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WO2025043349A1 - Dérivés de pyrimidopyridone et de ptéridone utilisés en tant qu'inhibiteurs de kinase gcn2, compositions et utilisations associées - Google Patents

Dérivés de pyrimidopyridone et de ptéridone utilisés en tant qu'inhibiteurs de kinase gcn2, compositions et utilisations associées Download PDF

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WO2025043349A1
WO2025043349A1 PCT/CA2024/051124 CA2024051124W WO2025043349A1 WO 2025043349 A1 WO2025043349 A1 WO 2025043349A1 CA 2024051124 W CA2024051124 W CA 2024051124W WO 2025043349 A1 WO2025043349 A1 WO 2025043349A1
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chloro
methoxypyridine
oxo
pyrimidin
dihydropyrido
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Inventor
Rima AL-AWAR
Methvin Isaac
Radek LAUFER
David UEHLING
Robert Kenneth ROTTAPEL
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University Health Network
Ontario Institute for Cancer Research
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University Health Network
Ontario Institute for Cancer Research
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems

Definitions

  • 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.
  • GCN2 eukaryotic initiation factor 2 ⁇
  • ISR integrated stress response
  • ATF4 activating transcription factor 4
  • the GCN2 kinase mediated cellular adaptations to amino acid limitation occurs through the translational control of gene expression that is primarily executed by eIF2 ⁇ phosphorylation. Utilizing quantitative phosphoproteomics, Dokladal et al.
  • GCN2 targets auxiliary, physiologically relevant effectors, including eIF2 ⁇ and Gcn20, to fine-tune translational control in response to amino acid starvation (Molecular Cell 2021; 81 (9), P1879-1889.e6).
  • eIF2 ⁇ and Gcn20 auxiliary, physiologically relevant effectors
  • GCN2 also phosphorylates the ⁇ -subunit of the trimeric eIF2 G protein complex to promote its association with eIF5 which in turn contributes to the inhibition of translation initiation.
  • eIF2 ⁇ eukaryotic initiation factor 2 ⁇
  • 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].
  • PERK protein kinase–like endoplasmic reticulum kinase
  • PRK double-stranded RNA-dependent kinase
  • HRK heme-regulated inhibitor
  • ATF4 activating transcription factor 4
  • GCN2 can be important for cancer cell survival and tumor development.
  • GCN2 or ATF4 has been shown to decrease tumor growth in vivo [EMBO. J.2010, 29:2082–2096].
  • 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.
  • 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.
  • mutant tRNA synthetases activate the integrated stress response (ISR) through the sensor kinase (general control nonderepressible 2).
  • ISR integrated stress response
  • the chronic 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].
  • the small molecule inhibitors of GCN2 kinase have been described (WO2021165346, Black Belt TX LTD).
  • 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.
  • GCN2 kinase inhibitors with selectivity over other kinases.
  • the present invention includes a compound of Formula I, or a pharmaceutically acceptable salt, solvate and/or prodrug thereof: wherein R 1 is selected from H, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl and C3-10heterocycloalkyl, the latter four groups being optionally substituted with one or two R 8 ; X 1 is selected from N and CR 9 ; R 2 is selected from H, C1-6alkyl and C1-6haloalkyl; X 2 is selected from N and CR 10 ; R 3 , R 4 and R 5 are independently selected from H, halo, CN, C1-6alkyl and C1-6haloalkyl; X 3 is selected from N and CR 11 ; R 6 and R 7 are independently selected from H, halo, CN, C1-6alkyl, C1-6haloalkyl, OC1-6alkyl and OC1-6haloalkyl; each R 8 is independently selected from OR 12 , NR
  • the present application also includes a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier.
  • 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.
  • GCN2 general control nonderepressible 2
  • 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.
  • 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]
  • 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.
  • 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.
  • CMT Charcot-Marie-Tooth
  • 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 of one or more compounds of the application, in combination with an effective amount of the one or more cancer treatments.
  • 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.
  • 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.
  • and/or as used herein means that the listed items are present, or used, individually or in combination.
  • 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.
  • the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise.
  • an embodiment including “a compound” should be understood to present certain aspects with one compound, or two or more additional compounds.
  • 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.
  • 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.
  • 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.
  • 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.
  • reaction conditions 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.
  • 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.
  • 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.
  • 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, 3 rd Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).
  • cell refers to a single cell or a plurality of cells and includes a cell either in a cell culture or in a subject.
  • 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.
  • pharmaceutically acceptable means compatible with the treatment of subjects.
  • 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.
  • 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.
  • 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.
  • 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.
  • prodrug as used herein means a compound, or salt and/or solvate of a compound, that, after administration, is converted into an active drug.
  • 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.
  • 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.
  • 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.
  • 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).
