then suspended in Et2O (5 mL) using sonication. The mixture was aged overnight at room temperature, and the white precipitate was collected by filtration. The filtered cake was rinsed with an excess amount of Et2O to obtain cis-4-amino-N-methylcyclohexane-1-carboxamide,trifluoroacetic acid as a colorless gum (472.0 mg, 85%). Step 2: cis-4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide [ka]

[0302] cis-4-amino-N-methylcyclohexane-1-carboxamide, trifluoroacetic acid (0.102 g, 0.38 mmol) and K2CO3 (0.22 g, 1.6 mmol) were shaken in DMF (5 mL) at room temperature for 30 minutes. 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (0.100 g, 0.31 mmol) was added all at once, and shaking was continued at room temperature for a further 2 hours. Next, the reaction mixture was stirred overnight at room temperature, concentrated under reduced pressure, and deposited on Celite. Purification was then performed by flash chromatography using an aqueous CH2Cl2 / MeOH / concentrated NH4OH solution (89 / 10 / 1) in CH2Cl2 to obtain (1S,4S)-4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide as an off-white solid (49.0 mg, yield 38% based on 96% purity). MS(ESI)m / z[M+H] + 394.20 | 396.23. Step 3: (cis-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide (cis I-34)

[0303] (5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (56 mg, 0.15 mmol), Cs2CO3 (97 mg, 0.30 mmol), (cis 4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide (49 mg, 0.12 mmol), and PdCl2dppf (8.7 mg, 0.012 mmol) were used in 1,4-dioxane (6 mL) and H2O (3 mL), and the solution was prepared according to the general SMC method by heating at 100°C for 2 hours under Ar. CH2Cl2 / MeOH / concentrated NH4OH aqueous solution 89 / 10 / 1 was used. By purification by flash chromatography, (cis-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide was obtained as an off-white solid (41 mg, yield 53% based on 98% purity). MS(ESI)m / z[M+H] + 630.21. 1 H NMR(500 MHz,DMSO-d6)δ=10.57-10.39(m,1H),8.70-8.61(m,1H),8.48(d,J=2.4 Hz,1H),8.16(d,J=2.6 Hz,1H),7.88(br d,J=6.2 Hz,1H),7.79-7.70(m,1H),7.67-7.58(m,1H),7.24-7.19(m,1H),7.18-7.12(m,1 H),7.11-7.05(m,1H),4.10-4.00(m,1H),3.97(s,3H),3.56(s,3H),2.58(d,J=4.5 Hz,3H),2.28-2.19(m,1H),1.95-1.83(m,3H),1.82-1.72(m,1H),1.70-1.58(m,2H),1.57-1.47(m,2H). Example 37. trans-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclobutan-1-carboxamide (trans I-35) [ka] Step 1. trans-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclobutan-1-carboxamide [ka]

[0304] trans-aminocyclobutan-1-carboxylate hydrochloride (36 mg, 0.24 mmol) and 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (50 mg, 0.16 mmol) in NMP (3 mL) were treated with DIPEA (0.14 mL, 0.79 mmol) and stirred at room temperature for 2 days and 20 hours. MS(ESI)m / z[M+H] + 353.1. To the crude reaction mixture, MeNH2 (33% by weight in EtOH, 0.20 mL, 1.6 mmol) was added, and the reaction mixture was cooled to 0°C. TBTU (96 mg, 0.30 mmol) was added as a solid, and the reaction was stirred while cooling, then stirred at room temperature for a total of 1 day and 4 hours. MS(ESI)m / z[M+H] + 366.21|368.17. The reaction was diluted with H2O (6 mL) and then concentrated under reduced pressure to remove most of the volatile substances. Step 2. trans-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclobutan-1-carboxamide (trans I-35) The solution was prepared according to the general method of SMC by using 1,4-dioxane (6 mL) and H2O (3 mL), along with the crude (1r,3r)-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclobutan-1-carboxamide in 2 mL of NMP from the previous step, PdCl2dppf (11 mg, 0.016 mmol), Cs2CO3 (154 mg, 0.47 mmol), and (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (79 mg, 0.22 mmol), sealing the mixture and heating it at 90°C for 20 hours. Trans-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclobutan-1-carboxamide was obtained as a pale yellow solid (30.0 mg, yield 31% based on 97% purity). MS(ESI)m / z[M+H] + 602.29. 1 H NMR(500 MHz,DMSO-d6)δ ppm 10.37(br.s.,1 H),8.60-8.68(m,1 H),8.49(d,J=2.69 Hz,1 H),8.30(d,J=6.85 Hz,0.7 H),8.16(d,J=7.46 Hz,0.3 H),8.07(d,J=2.57 Hz,1 H),7.70-7.77(m,2 H),7.13-7.31(m,3 H),3.90(s,3 H),3.50-3.58(m,3 H),3.29-3.34(m,1 H),2.83-2.96(m,1 H),2.60(d,J=4.65 Hz,3 H),2.16-2.30(m,3 H), 1.83-1.98 (m, 1 H). Example 38. rac-(1R,3S)-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide((rac-(1R,3S)I-36) [ka] Step 1. rac-(1R,3S)-3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid [ka]

[0305] A mixture of cis-3-aminocyclohexanecarboxylic acid (500 mg, 3.5 mmol), di-tert-butyl dicarbonate (915 mg, 4.2 mmol), and NaHCO3 (880 mg, 10 mmol) in THF (6 mL) and H2O (6 mL) was stirred at 0°C and slowly warmed to room temperature. The reaction was then suspended and stirred at room temperature for 1 day and 18 hours. The reaction was then extracted with Et2O. The aqueous layer was carefully acidified to pH 4-5 with 1 M citric acid solution, resulting in a white precipitate, which was collected by filtration. The solid was rinsed with a small amount of Et2O and then dried to obtain rac-(1R,3S)-3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid as a white solid (783.0 mg, 93%). MS(ESI)m / z[M+H] + 244.27 Step 2. rac-(1R,3S)-3-amino-N-methylcyclohexane-1-carboxamide, TFA [ka]

[0306] rac-(1R,3S)-3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (200 mg, 0.82 mmol) and TBTU (317 mg, 0.99 mmol) were suspended in CH2Cl2 (10 mL) using sonication. DIPEA (0.29 mL, 1.6 mmol) was added, and the reaction was shaken at room temperature for several minutes. Then, MeNH2 (33 wt% in EtOH, 0.31 mL, 2.5 mmol) was added all at once at room temperature. Shaking was continued at room temperature for 1.5 hours. Crude rac-tert-butyl((1R,3S)-3-(methylcarbamoyl)cyclohexyl)carbamate was obtained by evaporating volatile substances under reduced pressure. MS(ESI)m / z[M+H] + 257.29.

[0307] Next, the entire residue was shaken at room temperature for 1.5 hours with CH2Cl2 (6 mL) and TFA (1.0 mL, 13 mmol). The reaction mixture was then aged overnight at -20°C. Crude rac-(1R,3S)-3-amino-N-methylcyclohexane-1-carboxamide,TFA was obtained as a colorless gum-like substance by concentration under reduced pressure and drying under vacuum, and this was used in the next step without further purification. Step 3. rac-(1R,3S)-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide((rac-(1R,3S)I-36)

[0308] K2CO3 (373 mg, 2.7 mmol) and crude rac-(1R,3S)-3-amino-N-methylcyclohexane-1-carboxamide TFA (73 mg, 0.27 mmol) were shaken in NMP (1.5 mL) at room temperature for 10 minutes, and then 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (95 mg, 0.297 mmol)) was added as a solid at room temperature. The mixture was stirred overnight (3 days and 20 hours) at room temperature. After the reaction was complete, the entire crude substance containing rac-(1R,3S)-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide was mixed with MeOH and concentrated under reduced pressure. MS(ESI)m / z[M+H] + 394.27 | 396.23.

