Pyrimidopyridone and pteridone derivatives as inhibitors of the GCN2 kinase, compositions and uses thereof

Abstract

The present application relates to pyrimidopyridone and pteridone compounds of Formula I, to processes for their preparation and to compositions comprising them More particularly, the present application relates to compound of Formula I that have activity as inhibitors of the general control nonderepressible 2 (GCN2) kinase and to their use in the treatment of diseases, disorders or conditions treatable by inhibiting GCN2 kinase such as cancers and neuronal diseases.

Description

TITLE: PYRIMIDOPYRIDONE AND PTERIDONE DERIVATIVES AS INHIBITORS OF THE GCN2 KINASE, COMPOSITIONS AND USES THEREOF

[0001] The present application claims the benefit of priority from co-pending U.S. provisional patent application no. 63 / 535,418 filed on August 30, 2023, the contents of which are incorporated herein by reference in the entirety. FIELD

[0002] The present application relates to pyrimidopyridone and pteridone compounds that have activity as inhibitors of the general control nonderepressible 2 (GCN2) kinase, to processes for their preparation, to compositions comprising them, and to their use, for example, in therapy. More particularly, the present application relates to compounds useful in the treatment of diseases, disorders or conditions treatable by inhibiting GCN2 kinase such as cancers and neuronal diseases. BACKGROUND

[0003] The eukaryotic initiation factor 2α (eIF2α) kinase general control nonderepressible 2 (GCN2) drives cellular adaptation to amino acid limitation by activating the integrated stress response (ISR) that induces activating transcription factor 4 (ATF4). The GCN2 kinase mediated cellular adaptations to amino acid limitation occurs through the translational control of gene expression that is primarily executed by eIF2α phosphorylation. Utilizing quantitative phosphoproteomics, Dokladal et al. recently demonstrated that GCN2 targets auxiliary, physiologically relevant effectors, including eIF2β and Gcn20, to fine-tune translational control 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 trimeric eIF2 G protein complex to promote its association with eIF5 which in turn contributes to the inhibition of translation initiation.

[0004] Under distinct stress conditions, cellular ISR is activated by four eukaryotic initiation factor 2 α (eIF2α) kinases: GCN2, protein kinase–like endoplasmic reticulum kinase (PERK), double-stranded RNA-dependent kinase (PRK), and heme-regulated inhibitor (HRK) [Nat Rev Mol Cell Biol 2016, 17:213–226]. These four eIF2α kinases commonly phosphorylate eIF2α at S51, thereby reducing general protein synthesis. However, specific mRNAs with an upstream open reading frame, such as activating transcription factor 4 (ATF4), are selectively translated by delaying translation re-initiation via eIF2α phosphorylation. ATF4 is a key transcription factor for stress adaptation and subsequentlydrives 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 undergo amino acid deprivation, partly because abnormal proliferation increases the need for amino acids to produce proteins, lipids, and nucleic acids, and partly because insufficient and disorganized formation of blood vessels leads to a supply shortage of amino acids. Thus, GCN2 can be important for cancer cell survival and tumor development. Moreover, knockout of GCN2 or ATF4 has been shown to decrease tumor growth in vivo [EMBO. J.2010, 29:2082–2096]. In addition, the GCN2 arm of the ISR has been shown to protect cancer cells from intrinsic stress induced by the c-Myc oncogene [Nat Cell Biol 2019, 21:1413–1424; Nat Cell Biol 2019, 21:889–899). GCN2 can also be involved in resistance to cancer chemotherapy because sensitization to the antitumor agent L-asparaginase (L-ASNase) is elicited by GCN2 inhibition in cancer cells that express asparagine synthetase (ASNS) at low levels [Proc Natl Acad Sci USA 2018, 115: E7776–E7785]. ASNS catalyzes the biosynthesis of asparagine (Asn) from aspartate and is highly responsive to cellular stress, in particular to intracellular amino acid depletion. ATF4 induces ASNS, [J Biol Chem. 2017;292(49):19952-19958] which in turn sustains Asn levels and suppresses apoptosis while intracellular depletion of Asn induces apoptosis. Thus, ASNS plays a role during tumor cell accumulation and progression by maintaining cell viability. Elevated ASNS protein expression is also associated with resistance to asparaginase therapy [J Biol Chem.2017;292(49):19952-19958]. Therefore, ASNS high tumors should be sensitive to inhibition of ASNS activity when combined with L-ASNase and GCN2 inhibition. This combination is a viable strategy to control the growth, proliferation, and migration of cancer cells, eliminate them, or enhance their sensitivity to existing chemotherapy drugs or radiotherapy. It has been suggested that the GCN2- mediated ISR pathway provides promising targets for cancer therapy. Hence, disruption of this pro-oncogenic stress-induced pathway by inhibiting GCN2 is an attractive therapeutic strategy.

[0006] Another important therapeutic area in which ISR activation is implicated is neuronal disease or neuropathy [Science 2021, 373, 1161–1166]. Dominant mutations in ubiquitously expressed transfer RNA (tRNA) synthetase genes cause axonal peripheral neuropathy, accounting for at least six forms of Charcot-Marie-Tooth (CMT) disease. Genetic evidence in mouse and Drosophila models suggests a gain-of-function mechanism. It has been shown that mutant tRNA synthetases activate the integrated stress response (ISR) through the sensor kinase (general control nonderepressible 2). Thechronic activation of the ISR contributed to the pathophysiology, and genetic deletion or pharmacological inhibition of GCN2 alleviated the peripheral neuropathy. The activation of GCN2 suggests that the aberrant activity of the mutant tRNA synthetases is still related to translation and that inhibiting GCN2 or the ISR may represent a therapeutic strategy in CMT [Science 2021, 373, 1156–1161].

[0007] Recently, the small molecule inhibitors of GCN2 kinase have been described (WO2021165346, Black Belt TX LTD).

[0008] There remains a need for potent GCN2 kinase inhibitors for the treatment of, for example, cancers and peripheral neuropathy. Also, there is a need for GCN2 kinase inhibitors with selectivity over other kinases. SUMMARY

[0009] The Applicants have developed novel inhibitors of general control nonderepressible 2 (GCN2) kinase.

[0010] Accordingly, the present invention includes a compound of Formula I, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:wherein R1is selected from H, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl and C3-10heterocycloalkyl, the latter four groups being optionally substituted with one or two R8; X1is selected from N and CR9; R2is selected from H, C1-6alkyl and C1-6haloalkyl; X2is selected from N and CR10; R3, R4and R5are independently selected from H, halo, CN, C1-6alkyl and C1-6haloalkyl; X3is selected from N and CR11; R6and R7are independently selected from H, halo, CN, C1-6alkyl, C1-6haloalkyl, OC1-6alkyl and OC1-6haloalkyl; each R8is independently selected from OR12, NR12R13, C(O)NR12R13, C(O)OR12, =O, halo, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2- C3-10cycloalkyl and C3-10heterocycloalkyl,wherein all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR14, NR14R15and C1-6alkyl; R9, R10and R11are independently selected from H, halo, C1-6alkyl and C1-6haloalkyl; R12is selected from H, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl and C3-10heterocycloalkyl, the latter four groups being optionally substituted with one or two substituents selected from halo, OH, OC1-4alkyl and OC1-4fluoroalkyl; and R13, R14and R15are independently selected from H, C1-6alkyl and C1-6haloalkyl.

[0011] The present application also includes a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier.

[0012] The present application further includes a method of inhibiting general control nonderepressible 2 (GCN2) in a cell, either in a biological sample or in a patient, comprising administering an effective amount of one or more compounds of the application to the cell.

[0013] The present application also includes a method of treating a disease, disorder or condition that is treatable by inhibiting GCN2, comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.

[0014] The present application as also includes a method of treating a disease, disorder or condition that is treatable by inhibiting GCN2 comprising administering a therapeutically effective amount of one or more compounds of the application in combination with another known agent useful for treatment of the disease, disorder or condition treatable by inhibiting GCN2 to a subject in need thereof

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

[0016] In some embodiments, the disease, disorder or condition that is treatable by inhibiting GCN2, is cancer and / or a peripheral neuropathy including Charcot-Marie-Tooth (CMT) peripheral neuropathy.

[0017] The present application also includes a method of improving the efficacy of one or more cancer treatments for treating cancer comprising administering an effective amount ofone or more compounds of the application, in combination with an effective amount of the one or more cancer treatments.

[0018] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the application, are given by way of illustration only and the scope of the claims should not be limited by these embodiments but should be given the broadest interpretation consistent with the description as a whole. DETAILED DESCRIPTION I. Definitions

[0019] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the present application herein described for which they are suitable as would be understood by a person skilled in the art.

[0020] All features disclosed in the specification, including the claims, abstract, and drawings, and all the steps in any method or process disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. Each feature disclosed in the specification, including the claims, abstract, and drawings, can be replaced by alternative features serving the same, equivalent, or similar purpose, unless expressly stated otherwise

[0021] The term “compound of the application” or “compound of the present application” and the like as used herein refers to a compound of Formula I, including pharmaceutically acceptable salts, solvates and / or prodrugs thereof.

[0022] The term “composition of the application” or “composition of the present application” and the like as used herein refers to a composition comprising one or more compounds the application and at least one additional ingredient.

[0023] The term “and / or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of” or “one or more” of the listed items is used or present. The term “and / or” with respect to pharmaceutically acceptable salts and / or solvates thereof means that the compounds of the application exist as individual salts and hydrates, as well as a combination of, for example, a solvate of a salt of a compound the application.

[0024] As used in the present application, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise. For example, an embodiment including “a compound” should be understood to present certain aspects with one compound, or two or more additional compounds.

[0025] In embodiments comprising an “additional” or “second” component, such as an additional or second compound, the second component as used herein is chemically different from the other components or first component. A “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly 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, unrecited elements or process / method steps.

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

[0028] The term “consisting essentially of”, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps as well as those that do not materially affect the basic and novel characteristic(s) of these features, elements, components, groups, integers, and / or steps.

[0029] Terms of degree such as “substantially”, “about” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ^5% of the modified term if this deviation would not negate the meaning of the word it modifies.

[0030] The term “suitable” as used herein means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, the identity of the molecule(s) to be transformed and / or the specific use for the compound, but the selection would be well within the skill of a person trained in the art. All process / method steps described herein are to be conducted under conditions sufficient to provide the product shown. A person skilled in the art would understand that all reactionconditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so.

[0031] The present application refers to a number of chemical terms and abbreviations used by those skilled in the art. Nevertheless, definitions of selected terms are provided for clarity and consistency.

[0032] The term “protecting group” or “PG” and the like as used herein refers to a chemical moiety which protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule. The selection of a suitable protecting group can be made by a person skilled in the art. Many conventional protecting groups are known in the art, for example as described in “Protective Groups in Organic Chemistry” McOmie, J.F.W. Ed., Plenum Press, 1973, in Greene, T.W. and Wuts, P.G.M., “Protective Groups in Organic Synthesis”, John Wiley & Sons, 3rdEdition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0033] The term “cell” as used herein refers to a single cell or a plurality of cells and includes a cell either in a cell culture or in a subject.

[0034] The term “subject” as used herein includes all members of the animal kingdom including mammals. Thus, the methods and uses of the present application are applicable to both human therapy and veterinary applications.

[0035] The term “pharmaceutically acceptable” means compatible with the treatment of subjects.

[0036] The term “pharmaceutically acceptable carrier” means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with an active ingredient (for example, one or more compounds of the application) to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to a subject.

[0037] The term “pharmaceutically acceptable salt” means either an acid addition salt or a base addition salt which is suitable for, or compatible with the treatment of subjects.

[0038] An acid addition salt suitable for, or compatible with, the treatment of subjects 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 of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound.

[0040] The term “prodrug” as used herein means a compound, or salt and / or solvate of a compound, that, after administration, is converted into an active drug.

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

[0042] The term “inert organic solvent” as used herein refers to a solvent that is generally considered as non-reactive with the functional groups that are present in the compounds to be combined together in any given reaction so that it does not interfere with or inhibit the desired synthetic transformation. Organic solvents are typically non-polar and dissolve compounds that are nonsoluble in aqueous solutions.

[0043] The term “alkyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “Cn1-n2”. For example, the term C1-10alkyl means an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0044] The terms “halo” or “halogen” as used herein, whether it is used alone or as part of another group, refers to a halogen atom and includes fluoro, chloro, bromo and iodo.

[0045] The term “haloalkyl” as used herein refers to an alkyl group as defined above in which one or more of the available hydrogen atoms have been replaced with a halogen atom. Thus, for example, “C1-6 haloalkyl” (or “C1-C6 haloalkyl”) refers to a C1 to C6 linear or branched alkyl group as defined above with one or more halogen substituents.

[0046] The term “fluoroalkyl” as used herein refers to an haloalkyl group as defined above wherein the halogen atom is fluoro.

[0047] The term "chloroalkyl" as used herein refers to an haloalkyl group as defined above wherein the halogen atom is chloro.

[0048] The term “available”, as in “available hydrogen atoms” or “available atoms” refers to atoms that would be known to a person skilled in the art to be capable of replacement by another atom or group.

[0049] The term “alkenyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkyl groups containing at least one double bond. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “Cn1-n2”. For example, the term C2-6alkenyl means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms and at least one double bond.

[0050] The term “alkynyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkynyl groups containing at least one triple bond. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “Cn1-n2”. For example, the term C2-6alkynyl means an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms.

[0051] The term “cycloalkyl,” as used herein, whether it is used alone or as part of another group, means a saturated carbocyclic group containing from 3 to 20 carbon atoms and one or more rings. The number of carbon atoms that are possible in the referenced cycloalkyl group are indicated by the numerical prefix “Cn1-n2”. For example, the term C3-10cycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0052] The term “heterocycloalkyl” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing at least one non-aromatic ring containing from 3 to 10 atoms in which one or more of the atoms are a heteromoiety selected from O, S, S(O), SO2, N, NH and N(C1-6alkyl), and the remaining atoms are C. Heterocycloalkyl groups are either saturated or unsaturated (i.e. contain one or more double bonds). When a heterocycloalkyl group contains the prefix Cn1-n2 this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteroatom as defined above. Heterocycloalkyl groups are optionally benzofused.

[0053] All cyclic groups, including aryl, heteroaryl, heterocyclo and cycloalkyl groups, contain one (i.e. are monocyclic) or more than one ring (i.e. are polycyclic). When a cyclic group contains more than one ring, the rings may be fused, bridged or spirofused.

[0054] The term “benzofused” as used herein refers to a polycyclic group in which a benzene ring is fused with another ring.

[0055] A first ring being “fused” with a second ring means the first ring and the second ring share two adjacent atoms there between.

[0056] A first ring being “bridged” with a second ring means the first ring and the second ring share two non-adjacent atoms there between.

[0057] A first ring being “spirofused” with a second ring means the first ring and the second ring share one atom there between.

[0058] The term “optionally substituted” as used herein means that the referenced group is unsubstituted or substituted.

[0059] The term “substituted” as used herein means that the referenced atom contains at least one substituent group other that a hydrogen atom.

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

[0061] The symbol when drawn perpendicularly across a bond indicates a point of covalent attachment of a chemical group.

[0062] The term “LCMS” as used herein refers to liquid chromatography-mass spectrometry.

[0063] The term “NMR” as used herein refers to nuclear magnetic resonance.

[0064] The term “aq.” as used herein refers to aqueous.

[0065] The term “N” as used herein, for example in “4N”, refers to the unit symbol of normality to denote "eq / L".

[0066] The term “M” as used herein, for example in 4M, refers to the unit symbol of molarity to denote "moles / L".

[0067] The term “DIPEA” as used herein refers to N,N-diisopropyl ethylamine.

[0068] The term “DMF” as used herein refers to dimethylformamide.

[0069] The term “THF” as used herein refers to tetrahydrofuran.

[0070] The term “DMSO” as used herein refers to dimethylsulfoxide.

[0071] The term “EtOAc” as used herein refers to ethyl acetate.

[0072] The term “MeOH” as used herein refers to methanol.

[0073] The term “EtOH” as used herein refers to ethanol.

[0074] The term “MeCN” or “ACN” as used refers to acetonitrile.

[0075] The term “HCl” as used herein refers to hydrochloric acid.

[0076] The term “TFA” as used herein refers to trifluoroacetic acid.

[0077] The term “Hex” as used herein refers to hexanes.

[0078] The term “dppf” as used herein refers to 1,1'-bis(diphenylphosphino)ferrocene.

[0079] The term “RT” or “rt” as used herein refers to room temperature.

[0080] The term “HPLC” as used herein refers to high-performance liquid chromatography.

[0081] The term “TEA” or “Et3N” as used herein refer to triethylamine.

[0082] The term “EDTA” as used herein refers to ethylenediaminetetraacetic acid.

[0083] The term “ATP” as used herein refers to adenosine triphosphate.

[0084] The term “FBS” as used herein refers to fetal bovine serum.

[0085] The term “MEM” as used herein refers to Minimum Essential Medium.

[0086] The term “treating” or “treatment” as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of a disease, disorder or condition, stabilized (i.e. not worsening) state of a disease, disorder or condition, preventing spread of a disease, disorder or condition, delay or slowing of a disease, disorder or condition progression, amelioration or palliation of a disease, disorder or condition state, diminishment of the reoccurrence of a disease, disorder or condition, and remission (whether partial or total), whether detectable or undetectable. “Treating” and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. “Treating” and “treatment” as used herein also include prophylactic treatment.

[0087] “Palliating” a disease, disorder or condition means that the extent and / or undesirable clinical manifestations of the disease, disorder or condition are lessened and / or time course of the progression is slowed or lengthened, as compared to not treating the disease, disorder or condition.

[0088] The term “prevention” or “prophylaxis”, or synonym thereto, as used herein refers to a reduction in the risk or probability of a subject becoming afflicted with a disease,disorder or condition treatable by inhibition of GCN2 or manifesting a symptom associated with a disease, disorder or condition treatable by inhibition of GCN2.

[0089] As used herein, the term “effective amount” or “therapeutically effective amount” means an amount of a compound, or one or more compounds, of the application that is effective, at dosages and for periods of time necessary to achieve the desired result.

[0090] The term “disease, disorder or condition treatable by inhibiting GCN2” means that the disease, disorder or condition to be treated is affected by, modulated by and / or has some biological basis, either direct or indirect, that includes GCN2 activity, in particular, increased GCN2 activity. These diseases respond favourably when GCN2 activity associated with the disease, disorder or condition is inhibited by one or more of the compounds or compositions of the application.

[0091] The expression “inhibiting GCN2” as used herein refers to inhibiting, blocking and / or disrupting the kinase activity or function of GCN2 in a cell. The inhibiting, blocking and / or disrupting causes a therapeutic effect in the cell.

[0092] By “inhibiting, blocking and / or disrupting” it is meant any detectable inhibition, block and / or disruption in the presence of a compound compared to otherwise the same conditions, except for in the absence in the compound.

[0093] The term “GCN2” as used herein refers to General Control Nonderepressible 2, or any functional mutant or analogous forms thereof.

[0094] The expression “low asparagine synthetase (ASNS) expression” as used herein means any detectable decrease or reduction in the level of asparagine synthetase (ASNS) in a cancer cell, under otherwise the same conditions, except in a healthy cell.

[0095] The expression “asparagine synthetase (ASNS) overexpression or dysregulation” as used herein means any detectable increase in the level of asparagine synthetase (ASNS) in a cancer cell, under otherwise the same conditions, except in a healthy cell.

[0096] The expression “low glutaminase expression” as used herein means any detectable decrease or reduction in the level of glutaminase (e.g., GLS1) in a cancer cell, under otherwise the same conditions, except in a healthy cell.

[0097] The expression “glutaminase overexpression or dysregulation” as used herein means any detectable increase in the level of glutaminase (e.g., GLS1) in a cancer cell, under otherwise the same conditions, except in a healthy cell.

[0098] The term “GLS1” as used herein refers to the “kidney type” glutaminase or any functional mutant or analogous forms thereof.

[0099] The term “administered” as used herein means administration of a therapeutically effective amount of a compound, or one or more compounds, or a composition of the application to a cell or a subject.

[0100] The term “neoplastic disorder” as used herein refers to a disease, disorder or condition characterized by cells that have the capacity for autonomous growth or replication, e.g., an abnormal state or condition characterized by proliferative cell growth. The term “neoplasm” as used herein refers to a mass of tissue resulting from the abnormal growth and / or division of cells in a subject having a neoplastic disorder. Neoplasms can be benign (such as uterine fibroids and melanocytic nevi), potentially malignant (such as carcinoma in situ) or malignant (i.e., cancer).

[0101] The term “fibrosis” as used herein refers to a disease, disorder or condition the thickening and scarring of connective tissue, usually as a result of injury. II. Compounds of the Application

[0102] Pyrimidopyridone and pteridone compounds of the present application were prepared and found to inhibit kinase general control nonderepressible 2 (GCN2).

[0103] Accordingly, the present application includes a compound of Formula I, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:wherein R1is selected from H, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl and C3-10heterocycloalkyl, the latter four groups being optionally substituted with one or two R8; X1is selected from N and CR9; R2is selected from H, C1-6alkyl and C1-X2is selected from N and CR10; R3, R4and R5are independently selected from H, halo, CN, C1-6alkyl and C1-6haloalkyl; X3is selected from N and CR11; R6and R7are independently selected from H, halo, CN, C1-6alkyl, C1-6haloalkyl, OC1-6alkyl and OC1-6haloalkyl; each R8is independently selected from OR12, NR12R13, C(O)NR12R13, C(O)OR12, =O, halo, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl and C3-10heterocycloalkyl, wherein all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR14, NR14R15and C1-6alkyl; R9, R10and R11are independently selected from H, halo, C1-6alkyl and C1-6haloalkyl; R12is selected from H, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl and C3-10heterocycloalkyl, the latter four groups being optionally substituted with one or two substituents selected from halo, OH, OC1-4alkyl and OC1-4fluoroalkyl; and R13, R14and R15are independently selected from H, C1-6alkyl and C1-6haloalkyl.

[0104] The present application also includes a compound of Formula I, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:wherein R1is selected from H, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl and C3-10heterocycloalkyl, the latter four groups being optionally substituted with one or two R8; X1is selected from N and CR9; R2is selected from H, C1-6alkyl and C1-6haloalkyl; X2is selected from N and CR10; R3, R4and R5are independently selected H, halo, CN, C1-6alkyl and C1-6haloalkyl;X3is selected from N and CR11; R6and R7are independently selected from H, halo, CN, C1-6alkyl, C1-6haloalkyl, OC1-6alkyl and OC1-6haloalkyl; each R8is independently selected from OR12, NR12R13, C(O)NR12R13, halo, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl and C3-10heterocycloalkyl, wherein all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR14, NR14R15and C1-6alkyl; R9, R10and R11are independently selected from H, halo, C1-6alkyl and C1-6haloalkyl; R12is selected from H, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl and C3-10heterocycloalkyl, the latter four groups being optionally substituted with one or two substituents selected from halo, OH, OC1-4alkyl and OC1-4fluoroalkyl; and R13, R14and R15are independently selected from H, C1-6alkyl and C1-6haloalkyl.

[0105] In some embodiments, R1is selected from H, C1-6alkyl, C1-6haloalkyl, C3- 10cycloalkyl and C3-10heterocycloalkyl, the latter four groups being optionally substituted with one R8. In some embodiments, R1is selected from C3-10cycloalkyl and C3- 10heteroycloalkyl, each of which is optionally substituted with one or two R8.

[0106] In some embodiments, R1is selected from H, C1-6alkyl and C1-6haloalkyl. In some embodiments, R1is selected from H, C1-4alkyl and C1-4haloalkyl. In some embodiments, R1is selected from H, C1-4alkyl and C1-4fluoroalkyl. In some embodiments, R1is selected from H, CH3, CF3, CHF2, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3 and CH(CH3)3. In some embodiments, R1is selected from H, CH3, CH2CH3 and CH(CH3)2.

[0107] In some embodiments, R1is C3-10cycloalkyl optionally substituted with one or two R8. In some embodiments, R1is a monocyclic C3-10cycloalkyl or a bicyclic C5- 10cycloalkyl, each of which is optionally substituted with one or two R8. In some embodiments, R1is monocyclic C3-8cycloalkyl optionally substituted with one or two R8. In some embodiments, the monocyclic C3-8cycloalkyl in R1is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each of which is optionally substituted with one or two R8. In some embodiments, R1is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each of which is optionally substituted with one R8. In some embodiments, R1is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each of which are unsubstituted. In some embodiments, R1is cyclopropyl. In some embodiments, R1is selected from cyclopentyl and cyclohexyl, each ofwhich is substituted with one or two R8. In some embodiments, R1is cyclohexyl substituted with one or two R8. In some embodiments, R1is selected from cyclobutyl and cyclohexyl, each of which is substituted with one R8. In some embodiments, R1is cyclobutyl substituted with one R8. In some embodiments, R1is cyclohexyl substituted with one R8.

[0108] In some embodiments, R1is a spirofused C5-10cycloalkyl or a bridged C5-10cycloalkyl each of which is optionally substituted with one or two R8. In some embodiments, the spirofused C5-10cycloalkyl is 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 is optionally substituted with one or two R8. In some embodiment, the spirofused C6- 10cycloalkyl is spiro[3.3]heptane substituted optionally with one or two R8. In some embodiments, the spirofused C5-10cycloalkyl.

[0109] In some embodiments, R1is a bridged C5-10cycloalkyl optionally substituted with one or two R8. In some embodiments, the bridged C5-10cycloalkyl is selected from a bicyclopentanyl, a bicycloheptanyl and a bicyclooctanyl each of which optionally substituted with one or two R8. In some embodiments, the bridged C5-10cycloalkyl is selected from a bicyclopentanyl, a bicycloheptanyl and a bicyclooctanyl each of which is optionally substituted with one R8. In some embodiments, the bridged C5-10cycloalkyl is selected from, .