  • a cyclic group contains more than one ring
  • the rings may be fused, bridged or spirofused.
  • the term “benzofused” as used herein refers to a polycyclic group in which a benzene ring is fused with another ring.
  • a first ring being “fused” with a second ring means the first ring and the second ring share two adjacent atoms there between.
  • a first ring being “bridged” with a second ring means the first ring and the second ring share two non-adjacent atoms there between.
  • a first ring being “spirofused” with a second ring means the first ring and the second ring share one atom there between.
  • the term “optionally substituted” as used herein means that the referenced group is unsubstituted or substituted.
  • substituted means that the referenced atom contains at least one substituent group other that a hydrogen atom.
  • substituents 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.
  • the symbol when drawn perpendicularly across a bond indicates a point of covalent attachment of a chemical group.
  • the term “LCMS” as used herein refers to liquid chromatography-mass spectrometry.
  • NMR nuclear magnetic resonance
  • aq. refers to aqueous.
  • N as used herein, for example in “4N”, refers to the unit symbol of normality to denote "eq/L”.
  • M as used herein, for example in 4M, refers to the unit symbol of molarity to denote "moles/L”.
  • DIPEA as used herein refers to N,N-diisopropyl ethylamine.
  • DMF dimethylformamide.
  • THF tetrahydrofuran
  • DMSO dimethylsulfoxide
  • EtOAc ethyl acetate
  • MeOH methanol
  • EtOH ethanol
  • MeCN acetonitrile
  • HCl hydrochloric acid
  • TFA trifluoroacetic acid
  • Hex refers to hexanes.
  • dppf 1,1'-bis(diphenylphosphino)ferrocene.
  • RT room temperature.
  • HPLC high-performance liquid chromatography.
  • TAA triethylamine
  • EDTA refers to ethylenediaminetetraacetic acid.
  • ATP refers to adenosine triphosphate.
  • FBS refers to fetal bovine serum.
  • MEM refers to Minimum Essential Medium.
  • 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.
  • 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.
  • “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.
  • 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.
  • 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.
  • 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.
  • inhibiting GCN2 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.
  • 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.
  • GCN2 refers to General Control Nonderepressible 2, or any functional mutant or analogous forms thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • the term “GLS1” as used herein refers to the “kidney type” glutaminase or any functional mutant or analogous forms thereof.
  • 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.
  • neoplastic disorder 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.
  • neoplasm 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).
  • fibrosis refers to a disease, disorder or condition the thickening and scarring of connective tissue, usually as a result of injury.
  • the present application includes a compound of Formula I, or a pharmaceutically acceptable salt, solvate and/or prodrug thereof: wherein R 1 is selected from H, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl and C3-10heterocycloalkyl, the latter four groups being optionally substituted with one or two R 8 ; X 1 is selected from N and CR 9 ; R 2 is selected from H, C1-6alkyl and C1- X 2 is selected from N and CR 10 ; R 3 , R 4 and R 5 are independently selected from H, halo, CN, C 1-6 alkyl and C 1-6 haloalkyl; X 3 is selected from N and CR 11 ; R 6 and R 7 are independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl and OC 1-6 haloalkyl; each R 8 is independently selected from OR 12
  • the present application also includes a compound of Formula I, or a pharmaceutically acceptable salt, solvate and/or prodrug thereof: wherein R 1 is selected from H, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl and C3-10heterocycloalkyl, the latter four groups being optionally substituted with one or two R 8 ; X 1 is selected from N and CR 9 ; R 2 is selected from H, C1-6alkyl and C1-6haloalkyl; X 2 is selected from N and CR 10 ; R 3 , R 4 and R 5 are independently selected H, halo, CN, C1-6alkyl and C1-6haloalkyl; X 3 is selected from N and CR 11 ; R 6 and R 7 are independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl and OC 1-6 haloalkyl; each R 8 is independently selected from OR 12
  • R 1 is selected from H, C1-6alkyl, C1-6haloalkyl, C3- 10cycloalkyl and C3-10heterocycloalkyl, the latter four groups being optionally substituted with one R 8 .
  • R 1 is selected from C3-10cycloalkyl and C3- 10heteroycloalkyl, each of which is optionally substituted with one or two R 8 .
  • R 1 is selected from H, C1-6alkyl and C1-6haloalkyl.
  • R 1 is selected from H, C1-4alkyl and C1-4haloalkyl.
  • R 1 is selected from H, C1-4alkyl and C1-4fluoroalkyl. In some embodiments, R 1 is selected from H, CH3, CF3, CHF2, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3 and CH(CH3)3. In some embodiments, R 1 is selected from H, CH3, CH2CH3 and CH(CH3)2. [00107] In some embodiments, R 1 is C3-10cycloalkyl optionally substituted with one or two R 8 . In some embodiments, R 1 is a monocyclic C3-10cycloalkyl or a bicyclic C5- 10cycloalkyl, each of which is optionally substituted with one or two R 8 .
