WO2023159322A1

WO2023159322A1 - Quinazoline derivatives as inhibitors of the gcn2 kinase, compositions and uses thereof

Info

Publication number: WO2023159322A1
Application number: PCT/CA2023/050244
Authority: WO
Inventors: Rima AL-AWAR; Methvin Isaac; Radek LAUFER; David UEHLING; Brian Wilson; Robert Kenneth ROTTAPEL
Original assignee: Ontario Institute For Cancer Research (Oicr); University Health Network
Priority date: 2022-02-25
Filing date: 2023-02-27
Publication date: 2023-08-31

Abstract

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

Description

TITLE: QUINAZOLINE DERIVATIVES AS INHIBITORS OF THE GCN2 KINASE, COMPOSITIONS AND USES THEREOF RELATED APPLICATIONS [0001] The present application claims the benefit of priority of co-pending United States provisional patent application no.63/314,101 filed on February 25, 2022, the contents of which are incorporated herein by reference in their entirety. FIELD [0002] The present application relates to quinazoline compounds that have activity as inhibitors of the general control nonderepressible 2 (GCN2) kinase, to processes for their preparation, to compositions comprising them, and to their use, for example, in therapy. More particularly, the present application relates to compounds useful in the treatment of diseases, disorders or conditions treatable by inhibiting GCN2 kinase such as cancers and neuronal diseases. BACKGROUND [0003] The eukaryotic initiation factor 2α (eIF2α) kinase general control nonderepressible 2 (GCN2) drives cellular adaptation to amino acid limitation by activating the integrated stress response (ISR) that induces activating transcription factor 4 (ATF4). The GCN2 kinase mediated cellular adaptations to amino acid limitation occurs through the translational control of gene expression that is primarily executed by eIF2α phosphorylation. Utilizing quantitative phosphoproteomics, Dokladal et al. recently demonstrated that GCN2 targets auxiliary, physiologically relevant effectors, including eIF2β and Gcn20, to fine-tune translational control in response to amino acid starvation (Molecular Cell 2021; 81 (9), P1879-1889.e6). In addition to phosphorylating the eIF2-α subunit, GCN2 also phosphorylates the β-subunit of the trimeric eIF2 G protein complex to promote its association with eIF5 which in turn contributes to the inhibition of translation initiation. [0004] Under distinct stress conditions, cellular ISR is activated by four eukaryotic initiation factor 2 α (eIF2α) kinases: GCN2, protein kinase–like endoplasmic reticulum kinase (PERK), double-stranded RNA-dependent kinase (PRK), and heme-regulated inhibitor (HRK) [Nat Rev Mol Cell Biol 2016, 17:213–226]. These four eIF2α kinases commonly phosphorylate eIF2α at S51, thereby reducing general protein synthesis. However, specific mRNAs with an upstream open reading frame, such as activating transcription factor 4 (ATF4), are selectively translated by delaying translation re-initiation via eIF2α phosphorylation. ATF4 is a key transcription factor for stress adaptation and subsequently drives transcription of genes involved in processes, such as protein folding, amino acid metabolism, and autophagy [Nat Rev Mol Cell Biol 2019, 20:436–450]. [0005] Within tumors, cancer cells often undergo amino acid deprivation, partly because abnormal proliferation increases the need for amino acids to produce proteins, lipids, and nucleic acids, and partly because insufficient and disorganized formation of blood vessels leads to a supply shortage of amino acids. Thus, GCN2 can be important for cancer cell survival and tumor development. Moreover, knockout of GCN2 or ATF4 has been shown to decrease tumor growth in vivo [EMBO. J.2010, 29:2082–2096]. In addition, the GCN2 arm of the ISR has been shown to protect cancer cells from intrinsic stress induced by the c-Myc oncogene [Nat Cell Biol 2019, 21:1413–1424; Nat Cell Biol 2019, 21:889–899). GCN2 can also be involved in resistance to cancer chemotherapy because sensitization to the antitumor agent L-asparaginase (L-ASNase) is elicited by GCN2 inhibition in cancer cells that express asparagine synthetase (ASNS) at low levels [Proc Natl Acad Sci USA 2018, 115: E7776–E7785]. ASNS catalyzes the biosynthesis of asparagine (Asn) from aspartate and is highly responsive to cellular stress, in particular to intracellular amino acid depletion. ATF4 induces ASNS, [J Biol Chem. 2017;292(49):19952-19958] which in turn sustains Asn levels and suppresses apoptosis while intracellular depletion of Asn induces apoptosis. Thus, ASNS plays a role during tumor cell accumulation and progression by maintaining cell viability. Elevated ASNS protein expression is also associated with resistance to asparaginase therapy [J Biol Chem.2017;292(49):19952-19958]. Therefore, ASNS high tumors should be sensitive to inhibition of ASNS activity when combined with L-ASNase and GCN2 inhibition. This combination is a viable strategy to control the growth, proliferation, and migration of cancer cells, eliminate them, or enhance their sensitivity to existing chemotherapy drugs or radiotherapy. It has been suggested that the GCN2- mediated ISR pathway provides promising targets for cancer therapy. Hence, disruption of this pro-oncogenic stress-induced pathway by inhibiting GCN2 is thus an attractive therapeutic strategy. [0006] Another important therapeutic area in which ISR activation is implicated is neuronal disease or neuropathy [Science 2021, 373, 1161–1166]. Dominant mutations in ubiquitously expressed transfer RNA (tRNA) synthetase genes cause axonal peripheral neuropathy, accounting for at least six forms of Charcot-Marie-Tooth (CMT) disease. Genetic evidence in mouse and Drosophila models suggests a gain-of-function mechanism. It has been shown that mutant tRNA synthetases activate the integrated stress response (ISR) through the sensor kinase GCN2 (general control nonderepressible 2). 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]. [0007] Recently, the small molecule inhibitors of GCN2 kinase have been described (WO2021165346, Black Belt TX LTD). There remains a need to provide potent GCN2 kinase inhibitors for the treatment of, for example, cancers and peripheral neuropathy. Also, there is a need to provide GCN2 kinase inhibitors with selectivity over other kinases. SUMMARY [0008] The Applicants have developed novel inhibitors of general control nonderepressible 2 (GCN2) kinase. [0009] Accordingly, the present invention includes a compound of Formula I, or a pharmaceutically acceptable salt, solvate and/or prodrug thereof: (I) wherein R¹ is selected from C_3-10cycloalkyl substituted with one or two R⁹, C_3-10heteroycloalkyl substituted with one or two R¹⁰, C_1-6alkyleneC_3-10cycloalkyl optionally substituted with one or two R¹¹, and C_1-6alkyleneC_3-10heterocycloalkyl optionally substituted with one or two R¹²; R² and R³ are independently selected from H, halo, CN and C_1-6alkyl; R⁴, R⁵ and R⁶ are independently selected from H, halo, CN and C_1-6alkyl; R⁷ is selected from H, C_1-6alkyl and OC_1-6alkyl, the latter two groups being optionally substituted with one or more substituents selected from OH and halo; R⁸ is selected from H, halo, CN, C_1-6alkyl and OC_1-6alkyl, the latter two groups being optionally substituted with one or more substituents selected from OH and halo; each R⁹ is independently selected from NR¹³R¹⁴, C_1-6alkyleneNR¹³R¹⁴, C_1-6alkyl, C_2- ₆alkenyl, C_2-6alkynyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, the latter two groups being optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1- ₆alkyl; each R¹⁰ is independently selected from NR¹⁵R¹⁶, C_1-6alkyleneNR¹⁵R¹⁶, C_1-6alkyl, C_2- ₆alkenyl, C_2-6alkynyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, the latter two groups being optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1- ₆alkyl; each R¹¹ is independently selected from OH, NR¹⁷R¹⁸, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, wherein all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR¹⁹, NR¹⁹R²⁰ and C_1-6alkyl; each R¹² is independently selected from OH, NR²¹R²², C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, wherein all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR²³, NR²³R²⁴ and C_1-6alkyl; R^13, R¹⁵, R¹⁷ and R²¹ are independently selected from H, C_1-6alkyl, C_3-10cycloalkyl and C_3- ₁₀heterocycloalkyl, the latter three groups being optionally substituted with one or two substituents selected from halo, OH and OC_1-6alkyl; R¹⁴, R¹⁶, R¹⁸, R¹⁹, R²⁰, R²², R²³ and R²⁴ are independently selected from H and C_1-6alkyl; and X is CH or N. [0010] The present application also includes a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier. [0011] 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. [0012] 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. [0013] 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 a disease, disorder or condition treatable by inhibiting GCN2 to a subject in need thereof [0014] In some embodiments the disease, disorder or condition that is treatable by inhibiting GCN2, is cancer and the one or more compounds of the application are administered or used in combination with one or more additional cancer treatments. such as radiotherapy, chemotherapy (e.g. cisplatin), targeted therapies such as antibody therapies (including anti-PD1 and/or anti-PD-L1 antibodies) and small molecule therapies such as tyrosine-kinase inhibitors therapies, glutaminase inhibitors (e.g., glutaminase-1 (GLS1) inhibitors), and asparagine synthetase (ASNS) inhibitors, immunotherapy, hormonal therapy and anti-angiogenic therapies. [0015] In some embodiments, the disease, disorder or condition that is treatable by inhibiting GCN2, is cancer and/or a peripheral neuropathy including Charcot-Marie-Tooth (CMT) peripheral neuropathy. [0016] The present application also includes a method of improving the efficacy of one or more additional cancer treatments for treating cancer comprising administering an effective amount of one or more compounds of the application or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with an effective amount of the one or more additional cancer treatments. [0017] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the application, are given by way of illustration only and the scope of the claims should not be limited by these embodiments but should be given the broadest interpretation consistent with the description as a whole. DETAILED DESCRIPTION I. Definitions [0018] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the present application herein described for which they are suitable as would be understood by a person skilled in the art. [0019] All features disclosed in the specification, including the claims, abstract, and drawings, and all the steps in any method or process disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. Each feature disclosed in the specification, including the claims, abstract, and drawings, can be replaced by alternative features serving the same, equivalent, or similar purpose, unless expressly stated otherwise [0020] The term “compound of the application” or “compound of the present application” and the like as used herein refers to a compound of Formula I, including pharmaceutically acceptable salts, solvates and/or prodrugs thereof. [0021] The term “composition of the application” or “composition of the present application” and the like as used herein refers to a composition comprising one or more compounds the application and at least one additional ingredient. [0022] The term “and/or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of” or “one or more” of the listed items is used or present. The term “and/or” with respect to pharmaceutically acceptable salts and/or solvates thereof means that the compounds of the application exist as individual salts and hydrates, as well as a combination of, for example, a solvate of a salt of a compound of the application. [0023] As used in the present application, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise. For example, an embodiment including “a compound” should be understood to present certain aspects with one compound, or two or more additional compounds. [0024] In embodiments comprising an “additional” or “second” component, such as an additional or second compound, the second component as used herein is chemically different from the other components or first component. A “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly different. [0025] As used herein, the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process/method steps. [0026] As used herein, the word “consisting” and its derivatives, are intended to be close ended terms that specify the presence of stated features, elements, components, groups, integers, and/or steps, and also exclude the presence of other unstated features, elements, components, groups, integers and/or steps. [0027] 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. [0028] Terms of degree such as “substantially”, “about” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ^5% of the modified term if this deviation would not negate the meaning of the word it modifies. [0029] The term “suitable” as used herein means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, the identity of the molecule(s) to be transformed and/or the specific use for the compound, but the selection would be well within the skill