[0110] In some embodiments, R1is C3-10heterocycloalkyl optionally substituted with one or two R8. In some embodiments, R1is C3-10heterocycloalkyl optionally substituted with one R8. In some embodiments, R1is C3-6heterocycloalkyl optionally substituted with one R8. In some embodiments, R1is selected from aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl and thiepanyl, each of which is optionally substituted with one or two R8. In some embodiments, R1is selected from thietanyl, tetrahydrofuranyl, tetrahydropyranyl,thiomorpholinyl, aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl, each of which is optionally substituted with one R8. In some embodiments, R1is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one R8. In some embodiments, R1is selected from oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, each of which is optionally substituted with one R8. In some embodiments, R1is selected from oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, each of which is unsubstituted.

[0111] In some embodiments, X1is selected from N and CH. In some embodiments, X1is N. In some embodiments, X1is CH.

[0112] In some embodiments, R2is selected from H, C1-4alkyl and C1-4haloalkyl. In some embodiments, R2is selected from is selected from H, C1-4alkyl and C1-4fluoroalkyl. In some embodiments, R2is selected from H, CH3, CF3, CHF2, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3 and CH(CH3)3. In some embodiments, R2is selected from H, CH3, CH2CH3 and CH(CH3)2. In some embodiments, R2is selected from H, CH3 and CH(CH3)2. In some embodiments, R2is selected from H and CH3.

[0113] In some embodiments X2is selected from N and CH. In some embodiments, X1is N. In some embodiments X2is CH.

[0114] In some embodiments, R3, R4and R5are not all H. In some embodiments, R3, R4and R5are independently selected from H, halo, CN, C1-4alkyl and C1-4haloalkyl. In some embodiments, at least one of R3, R4and R5is selected from halo, CN and C1- 4haloalkyl. In some embodiments, at least one of R3and R5is selected from halo, CN and C1-4haloalkyl. In some embodiments, at least one of R3, R4and R5is selected from halo and CN. In some embodiments, at least one of R3and R5is selected from halo and CN. In some embodiments, at least one of R3, R4and R5is halo. In some embodiments, at least one of R3and R5is halo. In some embodiments, R3, R4and R5are independently selected from H, Cl, F, Br, CN, C1-4alkyl and C1-4fluoroalkyl. In some embodiments, at least one of R3, R4and R5is selected from F, Cl, Br, CN and C1-4fluoroalkyl. In some embodiments, at least one of R3and R5is selected from F, Cl, Br, CN and C1-4fluoroalkyl. In some embodiments, R3, R4and R5are independently selected from H, Cl, F, CN, CH3 and CF3. In some embodiments, at least one of R3, R4and R5is selected from Cl, F, CN and CF3. In some embodiments, at least one of R3, R4and R5is selected from Cl, F and CN. In some embodiments, at least one of R3and R5is selected from Cl, F and CN. In some embodiments, R3, R4and R5are selected from H, F and CN. In someembodiments, at least one of R3, R4and R5is selected from F and CN. In some embodiments, at least one of R3and R5is selected from F and CN. In some embodiments, at least one of R3and R5is selected from F and CN and R4is H. In some embodiments, R3is CN, R4is H and R5is H. In some embodiments, R3is H, R4is H and R5is CN. In some embodiments, R3and R5are independently selected from H, F and CN and R4is H. In some embodiments, R3and R5are independently selected from H and F and R4is H. In some embodiments, at least one of R3and R5is F. In some embodiments, at least one of R3and R5is F and R4is H. In some embodiments, R3and R5are both F and R4is H. In some embodiments, R3is F, R4is H and R5is F. In some embodiments, R3is F, R4is H and R5is H. In some embodiments, R3is H, R4is H and R5is F.

[0115] In some embodiments, X3is selected from N and CH. In some embodiments, X3is CH.

[0116] In some embodiments, R6and R7are independently selected from H, Cl, F, Br, CN, C1-4alkyl, C1-4fluoroalkyl, OC1-4alkyl and OC1-4fluoroalkyl. In some embodiments, R6and R7are independently selected from H, Cl, F, CN, CH3, CHF2, CF3, CH2CH3, OCH3, OCHF2 and OCF3. In some embodiments, R6and R7are independently selected from Cl, F, CH3, CF3, CHF2, CH2CH3, OCH3, OCHF2 and OCF3. In some embodiments, R6is selected from OCH3 and OCF3 and R7is selected from Cl, F, CH3, and CF3. In some embodiments, R6is selected from OCH3 and OCF3 and R7is Cl. In some embodiments, R6is OCH3 and R7is Cl.

[0117] In some embodiments, each R8is independently selected from OR12, C(O)NR12R13, C(O)OR12, =O, NR12R13, halo, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4alkynyl, C3-10cycloalkyl and C3-10heterocycloalkyl, wherein all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR14, NR14R15and C1-4alkyl. In some embodiments, each R8is independently selected from OR12, C(O)NR12R13, NR12R13, halo, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2- 4alkynyl, C3-10cycloalkyl and C3-10heterocycloalkyl, wherein all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR14, NR14R15and C1-4alkyl. In some embodiments, each R8is independently selected from OR12, C(O)NR12R13, C(O)OR12, =O, NR12R13, Cl, F, Br, C1-4alkyl, C1-4fluoroalkyl, C3-6cycloalkyl and C3-6heterocycloalkyl, wherein all alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from Cl, Br, F, OR14, NR14R15and C1-4alkyl. In embodiments, each R8is independentlyselected from OR12, C(O)NR12R13, NR12R13, Cl, F, Br, C1-4alkyl, C1-4fluoroalkyl, C3-6cycloalkyl and C3-6heterocycloalkyl, wherein all alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from Cl, Br, F, OR14, NR14R15and C1-4alkyl. In some embodiments, each R8is independently selected from OR12, NR12R13, C(O)NR12R13, C(O)OR12, =O, Cl, F, CH3, CHF2, CH3CH3and CF3.In some embodiments, each R8is independently selected from OR12, NR12R13, C(O)NR12R13, Cl, F, CH3, CHF2, CH3CH3and CF3. In some embodiments, each R8is independently selected from Cl, F, CH3, CHF2, CH3CH3and CF3. In some embodiments, each R8is independently selected from CH3, CHF2, CH3CH3 and CF3. In some embodiments, each R8is independently selected from OR12,NR12R13and C(O)NR12R13. In some embodiments, each R8is independently selected from NR12R13and C(O)NR12R13. In some embodiments, each R8is independently selected from =O and C(O)OR12. In some embodiments, each R8is =O. In some embodiments, each R8is C(O)OR12. In some embodiments when each R8is independently selected from OR12, C(O)NR12R13, C(O)OR12, =O, NR12R13, C3-10cycloalkyl and C3-10heterocycloalkyl, R1is substituted with only one R8.

[0118] In some embodiments, R9, R10and R11are independently selected from H, Cl, Br, F, C1-4alkyl and C1-4fluoroalkyl. In some embodiments, R9, R10and R11are independently selected from H, Cl, F, CH3, CF3, CHF2, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3 and CH(CH3)3. In some embodiments, R9, R10and R11are independently selected from H, Cl, F, CH3 and CF3. In some embodiments, R9, R10and R11are independently selected from H and F. In some embodiments, R9, R10and R11are H.

[0119] In some embodiments, R12is selected from H, C1-4alkyl, C1-4fluoroalkyl, C3- 10cycloalkyl and C3-10heterocycloalkyl, the latter four groups being optionally substituted with one or two substituents selected from Cl, F, Br, OH, OCH3 and OCF3. In some embodiments, R12is selected from H, CH3, CF3, CHF2, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3 and CH(CH3)3. In some embodiments, R12is selected from H, CH3 and CF3. In some embodiments, R12is selected from H and CH3. In some embodiments, R12is CH3.

[0120] In some embodiments, R13is selected from H, C1-4alkyl and C1-4fluoroalkyl. In some embodiments, R13is selected from H, CH3, CF3, CHF2, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3and CH(CH3)3. In some embodiments, R13is selected from H, CH3and CF3. In some embodiments, R13is selected from H and CH3.

[0121] In some embodiments, R14and R15are independently selected from H, C1-4alkyl and C1-4fluoroalkyl. In some embodiments, R14and R15are independently selected from H, CH3, CF3, CHF2, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3and CH(CH3)3. In some embodiments, R14and R15are independently selected from H, CH3and CF3. In some embodiments, R14and R15are independently selected from H and CH3.

[0122] In some embodiments, the compounds of Formula I are selected from:Compound I.D. Structure CHEMICAL NAME N-(3-(2-Amino-8-isopropyl-7- I-1 oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)-2,4- difluorophenyl)-5-chloro-2- methoxypyridine-3- sulfonamide; trans-5-Chloro-N-(3-(2-((4- (dimethylamino)cyclohexyl)ami trans I-2 no)-8-ethyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6- yl)-2-fluorophenyl)-2- methoxypyridine-3- sulfonamide; trans-5-Chloro-N-(3-(2-((4- (dimethylamino)cyclohexyl)ami trans I-3 no)-8-ethyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6- yl)-4-fluorophenyl)-2- methoxypyridine-3- sulfonamide; trans-5-Chloro-N-(3-(2-((4- (dimethylamino)cyclohexyl)ami trans I-4 no)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6- yl)-2,4-difluorophenyl)-2- methoxypyridine-3- sulfonamide;N-(3-(2-Amino-8-methyl-7-oxo- 7,8-dihydropyrido[2,3- I-5 d]pyrimidin-6-yl)-2,4- difluorophenyl)-5-chloro-2- methoxypyridine-3- sulfonamide; 5-Chloro-N-(2,4-difluoro-3-(8- methyl-2-(methylamino)-7-oxo- I-6 7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)phenyl)-2- methoxypyridine-3- sulfonamide; trans-5-Chloro-N-(3-(2-((4- (dimethylamino)cyclohexyl)ami trans I-7 no)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6- yl)-4-fluorophenyl)-2- methoxypyridine-3- sulfonamide; 5-Chloro-N-(4-fluoro-3-(8- I-8 methyl-2-(methylamino)-7-oxo- 7,8-dihydropteridin-6- yl)phenyl)-2-methoxypyridine-3- sulfonamide;trans-5-Chloro-N-(3-(2-((4- (dimethylamino)cyclohexyl)ami trans I-9 no)-8-methyl-7-oxo-7,8- dihydropteridin-6-yl)-4- fluorophenyl)-2- methoxypyridine-3- sulfonamide; trans-5-Chloro-N-(3-(2-((4- (dimethylamino)cyclohexyl)ami trans I-10 no)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6- yl)-2-fluorophenyl)-2- methoxypyridine-3- sulfonamide; trans-5-Chloro-N-(2-cyano-3-(2- ((4- trans I-11 (dimethylamino)cyclohexyl)ami no)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6- yl)phenyl)-2-methoxypyridine-3- sulfonamide; 5-Chloro-N-(2-fluoro-3-(2- I-12 (methylamino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6- yl)phenyl)-2-methoxypyridine-3- sulfonamide;5-Chloro-N-(4-fluoro-3-(2- I-13 (isopropylamino)-8-methyl-7- oxo-7,8-dihydropteridin-6- yl)phenyl)-2-methoxypyridine-3- sulfonamide; 5-Chloro-N-(3-(2-(ethylamino)- 8-methyl-7-oxo-7,8- I-14 dihydropteridin-6-yl)-4- fluorophenyl)-2- methoxypyridine-3- sulfonamide; 5-Chloro-N-(2,4-difluoro-3-(8- I-15 methyl-2-(methylamino)-7-oxo- 7,8-dihydropteridin-6- yl)phenyl)-2-methoxypyridine-3- sulfonamide; 5-Chloro-N-(3-(2-(ethylamino)- 8-methyl-7-oxo-7,8- I-16 dihydropyrido[2,3-d]pyrimidin-6- yl)-2,4-difluorophenyl)-2- methoxypyridine-3- sulfonamide; 5-Chloro-N-(3-(2-(ethylamino)- 7-oxo-7,8-dihydropyrido[2,3- I-17 d]pyrimidin-6-yl)-4- fluorophenyl)-2- methoxypyridine-3- sulfonamide;5Cchloro-N-(4-fluoro-3-(2- I-18 (isopropylamino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6- yl)phenyl)-2-methoxypyridine-3- sulfonamide; 5-Chloro-N-(4-fluoro-3-(2- (isopropylamino)-8-methyl-7- I-19 oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)phenyl)-2- methoxypyridine-3- sulfonamide; 5-Chloro-N-(2-fluoro-3-(8- I-20 methyl-2-(methylamino)-7-oxo- 7,8-dihydropteridin-6- yl)phenyl)-2-methoxypyridine-3- sulfonamide; 5-Chloro-N-(3-(2- (cyclopropylamino)-8-methyl-7- I-21 oxo-7,8-dihydropteridin-6-yl)-4- fluorophenyl)-2- methoxypyridine-3- sulfonamide;(R)-5-Chloro-N-(4-fluoro-3-(8- methyl-7-oxo-2- (R)-I-22 ((tetrahydrofuran-3-yl)amino)- 7,8-dihydropteridin-6- yl)phenyl)-2-methoxypyridine-3- sulfonamide; 5-Chloro-N-(4-fluoro-3-(8- I-23 methyl-2-(oxetan-3-ylamino)-7- oxo-7,8-dihydropteridin-6- yl)phenyl)-2-methoxypyridine-3- sulfonamide; 5-Chloro-N-(4-fluoro-3-(8- methyl-7-oxo-2-((tetrahydro-2H- I-24 pyran-4-yl)amino)-7,8- dihydropteridin-6-yl)phenyl)-2- methoxypyridine-3- sulfonamide;5-Chloro-N-(3-(2-(ethylamino)- 7-oxo-7,8-dihydropyrido[2,3- I-25 d]pyrimidin-6-yl)-2- fluorophenyl)-2- methoxypyridine-3- sulfonamide; 5-Chloro-N-(4-fluoro-3-(2- I-26 (methylamino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6- yl)phenyl)-2-methoxypyridine-3- sulfonamide; 5-Chloro-N-(4-fluoro-3-(8- methyl-2-(methylamino)-7-oxo- I-27 7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)phenyl)-2- methoxypyridine-3- sulfonamide; 5-Chloro-N-(2-fluoro-3-(8- methyl-2-(methylamino)-7-oxo- I-28 7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)phenyl)-2- methoxypyridine-3- sulfonamide; N-(3-(2-Amino-8-methyl-7-oxo- 7,8-dihydropyrido[2,3- I-29 d]pyrimidin-6-yl)-4- fluorophenyl)-5-chloro-2- methoxypyridine-3- sulfonamide;N-(3-(2-Amino-8-methyl-7-oxo- 7,8-dihydropyrido[2,3- I-30 d]pyrimidin-6-yl)-2- fluorophenyl)-5-chloro-2- methoxypyridine-3- sulfonamide; 5-Chloro-N-(5-fluoro-4-(8- methyl-2-(methylamino)-7-oxo- I-31 7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)pyridin-2-yl)-2- methoxypyridine-3- sulfonamide; 5-Chloro-N-(3-fluoro-4-(2- (methylamino)-7-oxo-7,8- I-32 dihydropyrido[2,3-d]pyrimidin-6- yl)pyridin-2-yl)-2- methoxypyridine-3- sulfonamide; trans-4-((6-(5-((5-Chloro-2- methoxypyridine)-3- trans I-33 sulfonamido)-2-fluorophenyl)-8- methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2- yl)amino)cyclohexane-1- carboxamide; cis-4-((6-(5-((5-Chloro-2- methoxypyridine)-3- cis I-33 sulfonamido)-2-fluorophenyl)-8- methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2- yl)amino)cyclohexane-1- carboxamide; trans-4-((6-(5-((5-Chloro-2- methoxypyridine)-3- sulfonamido)-2-fluorophenyl)-8- trans I-34 methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-N- methylcyclohexane-1- carboxamide;cis-4-((6-(5-((5-Chloro-2- methoxypyridine)-3- sulfonamido)-2-fluorophenyl)-8- cis I-34 methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-N- methylcyclohexane-1- carboxamide; trans-3-((6-(3-((5-Chloro-2- methoxypyridine)-3- trans I-35 sulfonamido)-2-fluorophenyl)-8- methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-N-methylcyclobutane- 1-carboxamide rac-(1R,3S)-3-((6-(3-((5-Chloro- 2-methoxypyridine)-3- rac-(1R,3S) sulfonamido)-2-fluorophenyl)-8- I-36 methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-N- methylcyclohexane-1- carboxamide; rac-(1R,3R)-3-((6-(3-((5-Chloro- 2-methoxypyridine)-3- rac-(1R,3R) sulfonamido)-2-fluorophenyl)-8- I-36 methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-N- methylcyclohexane-1- and carboxamide; cis-3-((6-(3-((5-Chloro-2- methoxypyridine)-3- cis I-37 sulfonamido)-2-fluorophenyl)-8- methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2- yl)amino)cyclobutane-1- carboxamide; Potassium ((5-chloro-2- methoxypyridin-3-yl)sulfonyl)(2- I-38.K fluoro-3-(2-(methylamino)-7- oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)phenyl)amide;Potassium ((5-chloro-2- methoxypyridin-3-yl)sulfonyl)(3- I-25.K (2-(ethylamino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6- yl)-2-fluorophenyl)amide; 4-((6-(3-((5-Chloro-2- methoxypyridine)-3- sulfonamido)-2-fluorophenyl)-8- I-39A / 39B methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-1-fluorocyclohexane- 1-carboxamide; (1R,3S)-3-((6-(3-((5-Chloro-2- methoxypyridine)-3- sulfonamido)-2-fluorophenyl)-8- cis I-40 methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2- yl)amino)cyclopentane-1- carboxamide; 5-Chloro-N-(2-fluoro-3-(8- methyl-7-oxo-2-((6- I-41 oxopiperidin-3-yl)amino)-7,8- dihydropyrido[2,3-d]pyrimidin-6- yl)phenyl)-2-methoxypyridine-3- sulfonamide; tert-Butyl 3-((6-(3-((5-chloro-2- methoxypyridine)-3- sulfonamido)-2-fluorophenyl)-8- I-42 methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2- yl)amino)azetidine-1- carboxylate; Ethyl 4-((6-(3-((5-chloro-2- methoxypyridine)-3- sulfonamido)-2-fluorophenyl)-8- I-43 methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2- yl)amino)piperidine-1- carboxylate;N-(3-(2-((1-Acetylpiperidin-4- yl)amino)-8-methyl-7-oxo-7,8- I-44 dihydropyrido[2,3-d]pyrimidin-6- yl)-2-fluorophenyl)-5-chloro-2- methoxypyridine-3- sulfonamide; (R)-5-Chloro-N-(2-fluoro-3-(8- methyl-7-oxo-2-((5- (R)-I-45 oxopyrrolidin-3-yl)amino)-7,8- dihydropyrido[2,3-d]pyrimidin-6- yl)phenyl)-2-methoxypyridine-3- sulfonamide; (S)-5-Chloro-N-(2-fluoro-3-(8- methyl-7-oxo-2-((5- (S)-I-45 oxopyrrolidin-3-yl)amino)-7,8- dihydropyrido[2,3-d]pyrimidin-6- yl)phenyl)-2-methoxypyridine-3- sulfonamide; 5-Chloro-N-(2-fluoro-3-(2- (isopropylamino)-7-oxo-7,8- I-46 dihydropyrido[2,3-d]pyrimidin-6- yl)phenyl)-2-methoxypyridine-3- sulfonamide; 5-Chloro-N-(3-(2- (cyclopropylamino)-7-oxo-7,8- I-47 dihydropyrido[2,3-d]pyrimidin-6- yl)-4-fluorophenyl)-2- methoxypyridine-3- sulfonamide; 5-Chloro-N-(3-(2- (cyclopropylamino)-7-oxo-7,8- I-48 dihydropyrido[2,3-d]pyrimidin-6- yl)-2-fluorophenyl)-2- methoxypyridine-3- sulfonamide; 5-Chloro-N-(3-(2-(ethylamino)- 7-oxo-7,8-dihydropyrido[2,3- I-49 d]pyrimidin-6-yl)-2,4- difluorophenyl)-2- methoxypyridine-3- sulfonamide; and5-Chloro-N-(2,4-difluoro-3-(2- (methylamino)-7-oxo-7,8- I-50 dihydropyrido[2,3-d]pyrimidin-6- yl)phenyl)-2-methoxypyridine-3- sulfonamide; or a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

[0123] In some embodiments the pharmaceutically acceptable salt is an acid addition salt or a base addition salt. The selection of a suitable salt may be made by a person skilled in the art (see, for example, S. M. Berge, et aI., "Pharmaceutical Salts," J. Pharm. Sci.1977, 66, 1-19).

[0124] An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound. Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids. Illustrative of such organic acids are, for example, acetic, formic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2- phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid. In an embodiment, the mono- or di-acid salts are formed, and such salts exist in either a hydrated, solvated or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the application for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. In some embodiments, the acid addition salt is a hydrochloric or formic acid addition salt.

[0125] A base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound. Acidic compounds that form a basic salt include, for example, compoundscomprising a carboxylic acid group. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide as well as ammonia. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The selection of the appropriate salt may be useful, for example, so that an ester functionality, if any, elsewhere in a compound is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.

[0126] Solvates of compounds of the application include, for example, those made with solvents that are pharmaceutically acceptable. Examples of such solvents include water (resulting solvate is called a hydrate) and ethanol and the like. Suitable solvents are physiologically tolerable at the dosage administered.

[0127] In some embodiments of the present application, the compounds described herein have at least one asymmetric center. Where compounds possess more than one asymmetric center, they may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present application. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (for example, less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of the present application having an alternate stereochemistry. It is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the present application.

[0128] The compounds of the present application may also exist in different tautomeric forms and it is intended that any tautomeric forms which the compounds form, as well as mixtures thereof, are included within the scope of the present application.

[0129] The compounds of the present application may further exist in varying polymorphic forms and it is contemplated that any polymorphs, or mixtures thereof, which form are included within the scope of the present application.

[0130] The compounds of the present application may further be radiolabeled and accordingly all radiolabeled versions of the compounds of the application are included within the scope of the present application. The compounds of the application also include those in which one or more radioactive atoms are incorporated within their structure. III. Compositions of the Application

[0131] The compounds of the present application are suitably formulated in a conventional manner into compositions using one or more carriers. Accordingly, the present application also includes a composition comprising one or more compounds of the application and a carrier. The compounds of the application are suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present application further includes a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier. In embodiments of the application the pharmaceutical compositions are used in the treatment of any of the diseases, disorders or conditions described herein.

[0132] The compounds of the application are administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. For example, a compound of the application is administered by oral, inhalation, parenteral, buccal, sublingual, nasal, rectal, vaginal, patch, pump, minipump, topical or transdermal administration and the pharmaceutical compositions formulated accordingly. In some embodiments, administration is by means of a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington’s Pharmaceutical Sciences (2000 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.

[0133] Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract, and includes, for example intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (for example, by use of an aerosol), intrathecal, rectal and topical (including the use of a patchor other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0134] In some embodiments, a compound of the application is orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it is enclosed in hard or soft shell gelatin capsules, or it is compressed into tablets, or it is incorporated directly with the food of the diet. In some embodiments, the compound is incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions, and the like. In the case of tablets, carriers that are used include lactose, corn starch, sodium citrate and salts of phosphoric acid. Pharmaceutically acceptable excipients include binding agents (e.g., pregelatinized maize 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 sulphate). In embodiments, the tablets are coated by methods well known in the art. In the case of tablets, capsules, caplets, pellets or granules for oral administration, pH sensitive enteric coatings, such as Eudragits™ designed to control the release of active ingredients are optionally used. Oral dosage forms also include modified release, for example immediate release and timed-release, formulations. Examples of modified-release formulations include, for example, sustained-release (SR), extended- release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet. Timed-release compositions are formulated, for example as liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. In some embodiments, liposomes are formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. For oral administration in a capsule form, useful carriers or diluents include lactose and dried corn starch.

[0135] In some embodiments, liquid preparations for oral administration take the form of, for example, solutions, syrups or or they are suitably presented as adry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, the compound of the application is suitably suspended or dissolved in an oily phase that is combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents are added. Such liquid preparations for oral administration are prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0136] It is also possible to freeze-dry the compounds of the application and use the lyophilizates obtained, for example, for the preparation of products for injection.

[0137] In some embodiments, a compound of the application is administered parenterally. For example, solutions of a compound of the application are prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. A person skilled in the art would know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds of the application are usually prepared, and the pH’s of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments or droppable liquids are delivered, for example, by ocular delivery systems known to the art such as applicators or eye droppers. In some embodiment, such compositions include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzyl chromium chloride, and the usual quantities of diluents or carriers. For pulmonary administration, diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.

[0138] In some embodiments, a compound of the application is formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection are, for example, presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. In some embodiments, the compositions take such forms as sterile suspensions, solutions oremulsions in oily or aqueous vehicles, and contain formulating agents such as suspending, stabilizing and / or dispersing agents. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. Alternatively, the compounds of the application are suitably in a sterile powder form for reconstitution with a suitable vehicle, e.g., 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 administration or administration by inhalation, the compounds of the application are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a 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 single or multidose quantities in sterile form in a sealed container, which, for example, take the form of a cartridge or refill for use with an atomising device. Alternatively, the sealed container is a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which is, for example, a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. Suitable propellants include but are not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to deliver a metered amount. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator are, for example, formulated containing a powder mix of a compound of the application and a suitable powder base such as lactose or starch. The aerosol dosage forms can also take the form of a pump-atomizer.