  • R 1 is monocyclic C3-8cycloalkyl optionally substituted with one or two R 8 .
  • the monocyclic C3-8cycloalkyl in R 1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each of which is optionally substituted with one or two R 8 .
  • R 1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each of which is optionally substituted with one R 8 .
  • R 1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each of which are unsubstituted. In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is selected from cyclopentyl and cyclohexyl, each of which is substituted with one or two R 8 . In some embodiments, R 1 is cyclohexyl substituted with one or two R 8 . In some embodiments, R 1 is selected from cyclobutyl and cyclohexyl, each of which is substituted with one R 8 .
  • R 1 is cyclobutyl substituted with one R 8 . In some embodiments, R 1 is cyclohexyl substituted with one R 8 . [00108] In some embodiments, R 1 is a spirofused C 5-10 cycloalkyl or a bridged C 5- 10 cycloalkyl each of which is optionally substituted with one or two R 8 .
  • the spirofused C 5-10 cycloalkyl 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 R 8 .
  • the spirofused C6- 10cycloalkyl is spiro[3.3]heptane substituted optionally with one or two R 8 .
  • the spirofused C 5-10 cycloalkyl 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 R 8 .
  • the spirofused C6- 10cycloalkyl is spiro[
  • R 1 is a bridged C 5-10 cycloalkyl optionally substituted with one or two R 8 .
  • the bridged C 5-10 cycloalkyl is selected from a bicyclopentanyl, a bicycloheptanyl and a bicyclooctanyl each of which optionally substituted with one or two R 8 .
  • the bridged C5-10cycloalkyl is selected from a bicyclopentanyl, a bicycloheptanyl and a bicyclooctanyl each of which is optionally substituted with one R 8 .
  • the bridged C5-10cycloalkyl is selected from , .
  • R 1 is C 3-10 heterocycloalkyl optionally substituted with one or two R 8 . In some embodiments, R 1 is C 3-10 heterocycloalkyl optionally substituted with one R 8 . In some embodiments, R 1 is C 3-6 heterocycloalkyl optionally substituted with one R 8 .
  • R 1 is selected from thietanyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl, each of which is optionally substituted with one R 8 .
  • R 1 is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one R 8 .
  • R 2 is selected from is selected from H, C1-4alkyl and C1-4fluoroalkyl. In some embodiments, R 2 is selected from H, CH3, CF3, CHF2, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3 and CH(CH3)3. In some embodiments, R 2 is selected from H, CH3, CH2CH3 and CH(CH3)2. In some embodiments, R 2 is selected from H, CH3 and CH(CH3)2. In some embodiments, R 2 is selected from H and CH3. [00113] In some embodiments X 2 is selected from N and CH. In some embodiments, X 1 is N. In some embodiments X 2 is CH.
  • R 3 , R 4 and R 5 are not all H. In some embodiments, R 3 , R 4 and R 5 are independently selected from H, halo, CN, C1-4alkyl and C1-4haloalkyl. In some embodiments, at least one of R 3 , R 4 and R 5 is selected from halo, CN and C1- 4haloalkyl. In some embodiments, at least one of R 3 and R 5 is selected from halo, CN and C1-4haloalkyl. In some embodiments, at least one of R 3 , R 4 and R 5 is selected from halo and CN. In some embodiments, at least one of R 3 and R 5 is selected from halo and CN.
  • At least one of R 3 , R 4 and R 5 is halo. In some embodiments, at least one of R 3 and R 5 is halo. In some embodiments, R 3 , R 4 and R 5 are independently selected from H, Cl, F, Br, CN, C1-4alkyl and C1-4fluoroalkyl. In some embodiments, at least one of R 3 , R 4 and R 5 is selected from F, Cl, Br, CN and C1-4fluoroalkyl. In some embodiments, at least one of R 3 and R 5 is selected from F, Cl, Br, CN and C1-4fluoroalkyl.
  • R 3 , R 4 and R 5 are independently selected from H, Cl, F, CN, CH3 and CF3. In some embodiments, at least one of R 3 , R 4 and R 5 is selected from Cl, F, CN and CF3. In some embodiments, at least one of R 3 , R 4 and R 5 is selected from Cl, F and CN. In some embodiments, at least one of R 3 and R 5 is selected from Cl, F and CN. In some embodiments, R 3 , R 4 and R 5 are selected from H, F and CN. In some embodiments, at least one of R 3 , R 4 and R 5 is selected from F and CN. In some embodiments, at least one of R 3 and R 5 is selected from F and CN. In some embodiments, at least one of R 3 and R 5 is selected from F and CN.
  • R 3 and R 5 is selected from F and CN and R 4 is H.