of a person trained in the art. All process/method steps described herein are to be conducted under conditions sufficient to provide the product shown. A person skilled in the art would understand that all 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. [0030] 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. [0031] The term “protecting group” or “PG” and the like as used herein refers to a chemical moiety which protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule. The selection of a suitable protecting group can be made by a person skilled in the art. Many conventional protecting groups are known in the art, for example as described in “Protective Groups in Organic Chemistry” McOmie, J.F.W. Ed., Plenum Press, 1973, in Greene, T.W. and Wuts, P.G.M., “Protective Groups in Organic Synthesis”, John Wiley & Sons, 3^rd Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas). [0032] The term “cell” as used herein refers to a single cell or a plurality of cells and includes a cell either in a cell culture or in a subject. [0033] The term “subject” as used herein includes all members of the animal kingdom including mammals. Thus, the methods and uses of the present application are applicable to both human therapy and veterinary applications. [0034] The term “pharmaceutically acceptable” means compatible with the treatment of subjects. [0035] The term “pharmaceutically acceptable carrier” means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with an active ingredient (for example, one or more compounds of the application) to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to a subject. [0036] The term “pharmaceutically acceptable salt” means either an acid addition salt or a base addition salt which is suitable for, or compatible with the treatment of subjects. [0037] 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. [0038] 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. [0039] The term “prodrug” as used herein means a compound, or salt and/or solvate of a compound, that, after administration, is converted into an active drug. [0040] The term “solvate” as used herein means a compound, or a salt or prodrug of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice. [0041] The term “inert organic solvent” as used herein refers to a solvent that is generally considered as non-reactive with the functional groups that are present in the compounds to be combined together in any given reaction so that it does not interfere with or inhibit the desired synthetic transformation. Organic solvents are typically non-polar and dissolve compounds that are nonsoluble in aqueous solutions. [0042] The term “alkyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “C_n1-n2”. For example, the term C_1-10alkyl means an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. [0043] The term “alkylene”, whether it is used alone or as part of another group, means straight or branched chain, saturated alkylene group, that is, a saturated carbon chain that contains substituents on two of its ends. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “C_n1-n2”. For example, the term C_1- ₁₀alkylene means an alkylene group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. All alkyl groups are optionally fluorosubstituted unless otherwise indicated. [0044] The term “alkenyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkyl groups containing at least one double bond. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “C_n1-n2”. For example, the term C_2-6alkenyl means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms and at least one double bond. [0045] The term “alkynyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkynyl groups containing at least one triple bond. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “C_n1-n2”. For example, the term C_2-6alkynyl means an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms. [0046] The term “cycloalkyl,” as used herein, whether it is used alone or as part of another group, means a saturated carbocyclic group containing from 3 to 20 carbon atoms and one or more rings. The number of carbon atoms that are possible in the referenced cycloalkyl group are indicated by the numerical prefix “C_n1-n2”. For example, the term C_3-10cycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. [0047] The term “heterocycloalkyl” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing at least one non-aromatic ring containing from 3 to 10 atoms in which one or more of the atoms are a heteromoiety selected from O, S, S(O), SO₂, N, NH and N(C_1-6alkyl), and the remaining atoms are C. Heterocycloalkyl groups are either saturated or unsaturated (i.e. contain one or more double bonds). When a heterocycloalkyl group contains the prefix C_n1-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. [0048] All cyclic groups, including aryl, heteroaryl, heterocyclo and cycloalkyl groups, contain one (i.e. are monocyclic) or more than one ring (i.e. are polycyclic). When a cyclic group contains more than one ring, the rings may be fused, bridged or spirofused. [0049] The term “benzofused” as used herein refers to a polycyclic group in which a benzene ring is fused with another ring. [0050] A first ring being “fused” with a second ring means the first ring and the second ring share two adjacent atoms there between. [0051] A first ring being “bridged” with a second ring means the first ring and the second ring share two non-adjacent atoms there between. [0052] A first ring being “spirofused” with a second ring means the first ring and the second ring share one atom there between. [0053] The terms “halo” or “halogen” as used herein, whether it is used alone or as part of another group, refers to a halogen atom and includes fluoro, chloro, bromo and iodo. [0054] The term “available”, as in “available hydrogen atoms” or “available atoms” refers to atoms that would be known to a person skilled in the art to be capable of replacement by another atom or group. [0055] The term “optionally substituted” as used herein means that the referenced group is unsubstituted or substituted. [0056] 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. [0057] The symbol when drawn perpendicularly across a bond indicates a point of covalent attachment of a chemical group [0058] . [0059] The term “LCMS” as used herein refers to liquid chromatography-mass spectrometry. [0060] The term “NMR” as used herein refers to nuclear magnetic resonance. [0061] The term “aq.” as used herein refers to aqueous. [0062] The term “N” as used herein, for example in “4N”, refers to the unit symbol of normality to denote "eq/L". [0063] The term “M” as used herein, for example in 4M, refers to the unit symbol of molarity to denote "moles/L". [0064] The term “DIPEA” as used herein refers to N,N-diisopropyl ethylamine. [0065] The term “DMF” as used herein refers to dimethylformamide. [0066] The term “THF” as used herein refers to tetrahydrofuran. [0067] The term “DMSO” as used herein refers to dimethylsulfoxide. [0068] The term “EtOAc” as used herein refers to ethyl acetate. [0069] The term “MeOH” as used herein refers to methanol. [0070] The term “EtOH” as used herein refers to ethanol. [0071] The term “MeCN” or “ACN” as used herein refers to acetonitrile. [0072] The term “HCl” as used herein refers to hydrochloric acid. [0073] The term “TFA” as used herein refers to trifluoroacetic acid. [0074] The term “Hex” as used herein refers to hexanes. [0075] The term “PBS” as used herein refers to phosphate-based buffer. [0076] The term “IPA” as used herein refers to isopropyl alcohol. [0077] The term “dppf” as used herein refers to 1,1'-bis(diphenylphosphino)ferrocene. [0078] The term “RT” as used herein refers to room temperature. [0079] The term “HPLC” as used herein refers to high-performance liquid chromatography. [0080] The term “PPA” as used herein refers to polyphosphoric acid. [0081] The term “TEA” or “Et3N” as used herein refer to triethylamine. [0082] The term “EDTA” as used herein refers to ethylenediaminetetraacetic acid. [0083] The term “ATP” as used herein refers to adenosine triphosphate. [0084] The term “FBS” as used herein refers to fetal bovine serum. [0085] The term “MEM” as used herein refers to Minimum Essential Medium. [0086] The term “treating” or “treatment” as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of a disease, disorder or condition, stabilized (i.e. not worsening) state of a disease, disorder or condition, preventing spread of a disease, disorder or condition, delay or slowing of a disease, disorder or condition progression, amelioration or palliation of a disease, disorder or condition state diminishment of the reoccurrence of a disease disorder or condition and remission (whether partial or total), whether detectable or undetectable. “Treating” and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. “Treating” and “treatment” as used herein also include prophylactic treatment. [0087] “Palliating” a disease, disorder or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to not treating the disease, disorder or condition. [0088] The term “prevention” or “prophylaxis”, or synonym thereto, as used herein refers to a reduction in the risk or probability of a subject becoming afflicted with a disease, disorder or condition treatable by inhibition of GCN2 or manifesting a symptom associated with a disease, disorder or condition treatable by inhibition of GCN2. [0089] As used herein, the term “effective amount” or “therapeutically effective amount” means an amount of a compound, or one or more compounds, of the application that is effective, at dosages and for periods of time necessary to achieve the desired result. [0090] The term “disease, disorder or condition treatable by inhibiting GCN2” means that the disease, disorder or condition to be treated is affected by, modulated by and/or has some biological basis, either direct or indirect, that includes GCN2 activity, in particular, increased GCN2 activity. These diseases respond favourably when GCN2 activity associated with the disease, disorder or condition is inhibited by one or more of the compounds or compositions of the application. [0091] The expression “inhibiting GCN2” as used herein refers to inhibiting, blocking and/or disrupting the kinase activity or function of GCN2 in a cell. The inhibiting, blocking and/or disrupting causes a therapeutic effect in the cell. [0092] By “inhibiting, blocking and/or disrupting” it is meant any detectable inhibition, block and/or disruption in the presence of a compound compared to otherwise the same conditions, except for in the absence in the compound. [0093] The term “GCN2” as used herein refers to General Control Nonderepressible 2, or any functional mutant or analogous forms thereof. [0094] The expression “low asparagine synthetase (ASNS) expression” as used herein means any detectable decrease or reduction in the level of asparagine synthetase (ASNS) in a cancer cell, under otherwise the same conditions, except in a healthy cell. [0095] The expression “asparagine synthetase (ASNS) overexpression or dysregulation” as used herein means any detectable increase in the level of asparagine synthetase (ASNS) in a cancer cell, under otherwise the same conditions, except in a healthy cell. [0096] The expression “low glutaminase expression” as used herein means any detectable decrease or reduction in the level of glutaminase (e.g., GLS1) in a cancer cell, under otherwise the same conditions, except in a healthy cell. [0097] The expression “glutaminase overexpression or dysregulation” as used herein means any detectable increase in the level of glutaminase (e.g., GLS1) in a cancer cell, under otherwise the same conditions, except in a healthy cell. [0098] The term “GLS1” as used herein refers to the “kidney type” glutaminase or any functional mutant or analogous forms thereof. [0099] The term “administered” as used herein means administration of a therapeutically effective amount of a compound, or one or more compounds, or a composition of the application to a cell or a subject. [00100] The term “neoplastic disorder” as used herein refers to a disease, disorder or condition characterized by cells that have the capacity for autonomous growth or replication, e.g., an abnormal state or condition characterized by proliferative cell growth. The term “neoplasm” as used herein refers to a mass of tissue resulting from the abnormal growth and/or division of cells in a subject having a neoplastic disorder. Neoplasms can be benign (such as uterine fibroids and melanocytic nevi), potentially malignant (such as carcinoma in situ) or malignant (i.e., cancer). [00101] The term “fibrosis” as used herein refers to a disease, disorder or condition the thickening and scarring of connective tissue, usually as a result of injury. II. Compounds of the Application [00102] Quinazoline compounds of the present application were prepared and found to inhibit kinase general control nonderepressible 2 (GCN2). The compounds of the application were surprisingly found to exhibit significantly improved human microsomal metabolic stability and solubility properties compared to known quinazoline compounds in the art. [00103] Accordingly, the present application includes a compound of Formula I, or a pharmaceutically acceptable salt, solvate and/or prodrug thereof: (I) wherein R¹ is selected from C_3-10cycloalkyl substituted