[0309] Next, using Pd(dppf)Cl2 (19.79 mg, 0.027 mmol), Cs2CO3 (264 mg, 0.810 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (136 mg, 0.38 mmol), H2O (3 mL), and 1,4-dioxane (6 mL), the entirety of crude rac-(1R,3S)-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide in the residual NMP was used according to the general method SMC. The solution was purified by flash chromatography (using an aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in SiO2, CH2Cl2, 89 / 10 / 1). The collected solid was triturated with Et2O using sonication to obtain rac-(1R,3S)-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide as a white solid (10.4 mg, 6% based on 95% purity). The yield is reported for all steps combined from rac-(1R,3S)-3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid. MS(ESI)m / z[M+H] + 630.43

[0310] 1 H NMR(500 MHz,DMSO)δ 10.36(s,1H),8.70-8.59(m,1H),8.47(s,1H),8.07(d,J=2.4 Hz,1H),7.95(d,J=7.8 Hz,0.6H),7.82(d,J=7.3 Hz,0.4 H),7.76-7.68(m,2H),7.32-7.09(m,3H),3.98-3.82(m,4H),3.59-3.50(m,3H),2.58-2 .54(m,3H),2.31-2.21(m,1H),2.02-1.75(m,2H),1.75-1.65(m,1H),1.48-1.18(m,5H). Example 39. rac-(1R,3R)-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide((rac-(1R,3R)I-36) [ka] Step 1. rac-(1R,3R)-3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid [ka]

[0311] A mixture of di-tert-butyl dicarbonate (729 mg, 3.3 ml), rac-(1R,3R)-3-aminocyclohexane-1-carboxylic acid hydrochloride (500 mg, 2.8 ml), and NaHCO3 (701 mg, 8.35 mmol) in THF (6 mL) and H2O (6 mL) was stirred at 0°C and slowly warmed to room temperature. The reaction was then suspended and stirred at room temperature for 1 day and 18 hours. Next, the reaction was extracted with Et2O. The aqueous layer was carefully acidified to pH 4-5 with 1 M citric acid aqueous solution and extracted with DCM (3 times). The combined organic extracts were concentrated under reduced pressure and dried to obtain rac-(1R,3R)-3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid as a white solid (138 mg, 20%). MS(ESI)m / z[M+H] + 244.27. Step 2. rac-(1R,3R)-3-amino-N-methylcyclohexane-1-carboxamide, TFA [ka]

[0312] rac-(1R,3R)-3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (138 mg, 0.57 mmol) and TBTU (219 mg, 0.68 mmol) were suspended in CH2Cl2 (6 mL) by sonication. DIPEA (0.198 mL, 1.134 mmol) was added, and the reaction was shaken at room temperature for several minutes. Then, MeNH2 (33 wt% in EtOH, 0.21 mL, 1.7 mmol) was added all at once at room temperature. Shaking was continued at room temperature for 1.5 hours. Crude rac-tert-butyl((1R,3R)-3-(methylcarbamoyl)cyclohexyl)carbamate was obtained by evaporating volatile substances under reduced pressure. MS(ESI)m / z[M+H] + 257.36.

[0313] Next, the entire residue was shaken with CH2Cl2 (6 mL) and TFA (0.7 mL, 9 mmol) at room temperature for 1.5 hours. The reaction mixture was then aged overnight at -20°C. Crude rac-(1R,3S)-3-amino-N-methylcyclohexane-1-carboxamide,TFA was obtained as a colorless gum-like substance by concentration under reduced pressure and drying under vacuum, and this was used in the next step without further purification. Step 3. rac-(1R,3R)-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide((rac-(1R,3R)I-36)

[0314] Crude rac-(1R,3S)-3-amino-N-methylcyclohexane-1-carboxamide, TFA (74 mg, 0.27 mmol) and K2CO3 (378 mg, 2.7 mmol) were shaken in NMP (1.5 mL) at room temperature for 15 minutes, and then 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (96 mg, 0.30 mmol) was added at room temperature. The mixture was stirred at room temperature for 3 days and 20 hours. The entire crude substance containing rac-(1R,3R)-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide was diluted with MeOH and concentrated under reduced pressure. MS(ESI)m / z[M+H] + 394.27|396.23. Next, using Pd(dppf)Cl2 (20 mg, 0.027 mmol), Cs2CO3 (268 mg, 0.82 mmol), and (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (138 mg, 0.38 mmol), H2O (3 mL), and 1,4-dioxane (6 mL), the entirety of crude rac-(1R,3R)-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide in the residual NMP was used according to the general method SMC. Purification by flash chromatography (using an aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in SiO2, CH2Cl2, 89 / 10 / 1) yielded rac-(1R,3R)-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide as a white solid (11.2 mg, yield 6% based on 99% purity). MS(ESI)m / z[M+H] + 630.43. 1H NMR(500 MHz,DMSO-d6)δ ppm 10.36(br.s.,1 H),8.58-8.72(m,1 H),8.48(d,J=2.69 Hz,1 H),8.07(d,J=2.57 Hz,1 H),7.79(d,J=7.21 Hz,0.6 H),7.75(s,1 H),7.67-7.59(m,0.4 H),7.53-7.60(m,1 H),7.12-7.31(m,3 H),4.14-4.33(m,1 H),3.90(s,3 H),3.55(s,3 H),2.56(d,J=4.52 Hz,3H),1.47-1.89(m,9H). Example 40. cis-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclobutan-1-carboxamide (cis-I-37) [ka] Step 1. (1S,3S)-3-aminocyclobutane-1-carboxamide, trifluoroacetic acid [ka]

[0315] A suspension of cis-3-aminocyclobutane-1-carboxylic acid (200 mg, 1.74 mmol) and Boc2O (398 mg, 1.82 mmol) in CH2Cl2 (10 mL) and DIPEA (0.91 mL, 5.21 mmol) was sonicated and then stirred at room temperature for 3 days and 21 hours. TBTU (586 mg, 1.824 mmol) was added at room temperature, and the reaction was shaken at room temperature for 5 minutes, after which 4-methoxybenzylamine (0.24 mL, 1.8 mmol) was added. Stirring at room temperature was continued for 21 hours. The white solid was collected by filtration, rinsed with DCM, and dried under vacuum to obtain tert-butyl (cis-3-((4-methoxybenzyl)carbamoyl)cyclobutyl)carbamate as a white solid (432.0 mg, yield 54% based on purity 72%). MS(ESI)m / z[M+H] + 335.37. Tert-butyl (cis-3-((4-methoxybenzyl)carbamoyl)cyclobutyl)carbamate (209 mg, 0.62 mmol) was dissolved in TFA (1.0 mL, 13.7 mmol) and stirred at room temperature for 5 days and 20 hours. The reaction mixture was then heated overnight at 60°C. The solvent was removed under reduced pressure, and then under high vacuum, leaving a reddish, rubbery substance, which was used entirely in the next step. Step 2. cis-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclobutan-1-carboxamide [ka]

[0316] A suspension of cis-3-aminocyclobutan-1-carboxamide, trifluoroacetic acid (143 mg, 0.63 mmol) (all the residue from the previous step) and K2CO3 (346 mg, 2.507 mmol) in DMF (3 mL) is shaken at room temperature for 10 minutes, then...