  • R 3 is CN, R 4 is H and R 5 is H.
  • R 3 is H, R 4 is H and R 5 is CN.
  • R 3 and R 5 are independently selected from H, F and CN and R 4 is H.
  • R 3 and R 5 are independently selected from H and F and R 4 is H.
  • at least one of R 3 and R 5 is F.
  • at least one of R 3 and R 5 is F and R 4 is H.
  • R 3 and R 5 are both F and R 4 is H.
  • R 3 is F, R 4 is H and R 5 is F. In some embodiments, R 3 is F, R 4 is H and R 5 is H. In some embodiments, R 3 is H, R 4 is H and R 5 is F. [00115] In some embodiments, X 3 is selected from N and CH. In some embodiments, X 3 is CH. [00116] In some embodiments, R 6 and R 7 are independently selected from H, Cl, F, Br, CN, C1-4alkyl, C1-4fluoroalkyl, OC1-4alkyl and OC1-4fluoroalkyl.
  • R 6 and R 7 are independently selected from H, Cl, F, CN, CH3, CHF2, CF3, CH2CH3, OCH3, OCHF2 and OCF3. In some embodiments, R 6 and R 7 are independently selected from Cl, F, CH3, CF3, CHF2, CH2CH3, OCH3, OCHF2 and OCF3. In some embodiments, R 6 is selected from OCH3 and OCF3 and R 7 is selected from Cl, F, CH3, and CF3. In some embodiments, R 6 is selected from OCH3 and OCF3 and R 7 is Cl. In some embodiments, R 6 is OCH3 and R 7 is Cl.
  • each R 8 is independently selected from OR 12 , C(O)NR 12 R 13 , NR 12 R 13 , 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, OR 14 , NR 14 R 15 and C1-4alkyl.
  • each R 8 is independently selected from OR 12 , C(O)NR 12 R 13 , NR 12 R 13 , Cl, F, Br, C 1-4 alkyl, C 1-4 fluoroalkyl, C 3- 6 cycloalkyl and C 3-6 heterocycloalkyl, wherein all alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from Cl, Br, F, OR 14 , NR 14 R 15 and C 1-4 alkyl.
  • each R 8 is independently selected from OR 12 , NR 12 R 13 , C(O)NR 12 R 13 , Cl, F, CH 3 , CHF 2 , CH 3 CH 3 and CF 3 .
  • each R 8 is independently selected from Cl, F, CH 3 , CHF 2 , CH 3 CH 3 and CF 3 .
  • each R 8 is independently selected from CH3, CHF2, CH3CH3 and CF3.
  • R 9 , R 10 and R 11 are independently selected from H, Cl, Br, F, C1-4alkyl and C1-4fluoroalkyl. In some embodiments, R 9 , R 10 and R 11 are independently selected from H, Cl, F, CH3, CF3, CHF2, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3 and CH(CH3)3. In some embodiments, R 9 , R 10 and R 11 are independently selected from H, Cl, F, CH3 and CF3. In some embodiments, R 9 , R 10 and R 11 are independently selected from H and F. In some embodiments, R 9 , R 10 and R 11 are H.
  • R 12 is 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.
  • R 12 is selected from H, CH3, CF3, CHF2, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3 and CH(CH3)3.
  • R 12 is selected from H, CH3 and CF3.
  • R 12 is selected from H and CH3.
  • R 12 is CH3.
  • R 13 is selected from H, C1-4alkyl and C1-4fluoroalkyl. In some embodiments, R 13 is selected from H, CH 3 , CF 3 , CHF 2 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 and CH(CH 3 ) 3 . In some embodiments, R 13 is selected from H, CH 3 and CF 3 . In some embodiments, R 13 is selected from H and CH 3 . [00121] In some embodiments, R 14 and R 15 are independently selected from H, C 1- 4 alkyl and C 1-4 fluoroalkyl.
  • R 14 and R 15 are independently selected from H, CH 3 , CF 3 , CHF 2 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 and CH(CH 3 ) 3 . In some embodiments, R 14 and R 15 are independently selected from H, CH 3 and CF 3 . In some embodiments, R 14 and R 15 are independently selected from H and CH 3 . [00122] In some embodiments, the compounds of Formula I are selected from:
  • the pharmaceutically acceptable salt is an acid addition salt or a base addition salt.
  • 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).
  • 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.
  • 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.
  • the mono- or di-acid salts are formed, and such salts exist in either a hydrated, solvated or substantially anhydrous form.
  • 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.
  • the acid addition salt is a hydrochloric or formic acid addition salt.
  • 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, compounds comprising 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.
  • organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicycl
  • 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.
  • 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.
  • the compounds described herein have at least one asymmetric center.
  • 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.
  • 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.
  • 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 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. [00132] 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.
  • 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.
  • 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.