[0140] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein a compound of the application is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0141] Suppository forms of the compounds of the application are useful for vaginal, urethral and rectal administrations. Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature. The substances commonly used to create such vehicles include but are not limited to theobroma oil (also known as cocoa butter), glycerinated gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. See, for example: Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533 for further discussion of suppository dosage forms.

[0142] In some embodiments a compound of the application is coupled with soluble polymers as targetable drug carriers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, a compound of the application is coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.

[0143] In some embodiments, compounds of the application may be coupled with viral, non-viral or other vectors. Viral vectors may include retrovirus, lentivirus, adenovirus, herpesvirus, poxvirus, alphavirus, vaccinia virus or adeno-associated viruses. Non-viral vectors may include nanoparticles, cationic lipids, cationic polymers, metallic nanoparticles, nanorods, liposomes, micelles, microbubbles, cell-penetrating peptides, or lipospheres. Nanoparticles may include silica, lipid, carbohydrate, or other pharmaceutically acceptable polymers.

[0144] A compound of the application including pharmaceutically acceptable salts and / or solvates thereof is suitably used on their own but will generally be administered in the form of a pharmaceutical composition in which the one or more compounds of the application (the active ingredient) is in association with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the active ingredient, and from about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90wt% of a pharmaceutically acceptable carrier, all percentages by weight being based on the total composition. IV. Methods and Uses of the Application

[0145] The compounds of the application have been shown to inhibit or block general control nonderepressible 2 (GCN2) kinase, to attenuate the transcriptional function of ATF4 target gene expression. Therefore, the compounds of the application are useful for inhibiting GCN2.

[0146] Accordingly, the present application includes a method of inhibiting general control nonderepressible 2 (GCN2) in a cell, either in a biological sample or in a patient, comprising administering an effective amount of one or more compounds of the application to the cell.

[0147] The present application also includes a use of one or more compounds of the application for inhibiting GCN2 in a cell as well as a use of one or more compounds of the application for the preparation of a medicament for inhibiting GCN2 in a cell. The application further includes one or more compounds of the application for use in inhibiting GCN2 in a cell.

[0148] As the compounds of the application have been shown to be capable of inhibiting GCN2 protein activity, the compounds of the application are useful for treating diseases, disorders or conditions by inhibiting GCN2. Therefore, the compounds of the present application are useful as medicaments. Accordingly, the present application includes a compound of the application for use as a medicament.

[0149] Accordingly, the present application also includes a method of treating a disease, disorder or condition that is treatable by inhibiting GCN2, comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.

[0150] The present application also includes a use of one or more compounds of the application for treatment of a disease, disorder or condition that is treatable by inhibiting GCN2, as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a disease, disorder or condition that is treatable by inhibiting GCN2. The application further includes one or more compounds of the application for use in treating a disease, disorder or condition that is treatable by inhibiting GCN2.

[0151] “GCN2” is a protein kinase that belongs to the family of eukaryotic initiation factor 2 α (eIF2α) kinases. In some embodiments, this serine / threonine-protein kinase is an enzyme that in humans is encoded by the GCN2 or EIF2AK4 (Gene ID: 851877) comprising the amino acid sequence disclosed in Mol. Cell. Biol.1995,15 (8): 4497–506.

[0152] In some embodiments, the disease, disorder or condition that is treatable by inhibiting GCN2 is a neoplastic disorder. Accordingly, the present application also includes a method of treating a neoplastic disorder comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof. The present application also includes a use of one or more compounds of the application for treatment of a neoplastic disorder as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a neoplastic disorder. The application further includes one or more compounds of the application for use in treating a neoplastic disorder. In some embodiments, the treatment is in an amount effective to ameliorate at least one symptom of the neoplastic disorder, for example, reduced cell proliferation or reduced tumor mass, among others, in a subject in need of such treatment.

[0153] Neoplasms can be benign (such as uterine fibroids and melanocytic nevi), potentially malignant (such as carcinoma in situ) or malignant (i.e. cancer). Exemplary neoplastic disorders include the so-called solid tumours and liquid tumours, including but not limited to carcinoma, sarcoma, metastatic disorders (e.g., tumors arising from the prostate), hematopoietic neoplastic disorders, (e.g., leukemias, lymphomas, myeloma and other malignant plasma cell disorders), metastatic tumors and other cancers. Prevalent cancers include breast, prostate, colon, lung, liver, brain, ovarian and pancreatic cancers.

[0154] Compounds of the application have been demonstrated to inhibit the growth of cancer cells. In some embodiments, the disease, disorder or condition that is treatable by inhibiting GCN2, is cancer.

[0155] Accordingly, the present application also includes a method of treating cancer comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof. The present application also includes a use of one or more compounds of the application for treatment of cancer as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of cancer. The application further includes one or more compounds of the application for use in treating cancer. In an embodiment, the compound is administered for the prevention of cancer in a subject such mammal having a predisposition for cancer.

[0156] In some embodiments, the cancer is selected from, but not limited to: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS- Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma / Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma / Malignant Glioma, Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor, Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male; Bronchial Adenomas / Carcinoids, Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma / Malignant Glioma, Childhood; Cervical Cancer; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-CeIl Lymphoma; Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family of Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; Kidney Cancer; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia, Acute Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, AcuteMyeloid, Adult; Leukemia, Acute Myeloid, Childhood; Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoblastic Leukemia, Adult Acute; Lymphoblastic Leukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma, AIDS-Related; Lymphoma, Central Nervous System (Primary); Lymphoma, Cutaneous T-CeIl; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's, Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's, Adult; Lymphoma, Non-Hodgkin's, Childhood; Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma / Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma; Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood; Non- Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer; Osteosarcoma / Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm / Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma (Osteosarcoma) / Malignant Fibrous Histiocytoma of Bone; Sarcoma, Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma,Soft Tissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft Tissue Sarcoma, Childhood; Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer, Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood; T-CeIl Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood; Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Cancer of, Childhood; Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom's Macro globulinemia; and Wilms' Tumor. Metastases of the aforementioned cancers can also be treated in accordance with the methods described herein.

[0157] In some embodiments, the cancer is any cancer in which the cells show increased expression of the gene(s) encoding GCN2 or activation of GCN2 under stress conditions. By “increased expression” it is meant any increase in expression of the gene(s) encoding GCN2 in the cell compared to expression of the gene(s) encoding GCN2 in a corresponding normal or healthy cell.

[0158] In some embodiments, the cancer is selected from one or more of solid tumors, breast cancer, colon 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 disease, disorder or condition that is treatable by inhibiting GCN2, is a disease, disorder or condition associated with an uncontrolled and / or abnormal cellular activity affected directly or indirectly by inhibiting GCN2. In another embodiment, the uncontrolled and / or abnormal cellular activity that is affected directly or indirectly by inhibiting GCN2 is proliferative activity in a cell.

[0160] Accordingly, the application also includes a method of inhibiting proliferative activity in a cell, comprising administering an effective amount of one or more compounds of the application to the cell. The present application also includes a use of one or more compounds of the application for inhibition of proliferative activity in a cell as well as a use of one or more compounds of the application for the preparation of a medicament for inhibition of proliferative activity in a cell. The application further includes one or more compounds of the application for use in inhibiting proliferative activity in a cell.

[0161] The present application also includes a method of inhibiting uncontrolled and / or abnormal cellular activities affected directly or indirectly by inhibiting GCN2 in a cell, either in a biological sample or in a subject, comprising administering an effective amount of one or more compounds of the application to the cell. The application also includes a use of one or more compounds of the application for inhibition of uncontrolled and / or abnormal cellular activities affected directly or indirectly by inhibiting GCN2 in a cell as well as a use of one or more compounds of the application for the preparation of a medicament for inhibition of uncontrolled and / or abnormal cellular activities affected directly or indirectly by inhibiting GCN2 in a cell. The application further includes one or more compounds of the application for use in inhibiting uncontrolled and / or abnormal cellular activities affected directly or indirectly by inhibiting GCN2 in a cell.

[0162] In some embodiments, the disease, disorder or condition that is treatable by inhibiting GCN2 is a peripheral neuropathy. Accordingly, the present application also includes a method of treating a peripheral neuropathy comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof. The present application also includes a use of one or more compounds of the application for treatment of a peripheral neuropathy as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a peripheral neuropathy. The application further includes one or more compounds of the application for use in treating a peripheral neuropathy.

[0163] In some embodiments, the peripheral neuropathy is Charcot-Marie-Tooth (CMT) peripheral neuropathy. Heterozygous mutations in six genes encoding cytoplasmic aminoacyl-tRNA synthetases (AARSs) cause axonal and intermediate forms of CMT peripheral neuropathy. Heterozygous mutations in six genes encoding cytoplasmic aminoacyl-tRNA synthetases (AARSs) cause axonal and intermediate forms of Charcot- Marie-Tooth (CMT) peripheral neuropathy. AARSs are ubiquitously expressed enzymes that covalently attach amino acids to their cognate tRNAs (tRNA aminoacylation).Aminoacylated tRNAs are used by the ribosome for mRNA translation. In Charcot-Marie- Tooth (CMT) peripheral neuropathy, mutant tRNA synthetases activate the integrated stress response (ISR) through the sensor kinase GCN2. The chronic activation of the ISR contributed to the pathophysiology, and genetic deletion or pharmacological inhibition of GCN2 alleviated the peripheral neuropathy. Therefore, in some embodiments, the disease, disorder or condition that is treatable by inhibiting GCN2, is a Charcot-Marie-Tooth (CMT) peripheral neuropathy.

[0164] Accordingly, the present application also includes a method of treating Charcot-Marie-Tooth (CMT) peripheral neuropathy comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof. The present application also includes a use of one or more compounds of the application for treatment of Charcot-Marie-Tooth (CMT) peripheral neuropathy as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of Charcot-Marie-Tooth (CMT) peripheral neuropathy. The application further includes one or more compounds of the application for use in treating Charcot-Marie-Tooth (CMT) peripheral neuropathy.

[0165] The present application also includes a method of treating a disease, disorder or condition that is treatable by inhibiting GCN2 comprising administering, to a subject in need thereof, a therapeutically effective amount of one or more compounds of the application in combination with another known agent useful for treatment of a disease, disorder or condition treatable by inhibiting GCN2. The present application also includes a use of one or more compounds of the application in combination with another known agent useful for treatment of a disease, disorder or condition treatable by inhibiting GCN2, as well as a use of one or more compounds of the application in combination with another known agent useful for treatment of a disease, disorder or condition treatable by inhibiting GCN2 for the preparation of a medicament for treatment of a disease, disorder or condition treatable by inhibiting GCN2. The application further includes one or more compounds of the application in combination with another known agent useful for treatment of a disease, disorder or condition treatable by inhibiting GCN2 for use in treating a disease, disorder or condition treatable by inhibiting GCN2.

[0166] In an embodiment, the disease, disorder or condition treatable by inhibiting GCN2 is cancer and / or peripheral neuropathy.

[0167] In some embodiments, GCN2 is inhibited in the uses and methods of the application.

[0168] In an embodiment, the “subject in need thereof” is a subject having the disease, disorder or condition to be treated.

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

[0170] In some embodiments the disease, disorder or condition that is treatable by inhibiting GCN2, is cancer and the one or more compounds of the application are administered or used in combination with one or more additional cancer treatments. In another embodiment, the one or more additional cancer treatments is selected from one or more radiotherapy, chemotherapy, targeted therapies such as antibody therapies (including anti-PD1 and / or anti-PD-L1 antibodies) and small molecule therapies such as tyrosine-kinase inhibitors therapies, glutaminase inhibitors (e.g., glutaminase-1 (GLS1) inhibitors), and asparagine synthetase (ASNS) inhibitors, immunotherapy, hormonal therapy and anti-angiogenic therapies.

[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 is treatable by inhibiting GCN2 is cancer, and the one or more compounds of the application 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 is treatable by inhibiting GCN2 is cancer, and the one or more compounds of the application 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 synthetase (ASNS) inhibitor. Therefore, in some embodiments the disease, disorder or condition that is treatable by inhibiting GCN2, is cancer and the one or more compounds of the application are administered or used in combination one or more glutaminase inhibitors (e.g., GLS1 inhibitors), and / or or asparagine synthetase (ASNS) inhibitors.

[0173] In some embodiments the disease, disorder or condition that is treatable by inhibiting GCN2, is cancer and the one or more compounds of the application are administered or used in combination one or more glutaminase inhibitors (e.g., GLS1inhibitors), and / or asparagine synthetase (ASNS) inhibitors and / or L-asparaginase (L- ASNase).

[0174] Asparagine deprivation by L-asparaginase (L-ASNase) is an effective therapeutic strategy in cancer, with resistance occurring due to upregulation of asparagine synthetase (ASNS), the only human enzyme synthetizing asparagine (Annu. Rev. Biochem.2006, 75 (1), 629–654). L-Asparaginase efficacy in solid tumors is limited by dose-related toxicities (OncoTargets and Therapy 2017, pp 1413–1422). Large-scale loss of function genetic in vitro screens identified ASNS as a cancer dependency in several solid malignancies (Cell 2017, 170 (3), 564–576.e16. Cell 2017, 170 (3), 577–592.e10). Genome-wide CRISPR screens have revealed that cancer cell resistance mechanisms are elicited by a GCN2-ATF4 axis aimed at restoring amino acid levels to promote survival. Hence, pharmacological inhibition of GCN2 synergizes with L-asparaginase-mediated asparagine deprivation in ASNS deficient cells suggesting novel potential therapeutic combinations in cancer treatment.

[0175] Therefore, in some embodiments, the present application also includes a method of improving the efficacy of one or more cancer treatments for treating cancer comprising administering, to a subject in need thereof, an effective amount of one or more compounds of the application, in combination with an effective amount of the one or more cancer treatments to a subject in need thereof.

[0176] The present application also includes a use of one or more compounds of the application in combination with one or more cancer treatments for improving the efficacy of the one or more cancer treatments for treating cancer, as well as a use of one or more compounds of the application in combination with one or more cancer treatments for improving the efficacy of the one or more cancer treatments for treating cancer. The application further includes one or more compounds of the application in combination with one or more cancer treatments for use in improving the efficacy of the one or more cancer treatments for treating cancer.

[0177] In some embodiments, the one or more cancer treatments is selected from one or more radiotherapy, chemotherapy, targeted therapies such as antibody therapies (including anti-PD1 and / or anti-PD-L1 antibodies) and small molecule therapies such as tyrosine-kinase inhibitors therapies, glutaminase inhibitors (e.g.,GLS1 inhibitors), and / or asparagine synthetase (ASNS) inhibitors, immunotherapy, hormonal therapy and anti- angiogenic therapies.

[0178] In some embodiments, the chemotherapy is a chemotherapeutic agent. In some embodiments, chemotherapeutic agent is cisplatin. Therefore, in some embodiments, the one or more compounds of the application are administered or used in combination with cisplatin for improving the efficacy of cisplatin for treating cancer.

[0179] In some embodiments, the chemotherapeutic agent is L-asparaginase (L- ASNase). Therefore, in some embodiments, the one or more compounds of the application are administered or used in combination with L-asparaginase (L-ASNase) for improving the efficacy of L-ASNase for treating cancer.

[0180] In some embodiments, the small molecule therapy is a glutaminase inhibitor (e.g., GLS1 inhibitor) or an asparagine synthetase (ASNS) inhibitor. Therefore, in some embodiments, the one or more compounds of the application are administered or used in combination with one or more glutaminase inhibitors (e.g.,GLS1 inhibitors) and / or one or more asparagine synthetase (ASNS) inhibitors for improving the efficacy the one or more glutaminase inhibitors (e.g.,GLS1 inhibitors) or the one or more ASNS inhibitors for treating cancer.

[0181] In some embodiments, the cancer is associated with low asparagine synthetase (ASNS) expression. In some embodiment, the cancer is associated with low asparagine synthetase (ASNS) expression and the chemotherapeutic agent is L- asparaginase (L-ASNase). Accordingly, in some embodiments, the one or more compounds of the application are administered or used in combination with L-asparaginase (L-ASNase) for improving the efficacy of L-ASNase for treating a cancer is associated with low asparagine synthetase (ASNS) expression.

[0182] In some embodiments, the cancer is associated with asparagine synthetase (ASNS) overexpression or dysregulation. In some embodiments, the cancer is associated with asparagine synthetase (ASNS) overexpression or dysregulation and the chemotherapeutic agents are one or more asparagine synthetase (ASNS) inhibitors and / or L-asparaginase Therefore, in some embodiments, the one or more compounds of the application are administered or used in combination with one or more asparagine synthetase (ASNS) inhibitors and / or with L-asparaginase for treating a cancer associated with asparagine synthetase (ASNS) overexpression or dysregulation. In some embodiments, the chemotherapeutic agents are one or more asparagine synthetase (ASNS) inhibitors and L-asparaginase

[0183] In some embodiments, the cancer is associated with low asparagine synthetase (ASNS) expression and low glutaminase (e.g. GLS1) expression. In some embodiments, the cancer is associated with low asparagine synthetase (ASNS) expression and low glutaminase (e.g. GLS1) expression and the chemotherapeutic agents are L- asparaginase (L-ASNase) and / or one or more glutaminase inhibitors. Accordingly, in some embodiments, the one or more compounds of the application are administered or used in combination with L-asparaginase (L-ASNase) and / or one or more glutaminase inhibitors for improving the efficacy of L-ASNase and / or the one or more glutaminase inhibitors for treating a cancer associated with low asparagine synthetase (ASNS) expression and low glutaminase (e.g. GLS1) expression. In some embodiments, the glutaminase inhibitor is a GLS1 inhibitor. In some embodiments, the chemotherapeutic agents are L-asparaginase (L-ASNase) and one or more glutaminase inhibitors.

[0184] In some embodiments, the cancer is associated with asparagine synthetase (ASNS) overexpression or dysregulation and glutaminase (e.g. GLS1) overexpression or dysregulation. In some embodiments, the cancer is associated with asparagine synthetase (ASNS) overexpression or dysregulation and glutaminase (e.g. GLS1) overexpression or dysregulation and the chemotherapeutic agents are L-asparaginase (L-ASNase), one or more glutaminase inhibitors and / or one or more asparagine synthetase (ASNS) inhibitors. Therefore, in some embodiments, the one or more compounds of the application are administered or used in combination with L-asparaginase (L-ASNase) and / or one or more glutaminase inhibitors and / or one or more asparagine synthetase (ASNS) inhibitors for improving the efficacy of L-ASNase and / or the one or more glutaminase inhibitors and / or the one or more asparagine synthetase (ASNS) inhibitors for treating a cancer associated with asparagine synthetase (ASNS) overexpression or dysregulation and glutaminase (e.g. GLS1) overexpression or dysregulation. In some embodiments, the glutaminase inhibitors 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 synthetase (ASNS) inhibitors.

[0185] Compounds of the application are either used alone or in combination with other known agents useful for treating diseases, disorders or conditions treatable by inhibiting GCN2. When used in combination with other agents useful in treating diseases, disorders or conditions that are treatable by inhibiting GCN2, it is an embodiment that the compounds of the application are administered contemporaneously with those agents. As used herein, “contemporaneous of two substances to a subject meansproviding each of the two substances so that they are both biologically active in the individual at the same time. The exact details of the administration will depend on the pharmacokinetics of the two substances in the presence of each other and can include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of administration of the other, if the pharmacokinetics are suitable. Design of suitable dosing regimens is routine for one skilled in the art. In particular embodiments, two substances will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition that contains both substances. It is a further embodiment of the present application that a combination of agents is administered to a subject in a non-contemporaneous fashion. In some embodiments, compounds of the present application are administered with another therapeutic agent 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 compounds of the application (e.g. a compound of Formula I), an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0186] Treatment methods comprise administering to a subject a therapeutically effective amount of one or more of the compounds of the application and optionally consist of a single administration, or alternatively comprise a series of administrations, and optionally comprise concurrent administration or use of one or more other therapeutic agents. For example, in some embodiments, the compounds of the application are administered at least once a week. In some embodiments, the compounds are administered to the subject from about one time per two or three weeks, or about one time per week to about once daily for a given treatment. In another embodiment, the compounds are administered 2, 3, 4, 5 or 6 times daily. The length of the treatment period depends on a variety of factors, such as the severity of the disease, disorder or condition, the age of the subject, the concentration and / or the activity of the compounds of the application, and / or a combination thereof. It will also be appreciated that the effective dosage of the compound used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compounds are administered to the subject in an amount and for duration sufficient to treat the subject. In some embodiments treatment comprise prophylactic treatment. For example, a subject with early cancer can be treated to preventprogression, or alternatively a subject in remission can be treated with a compound or composition of the application to prevent recurrence.

[0187] The dosage of compounds of the application varies depending on many factors such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate of the compound in the subject to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. Compounds of the application may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. Dosages will generally be selected to maintain a serum level of compounds of the application from about 0.01 µg / cc to about 1000 µg / cc, or about 0.1 µg / cc to about 100 µg / cc. As a representative example, oral dosages of one or more compounds of the application will range between about 0.05 mg per day to about 1000 mg per day for an adult, suitably about 0.1 mg per day to about 500 mg per day, more suitably about 1 mg per day to about 200 mg per day. For parenteral administration, a representative amount is from about 0.001 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg or about 0.1 mg / kg to about 1 mg / kg will be administered. For oral administration, a representative amount is from about 0.001 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg or about 0.1 mg / kg to about 1 mg / kg. For administration in suppository form, a representative amount is from about 0.1 mg / kg to about 10 mg / kg or about 0.1 mg / kg to about 1 mg / kg. Compounds of the application may be administered in a single daily, weekly or monthly dose or the total daily dose may be divided into two, three or four daily doses.

[0188] In an embodiment, effective amounts vary according to factors such as the disease state, age, sex and / or weight of the subject. In a further embodiment, the amount of a given compound or compounds that will correspond to an effective amount will vary depending upon factors, such as the given drug(s) or compound(s), the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.

[0189] To be clear, in the above, the term “a compound” also includes embodiments wherein one or more compounds are referenced. Likewise, the term“compounds of the application” also includes embodiments wherein only one compound is referenced. V. Methods of Preparation of Compounds of the Application

[0190] Compounds of the present application can be prepared by various synthetic processes. The choice of particular structural features and / or substituents may influence the selection of one process over another. The selection of a particular process to prepare a given compound of Formula I is within the purview of the person of skill in the art. Some starting materials for preparing compounds of the present application are available from commercial chemical sources. Other starting materials, for example as described below, are readily prepared from available precursors using straightforward transformations that are well known in the art.

[0191] The compounds of Formula I generally can be prepared according to the processes illustrated in the Schemes below. In the structural formulae shown below the variables are as defined in Formula I unless otherwise stated. A person skilled in the art would appreciate that many of the reactions depicted in the Schemes below would be sensitive to oxygen and water and would know to perform the reaction under an anhydrous, inert atmosphere if needed. Reaction temperatures and times are presented for illustrative purposes only and may be varied to optimize yield as would be understood by a person skilled in the art.

[0192] Accordingly, in some embodiments, the compounds of Formula I, are prepared as shown in Scheme 1.Scheme 1

[0193] The commercially available 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin- 7(8h)-one (Hal = Br, X1= C or N, Formula A) is oxidized with suitable oxidizing agents such as meta-chloroperoxybenzoic acid (m-CPBA) to the sulfoxide intermediate compounds of Formula B. Compounds of Formula B are then coupled to suitable amines of Formula C, or a protected version thereof, in the presence of a suitable base such as Cs2CO3or DIPEA and in a suitable solvent such as, iPrOH, MeCN or DMF to afford intermediate compounds of Formula D. Treatment of compounds of Formula D with boronate esters or boronic acids of Formula G (wherein Raand Rbare independently C1-6 alkyl, or are joined to form, together with the B and O atoms therebetween, a 4 to 6 membered saturated or unsaturated ring optionally substituted with one or two C1-3alkyls) using suitable conditions such the Suzuki- Miyaura coupling conditions provide compounds of Formula I.

[0194] Boronate esters or boronic acids of Formula G are prepared, for example, by coupling aryl sulfonyl compounds of Formula E wherein Y' is a halogen such as Cl with boronate esters or boronic acid aniline compounds of Formula F in the presence of a suitable base such as pyridine.Scheme 2

[0195] In some embodiments, compounds of Formula I are prepared as shown in Scheme 2. Therefore intermediate compounds of Formula D wherein Hal is halogen such as Br are coupled with substituted-3-anilino-boronate compounds of Formula F (prepared from commercially available or synthesized corresponding 3-halo-aniline compounds under standard boronylation conditions such as Miyaura borylation conditions using (pinacolato)diboron in basic conditions with a suitable catalyst such as PdCl2(dppf) ([1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride: CH2Cl2 complex), under suitable coupling conditions such as the Suzuki-Miyaura coupling conditions, provides intermediate compounds of Formula J. of the compounds of Formula J withheterocyclic containing sulfonyl halide compounds of Formula E wherein Y' is halogen, under for example basic conditions, provides the compounds of Formula I.Scheme 3

[0196] In some embodiments, compounds of Formula I are prepared as shown in Scheme 3. Therefore compounds of Formula A are boronated, for example under standard borylation conditions such as Miyaura borylation conditions, for example, in the presence of suitable reagents such as bispinacolatodiboron, PdCl2dppf:CH2Cl2complex, and a base such as KOAc and in a suitable solvent such as dioxane at a suitable temperature, such as 100-110oC to provide the boronated compounds of Formula K wherein Rcand Rdare independently C1-6alkyl, or are joined to form, together with the B and O atoms therebetween, a 4 to 6 membered saturated or unsaturated ring optionally substituted with one or two C1-3alkyls. Subsequent treatment of the compounds of Formula K with various halo-sulfonamides of Formula H wherein Y'' is halogen (prepared by coupling the corresponding sulfonyl halide compounds of Formula E wherein Y' is halogen with the aniline compounds of Formula M for example under suitable coupling conditions) using suitable conditions such the Suzuki-Miyaura coupling conditions provide compounds of Formula L. Oxidation with suitable oxidizing such as meta-chloroperoxybenzoic acid(m-CPBA) of the compounds of Formula L to the intermediate sulfoxide followed by coupling with various suitable amine compounds of Formula C under basic conditions provides the compounds of Formula I.Scheme 4

[0197] In some embodiments, compounds of Formula I are prepared as shown in Scheme 4. Therefore coupling of compounds of Formula N with sulfonyl halide compounds of Formula E wherein Y' is halogen under suitable coupling conditions such as in the presence of base (e.g. pyridine) provides compounds of Formula L. Oxidation with suitable oxidizing agents such as meta-chloroperoxybenzoic acid (m-CPBA) of compounds of Formula L to the intermediate sulfoxide followed by coupling with various suitable amine compounds of Formula C under basic conditions provides the compounds of Formula I.