[0317] 6-Bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (219 mg, 0.69 mmol) was added all at once. The mixture was stirred at room temperature for 3 days and 17 hours. The reaction mixture was concentrated under reduced pressure, deposited on Celite, and purified by flash chromatography using CH2Cl2 / MeOH / concentrated NH4OH aqueous solution 89 / 10 / 1 in CH2Cl2 to obtain cis-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclobutan-1-carboxamide as a beige solid (68.0 mg, yield 30% based on 97% purity). MS(ESI)m / z[M+H] + 352.22 | 354.17. Step 3. cis-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclobutan-1-carboxamide (cis-I-37)

[0318] The following preparations were made according to the general SMC method by heating 1,4-dioxane (4 mL) and H2O (2 mL) with cis-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclobutan-1-carboxamide (68 mg, 0.18 mmol), Cs2CO3 (153 mg, 0.47 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (88 mg, 0.24 mmol), and Pd(dppf)Cl2*CH2Cl2 (15 mg, 0.019 mmol) in a microwave reactor at 100°C for 2.5 hours. Purification by flash chromatography using an aqueous CH2Cl2 / MeOH / concentrated NH4OH solution 89 / 10 / 1 in CH2Cl2 yielded (cis-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclobutan-1-carboxamide as a beige solid (42.0 mg, yield 38%). MS(ESI)m / z[M+H] + 588.38. 1 H NMR(500 MHz,DMSO)δ 8.68-8.59(m,1H),8.48(s,1H),8.23(d,J=6.3 Hz,0.7H),8.11(d,J=5.9 Hz,0.3H),8.06(s,1H),7.74(s,1H),7.31-7.20(m,3H),7.17(t,J=7.7 Hz,1H),6.76(s,1H),4.45-4.34(m,0.5H),4.33-4.24(m,1H),4.16(q,J=5.0 Hz,0.5H),3.89(s,3H),3.62-3.50(m,3H),2.78-2.62(m,1H),2.47-2.31(m,1H),2.22-2.06(m,2H). Example 41: Potassium ((5-chloro-2-methoxypyridine-3-yl)sulfonyl)(2-fluoro-3-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)amide (I-38 K salt) [ka]

[0319] 5-Chloro-N-(2-fluoro-3-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (272 mg, 0.55 mmol) was suspended in EtOH (80 mL) using sonication. KOH aqueous solution (0.5 M, 1.11 mL, 0.55 mmol) was added dropwise at room temperature. The reaction was sonicated and diluted with H2O (70 mL). After repeated short-duration sonication, excess EtOH was removed under reduced pressure, and the remaining substance was freeze-dried to obtain potassium ((5-chloro-2-methoxypyridine-3-yl)sulfonyl)(2-fluoro-3-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)amide as a pale yellow, light powder (291.0 mg, 99%). MS(ESI)m / z[M+H] + 491.4. 1 H NMR(500 MHz,DMSO-d6)δ 8.62-8.44(m,1H),8.11(s,1H),7.91(s,1H),7.59(s,1H),7.53(brs,0.7H),7.35(brs,0.3H),6.98(t,J=8.1 Hz,1H),6.69(t,J=7.6 Hz,1H),6.46(t,J=6.1 Hz,1H),3.75(s,3H),2.80(d,J=3.6 Hz,3H). 19 F NMR(471 MHz,DMSO-d6)δ-128.40,-128.53. Example 42: Potassium ((5-chloro-2-methoxypyridine-3-yl)sulfonyl)(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)amide (I-25 K salt) [ka]

[0320] 5-Chloro-N-(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide (374.6 mg, 0.742 mmol) was suspended in EtOH (110 mL) and H2O (100 mL) using sonication. A 0.5 M aqueous KOH solution (1.52 g, 0.74 mmol) was added dropwise at room temperature. After sonication, excess EtOH was removed under reduced pressure, and the aqueous sample was freeze-dried to obtain a pale yellow powder (361 mg, 89%). MS(ESI)m / z[M+H] + 505.16

[0321] 1 H NMR(500 MHz,DMSO-d6)δ 11.76(brs,1H),8.66-8.48(m,1H),8.17(s,1H),7.97(s,1H),7.64(s,1.6H),7.48(s,0.4H),7.05(t,J=7.8 Hz,1H),6.76(t,J=7.0 Hz,1H),6.54(s,1H),3.81(s,3H),1.18-1.00(m,3H). Example 43A 4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-1-fluorocyclohexane-1-carboxamide (I-39A) [(Isomer A, one of the two possible isomers, which has not yet been assigned: (1s,4s) and (1r,4r))] [ka]

[0322] Step 1. A mixture of (1s,4s)-4-amino-1-fluorocyclohexane-1-carboxamide,CF3COOH and (1r,4r)-4-amino-1-fluorocyclohexane-1-carboxamide,CF3COOH. [ka]

[0323] A mixture of TBTU (295 mg, 0.92 mmol), 4-(tert-butoxycarbonylamino)-1-fluorocyclohexanecarboxylic acid (200 mg, 0.76 mmol), and DIPEA (0.40 mL, 2.3 mmol) in DMF (4 mL) was stirred at room temperature for 10 minutes, and then NH4Cl (82 mg, 1.53 mmol) was added as a solid. The reaction was shaken at room temperature for 4.7 hours, then stirred overnight at room temperature. Subsequently, 4-methoxybenzylamine (0.10 mL, 0.76 mmol) was added at room temperature, and the reaction mixture was shaken at room temperature for 1 hour. An additional TBTU (246 mg, 0.76 mmol) was added all at once at room temperature, and stirring at room temperature was continued for 7 days. The reaction was diluted with Et2O, washed sequentially with 1 M aqueous HCl and H2O, and finally washed with saturated aqueous NaHCO3. The organic layer was separated and concentrated under reduced pressure to obtain a crude mixture (229.0 mg) of tert-butyl(4-fluoro-4-((4-methoxybenzyl)carbamoyl)cyclohexyl)carbamate and tert-butyl(4-carbamoyl-4-fluorocyclohexyl)carbamate as a pale yellow solid. The entire mixture was stirred with CH2Cl2 (6 mL) and TFA (0.94 mL, 12 mmol) at room temperature for 3 hours. Concentration of this mixture under reduced pressure yielded crude 4-amino-1-fluorocyclohexane-1-carboxamide,CF3COOH, which was used directly in the next step. MS(ESI)m / z[M+H] + 161.22.

[0324] Step 2. (1s,4s)-4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-1-fluorocyclohexane-1-carboxamide and (1r,4r)-4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-1-fluorocyclohexane-1-carboxamide [ka]

[0325] A suspension of K2CO3 (212 mg, 1.53 mmol) and 4-amino-1-fluorocyclohexane-1-carboxamide,CF3COOH (105 mg, 0.38 mmol) in DMF (3 mL) was shaken at room temperature for 10 minutes. Then, 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (128 mg, 0.40 mmol) was added all at once, and shaking was continued at room temperature for 10 minutes, followed by stirring at room temperature for 2 days and 19 hours. The reaction mixture was concentrated under reduced pressure, attached to Celite, and purified by flash chromatography (SiO2, CH2Cl2 / MeOH / concentrated NH4OH aqueous solution 89 / 10 / 1), followed by preparative HPLC (C 18 When purified with MeCN in H2O (0.1% HCO2H), two isomers ("Isomer 1" and "Isomer 2") were separated. "Isomer 1," which eluted first, was a white solid (8.0 mg, yield 5% based on 95% purity) MS(ESI) m / z[M+H]. + Assuming 398.5|400.4, and "Isomer 2" is a white solid (10 mg, yield 6% based on purity 93%) MS(ESI) m / z[M+H] + They were isolated separately as 398.5|400.4.

[0326] Step 3.4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-1-fluorocyclohexane-1-carboxamide (from "isomer 2") (I-39A)

[0327] The solution was prepared by conventional SMC by heating 1,4-dioxane (4 mL) and H2O (2 mL) containing 4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-1-fluorocyclohexane-1-carboxamide ("isomer 2", 10 mg, 95%, 0.023 mmol), Cs2CO3 (31 mg, 0.095 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (14 mg, 0.038 mmol), and PdCl2dppf*CH2Cl2 (3.9 mg, 4.8 μmol) at 100°C for 2.8 hours. Purification by flash chromatography (using an aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in SiO2, CH2Cl2, 89 / 10 / 1) yielded 4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-1-fluorocyclohexane-1-carboxamide as a white solid (11 mg, yield 72% based on 99% purity). MS(ESI)m / z[M+H] + 634.57. 1 H NMR(500 MHz,DMSO-d6)δ 10.37(s,1H),8.66(s,1H),8.46(s,1H),8.08-7.99(m,1.6H),7.90(brs,0.4H),7.75(s,1H),7.53(s,1H),7.37-6 .99(m,4H),4.17-4.04(m,1H),4.04(s,3H),3.89(s,3H),2.28-2.07(m,2H),2.03-1.77(m,4H),1.71-1.48(m,2H). Example 40B: 4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-1-fluorocyclohexane-1-carboxamide (unassigned isomer B(I-39B): (1s,4s) and (1r,4r) of the two possible isomers) [ka]

[0328] It was prepared by conventional SMC by heating 1,4-dioxane (4 mL) and H2O (2 mL) with 4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-1-fluorocyclohexane-1-carboxamide ("isomer 1", 8 mg, 95%, 0.02 mmol), Cs2CO3 (24 mg, 0.075 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (11 mg, 0.03 mmol), and PdCl2dppf*CH2Cl2 (3.0 mg, 3.7 μmol) in a microwave reactor at 100°C for 2.6 hours. The compound was purified by flash chromatography (89 / 10 / 1 aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in SiO2, CH2Cl2) and then triturated using sonication with Et2O to obtain 4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-1-fluorocyclohexane-1-carboxamide as a white solid (4 mg, yield 32% based on 95% purity).