  • 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 patch or other transdermal delivery device) modes of administration.
  • Parenteral administration may be by continuous infusion over a selected period of time.
  • 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.
  • 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.
  • 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).
  • the tablets are coated by methods well known in the art.
  • Oral dosage forms also include modified release, for example immediate release and timed-release, formulations.
  • 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.
  • SR sustained-release
  • ER extended- release
  • CR controlled-release
  • Contin continuous-release
  • 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.
  • liposomes are formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • useful carriers or diluents include lactose and dried corn starch.
  • liquid preparations for oral administration take the form of, for example, solutions, syrups or or they are suitably presented as a dry product for constitution with water or other suitable vehicle before use.
  • 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).
  • 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
  • preservatives e.g., methyl or propyl p-hydroxybenzoates or sorbic acid
  • Useful diluents include lactose and high mole
  • a compound of the application is administered parenterally.
  • solutions of a compound of the application are prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • 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.
  • sterile solutions of the compounds of the application are usually prepared, and the pH’s of the solutions are suitably adjusted and buffered.
  • ointments or droppable liquids are delivered, for example, by ocular delivery systems known to the art such as applicators or eye droppers.
  • ocular delivery systems known to the art such as applicators or eye droppers.
  • 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.
  • diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.
  • 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.
  • the compositions take such forms as sterile suspensions, solutions or emulsions 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.
  • compositions for nasal administration are conveniently formulated as aerosols, drops, gels and powders.
  • 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.
  • 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.
  • 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.
  • the dosage unit is suitably determined by providing a valve to deliver a metered amount.
  • 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.
  • 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.
  • 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. [00142] 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.
  • 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.
  • 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.
  • 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.
  • 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 99.90 wt% of a pharmaceutically acceptable carrier, all percentages by weight being based on the total composition. IV.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • GCN2 is a protein kinase that belongs to the family of eukaryotic initiation factor 2 ⁇ (eIF2 ⁇ ) 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. [00152] In some embodiments, the disease, disorder or condition that is treatable by inhibiting GCN2 is a neoplastic disorder.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compound is administered for the prevention of cancer in a subject such mammal having a predisposition for cancer.
  • 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, Ep
  • 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.
  • 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.
  • 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.
  • the cancer is breast cancer.
  • the cancer is skin cancer.
  • the cancer is head and neck cancer.
  • the cancer is colorectal cancer (CRC).
  • the cancer is lung cancer.
  • the cancer is pancreatic cancer.
  • the cancer is ovarian cancer.
  • the cancer is prostate cancer.
  • the cancer is glioblastoma.
  • the bone cancer is osteosarcoma.
  • 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.
  • the uncontrolled and/or abnormal cellular activity that is affected directly or indirectly by inhibiting GCN2 is proliferative activity in a cell.
  • 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.
  • 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.
  • the disease, disorder or condition that is treatable by inhibiting GCN2 is a peripheral neuropathy.
  • 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.
  • the peripheral neuropathy is Charcot-Marie-Tooth (CMT) peripheral neuropathy.
  • AARSs cytoplasmic aminoacyl-tRNA synthetases
  • CMT Charcot- Marie-Tooth
  • 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.
  • 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.
  • 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.
  • the disease, disorder or condition treatable by inhibiting GCN2 is cancer and/or peripheral neuropathy.
  • GCN2 is inhibited in the uses and methods of the application.
  • the “subject in need thereof” is a subject having the disease, disorder or condition to be treated.
  • the subject is a mammal. In another embodiment, the subject is human.
  • 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.
  • 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.
  • 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.
  • the chemotherapy is a chemotherapeutic agent.
  • the chemotherapeutic agent is cisp
  • 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.
  • 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).
  • the small molecule therapy is a glutaminase (e.g., glutaminase-1, (GLS1)) inhibitor or an asparagine synthetase (ASNS) inhibitor.
  • 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.
  • glutaminase inhibitors e.g., GLS1 inhibitors
  • ASNS asparagine synthetase
  • L-ASNase L-asparaginase
  • 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.
  • 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.
  • 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.
  • the chemotherapy is a chemotherapeutic agent.
  • chemotherapeutic agent is cisplatin.
  • 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.
  • 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.
  • the small molecule therapy is a glutaminase inhibitor (e.g., GLS1 inhibitor) or an asparagine synthetase (ASNS) inhibitor.
  • 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.
  • the cancer is associated with low asparagine synthetase (ASNS) expression.
  • the cancer is associated with low asparagine synthetase (ASNS) expression and the chemotherapeutic agent is L- asparaginase (L-ASNase).
  • 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.
  • L-ASNase L-asparaginase
  • ASNS asparagine synthetase
  • ASNS asparagine synthetase
  • 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.