[0198] In some embodiments, compounds of Formula I are prepared as shown in Scheme 5. Therefore the intermediate compounds of Formula D wherein Hal is halogen such as Br are coupled with boronate compounds of Formula G under suitable coupling conditions such as the Suzuki-Miyaura coupling conditions to provide the compounds of Formula I.Scheme 6

[0199] In some embodiments, compounds of Formula I wherein R2= H are prepared as shown in Scheme 6. Therefore the intermediate compounds of Formula O wherein R2is a suitable protecting group such as p-methoxybenzyl (PMB) are deprotected under acidic conditions to provide compounds of Formula I wherein R2= H.Scheme 7

[0200] In some embodiments, as shown in Scheme 7, compounds of Formula N wherein X1= N (compounds of Formula N-1) are prepared from the readily available 2,4- dichloro-5-nitropyrimidine (compound of P). Nitro- reduction under suitableconditions such as in the presence of Fe to the amine compounds of Formula Q followed by substitution with a suitable amine (e.g. R2NH2) under suitable conditions such as in the presence of base such as DIPEA give intermediate compounds of Formula R. Cyclization of compounds of Formula R with ethyl gloxalate followed by substitution with sodium thiomethioxide provides intermediate methylthio compounds of Formula T. Radical- mediated coupling with t-butyl nitrite gives intermediate compounds of Formula V. Subsequent amination under suitable conditions such as in the presence of diphenylmethanimine, Xantphos, Pd(OAc)2and Cs2CO3afford the compounds of Formula N-I.Scheme 8

[0201] In some embodiments, as shown in Scheme 7, intermediate boronate esters or boronic acids of Formula F are prepared under standard borylation conditions such as under Miyaura borylation conditions from the corresponding halo derivative compound of Formula W (wherein Hal’ is a halogen such as Br), for example, in the presence of suitable reagents such as bispinacolatodiboron, PdCl2dppf:CH2Cl2 complex and a base such as potassium acetate (KOAc) in a suitable solvent such as dioxane at a suitable temperature, such as 100-110oC.Scheme 9

[0202] In some embodiments, as shown in Scheme 9, intermediate compounds of Formula D where Hal is Br (compounds of Formula D-1) are prepared from compounds of Formula Z wherein Hal’’ is halogen such as Cl by reaction with various suitable amino compounds of Formula C under suitable conditions such as in the presence of base, for example, KOAc or DIPEA, to provide of Formula AA. Subsequent brominationof compounds of Formula AA, for example, with Br2in a suitable solvent such as acetonitrile (MeCN) provides the compounds of Formula D-1.

[0203] Generally, the reactions described above are performed in a suitable inert organic solvent and at temperatures and for times that will optimize the yield of the desired compounds. 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), toluene, and the like.

[0204] Salts of the compounds of the application are generally formed by dissolving the neutral compound in an inert organic solvent and adding either the desired acid or base and isolating the resulting salt by either filtration or other known means.

[0205] The formation of a desired compound salt is achieved using standard techniques. For example, the neutral compound is treated with an acid or base in a suitable solvent and the formed salt is isolated by filtration, extraction or any other suitable method.

[0206] The formation of solvates will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a “hydrate”. The formation of solvates of the compounds of the application will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art.

[0207] Prodrugs of the compounds of the present application may be, for example, conventional esters formed with available hydroxy, thiol, amino or carboxyl groups. For example, available hydroxy or amino groups may be acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g. an acid chloride in pyridine).

[0208] Throughout the processes described herein it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art. Conventional procedures for using such protecting groups as wellas examples of suitable protecting groups are described, for example, in “Protective Groups in Organic Synthesis”, T.W. Green, P.G.M. Wuts, Wiley-Interscience, New York, (1999). It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to one skilled in the art. Examples of transformations are given herein, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are given in “Comprehensive Organic Transformations – A Guide to Functional Group Preparations” R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “Advanced Organic Chemistry”, March, 4th ed. McGraw Hill (1992) or, “Organic Synthesis”, Smith, McGraw Hill, (1994). Techniques for purification of intermediates and final products include, for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by one skilled in the art.

[0209] The products of the processes of the application may be isolated according to known methods, for example, the compounds may be isolated by evaporation of the solvent, by filtration, centrifugation, chromatography or other suitable method.

[0210] One skilled in the art will recognize that where a reaction step of the present application is carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems EXAMPLES

[0211] The following non-limiting examples are illustrative of the present application: A. Synthesis and Characterization of Exemplary Compounds of the Application GENERAL METHODS General Method MB (Miyaura borylation)

[0212] A degassed 1,4-dioxane mixture of aryl halide (1.0 equiv), B2pin2(1.3 equiv), KOAc (3.5 equiv) and typically PdCl2(dppf)*CH2Cl2or PdCl2(dppf) (0.1 equiv) were heated sealed under Ar in a microwave reactor (typically, 90-100oC) or oil bath (typically, 100-110oC). The crude mixture was then most often used directly in the following Suzuki-Miyaura cross coupling step as a crude mixture without further purification. General Method SMC (Suzuki Miyaura Cross-coupling)

[0213] A vial equipped with a stirring bar, filled with Ar or N2, was charged with aryl boronic acid or aryl boronic ester (typically 1-1.5 equiv, in most instances aryl boronic esters were used as crude mixtures in 1,4-dioxane), base (Cs2CO3 typically 3 equiv), aryl halide (typically 1 equiv), catalyst / ligand (most often one of: PdCl2(dppf)*CH2Cl2 or PdCl2(dppf); typically, 0.1 equiv). The vial was sealed, H2O and organic solvent or a mixture of organic solvents (DME or 1,4-dioxane) were added. The reaction mixture was degassed with Ar or N2 by repeated evacuation and refill with the inert gas and then heated, sealed in a microwave reactor or an oil bath for the time specified. After the reaction was deemed complete by LCMS analysis, the mixture was concentrated under reduced pressure, deposited on a plug of Celite or a SiO2 samplet and purified by flash chromatography (typically using SiO₂ InnoFlash® cartridge or SiO₂ Biotage® cartridge or SiO₂ RediSep®Rf cartridge and hexanes-EtOAc or CH2Cl2–MeOH or CH2Cl2–MeOH-NH3or CH2Cl2–MeOH- conc aq NH3(89:9:1 v / v / v) in CH2Cl2) or preparative HPLC (typically using Biotage® SNAP KP-C₁₈-HS cartridge or RedisSep®Rբ C₁₈ and MeOH in H₂O + 0.05 % TFA or MeCN in H2O + 0.1 % formic acid), optionally followed by a filtration through a Waters PoraPak™ CX column or an Isolute™ CSX-2 column, rinsing with MeOH and eluting the desired material with 2 M NH₃ in MeOH. General Method NS (N-sulfonylation)

[0214] A solution of substituted 3-bromoaniline (1 equiv) and anh pyridine (typically 1.5-2.0 equiv) in CH₂Cl₂ (typically 0.06-0.19 M) was treated with one portion of solid aryl- sulfonyl chloride (typically, 1 equiv) at 0oC. The reaction was allowed slowly to reach rt and stirring was continued overnight. The reaction mixture was then concentrated under reduced pressure onto Celite or alternatively washed by extraction with H₂O, the organic extracts were concentrated under reduced pressure and after depositing on Biotage® samplet or Celite, purified by flash chromatography on silica gel using one of the cartridges: InnoFlash®, Biotage®, RediSep®Rf. General Method MO (mCPBA mediated

[0215] To a suspension of methylthioheteroaryl (1 equiv) in CH2Cl2was added 3- chloroperbenzoic acid (mCPBA) (typically 1.1-2.2 equiv., technical grade, <77 %) either as a solid or in a small amount of CH2Cl2at 0 °C. The reaction was then allowed to slowly warm to rt and then was stirred at rt until completion. The resultant mixture of the sulfoxide and sulfone intermediates was either washed by extraction with satd aq NaHCO3followed by concentration of the organic layer or simply concentrated under reduced pressure and used crude without a workup or further purification. INTERMEDIATES Intermediate 1: N-(3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide

[0216] To a stirred solution of 5-chloro-2-methoxypyridine-3-sulfonyl chloride (20 g, 83 mmol) in pyridine (200 mL) was added 3-bromo-2,4-difluoroaniline (15.5 g, 74.3 mmol) and the resulting reaction mixture was stirred at rt for 1 h. After completion, the reaction mixture was quenched with 2 M aq HCl (500 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (3 x 300 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude material was triturated with 2 % EtOAc in hexanes to afford 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 / 414.8.1H 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]pyrimidin-7(8H)-oneStep 1.6-bromo-8-methyl-2- 7(8H)-one

[0217] To a cooled solution of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one (10 g, 37 mmol) in DMF (150 mL), K2CO3(7.6 g, 55 mmol) was added at -5° C under N2. The reaction mixture was stirred at -5° C for 10 min followed by an addition of MeI (6.26 g, 44.1 mmol) at -5° C. The reaction was further stirred with cooling for 45 min. Later, the reaction mixture was diluted with ice-cold H2O (150 mL), filtered, washed with hexanes and dried under vacuum to afford 6-bromo-8-methyl-2-(methylthio)pyrido[2,3- d]pyrimidin-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]pyrimidin-7(8H)-one

[0218] To a cooled solution of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3- d]pyrimidin-7(8H)-one (3 g, 10.5 mmol) in CH2Cl2 (45 mL) at 0 °C under N2, m-CPBA (7.3 g, 41.9 mmol) was added in portions. Later the reaction mixture was stirred at rt for 16 h before being diluted with satd. aq NaHCO3 (150 mL) and extracted with CH2Cl2 (3 x 60 mL). The combined organic layers were dried (anh Na2SO4), concentrated under reduced pressure. Trituration with 20 % EtOAc in hexanes afforded 6-bromo-8-methyl-2- (methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one as a light brown solid (2.4 g, 72 %). MS (ESI) m / z [M+H]+318.0 / 320.0.1H 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)pteridin-7(8H)-oneStep1. 2,4-Dichloropyrimidin-5-amine

[0219] To the stirred 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 then stirred at rt for 5 h. The reaction was filtered through Celite and the filterbed was rinsed with EtOAc (300 mL). The filtrate was concentrated under reduced pressure. The solid residue was triturated with hexanes to afford 2,4-dichloropyrimidin-5- amine as an orange solid (3 g, 71 %). MS (ESI) m / z [M+H]+164.0. Step 2.2-chloro-N4-methylpyrimidine-4,5-diamine

[0220] To the stirred solution of 2,4-dichloropyrimidin-5-amine (3 g, 18 mmol) in EtOH (30 mL), DIPEA (6.3 mL, 36 mmol) was added at rt. The reaction mixture was then stirred for 10 min before MeNH2(2 M solution in THF, 19 mL, 37 mmol) was added dropwise. Later, the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was subsequently concentrated under reduced pressure. The crude product was triturated with methyl tert-butyl ether to afford 2-chloro-N4-methylpyrimidine-4,5-diamine as a dark violet semi solid (2.8 g, 96 %). MS (ESI) m / z [M+H]+159.04. Step 3.2-Chloro-8-methylpteridin-7(8H)-one

[0221] To stirred solution of 2-chloro-N4-methylpyrimidine-4,5-diamine (11 g, 70 mmol) in EtOH (110 mL), a solution of ethyl glyoxalate in PhMe (30 %, 7.07 mL, 69.6 mmol) was added dropwise and the reaction mixture was stirred at 80 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure. The crude product was triturated with methyl tert-butyl ether to afford of 2-chloro-8-methylpteridin- 7(8H)-one as a white solid (4.5 g, 33 %). MS (ESI) m / z [M+H]+197.0. Step 4. 8-methyl-2-(methylthio)pteridin-7(8H)-one

[0222] To stirred solution of 2-chloro-8-methylpteridin-7(8H)-one (1.6 g, 8.1 mmol) in THF (16 mL), MeSNa (0.91 g, 13 mmol) was added in portions. The reaction mixture was stirred at 80 °C for 16 h, then later diluted with H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (anh Na2SO4) and concentratedunder reduced pressure. The crude material was purified by flash chromatography using EtOAc in hexanes to afford 8-methyl-2-(methylthio)pteridin-7(8H)-one as an off-white solid (0.9 g, 53%).1H 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)pteridin-7(8H)-one

[0223] To a solution of 5-bromo-2-fluoroaniline (1.8 g, 9.5 mmol) in MeCN (50 mL) under N2, tert-butyl nitrite (1.48 g, 14.3 mmol) was added at 0 °C. The resulting solution was stirred for 30 min at 0 °C. Later a solution of 8-methyl-2-(methylthio)pteridin-7(8H)- one (0.5 g, 2.4 mmol) in MeCN (5 mL) was added at 0°C. Subsequently, the reaction mixture was stirred at rt for 16 h. The reaction mixture was then diluted with H2O (100 mL) and extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were dried (anh Na2SO4) and concentrated under reduced pressure. Purified by flash chromatography using EtOAc in hexanes to afford 6-(5-bromo-2-fluorophenyl)-8-methyl-2- (methylthio)pteridin-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)pteridin-7(8H)-one

[0224] To a solution of 6-(5-bromo-2-fluorophenyl)-8-methyl-2-(methylthio)pteridin- 7(8H)-one (1.1 g, 2.9 mmol) in 1,4-dioxane (11 mL), diphenylmethanimine (0.57 g, 3.2 mmol), Xantphos (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 with N2for 10 min and stirred at 100 °C for 3 h. After completion, the reaction mixture was acidified using 2 M aq HCl solution (to pH=2) and extracted with EtOAc (3 x 100 mL). The organic layer was discarded, and the aqueous layer was basified by 2 M aq NaOH and extracted with EtOAc (3 x 100 mL). The combined organic were dried (anh Na2SO4), concentratedunder reduced pressure. The crude material was purified by column chromatography using 60-120 silica and EtOAc in hexanes to afford 6-(5-amino-2-fluorophenyl)-8-methyl-2- (methylthio)pteridin-7(8H)-one as an orange solid (0.8 g, 87 %). MS (ESI) m / z [M+H]+318.2.1H 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-methylpteridin-7(8H)-Step 1.2-((1R,4R4-(dimethylamino)cyclohexyl)amino)-8-methylpteridin-7(8H)-one

[0225] To a stirred solution of 2-chloro-8-methylpteridin-7(8H)-one (1.7 g, 88 mmol) in DMF (17 mL), trans N1,N1-dimethylcyclohexane-1,4-diamine (1.69 g, 95.4 mmol) and K2CO3 (3.5 g, 26 mmol) were added at rt. Stirring was continued at rt for 16 h. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (25 mL), dried (anh Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography using MeOH in CH2Cl2 to afford 2-((4- (dimethylamino)cyclohexyl)amino)-8-methylpteridin-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-methylpteridin-7(8H)-one*HBr

[0226] To a solution of 2-((4-(dimethylamino)cyclohexyl)amino)-8-methylpteridin- 7(8H)-one (0.5 g, 1.6 mmol) in MeCN (5.0 ml) was added Br2 (0.5 mL, 12 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. After completion, the reaction mixture was directly injected onto a silica column and by column chromatography using MeOHin CH2Cl2. Trituration with n-pentane and Et2O afforded 6-bromo-2-((4- (dimethylamino)cyclohexyl)amino)-8-methylpteridin-7(8H)-one*HBr as a brown solid (0.467 g, 73 %). 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, 3H) 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- sulfonamido)-2-fluorophenyl)boronic acid

[0227] To a stirred solution of 5-chloro-2-methoxypyridine-3-sulfonyl chloride (4.0 g, 17 mmol) in pyridine (40 mL) was added 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)aniline (4.0 g, 17 mmol) and the resulting reaction mixture was stirred at rt for 1 h. After completion, the reaction mixture was directly loaded onto silica gel and purified by column chromatography using MeOH in CH2Cl2. Trituration with CH2Cl2 and Et2O afforded 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- sulfonamido)-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-sulfonamido)-2-fluorophenyl)boronic acid

[0228] To a cooled solution of 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline (2.5 g, 10.5 mmol) in anh pyridine (30 mL) was added 5-chloro-2- methoxypyridine-3-sulfonyl chloride (2.5 g, 10.3 mmol) at 0 °C and the reaction mixture was stirred at rt for 16 h. After completion, the reaction mixture was directly loaded onto a silica gel column and purified using MeOH in CH2Cl2 to afford (3-((5-chloro-2- methoxypyridine)-3-sulfonamido)-2-fluorophenyl)boronic acid as a brown solid (2.8 g, 74 %). MS (ESI) m / z [M-H]- 359.3.Intermediate 7: 6-bromo-8-methyl-2-(methylamino)pteridin-7(8H)-oneStep 1: 8-methyl-2-(methylamino) -one

[0229] A solution of 2-chloro-8-methylpteridin-7(8H)-one (0.9 g, 4.57 mmol) in EtOH (9 mL) and DIPEA (1.1 g, 8.5 mmol) was stirred for 15 min at rt before MeNH2 (2 M in THF 2.5 mL, 5.0 mmol) was added dropwise at rt. The reaction mixture was stirred at rt for 16 h and later filtered, rinsed with EtOAc, dried under vacuum to afford 8-methyl-2- (methylamino)pteridin-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)pteridin-7(8H)-one

[0230] To the stirred solution of 8-methyl-2-(methylamino)pteridin-7(8H)-one (0.8 g, 4.2 mmol) in MeCN (16 mL), Br2 (4 g, 25.1 mmol) was added dropwise at 0 °C. Stirring was continued at the temperature for 2 h. After completion, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried (anh Na2SO4) and concentrated under reduced pressure. The crude was purified by preparative HPLC to afford 6-bromo-8-methyl-2-(methylamino)pteridin-7(8H)- one as a light yellow solid (0.15 g, 13 %).1H 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

[0231] A solution of 3-bromo-2,4-difluoroaniline (15 g, 72.1 mmol), Pd(dppf)Cl2(5.27 g, 7.21 mmol) and B2pin2(27.4 g, 108.1 mmol), KOAc (21.2 g, 216.3 mmol) in 1,4- dioxane (275 mL) under N2was stirred at °C for 16 h. After completion, the solid wasremoved by filtration and rinsed with CH2Cl2(150 mL). The filtrate was concentrated under reduced pressure and purified by column chromatography using EtOAc in hexane (Hex) to afford 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 (the 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). EXEMPLARY COMPOUNDS OF THE APPLICATION Example 1: N-(3-(2-amino-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4- difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (I-1)Step 1.6-bromo-8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0232] A capped, dry microwave vial charged with 6-bromo-2- (methylthio)pyrido[2,3-d]pyrimidin-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. Anh DMF(10 mL) was added and after 10 min of stirring at rt, the reaction mixture was heated at 50oC for 30 min. i-PrI (0.276 mL, 2.76 mmol) was added in one portion at rt. After brief stirring at rt, the reaction was placed in an oil bath at 40oC for 1.5 h and then aged at rt for 3 d 18 h. DMF was removed under reduced pressure and the material was suspended in EtOH. H2O was added the solid was collected by filtration. The filter cake was rinsed with H2O and dried in vacuo to afford 6-bromo-8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one as an off white solid (565 mg, 75 % yield based on purity of 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]pyrimidin-6-yl)boronic acid

[0233] Prepared by General Method MB using 6-bromo-8-isopropyl-2- (methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.49 mmol, 77 % purity), B2pin2(162 mg, 0.64 mmol), KOAc (168 mg, 1.72 mmol) and PdCl2dppf•CH2Cl2(40.0 mg, 0.049 mmol) in anh 1,4-dioxane (12 mL); by heating sealed in an oil bath at 100oC for 2 h. Later the reaction was left standing at rt overnight. Subsequently the sealed reaction was heated at 120oC in an oil bath for 3.5 h. The crude mixture was used directly in the following 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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide

[0234] Prepared by General Method SMC 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]pyrimidin-6-yl)boronic acid (137 mg, 0.152 mmol) (in 12 mL dioxane, 31 %) and PdCl2dppf•CH2Cl2(14.79 mg, 0.018 mmol) and H2O (6 mL); by heating sealed in a microwave reactor for at 90 °C for 2 h. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by preparative HPLC (C₁₈ column using MeCN in H₂O + 0.1 % HCO2H) to afford 5-chloro-N-(2,4-difluoro-3-(8-isopropyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a yellow solid (63.0 mg, 40 % yield based on the purity of 55 %) . MS (ESI) m / z [M+H]⁺ 568.25. Step 4. N-(3-(2-amino-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4- difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (I-1)

[0235] Prepared by General Method MO using 5-chloro-N-(2,4-difluoro-3-(8- isopropyl-2-(methylthio)-7-oxo-7,8- [2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (63 mg, 0.061 mmol, 55 %), mCPBA (26 mg, 0.13 mmol) in CH2Cl2(6 mL) and later another portion of 3-chloroperbenzoic acid (8.2 mg, 0.043 mmol). After the reaction was complete, satd aq NaHCO3(5 mL) was added. After stirring, the layers were separated, and the organic phase was concentrated under reduced pressure and dried under high vacuum to yield the crude material as an orange solid that was taken into i-PrOH (9 mL) and sonicated before aq NH4OH (28-30% 0.32 mL, 2.4 mmol) was added dropwise at rt for 30 min. Another portion of aq NH4OH(28-30%, 0.32 mL, 2.4 mmol) was added at rt and the mixture was left stirring at rt overnight. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by preparative HPLC (C₁₈, MeCN in H₂O + 0.1 % HCO2H), then filtered through a Waters PoraPak CX column, rinsing with MeOH and eluting with 2 M NH₃ in MeOH to afford N-(3-(2-amino-8- isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-5-chloro-2- methoxypyridine-3-sulfonamide compound as an off white solid (8.0 mg, 24 % based on the purity of 97 %). MS (ESI) m / z [M+H]⁺ 537.25.1H 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]pyrimidin-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide (trans I-2)Step 1: 6-bromo-8-ethyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0236] A capped, dry microwave vial charged with 6-bromo-2- (methylthio)pyrido[2,3-d]pyrimidin-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. Anh DMF(10 mL) was added. After 10 min of stirring at rt, the reaction mixture was heated in an oil bath at 50oC for 30min before it was treated with EtBr (0.21 mL, 2.8 mmol) added in one portion at rt. After brief stirring at rt, the reaction was stirred in an oil bath at 40oC for 1.5 h. After standing at rt overnight, DMF was removed under reduced pressure, the material was suspended in EtOH. H2O was added and the mixture was concentrated to remove EtOH. The material was filtered, and the filter cake was rinsed with xs H2O to afford 6-bromo-8-ethyl-2- (methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one as a tan solid (543.0 mg, 65 % yield based on purity of 66 %). MS (ESI) m / z [M+H]⁺ 300.13 / 302.09 2: trans-6-bromo-2- -8- d]

[0237] Prepared by General Method MO using 6-bromo-8-ethyl-2- (methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.44 mmol, 66 %) in CH2Cl2 (6 mL) and mCPBA (93 mg, 0.48 mmol) in CH2Cl2 (~ 1mL) at 0 °C. After 1.5 h, the reaction was cooled again to 0oC and mCPBA (45 mg, 0.26 mmol) was added as a slurry in CH2Cl2 (1 mL). The reaction was allowed to warm to rt. After completion, sat aq NaHCO3 (5 mL) was added. The layers were separated, and 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 rt. After sonication to remove chunks of solid the reaction was stirred at rt overnight. Later, the reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by preparative HPLC (C₁₈, MeCN in H₂O + 0.1 % HCO2H) to afford trans-6-bromo-2-((4-(dimethylamino)cyclohexyl)amino)-8- ethylpyrido[2,3-d]pyrimidin-7(8H)-one as pale yellow solid (198 mg, quant). 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]pyrimidin-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide (trans I-2)

[0238] Prepared by General Method SMC using 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, mmol, crude 0.04 M in dioxane), 6-bromo-2-((4-(dimethylamino)cyclohexyl)amino)-8-ethylpyrido[2,3-d]pyrimidin-7(8H)-one (89 mg, 0.23 mmol) and PdCl2dppf•CH2Cl2(18 mg, 0.023 mmol) in H2O (2 mL); by heating sealed in a microwave reactor at 90 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography using MeOH in CH2Cl2. The isolated material was filtered through a Waters PoraPak CX column to afford trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide as an off white solid (66 mg, 46 % yield).1H 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]pyrimidin-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide (trans I-3)

[0239] Prepared by General Method SMC using 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]pyrimidin-7(8H)-one (89 mg, 0.23 mmol) and PdCl2dppf•CH2Cl2 (18 mg, 0.023 mmol) in H2O (3 mL) and DME (5.4 mL); by heating in an oil bath at 110-90 °C for 2.8 h. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography in SiO2 using MeOH in CH₂Cl₂. The collected material was later filtered through a Waters PoraPak CX column to afford 5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide as a beige solid (63 mg, 42 % yield based on purity of 95 %).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]pyrimidin-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3- sulfonamide (trans I-4)Step 1. (8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)boronic acid