[0329] MS(ESI)m / z[M+H] + 634.42. 1 H NMR(500 MHz,DMSO-d6)δ 8.69-8.59(m,1H),8.35(s,0.7H),8.22(s,0.3H),8.03(s,1H),7.93(d,J=7.3 Hz,0.7H),7.82-7.77(m,0.3H),7.72(s,1H),7.56(s,1H),7.35(s,1H),7.22-7.15(m,1H) ,7.05-6.81(m,2H),4.01-3.89(m,1H),3.85(s,3H),2.09-1.79(m,6H),1.68-1.52(m,2H). 19F NMR(471 MHz,DMSO-d6)δ-73.49,-163.19,-163.31. Example 44. (1R,3S)-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclopentan-1-carboxamide (cis I-40) [ka]

[0330] Step 1. (1R,3S)-3-amino-N-(4-methoxybenzyl)cyclopentan-1-carboxamide, trifluoroacetic acid

[0331] [ka]

[0332] (1R,3S)-3-aminocyclopentane-1-carboxylate hydrochloride (315 mg, 1.90 mmol) and Boc2O (436 mg, 2.0 mmol) were suspended in CH2Cl2 (10 mL) at room temperature. DIPEA (0.99 mL, 5.7 mmol) was added all at once, and the reaction was stirred for 3 days and 21 hours. Then, TBTU (641 mg, 2.0 mmol) was added at room temperature, and the reaction was shaken at room temperature for 5 minutes, after which 4-methoxybenzylamine (0.27 mL, 2.1 mmol) was added at room temperature. Stirring was continued overnight at room temperature. Next, the reaction mixture was diluted with Et2O, washed (once with 1 M aqueous HCl solution and twice with H2O), and concentrated under reduced pressure to obtain crude tert-butyl((1S,3R)-3-((4-methoxybenzyl)carbamoyl)cyclopentyl)carbamate as a white solid. The substance was taken in CH2Cl2 (7 mL) and stirred with TFA (1.0 mL, 13 mmol) at room temperature for 21 hours. The solvent was removed under reduced pressure, and the residue was dried under high vacuum to obtain (1R,3S)-3-amino-N-(4-methoxybenzyl)cyclopentane-1-carboxamide,trifluoroacetic acid as a pale orange gum (MS(ESI)m / z[M+H]+249.28).

[0333] Step 2. (1R,3S)-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-(4-methoxybenzyl)cyclopentan-1-carboxamide [ka]

[0334] A suspension of K2CO3 (305 mg, 2.21 mmol) and (1R,3S)-3-amino-N-(4-methoxybenzyl)cyclopentan-1-carboxamide,CF3COOH (200 mg, 0.55 mmol) in DMF (3 mL) was shaken at room temperature for 5 minutes. 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (184 mg, 0.580 mmol) was added all at once, and shaking was continued at room temperature for 1 minute. The mixture was then stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, deposited on Celite, and purified twice by flash chromatography (SiO2, CH2Cl2 / MeOH / concentrated NH4OH aqueous solution in CH2Cl2 89 / 10 / 1) to obtain (1R,3S)-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-(4-methoxybenzyl)cyclopentan-1-carboxamide as a transparent thin film (55 mg, 21% yield in 2 steps). MS(ESI)m / z[M+H] + 486.35 | 488.39

[0335] Step 3. (1R,3S)-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclopentan-1-carboxamide [ka]

[0336] (1R,3S)-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-(4-methoxybenzyl)cyclopentan-1-carboxamide (55 mg, 0.11 mmol) was dissolved in TFA (1.4 mL, 18 mmol) and stirred sequentially at 60°C for 10 minutes, 50°C for 3 days, room temperature for 8 days, and finally at 65°C for 19 hours. The reaction mixture was concentrated under reduced pressure to obtain (1R,3S)-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclopentan-1-carboxamide as a gray solid (41 mg, yield 94% based on purity 94%). The substance was used in the next step without further purification. MS(ESI)m / z[M+H] + 366.29 | 368.32.

[0337] Step 4. (1R,3S)-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclopentan-1-carboxamide (cis I-40)

[0338] (1R,3S)-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclopentan-1-carboxamide (41.4 mg, 0.11 mmol), Cs2CO3 (242 mg, 0.74 mmol), H2O (2 mL), Pd(dppf)Cl2*CH2Cl2 (8.7 mg, 11 μmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (54 mg, 0.15 mmol), and 1,4-dioxane (4 mL) were used and prepared according to the general SMC method by heating at 100°C for 2.6 hours. By purification by flash chromatography (SiO2, CH2Cl2 aqueous solution 89 / 10 / 1 in CH2Cl2 containing CH2Cl2), (1R,3S)-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclopentan-1-carboxamide was obtained as a white solid (13.0 mg, yield 20% based on 98% purity). MS(ESI)m / z[M+H] + 602.52. 1 H NMR(500 MHz,DMSO-d6)δ 10.35(s,1H),8.68-8.57(m,1H),8.46(s,1H),8.05(s,1.7H),7.92(d,J=6.8 Hz,0.3H),7.73(s,1H),7.38(s,2H),7.29-7.07(m,2H),6.81(s,1H),4.38-4.24(m,1H),3.85(s,3H),3.5 6(s,3H),2.75-2.67(m,1H),2.24-2.04(m,1H),2.00-1.89(m,1H),1.86-1.76(m,2H),1.75-1.54(m,2H). 19 F NMR(471 MHz,DMSO-d6)δ-124.26. Example 45: 5-Chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((6-oxopiperidine-3-yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide[(I-41)] [ka]

[0339] Step 1. 6-Bromo-8-methyl-2-((6-oxopiperidine-3-yl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0340] A suspension of K2CO3 (130 mg, 0.94 mmol), 5-aminopiperidine-2-one (97 mg, 0.85 mmol), and 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (150 mg, 0.47 mmol) in DMF (5 mL) was shaken at room temperature for 3.7 hours, and then stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, deposited on Celite, and purified by flash chromatography (SiO2, CH2Cl2 / MeOH / concentrated NH4OH aqueous solution 89 / 10 / 1) to obtain 6-bromo-8-methyl-2-((6-oxopiperidine-3-yl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one as a beige solid (33.0 mg, yield 19% based on 95% purity). MS(ESI)m / z[M+H] + 352.22,354.17

[0341] Step 2.5-Chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((6-oxopiperidine-3-yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-41)

[0342] A conventional SMC (Sodium Chloride Compound) was prepared by heating 1,4-dioxane (4 mL) and H2O (2 mL) with 6-bromo-8-methyl-2-((6-oxopiperidine-3-yl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one (33 mg, 0.094 mmol), Cs2CO3 (153 mg, 0.47 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (61 mg, 0.17 mmol), and PdCl2dppf*CH2Cl2 (11 mg, 0.014 mmol) at 100°C for 2 hours. The compound was purified by flash chromatography (89 / 10 / 1 aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in SiO2, CH2Cl2) and then tritulated with MeOH to obtain 5-chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((6-oxopiperidine-3-yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a beige solid (10 mg, yield 17% based on 93% purity). MS(ESI)m / z[M+H] + 588.4. 1 H NMR(500 MHz,DMSO-d6)δ 10.38(s,1H),8.73-8.63(m,1H),8.46(s,1H),8.10-8.03(m,1H),7.94(s,1H),7.77(s,1H),7.47(s,1H),7.27(t,J=7.0 Hz,1H),7.23-7.10(m,2H),4.22(br.s,1H),3.88(s,3H),3.55(s,3H),3. 20-3.06(m,1H),2.40-2.20(m,3H),2.11-1.95(m,1H),1.93-1.74(m,1H). 19 F NMR(471 MHz,DMSO-d6)δ-123.95. Example 46: tert-butyl3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)azetidine-1-carboxylate(I-42) [ka]