  • ASNS asparagine synthetase
  • ASNS asparagine synthetase
  • the chemotherapeutic agents are one or more asparagine synthetase (ASNS) inhibitors and L-asparaginase [00183]
  • ASNS asparagine synthetase
  • the cancer is associated with low asparagine synthetase (ASNS) expression and low glutaminase (e.g. GLS1) expression.
  • ASNS low asparagine synthetase
  • ASNS low glutaminase
  • GLS1 low glutaminase
  • the chemotherapeutic agents are L- asparaginase (L-ASNase) and/or one or more glutaminase inhibitors.
  • 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.
  • the glutaminase inhibitor is a GLS1 inhibitor.
  • the chemotherapeutic agents are L-asparaginase (L-ASNase) and one or more glutaminase inhibitors.
  • the cancer is associated with asparagine synthetase (ASNS) overexpression or dysregulation and glutaminase (e.g. GLS1) overexpression or dysregulation.
  • ASNS asparagine synthetase
  • GLS1 glutaminase
  • 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.
  • L-ASNase L-asparaginase
  • ASNS asparagine synthetase inhibitors
  • ASNS asparagine synthetase
  • 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.
  • the glutaminase inhibitors is a GLS1 inhibitor.
  • the chemotherapeutic agents are L- asparaginase (L-ASNase), one or more glutaminase inhibitors and one or more asparagine synthetase (ASNS) inhibitors.
  • L-ASNase L- asparaginase
  • ASNS asparagine synthetase
  • 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.
  • the compounds of the application are administered contemporaneously with those agents.
  • “contemporaneous of two substances to a subject means providing each of the two substances so that they are both biologically active in the individual at the same time.
  • 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.
  • 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.
  • 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.
  • the compounds of the application are administered at least once a week.
  • 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.
  • 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.
  • a subject with early cancer can be treated to prevent progression, or alternatively a subject in remission can be treated with a compound or composition of the application to prevent recurrence.
  • 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 ⁇ g/cc to about 1000 ⁇ g/cc, or about 0.1 ⁇ g/cc to about 100 ⁇ g/cc.
  • 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.
  • 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.
  • 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.
  • 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. [00188]
  • effective amounts vary according to factors such as the disease state, age, sex and/or weight of the subject.
  • 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.
  • the term “a compound” also includes embodiments wherein one or more compounds are referenced.
  • the term “compounds of the application” also includes embodiments wherein only one compound is referenced. V. Methods of Preparation of Compounds of the Application [00190] Compounds of the present application can be prepared by various synthetic processes.
  • 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 [00195] In some embodiments, compounds of Formula I are prepared as shown in Scheme 2.
  • 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, PdCl 2 dppf:CH 2 Cl 2 complex, and a base such as KOAc and in a suitable solvent such as dioxane at a suitable temperature, such as 100-110 o C to provide the boronated compounds of Formula K wherein R c and R d are independently C 1-6 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 C 1-3 alkyls.
  • suitable reagents such as bispinacolatodiboron, PdCl 2 dppf:CH 2 Cl 2 complex
  • a base such as KOAc
  • a suitable solvent such as dioxane
  • 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 100-110 o C.
  • 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 100-110 o C.
  • 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.
  • 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.
  • solvates will vary depending on the compound and the solvate.
  • 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.
  • suitable conditions to form a particular solvate can be made by a person skilled in the art.
  • 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.
  • 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.
  • Prodrugs of the compounds of the present application may be, for example, conventional esters formed with available hydroxy, thiol, amino or carboxyl groups.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 NaHCO 3 followed by concentration of the organic layer or simply concentrated under reduced pressure and used crude without a workup or further purification.
  • Step 2.6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one [00218] 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.
  • Step 3.2-Chloro-8-methylpteridin-7(8H)-one To stirred solution of 2-chloro-N 4 -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.
  • 6-(5-bromo-2-fluorophenyl)-8-methyl-2-(methylthio)pteridin-7(8H)-one [00223] To a solution of 5-bromo-2-fluoroaniline (1.8 g, 9.5 mmol) in MeCN (50 mL) under N 2 , 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.
  • reaction mixture was stirred at rt for 16 h.
  • the reaction mixture was then diluted with H 2 O (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 %).
  • reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by preparative HPLC (C18, MeCN in H2O + 0.1 % HCO 2 H), 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 %).
  • 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
  • reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography using MeOH in CH 2 Cl 2 .
  • 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).
  • 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) [00239] Prepared by General Method SMC using Cs 2 CO 3 (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-ethylpyr
  • 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 %).
  • 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).
  • 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) [00244] To a cold (-78 o C) 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 CH 2 Cl 2 (2 mL).
  • 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] [00245] 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).
  • 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 %).
  • 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 [00247] 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, 0.68 mmol) were cooled
  • 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) [00249] To a cold (-78 o C) 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 CH 2 Cl 2 (10 mL), mCPBA (35 mg, 0.14 mmol) was added in CH 2 Cl 2 (2 mL).