with one or two R⁹, C_3-10heteroycloalkyl substituted with one or two R¹⁰, C_1-6alkyleneC_3-10cycloalkyl optionally substituted with one or two R¹¹, and C_1-6alkyleneC_3-10heterocycloalkyl optionally substituted with one or two R¹²; R² and R³ are independently selected from H, halo, CN and C_1-6alkyl; R⁴, R⁵ and R⁶ are independently selected from H, halo, CN and C_1-6alkyl; R⁷ is selected from H, C_1-6alkyl and OC_1-6alkyl, the latter two groups being optionally substituted with one or more substituents selected from OH and halo; R⁸ is selected from H, halo, CN, C_1-6alkyl and OC_1-6alkyl, the latter two groups being optionally substituted with one or more substituents selected from OH and halo; each R⁹ is independently selected from NR¹³R¹⁴, C_1-6alkyleneNR¹³R¹⁴, C_1-6alkyl, C_2- ₆alkenyl, C_2-6alkynyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, the latter two groups being optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1- ₆alkyl; each R¹⁰ is independently selected from NR¹⁵R¹⁶, C_1-6alkyleneNR¹⁵R¹⁶, C_1-6alkyl, C_2- ₆alkenyl, C_2-6alkynyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, the latter two groups being optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1- ₆alkyl; each R¹¹ is independently selected from OH, NR¹⁷R¹⁸, C_1-6alkyl, C_2-6alkenyl, C_2-6alkyny, C_3- ₁₀cycloalkyl and C_3-10heterocycloalkyl, wherein all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR¹⁹, NR¹⁹R²⁰ and C_1-6alkyl; each R¹² is independently selected from OH, NR²¹R²², C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, wherein all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR²³, NR²³R²⁴ and C_1-6alkyl; R¹³ _, R¹⁵, R¹⁷ and R²¹ are independently selected from H, C_1-6alkyl, C_3-10cycloalkyl and C_3- ₁₀heterocycloalkyl, the latter three groups being optionally substituted with one or two substituents selected from halo, OH and OC_1-6alkyl; R¹⁴, R¹⁶, R¹⁸, R¹⁹, R²⁰, R²², R²³ and R²⁴ are independently selected from H and C_1-6alkyl; and X is CH or N. [00104] In some embodiments, R¹ is selected from C_3-10cycloalkyl substituted with one or two R⁹, C_3-10heteroycloalkyl substituted with one or two R¹⁰, C_1-4alkyleneC₃- ₁₀cycloalkyl optionally substituted with one or two R¹¹, and C_1-4alkyleneC₃- ₁₀heterocycloalkyl optionally substituted with one or two R¹². [00105] In some embodiments, R¹ is C_3-10cycloalkyl substituted with one or two R⁹. In some embodiments, R¹ is a monocyclic C_3-10cycloalkyl or a bicyclic C_5-10cycloalkyl, each of which is substituted with one or two R⁹. [00106] In some embodiments, R¹ is a monocyclic C_3-10cycloalkyl or a bicyclic C_5- ₁₀cycloalkyl, each of which is substituted with one or two R⁹. In some embodiments, R¹ is monocyclic C_{3- 8}cycloalkyl substituted with one or two R⁹. In some embodiments, the monocyclic C_{3- 8}cycloalkyl in R¹ is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each of which is substituted with one or two R⁹. In some embodiments, R¹ is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each of which is substituted with one R⁹. In some embodiments, R¹ is cyclohexyl substituted with one or two R⁹. In some embodiments, R¹ is cyclohexyl substituted with one R⁹. [00107] In some embodiments, R¹ is a bicyclic C_5-10cycloalkyl substituted with one or two R⁹. In some embodiments, R¹ is a spirofused C_5-10cycloalkyl or a bridged C_5- ₁₀cycloalkyl each of which is substituted with one or two R⁹. Therefore, in some embodiments, R¹ is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spirofused C_5-10cycloalkyl and bridged C_5-10cycloalkyl, each of which is substituted with one or two R⁹. [00108] In some embodiments, the spirofused C_5-10cycloalkyl is selected from spiro[3.3]heptane, spiro[4.4]nonane, spiro[5.4]decane, spiro[4.5]octane and spiro[5.2]octane each of which is substituted with one or two R⁹. In some embodiment, the spirofused C_6-10cycloalkyl is spiro[3.3]heptane substituted with one or two R⁹. In some embodiments, the spirofused C_5-10cycloalkyl is . [00109] In some embodiments, R¹ is a bridged C_5-10cycloalkyl substituted with one or two R⁹. In some embodiments, the bridged C_5-10cycloalkyl is selected from a bicyclopentanyl, a bicycloheptanyl and a bicyclooctanyl each of which substituted with one or two R⁹. In some embodiments, the bridged C_5-10cycloalkyl is selected from a bicyclopentanyl, a bicycloheptanyl and a bicyclooctanyl each of which is substituted with one R⁹. In some embodiments, the bridged C_5-10cycloalkyl is selected from , , and . [00110] In some embodiments, each R⁹ is independently selected from NR¹³R¹⁴, C_1- ₄alkyleneNR¹³R¹⁴, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-10cycloalkyl and C_3- ₁₀heterocycloalkyl, the latter two groups being optionally substituted with one or two substituents selected from halo, C_1-4alkyl and OC_1-4alkyl. In some embodiments, each R⁹ is independently selected from NR¹³R¹⁴, C_1-4alkyleneNR¹³R¹⁴, C_1-4alkyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, the latter two groups being optionally substituted with one or two substituents selected from halo, C_1-4alkyl and OC_1-4alkyl. [00111] In some embodiments, each R⁹ is independently selected from NR¹³R¹⁴, C_1- ₄alkyleneNR¹³R¹⁴, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-10cycloalkyl and C_3- ₁₀heterocycloalkyl, the latter two groups being optionally substituted with C_1-4alkyl. In some embodiments, each R⁹ is independently selected from NR¹³R¹⁴, C_1-4alkyleneNR¹³R¹⁴, C_1- ₄alkyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, the latter two groups being optionally substituted with C_1-4alkyl. [00112] In some embodiments, each R⁹ is independently selected from NR¹³R¹⁴, C_1- ₄alkyleneNR¹³R¹⁴ and C_3-10heterocycloalkyl, the latter group being optionally substituted with one or two substituents selected from halo, C_1-4alkyl and OC_1-4alkyl. Therefore, in some embodiments R¹ is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spirofused C_5-10cycloalkyl and bridged C_5-10cycloalkyl, each of which is substituted with one R⁹ and R⁹ is selected from NR¹³R¹⁴, C_1-4alkyleneNR¹³R¹⁴ and C_3- ₁₀heterocycloalkyl the latter group being optionally substituted with one or two substituents selected from halo, C_1-4alkyl and OC_1-4alkyl. [00113] In some embodiments, each R⁹ is independently selected from NR¹³R¹⁴, C_1- ₄alkyleneNR¹³R¹⁴ and C_3-10heterocycloalkyl, the latter group being optionally substituted with C_1-6alkyl. Therefore, in some embodiments R¹ is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spirofused C_5-10cycloalkyl and bridged C_5- ₁₀cycloalkyl, each of which is substituted with one R⁹ and R⁹ is selected from NR¹³R¹⁴, C_1- ₄alkyleneNR¹³R¹⁴ and C_3-10heterocycloalkyl the latter group being optionally substituted with C_1-6alkyl. [00114] In some embodiments, each R⁹ is independently selected from NR¹³R¹⁴ and C_1-4alkyleneNR¹³R¹⁴. In some embodiments, each R⁹ is independently selected from NR¹³R¹⁴, CH₂NR¹³R¹⁴ and CH₂CH₂NR¹³R¹⁴. In some embodiments, each R⁹ is independently NR¹³R¹⁴. In some embodiments, R⁹ is independently selected from CH₂NR¹³R¹⁴ and CH₂CH₂NR¹³R¹⁴. [00115] In some embodiments, R¹³ is selected from H, C_1-4alkyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, the latter three groups being optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. In some embodiments, R¹³ is independently selected from H, C_1-4alkyl, C_3-6cycloalkyl and C_4-6heterocycloalkyl, the latter three groups being optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. [00116] In some embodiments, R¹³ is selected from H and C_1-4alkyl optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. [00117] In some embodiments, R¹³ is C_1-4alkyl optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. In some embodiments, R¹³ is C_1-4alkyl optionally substituted with one OC_1-4alkyl. In some embodiments, R¹³ isC_1-3alkyl optionally substituted with one OC_1-3alkyl. [00118] In some embodiments, R¹³ is selected from H and C_1-4alkyl. In some embodiments, R¹³ is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, R¹³ is selected from H, CH₃, CH₂CH₃ and CH(CH₃)₂. In some embodiments, R¹³ is selected from H and CH₃. In some embodiments, R¹³ is CH₃. [00119] In some embodiments, R¹³ is C_4-6heterocycloalkyl optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. In some embodiments, the C_4- ₆heterocycloalkyl in R¹³ is selected from oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. In some embodiments, the C_4-6heterocycloalkyl in R¹³ is oxetanyl optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. [00120] In some embodiments, R¹⁴ is selected from H and C_1-4alkyl. In some embodiments, R¹⁴ is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, R¹⁴ is selected from H, CH₃, CH₂CH₃ and CH(CH₃)₂. In some embodiments, R¹⁴ is selected from H and CH₃. In some embodiments, R¹⁴ is CH₃. [00121] In some embodiments, R¹³ and R¹⁴ are independently selected from H and C_1-4alkyl. In some embodiments, R¹³ and R¹⁴ are independently selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, R¹³ and R¹⁴ are independently selected from H, CH₃, CH₂CH₃ and CH(CH₃)₂. [00122] In some embodiments, R¹³ and R¹⁴ are both CH₃ or R¹³ and R¹⁴ are both CH₂CH₃. In some embodiments, R¹³ and R¹⁴ are independently selected from H and CH₃. In some embodiments, R¹³ and R¹⁴ are both CH₃.In some embodiments, one of R¹³ and R¹⁴ is H and the other is CH₃ or CH₂CH₃ or CH(CH₃)₂. In some embodiments, one of R¹³ and R¹⁴ is CH₃ and the other is CH₂CH₃ or CH(CH₃)₂. [00123] In some embodiments, each R⁹ is independently C_3-10heterocycloalkyl optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1- ₆alkyl. In some embodiments, each R⁹ is independently C_3-6heterocycloalkyl optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1-6alkyl. In some embodiments, each R⁹ is independently C_3-6heterocycloalkyl including 1 to 2 ring heteromoieties selected from O, S, N, NH and N(C_1-6alkyl), and optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1-6alkyl. In some embodiments, each R⁹ is independently selected from aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl oxepanyl and thiepanyl, each of which is optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1-6alkyl. In some embodiments, each R⁹ is independently selected from thietanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, each of which is optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1-6alkyl. In some embodiments, each R⁹ is independently a C₃-₆heterocycloalkyl including at least one ring heteromoiety selected from NH and N(C_1-4alkyl) and optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1-6alkyl. In some embodiments, each R⁹ is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or two substituents selected from F, Cl, C_1-4alkyl and OC_1-4alkyl. In some embodiments, each R⁹ is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is each of which is optionally substituted with one or two substituents selected from F, Cl, CH₃ and OCH₃. In some embodiments, each R⁹ is independently selected from pyrrolidinyl and morpholinyl, each of which is each of which is optionally substituted with one or two substituents selected from F, Cl, CH₃ and OCH₃. [00124] In some embodiments, each R⁹ is independently C_3-10heterocycloalkyl optionally substituted with C_1-6alkyl. In some embodiments, each R⁹ is independently C_3- 6heterocycloalkyl optionally substituted with C_1-6alkyl. In some embodiments, each R⁹ is independently C_3-6heterocycloalkyl including 1 to 2 ring heteromoieties selected from O, S, N, NH and N(C_1-6alkyl), and optionally substituted with C_1-6alkyl. In some embodiments, each R⁹ is independently C_3-6heterocycloalkyl including 1 to 2 ring heteromoieties selected from O, S, NH and N(C_1-4alkyl), and optionally substituted with C_1-6alkyl. In some embodiments, each R⁹ is independently selected from aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl oxepanyl and thiepanyl, each of which is optionally substituted with C_1-6alkyl. In some embodiments, each R⁹ is independently selected from thietanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, each of which is optionally substituted with C_1-6alkyl. In some embodiments, each R⁹ is independently a C_3-6heterocycloalkyl including at least one ring heteromoiety selected from NH and N(C_1-4alkyl) optionally substituted with C_1-6alkyl. In some embodiments, each R⁹ is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with C_1-4alkyl. In some embodiments, each R⁹ is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with CH₃. [00125] In some embodiments, each R⁹ is independently selected from C_1-4alkyl, C_2- ₄alkenyl and C_2-4alkynyl. In some embodiments, each R⁹ is independently C_1-4alkyl. In some embodiments, each R⁹ is independently selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, each R⁹ is independently selected from CH₃, CH₂CH₃ and CH(CH₃)₂. [00126] In some embodiments, each R⁹ is independently C_3-10cycloalkyl optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1-6alkyl. In some embodiments, each R⁹ is independently C_3-8cycloalkyl optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1-6alkyl. In some embodiments, each R⁹ is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl each of which is optionally substituted with one or two substituents selected from F, Cl, C_1-4alkyl and OC_1-4alkyl. [00127] In some embodiments, each R⁹ is independently C_3-10cycloalkyl