[0343] Step 1. tert-butyl 3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)azetidine-1-carboxylate [ka]

[0344] A suspension of K2CO3 (174 mg, 1.257 mmol), 1-Boc-3-(amino)azetidine (206 mg, 1.2 mmol), and 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (200 mg, 0.63 mmol) in DMF (5 mL) was shaken at room temperature for 10 minutes, and then stirred overnight at room temperature (1 day and 19 hours). The reaction mixture was concentrated under reduced pressure, deposited on Celite, and purified by flash chromatography (SiO2, CH2Cl2 / MeOH / concentrated NH4OH aqueous solution in CH2Cl2 89 / 10 / 1) to obtain tert-butyl 3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)azetidine-1-carboxylate as a white solid (102 mg, 39%). MS(ESI)m / z[M+H] + 410.45 | 412.40

[0345] Step 2. tert-butyl3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)azetidine-1-carboxylate(I-42)

[0346] Using 1,4-dioxane (4 mL) and H2O (2 mL), tert-butyl 3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)azetidine-1-carboxylate (50 mg, 0.12 mmol), Cs2CO3 (199 mg, 0.61 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (79 mg, 0.22 mmol), and PdCl2(dppf)*CH2Cl2 (15 mg, 0.018 mmol) were used. The compound was prepared by conventional SMC by heating at 90°C for 90 minutes in a chlorowave reactor; and purified by flash chromatography (89 / 10 / 1 aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in SiO2, CH2Cl2) to obtain tert-butyl 3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)azetidine-1-carboxylate as a white solid (39 mg, yield 50%). MS(ESI)m / z[M+H] + 646.5. 1 H NMR(500 MHz,DMSO-d6)δ 10.37(brs,1H),8.67(s,1H),8.53-8.50(m,1H),8.48-8.39(m,1H),8.06(s,1H),7.78(s,1H),7.33-6.92 (m,3H),4.71-4.52(m,1H),4.28-4.09(m,2H),3.88(s,3H),3.90-3.76(m,1H),3.53(s,3H),1.39(s,9H). 19 F NMR(471 MHz,DMSO-d6)δ-123.92. Example 47: Ethyl 4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)piperidine-1-carboxylate (I-43) [ka]

[0347] Step 1. Ethyl 4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)piperidine-1-carboxylate [ka]

[0348] A suspension of K2CO3 (174 mg, 1.3 mmol), ethyl 4-aminopiperidine-1-carboxylate (173 mg, 1.0 mmol), and 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (200 mg, 0.63 mmol) in DMF (5 mL) was stirred at room temperature for 2 days. The reaction was concentrated under reduced pressure, deposited on Celite, and purified by flash chromatography (SiO2, CH2Cl2 / MeOH / concentrated NH4OH aqueous solution 89 / 10 / 1) to obtain ethyl 4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)piperidine-1-carboxylate as a pale yellow solid (51.0 mg, yield 19% based on 95% purity). MS(ESI)m / z[M+H] + 410.30 | 412.25

[0349] Step 2. Ethyl 4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)piperidine-1-carboxylate(I-43)

[0350] The solution was prepared by conventional SMC by heating 1,4-dioxane (6 mL) and H2O (3 mL) with ethyl 4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)piperidine-1-carboxylate (51 mg, 0.12 mmol), Cs2CO3 (192 mg, 0.59 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (77 mg, 0.21 mmol), and PdCl2(dppf)*CH2Cl2 (14 mg, 0.018 mmol) at 90°C for 2 hours. Ethyl 4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)piperidine-1-carboxylate was obtained as an off-white solid (18 mg, yield 22% based on 95% purity). MS(ESI)m / z[M+H] + 646.5. 1 H NMR(500 MHz,DMSO-d6)δ 10.37(s,1H),8.75-8.58(m,1H),8.48(s,1H),8.07(s,1H),7.99(d,J=6.2 Hz,0.6H),7.85(s,0.4H),7.75(s,1H),7.30-7.12(m,3H),4.13-3.92(m,5H),3.89(s,3H), 3.61-3.50(m,3H),3.09-2.78(m,2H),2.01-1.81(m,2H),1.51-1.37(m,2H),1.19(t,J=7.0 Hz,3H). 19 F NMR(471 MHz,DMSO-d6)δ-123.96. Example 48: N-(3-(2-((1-acetylpiperidine-4-yl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide(I-44) [ka]

[0351] Step 1.2-((1-acetylpiperidine-4-yl)amino)-6-bromo-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0352] A suspension of K2CO3 (174 mg, 1.257 mmol), 1-acetylpiperidine-4-amine (134 mg, 0.94 mmol), and 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (200 mg, 0.63 mmol) was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, deposited on Celite, and purified by flash chromatography (SiO2, CH2Cl2 in CH2Cl2 / / MeOH / concentrated NH4OH aqueous solution 89 / 10 / 1) to obtain 2-((1-acetylpiperidine-4-yl)amino)-6-bromo-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one as a colorless thin film (25.0 mg, yield 10% based on 97% purity). MS(ESI)m / z[M+H] + 380.28 | 382.2.

[0353] Step 2. N-(3-(2-((1-acetylpiperidine-4-yl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide(I-44)

[0354] The solution was prepared by conventional SMC by heating 1,4-dioxane (10 mL) and H2O (5 mL) with 2-((1-acetylpiperidine-4-yl)amino)-6-bromo-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one (25 mg, 0.064 mmol), Cs2CO3 (104 mg, 0.32 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (41 mg, 0.11 mmol), and PdCl2(dppf)*CH2Cl2 (7.8 mg, 9.6 μmol). Purification by flash chromatography (SiO2, CH2Cl2 / MeOH / concentrated NH4OH aqueous solution in CH2Cl2 89 / 10 / 1) yielded N-(3-(2-((1-acetylpiperidine-4-yl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide as an off-white solid (18 mg, yield 45% based on 99% purity). MS(ESI)m / z[M+H] + 616.4. 1 H NMR(500 MHz,DMSO-d6)δ 10.37(s,1H),8.72-8.59(m,1H),8.48(s,1H),8.07(s,1H),8.02(d,J=7.2 Hz,0.6H),7.87(d,J=7.0 Hz,0.4H),7.76(s,1H),7.31-7.09(m,3H),4.33-4.23(m,1H),4.18-4.01(m,1H),3.89(s,3H),3.83(d,J=13.4 Hz,1H),3.62-3.51(m,3H),3.25-3.09(m,1H),2.85-2.66(m,1H),2.02(s,3H),1.98-1.75(m,2H),1.56-1.44(m,1H),1.41-1.32(m,1H). 19 F NMR(471 MHz,DMSO-d6)δ-123.97. Example 49: (R)-5-chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((5-oxopyrrolidine-3-yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide ((R)I-45) [ka]

[0355] Step 1. (R)-6-bromo-8-methyl-2-((5-oxopyrrolidine-3-yl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0356] K2CO3 (174 mg, 1.26 mmol) and (R)-4-aminopyrrolidine-2-one hydrochloride (129 mg, 0.94 mmol) were shaken in DMF (5 mL) at room temperature for 10 minutes. Then, 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (200 mg, 0.63 mmol) was added all at once as a solid at room temperature. The reaction mixture was then stirred overnight at room temperature. The reaction was concentrated and used crudely in the next step. MS(ESI)m / z[M+H] + 338.15.