  • 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.
  • 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) [00250] Prepared by General Method SMC using PdCl 2 dppf•CH 2 Cl 2 (15.0 mg, 0.018 mmol, Cs 2 CO 3 (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), H 2 O (1.8 mL) and (3-((5-chloro-2-methoxypyridine)-3-sulfonamid
  • 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.
  • 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 [00254] 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).
  • 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) [00257] 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).
  • 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 [00258] 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)(
  • 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 [00260] 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 EtNH 2 (66-72% in H 2 O, 1.5 mL, 19 mmol) was stirred at rt for 1 d.
  • 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 [00263] 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 CH 2 Cl 2 (100 mL) was slowly allowed to warm to rt and stirred for the total time of 1 d and 19 h.
  • 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 [00266] 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.
  • 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
  • i-PrOH 10 mL
  • i-PrNH2 2.43 mL, 28d mmol
  • 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) [00269] Prepared by General Method SMC using 6-bromo-2-(isopropylamino)-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one (77 mg, 0.26 mmol), PdCl 2 dppf•CH 2 Cl 2 (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- dioxan
  • reaction was then stirred allowing slowly to warm to rt and then was stirred at rt overnight.
  • 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.
  • 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) [00273] 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, a 1 /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-sulfon
  • 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) [00274] 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, a 1 / 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
  • 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) [00275] 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, a 1 /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.
  • 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 [00276] To a cold (0 o C) 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.
  • 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 EtNH 2 (66-72% in H 2 O, 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).
  • 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) [00279] 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 H 2 O (5 mL) and 1,4- dioxane (10 mL); by heating sealed in a
  • 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
  • MeNH 2 40 wt % in H 2 O, 3.4 mL, 39 mmol
  • 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) [00281] 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), Cs 2 CO 3 (303 mg, 0.93 mmol) and PdCl 2 dppf•CH 2 Cl 2 (15 mg, 0.019 mmol) in 1,4-dioxane (4 mL) and H 2 O (2 mL
  • 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) [00282] 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), Cs 2 CO 3 (303 mg, 0.93 mmol) and PdCl 2 dppf•CH 2 Cl 2 (15 mg, 0.019 mmol) in 1,4-diox
  • 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 H 2 O. The beige precipitate was redissolved in CH 2 Cl 2 /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 %).
  • 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) [00284] 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), Cs 2 CO 3 (192 mg, 0.59 mmol) and PdCl 2 dppf (17 mg, 0.024 mmol) in H 2 O (2 mL) and 1,4-dioxane (4 mL); by heating sealed in a microwave reactor at 90
  • 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) [00285] 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), Cs 2 CO 3 (192 mg, 0.59 mmol) and PdCl 2 dppf (17 mg, 0.024 mmol) in H 2 O (2 mL) and 1,4-dioxane (4 mL); by heating sealed in a microwave reactor at 90 °
  • 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).
  • 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
  • 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.
  • Step 2 (8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)boronic acid
  • 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
  • PdCl2dppf 38 mg, 0.052 mmol
  • 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
  • Step 2 (2-(methylamino)-7-oxo-7,8- pyrimidin-6-yl)boronic acid
  • 6-bromo-2- (methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one 150 mg, 0.59 mmol
  • B 2 pin 2 224 mg, 0.88 mmol
  • KOAc 202 mg, 2.06 mmol
  • PdCl 2 dppf 55.9 mg, 0.076 mmol
  • 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) [00291] Prepared by General Method SMC using 5-chloro-N-(3-fluoro-4-iodopyridin- 2-yl)-2-methoxypyridine-3-sulfonamide (80 mg, 0.18 mmol), PdCl 2 dppf (13 mg, 0.018 mmol), Cs 2 CO 3 (176 mg, 0.54 mmol) in H 2 O (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
  • 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 [00292] 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 NH 4 Cl (220 mg, 4.1 mmol) was added as a solid.
  • Step 2 trans 4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)cyclohexane-1-carboxamide 4-aminocyclohexane-1- carboxamide*trifluoroacetic acid (168 mg, 0.66 mmol) and K 2 CO 3 (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.
  • 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
  • Step 2 cis-4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)cyclohexane-1-carboxamide
  • 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) [00297] 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
  • 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
  • Step 2 trans-4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)- N-methylcyclohexane-1-carboxamide
  • a DMF 5 mL
  • 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.
  • 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
  • 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
  • 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.
  • 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) [00303] 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
  • 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- [00304] 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.