[0240] Prepared by General Method MB using 6-bromo-8-methyl-2- (methylthio)pyrido[2,3-d]pyrimidin-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 anh 1,4- dioxane (10 mL); by heating in an oil bath at 100oC for 3 d 20 h. The crude mixture was used directly 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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide

[0241] Prepared by General Method SMC using (8-methyl-2-(methylthio)-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)boronic acid (88 mg, 0.35 mmol, crude 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) by heating sealed in oil bath at 90 °C -100oC for 4 h. Later, thereaction mixture was cooled to rt 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 - 100oC for the total of 1 d 19 h. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (SiO₂, using MeOH in CH₂Cl₂), followed by flash chromatography (SiO₂, using EtOAc in CH₂Cl₂) to afford 5-chloro-N-(2,4- difluoro-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2- methoxypyridine-3-sulfonamide as an off-white solid (29 mg, 14 % based on the purity of 90 %). Step 3. trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (29 mg, 0.054 mmol, 90 %) in CH2Cl2 (10 mL) was added mCPBA (15.5 mg, 0.081 mmol) in CH2Cl2 (1 mL) at 0 °C. The stirring was continued allowing the mixture to slowly to warm to rt for the total time of 1.9 h. Satd aq NaHCO3 (5 mL) was added. After stirring, the layers were separated. The organic layer was filtered through a plug of anh Na2SO4, concentrated, and dried under high vacuum. The resultant crude material, 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) with sonication. The suspension was stirred at rt for 6 d. Subsequently the reaction mixture was concentrated on Celite and purified by preparative HPLC (C₁₈, using MeCN in H₂O + 0.1 % HCO₂H) to afford trans-5-chloro-N-(3- (2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide formic acid salt as a white solid (15.8 mg, 43 % yield).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]pyrimidin-6-yl)-2,4- difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (I-5)

[0243] To a suspension of 5-chloro-N-(2,4-difluoro-3-(8-methyl-2-(methylthio)-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (40 mg, 0.074 mmol)) in CH2Cl2 (10 mL) was added mCPBA (19 mg, 0.078 mmol) in CH2Cl2 (2 mL) at 0 °C. Stirring with cooling was continued allowing the mixture to slowly warm to rt for the total time of 2 h. Later the reaction was aged overnight at -20oC. After warming to rt, satd aq NaHCO3 (5 mL) was added. After stirring at rt, the organic layer was separated, filtered through a plug of anh Na2SO4, concentrated, and dried in vacuo. The residue was briefly sonicated in i-PrOH (8 mL) and aq NH4OH (0.96 mL, 7.4 mmol) was added dropwise at rt. The reaction was stirred vigorously at rt for 1.5 h, later concentrated on Celite and purified by preparative HPLC (C₁₈, using MeCN in H₂O + 0.1 % HCO₂H) to afford N-(3-(2- amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-5- chloro-2-methoxypyridine-3-sulfonamide*formic acid as a white solid (10 mg, 24 % yield). MS (ESI) m / z [M+H]⁺ 509.18.1H 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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-6)

[0244] To a cold (-78oC) solution of 5-chloro-N-(2,4-difluoro-3-(8-methyl-2- (methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3- sulfonamide (42 mg, 0.078 mmol) in CH2Cl2 (10 mL) was added mCPBA (20 mg, 0.082 mmol) in CH2Cl2(2 mL). Stirring was continued allowing the mixture slowly to warm to rt for the total time of 1.5 h. Later satd aq was added, and after brief stirring theorganic layer was separated, concentrated to remove CH2Cl2. The recovered solid was vigorously stirred in i-PrOH (8 mL) and MeNH2 (2.0M in THF, 0.97 mL, 1.9 mmol) at rt for 19.5 h. The reaction mixture was then concentrated on Celite and purified by preparative HPLC (C₁₈, using MeCN in H₂O + 0.1 % HCO₂H) to afford 5-chloro-N-(2,4-difluoro-3-(8- methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2- methoxypyridine-3-sulfonamide*formic acid as a white solid (10 mg, 23 %). MS (ESI) m / z [M+H]⁺ 523.25.1H 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]pyrimidin-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide (trans I-7) d]

[0245] The 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]pyrimidin-7(8H)-one (100 mg, 0.31 mmol) were taken in DMSO (5 mL). DIPEA (0.55 mL, 3.1 mmol) was added, and the reaction mixture was heated at 50oC for 2 d, 19 h. The reaction was then partitioned between H₂O and EtOAc. The aq phase was extracted with EtOAc (2x). The combined organic layers were concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (SiO₂, using MeOH in CH₂Cl₂ 0 to 85 % and then 2 M NH3-MeOH in CH₂Cl₂) to afford trans-6-bromo-2-((4- (dimethylamino)cyclohexyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one as a light orange film (55 mg, 45 % yield based on purity of 98 %). MS (ESI) m / z [M+H]⁺ 380.28 / 382.29Step 2. trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide (trans I-7)

[0246] Prepared by General Method SMC 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]pyrimidin-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); by heating, sealed in an oil bath at 80 °C for 2.5 d. The reaction mixture was then concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (SiO₂, using MeOH in CH₂Cl₂) followed by preparative HPLC (C₁₈, using MeCN in H₂O + 0.1 % HCO₂H) to afford trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide, formic acid as a white powder (20 mg, 21 % yld based on the purity of 98 %). MS (ESI) m / z [M+H]⁺ 616.36.1H 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-dihydropteridin-6- yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-8)Step 1: 5-chloro-N-(4-fluoro-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropteridin-6- yl)phenyl)-2-methoxypyridine-3-sulfonamide

[0247] 6-(5-amino-2-fluorophenyl)-8-methyl-2-(methylthio)pteridin-7(8H)-one (200 mg, 0.62 mmol, 98 %) and 5-chloro-2- 3-sulfonyl chloride (164 mg, 0.68mmol) were cooled in at -10oC before CH2Cl2(20 mL) was added. After additional cooling (10 min), pyridine (0.25 mL, 3.1 mmol) was added and the vial was removed from the cooling bath allowing the mixture to warm with stirring to rt. The reaction was stirred at rt for 4 d before being concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (SiO₂, using EtOAc in CH₂Cl₂) to afford 5-chloro-N-(4-fluoro-3-(8- methyl-2-(methylthio)-7-oxo-7,8-dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3- sulfonamide as a light orange solid (259 mg, 80 % yield). MS (ESI) m / z [M+H]⁺523.25. Step 2. 5-chloro-N-(4-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridin-6- yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-8)

[0248] To a cold (-10oC) solution of 5-chloro-N-(4-fluoro-3-(8-methyl-2- (methylthio)-7-oxo-7,8-dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (60 mg, 0.11 mmol) in CH2Cl2 (10 mL) mCPBA (30 mg, 0.12 mmol) was added in CH2Cl2 (2 mL). The reaction was allowed to warm to rt and stirring was continued at rt for the total time of 18 h. 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 1.5 h of stirring at rt, the material was deposited on Celite and purified by preparative HPLC (C₁₈, using MeCN in H₂O + 0.1 % HCO₂H) to afford 5-chloro-N-(4-fluoro-3-(8-methyl-2-(methylamino)-7-oxo- 7,8-dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide*formic acid as a pale yellow solid (25 mg, 39 % based on the purity of 99 %). MS (ESI) m / z [M+H]⁺ 506.25.1H 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-dihydropteridin-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide (trans I-9)

[0249] To a cold (-78oC) solution of 5-chloro-N-(4-fluoro-3-(8-methyl-2- (methylthio)-7-oxo-7,8-dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (70 mg, 0.134 mmol) in CH2Cl2(10 mL), mCPBA (35 mg, 0.14 mmol) was added in CH2Cl2(2 mL). The reaction was then allowed slowly warm to rt and then was stirred at rt for thetotal time of 18 h. CH2Cl2was removed under reduced pressure. trans-N1,N1- dimethylcyclohexane-1,4-diamine*2HCl (89 mg, 0.41 mmol) was added. The entire material was suspended in i-PrOH (8 mL) and after sonication, DIPEA (0.23 mL, 1.3 mmol) was added. The mixture was stirred vigorously at rt for 2.5 h. Later more i-PrOH (8 mL) was added and after brief sonication, the stirring was continued at rt overnight. The reaction was later heated in an oil bath at 50oC for 3 h. Subsequently, the reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by preparative HPLC (C₁₈, using MeCN in H₂O + 0.1 % HCO₂H) to afford 5-chloro-N-(3-(2-((4- (dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropteridin-6-yl)-4- fluorophenyl)-2-methoxypyridine-3-sulfonamide as a light yellow solid (16.5 mg, 18 % yield based on purity of 98 %). MS (ESI) m / z [M+H]⁺ 617.30.1H 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]pyrimidin-6-yl)-2-fluorophenyl)-2-methoxypyridine-3- sulfonamide (trans I-10)

[0250] Prepared by General Method SMC using 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]pyrimidin-7(8H)-one (70 mg, 0.18 mmol), H2O (1.8 mL) and (3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2- fluorophenyl)boronic acid (3.5 mL, 0.18 mmol, 0.052 M crude in 1,4-dioxane); by heating, sealed in a microwave reactor at 90 °C for 100 min. Purified by flash chromatography (SiO2, using MeOH in CH₂Cl₂) and then by preparative HPLC (C₁₈, using MeCN in H₂O + 0.1 % HCO₂H) to afford trans-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-2-methoxypyridine-3- sulfonamide, formic acid as a white solid (23 mg, 17 % yield based on purity of 99 %). 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, 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., 1H), 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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3- sulfonamide (trans I-11)Step 1. N-(3-bromo-2-cyanophenyl)-5-chloro-N-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)- 2-methoxypyridine-3-sulfonamide

[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 at -78oC before CH2Cl2 (10 mL) and pyridine (0.51 mL, 6.3 mmol) were added. The reaction mixture was then removed from the cooling bath and stirred at rt for 2 d. Later, another portion of 5- chloro-2-methoxypyridine-3-sulfonyl chloride (307 mg, 1.27 mmol) was added at rt and the stirring was continued for 3 d. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (SiO₂, using EtOAc in hexanes) to afford N-(3-bromo-2-cyanophenyl)-5-chloro-N-((5-chloro-2-methoxypyridin-3- yl)sulfonyl)-2-methoxypyridine-3-sulfonamide as white powder (333 mg, 43 %). MS (ESI) m / z [M+H]⁺ 606.99 / 609.1. Step 2. (3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-cyanophenyl)boronic acid

[0252] Prepared by General Method MB using N-(3-bromo-2-cyanophenyl)-5- chloro-N-((5-chloro-2-methoxypyridin-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) in 1,4-dioxane (5 mL); by heating sealed in a microwave reactor at 100 °C for 2 h and then at 100oC in an oil bath for 1 d 19 h. The entire crude material was used in the following 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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (trans I-11)

[0253] Prepared by General Method SMC using (3-((5-chloro-2-methoxypyridine)- 3-sulfonamido)-2-cyanophenyl)boronic acid (4.9 mL, 0.16 mmol, 5.0 mL, 0.033 M crude 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]pyrimidin-7(8H)- one (62 mg, 0.16 mmol) and H2O (2.5 mL); by heating sealed in a microwave reactor at 90 °C for 2 h. Purified by flash chromatography (using MeOH in CH2Cl2) and repurified by preparative HPLC (C₁₈,using MeCN in H₂O + 0.1 % HCO₂H) to afford trans-5-chloro-N-(2- cyano-3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide 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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-12)Step 1.6-bromo-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

[0254] Prepared by General Method NS using an i-PrOH (20 mL) suspension of 6- bromo-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (600 mg, 2.082 mmol) and MeNH2 (40 wt % in H2O, 3.6 mL, 42 mmol). The reaction was shaken for 10 min at rt and then stirred at rt for 19 h. Later, the reaction was again shaken at rt for 2 h. A filtration and rinsing with EtOH yielded 6-bromo-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one as a white solid (414 mg, 78 % yield). 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]pyrimidin- 6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-12)

[0255] Prepared by General Method SMC using Cs2CO3(644 mg, 1.98 mmol), (3- ((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)boronic acid (261 mg, 0.72 mmol), 6-bromo-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (168 mg, 0.66 mmol) and PdCl2dppf•CH2Cl2(54 mg, 0.066 mmol) in H2O (5 mL) and 1,4-dioxane (10 mL); by heating sealed in an oil bath for 22 h at 95 °C. The crude mixture was then cooled to rt, partitioned between H2O and CH2Cl2. The aq layer was extracted with 2 %v / v MeOH in CH2Cl2(2x). The combined organic layers were concentrated under reduced pressure, deposited on Celite and purified by flash chromatography to afford 5-chloro-N-(2-fluoro-3- (2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine- 3-sulfonamide as a white solid (62.0 mg, 19 % yield). MS (ESI) m / z [M+H]⁺491.27.1H 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- dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-13)

[0256] To a cold (0oC) solution of 5-chloro-N-(4-fluoro-3-(8-methyl-2-(methylthio)- 7-oxo-7,8-dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (129 mg, 0.25 mmol) in CH2Cl2(20 mL) was added mCPBA (64 mg, 0.26 mmol) in CH2Cl2(1-2 mL) and stirred allowing slowly to warm to rt for the total time of 4 h. 50 % of the crude mixture was concentrated to remove CH2Cl2. The solid residue was suspended in i-PrOH (6 mL) and treated with i-PrNH2(0.32 mL, 3.7 mmol) at rt. The suspension was stirred at rt for 1 d 19 h before it was concentrated unto Celite and purified by preparative HPLC (C₁₈, MeCN in H₂O + 0.1 % HCO₂H) to afford 5-chloro-N-(4-fluoro-3-(2-(isopropylamino)-8-methyl-7-oxo- 7,8-dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as an off white solid (28 mg, 40 % yield based on purity of 94 %). MS (ESI) m / z [M+H]⁺ 534.53.1H 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 signal for N-Me is assumed to be obscured by the “H2O” peak. Example 14: 5-chloro-N-(3-(2-(ethylamino)-8-methyl-7-oxo-7,8-dihydropteridin-6-yl)-4- fluorophenyl)-2-methoxypyridine-3-sulfonamide (I-14)

[0257] Prepared following the same method as 5-chloro-N-(4-fluoro-3-(2- (isopropylamino)-8-methyl-7-oxo-7,8-dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3- sulfonamide using EtNH2 (66-72% in H2O) to afford 5-chloro-N-(3-(2-(ethylamino)-8- methyl-7-oxo-7,8-dihydropteridin-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide as a pale yellow solid (25.0 mg, 40 % yield). MS (ESI) m / z [M-H]- 518.31.1H NMR (500 MHz, DMSO-d6) δ ppm 10.55 (br. s., 1 H), - 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 signal for N-Me is assumed to be obscured by the “H2O” peak. Example 15: 5-chloro-N-(2,4-difluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8- dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-15)Step 1.6-(3-amino-2,6-difluorophenyl)-8-methyl-2-(methylamino)pteridin-7(8H)-one

[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)pteridin-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). The vial was sealed and degassed. The mixture was then heated sealed in a microwave reactor at 65 °C for 5 h. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (using MeOH in CH₂Cl₂) to afford 6-(3-amino-2,6- difluorophenyl)-8-methyl-2-(methylamino)pteridin-7(8H)-one as a light yellow solid (67 mg, 84 % yield). 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-dihydropteridin-6- yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-15)

[0259] Prepared by General Method NS using CH2Cl2(11 mL), 6-(3-amino-2,6- difluorophenyl)-8-methyl-2-(methylamino)pteridin-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, deposited on Celite and purified by flash chromatography (using MeOH in CH₂Cl₂) followed by preparative HPLC (C₁₈, MeCN in H₂O + 0.1 % HCO₂H) to afford 5-chloro-N-(2,4-difluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridin-6- yl)phenyl)-2-methoxypyridine-3-sulfonamide as a white solid with a very faint yellow tint (43 mg, 39 % yield based on purity of 97 %). MS (ESI) m / z [M+H]⁺ 524.39.1H 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 signal for N-Me is hidden under the solvent peak. Example 16: 5-chloro-N-(3-(2-(ethylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (I-16)Step 1.6-bromo-2-(ethylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0260] A mixture of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin- 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 rt for 1 d. A solid was collected by filtration. rinsed with EtOH to afford 6-bromo-2-(ethylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one as a white solid (227 mg, 85 % yield). 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]pyrimidin- 7(8H)-one

[0261] Prepared by General Method SMC using 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]pyrimidin-7(8H)-one (60 mg, 0.21 mmol), chloro(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl- (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (25 mg, 0.032 mmol) and K3PO4(157 mg, 0.74 mmol) in1,4-dioxane (5 mL) and H2O (0.5 mL); by heating sealed in a microwave reactor at 65 °C for 10 h. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (using MeOH in CH₂Cl₂) to afford 6-(3-amino-2,6-difluorophenyl)-2- (ethylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one as a light tan solid (83 mg, quant 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]pyrimidin-6- yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (I-16)

[0262] Prepared by General Method NS, using CH2Cl2 (11 mL), 6-(3-amino-2,6- difluorophenyl)-2-(ethylamino)-8-methylpyrido[2,3-d]pyrimidin-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 rt for 1 d 18 h the reaction mixture was concentrated under reduced pressure, deposited on Celite and by preparative HPLC (C₁₈, MeCN in H₂O + 0.1 % HCO₂H) and later repurified twice by flash chromatography (using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂) to afford 5-chloro-N-(3-(2-(ethylamino)- 8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-2- methoxypyridine-3-sulfonamide as a white solid (9.0 mg, 8 % yield). MS (ESI) m / z [M+H]⁺ 537.42.1H 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]pyrimidin-6-yl)- 4-fluorophenyl)-2-methoxypyridine-3-sulfonamide (I-17)Step 1.6-bromo-2-(methylsulfinyl) 7(8H)-one

[0263] A cold (0 °C) suspension of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin- 7(8H)-one (500 mg, 1.8 mmol) and mCPBA (476 mg, 1.9 mmol) in CH2Cl2(100 mL) was slowly allowed to warm to rt and stirred for the total time of 1 d and 19 h. The product was isolated by filtration and rinsed with CH2Cl2to afford 6-bromo-2-(methylsulfinyl)pyrido[2,3- d]pyrimidin-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]pyrimidin-7(8H)-one

[0264] To a suspension of 6-bromo-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)- one (100 mg, 0.35 mmol) in i-PrOH (10 mL) was added EtNH2(66-72% in H2O, 0.55 mL, 6.9 mmol) in one portion. After stirring at rt for 21 h, the product was collected by filtration, rinsed with EtOH to afford 6-bromo-2-(ethylamino)pyrido[2,3-d]pyrimidin-7(8H)-one as a white solid (70 mg, 75 % yield). 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]pyrimidin-6-yl)-4- fluorophenyl)-2-methoxypyridine-3-sulfonamide (I-17)

[0265] Prepared by General Method SMC using 6-bromo-2-(ethylamino)pyrido[2,3- d]pyrimidin-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-sulfonamido)-2- fluorophenyl)boronic acid (113 mg, 0.31 mmol), H2O (2 mL) and 1,4-dioxane (4 mL); by heating sealed in a microwave reactor at 100 °C for 2.5 h. Purified by flash chromatography (using MeOH in CH₂Cl₂) then by preparative HPLC (C₁₈, MeCN in H₂O + 0.1 % HCO₂H) to afford 5-chloro-N-(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4- fluorophenyl)-2-methoxypyridine-3-sulfonamide as a white solid (20.0 mg, 18 % yield). MS (ESI) m / z [M+H]⁺ 505.33.1H 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., 0.5H),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). (a CH2's signal is obscured by “solvent / H2O” peaks).Example 18: 5-chloro-N-(4-fluoro-3-(2-(isopropylamino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-18)Step 1.6-bromo-2-(isopropylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

[0266] To a suspension of 6-bromo-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)- one (100 mg, 0.35 mmol) in i-PrOH (10 mL) was added i-PrNH2 (0.60 mL, 6.9 mmol) in one portion. After stirring at rt for 3 d the product was collected by filtration, rinsed with EtOH to afford 6-bromo-2-(isopropylamino)pyrido[2,3-d]pyrimidin-7(8H)-one as a white solid (84.0 mg, 85 % yield). 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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-18)

[0267] Prepared by General Method SMC using 6-bromo-2- (isopropylamino)pyrido[2,3-d]pyrimidin-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-sulfonamido)-2-fluorophenyl)boronic acid (112 mg, 0.31 mmol), H2O (2 mL) and 1,4- dioxane (4 mL); by heating sealed in a microwave reactor at 100 °C for 2.5 h. Purified by flash chromatography (using MeOH in CH₂Cl₂) then by preparative HPLC (C₁₈, MeCN in H₂O + 0.1 % HCO₂H) followed by trituration with MeCN to afford 5-chloro-N-(4-fluoro-3-(2- (isopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine- 3-sulfonamide as a white solid (12.0 mg, 9 % yield based on purity of 95 %). MS (ESI) m / z [M+H]⁺ 519.31.1H 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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-19)Step 1: 6-bromo-2-(isopropylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0268] To a suspension of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3- d]pyrimidin-7(8H)-one (300 mg, 0.94 mmol) in i-PrOH (10 mL) was added i-PrNH2 (2.43 mL, 28d mmol) dropwise. After stirring at rt for 1 d 3 h the product was collected by filtration and rinsed with EtOH to afford 6-bromo-2-(isopropylamino)-8-methylpyrido[2,3-d]pyrimidin- 7(8H)-one as a white solid (110.0 mg, 39 % yield). 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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-19)

[0269] Prepared by General Method SMC using 6-bromo-2-(isopropylamino)-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one (77 mg, 0.26 mmol), PdCl2dppf•CH2Cl2(21 mg, 0.026 mmol), Cs2CO3 (211 mg, 0.65 mmol), (5-((5-chloro-2-methoxypyridine)-3- sulfonamido)-2-fluorophenyl)boronic acid (112 mg, 0.31 mmol) in H2O (2 mL) and 1,4- dioxane (4 mL); by heating using a microwave rector at 90 °C for 1.5 h. Purified by flash chromatography (using MeOH in CH₂Cl₂) followed by preparative HPLC (C₁₈, MeCN in H₂O + 0.1 % HCO₂H) to afford 5-chloro-N-(4-fluoro-3-(2-(isopropylamino)-8-methyl-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as an off white powder (73.0 mg, 53 % yield).1H 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's signal is obscured). MS (ESI) m / z [M+H]⁺ 533.48.Example 20: 5-chloro-N-(2-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridin- 6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-20)

[0270] Prepared by General Method SMC using 6-bromo-8-methyl-2- (methylamino)pteridin-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-sulfonamido)- 2-fluorophenyl)boronic acid (108 mg, 0.30 mmol), 1,4-dioxane (4.8 mL) and H2O (2.4 mL); by heating sealed in a microwave reactor at 90 °C for 1.5 h. Purified by flash chromatography (using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂) to afford 5- chloro-N-(2-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridin-6-yl)phenyl)-2- methoxypyridine-3-sulfonamide as a pale yellow solid (18.0 mg, 14 % yield). MS (ESI) m / z [M+H]⁺ 506.41.1H 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 under solvent peak Example 21: 5-chloro-N-(3-(2-(cyclopropylamino)-8-methyl-7-oxo-7,8-dihydropteridin-6- yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide (I-21)

[0271] To a stirred, cold (0oC) suspension of 5-chloro-N-(4-fluoro-3-(8-methyl-2- (methylthio)-7-oxo-7,8-dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (350 mg, 0.67 mmol) in CH2Cl2 (20 mL) was added mCPBA (173 mg, 0.70 mmol) as a solid and CH2Cl2 (1 mL) was used to complete the transfer of mCPBA. The reaction was then stirred allowing slowly to warm to rt and then was stirred at rt overnight. The conversion was complete at this point and the reaction mixture was composed of 5-chloro-N-(4-fluoro-3-(8- methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide and 5-chloro-N-(4-fluoro-3-(8-methyl-2-(methylsulfonyl)-7-oxo-7,8- dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide. The reaction mixture was split in six equal parts by volume, each part was concentrated under reduced pressure and used in the subsequent SNAr step without further purification. MS (ESI) m / z [M+H]⁺ 539.30 and 555.29.