[0357] Step 2. (R)-5-chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((5-oxopyrrolidine-3-yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide((R)I-45)

[0358] (R)-6-bromo-8-methyl-2-((5-oxopyrrolidine-3-yl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one (70 mg, 0.21 mmol), Cs2CO3 (337 mg, 1.0 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (134 mg, 0.37 mmol), and PdCl2(dppf)*CH2Cl2 (25 mg, 0.031 mmol) were used in 1,4-dioxane (4 mL) and H2O (2 mL), and the mixture was heated in a microwave reactor at 100°C for 2 hours by conventional SMC method. Preparative HPLC (C) 18 The solution was purified by MeCN in H2O + 0.1% HCO2H, followed by two flash chromatography steps (MeOH in SiO2, CH2Cl2) and (89 / 10 / 1 aqueous solution of CH2Cl2 / MeOH / concentrated NH4OH in SiO2, CH2Cl2) to obtain (R)-5-chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((5-oxopyrrolidine-3-yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a white solid (6.0 mg, 5% yield in 2 steps). MS(ESI)m / z[M+H] + 574.2. 1 H NMR(500 MHz,CD3OD)δ 8.49(s,1H),8.21(d,J=2.6 Hz,1H),7.98(d,J=2.6 Hz,1H),7.63(s,1H),7.42-7.34(m,1H),7.11(dd,J=10.1 Hz,3.9 Hz,1H),7.05(t,J=7.9 Hz,1H),4.48(s,2H),3.89(s,3H),3.79-3.70(m,1H),3.59(s,3H),3.38-3.27(m,1H),2.78-2.61(m,1H),2.44-2.28(m,1H). 19 F NMR(471 MHz,CD3OD)δ-127.74. Example 50: (S)-5-chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((5-oxopyrrolidine-3-yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide((S)I-45) [ka]

[0359] Step 1. (S)-6-bromo-8-methyl-2-((5-oxopyrrolidine-3-yl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0360] K2CO3 (174 mg, 1.3 mmol), (4S)-4-aminopyrrolidine-2-one (126 mg, 1.3 mmol), and 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (200 mg, 0.63 mmol) were shaken overnight at room temperature in DMF (5 mL). The reaction was concentrated, and the crude product was used in the next step. MS(ESI)m / z[M+H] + 338.2|340.2.

[0361] Step 2. (S)-5-chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((5-oxopyrrolidine-3-yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide((S)I-45)

[0362] (S)-6-bromo-8-methyl-2-((5-oxopyrrolidine-3-yl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one (70 mg, 0.21 mmol), Cs2CO3 (337 mg, 1.03 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (134 mg, 0.37 mmol), and PdCl2dppf*CH2Cl2 (25 mg, 0.031 mmol) were used in 1,4-dioxane (4 mL) and H2O (2 mL), and the mixture was heated in a microwave reactor at 100°C for 2 hours by the general method of SMC. The solution was purified by flash chromatography (SiO2, CH2Cl2 / MeOH / concentrated NH4OH aqueous solution in CH2Cl2 89 / 10 / 1, then MeOH in CH2Cl2), and then by preparative HPLC (C 18 (S)-5-chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((5-oxopyrrolidine-3-yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide was obtained as a white solid (4 mg, 3% yield in 2 steps based on 98% purity). MS(ESI)m / z[M+H] + 574.2. 1 H NMR(500 MHz,CD3OD)δ 8.49(s,1H),8.20(d,J=2.6 Hz,1H),7.98(d,J=2.6 Hz,1H),7.63(s,1H),7.36(dd,J=10.7,4.6 Hz,1H),7.10(t,J=6.3 Hz,1H),7.04(t,J=7.9 Hz,1H),4.51(s,3H),3.82-3.70(m,1H),3.59(s,3H),3.39-3.26(m,1H),2.78-2.63(m,1H),2.44-2.28(m,1H). 19 F NMR(471 MHz,CD3OD)δ-127.81. Example 51 5-Chloro-N-(2-fluoro-3-(2-(isopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-46) [ka]

[0363] The solution was prepared by conventional SMC by heating overnight at 100°C using H2O (2.5 mL) and 1,4-dioxane (5 mL) with 6-bromo-2-(isopropylamino)pyrido[2,3-d]pyrimidine-7(8H)-one (11 mg, 0.039 mmol), Cs2CO3 (51 mg, 0.15 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (25.2 mg, 0.070 mmol), and Pd(dppf)Cl2*CH2Cl2 (4.8 mg, 5.8 μmol). The solution was purified by flash chromatography (SiO2, MeOH in CH2Cl2), and then purified by preparative HPLC (C 18 By purification with MeCN in H2O + 0.1% HCO2H, 5-chloro-N-(2-fluoro-3-(2-(isopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide was obtained as a white solid (1.0 mg, yield 5%). MS(ESI)m / z[M+H] + 519.1. Example 52: 5-Chloro-N-(3-(2-(cyclopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide(I-47) [ka]

[0364] Step 1.6-Bromo-2-(cyclopropylamino)pyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0365] 6-bromo-2-(methylsulfinyl)pyrido[2,3-d]pyrimidine-7(8H)-one (120 mg, 0.42 mmol) was added in a single dose of c-PrNH2 (0.58 mL, 8.3 mmol) to a suspension of 6-bromo-2-(methylsulfinyl)pyrido[2,3-d]pyrimidine-7(8H)-one in i-PrOH (10 mL). The suspension was shaken at room temperature for 1.5 hours, then stirred at room temperature for 3 days and 18 hours (r 3 d 18 h). The solid was collected by filtration and rinsed with i-PrOH to obtain 6-bromo-2-(cyclopropylamino)pyrido[2,3-d]pyrimidine-7(8H)-one as a white solid (111 mg, yield 94% based on 99% purity). MS(ESI)m / z[M+H] + 281.03 | 283.06.

[0366] Step 2.5-Chloro-N-(3-(2-(cyclopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide(I-47)

[0367] The solution was prepared by conventional SMC using 1,4-dioxane (4 mL) and H2O (2 mL) containing 6-bromo-2-(cyclopropylamino)pyrido[2,3-d]pyrimidine-7(8H)-one (55.5 mg, 0.19 mmol), Cs2CO3 (191 mg, 0.59 mmol), (5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (106 mg, 0.29 mmol), and Pd(dppf)Cl2*CH2Cl2 (24 mg, 0.029 mmol). The solution was heated in a microwave reactor at 100°C for 2 hours. It was purified by flash chromatography (MeOH in SiO2 and CH2Cl2). The solid crystallized from MeOH / CH2Cl2 was collected by filtration and rinsed with a small amount of CH2Cl2 to obtain 5-chloro-N-(3-(2-(cyclopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide as an off-white solid (32 mg, yield 30% based on 95% purity). MS(ESI)m / z[MH] - 515.0. 1 H NMR(500 MHz,DMSO-d6)δ 12.15-11.92(m,1H),10.47(s,1H),8.75-8.54(m,1H),8.48(d,J=2.6 Hz,1H),8.16(d,J=2.6 Hz,1H),8.06-7.79(m,1H),7.74(s,1H),7.23(dd,J=6.4,2.7 Hz,1H),7.16(t,J=9.2 Hz,1H),7.11-7.06(m,1H),3.98(s,3H),2.96-2.81(m,1H),0.71(d,J=5.4 Hz,2H),0.56(s,2H). 19 F NMR(471 MHz,DMSO-d6)δ-119.06. Example 53: 5-Chloro-N-(3-(2-(cyclopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide(I-48) [ka]

[0368] The solution was prepared by conventional SMC using 1,4-dioxane (4 mL) and H2O (2 mL) containing 6-bromo-2-(cyclopropylamino)pyrido[2,3-d]pyrimidine-7(8H)-one (55.5 mg, 0.195 mmol), Cs2CO3 (191 mg, 0.59 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)boronic acid (106 mg, 0.29 mmol), and Pd(dppf)Cl2*CH2Cl2 (24 mg, 0.029 mmol). The solution was heated in a microwave reactor at 100°C for 2 hours. It was purified by flash chromatography (MeOH in SiO2 and CH2Cl2). The solid crystallized from MeOH / CH2Cl2 was collected by filtration and rinsed with a small amount of MeOH to obtain 5-chloro-N-(3-(2-(cyclopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide as a white solid (6 mg, yield 6%). MS(ESI)m / z[M+H] + 517.1. 1 H NMR(500 MHz,DMSO-d6)δ 12.14-11.86(m,1H),10.41(s,1H),8.74-8.59(m,1H),8.55(d,J=2.3 Hz,1H),8.13(d,J=2.6 Hz,1H),8.05-7.84(m,1H),7.78(s,1H),7.37-7.27(m,2H),7.22(t,J=7.7 Hz,1H),3.96(s,3H),2.96-2.85(m,1H),0.76(d,J=5.3 Hz,2H),0.61(s,2H). 19 F NMR(471 MHz,DMSO-d6)δ-124.13. Example 54: 5-Chloro-N-(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide(I-49) [ka]