  • DIPEA 0.14 mL, 0.79 mmol
  • 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, PdCl 2 dppf (11 mg, 0.016 mmol), Cs 2 CO 3 (154 mg, 0.47 mmol), (3-((5-chloro-2-methoxypyridine)-3-sulfon
  • 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-amino-N- 1- TFA [00306] 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 CH 2 Cl 2 (10 mL). DIPEA (0.29 mL, 1.6 mmol) was added and the reaction was shaken at rt for a few minutes before MeNH 2 (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.
  • 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-amino-N- 1-carboxamide,TFA [00312] 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 CH 2 Cl 2 (6 mL). DIPEA (0.198 mL, 1.134 mmol) was added and the reaction was shaken at rt for a few minutes before MeNH 2 (33 wt. % in EtOH, 0.21 mL, 1.7 mmol) was added in one portion at rt.
  • 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) [00319] 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.
  • 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) [00320] 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.
  • 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)) [00322] Step 1.
  • 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) [00327] 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
  • 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)) [00328] 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
  • 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.
  • 6-Bromo-8-methyl-2-((6-oxopiperidin-3-yl)amino)pyrido[2,3- d]pyrimidin-7(8H)-one A DMF (5 mL) suspension of K 2 CO 3 (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.
  • 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) [00347] Step 1.
  • Ethyl 4-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)piperidine-1-carboxylate [00348] A DMF (5 mL) suspension of K 2 CO 3 (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.
  • 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) [00369] 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 EtNH 2 (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 residue was dried under high vacuum.
  • 6-Bromo-8-(4-methoxybenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin- 7(8H)-one [00371] 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.
  • 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.
  • halofuginone an inhibitor of glutamyl-prolyl tRNA synthetase
  • borrelidin an inhibitor of threonyl-tRNA synthetase
  • L-asparaginase which activates GCN2 kinase activity by triggering the amino acid starvation response.
  • SKOV3 or U2OS cells are pretreated with exemplary GCN2 inhibitor compounds of the application (1 nM to 1 ⁇ M) for 1 hour, stimulated with borrelidin (10 ⁇ M) for 1 hour, then lysed and analyzed with the AlphaScreen SureFire kit, which utilizes an antibody based method to quantitatively detect phospho-eIF2 ⁇ in an HTS format.
  • 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.

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Abstract

La présente invention concerne des composés de pyrimidopyridone et de ptéridone de formule I, des procédés pour leur préparation et des compositions les comprenant. Plus particulièrement, la présente invention concerne un composé de formule I qui a une activité en tant qu'inhibiteurs de la kinase 2 non dépressible de régulation générale (GCN2) et leur utilisation dans le traitement de maladies, de troubles ou d'états pouvant être traités par inhibition de la kinase GCN2 telle que des cancers et des maladies neuronales.
PCT/CA2024/051124 2023-08-30 2024-08-29 Dérivés de pyrimidopyridone et de ptéridone utilisés en tant qu'inhibiteurs de kinase gcn2, compositions et utilisations associées Pending WO2025043349A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021165346A1 (fr) * 2020-02-17 2021-08-26 Black Belt Tx Ltd Composés modulateurs de gcn2
WO2022109001A1 (fr) * 2020-11-18 2022-05-27 Deciphera Pharmaceuticals, Llc Inhibiteurs des kinases gcn2 et perk et leurs méthodes d'utilisation
WO2023159322A1 (fr) * 2022-02-25 2023-08-31 Ontario Institute For Cancer Research (Oicr) Dérivés de quinazoline utilisés en tant qu'inhibiteurs de la gcn2 kinase, compositions et utilisations associées
WO2023218195A1 (fr) * 2022-05-11 2023-11-16 Ip2Ipo Innovations Limited Inhibiteur de gcn2
WO2023239165A1 (fr) * 2022-06-08 2023-12-14 한국화학연구원 Dérivés de phénylsulfonamide, leur procédé de préparation et composition pharmaceutique pour la prévention ou le traitement du cancer les contenant en tant que principe actif

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021165346A1 (fr) * 2020-02-17 2021-08-26 Black Belt Tx Ltd Composés modulateurs de gcn2
WO2022109001A1 (fr) * 2020-11-18 2022-05-27 Deciphera Pharmaceuticals, Llc Inhibiteurs des kinases gcn2 et perk et leurs méthodes d'utilisation
WO2023159322A1 (fr) * 2022-02-25 2023-08-31 Ontario Institute For Cancer Research (Oicr) Dérivés de quinazoline utilisés en tant qu'inhibiteurs de la gcn2 kinase, compositions et utilisations associées
WO2023218195A1 (fr) * 2022-05-11 2023-11-16 Ip2Ipo Innovations Limited Inhibiteur de gcn2
WO2023239165A1 (fr) * 2022-06-08 2023-12-14 한국화학연구원 Dérivés de phénylsulfonamide, leur procédé de préparation et composition pharmaceutique pour la prévention ou le traitement du cancer les contenant en tant que principe actif

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