[0272] A1 / 6 portion of the solid material derived from the mCPBA oxidation step was suspended in i-PrOH (10 mL) and treated with c-PrNH2(0.23 mL, 3.3 mmol) and than shaken at rt for 3 d 22 h. A solid was collected by filtration, rinsed with EtOH to afford 5- chloro-N-(3-(2-(cyclopropylamino)-8-methyl-7-oxo-7,8-dihydropteridin-6-yl)-4- fluorophenyl)-2-methoxypyridine-3-sulfonamide as a pale yellow solid (49.3, 83 % yield). MS (ESI) m / z [M+H]⁺ 532.28.1H NMR (500 MHz, DMSO-d6) δ ppm 9.99 - 10.94 (m, 1 H), 8.62 - 8.80 (m, 1 H), 8.41 - 8.50 (m, 1 H), 8.17 - 8.33 (m, 1 H), 8.02 - 8.15 (m, 1 H), 7.29 (d, J=6.36 Hz, 1 H), 7.12 - 7.22 (m, 2 H), 3.95 (s, 3 H), 2.89 (br. s., 1 H), 0.76 (br. s., 2 H), 0.56 (br. s., 2 H) a signal corresponding to N-Me is obscured by solvent peaks. Example 22: (R)-5-chloro-N-(4-fluoro-3-(8-methyl-7-oxo-2-((tetrahydrofuran-3-yl)amino)- 7,8-dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide ((R)-I-22)

[0273] Similarly to the synthesis of 5-chloro-N-(3-(2-(cyclopropylamino)-8-methyl- 7-oxo-7,8-dihydropteridin-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide, a1 / 6 portion of the mCPBA oxidation products derived from 5-chloro-N-(4-fluoro-3-(8-methyl-2- (methylthio)-7-oxo-7,8-dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (350 mg, 0.669 mmol) was suspended in i-PrOH (10 mL) and treated with (R)-3- aminotetrahydrofuran (0.29 mL, 3.3 mmol) and shaken at rt 3 d 22 h. A solid was collected by filtration, rinsed with EtOH to afford (R)-5-chloro-N-(4-fluoro-3-(8-methyl-7-oxo-2- ((tetrahydrofuran-3-yl)amino)-7,8-dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3- sulfonamide as a pale yellow solid (46 mg, 73 % yield based on purity of 99 %). MS (ESI) m / z [M+H]⁺ 562.37.1H 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-(oxetan-3-ylamino)-7-oxo-7,8- dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-23)

[0274] Similarly to the synthesis of 5-chloro-N-(3-(2-(cyclopropylamino)-8-methyl- 7-oxo-7,8-dihydropteridin-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide, a1 / 6portion of the mCPBA oxidation products derived from 5-chloro-N-(4-fluoro-3-(8-methyl-2- (methylthio)-7-oxo-7,8-dihydropteridin-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 rt for 3 d 22 h. A solid was collected by filtration, rinsed with EtOH to afford 5-chloro-N-(4-fluoro-3-(8-methyl-2-(oxetan-3- ylamino)-7-oxo-7,8-dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a pale yellow solid (30.3 mg, 47 % yield based on the purity of 95 %). MS (ESI) m / z [M+H]⁺ 548.38.1H 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). N-Me signal is obscured by the solvent peaks. Example 24: 5-chloro-N-(4-fluoro-3-(8-methyl-7-oxo-2-((tetrahydro-2H-pyran-4-yl)amino)- 7,8-dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-24)

[0275] Similarly to the synthesis of 5-chloro-N-(3-(2-(cyclopropylamino)-8-methyl- 7-oxo-7,8-dihydropteridin-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide, a1 / 6 portion of the mCPBA oxidation products derived from 5-chloro-N-(4-fluoro-3-(8-methyl-2- (methylthio)-7-oxo-7,8-dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (350 mg, 0.67 mmol) was suspended in i-PrOH (10 mL) and treated with tetrahydro-pyran-4-ylamine (113 mg, 1.1 mmol). The reaction mixture was shaken at rt for 3 d 22 h. A solid was collected by filtration, rinsed with EtOH to afford 5-chloro-N-(4-fluoro-3-(8-methyl-7- oxo-2-((tetrahydro-2H-pyran-4-yl)amino)-7,8-dihydropteridin-6-yl)phenyl)-2- methoxypyridine-3-sulfonamide as a pale yellow solid (39.4 mg, 61 % yield based on the purity of 99 %). MS (ESI) m / z [M-H]- 574.34.1H 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 H). CH and N-Me signals are obscured by the peaks due to the solvent. Example 25: 5-chloro-N-(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)- 2-fluorophenyl)-2-methoxypyridine-3-sulfonamide (I-25)Step 1; 6-bromo-2-(ethylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

[0276] To a cold (0oC) suspension of 6-bromo-2-(methylthio)pyrido[2,3- d]pyrimidin-7(8H)-one (800 mg, 2.9 mmol) in CH2Cl2 (200 mL) was added mCPBA (761 mg, 3.1 mmol) as a solid. The reaction mixture was then stirred allowing slowly to warm to rt for the total time of 1 d 19 h. The material was collected by filtration after a rinse with CH2Cl2 to afford 6-bromo-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one as a white solid (759.0 mg, 86 % yield based on purity of 96 %). MS (ESI) m / z [M+H]⁺288.13|290.16.

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

[0278] Prepared by General Method SMC using Cs2CO3(465 mg, 1.427 mmol), (3- ((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)boronic acid (171 mg, 0.48 mmol), 6-bromo-2-(ethylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (128 mg, 0.48 mmol), PdCl2dppf•CH2Cl2(39 mg, 0.048 mmol) in H2O (5 mL) and 1,4-dioxane (10 mL); by heating sealed in an oil bath at 95 °C for 23 h. The reaction mixture was cooled to rt, partitioned between H2O and CH2Cl2. The aq layer was extracted with CH2Cl2with small amount of MeOH (2x). The combined organic layers were concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (using MeOH|CH₂Cl₂|conc aq NH4OH 89:10:1) to afford 5-chloro-N-(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide as a white solid (60.0 mg, 25 % yield). MS (ESI) m / z [M+H]⁺ 505.29.1H 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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-26)

[0279] Prepared by General Method SMC using 6-bromo-2- (methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (120 mg, 0.47 mmol), PdCl2dppf•CH2Cl2 (38 mg, 0.047 mmol), Cs2CO3 (383 mg, 1.2 mmol), (5-((5-chloro-2-methoxypyridine)-3- sulfonamido)-2-fluorophenyl)boronic acid (204 mg, 0.56 mmol) in H2O (5 mL) and 1,4- dioxane (10 mL); by heating sealed in a microwave reactor at 100 °C for 4 h. The reaction mixture was partitioned between H2O and CH2Cl2. The aq layer was extracted with CH2Cl2 with a small amount of MeOH (2x). The combined organic layers were concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (using MeOH|CH₂Cl₂|conc aq NH4OH 89:10:1) to afford 5-chloro-N-(4-fluoro-3-(2-(methylamino)- 7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a white solid (129.0 mg, 56 % yield). MS (ESI) m / z [M+H]⁺ 491.35.1H 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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-27)Step 1: 6-bromo-8-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

[0280] To a suspension of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3- d]pyrimidin-7(8H)-one (500 mg, 1.57 mmol) in i-PrOH (17 mL) was added MeNH2(40 wt % in H2O, 3.4 mL, 39 mmol) at rt and the reaction mixture was shaken at rt for 6 d 23 h. The precipitate was collected by filtration, rinsed with i-PrOH to afford 6-bromo-8-methyl-2- (methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one as a white solid (345.0 mg, 82 % yield). 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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-27)

[0281] Prepared by General Method SMC using 6-bromo-8-methyl-2- (methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.37 mmol), (5-((5-chloro-2- methoxypyridine)-3-sulfonamido)-2-fluorophenyl)boronic acid (147 mg, 0.41 mmol), Cs2CO3(303 mg, 0.93 mmol) and PdCl2dppf•CH2Cl2(15 mg, 0.019 mmol) in 1,4-dioxane (4 mL) and H2O (2 mL); by heating sealed in a microwave reactor at 90 °C for 3 h. The reaction mixture was cooled to rt, diluted with H2O (30 mL) and treated with 1 M aq HCl (1 mL). The solid was collected by filtration and the filter cake was rinsed with H2O. The beige precipitate was dissolved in CH2Cl2 / MeOH, deposited dry on Celite and purified by flash chromatography (using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂) to afford 5-chloro-N-(4-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as an off white solid (75.0 mg, 40 %). MS (ESI) m / z [M+H]⁺ 505.34.1H 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 signal corresponding to Me is obscured by the peaks due to the solvent. Example 28: 5-chloro-N-(2-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-28)

[0282] Prepared by General Method SMC using 6-bromo-8-methyl-2- (methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.37 mmol), (3-((5-chloro-2- methoxypyridine)-3-sulfonamido)-2-fluorophenyl)boronic acid (134 mg, 0.37 mmol), Cs2CO3(303 mg, 0.93 mmol) and PdCl2dppf•CH2Cl2(15 mg, 0.019 mmol) in 1,4-dioxane (4 mL) and H2O (2 mL); by heating in a microwave reactor at 90 °C for 3 h. The reaction mixture was diluted with H2O (30 mL) and treated with 1 M aq HCl (1 mL). The solid was collected by filtration and the filter cake was rinsed with H2O. The beige precipitate was redissolved in CH2Cl2 / MeOH, deposited dry on Celite and purified by flash chromatography (using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂) to afford 5-chloro-N-(2-fluoro-3- (8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2- methoxypyridine-3-sulfonamide as a white solid (70.0 mg, 37 %). MS (ESI) m / z [M+H]⁺ 505.34.1H 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 signal for Me is obscured by the peaks due to the solvent.Example 29: N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4- fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (I-29)Step 1: 2-amino-6-bromo-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0283] To a suspension of 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3- d]pyrimidin-7(8H)-one (511 mg, 1.61 mmol) in i-PrOH (15 mL) was added NH3 (7 N in MeOH, 4.6 mL, 32 mmol) at rt. The mixture was shaken at rt for 1.2 h. The reaction mixture was diluted with 1 M aq KOH (10 mL, 10 mmol), shaken for several minutes, the left sitting at rt overnight. A yellow precipitate was collected by filtration, rinsed with H2O to afford 2- amino-6-bromo-8-methylpyrido[2,3-d]pyrimidin-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]pyrimidin-6-yl)-4- fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (I-29)

[0284] Prepared by General Method SMC using (5-((5-chloro-2-methoxypyridine)- 3-sulfonamido)-2-fluorophenyl)boronic acid (85 mg, 0.23 mmol), 2-amino-6-bromo-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one (60 mg, 0.23 mmol), Cs2CO3(192 mg, 0.59 mmol) and PdCl2dppf (17 mg, 0.024 mmol) in H2O (2 mL) and 1,4-dioxane (4 mL); by heating sealed in a microwave reactor at 90 °C for 2 h. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂ to afford N-(3-(2-amino-8-methyl-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-fluorophenyl)-5-chloro-2-methoxypyridine-3- sulfonamide as a white solid (48 mg, 42 % yield). MS (ESI) m / z [M+H]⁺ 491.20.1H 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, 2H), 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]pyrimidin-6-yl)-2- fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (I-30)

[0285] Prepared by General Method SMC using 2-amino-6-bromo-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one (60 mg, 0.23 mmol), (3-((5-chloro-2- methoxypyridine)-3-sulfonamido)-2-fluorophenyl)boronic acid (85 mg, 0.23 mmol), Cs2CO3(192 mg, 0.59 mmol) and PdCl2dppf (17 mg, 0.024 mmol) in H2O (2 mL) and 1,4-dioxane (4 mL); by heating sealed in a microwave reactor at 90 °C for 2 h. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (12 g SiO₂ RediSep GOLD® Cartridge, using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂). Later the collected solid was dissolved in MeOH and filtered through a Waters PoraPak CX, rinsing with MeOH and eluting with 1.4 M NH₃ in MeOH to afford N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2- fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamides a white solid (33.4 mg, 29 % yield). MS (ESI) m / z [M+H]⁺ 491.20.1H 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]pyrimidin-6-yl)pyridin-2-yl)-2-methoxypyridine-3-sulfonamide (I-31)Step 1: 5-chloro-N-(5-fluoro-4- 2- -2- 3-sulfonamide

[0286] 5-fluoro-4-iodopyridin-2-amine (0.70 g, 2.9 mmol) was added to anh pyridine (7 mL) at 0 °C and the reaction mixture was stirred at rt for 2 h. Later 5-chloro-2- methoxypyridine-3-sulfonyl chloride (0.70 g, 2.9 mmol) was added at 0 °C and the reaction mixture was then stirred at rt for 2 h. Another batch of 5-chloro-2-methoxypyridine-3- sulfonyl chloride (1 equiv) was added at 0 °C and stirring was continued for 16 h at rt. The reaction mixture was then diluted with 10 % citric acid solution (40 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (anh Na2SO4),concentrated under reduced pressure. Purified by column chromatography using EtOAc in hexanes to afford 5-chloro-N-(5-fluoro-4-iodopyridin-2-yl)-2-methoxypyridine-3-sulfonamide as white solid (0.70 g, 55 %).1H 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]pyrimidin-6-yl)boronic acid

[0287] Prepared by General Method MB using 6-bromo-8-methyl-2- (methylamino)pyrido[2,3-d]pyrimidin-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 anh 1,4-dioxane (10 mL); by heating in an oil bath at 100oC for 4 h. The crude reaction mixture (0.052 M) was used directly in the following 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]pyrimidin-6-yl)pyridin-2-yl)-2-methoxypyridine-3-sulfonamide (I-31)

[0288] Prepared by General Method SMC using 5-chloro-N-(5-fluoro-4-iodopyridin- 2-yl)-2-methoxypyridine-3-sulfonamide (80 mg, 0.18 mmol), PdCl2dppf (13.2 mg, 0.018 mmol), Cs2CO3 (176 mg, 0.54 mmol) in H2O (2.1 mL) and crude (8-methyl-2-(methylamino)- 7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)boronic acid (4.2 mL, 0.22 mmol, 0.052 M in 1,4-dioxane); by heating sealed in a microwave reactor at 65 °C for 3 h and then at 90oC for 3 h. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂ to yield a solid that was Et2O to afford 5-chloro-N-(5-fluoro-4-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)pyridin-2-yl)-2- methoxypyridine-3-sulfonamide as an off white solid (13.4 mg, 15 % yield). MS (ESI) m / z [M+H]⁺ 506.17.1H 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]pyrimidin-6-yl)pyridin-2-yl)-2-methoxypyridine-3-sulfonamide (I-32)Step 1: 5-chloro-N-(3-fluoro-4-iodopyridin-2-yl)-2-methoxypyridine-3-sulfonamide

[0289] To a cooled solution of t-BuOK(0.7 g, 6.3 mmol) in THF (5 mL), 3-fluoro-4- iodopyridin-2-amine (0.50 g, 2.1 mmol) was added at 0°C. Stirring was continued at rt for 1 h before 5-chloro-2-methoxypyridine-3-sulfonyl chloride (0.51 g, 2.1 mmol) was added at 0 °C. After stirring at rt for 4 h, the reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried (anh Na2SO4) and concentrated under reduced pressure. Purified by column chromatography using hexanes and EtOAc to afford 5-chloro-N-(3-fluoro-4-iodopyridin-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- pyrimidin-6-yl)boronic acid

[0290] Prepared by General Method MB using 6-bromo-2- (methylamino)pyrido[2,3-d]pyrimidin-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 anh 1,4- dioxane (24 mL); by heating in an oil bath at 105 °C for 1 d 19 h. The crude mixture was estimated to be 84 % (2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6- yl)boronic acid. The reaction mixture was used crude in the following 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]pyrimidin- 6-yl)pyridin-2-yl)-2-methoxypyridine-3-sulfonamide (I-32)

[0291] Prepared by General Method SMC using 5-chloro-N-(3-fluoro-4-iodopyridin- 2-yl)-2-methoxypyridine-3-sulfonamide (80 mg, 0.18 mmol), PdCl2dppf (13 mg, 0.018 mmol), Cs2CO3(176 mg, 0.54 mmol) in H2O (4.3 mL) and crude (2-(methylamino)-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)boronic acid in 1,4-dioxane (8.7 mL, 0.22 mmol); by heating sealed in a microwave reactor at 60 °C for 2.5 h and then at 100 °C for 2 h. Purified by flash chromatography using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂ 0-100 % then MeOH in CH₂Cl₂ to afford a brown solid that was triturated with Et2O and then multiple times with MeCN until yielding 5-chloro-N-(3-fluoro-4-(2-(methylamino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl)pyridin-2-yl)-2-methoxypyridine-3-sulfonamide as a grey solid (30.0 mg, 33 % based on the purity of 97 %). MS (ESI) m / z [M+H]⁺ 492.22.1H 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-sulfonamido)-2- fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexane- 1-carboxamide (trans I-33)Step 1: trans-4-aminocyclohexane-1-carboxamide*trifluoroacetic acid

[0292] A DMF (3 mL) 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) was stirred at rt for 30 min before NH4Cl (220 mg, 4.1 mmol) was added as a solid. The reaction was mixed at rt overnight then diluted with Et2O, washed with 0.1 M aq HCl. The organic layer was separated and concentrated under reduced pressure yielding a white solid (100 mg). Another crop of the white solid was collected by filtration of the aq layer. The filter cake was rinsed with xs H2O. The two crops were combined to afford tert-butyl (trans-4-carbamoylcyclohexyl)carbamate (476.0 mg, 96 %). The entire material was stirred in CH2Cl2 (5 mL) and TFA (0.16 mL, 2.0 mmol) at rt for 1 d 18 h. The reaction mixture was then concentrated under reduced pressure, dried in vacuo to afford trans 4-aminocyclohexane-1-carboxamide*trifluoroacetic acid as a pale yellow gum (505 mg, 96 %) that was used directly in the following step. Step 2: trans 4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)cyclohexane-1-carboxamide4-aminocyclohexane-1- carboxamide*trifluoroacetic acid (168 mg, 0.66 mmol) and K2CO3(453 mg, 3.3 mmol) was stirred at rt for 0.2 h. 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (217 mg, 0.68 mmol) was added in one portion and stirring was continued at rt for 2.5 h before H2O (4 mL) was added. The solvents were removed by evaporation under reduced pressure, the residue was redissolved in MeOH, deposited on Celite and purified by flash chromatography using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂ and later MeOH in CH2Cl2to afford trans-4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)cyclohexane-1-carboxamide as an off white solid (216 mg, purity of 77%). MS (ESI) m / z [M+H]⁺ 380.20|382.16Step 3: trans-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexane-1-carboxamide (trans I-33)

[0294] Prepared by General Method SMC using (5-((5-chloro-2-methoxypyridine)- 3-sulfonamido)-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]pyrimidin-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); by heating sealed in a microwave reactor at 90 °C for 2 h. Purified by flash chromatography using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂ to afford trans-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2- fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexane- 1-carboxamide as an off white solid (38.0 mg, 28 % yield based on purity of 99.7%) . MS (ESI) m / z [M+H]⁺ 616.21.1H 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-sulfonamido)-2-fluorophenyl)-8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexane-1-carboxamide (cis I-33)Step 1: cis-4-aminocyclohexane-1-carboxamide*TFA

[0295] A DMF (3 mL) mixture of TBTU (693 mg, 2.2 mmol) and cis-4-((tert- butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (500 mg, 2.0 mmol) was treated with DIPEA (1.1 mL, 6.2 mmol). After 30 min of stirring at rt NH4Cl (220 mg, 4.1 mmol) was added as a solid. The reaction was mixed at rt overnight before being diluted with Et2O,washed with 0.1 M aq HCl. The organic layer was concentrated under reduced pressure yielding an off-white solid that was then dissolved and stirred in CH2Cl2(5 mL) and TFA (0.79 mL, 10 mmol) at rt for 1 d 18 h. The reaction mixture was concentrated under reduced pressure and dried in vacuo to afford 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]pyrimidin-2- yl)amino)cyclohexane-1-carboxamide

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

[0297] Prepared by General Method SMC using (5-((5-chloro-2-methoxypyridine)- 3-sulfonamido)-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]pyrimidin-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); by heating at 100 °C for 2.5 h. Purified by flash chromatography using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂ to afford cis-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8-methyl-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexane-1-carboxamide as a beige solid (42.0 mg, 42 % yield based on purity of 97 %). MS (ESI) m / z [M+H]⁺ 616.29.1H 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 - 3.98 (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-sulfonamido)-2-fluorophenyl)- 8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-methylcyclohexane-1- carboxamide (trans I-34)Step 1: trans-4-amino-N-methylcyclohexane-1-carboxamide, Trifluoroacetic Acid

[0298] A DMF (3 mL) suspension of TBTU (693 mg, 2.2 mmol) and trans-4-((tert- butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (500 mg, 2.0 mmol) was treated with DIPEA (1.074 mL, 6.17 mmol). After 10 min of stirring at rt MeNH2*HCl (166 mg, 2.5 mmol) was added as a solid. The reaction was stirred with shaken for 30 min and then stirred at rt 2 d. The reaction was then diluted with Et2O, washed with 0.1 M aq HCl. The organic layer was concentrated under reduced pressure. Another crop off white solid was collected by a filtration of the aq layer. The filtered solid was rinsed with xs H2O, combined with the material from the Et2O layer and dried to afford tert-butyl trans-4- (methylcarbamoyl)cyclohexyl)carbamate as a white solid (417 mg, 79 % yield). MS (ESI) m / z [M+H]⁺ 257.36. The entire material was stirred in CH2Cl2 (5 mL) and TFA (0.71 mL, 9.2 mmol)) at rt for 2 d. The reaction was concentrated under reduced pressure. The material was sonicated with Et2O (5 mL) and filtered after overnight standing at rt. The filter cake was rinsed with xs Et2O to afford trans-4-amino-N-methylcyclohexane-1- carboxamide, trifluoroacetic acid as a white solid (370.0 mg, 67 %). MS (ESI) m / z [M+H]⁺ 157.33. Step 2: trans-4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)- N-methylcyclohexane-1-carboxamide

[0299] A DMF (5 mL) 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) was shaken at rt for 30 min before 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin- 7(8H)-one (0.100 g, 0.31 mmol) was added in one portion. The reaction mixture was then shaken for 2 h and then stirred at rt for 5 d. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂ to afford trans-4-((6-bromo-8-methyl-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-methylcyclohexane-1-carboxamide as a white solid (39.0 mg, 32 % yield). MS (ESI) m / z [M+H]⁺ 394.20|396.23. 8-

[0300] (5-((5-chloro-2-methoxypyridine)-3-sulfonamido)-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]pyrimidin-2-yl)amino)-N-methylcyclohexane-1-carboxamide (39 mg, 0.099 mmol) and PdCl2dppf (7 mg, 0.010 mmol) in 1,4-dioxane (6 mL) and H2O (3 mL) was degassed with a stream of Ar. The reaction was then heated at 100 °C for 2.1 h. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography using u CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂ to afford trans-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-methylcyclohexane-1- carboxamide (29 mg, 46 % yield based on purity of 98 %) as a white solid. MS (ESI) m / z [M+H]⁺ 630.28.1H 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-sulfonamido)-2-fluorophenyl)-8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-methylcyclohexane-1- carboxamide (cis I-34)Step 1: cis-4-amino-N-methylcyclohexane-1-carboxamide, trifluoroacetic acid

[0301] A DMF (3 mL) suspension of TBTU (693 mg, 2.2 mmol) and cis-4-((tert- butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (500 mg, 2.0 mmol) was treated with DIPEA (1.1 mL, 6.2 mmol). After 10 min of stirring at rt MeNH2*HCl (166 mg, 2.5 mmol) was added as a solid. The reaction mixture was shaken at rt for 30 min and then stirred at rt overnight before being diluted with Et2O and later washed with 0.1 M aq HCl. Concentration of the organic layer under reduced pressure yielded tert-butyl (cis-4- (methylcarbamoyl)cyclohexyl)carbamate as a pale yellow oil (640.0 mg). The entire material was stirred in CH2Cl2 (5 mL) and TFA (0.71 mL, 9.2 mmol) at rt overnight. The reaction solution was concentrated under reduced pressure than briefly dried under high vacuum to afford a white solid that was suspended in Et2O (5 mL) with sonication. The mixture was aged overnight at rt then the white precipitate was collected by filtration and the filter cake was rinsed with xs Et2O to afford 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]pyrimidin-2-yl)amino)-N- methylcyclohexane-1-carboxamide

[0302] cis-4-amino-N-methylcyclohexane-1-carboxamide, trifluoroacetic acid (0.102 g, 0.38 mmol) and K2CO3 (0.22 g, were shaken in DMF (5 mL) at rt for 30min. 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.100 g, 0.31 mmol) was added in one portion and shaking was continued at rt for another 2 h. The reaction mixture was subsequently stirred overnight at rt before being concentrated under reduced pressure, deposited on Celite and purified by flash chromatography using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂ to afford (1S,4S)-4-((6-bromo-8-methyl- 7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-methylcyclohexane-1-carboxamide as an off-white solid (49.0 mg, 38 % yield based on purity of 96 %). MS (ESI) m / z [M+H]⁺ 394.20|396.23. Step 3: (cis-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-methylcyclohexane-1- carboxamide (cis I-34)

[0303] Prepared by following General Method SMC using (5-((5-chloro-2- methoxypyridine)-3-sulfonamido)-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]pyrimidin-2- yl)amino)-N-methylcyclohexane-1-carboxamide (49 mg, 0.12 mmol) and PdCl2dppf (8.7 mg, 0.012 mmol) in 1,4-dioxane (6 mL) and H2O (3 mL); by heating under Ar at 100 °C for 2 h. Purified by flash chromatography, using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂ to afford (cis-4-((6-(5-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2- fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N- methylcyclohexane-1-carboxamide as an off white solid (41 mg , 53 % yield based on purity of 98 %). MS (ESI) m / z [M+H]⁺ 630.21.1H 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, 1H), 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-sulfonamido)-2-fluorophenyl)- 8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-methylcyclobutane-1- carboxamide (trans I-35) - N-

[0304] Trans-aminocyclobutane-1-carboxylic acid hydrochloride (36 mg, 0.24 mmol) and 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (50 mg, 0.16 mmol) in NMP (3 mL) was treated with DIPEA (0.14 mL, 0.79 mmol) and stirred at rt for 2 d 20 h. MS (ESI) m / z [M+H]⁺ 353.1. To the crude reaction mixture, MeNH2 (33 %wt 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 with the cooling and then at rt for the total of 1 d 4 h. 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 the majority of the volatiles. Step 2. trans-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-methylcyclobutane-1- carboxamide (trans I-35) Prepared by following General Method SMC using the entire crude (1r,3r)-3-((6-bromo-8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-methylcyclobutane-1- carboxamide in NMP (2 mL) from the previous step, PdCl2dppf (11 mg, 0.016 mmol), Cs2CO3(154 mg, 0.47 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2- fluorophenyl)boronic acid (79 mg, 0.22 mmol) in 1,4-dioxane (6 mL) and H2O (3 mL); by heating sealed at 90 °C for 20 h. Purified by flash chromatography twice, using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 to afford trans-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-N-methylcyclobutane-1-carboxamide as a pale yellow solid (30.0 mg, 31 % yield based on purity of 97 %). MS (ESI) m / z [M+H]⁺ 602.29.1H 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-sulfonamido)-2- fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N- methylcyclohexane-1-carboxamide((rac-(1R,3S) I-36)Step 1. rac-(1R,3S)-3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid

[0305] A THF (6 mL) and H2O (6 mL) 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) was stirred at 0oC allowing slowly to warm to rt. The reaction was later stirred at rt as a suspension for 1 d 18 h. The reaction was then extracted with Et2O. The aq phase was carefully acidified with 1 M aq citric acid to pH 4-5 yielding a white ppt that was collected by filtration. The solid was rinsed with a small amount of Et2O and then dried to afford 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- 1- TFA

[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 with sonication in CH2Cl2(10 mL). DIPEA (0.29 mL, 1.6 mmol) was added and the reaction was shaken at rt for a few minutes before MeNH2(33 wt. % in EtOH, 0.31 mL, 2.5 mmol) was added in one portion at rt. The shaking was continued at rt for 1.5 h. Crude rac-tert-butyl ((1R,3S)-3- (methylcarbamoyl)cyclohexyl)carbamate was obtained by evaporation of the volatiles under reduced pressure. MS (ESI) m / z [M+H]⁺ 257.29.