[0369] 5-chloro-N-(2,4-difluoro-3-(8-(4-methoxybenzyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (122 mg, 0.18 mmol) in i-PrOH (5 mL) was treated with EtNH2 (66-72% in H2O, 0.45 mL, 5.5 mmol), shaken at room temperature for 4.3 hours, and then stirred for 20 hours. The reaction mixture was concentrated under reduced pressure, and the remaining white foam was dissolved in TFA (2.0 mL, 26 mmol), then heated at 60°C for 1.3 hours, followed by heating at 70°C for 1.5 hours. The reaction mixture was cooled to room temperature. Anisole (0.020 mL, 0.18 mmol) was added, and the reaction mixture was stirred at room temperature for 1 day and 19 hours. Volatile substances were removed under high pressure, and the solid residue was dried under high vacuum. The residue was then stirred with PdCl2 (32.7 mg, 0.184 mmol) in siRNA (40 mL) and ice AcOH (10 mL) under H2 (1 atm) at room temperature for 3 days and 20 hours, followed by shaking under H2 (2 bar) at room temperature for 2 hours. The reaction was filtered through Celite, concentrated under reduced pressure, and dried under high vacuum. The solid residue was treated with trifluoromethanesulfonic acid (2.0 mL, 23 mmol) while stirring in an ice-H2O bath. The reaction mixture was vigorously stirred in a cooling bath for 5 minutes, followed by stirring without the cooling bath for 1.3 hours. Ice-H2O was then carefully added, forming a gray, viscous precipitate, which was collected by filtration, rinsed with excess H2O, and then purified by flash chromatography (MeOH in SiO2, CH2Cl2). The substance was further triturated with 5% MeOH in DCM, followed by Et2O, to obtain 5-chloro-N-(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide as an off-white solid (16 mg, yield 17%). 1H NMR(500 MHz,DMSO-d6)δ 12.15-11.97(m,1H),10.35(s,1H),8.72-8.54(m,1H),8.50(d,J=2.3 Hz,1H),8.06(d,J=2.6 Hz,1H),7.88(s,0.7H),7.77(s,1H),7.72(s,0.3H),7.36-7.26(m,1H),7.13(t,J=8.6 Hz,1H),3.91(s,3H),3.43-3.36(m,2H),1.15(t,J=6.8 Hz,3H). 19 F NMR(471 MHz,DMSO-d6)δ-113.12,-119.70. Example 55: 5-Chloro-N-(2,4-difluoro-3-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-50) [ka]

[0370] Step 1: 6-Bromo-8-(4-methoxybenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0371] To a solution of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one (4.0 g, 14.7 mmol) in DMF (100 mL), NaH (60%, 0.88 g, 37 mmol) was gradually added, and the reaction mixture was stirred at room temperature for 1 hour. After 1 hour, 1-(chloromethyl)-4-methoxybenzene (4.83 g, 31 mmol) was added, and the reaction mixture was stirred at room temperature for a further 16 hours. Next, the reaction mixture was diluted with H2O (150 mL) and extracted with SiO (150 mL x 3). The combined organic layer was dried (anhydrous Na2SO4), concentrated, purified by flash chromatography, and triturated with Et2O to obtain 6-bromo-8-(4-methoxybenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one as a white solid (2.5 g, 43%). LCMS:[M+H] + 392.1.

[0372] Step 2.6-(3-amino-2,6-difluorophenyl)-8-(4-methoxybenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one [ka]

[0373] In a sealed vial, XPhos Pd G2 (108 mg, 0.14 mmol), 6-bromo-8-(4-methoxybenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one (300 mg, 0.76 mmol), K3PO4 (649 mg, 3.1 mmol), 2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (585 mg, 2.3 mmol), 1,4-dioxane (20 mL), and H2O (2 mL) were degassed with Ar, and then heated in a microwave reactor at 65°C for 18 hours. The reaction mixture was concentrated under reduced pressure, attached to Celite, and purified by flash chromatography (SiO2, SiO in hexane) to obtain 6-(3-amino-2,6-difluorophenyl)-8-(4-methoxybenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one as a pale yellow solid (221.0 mg, yield 66%). MS(ESI)m / z[M+H] + 441.37.

[0374] Step 3: 5-Chloro-N-(2,4-difluoro-3-(8-(4-methoxybenzyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [ka]

[0375] 6-(3-amino-2,6-difluorophenyl)-8-(4-methoxybenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one (221 mg, 0.50 mmol) and 5-chloro-2-methoxypyridine-3-sulfonyl chloride (182 mg, 0.75 mmol) were dissolved in CH2Cl2 (20 mL), to which pyridine (0.81 mL, 10 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours, and then stirred at room temperature for 7 days. The reaction was washed (once with 1M aqueous HCl, twice with H2O, and once with 1M aqueous HCl), the organic phase was concentrated under reduced pressure, attached to Celite, and purified by flash chromatography (SiO2, ELISA in hexane) to obtain 5-chloro-N-(2,4-difluoro-3-(8-(4-methoxybenzyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a white solid (245 mg, yield 73% based on 97% purity). MS(ESI)m / z[M+H] + 646.39

[0376] Step 4. 5-Chloro-N-(2,4-difluoro-3-(8-(4-methoxybenzyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [ka]

[0377] A cold (0°C) CH2Cl2 (12 mL) solution of 5-chloro-N-(2,4-difluoro-3-(8-(4-methoxybenzyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (245 mg, 0.37 mmol) was treated by adding mCPBA (102 mg, 0.441 mmol, approximately 75%) as a solid in one go. The reaction mixture was stirred for 0.9 hours while cooling and stored overnight at -20°C. The substance was then warmed to room temperature, concentrated to dryness under reduced pressure, and used crudely in the next step. MS(ESI)m / z[MH] - 660.46

[0378] Step 5. 5-Chloro-N-(2,4-difluoro-3-(8-(4-methoxybenzyl)-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [ka]

[0379] Crude 5-chloro-N-(2,4-difluoro-3-(8-(4-methoxybenzyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (122 mg, 0.18 mmol) was mixed with K2CO3 solids (293 mg, 2.1 mmol), MeNH2*HCl (81 mg, 1.2 mmol), and DMF (4.0 mL). The reaction was shaken at room temperature for 4.6 hours, then stirred for 20 hours. The mixture was concentrated under reduced pressure and then dried under high vacuum. The solid residue was suspended in H2O, filtered, rinsed with H2O, and dried to obtain 5-chloro-N-(2,4-difluoro-3-(8-(4-methoxybenzyl)-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a yellowish-brown solid (117 mg, quantitative). MS(ESI)m / z[M+H]+ 629.53

[0380] Step 6.5-Chloro-N-(2,4-difluoro-3-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide(I-50)

[0381] 5-Chloro-N-(2,4-difluoro-3-(8-(4-methoxybenzyl)-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (117 mg, 0.19 mmol) was treated all at once with trifluoromethanesulfonic acid (1.0 mL, 11 mmol) while cooling in an ice-H2O bath. The reaction mixture was vigorously stirred in the cooling bath for 5 minutes, then stirred for 1.4 hours without the cooling bath. Ice-H2O was carefully added to form a precipitate. The solid was filtered, rinsed with excess H2O, and subjected to preparative HPLC (C 18 Purified using MeCN + 0.1% HCO2H in H2O. MS(ESI)m / z[M+H] + 509.30. 1 H NMR(500 MHz,DMSO-d6)δ 12.06(s,0.7H),11.94(s,0.3H),10.28(s,1H),8.60(s,0.3H),8.51(s,0.7H),8.43(d,J=2.6 Hz,1H),7.99(d,J=2.6 Hz,1H),7.77-7.72(m,0.7H),7.70(brs,0.3H),7.55(s,1H),7.28-7.19(m,1H),7.07(t,J=8.8 Hz,1H),3.84(s,3H),2.80(d,J=4.6 Hz,3H).