optionally substituted with C_1-6alkyl. In some embodiments, each R⁹ is independently C_{3- 8}cycloalkyl optionally substituted with C_1-6alkyl. In some embodiments, each R⁹ is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl each of which is optionally substituted with C_1-6alkyl. [00128] In some embodiments, R¹ is C_3-10heterocycloalkyl substituted with one or two R¹⁰. [00129] In some embodiments, R¹ is selected from a monocyclic C_3- ₁₀heterocycloalkyl or bicyclic C_5-10heterocycloalkyl substituted with one or two R¹⁰. In some embodiments, R¹ is monocyclic C_{3- 8}heterocycloalkyl substituted with one or two R¹⁰. In some embodiments, the monocyclic C_{3- 8}heterocycloalkyl in R¹ is selected from aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl oxepanyl and thiepanyl, each of which is substituted with one or two R¹⁰. In some embodiments, R¹ is a C_3-6heterocycloalkyl including at least one ring heteromoiety selected from NH and N(C_1-6alkyl), and substituted with one or two R¹⁰. In some embodiments, R¹ is selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is substituted with one R¹⁰. In some embodiments, R¹ is selected from azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl, each of which is substituted with one R¹⁰. [00130] In some embodiments, R¹ is a bicyclic C_5-10heterocycloalkyl substituted with one or two R¹⁰. In some embodiments, the bicyclic C_5-10heterocycloalkyl is a spirofused C_5- ₁₀heterocycloalkyl, a fused C_5-10heterocycloalkyl or a bridged C₅-₁₀heterocycloalkyl each of which is substituted with one or two R¹⁰. [00131] In some embodiments, the spirofused C_5-10heterocycloalkyl is selected from an azaspiro[4.4]nonane, an azaspiro[3.5]nonane, an azaspiro[5.4]decane and an azaspiro[5.2]octane each of which is substituted with one or two R¹⁰. In some embodiments, the spirofused C_5-10heterocycloalkyl is an azaspiro[3.5]nonane substituted with one or two R¹⁰. In some embodiments, the spirofused C_5-10heterocycloalkyl is . [00132] In some embodiments, the fused C_5-10heterocycloalkyl is selected from an octahydroindolyl, an octahydroisoindolyl, a decahydroquinolyl and a decahydroisoquinolyl each of which is substituted with one or two R¹⁰. In some embodiments, the fused C_5- ₁₀heterocycloalkyl is selected from . [00133] In some embodiments, R¹ is a bridged C_5-10heterocycloalkyl substituted with one or two R¹⁰. In some embodiments, the bridged C_5-10heterocycloalkyl is selected from an azabicyclohexanyl, an azabicycloheptanyl a diazabicycloheptanyl, an azabicyclooctany or a diazabicyclooctanyl each of which is substituted with one or two R¹⁰. [00134] In some embodiments, each R¹⁰ is independently selected from NR¹⁵R¹⁶, C_1- ₄alkyleneNR¹⁵R¹⁶, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-10cycloalkyl and C_3- ₁₀heterocycloalkyl, the latter two groups being optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1-6alkyl. In some embodiments, each R¹⁰ is independently selected from NR¹⁵R¹⁶, C_1-4alkyleneNR¹⁵R¹⁶, C_1-4alkyl, C_2-4alkenyl, C_2- ₄alkynyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, the latter two groups being optionally substituted with C_1-4alkyl. [00135] In some embodiments, each R¹⁰ is independently selected from NR¹⁵R¹⁶, C_1- ₄alkyleneNR¹⁵R¹⁶ and C_3-10heterocycloalkyl, the latter group being optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1-6alkyl. In some embodiments, each R¹⁰ is independently selected from NR¹⁵R¹⁶ _, C_1-4alkyleneNR¹⁵R¹⁶ and C_3-10heterocycloalkyl, the latter group being optionally substituted with C_1-4alkyl. [00136] In some embodiments, each R¹⁰ is independently selected from NR¹⁵R¹⁶ and C_1-4alkyleneNR¹⁵R¹⁶. In some embodiments, each R¹⁰ is independently selected from NR¹⁵R¹⁶, CH₂NR¹⁵R¹⁶ and CH₂CH₂NR¹⁵R¹⁶. In some embodiments, each R¹⁰ is independently NR¹⁵R¹⁶. In some embodiments, each R¹⁰ is independently selected from CH₂NR¹⁵R¹⁶ and CH₂CH₂NR¹⁵R¹⁶. [00137] In some embodiments, R¹⁵ is selected from H, C_1-4alkyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, the latter three groups being optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. In some embodiments, R¹⁵ is independently selected from H, C_1-4alkyl, C_3-6cycloalkyl and C_4-6heterocycloalkyl, the latter three groups being optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. [00138] In some embodiments, R¹⁵ is selected from H and C_1-4alkyl optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. [00139] In some embodiments, R¹⁵ is C_1-4alkyl optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. In some embodiments, R¹⁵ is C_1-4alkyl optionally substituted with one OC_1-4alkyl. In some embodiments, R¹⁵ is C_1-3alkyl optionally substituted with one OC_1-3alkyl. [00140] In some embodiments, R¹⁵ is selected from H and C_1-4alkyl. In some embodiments, R¹⁵ is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, R¹⁵ is selected from H, CH₃, CH₂CH₃ and CH(CH₃)₂. In some embodiments, R¹⁵ is selected from H and CH₃. In some embodiments, R¹⁵ is CH₃. [00141] In some embodiments, R¹⁵ is C_4-6heterocycloalkyl optionally substituted with one or two substituents independently selected from OH and OC_1-4alkyl. In some embodiments, the C_4-6heterocycloalkyl in R¹⁵ is selected from oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. [00142] In some embodiments, R¹⁶ is selected from H and C_1-4alkyl. In some embodiments, R¹⁶ is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, R¹⁶ is selected from H, CH₃, CH₂CH₃ and CH(CH₃)₂. In some embodiments, R¹⁶ is selected from H and CH₃. In some embodiments, R¹⁶ is CH₃. [00143] In some embodiments, R¹⁵ and R¹⁶ are independently selected from H and C_1-4alkyl. In some embodiments, R¹⁵ and R¹⁶ are independently selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, R¹⁵ and R¹⁶ are independently selected from H, CH₃, CH₂CH₃ and CH(CH₃)₂. In some embodiments, R¹⁵ and R¹⁶ are both CH₃ or R¹⁵ and R¹⁶ are both CH₂CH₃. In some embodiments, R¹⁵ and R¹⁶ are both CH_3. In some embodiments, R¹⁵ and R¹⁶ are independently selected from H and CH₃. In some embodiments, one of R¹⁵ and R¹⁶ is H and the other is CH₃ or CH₂CH₃ or CH(CH₃)₂. In some embodiments, one of R¹⁵ and R¹⁶ is CH₃ and the other is CH₂CH₃ or CH(CH₃)₂. [00144] In some embodiments, each R¹⁰ is independently C_3-10heterocycloalkyl optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1- ₆alkyl. In some embodiments, each R¹⁰ is independently C_3-6heterocycloalkyl optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1-6alkyl. In some embodiments, each R¹⁰ is independently C_3-6heterocycloalkyl including 1 to 2 ring heteromoieties selected from O, S, N, NH and N(C_1-6alkyl) and optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1-6alkyl. In some embodiments, each R¹⁰ is independently C_3-6heterocycloalkyl including 1 to 2 ring heteromoieties selected from O, S, NH and N(C_1-4alkyl), and optionally substituted with C_1-6alkyl. [00145] In some embodiments, each R¹⁰ is independently selected from aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl oxepanyl and thiepanyl, each of which is optionally substituted with C_1- ₆alkyl. In some embodiments, each R¹⁰ is independently selected from thietanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1-6alkyl. In some embodiments, each R¹⁰ is independently C_3-6heterocycloalkyl including at least one ring heteromoiety selected from NH and N(C_1-4alkyl) and optionally substituted with one or two substituents selected from F, Cl, C_1-4alkyl and OC_1-4alkyl. In some embodiments, each R¹⁰ is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or two substituents selected from F, Cl, C_1- ₄alkyl and OC_1-4alkyl. In some embodiments, each R¹⁰ is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or two substituents selected from F, Cl, CH₃ and OCH₃. [00146] In some embodiments, each R¹⁰ is independently C_3-10heterocycloalkyl optionally substituted with C_1-6alkyl. In some embodiments, each R¹⁰ is independently C_3- ₆heterocycloalkyl optionally substituted with C_1-6alkyl. In some embodiments, each R¹⁰ is independently C_3-6heterocycloalkyl including 1 to 2 ring heteromoieties selected from O, S, N, NH and N(C_1-6alkyl) optionally substituted with C_1-6alkyl. In some embodiments, each R¹⁰ is independently C_3-6heterocycloalkyl including 1 to 2 ring heteromoieties selected from O, S, NH and N(C_1-4alkyl), and optionally substituted with C_1-6alkyl. In some embodiments, each R¹⁰ is independently selected from aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl oxepanyl and thiepanyl, each of which is optionally substituted with C_1-6alkyl. In some embodiments, each R¹⁰ is independently selected from thietanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with C_1-6alkyl. In some embodiments, each R¹⁰ is independently C_3-6heterocycloalkyl including at least one ring heteromoiety selected from NH and N(C_1-4alkyl). In some embodiments, each R¹⁰ is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with C_1-4alkyl. In some embodiments, each R¹⁰ is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with CH₃. [00147] In some embodiments, each R¹⁰ is independently selected from C_1-4alkyl, C_2-4alkenyl and C_2-4alkynyl. In some embodiments, each R¹⁰ is independently C_1-4alkyl. In some embodiments, each R¹⁰ is independently selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, each R¹⁰ is independently selected from CH₃, CH₂CH₃ and CH(CH₃)₂. [00148] In some embodiments, each R¹⁰ is independently C_3-10cycloalkyl optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1-6alkyl. In some embodiments, each R¹⁰ is independently C_3-8cycloalkyl optionally substituted with one or two substituents selected from F, Cl, C_1-4alkyl and OC_1-4alkyl. In some embodiments, each R¹⁰ is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl each of which is optionally substituted with one or two substituents selected from F, Cl, C_1-4alkyl and OC_1-4alkyl. In some embodiments, each R¹⁰ is independently C_3- ₁₀cycloalkyl optionally substituted with C_1-6alkyl. In some embodiments, each R¹⁰ is independently C_3-8cycloalkyl optionally substituted with C_1-6alkyl. In some embodiments, each R¹⁰ is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl each of which is optionally substituted with C_1-6alkyl. [00149] In some embodiments, R¹ is selected from C_1-4alkyleneC_3-10cycloalkyl optionally substituted with one or two R¹¹, and C_1-4alkyleneC_3-10heterocycloalkyl optionally substituted with one or two R¹². [00150] In some embodiments, R¹ is C_1-4alkyleneC_3-10cycloalkyl optionally substituted with one or two R¹¹. In some embodiments, the C_3-10cycloalkyl in the C_1- ₄alkyleneC_3-10cycloalkyl is monocyclic C_3-10cycloalkyl or bicyclic C_5-10cycloalkyl, each of which is optionally substituted with one or two R¹¹. In some embodiments, R¹ is C_1- ₄alkyleneC_{3- 8}cycloalkyl optionally substituted with one or two R¹¹ and the C_{3- 8}cycloalkyl in the C_1-4alkyleneC_{3- 8}cycloalkyl is monocyclic C_{3- 8}cycloalkyl or bicyclic C_5-8cycloalkyl. [00151] In some embodiments, the cycloalkyl in the C_1-4alkyleneC_{3- 8}cycloalkyl is monocyclic C_{3- 8}cycloalkyl optionally substituted with one or two R¹¹. In some embodiments, the monocyclic C_{3- 8}cycloalkyl in the C_1-4alkyleneC_{3- 8}cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each of which is optionally substituted with one or two R¹¹. In some embodiments, the monocyclic C_{3- 8}cycloalkyl in the C_1- ₄alkyleneC_{3- 8}cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each of which is optionally substituted with one R¹¹. [00152] In some embodiments, the cycloalkyl in the C_1-4alkyleneC_3-10cycloalkyl is bicyclic C_5-10cycloalkyl optionally substituted with one or two R¹¹. In some embodiments, the cycloalkyl in the C_1-4alkyleneC_{3- 8}cycloalkyl is a spirofused C_5-10cycloalkyl or a bridged C_5-10cycloalkyl each of which is optionally substituted with one or two R¹¹. Therefore, in some embodiments, the cycloalkyl in the C_1-4alkyleneC_3-10cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spirofused C_5-10cycloalkyl, and bridged C_5-10cycloalkyl, each of which is optionally substituted with one or two R¹¹. In some embodiments, the cycloalkyl in the C_1-4alkyleneC_3-10cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spirofused C_5-10cycloalkyl and bridged C_5- ₁₀cycloalkyl, each of which is substituted with one or two R¹¹. [00153] In some embodiments, the cycloalkyl in the C_1-4alkyleneC_3-10cycloalkyl is a spirofused C_5-10cycloalkyl 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 R¹¹. In some embodiment, the spirofused C₅-₁₀cycloalkyl is spiro[3.3]heptane optionally substituted with one or two R¹¹. In some embodiment, the spirofused C_5-10cycloalkyl is spiro[3.3]heptane substituted with one or two R¹¹. [00154] In some embodiments, the cycloalkyl in the C_1-4alkyleneC_3-10cycloalkyl is a bridged C_5-10cycloalkyl optionally substituted with one or two R¹¹. In some embodiments, the bridged C_5-10cycloalkyl is selected from a bicyclopentanyl, a bicycloheptanyl and a bicyclooctanyl each of which is optionally substituted with one or two R¹¹. In some embodiments, the bridged C_5-10cycloalkyl is selected from a bicyclopentanyl, a bicycloheptanyl and a bicyclooctanyl each of which is optionally substituted with one R¹¹. [00155] In some embodiments, R¹ is C_1-3alkylene C_{3- 8}cycloalkyl optionally substituted with one or two R¹¹. In some