[0307] The entire residue was then shaken with CH2Cl2(6 mL) and TFA (1.0 mL, 13 mmol) at rt for 1.5 h. The reaction mixture was then aged at -20oC overnight. Concentration under reduced pressure and drying in vacuo afforded crude rac-(1R,3S)-3- amino-N-methylcyclohexane-1-carboxamide, TFA as colorless gum that was used in the following step without further purification. Step 3. rac-(1R,3S)-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2- fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-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-carboxamideTFA (73 mg, 0.27 mmol) were shaken in NMP (1.5 mL) at rt for 10 min before 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)- one (95 mg, 0.297 mmol)) was added as a solid at rt. The mixture was stirred at rt overnight for 3 d 20 h. After the reaction completion, the entire crude material containing rac-(1R,3S)- 3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-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] The entire crude rac-(1R,3S)-3-((6-bromo-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-methylcyclohexane-1-carboxamide in residual NMP was used then used following the General Method SMC using Pd(dppf)Cl2(19.79 mg, 0.027 mmol), Cs2CO3(264 mg, 0.810 mmol), (3-((5-chloro-2-methoxypyridine)-3- sulfonamido)-2-fluorophenyl)boronic acid (136 mg, 0.38 mmol), H2O (3 mL) and 1,4- dioxane (6 mL); by heating at 100 °C for 2.4 h. Purified by flash chromatography (SiO₂ using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂). The collected solid material was triturated using sonication Et2O to afford rac-(1R,3S)-3-((6-(3-((5-chloro-2- methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-N- carboxamide as a white solid (10.4 mg, 6% based on the purity of 95 %). The yield is reported for all the steps combined from rac- (1R,3S)-3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid. MS (ESI) m / z [M+H]⁺ 630.43

[0310] 1H 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-sulfonamido)-2- fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N- methylcyclohexane-1-carboxamide ((rac-(1R,3R) I-36)Step 1. rac-(1R,3R)-3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid

[0311] A THF (6 mL) and H2O (6 mL) mixture of Di-tert-butyl dicarbonate (729 mg, 3.3 mm, rac-(1R,3R)-3-aminocyclohexane-1-carboxylic acid hydrochloride (500 mg, 2.8 mmand NaHCO3 (701 mg, 8.35 mmol) was stirred at 0oC allowing slowly to warm to rt. The reaction was later stirred at rt as a suspension for 1 d 18 h. The reaction was then extracted with Et2O The aq phase was carefully acidified with 1 M aq citric acid to pH 4-5 and extracted with DCM (3x). The combined organic extracts were concentrated under reduced pressure and dried to afford 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- 1-carboxamide,TFA

[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 with sonication in CH2Cl2(6 mL). DIPEA (0.198 mL, 1.134 mmol) was added and the reaction was shaken at rt for a few minutes before MeNH2(33 wt. % in EtOH, 0.21 mL, 1.7 mmol) was added in one portion at rt. The shaking was continued at rt for 1.5 h. Crude rac-tert-butyl ((1R,3R)- 3-(methylcarbamoyl)cyclohexyl)carbamate was obtained by evaporation of the volatiles under reduced pressure. MS (ESI) m / z [M+H]⁺ 257.36.

[0313] The entire residue was then shaken with CH2Cl2(6 mL) and TFA (0.7 mL, 9 mmol) at rt for 1.5 h. The reaction mixture was then aged at -20oC overnight. Concentration under reduced pressure and drying in vacuo afforded crude rac-(1R,3S)-3- amino-N-methylcyclohexane-1-carboxamide, TFA as colorless gum that was used in the following step without further purification. Step 3. rac-(1R,3R)-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2- fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-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 rt for 15 min before 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (96 mg, 0.30 mmol) was added.at rt. The mixture was stirred at rt for 3 d 20 h. The entire crude material containing rac-(1R,3R)-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-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. The entire crude rac-(1R,3R)-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-N-methylcyclohexane-1-carboxamide in residual NMP was used then used following the General Method SMC using Pd(dppf)Cl2(20 mg, 0.027 mmol), Cs2CO3(268 mg, 0.82 mmol) and (3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2- fluorophenyl)boronic acid (138 mg, 0.38 mmol), H2O (3 mL) and 1,4-dioxane (6 mL); by heating at 100 °C for 2.3 h. Purified by flash chromatography (SiO2using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂) to afford rac-(1R,3R)-3-((6-(3-((5- chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-methylcyclohexane-1-carboxamide as a white solid (11.2 mg, 6 % yield based on purity of 99 %). 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, 1H), 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, 3 H), 1.47 - 1.89 (m, 9 H). Example 40. cis-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclobutane-1-carboxamide (cis- I-37)Step 1. (1S,3S)-3-aminocyclobutane-1-carboxamide, trifluoroacetic acid

[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 rt for 3 d 21 h. TBTU (586 mg, 1.824 mmol) was added at rt and the reaction was shaken at rt for 5 min before 4-methoxybenzylamine (0.24 mL, 1.8 mmol) was added. Stirring at rt was continued for 21 h. A white solid was collected by filtration, rinsed with DCM and dried in vacuo to afford tert-butyl (cis-3-((4- methoxybenzyl)carbamoyl)cyclobutyl)carbamate as a white solid (432.0 mg, 54 % yield based on purity of 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 rt for 5 d 20 h. Later the reaction mixture was heated at 60oC overnight. The solvent was removed under reduced pressure and then high vacuum leaving a red gum that was used entirely in the next step. Step 2. cis-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)cyclobutane-1-carboxamide

[0316] A DMF (3 mL) suspension of cis-3-aminocyclobutane-1-carboxamide, trifluoroacetic acid, (143 mg, 0.63 mmol) (entire residue from the previous step) and K2CO3(346 mg, 2.507 mmol) was shaken at rt for 10 min before

[0317] 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (219 mg, 0.69 mmol) was added in one portion. The stirring was continued at rt for 3 d 17 h. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂ to afford cis-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)cyclobutane-1-carboxamide as a beige solid (68.0 mg, 30 % yield based on purity of 97 %). MS (ESI) m / z [M+H]⁺ 352.22|354.17. Step 3. cis-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclobutane-1-carboxamide (cis- I-37)

[0318] Prepared following General Method SMC cis-3-((6-bromo-8-methyl-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclobutane-1-carboxamide (68 mg, 0.18 mmol), Cs2CO3 (153 mg, 0.47 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2- fluorophenyl)boronic acid (88 mg, 0.24 mmol) and Pd(dppf)Cl2*CH2Cl2 (15 mg, 0.019 mmol) in 1,4-dioxane (4 mL) and H2O (2 mL); by heating in a microwave reactor at 100 °C for 2.5 h. Purified by flash chromatography using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂ to afford (cis-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2- fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclobutane-1- carboxamide as a beige solid (42.0 mg, 38 % yield). MS (ESI) m / z [M+H]⁺ 588.38.1H 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-methoxypyridin-3-yl)sulfonyl)(2-fluoro-3-(2- (methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)amide (I-38 K salt)

[0319] 5-Chloro-N-(2-fluoro-3-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (272 mg, 0.55 mmol) was suspended in EtOH (80 mL) with sonication. Aq KOH (0.5 M, 1.11 mL, 0.55 mmol) was added dropwise at rt. The reaction was sonicated and diluted with H₂O (70 mL). After repeated brief sonication, the excess of EtOH was removed under reduced pressure and the remaining material was freeze dried to afford potassium ((5-chloro-2-methoxypyridin- 3-yl)sulfonyl)(2-fluoro-3-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6- yl)phenyl)amide as a pale yellow, light powder (291.0 mg, 99 %). MS (ESI) m / z [M+H]⁺ 491.4.1H 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).19F NMR (471 MHz, DMSO- d6) δ -128.40, -128.53. Example 42: Potassium ((5-chloro-2-methoxypyridin-3-yl)sulfonyl)(3-(2-(ethylamino)-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)amide (I-25 K salt)

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

[0321] 1H 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-sulfonamido)-2-fluorophenyl)-8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1-fluorocyclohexane-1- carboxamide (I-39A) (unassigned isomer A from the two possible isomers: (1s,4s) and (1r,4r))

[0322] Step 1. A mixture of (1s,4s)-4-amino-1-fluorocyclohexane-1-carboxamide4- Amino-1-fluorocyclohexane-1-carboxamide, CF3COOH and (1r,4r)-4-amino-1- fluorocyclohexane-1-carboxamide, CF3COOH

[0323] A DMF (4 mL) mixture of TBTU (295 mg, 0.92 mmol)), 4-(tert- butoxycarbonylamino)-1-fluoro-cyclohexanecarboxylic acid (200 mg, 0.76 mmol)) and DIPEA (0.40 mL, 2.3 mmol) was stirred at rt for 10 min before NH4Cl (82 mg, 1.53 mmol) was added as a solid. The reaction was shaken at rt for 4.7 h and then stirred at rt overnight. Later, 4-methoxybenzylamine (0.10 mL, 0.76 mmol) was added at rt and the reaction mixture was shaken at rt for 1 h. Additional TBTU (246 mg, 0.76 mmol) was added in one portion at rt and stirring at rt was continued for 7 d. The reaction was diluted with Et2O and washed in sequence with 1 M aq HCl, H₂O and finally with satd. aq NaHCO3. The organic layer was separated and concentrated under reduced pressure yielding crude mixture of tert-butyl (4-fluoro-4-((4-methoxybenzyl)carbamoyl)cyclohexyl)carbamate and tert-butyl (4-carbamoyl-4-fluorocyclohexyl)carbamate (229.0 mg) as a light yellow solid. The entire material was stirred with CH2Cl2 (6 mL) and TFA (0.94 mL, 12 mmol) at rt for 3 h. The material was concentrated under reduced pressure to afford crude 4-amino-1- fluorocyclohexane-1-carboxamide, CF3COOH that was used directly in the following 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]pyrimidin-2-yl)amino)-1-fluorocyclohexane-1-carboxamide and (1r,4r)-4-((6-bromo-8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1-fluorocyclohexane-1- carboxamide

[0325] A DMF (3 mL) suspension of K2CO3 (212 mg, 1.53 mmol) and 4-amino-1- fluorocyclohexane-1-carboxamide, CF3COOH (105 mg, 0.38 mmol) was shaken at rt for 10 min before 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (128 mg, 0.40 mmol) was added in one portion and the shaking was continued at rt for 10 min followed by stirring at rt for 2 d 19 h. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (SiO₂, CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂) and then preparative HPLC (C₁₈, MeCN in H₂O + 0.1 % HCO₂H) to isolate two isomers (“isomer 1” and “isomer 2”) separately: earlier eluting “isomer 1” as a white solid (8.0 mg, 5 % yield based on purity of 95 %) MS (ESI) m / z [M+H]⁺398.5|400.4 and “isomer 2” as a white solid (10 mg, 6 % yield based on purity of 93 %) MS (ESI) m / z [M+H]⁺398.5|400.4.

[0326] Step 3. 4-((6-(3-((5-Chloro-2-methoxypyridine)-3-sulfonamido)-2- fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1- fluorocyclohexane-1-carboxamide (from “isomer 2”) (I-39A)

[0327] Prepared by General Method SMC using 4-((6-bromo-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-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-sulfonamido)-2-fluorophenyl)boronic acid (14 mg, 0.038 mmol) and PdCl2dppf*CH2Cl2(3.9 mg, 4.8 µmol) in 1,4-dioxane (4 mL) and H₂O (2 mL); by heating at 100 °C for 2.8 h. Purified by flash chromatography (SiO2, using CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂) to afford 4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1-fluorocyclohexane-1- carboxamide as a white solid (11 mg, 72 % yield based on purity of 99%). MS (ESI) m / z [M+H]⁺ 634.57.1H 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), 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-sulfonamido)-2-fluorophenyl)-8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1-fluorocyclohexane-1- carboxamide (unassigned isomer B from the two possible isomers (I-39B): (1s,4s) and (1r,4r))

[0328] Prepared by General Method SMC using 4-((6-bromo-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-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-sulfonamido)-2-fluorophenyl)boronic acid (11 mg, 0.03 mmol) and PdCl2dppf*CH2Cl2 (3.0 mg, 3.7 µmol) in 1,4-dioxane (4 mL) and H₂O (2 mL); by heating in a microwave reactor at 100 °C for 2.6 h. Purified by flash chromatography (SiO₂, CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂) followed by a trituration with Et2O with sonication to afford 4-((6-(3-((5- chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1-fluorocyclohexane-1-carboxamide as a white solid (4 mg, 32 % yield based on purity of 95 %).

[0329] MS (ESI) m / z [M+H]⁺ 634.42.1H 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-sulfonamido)-2- fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclopentane- 1-carboxamide (cis I-40)

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

[0332] (1R,3S)-3-Aminocyclopentane-1-carboxylic acid hydrochloride (315 mg, 1.90 mmol) and Boc2O (436 mg, 2.0 mmol) were suspended in CH2Cl2 (10 mL) at rt. DIPEA (0.99 mL, 5.7 mmol) was added in one portion and the reaction was stirred for 3 d 21 h. Later, TBTU (641 mg, 2.0 mmol) was added at rt and the reaction was shaken at rt for 5 min before 4-methoxybenzylamine (0.27 mL, 2.1 mmol) was added at rt. Stirring was continued at rt overnight. The reaction mixture was then diluted with Et2O, washed (1 M aq HCl 1x, H₂O 2x), concentrated under reduced pressure to afford crude tert-butyl ((1S,3R)-3-((4-methoxybenzyl)carbamoyl)cyclopentyl)carbamate as a white solid. The material was taken into CH2Cl2 (7 mL) and was stirred with TFA (1.0 mL, 13 mmol) at rt for 21 h. The solvents were removed under reduced pressure and the residue was dried under high vacuum to afford (1R,3S)-3-amino-N-(4-methoxybenzyl)cyclopentane-1- carboxamide, trifluoroacetic acid a light 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]pyrimidin-2-yl)amino)-N-(4-methoxybenzyl)cyclopentane-1-carboxamide

[0334] A DMF (3 mL) suspension of K2CO3 (305 mg, 2.21 mmol) and (1R,3S)-3- amino-N-(4-methoxybenzyl)cyclopentane- CF3COOH (200 mg, 0.55 mmol)was shaken at rt for 5 min. 6-Bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin- 7(8H)-one (184 mg, 0.580 mmol) was added in one portion and the shaking was continued at rt for 1 min and then the mixture was stirred at rt for 20 h. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by two rounds of flash chromatography (SiO₂, CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂) to afford (1R,3S)-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-(4- methoxybenzyl)cyclopentane-1-carboxamide as a clear film (55 mg, 21 % yield for 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]pyrimidin-2-yl)amino)cyclopentane-1-carboxamide

[0336] (1R,3S)-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-N-(4-methoxybenzyl)cyclopentane-1-carboxamide (55 mg, 0.11 mmol) was dissolved in TFA (1.4 mL, 18 mmol) and stirred in sequence at 60 °C for 10 min, 50 °C for 3 d, rt for 8 d and finally at 65 °C for 19 h. The reaction mixture was concentrated under reduced pressure to afford (1R,3S)-3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)cyclopentane-1-carboxamide as a grey solid (41 mg, 94 % yield based on purity of 94 %). The material was used without further purification in the following step. MS (ESI) m / z [M+H]⁺ 366.29|368.32.

[0337] Step 4. (1R,3S)-3-((6-(3-((5-Chloro-2-methoxypyridine)-3-sulfonamido)-2- fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclopentane- 1-carboxamide (cis I-40)

[0338] Prepared following General Method SMC using (1R,3S)-3-((6-bromo-8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclopentane-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-sulfonamido)-2-fluorophenyl)boronic acid (54 mg, 0.15 mmol) and 1,4-dioxane (4 mL); by heating at 100 °C for 2.6 h. Purified by flash chromatography (SiO₂, CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂) to afford (1R,3S)-3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclopentane-1-carboxamide as a white solid (13.0 mg, 20 % yield based on purity of 98 %). MS (ESI) m / z [M+H]⁺ 602.52.1H 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), 3.56 (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).19F NMR (471 MHz, DMSO-d6) δ -124.26. Example 45: 5-Chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((6-oxopiperidin-3-yl)amino)-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-41)

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

[0340] A DMF (5 mL) suspension of K2CO3(130 mg, 0.94 mmol), 5-aminopiperidin- 2-one (97 mg, 0.85 mmol) and 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin- 7(8H)-one (150 mg, 0.47 mmol) was shaken at rt for 3.7 h and then stirred at rt overnight. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (SiO₂, CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂) to afford 6-bromo-8-methyl-2-((6-oxopiperidin-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one as a beige solid (33.0 mg, 19 % yield based on purity of 95 %). 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-oxopiperidin-3- yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-41)

[0342] Prepared by General Method SMC using 6-bromo-8-methyl-2-((6- oxopiperidin-3-yl)amino)pyrido[2,3-d] 7(8H)-one (33 mg, 0.094 mmol), Cs2CO3(153 mg, 0.47 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2- fluorophenyl)boronic acid (61 mg, 0.17 mmol) and PdCl2dppf*CH2Cl2(11 mg, 0.014 mmol) in 1,4-dioxane (4 mL) and H₂O (2 mL) by heating at 100 °C for 2 h; purified by flash chromatography (SiO₂, CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂) followed by a trituration with MeOH to afford 5-chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((6-oxopiperidin-3- yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a beige solid (10 mg, 17 % yield based on purity of 93 %). MS (ESI) m / z [M+H]⁺ 588.4.1H 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).19F NMR (471 MHz, DMSO-d6) δ -123.95. Example 46: tert-Butyl 3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2- fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)azetidine-1- carboxylate (I-42)

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

[0344] A DMF (5 mL) 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]pyrimidin-7(8H)-one (200 mg, 0.63 mmol) was shaken at rt for 10 min and then stirred at rt overnight for 1 d 19 h. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (SiO₂, CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂) to butyl 3-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)azetidine-1-carboxylate a white solid (102 mg, 39 %). MS (ESI) m / z [M+H]⁺ 410.45|412.40

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

[0346] Prepared by General Method SMC using tert-butyl 3-((6-bromo-8-methyl-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)azetidine-1-carboxylate (50 mg, 0.12 mmol), Cs2CO3(199 mg, 0.61 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2- fluorophenyl)boronic acid (79 mg, 0.22 mmol) and PdCl2(dppf)*CH2Cl2(15 mg, 0.018 mmol) in 1,4-dioxane (4 mL) and H₂O (2 mL), by heating in a microwave reactor at 90 °C for 90 min; purified by flash chromatography (SiO₂, CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂) to afford tert-butyl 3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2- fluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)azetidine-1- carboxylate as a white solid (39 mg, 50 % yield). MS (ESI) m / z [M+H]⁺ 646.5.1H 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).19F NMR (471 MHz, DMSO-d6) δ -123.92. Example 47: Ethyl 4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)- 8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (I- 43)

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

[0348] A DMF (5 mL) 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]pyrimidin-7(8H)-one (200 mg, 0.63 mmol) were stirred at rt for 2 d. The reaction was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (SiO2, CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂) to afford ethyl 4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)piperidine-1-carboxylate as a pale yellow solid (51.0 mg, 19 % yield based on purity of 95 %). MS (ESI) m / z [M+H]⁺ 410.30|412.25

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

[0350] Prepared by General Method SMC using ethyl 4-((6-bromo-8-methyl-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (51 mg, 0.12 mmol), Cs2CO3 (192 mg, 0.59 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2- fluorophenyl)boronic acid (77 mg, 0.21 mmol) and PdCl2(dppf)*CH2Cl2 (14 mg, 0.018 mmol) in 1,4-dioxane (6 mL) and H₂O (3 mL); by heating at 90 °C for 2 h; purified by flash chromatography (SiO₂, CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂) to afford ethyl 4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8-methyl-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate as an off white solid (18 mg, 22 % yield based on purity of 95 %). MS (ESI) m / z [M+H]⁺ 646.5.1H 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).19F NMR (471 MHz, DMSO-d6) δ -123.96. Example 48: N-(3-(2-((1-Acetylpiperidin-4-yl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)-2-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (I-44)

[0351] Step 1. 2-((1-acetylpiperidin-4-yl)amino)-6-bromo-8-methylpyrido[2,3- d]pyrimidin-7(8H)-one

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

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

[0354] Prepared by General Method SMC using 2-((1-acetylpiperidin-4-yl)amino)- 6-bromo-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (25 mg, 0.064 mmol), Cs2CO3 (104 mg, 0.32 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)boronic acid (41 mg, 0.11 mmol) and PdCl2(dppf)*CH2Cl2 (7.8 mg, 9.6 µmol) in 1,4-dioxane (10 mL) and H₂O (5 mL); by heating at 90 °C for 2.3 h; purified by flash chromatography (SiO₂, CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂) to afford N-(3-(2-((1-acetylpiperidin-4- yl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-5-chloro- 2-methoxypyridine-3-sulfonamide as an off white solid (18 mg, 45 % yield based on purity of 99 %). MS (ESI) m / z [M+H]⁺ 616.4.1H NMR(500 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.72 – 8.59 (m, 1H), 8.48 (s, 1H), 8.07 (s, 1H), (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).19F NMR (471 MHz, DMSO-d6) δ -123.97. Example 49: (R)-5-Chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((5-oxopyrrolidin-3-yl)amino)- 7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide ((R) I-45)

[0355] Step 1. (R)-6-Bromo-8-methyl-2-((5-oxopyrrolidin-3-yl)amino)pyrido[2,3- d]pyrimidin-7(8H)-one

[0356] K2CO3(174 mg, 1.26 mmol), (R)-4-aminopyrrolidin-2-one hydrochloride (129 mg, 0.94 mmol) were shaken in DMF (5 mL) at rt for 10 min before 6-bromo-8-methyl- 2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.63 mmol) was added as a solid in one portion at rt. The reaction mixture was then stirred at rt overnight. The reaction was concentrated and used crude in the following 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-oxopyrrolidin-3- yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide ((R) I-45)

[0358] Prepared by General Method SMC using (R)-6-bromo-8-methyl-2-((5- oxopyrrolidin-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (70 mg, 0.21 mmol), Cs2CO3(337 mg, 1.0 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2- fluorophenyl)boronic acid (134 mg, 0.37 mmol) and PdCl2(dppf)*CH2Cl2(25 mg, 0.031 mmol) in 1,4-dioxane (4 mL) and H₂O (2 mL); by heating in a microwave reactor at 100 °C for 2 h; purified by preparative HPLC (C₁₈, MeCN in H₂O + 0.1 % HCO₂H) followed by two rounds of flash chromatography (SiO2, MeOH in CH₂Cl₂) and (SiO₂, CH₂Cl₂ / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂) to afford (R)-5-chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((5-oxopyrrolidin-3-yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2- methoxypyridine-3-sulfonamide as a white solid (6.0 mg, 5 % yield over 2 steps). MS (ESI) m / z [M+H]⁺ 574.2.1H 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).19F NMR (471 MHz, CD3OD) δ -127.74. Example 50: (S)-5-Chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((5-oxopyrrolidin-3-yl)amino)- 7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide ((S) I-45)

[0359] Step 1. (S)-6-Bromo-8-methyl-2-((5-oxopyrrolidin-3-yl)amino)pyrido[2,3- d]pyrimidin-7(8H)-one

[0360] K2CO3(174 mg, 1.3 mmol), (4S)-4-aminopyrrolidin-2-one (126 mg, 1.3 mmol) and 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.63 mmol) were shaken in DMF(5 mL) at rt overnight. The reaction was concentrated and used crude material in the following 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-oxopyrrolidin-3- yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide ((S) I-45)

[0362] Prepared by General Method SMC using (S)-6-bromo-8-methyl-2-((5- oxopyrrolidin-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (70 mg, 0.21 mmol), Cs2CO3 (337 mg, 1.03 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2- fluorophenyl)boronic acid (134 mg, 0.37 mmol) and PdCl2dppf*CH2Cl2 (25 mg, 0.031 mmol) in 1,4-dioxane (4 mL) and H₂O (2 mL); by heating in a microwave reactor at 100 °C for 2 h; purified by flash chromatography aq NH₄OH 89 / 10 / 1 inCH₂Cl₂ and then MeOH in CH2Cl2) followed preparative HPLC (C₁₈, MeCN in H₂O + 0.1 % HCO₂H) and another flash chromatography (SiO₂, CH₂Cl₂ / / MeOH / conc aq NH₄OH 89 / 10 / 1 in CH₂Cl₂) to afford (S)-5-chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((5-oxopyrrolidin-3- yl)amino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a white solid (4 mg, 3 % yield for 2 steps based on purity of 98 %). MS (ESI) m / z [M+H]⁺ 574.2.1H 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).19F 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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-46)