[0382] 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. IC50 is shown here. 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 2-1] [Table 2-2]

[0383] 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.

[0384] Tumor cell growth inhibition assay: SKOV3 or OVCAR-8 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 plates were 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 plates were incubated at 37°C in a humidified 5% CO2 incubator. After 3–5 days, the plates were 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.

[0385] 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.

[0386] 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. ８ It may be arbitrarily replaced with; X １ N and CR ９ Selected from; R ２ is selected from H, C １～６ alkyl and C １～６ haloalkyl; 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; Each R ８ is OR １２ , NR １２ R １３ , C(O)NR １２ R １３ , C(O)OR １２ ,=O, Halo, 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, where 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 １０ and R １１ H, Halo, C １～６ Alkyl and C １～６ Selected independently from haloalkyl groups; 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 Fluoralkyl (OC 1-4 They 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. ８ 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 However, H, CH ３ CF ３ CHF ２ ,CH ２ CH ３ ,CH ２ CH ２ CH ３ , CH (CH ３ ) ２ , CH (CH ３ )CH ２ CH ３ and CH(CH ３ ) ３ A compound according to claim 3, selected from the above.

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

6. R １ is one or two R ８ monocyclic C optionally substituted with ３～８ The compound according to claim 5, which is cycloalkyl.

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

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

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 ８ 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 ８ 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 ８ 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 ８ 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.

16. X １ The compound according to any one of claims 1 to 15, wherein the compound is selected from N and CH.

17. R ２ However, H and CH ３ A compound according to any one of claims 1 to 16, selected from among them.

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 CF ３ ,CH ２ CH ３ , 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. Each R ８ 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 It may be optionally substituted with one or more substituents selected from alkyl groups, or Each R ８ However, OR １２ C(O)NR １２ R １３ , C(O)OR １２ ,=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 26, which may be optionally substituted with one or more substituents selected from alkyl groups.

28. Each R ８ However, OR １２ , NR １２ R １３ C(O)NR １２ R １３ Cl, F, CH ３ CHF ２ ,CH ３ CH ３ and CF ３ Selected independently of, Each R ８ However, OR １２ , NR １２ R １３ C(O)NR １２ R １３ , C(O)OR １２ ,=O,Cl,F,CH ３ CHF ２ ,CH ３ CH ３ and CF ３ A compound according to claim 27, independently selected from the above.

29. Each R ８ However, Cl, F, CH ３ CHF ２ ,CH ３ CH ３ and CF ３ A compound according to claim 18, independently selected from the above.

30. Each R ８ However, NR １２ R １３ and C(O)NR １２ R １３ Selected independently of, Each R ８ However, = O and C(O) OR １２ A compound according to claim 29, independently selected from the above.

31. R ９ , R １０ and R １１ However, H, Cl, Br, F, C １～４ Alkyl and C １～４ A compound according to any one of claims 1 to 15, independently selected from fluoroalkyls.

32. R ９ , R １０ and R １１ The compound according to claim 31, wherein is H.

33. 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 32, which may be optionally substituted with one or two substituents selected from the following.

34. R １２ However, H, CH ３ and CF ３ A compound according to claim 33, selected from the above.

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

36. R １３ However, H, C １～４ Alkyl and C １～４ A compound according to any one of claims 1 to 35, selected from fluoroalkyls.

37. R １３ However, H and CH ３ A compound according to claim 36, selected from the above.

38. R １４ and R １５ However, H, CH ３ and CF ３ A compound according to any one of claims 1 to 35, independently selected from the above.

39. R １４ and R １５ However, H and CH ３ A compound according to claim 38, independently selected from the above.

40. N-(3-(2-amino-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide; trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide; trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide; N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(2,4-difluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(4-Fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropteridine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide; trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide; trans-5-chloro-N-(2-cyano-3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(2-fluoro-3-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(4-Fluoro-3-(2-(isopropylamino)-8-methyl-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(ethylamino)-8-methyl-7-oxo-7,8-dihydropteridine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(2,4-difluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(ethylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide; 5C chloro-N-(4-fluoro-3-(2-(isopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(4-fluoro-3-(2-(isopropylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(2-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(cyclopropylamino)-8-methyl-7-oxo-7,8-dihydropteridine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide; (R)-5-chloro-N-(4-fluoro-3-(8-methyl-7-oxo-2-((tetrahydrofuran-3-yl)amino)-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(4-Fluoro-3-(8-methyl-2-(oxetane-3-ylamino)-7-oxo-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(4-fluoro-3-(8-methyl-7-oxo-2-((tetrahydro-2H-pyran-4-yl)amino)-7,8-dihydropteridine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(4-Fluoro-3-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(4-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(2-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(5-Fluoro-4-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)pyridine-2-yl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-fluoro-4-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)pyridine-2-yl)-2-methoxypyridine-3-sulfonamide; trans-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide; cis-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclohexane-1-carboxamide; trans-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide; cis-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide; trans-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclobutan-1-carboxamide; rac-(1R,3S)-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide; rac-(1R,3R)-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-N-methylcyclohexane-1-carboxamide; cis-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclobutan-1-carboxamide; Potassium ((5-chloro-2-methoxypyridine-3-yl)sulfonyl)(2-fluoro-3-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)amide; Potassium ((5-chloro-2-methoxypyridine-3-yl)sulfonyl)(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)amide; 4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)-1-fluorocyclohexane-1-carboxamide; (1R,3S)-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)cyclopentan-1-carboxamide; 5-Chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((6-oxopiperidine-3-yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; tert-butyl 3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)azetidine-1-carboxylate; Ethyl 4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamide)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2-yl)amino)piperidine-1-carboxylate; N-(3-(2-((1-acetylpiperidine-4-yl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; (R)-5-chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((5-oxopyrrolidine-3-yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; (S)-5-chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((5-oxopyrrolidine-3-yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(2-fluoro-3-(2-(isopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(cyclopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(cyclopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide; and 5-Chloro-N-(2,4-difluoro-3-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; The compound according to claim 1, or selected from a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

41. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 40, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, and a pharmaceutically acceptable carrier.

42. 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 40, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

43. 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 40, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

44. The method according to claim 43, wherein the disease, disorder, or condition that can be treated by inhibiting GCN2 is a neoplasm.

45. The method according to claim 43, wherein the disease, disorder, or condition that can be treated by inhibiting GCN2 is cancer.

46. The method according to claim 45, 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.

47. The method according to claim 43, wherein the disease, disorder, or condition that can be treated by inhibiting GCN2 is peripheral neuropathy.

48. The method according to claim 47, wherein the peripheral neuropathy is Charcot-Marie-Tooth (CMT) peripheral neuropathy.

49. 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 combination with another known active agent useful for treating the disease, disorder, or condition that can be treated by inhibiting GCN2, one or more of the compounds described in any one of claims 1 to 40, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

50. The method according to claim 49, wherein the disease, disorder, or condition that can be treated by inhibiting GCN2 is cancer and / or peripheral neuropathy.

51. The method according to claim 49, 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.

52. The method according to claim 51, wherein the one or more additional cancer treatments are chemotherapeutic agents, and the chemotherapeutic agent is cisplatin.

53. The method according to claim 51, wherein the one or more additional cancer treatments are chemotherapeutic agents, and the chemotherapeutic agent is L-asparaginase (L-ASNase).

54. The method according to claim 51, 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.

55. 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 40, or pharmaceutically acceptable salts, prodrugs and / or solvates thereof, in combination with an effective amount of one or more additional cancer treatments.

56. The method according to claim 55, wherein the one or more cancer treatments are chemotherapeutic agents, and the chemotherapeutic agent is cisplatin.

57. The method according to claim 55, wherein the one or more cancer treatments are chemotherapeutic agents, and the chemotherapeutic agent is L-asparaginase (L-ASNase).

58. The method according to claim 55, 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.

59. The method according to claim 53, wherein the cancer is associated with low asparagine synthetase (ASNS) expression, and the one or more additional cancer treatments are L-asparaginase (L-ASNase).

60. The method according to claim 53, 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-asparaginase.

61. The method according to claim 53, 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.

62. The method according to claim 53, 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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