embodiments, R¹ is CH₂C_{3- 8}cycloalkyl or CH₂CH₂C_{3- 8}cycloalkyl optionally substituted with one or two R¹¹. In some embodiments, R¹ is CH₂C_{3- 8}cycloalkyl or CH₂CH₂C_{3- 8}cycloalkyl optionally substituted with one or two R¹¹. [00156] In some embodiments, each R¹¹ is independently selected from OH, NR¹⁷R¹⁸, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_{3- 8}cycloalkyl and C_3-10heterocycloalkyl, wherein all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR¹⁹, NR¹⁹R²⁰ and C_1-6alkyl. In some embodiments, each R¹¹ is independently selected from OH, NR¹⁷R¹⁸, C_1-4alkyl, C_3- ₈cycloalkyl and C_3-10heterocycloalkyl, wherein all alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR¹⁹, NR¹⁹R²⁰ and C_1-6alkyl. [00157] In some embodiments, each R¹¹ is independently selected from OH, NR¹⁷R¹⁸, C_1-4alkyl, C_2-4alkenyl and C_2-4alkynyl C_{3- 8}cycloalkyl and C_3-10heterocycloalkyl, wherein all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from OR¹⁹, NR¹⁹R²⁰ and C_1-6alkyl. In some embodiments, each R¹¹ is independently selected from OH, NR¹⁷R¹⁸, C_1-4alkyl, C_3- ₈cycloalkyl and C_3-10heterocycloalkyl, wherein all alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from OR¹⁹, NR¹⁹R²⁰ and C_1- ₆alkyl. [00158] In some embodiments, each R¹¹ is independently selected from OH and NR¹⁷R¹⁸. In some embodiments, each R¹¹ is independently NR¹⁷R¹⁸. [00159] In some embodiments, R¹⁷ is selected from H, C_1-4alkyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, the latter three groups being optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. In some embodiments, R¹⁷ is selected from H, C_1-4alkyl, C_3-6cycloalkyl and C₄-₆heterocycloalkyl, the latter three groups being optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. [00160] In some embodiments, R¹⁷ is selected from H and C_1-4alkyl optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. [00161] In some embodiments, R¹⁷ is C_1-4alkyl optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. In some embodiments, R¹⁷ is C_1-4alkyl optionally substituted with one OC_1-4alkyl. In some embodiments, R¹⁷ is C_1-3alkyl optionally substituted with one OC_1-3alkyl. [00162] In some embodiments, R¹⁷ is selected from H and C_1-4alkyl. In some embodiments, R¹⁷ is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, R¹⁷ is selected from H, CH₃, CH₂CH₃ and CH(CH₃)₂. In some embodiments, R¹⁷ is selected from H and CH₃. In some embodiments, R¹⁷ is CH₃. [00163] In some embodiments, R¹⁷ is C_4-6heterocycloalkyl optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. In some embodiments, the C4- 6heterocycloalkyl in R¹⁷ is selected from oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. In some embodiments, the C_4-6heterocycloalkyl in R¹⁷ is oxetanyl optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. [00164] In some embodiments, R¹⁸ is selected from H and C_1-4alkyl. In some embodiments, R¹⁸ is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, R¹⁸ is selected from H, CH₃, CH₂CH₃ and CH(CH₃)₂. In some embodiments, R¹⁸ is selected from H and CH₃. In some embodiments, R¹⁸ is CH₃. [00165] In some embodiments, R¹⁷ and R¹⁸ are independently selected from H and C_1-4alkyl. In some embodiments, R¹⁷ and R¹⁸ are independently selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, R¹⁷ and R¹⁸ are independently selected from H, CH₃, CH₂CH₃ and CH(CH₃)₂. In some embodiments, R¹⁷ and R¹⁸ are both CH₃. In some embodiments, R¹⁷ and R¹⁸ are independently selected from H and CH₃. [00166] In some embodiments, each R¹¹ is independently selected from C_1-4alkyl, C_3-8cycloalkyl and C_3-10heterocycloalkyl, wherein all alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR¹⁹, NR¹⁹R²⁰ and C_1-4alkyl. In some embodiments, each R¹¹ is independently selected from C_1-4alkyl, C_3- ₈cycloalkyl and C_3-10heterocycloalkyl, wherein all alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from OR¹⁹, NR¹⁹R²⁰ and C_1- ₄alkyl. [00167] In some embodiments, each R¹¹ is independently C_1-4alkyl. In some embodiments, each R¹¹ is independently selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, each R¹² is independently selected from CH₃, CH₂CH₃ and CH(CH₃)₂. [00168] In some embodiments, each R¹¹ is independently C_1-4alkyl optionally substituted with one or more substituents selected from halo, OR¹⁹ and NR¹⁹R²⁰. In some embodiments, each R¹¹ is independently C_1-4alkyl optionally substituted with one or more substituents selected from F, Cl, OR¹⁹ and NR¹⁹R²⁰. In some embodiments, each R¹¹ is independently C_1-4alkyl optionally substituted with one or two OR¹⁹. In some embodiments, each R¹¹ is independently C_1-4alkyl optionally substituted with one or two NR¹⁹R²⁰. [00169] In some embodiments, each R¹¹ is independently C_1-4alkyl optionally substituted with one or more substituents independently selected from OR¹⁹ and NR¹⁹R²⁰. In some embodiments, each R¹¹ is independently C_1-4alkyl optionally substituted with one or two OR¹⁹. In some embodiments, each R¹¹ is independently C_1-4alkyl optionally substituted with one or two NR¹⁹R²⁰. [00170] In some embodiments, each R¹¹ is independently selected from C_3- ₁₀cycloalkyl and C_3-10heterocycloalkyl, wherein all cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, OR¹⁹, NR¹⁹R²⁰ and C_1-6alkyl. In some embodiments, each R¹¹ is independently selected from C_3-10cycloalkyl and C_3-10heterocycloalkyl, wherein all cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents independently selected from OR¹⁹, NR¹⁹R²⁰ and C_1-6alkyl. [00171] In some embodiments, each R¹¹ is independently C_3-10cycloalkyl optionally substituted with one or more substituents selected from F, Cl, OR¹⁹ and NR¹⁹R²⁰. In some embodiments, each R¹¹ is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl each of which is optionally substituted with one or two substituents selected from F, Cl, OR¹⁹ and NR¹⁹R²⁰. In some embodiments, each R¹¹ is independently C_3-10cycloalkyl optionally substituted with one or more substituents selected from OR¹⁹ and NR¹⁹R²⁰. In some embodiments, each R¹¹ is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl each of which is optionally substituted with one or two substituents selected from OR¹⁹ and NR¹⁹R²⁰. [00172] In some embodiments, each R¹¹ is independently C_3-10heterocycloalkyl, optionally substituted with one or more substituents selected from halo, OR¹⁹, NR¹⁹R²⁰ and C_1-4alkyl. In some embodiments, each R¹¹ is independently C_3-8heterocycloalkyl, optionally substituted with one or more substituents selected from halo, OR¹⁹, NR¹⁹R²⁰ and C_1-4alkyl. In some embodiments, each R¹¹ is independently C_3-6heterocycloalkyl including 1 to 2 ring heteromoieties selected from O, S, N, NH and N(C_1-6alkyl), and optionally substituted with one or more substituents selected from halo, OR¹⁹, NR¹⁹R²⁰ and C_1-4alkyl. In some embodiments, each R¹¹ is independently C_3-6heterocycloalkyl including 1 to 2 ring heteromoieties selected from O, S, NH and N(C_1-4alkyl), and optionally substituted with one to three substituents selected from F, Cl, OR¹⁹, NR¹⁹R²⁰ and C_1-4alkyl. In some embodiments, each R¹¹ is independently selected from aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl oxepanyl and thiepanyl, each of which is optionally substituted with one to three substituents selected from F, Cl, OR¹⁹, NR¹⁹R²⁰ and C_1-4alkyl. In some embodiments, each R¹¹ is independently selected from thietanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one to three substituents selected from F, Cl, OR¹⁹, NR¹⁹R²⁰ and C_1-4alkyl. In some embodiments, each R¹¹ is independently a C_3-6heterocycloalkyl including at least one ring heteromoiety selected from NH and N(C_1-4alkyl) optionally substituted with one to three substituents selected from F, Cl, OR¹⁹, NR¹⁹R²⁰ and C_1-4alkyl. In some embodiments, each R¹¹ is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or two substituents selected from F, Cl, OR¹⁹, NR¹⁹R²⁰ and C_1-4alkyl. In some embodiments, each R¹¹ is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or two substituents selected from F, Cl, OR¹⁹, NR¹⁹R²⁰ and C_1-4alkyl. In some embodiments, each R¹¹ is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or two substituents selected from F, Cl, CH₃ and CH₂CH₃. [00173] In some embodiments, each R¹¹ is independently C_3-10heterocycloalkyl, optionally substituted with one or more substituents selected from OR¹⁹, NR¹⁹R²⁰ and C_1- ₄alkyl. In some embodiments, each R¹¹ is independently C₃-₈heterocycloalkyl, optionally substituted with one or more substituents selected from OR¹⁹, NR¹⁹R²⁰ and C_1-4alkyl. In some embodiments, each R¹¹ is independently C_3-6heterocycloalkyl including 1 to 2 ring heteromoieties selected from O, S, N, NH and N(C_1-6alkyl), and optionally substituted with one or more substituents selected from OR¹⁹, NR¹⁹R²⁰ and C_1-4alkyl. In some embodiments, each R¹¹ is independently C_3-6heterocycloalkyl including 1 to 2 ring heteromoieties selected from O, S, NH and N(C_1-4alkyl), and optionally substituted with one or more substituents selected from OR¹⁹, NR¹⁹R²⁰ and C_1-4alkyl. In some embodiments, each R¹¹ is independently selected from aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl oxepanyl and thiepanyl, each of which is optionally substituted with one or more substituents selected from OR¹⁹, NR¹⁹R²⁰ and C_1- ₄alkyl. In some embodiments, each R¹¹ is independently selected from thietanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or more substituents selected from OR¹⁹, NR¹⁹R²⁰ and C_1-4alkyl. In some embodiments, each R¹¹ is independently a C_3-6heterocycloalkyl including at least one ring heteromoiety selected from NH and N(C_1-4alkyl) optionally substituted with one or more substituents selected from OR¹⁹, NR¹⁹R²⁰ and C_1-4alkyl. In some embodiments, each R¹¹ is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or two substituents selected from OR¹⁹, NR¹⁹R²⁰ and C_1-4alkyl. In some embodiments, each R¹¹ is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or two substituents selected from OR¹⁹, NR¹⁹R²⁰ and C_1-4alkyl. In some embodiments, each R¹¹ is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or two CH₃ and CH₂CH₃. [00174] In some embodiments, R¹⁹ and R²⁰ are independently selected from H and C_1-4alkyl In some embodiments R¹⁹ and R²⁰ are independently selected from H CH₃ CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, R¹⁹ and R²⁰ are independently selected from H, CH₃, CH₂CH₃ and CH(CH₃)₂. In some embodiments, R¹⁹ and R²⁰ are independently selected from H and CH₃. [00175] In some embodiments, R¹ is C_1-4alkyleneC_3-10heterocycloalkyl optionally substituted with one or two R¹². [00176] In some embodiments, the heterocycloalkyl in the C_1-4alkyleneC₃- ₁₀heterocycloalkyl is selected from a monocyclic C_3-10heterocycloalkyl or bicyclic C_5- ₁₀heterocycloalkyl optionally substituted with one or two R¹². In some embodiments, R¹ is C_1-4alkyleneC_{3- 8}heterocycloalkyl and the heterocycloalkyl in the C_1-4alkyleneC_3- ₁₀heterocycloalkyl is monocyclic C_{3- 8}heterocycloalkyl optionally substituted with one or two R¹². In some embodiments, the heterocycloalkyl in the C_1-4alkyleneC_{3- 8}heterocycloalkyl in R¹ is selected from aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl oxepanyl and thiepanyl, each of which is optionally substituted with one or two R¹². In some embodiments, the heterocycloalkyl in the C_1-4alkyleneC_3- ₈heterocycloalkyl of R¹ is C_3-6heterocycloalkyl including at least one ring heteromoiety selected from NH and N(C_1-6alkyl), and optionally substituted with one or two R¹². In some embodiments, the C_3-6heterocycloalkyl including at least one ring heteromoiety selected from NH and N(C_1-6alkyl) in the C_1-4alkyleneC_{3- 8}heterocycloalkyl of R¹ is selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one R¹². In some embodiments, the C_{3- 8}heterocycloalkyl including at least one ring heteromoiety selected from NH and N(C_1-6alkyl) in the C_1- ₄alkyleneC_{3- 8}heterocycloalkyl of R¹ is selected from azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl, each of which is optionally substituted with one R¹². [00177] In some embodiments, the heterocycloalkyl in the C_1-4alkyleneC_3- ₁₀heterocycloalkyl of R¹ is a bicyclic C_5-10heterocycloalkyl optionally substituted with one or two R¹². In some embodiments, the bicyclic C_5-10heterocycloalkyl is a spirofused C_5- ₁₀heterocycloalkyl, a fused C_5-10heterocycloalkyl or a bridged C_5-10heterocycloalkyl each of which is optionally substituted with one or two R¹². [00178] In some embodiments, the spirofused C_5-10heterocycloalkyl in the C_1- ₄alkyleneC_3-10heterocycloalkyl of R¹ is selected from an azaspiro[4.4]nonane, an azaspiro[3.5]nonane, an azaspiro[5.4]decane and an azaspiro[5.2]octane each of which is optionally substituted with one or two R¹². In some embodiments, the spirofused C_5- ₁₀cycloalkyl is an azaspiro[3.5]nonane optionally substituted with one or two R¹². [00179] In some embodiments, the fused C_3-10heterocycloalkyl in the C_1-4alkyleneC_3- ₁₀heterocycloalkyl of R¹ is selected from an octahydroindolyl, an octahydroisoindolyl, a decahydroquinolyl and a decahydroisoquinolyl each of which is optionally substituted with one or two R¹². [00180] In some embodiments, the heterocycloalkyl in the C_1-4alkyleneC_3- ₁₀heterocycloalkyl of R¹ is a bridged C_5-10heterocycloalkyl optionally substituted with one or two R¹². In some embodiments, the