[0363] Prepared by General Method SMC using 6-bromo-2- (isopropylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (11 mg, 0.039 mmol), Cs2CO3(51 mg, 0.15 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)boronic acid (25.2 mg, 0.070 mmol), Pd(dppf)Cl2*CH2Cl2(4.8 mg, 5.8 µmol) in H₂O (2.5 mL) and 1,4- dioxane (5 mL); by heating at 100 °C overnight; purified by flash chromatography (SiO₂, MeOH in CH₂Cl₂) followed by preparative HPLC (C18, MeCN in H₂O + 0.1 % HCO₂H) to afford 5-chloro-N-(2-fluoro-3-(2-(isopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a white solid (1.0 mg, 5 % yield). MS (ESI) m / z [M+H]⁺ 519.1. Example 52: 5-Chloro-N-(3-(2-(cyclopropylamino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)-4- -2- 3-sulfonamide (I-47)

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

[0365] To a suspension pyrido[2,3-d]pyrimidin-7(8H)- one (120 mg, 0.42 mmol) in i-PrOH (10 mL) was added c-PrNH2(0.58 mL, 8.3 mmol) in one portion. The suspension was shaken at rt for 1.5 h and then stirred at rt for r 3 d 18 h. The solid was collected by filtration, rinsed with i-PrOH to afford 6-bromo-2- (cyclopropylamino)pyrido[2,3-d]pyrimidin-7(8H)-one as a white solid (111 mg, 94 % yield based on purity of 99 %). 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]pyrimidin-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide (I-47)

[0367] Prepared by General Method SMC using 6-bromo-2- (cyclopropylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (55.5 mg, 0.19 mmol), Cs2CO3(191 mg, 0.59 mmol), (5-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)boronic acid (106 mg, 0.29 mmol) and Pd(dppf)Cl2*CH2Cl2(24 mg, 0.029 mmol) in 1,4-dioxane (4 mL) and H₂O (2 mL); heated in a microwave reactor at 100 °C for 2 h; purified by flash chromatography (SiO₂, MeOH in CH₂Cl₂). A solid crystallized out of MeOH / CH2Cl2 and was collected by filtration, rinsed with small amount of CH2Cl2 to afford 5-chloro-N-(3-(2- (cyclopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-fluorophenyl)-2- methoxypyridine-3-sulfonamide as an off white solid (32 mg, 30 % yield based on purity of 95 %). MS (ESI) m / z [M-H]- 515.0.1H 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).19F NMR (471 MHz, DMSO-d6) δ -119.06. Example 53: 5-Chloro-N-(3-(2-(cyclopropylamino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)-2-fluorophenyl)-2-methoxypyridine-3-sulfonamide (I-48)

[0368] Prepared by General Method SMC using 6-bromo-2- (cyclopropylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (55.5 mg, 0.195 mmol), Cs2CO3 (191 mg, 0.59 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)boronic acid (106 mg, 0.29 mmol) and Pd(dppf)Cl2*CH2Cl2 (24 mg, 0.029 mmol) in 1,4-dioxane (4 mL) and H₂O (2 mL), heated in a microwave reactor at 100 °C for 2 h; purified by flash chromatography (SiO₂, MeOH in CH₂Cl2). A solid crystallized out MeOH / CH2Cl2that was collected by filtration, rinsed with small amount of MeOH to afford 5-chloro-N-(3-(2- (cyclopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-2- methoxypyridine-3-sulfonamide a white solid (6 mg, 6 % yield). MS (ESI) m / z [M+H]⁺ 517.1.1H 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).19F NMR (471 MHz, DMSO-d6) δ -124.13. Example 54: 5-Chloro-N-(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)- 2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (I-49)

[0369] 5-Chloro-N-(2,4-difluoro-3-(8-(4-methoxybenzyl)-2-(methylsulfinyl)-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-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) and shaken at rt for 4.3 h and then stirred for 20 h. The reaction mixture was concentrated under reduced pressure leaving a white foam that was dissolved in TFA (2.0 mL, 26 mmol) and then heated at 60 °C for 1.3 h and subsequently at 70 °C for 1.5 h. The reaction was cooled to rt. Anisole (0.020 mL, 0.18 mmol) was added, and the reaction mixture was stirred rt for 1 d 19 h. The volatiles were under high pressure and solid residuewas dried under high vacuum. The material was then stirred with PdCl2(32.7 mg, 0.184 mmol) in EtOAc (40 mL) and gl AcOH (10 mL) under H2(1 atm) at rt for 3 d 20 h and then shaken at rt under H2(2 bar) for 2 h. The reaction was filtered through Celite and concentrated under reduced pressure, dried under high vacuum. The solid residue was treated with trifluoromethanesulfonic acid (2.0 mL, 23 mmol) while being stirred in an ice- H₂O bath. The reaction mixture was stirred vigorously within the cooling bath for 5 min and then without the cooling bath for 1.3 h. Later, ice-H₂O was added carefully causing a grey sticky precipitate to form that was collected by filtration and rinsed with xs H₂O and then purified by flash chromatography (SiO₂, MeOH in CH₂Cl₂). The material was further triturated with 5 % MeOH in DCM and then Et2O. to afford 5-chloro-N-(3-(2-(ethylamino)-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3- sulfonamide as an off white solid (16 mg, 17 % yield).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).19F 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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-50)

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

[0371] To a solution of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (4.0 g, 14.7 mmol) in DMF (100 mL); NaH (60 %, 0.88 g, 37 mmol) was added in portions and the reaction mixture was stirred at for 1 h. After 1 h, 1-(chloromethyl)-4-methoxybenzene (4.83 g, 31 mmol) was added and the reaction mixture was further stirred at rt for 16 h. The reaction mixture was then diluted with H₂O (150 mL) and extracted withEtOAc (3x 150 mL). The combined organic layers were dried (anh Na2SO4), concentrated,purified by flash chromatography and triturated with Et2O to afford 6-bromo-8-(4- methoxybenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-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]pyrimidin-7(8H)-one

[0373] In a sealed vial, XPhos Pd G2 (108 mg, 0.14 mmol), 6-bromo-8-(4- methoxybenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-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 then heated in a microwave reactor at 65 °C for 18 h. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (SiO₂, EtOAc in hexanes) to afford 6-(3-amino-2,6-difluorophenyl)-8-(4- methoxybenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one as a light yellow solid (221.0 mg, 66 % yield). 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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide

[0375] To a CH2Cl2(20 mL) solution of 6-(3-amino-2,6-difluorophenyl)-8-(4- methoxybenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (221 mg, 0.50 mmol) and 5-chloro-2-methoxypyridine-3-sulfonyl chloride (182 mg, 0.75 mmol) was added pyridine (0.81 mL, 10 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h and then the stirring was continued at rt for 7 d. The reaction was washed (1 M aq HCl 1x, H₂O 2x, 1 M aq HCl 1x) and the organic phase was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (SiO2, EtOAc in hexanes) to afford 5-chloro-N- (2,4-difluoro-3-(8-(4-methoxybenzyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a white solid (245 mg, 73 % yield based on purity of 97 %). 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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide

[0377] A cold (at 0oC) 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]pyrimidin-6-yl)phenyl)-2- methoxypyridine-3-sulfonamide (245 mg, 0.37 mmol) was treated with mCPBA (102 mg, 0.441 mmol, approx. 75 %) added as a solid in one portion. The reaction mixture was stirred with cooling for 0.9 h and stored at – 20oC overnight. The material was then warmed to rt and concentrated to dryness under reduced pressure and used crude in the following step. MS (ESI) m / z [M-H]- 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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide

[0379] The crude 5-chloro-N-(2,4-difluoro-3-(8-(4-methoxybenzyl)-2- (methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3- sulfonamide (122 mg, 0.18 mmol) was added solid K2CO3(293 mg, 2.1 mmol), MeNH2*HCl (81 mg, 1.2 mmol) and DMF (4.0 mL). The reaction was shaken at rt for 4.6 h and then stirred for 20 h. The mixture was concentrated under reduced pressure then dried under high vacuum. The solid residue was suspended in H₂O, filtered and rinsed with H₂O, dried to afford 5-chloro-N-(2,4-difluoro-3-(8-(4-methoxybenzyl)-2-(methylamino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as a tan solid (117 mg, quant). 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]pyrimidin-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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (117 mg, 0.19 mmol) was treated with trifluoromethanesulfonic acid (1.0 mL, 11 mmol) in one portion while being cooled an ice-H₂O bath. The reaction mixture was stirred vigorously within the cooling bath for 5 min and then without the cooling bath for 1.4 h. Ice-H₂O was carefully added causing a precipitate to form. The solid was filtered, rinsed with xs H₂O and purified by preparative HPLC (C₁₈, MeCN in H₂O + 0.1 % HCO₂H)). MS (ESI) m / z [M+H]⁺ 509.30.1H 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). B. Biological Assays GCN2 Enzymatic Assay

[0382] To identify small molecule GCN2 inhibitors, a biochemical GCN2 enzymatic assay was outsourced to Eurofins. This assay was done radiometrically which utilizes full-length, GST-tagged GCN2 (E556G) produced in insect cells. The kinase concentration is 18.5 nM with 70 uM ATP (Km=77 uM) and [g-33P]-ATP in a Tris buffer containing 300 uM of an optimized peptide substrate (RSRSRSRSRSRSRSR). The reaction was initiated by the addition of the Mg / ATP mix. After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of phosphoric acid to a concentration of 0.5%.10 μL of the reaction was then spotted onto a P30 filtermat and washed four times for 4 minutes in 0.425% phosphoric acid and once in methanol prior to drying and scintillation counting. The results are shown in Table 1 where IC50’s is reported in the following ranges: A: 0.1- 100 nM; B: 100-1000 nM; C: 1000-10000 nM; D: >10000 nM for the compounds of Formula (I) Table 1: IC50’s(nM) for exemplary compounds of the application for inhibition of GCN2 Compound I.D. GCN2 IC50 (nM) I-1 B trans I-2 A trans I-3Atrans I-4AI-5 A I-6 A transI-7 AI-8 A trans I-9 A trans I-10 A transI-11 AI-12 A I-13 A I-14 A I-15 B I-16 A I-17 A I-18 A I-19 A I-20 A I-21 A (R)-I-22 ACompound I.D. GCN2 IC50(nM) I-23 A I-24 A I-25 A I-26 A I-27 A I-28 A I-29 A I-30 A I-31 A I-32 A trans I-33 A cis I-33 B trans I-34 A cis I-34 B trans I-35 A rac-(1R,3S) I-36 B rac-(1R,3R) I-36 B cis I-37 A I-38 K A I-25 K A I-39A / B B / B cis I-40 A I-41 A I-42 B I-43 B I-44 B (R) I-45 A (S) I-45 A I-46 A I-47 A I-48 A I-49 A I-50 BCell-based phosho- eIF2α Assay:

[0383] To confirm target engagement in cells, an AlphaLISA assay (Perkin Elmer #TGREIR2S10K) was optimized to monitor eIF2α phosphorylation on Serine-51. This event is specifically catalyzed by GCN2 induced with halofuginone (an inhibitor of glutamyl-prolyl tRNA synthetase), borrelidin (an inhibitor of threonyl-tRNA synthetase) or L-asparaginase which activates GCN2 kinase activity by triggering the amino acid starvation response. SKOV3 or U2OS cells (seeded at 40,000 cells per well) are pretreated with exemplary GCN2 inhibitor compounds of the application (1 nM to 1 µM) for 1 hour, stimulated with borrelidin (10 µM) for 1 hour, then lysed and analyzed with the AlphaScreen SureFire kit, which utilizes an antibody based method to quantitatively detect phospho-eIF2α in an HTS format. Tumor Cell Growth Inhibition Assay:

[0384] SKOV3 or OVCAR-8 cells were seeded into a 384-well plate at 1,000 cells / well in 50ul medium (Alpha-MEM containing 10% FBS, 100 mg / ml Normocin, Invivogen and 50 mg / ml Gentamycin, Invitrogen). Plates were then incubated overnight for the cells to attach. An HP D300 digital dispenser was used to dose cells with ASNase, DMSO or test compounds across a 16-point range of concentrations (high dose of 10uM to low dose of 5nM). Plates were incubated in a humidified 5% CO2 incubator at 37oC. After 3-5 days, plates were removed from the incubator and equilibrated to room temperature. An equal volume of ATPlite assay reagent was then added to each well, and samples processed according to manufacturer’s instructions (Perkin Elmer). Luminescent signals were then measured using an Envision plate reader equipped with a US- Luminescence detector.

[0385] While the present application has been described with reference to what are presently considered to be the preferred examples, it is to be understood that the application is not limited to the disclosed examples. To the contrary, the present application is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.

[0386] All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defineddifferently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.

Claims

CLAIMS:

1. A compound of Formula I, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:wherein R1is selected from H, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl and C3-10heterocycloalkyl, the latter four groups being optionally substituted with one or two R8; X1is selected from N and CR9; R2is selected from H, C1-6alkyl and C1-6haloalkyl; X2is selected from N and CR10; R3, R4and R5are independently selected from H, halo, CN, C1-6alkyl and C1-6haloalkyl; X3is selected from N and CR11; R6and R7are independently selected from H, halo, CN, C1-6alkyl, C1-6haloalkyl, OC1-6alkyl and OC1-6haloalkyl; each R8is independently selected from OR12, NR12R13, C(O)NR12R13, C(O)OR12, =O, halo, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl and C3-10heterocycloalkyl, wherein all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR14, NR14R15and C1-6alkyl; R9, R10and R11are independently selected from H, halo, C1-6alkyl and C1-6haloalkyl; R12is selected from H, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl and C3-10heterocycloalkyl, the latter four groups being optionally substituted with one or two substituents selected from halo, OH, OC1-4alkyl and OC1-4fluoroalkyl; and R13, R14and R15are independently selected from H, C1-6alkyl and C1-6haloalkyl.

2. The compound of claim 1, wherein R1is selected from C3-10cycloalkyl and C3- 10heteroycloalkyl, each of which is optionally substituted with one or two R8.

3. The compound of claim 1, wherein R1is selected from H, C1-4alkyl and C1- 4fluoroalkyl.

4. The compound of claim 3, wherein R1is selected from H, CH3, CF3, CHF2, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3and CH(CH3)3.

5. The compound of claim 1, wherein R1is C3-10cycloalkyl optionally substituted with one or two R8.

6. The compound of claim 5, wherein R1is monocyclic C3-8cycloalkyl optionally substituted with one or two R8.

7. The compound of claim 6, wherein R1is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each of which is optionally substituted with one or two R8.

8. The compound of claim 7, wherein R1is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each of which is optionally substituted with one R8.

9. The compound of claim 8, wherein R1is selected from cyclobutyl and cyclohexyl, each of which is substituted with one R8.

10. The compound of claim 1, wherein R1is C3-10heterocycloalkyl optionally substituted with one or two R8.

11. The compound of claim 10, wherein R1is selected from aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl oxepanyl and thiepanyl, each of which is optionally substituted with one or two R8.

12. The compound of claim 11, wherein R1is selected from thietanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl, each of which is optionally substituted with one R8.

13. The compound of claim 12, wherein R1is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one R8.

14. The compound of claim 13, R1is selected from oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, each of which is optionally substituted with one R8.

15. The compound of claim 14, wherein R1is selected from oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, each of which is unsubstituted.

16. The compound of any one of claims 1 to 15, wherein X1is selected from N and CH.

17. The compound of any one of claims 1 to 16, wherein R2is selected from H and CH3.

18. The compound of any one of claims 1 to 17, wherein X2is selected from N and CH.

19. The compound of any one of claims 1 to 18, wherein, R3, R4and R5independently selected from H, Cl, F, Br, CN, C1-4alkyl and C1-4fluoroalkyl.

20. The compound of claim 19, wherein R3, R4and R5are independently selected from H, Cl, F, CN, CH3 and CF3.

21. The compound of any one of claims 1 to 18, wherein at least one of R3and R5is selected from halo and CN.

22. The compound of any one of claims 1 to 21, wherein X3is selected from N and CH.

23. The compound of any one of claims 1 to 22, wherein R6and R7are independently selected from H, Cl, F, Br, CN, C1-4alkyl, C1-4fluoroalkyl, OC1-4alkyl and OC1-4fluoroalkyl.

24. The compound of claim 23, wherein R6and R7are independently selected from H, Cl, F, CN, CH3, CF3, CH2CH3, OCH3, OCHF2, and OCF3.

25. The compound of claim 24, wherein R6is selected from OCH3 and OCF3 and R7is selected from Cl, F, CH3, and CF3.

26. The compound of claim 25, wherein R6is selected from OCH3 and OCF3 and R7is Cl.

27. The compound of any one of claims 1 to 26, wherein each R8is independently selected from OR12, NR12R13, C(O)NR12R13, Cl, F, Br, C1-4alkyl, C1-4fluoroalkyl, C3-6cycloalkyl and C3-6heterocycloalkyl, wherein all alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents from Cl, Br, F, OR14, NR14R15and C1-4alkyl or each R8is independently selected from OR12, C(O)NR12R13, C(O)OR12, =O, NR12R13, Cl, F, Br, C1-4alkyl, C1-4fluoroalkyl, C3-6cycloalkyl and C3-6heterocycloalkyl, wherein all alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from Cl, Br, F, OR14, NR14R15and C1-4alkyl..

28. The compound of claim 27, wherein each R8is independently selected from OR12, NR12R13, C(O)NR12R13, Cl, F, CH3, CHF2, CH3CH3 and CF3 or each R8is independently selected from OR12, NR12R13, C(O)NR12R13, C(O)OR12, =O, Cl, F, CH3, CHF2, CH3CH3 and CF3..

29. The compound of claim 18, wherein each R8is independently selected from Cl, F, CH3, CHF2, CH3CH3and CF3.

30. The compound of claim 29, wherein each R8is independently selected from NR12R13and C(O)NR12R13or each R8is independently selected from =O and C(O)OR12.

31. The compound of any one of claims 1 to 15, wherein R9, R10and R11are independently selected from H, Cl, Br, F, C1-4alkyl and C1-4fluoroalkyl.

32. The compound of claim 31, wherein R9, R10and R11are H.

33. The compound of any one of claims 1 to 32, wherein R12is selected from H, C1-4alkyl, C1-4fluoroalkyl, C3-10cycloalkyl and C3-10heterocycloalkyl, the latter four groups being optionally substituted with one or two substituents selected from Cl, F, Br, OH, OCH3and OCF3.

34. The compound of claim 33, wherein R12is selected from H, CH3 and CF3.

35. The compound of claim 34, wherein R12is selected from H and CH3.

36. The compound of any one of claims 1 to 35, wherein R13is selected from H, C1- 4alkyl and C1-4fluoroalkyl 37. The compound of claim 36, wherein R13is selected from H and CH3.

38. The compound of any one of claims 1 to 35, wherein R14and R15are independently selected from H, CH3and CF3.

39. The compound of claim 38, wherein R14and R15are independently selected from H and CH3.

40. The compound of claim 1, selected from: N-(3-(2-Amino-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-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]pyrimidin-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]pyrimidin-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]pyrimidin-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide; N-(3-(2-Amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-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]pyrimidin-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]pyrimidin-6-yl)-4-fluorophenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(4-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridin-6-yl)phenyl)- 2-methoxypyridine-3-sulfonamide; trans-5-Chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)-8-methyl-7-oxo-7,8- dihydropteridin-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]pyrimidin-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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(2-fluoro-3-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6- yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(4-fluoro-3-(2-(isopropylamino)-8-methyl-7-oxo-7,8-dihydropteridin-6- yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(ethylamino)-8-methyl-7-oxo-7,8-dihydropteridin-6-yl)-4-fluorophenyl)-2- methoxypyridine-3-sulfonamide;5-Chloro-N-(2,4-difluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridin-6- yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(ethylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4- difluorophenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4- fluorophenyl)-2-methoxypyridine-3-sulfonamide; 5Cchloro-N-(4-fluoro-3-(2-(isopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(2-fluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridin-6-yl)phenyl)- 2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(cyclopropylamino)-8-methyl-7-oxo-7,8-dihydropteridin-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- dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(4-fluoro-3-(8-methyl-2-(oxetan-3-ylamino)-7-oxo-7,8-dihydropteridin-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- dihydropteridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2- fluorophenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(4-fluoro-3-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-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]pyrimidin-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]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; N-(3-(2-Amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-fluorophenyl)-5- chloro-2-methoxypyridine-3-sulfonamide; N-(3-(2-Amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-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]pyrimidin-6-yl)pyridin-2-yl)-2-methoxypyridine-3-sulfonamide;5-Chloro-N-(3-fluoro-4-(2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6- yl)pyridin-2-yl)-2-methoxypyridine-3-sulfonamide; trans-4-((6-(5-((5-Chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8-methyl-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexane-1-carboxamide; cis-4-((6-(5-((5-Chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8-methyl-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclohexane-1-carboxamide; trans-4-((6-(5-((5-Chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8-methyl-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-methylcyclohexane-1-carboxamide; cis-4-((6-(5-((5-Chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8-methyl-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-methylcyclohexane-1-carboxamide; trans-3-((6-(3-((5-Chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8-methyl-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-methylcyclobutane-1-carboxamide rac-(1R,3S)-3-((6-(3-((5-Chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-methylcyclohexane-1- carboxamide; rac-(1R,3R)-3-((6-(3-((5-Chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-methylcyclohexane-1- carboxamide; cis-3-((6-(3-((5-Chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8-methyl-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclobutane-1-carboxamide; Potassium ((5-chloro-2-methoxypyridin-3-yl)sulfonyl)(2-fluoro-3-(2-(methylamino)-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)amide; Potassium ((5-chloro-2-methoxypyridin-3-yl)sulfonyl)(3-(2-(ethylamino)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)amide; 4-((6-(3-((5-Chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8-methyl-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1-fluorocyclohexane-1-carboxamide; (1R,3S)-3-((6-(3-((5-Chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8-methyl- 7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclopentane-1-carboxamide; 5-Chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((6-oxopiperidin-3-yl)amino)-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; tert-Butyl 3-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8-methyl- 7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)azetidine-1-carboxylate; Ethyl 4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-8-methyl-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate;N-(3-(2-((1-Acetylpiperidin-4-yl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin- 6-yl)-2-fluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; (R)-5-Chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((5-oxopyrrolidin-3-yl)amino)-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; (S)-5-Chloro-N-(2-fluoro-3-(8-methyl-7-oxo-2-((5-oxopyrrolidin-3-yl)amino)-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(2-fluoro-3-(2-(isopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6- yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(cyclopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4- fluorophenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(cyclopropylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2- fluorophenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(3-(2-(ethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-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]pyrimidin-6- yl)phenyl)-2-methoxypyridine-3-sulfonamide; or a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

41. A pharmaceutical composition comprising one or more compounds of 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 of inhibiting general control nonderepressible 2 (GCN2) in a cell, either in a biological sample or in a patient, comprising administering an effective amount of one or more compounds of any one of claims 1 to 40, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, to the cell.

43. A method of treating a disease, disorder or condition that is treatable by inhibiting GCN2, comprising administering a therapeutically effective amount of one or more compounds of any one of claims 1 to 40, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, to a subject in need thereof.

44. The method of claim 43, wherein the disease, disorder or condition that is treatable by inhibiting GCN2 is a neoplastic disorder.

45. The method of claim 43, wherein disease, disorder or condition that is treatable by inhibiting GCN2, is cancer.

46. The method of claim 45, wherein the cancer is selected from one or more of solid tumors, breast cancer, colon 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 of claim 43, wherein the disease, disorder or condition that is treatable by inhibiting GCN2 is a peripheral neuropathy.

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

49. A method of treating a disease, disorder or condition that is treatable by inhibiting GCN2 comprising administering a therapeutically effective amount of one or more compounds of any one of claims 1 to 40, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, in combination with another known agent useful for treatment of a disease, disorder or condition treatable by inhibiting GCN2 to a subject in need thereof.

50. The method of claim 49, wherein the disease, disorder or condition treatable by inhibiting GCN2 is cancer and / or peripheral neuropathy.

51. The method of claim 49, wherein the disease, disorder or condition that is treatable by inhibiting GCN2, is cancer and the one or more compounds of the application are administered or used in combination with one or more additional cancer treatments.

52. The method of claim 51, wherein the one or more additional cancer treatments is a chemotherapeutic agent and the chemotherapeutic agent is cisplatin.

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

54. The method of claim 51, wherein the one or more additional cancer treatments is small molecule therapy and the small molecule therapy is a glutaminase inhibitor or an asparagine synthetase (ASNS) inhibitor.

55. A method of improving the efficacy of one or more cancer treatments for treating cancer comprising administering an effective amount of one or more compounds of any one of claims 1 to 40, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, in combination with an effective amount of the one or more additional cancer treatments.

56. The method of claim 55, wherein the one or more cancer treatments is a chemotherapeutic agent and the chemotherapeutic agent is cisplatin.

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

58. The method of claim 55, wherein the one or more cancer treatments is small molecule therapy and the small molecule therapy is a glutaminase inhibitor or an asparagine synthetase (ASNS) inhibitor.

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

60. The method of claim 53, wherein the cancer is associated with asparagine synthetase (ASNS) overexpression or dysregulation and the one or more additional cancer treatments are one or more asparagine synthetase (ASNS) inhibitors and / or L- asparaginase.

61. The method of claim 53, wherein the cancer is associated with low asparagine synthetase (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 of claim 53, wherein cancer is associated with asparagine synthetase (ASNS) overexpression or dysregulation and glutaminase overexpression or dysregulation and the one or more additional cancer treatments are L-asparaginase (L-ASNase), one or more glutaminase inhibitors and / or one or more asparagine synthetase (ASNS) inhibitors.

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