bridged C_5-10heterocycloalkyl is selected from an azabicyclohexanyl, an azabicycloheptanyl a diazabicycloheptanyl, an azabicyclooctany and a diazabicyclooctanyl each of which is optionally substituted with one or two R¹². [00181] In some embodiments, R¹ is C_1-3alkyleneC_{3- 8}heterocycloalkyl optionally substituted with one or two R¹². In some embodiments, R¹ is CH₂C_{3- 8}heterocycloalkyl or CH₂CH₂C_{3- 8}heterocycloalkyl optionally substituted with one or two R¹². In some embodiments, R¹ is CH₂C_{3- 8}heterocycloalkyl or CH₂CH₂C_{3- 8}heterocycloalkyl optionally substituted with one or two R¹². [00182] In some embodiments, each R¹² is independently selected from OH, NR²¹R²², C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_{3- 8}cycloalkyl and C_{3- 8}heterocycloalkyl, wherein all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR²³, NR²³R²⁴ and C_1-6alkyl. In some embodiments, each R¹² is independently selected from OH, NR²¹R²², C_1-4alkyl, C_3- ₈cycloalkyl and C_{3- 8}heterocycloalkyl, wherein all alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR²³, NR²³R²⁴ and C_1-6alkyl. [00183] In some embodiments, each R¹² is independently selected from OH, NR²¹R²², C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_{3- 8}cycloalkyl and C_{3- 8}heterocycloalkyl, wherein all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from OR²³, NR²³R²⁴ and C_1-6alkyl. In some embodiments, each R¹² is independently selected from OH, NR²¹R²², C_1-4alkyl, C_{3- 8}cycloalkyl and C_3- ₈heterocycloalkyl, wherein all alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from OR²³, NR²³R²⁴ and C_1-6alkyl. [00184] In some embodiments, each R¹² is independently selected from OH and NR²¹R²². In some embodiments, each R¹² is independently NR²¹R²². [00185] In some embodiments, R²¹ is selected from H, C_1-4alkyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, the latter three groups being optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. In some embodiments, R²¹ is selected from H, C_1-4alkyl, C_3-6cycloalkyl and C_4-6heterocycloalkyl, the latter three groups being optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. [00186] In some embodiments, R²¹ is selected from H and C_1-4alkyl optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. [00187] In some embodiments, R²¹ is C_1-4alkyl optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. In some embodiments, R²¹ is C_1-4alkyl optionally substituted with one OC_1-4alkyl. In some embodiments, R²¹ is C_1-3alkyl optionally substituted with one OC_1-3alkyl. [00188] In some embodiments, R²¹ is selected from H and C_1-4alkyl. In some embodiments, R²¹ is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, R²¹ is selected from H, CH₃, CH₂CH₃ and CH(CH₃)₂. In some embodiments, R²¹ is selected from H and CH₃. In some embodiments, R²¹ is CH₃. [00189] In some embodiments, R²¹ is C_4-6heterocycloalkyl optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. In some embodiments, R²¹ is selected from oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. In some embodiments, R²¹ is oxetanyl optionally substituted with one or two substituents selected from OH and OC_1-4alkyl. [00190] In some embodiments, R²² is selected from H and C_1-4alkyl. In some embodiments, R²² is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, R²² is selected from H, CH₃, CH₂CH₃ and CH(CH₃)₂. In some embodiments, R²² is selected from H and CH₃. In some embodiments, R²² is CH₃. [00191] In some embodiments, R²¹ and R²² are independently selected from H and C_1-4alkyl. In some embodiments, R²¹ and R²² are independently selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, R²¹ and R²² are independently selected from H, CH₃, CH₂CH₃ and CH(CH₃)₂. In some embodiments, R²¹ and R²² are both CH_3. In some embodiments, R²¹ and R²² are independently selected from H and CH₃. [00192] In some embodiments, each R¹² is independently selected from C_1-4alkyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, wherein all alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR²³, NR²³R²⁴ and C_1-4alkyl. In some embodiments, each R¹² is independently selected from C_1-4alkyl, C_3- ₁₀cycloalkyl and C_3-10heterocycloalkyl, wherein all alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from OR²³, NR²³R²⁴ and C_1- ₄alkyl. [00193] In some embodiments, each R¹² is independently C_1-4alkyl. In some embodiments, each R¹² is independently selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, each R¹² is independently selected from CH₃, CH₂CH₃ and CH(CH₃)₂. [00194] In some embodiments, each R¹² is independently C_1-4alkyl optionally substituted with one or more substituents selected from halo, OR²³ and NR²³R²⁴. In some embodiments, each R¹² is independently C_1-4alkyl optionally substituted with one or more substituents selected from F, Cl, OR²³ and NR²³R²⁴. In some embodiments, each R¹² is independently C_1-4alkyl optionally substituted with one or two OR²³. In some embodiments, each R¹² is independently C_1-4alkyl optionally substituted with one or two NR²³R²⁴. [00195] In some embodiments, each R¹² is independently C_1-4alkyl optionally substituted with one or more substituents selected from OR²³ and NR²³R²⁴. In some embodiments, each R¹² is independently C_1-4alkyl optionally substituted with one or two OR²³. In some embodiments, each R¹² is independently C_1-4alkyl optionally substituted with one or two NR²³R²⁴. [00196] In some embodiments, each R¹² is independently selected from C_3- ₁₀cycloalkyl and C_3-10heterocycloalkyl, wherein all cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR²³, NR²³R²⁴ and C_1-6alkyl. In some embodiments, each R¹² is independently selected from C_3-10cycloalkyl and C_3-10heterocycloalkyl, wherein all cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from OR²³, NR²³R²⁴ and C_1-6alkyl. [00197] In some embodiments, each R¹² is independently C_3-10cycloalkyl optionally substituted with one or more substituents selected from F, Cl, OR²³ and NR²³R²⁴. In some embodiments, each R¹² is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl each of which is optionally substituted with one or two substituents selected from F, Cl, OR²³ and NR²³R²⁴. In some embodiments, each R¹² is independently C_3-10cycloalkyl optionally substituted with one or more substituents selected from OR²³ and NR²³R²⁴. In some embodiments, each R¹² is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl each of which is optionally substituted with one or two substituents selected from OR²³ and NR²³R²⁴. [00198] In some embodiments, each R¹² is independently C_3-10heterocycloalkyl optionally substituted with one or more substituents selected from halo, OR²³, NR²³R²⁴ and C_1-6alkyl. In some embodiments, each R¹² is independently C_3-6heterocycloalkyl optionally substituted with one or more substituents selected from halo, OR²³, NR²³R²⁴ and C_1-6alkyl. In some embodiments, each R¹² is independently C_3-6heterocycloalkyl including 1 to 2 ring heteromoieties selected from O, S, N, NH and N(C_1-6alkyl) optionally substituted with one to three substituents selected from F, Cl, OR²³, NR²³R²⁴ and C_1-6alkyl. In some embodiments, each R¹² is independently selected from aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl oxepanyl and thiepanyl, each of which is optionally substituted with one to three substituents selected from F, Cl, OR²³, NR²³R²⁴ and C_1-4alkyl. In some embodiments, each R¹² is independently selected from thietanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one to three substituents selected from F, Cl, OR²³, NR²³R²⁴ and C_1-4alkyl. In some embodiments, each R¹² is independently C_3-6heterocycloalkyl including at least one ring heteromoiety selected from NH and N(C_1-4alkyl) optionally substituted with one to three substituents selected from F, Cl, OR²³, NR²³R²⁴ and C_1-4alkyl. In some embodiments, each R¹² is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one to three substituents selected from F, Cl, OR²³, NR²³R²⁴ and C_1-4alkyl. In some embodiments, each R¹² is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or two substituents selected from F, Cl, OR²³, NR²³R²⁴ and C_1-4alkyl. In some embodiments, each R¹² is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or two substituents selected from F, Cl, CH₃ and CH₂CH₃. [00199] In some embodiments, each R¹² is independently C_3-10heterocycloalkyl optionally substituted with one or more substituents selected from OR²³, NR²³R²⁴ and C_1- ₆alkyl In some embodiments each R¹² is independently C_3-6heterocycloalkyl optionally substituted with one or more substituents selected from OR²³, NR²³R²⁴ and C_1-6alkyl. In some embodiments, each R¹² is independently C_3-6heterocycloalkyl including 1 to 2 ring heteromoieties selected from O, S, N, NH and N(C_1-6alkyl) optionally substituted with one or more substituents selected from OR²³, NR²³R²⁴ and C_1-6alkyl. In some embodiments, each R¹² is independently selected from aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl oxepanyl and thiepanyl, each of which is optionally substituted with one or more substituents selected from OR²³, NR²³R²⁴ and C_1-4alkyl. In some embodiments, each R¹² is independently selected from thietanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or more substituents selected from OR²³, NR²³R²⁴ and C_1-4alkyl. In some embodiments, each R¹² is independently C_3-6heterocycloalkyl including at least one ring heteromoiety selected from NH and N(C_1-4alkyl) optionally substituted with one or more substituents selected from OR²³, NR²³R²⁴ and C_1-4alkyl. In some embodiments, each R¹² is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or more substituents selected from OR²³, NR²³R²⁴ and C_1-4alkyl. In some embodiments, each R¹² is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or more C_1-4alkyl. In some embodiments, each R¹² is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one or two CH₃ and CH₂CH₃. [00200] In some embodiments, R²³ and R²⁴ are independently selected from H and C_1-4alkyl. In some embodiments, R²³ and R²⁴ are independently selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, R²³ and R²⁴ are independently selected from H, CH₃, CH₂CH₃ and CH(CH₃)₂. In some embodiments, R²³ and R²⁴ are independently selected from H and CH₃. [00201] In some embodiments, R¹ is selected from [00202] In some embodiments, R¹ is selected from [00203] In some embodiments, R¹ is selected from

[00204] In some embodiments, R² and R³ are independently selected from H, halo, CN and C_1-4alkyl. In some embodiments, R² and R³ are independently selected from H, F, Cl, CN, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, R² and R³ are independently selected from H, F, Cl, CN, CH₃, CH₂CH₃, CH₂CH₂CH and CH(CH₃)₂. In some embodiments, R² and R³ are independently selected from H, and CH₃. In some embodiments, R² and R³ are both H. [00205] In some embodiments, R⁴, R⁵ and R⁶ are independently selected from H, halo, CN and C_1-4alkyl. In some embodiments, R⁴, R⁵ and R⁶ are independently selected from H, F, Cl, CN and C_1-4alkyl. In some embodiments, R⁴, R⁵ and R⁶ are independently selected from H, F, Cl, CN, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃. In some embodiments, R⁴ and R⁵ are independently selected from H, F, Cl, CN, CH₃ and CH₂CH₃. In some embodiments, one of R⁴ and R⁵ is F and the other is H. In some embodiments, R⁴ and R⁵ are both H. In some embodiments, R⁶ is selected from H, F, Cl, CN, CH₃, CH₂CH₃, and CH(CH₃)₂. In some embodiments, R⁶ is selected from F, Cl and CN. In some embodiments, R⁶ is selected from H, F and Cl. In some embodiments, R⁶ is selected from H and F. In some embodiments, R⁶ is F. [00206] In some embodiments, R⁴, R⁵ and R⁶ are all H. In some embodiments, R⁴ and R⁵ are both H and R⁶ is F. [00207] In some embodiments, R⁷ is selected from H, C_1-4alkyl and OC_1-4alkyl, the latter two groups being optionally substituted with one or more of OH and halo. In some embodiments, R⁷ is selected from H, C_1-4alkyl and OC_1-4alkyl, the latter two groups being optionally substituted with one or more of OH, F and Cl. In some embodiments, R⁷ is selected from H, C_1-4alkyl and OC_1-4alkyl optionally substituted with one or more of OH and F. In some embodiments, R⁷ is selected from H, CH₃, CH₂CH₃, CF₂H, CF₃, CFH₂, CH₂CF₂H, CH₂CF₂H, OCH₃, OCH₂CH₃, OCF₂H, OCF₃, OCFH₂, OCH₂CF₂H and OCH₂CFH₂. In some embodiments, R⁷ is selected from H, CH₃, CF₃, CF₂H, OCH₃, OCH₂CH₃, OCF₂H and OCF₃. In some embodiments, R⁷ is selected from H, CH₃, CF₃, OCF₂H, OCH₃, and OCF₃. In some embodiments, R⁷ is selected from H, OCF₂H, OCH₃, and OCF₃. In some embodiments, R⁷ is selected from OCF₂H, OCH₃, and OCF₃. In some embodiments, R⁷ is OCH₃. [00208] In some embodiments, R⁸ is selected from H, halo, CN, C_1-4alkyl and OC_1- ₄alkyl, the latter two groups being optionally substituted with one or more of OH and halo. In some embodiments, R⁸ is selected from H, F, Cl, Br, CN, C_1-4alkyl and OC_1-4alkyl, the latter two groups being optionally substituted with one or more of OH, F and Cl. In some embodiments, R⁸ is selected from H, F, Cl, CN, and C_1-4alkyl optionally substituted with one or more of OH and F. In some embodiments, R⁸ is selected from H, F, Cl, CN, CH₃, CH₂CH₃, CF₂H, CF₃, CFH₂, CH₂CF₂H, CH₂CF₂H, OCH₃, OCH₂CH₃, OCF₂H, OCF₃, OCFH₂, OCH₂CF₂H and OCH₂CF₂H. In some embodiments, R⁸ is selected from H, F, Cl, CN, CH₃, CF₃, OCH₃, OCH₂CH₃ and OCF₃. In some embodiments, R⁸ is selected from H, F, Cl, CN, CH₃ and CF₃. In some embodiments, R⁸ is selected from H, F, Cl, CN and CF₃. In some embodiments, R⁸ is selected from F and Cl. In some embodiments, R⁸ is Cl. [00209] In some embodiments, X is N. In some embodiments, X is CH. [00210] In some embodiments, the compounds of Formula I are selected from:

o

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

[00211] In an embodiment the pharmaceutically acceptable salt is an acid addition salt or a base addition salt. The selection of a suitable salt may be made by a person skilled in the art (see, for example, S. M. Berge, et aI., "Pharmaceutical Salts," J. Pharm. Sci.1977, 66, 1-19). [00212] An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound. Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids. Illustrative of such organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2- phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid. In an embodiment, the mono- or di-acid salts are formed, and such salts exist in either a hydrated, solvated or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the application for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. [00213] 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 addition 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. 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. [00214] 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. [00215] In embodiments of the present application, the compounds described herein may have at least one asymmetric center. Where compounds possess more than one asymmetric center, they may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present application. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (for example, less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of the present application having an alternate stereochemistry. It is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the present application. [00216] 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. [00217] 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. [00218] 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 [00219] The compounds of the present application are suitably formulated in a conventional manner into compositions using one or more carriers. Accordingly, the present application also includes a composition comprising one or more compounds of the application and a carrier. The compounds of the application are suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present application further includes a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier. In embodiments of the application the pharmaceutical compositions are used in the treatment of any of the diseases, disorders or conditions described herein. [00220] The compounds of the application are administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. For example, a compound of the application is administered by oral, inhalation, parenteral, buccal, sublingual, nasal, rectal, vaginal, patch, pump, minipump, topical or transdermal administration and the pharmaceutical compositions formulated accordingly. In some embodiments, administration is by means of a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington’s Pharmaceutical Sciences (2000 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. [00221] 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. [00222] In some embodiments, a compound of the application is orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it is enclosed in hard or soft shell gelatin capsules, or it is compressed into tablets, or it is incorporated directly with the food of the diet. In some embodiments, the compound is incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions, and the like. In the case of tablets, carriers that are used include lactose, corn starch, sodium citrate and salts of phosphoric acid. Pharmaceutically acceptable excipients include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). In embodiments, the tablets are coated by methods well known in the art. In the case of tablets, capsules, caplets, pellets or granules for oral administration, pH sensitive enteric coatings, such as Eudragits™ designed to control the release of active ingredients are optionally used. Oral dosage forms also include modified release, for example immediate release and timed-release, formulations. Examples of modified-release formulations include, for example, sustained-release (SR), extended- release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet. Timed-release compositions are formulated, for example as liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. In some embodiments, liposomes are formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. For oral administration in a capsule form, useful carriers or diluents include lactose and dried corn starch. [00223] In some embodiments, liquid preparations for oral administration take the form of, for example, solutions, syrups or suspensions, or they are suitably presented as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and/or emulsions are administered orally, the compound of the application is suitably suspended or dissolved in an oily phase that is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents are added. Such liquid preparations for oral administration are prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols. [00224] It is also possible to freeze-dry the compounds of the application and use the lyophilizates obtained, for example, for the preparation of products for injection. [00225] In some embodiments, a compound of the application is administered parenterally. For example, solutions of a compound of the application are prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. A person skilled in the art would know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds of the application are usually prepared, and the pH’s of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments or droppable liquids are delivered, for example, by ocular delivery systems known to the art such as applicators or eye droppers. In some embodiment, such compositions include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzyl chromium chloride, and the usual quantities of diluents or carriers. For pulmonary administration, diluents or carriers will be selected to be appropriate to allow the formation of an aerosol. [00226] In some embodiments, a compound of the application is formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection are, for example, presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. In some embodiments, the compositions take such forms as sterile suspensions, solutions 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. Alternatively, the compounds of the application are suitably in a sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. [00227] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, gels and powders. For intranasal administration or administration by inhalation, the compounds of the application are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which, for example, take the form of a cartridge or refill for use with an atomising device. Alternatively, the sealed container is a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which is, for example, a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. Suitable propellants include but are not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to deliver a metered amount. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator are, for example, formulated containing a powder mix of a compound of the application and a suitable powder base such as lactose or starch. The aerosol dosage forms can also take the form of a pump-atomizer. [00228] 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. [00229] 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. [00230] In some embodiments a compound of the application is coupled with soluble polymers as targetable drug carriers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, a compound of the application is coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels. [00231] In some embodiments, compounds of the application may be coupled with viral, non-viral or other vectors. Viral vectors may include retrovirus, lentivirus, adenovirus, herpesvirus, poxvirus, alphavirus, vaccinia virus or adeno-associated viruses. Non-viral vectors may include nanoparticles, cationic lipids, cationic polymers, metallic nanoparticles, nanorods, liposomes, micelles, microbubbles, cell-penetrating peptides, or lipospheres. Nanoparticles may include silica, lipid, carbohydrate, or other pharmaceutically acceptable polymers. [00232] A compound of the application including pharmaceutically acceptable salts and/or solvates thereof is suitably used on their own but will generally be administered in the form of a pharmaceutical composition in which the one or more compounds of the application (the active ingredient) is in association with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the active ingredient, and from about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of a pharmaceutically acceptable carrier, all percentages by weight being based on the total composition. IV. Methods and Uses of the Application [00233] The compounds of the application have been shown to inhibit or block general control nonderepressible 2 (GCN2) kinase, to attenuate the transcriptional function of ATF4 target gene expression. Therefore, the compounds of the application are useful for inhibiting GCN2. [00234] Accordingly, the present application includes a method of inhibiting general control nonderepressible 2 (GCN2) in a cell, either in a biological sample or in a patient, comprising administering an effective amount of one or more compounds of the application to the cell. [00235] 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. [00236] As the compounds of the application have been shown to be capable of inhibiting GCN2 protein activity, the compounds of the application are useful for treating diseases, disorders or conditions by inhibiting GCN2. Therefore, the compounds of the present application are useful as medicaments. Accordingly, the present application includes a compound of the application for use as a medicament. [00237] Accordingly, the present application also includes a method of treating a disease, disorder or condition that is treatable by inhibiting GCN2, comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof. [00238] 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. [00239] “GCN2” is a protein kinase that belongs to the family of eukaryotic initiation factor 2 α (eIF2α) kinases. In some embodiments, this serine/threonine-protein kinase is an enzyme that in humans is encoded by the GCN2 or EIF2AK4 (Gene ID: 851877) comprising the amino acid sequence disclosed in Mol. Cell. Biol.1995,15 (8): 4497–506. [00240] In some embodiments, the disease, disorder or condition that is treatable by inhibiting GCN2 is a neoplastic disorder. Accordingly, the present application also includes a method of treating a neoplastic disorder comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof. The present application also includes a use of one or more compounds of the application for treatment of a neoplastic disorder as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a neoplastic disorder. The application further includes one or more compounds of the application for use in treating a neoplastic disorder. In some embodiments, the treatment is in an amount effective to ameliorate at least one symptom of the neoplastic disorder, for example, reduced cell proliferation or reduced tumor mass, among others, in a subject in need of such treatment. [00241] 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. [00242] Compounds of the application have been demonstrated to inhibit the growth of cancer cells. In some embodiments, the disease, disorder or condition that is treatable by inhibiting GCN2, is cancer. [00243] Accordingly, the present application also includes a method of treating cancer comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof. The present application also includes a use of one or more compounds of the application for treatment of cancer as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of cancer. The application further includes one or more compounds of the application for use in treating cancer. In an embodiment, the compound is administered for the prevention of cancer in a subject such as a mammal having a predisposition for cancer. [00244] In some embodiments, the cancer is selected from, but not limited to: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS- Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor, Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male; Bronchial Adenomas/Carcinoids, Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical Cancer; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-CeIl Lymphoma; Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family of Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; Kidney Cancer; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia, Acute Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood; Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoblastic Leukemia, Adult Acute; Lymphoblastic Leukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma, AIDS-Related; Lymphoma, Central Nervous System (Primary); Lymphoma, Cutaneous T-CeIl; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's, Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's, Adult; Lymphoma, Non-Hodgkin's, Childhood; Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma; Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood; Non- Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer; Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma (Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma, Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, Soft Tissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft Tissue Sarcoma, Childhood; Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer, Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood; T-CeIl Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood; Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Cancer of, Childhood; Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom's Macro globulinemia; and Wilms' Tumor. Metastases of the aforementioned cancers can also be treated in accordance with the methods described herein. [00245] In some embodiments, the cancer is any cancer in which the cells show increased expression of the gene(s) encoding GCN2 or activation of GCN2 under stress conditions. By “increased expression” it is meant any increase in expression of the gene(s) encoding GCN2 in the cell compared to expression of the gene(s) encoding GCN2 in a corresponding normal or healthy cell. [00246] In some embodiments, the cancer is selected from one or more of solid tumors, breast cancer, colon cancer, bladder cancer, skin cancer, head and neck cancer, liver cancer, lung cancer, pancreatic cancer, ovarian cancer, prostate cancer, bone cancer, and glioblastoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is osteosarcoma. [00247] In some embodiments, the disease, disorder or condition that is treatable by inhibiting GCN2, is a disease, disorder or condition associated with an uncontrolled and/or abnormal cellular activity affected directly or indirectly by inhibiting GCN2. In another embodiment, the uncontrolled and/or abnormal cellular activity that is affected directly or indirectly by inhibiting GCN2 is proliferative activity in a cell. [00248] Accordingly, the application also includes a method of inhibiting proliferative activity in a cell, comprising administering an effective amount of one or more compounds of the application to the cell. The present application also includes a use of one or more compounds of the application for inhibition of proliferative activity in a cell as well as a use of one or more compounds of the application for the preparation of a medicament for inhibition of proliferative activity in a cell. The application further includes one or more compounds of the application for use in inhibiting proliferative activity in a cell. [00249] 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. [00250] In some embodiments, the disease, disorder or condition that is treatable by inhibiting GCN2 is a peripheral neuropathy. Accordingly, the present application also includes a method of treating a peripheral neuropathy comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof. The present application also includes a use of one or more compounds of the application for treatment of a peripheral neuropathy as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a peripheral neuropathy. The application further includes one or more compounds of the application for use in treating a peripheral neuropathy. [00251] In some embodiments, the peripheral neuropathy is Charcot-Marie-Tooth (CMT) peripheral neuropathy. Heterozygous mutations in six genes encoding cytoplasmic aminoacyl-tRNA synthetases (AARSs) cause axonal and intermediate forms of CMT peripheral neuropathy. Heterozygous mutations in six genes encoding cytoplasmic aminoacyl-tRNA synthetases (AARSs) cause axonal and intermediate forms of Charcot- Marie-Tooth (CMT) peripheral neuropathy. AARSs are ubiquitously expressed enzymes that covalently attach amino acids to their cognate tRNAs (tRNA aminoacylation). Aminoacylated tRNAs are used by the ribosome for mRNA translation. In Charcot-Marie- Tooth (CMT) peripheral neuropathy, mutant tRNA synthetases activate the integrated stress response (ISR) through the sensor kinase GCN2. The chronic activation of the ISR contributed to the pathophysiology, and genetic deletion or pharmacological inhibition of GCN2 alleviated the peripheral neuropathy. Therefore, in some embodiments, the disease, disorder or condition that is treatable by inhibiting GCN2, is a Charcot-Marie-Tooth (CMT) peripheral neuropathy. [00252] Accordingly, the present application also includes a method of treating Charcot-Marie-Tooth (CMT) peripheral neuropathy comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof. The present application also includes a use of one or more compounds of the application for treatment of Charcot-Marie-Tooth (CMT) peripheral neuropathy as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of Charcot-Marie-Tooth (CMT) peripheral neuropathy. The application further includes one or more compounds of the application for use in treating Charcot-Marie-Tooth (CMT) peripheral neuropathy. [00253] 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 in combination with another known agent useful for treatment of a disease, disorder or condition treatable by inhibiting GCN2 to a subject in need thereof. 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. [00254] In an embodiment, the disease, disorder or condition treatable by inhibiting GCN2 is cancer and/or peripheral neuropathy. [00255] In some embodiments, GCN2 is inhibited in the uses and methods of the application. [00256] In an embodiment, the subject is subject having the disease, disorder or condition. [00257] In an embodiment, the subject is a mammal. In another embodiment, the subject is human. [00258] In some embodiments the disease, disorder or condition that is treatable by inhibiting GCN2, is cancer and the one or more compounds of the application are administered or used in combination with one or more additional cancer treatments. In another embodiment, the one or more additional cancer treatments is selected from one or more radiotherapy, chemotherapy, targeted therapies such as antibody therapies (including anti-PD1 and/or anti-PD-L1 antibodies) and small molecule therapies such as tyrosine-kinase inhibitors therapies, glutaminase inhibitors (e.g., glutaminase-1 (GLS1) inhibitors), and asparagine synthetase (ASNS) inhibitors, immunotherapy, hormonal therapy and anti-angiogenic therapies. [00259] In some embodiments, the chemotherapy is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is cisplatin. Therefore, in some embodiments the disease, disorder or condition that is treatable by inhibiting GCN2 is cancer, and the one or more compounds of the application are administered or used in combination with cisplatin. In some embodiments, the chemotherapeutic agent is L- asparaginase (L-ASNase). Therefore, in some embodiments the disease, disorder or condition that is treatable by inhibiting GCN2 is cancer, and the one or more compounds of the application are administered or used in combination with L-asparaginase (L-ASNase). [00260] In some embodiments, the small molecule therapy is a glutaminase (e.g., glutaminase-1, (GLS1)) inhibitor or an asparagine synthetase (ASNS) inhibitor. Therefore, in some embodiments the disease, disorder or condition that is treatable by inhibiting GCN2, is cancer and the one or more compounds of the application are administered or used in combination one or more glutaminase inhibitors (e.g., GLS1 inhibitors), and/or or asparagine synthetase (ASNS) inhibitors. [00261] In some embodiments the disease, disorder or condition that is treatable by inhibiting GCN2, is cancer and the one or more compounds of the application are administered or used in combination one or more glutaminase inhibitors (e.g., GLS1 inhibitors), and/or asparagine synthetase (ASNS) inhibitors and/or L-asparaginase (L- ASNase). [00262] Asparagine deprivation by L-asparaginase (L-ASNase) is an effective therapeutic strategy in cancer, with resistance occurring due to upregulation of asparagine synthetase (ASNS), the only human enzyme synthetizing asparagine (Annu. Rev. Biochem.2006, 75 (1), 629–654). L-Asparaginase efficacy in solid tumors is limited by dose-related toxicities (OncoTargets and Therapy 2017, pp 1413–1422). Large-scale loss of function genetic in vitro screens identified ASNS as a cancer dependency in several solid malignancies (Cell 2017, 170 (3), 564–576.e16. Cell 2017, 170 (3), 577–592.e10). Genome-wide CRISPR screens have revealed that cancer cell resistance mechanisms are elicited by a GCN2-ATF4 axis aimed at restoring amino acid levels to promote survival. Hence, pharmacological inhibition of GCN2 synergizes with L-asparaginase-mediated asparagine deprivation in ASNS deficient cells suggesting novel potential therapeutic combinations in cancer treatment. [00263] Therefore, in some embodiments, the present application also includes a method of improving the efficacy of one or more additional cancer treatments for treating cancer comprising administering an effective amount of one or more compounds of the application or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with an effective amount of the one or more additional cancer treatments or pharmaceutically acceptable salts, prodrugs and/or solvates thereof to a subject in need thereof. [00264] The present application also includes a use of one or more compounds of the application or pharmaceutically acceptable salts, prodrugs and/or solvates thereof to a subject in need thereof in combination with one or more additional cancer treatments for improving the efficacy of the one or more additional cancer treatments for treating cancer, as well as a use of one or more compounds of the application or pharmaceutically acceptable salts, prodrugs and/or solvates thereof to a subject in need thereof in combination with one or more additional cancer treatments for improving the efficacy of the one or more additional cancer treatments for treating cancer. The application further includes one or more compounds of the application or pharmaceutically acceptable salts, prodrugs and/or solvates thereof to a subject in need thereof in combination with one or more additional cancer treating for use in improving the efficacy of the one or more additional cancer treatments for treating cancer. [00265] In some embodiments, 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.,GLS1 inhibitors), and/or asparagine synthetase (ASNS) inhibitors, immunotherapy, hormonal therapy and anti-angiogenic therapies. [00266] In some embodiments, the chemotherapy is a chemotherapeutic agent. In some embodiments, chemotherapeutic agent is cisplatin. Therefore, in some embodiments, the one or more compounds of the application or pharmaceutically acceptable salts, prodrugs and/or solvates thereof are administered or used in combination with cisplatin for improving the efficacy of cisplatin for treating cancer. [00267] In some embodiments, the chemotherapeutic agent is L-asparaginase (L- ASNase). Therefore, in some embodiments, the one or more compounds of the application or pharmaceutically acceptable salts, prodrugs and/or solvates thereof are administered or used in combination with L-asparaginase (L-ASNase) for improving the efficacy of L- ASNase for treating cancer. [00268] In some embodiments, the small molecule therapy is a glutaminase inhibitor (e.g., GLS1 inhibitor) or an asparagine synthetase (ASNS) inhibitor. Therefore, in some embodiments, the one or more compounds of the application or pharmaceutically acceptable salts, prodrugs and/or solvates thereof 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 or pharmaceutically acceptable salts, prodrugs and/or solvates thereof for improving the efficacy the one or more glutaminase inhibitors (e.g.,GLS1 inhibitors) or the one or more ASNS inhibitors for treating cancer. [00269] In some embodiments, the cancer is associated with low asparagine synthetase (ASNS) expression. In some embodiment, the cancer is associated with low asparagine synthetase (ASNS) expression and the chemotherapeutic agent is L- asparaginase (L-ASNase). Accordingly, in some embodiments, the one or more compounds of the application or pharmaceutically acceptable salts, prodrugs and/or solvates thereof 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. [00270] In some embodiments, the cancer is associated with asparagine synthetase (ASNS) overexpression or dysregulation. In some embodiments, the cancer is associated with asparagine synthetase (ASNS) overexpression or dysregulation and the chemotherapeutic agents are one or more asparagine synthetase (ASNS) inhibitors and/or L-asparaginase Therefore, in some embodiments, the one or more compounds of the application or pharmaceutically acceptable salts, prodrugs and/or solvates thereof are administered or used in combination with one or more asparagine synthetase (ASNS) inhibitors and/or with L-asparaginase for treating a cancer associated with asparagine synthetase (ASNS) overexpression or dysregulation. In some embodiments, the chemotherapeutic agents are one or more asparagine synthetase (ASNS) inhibitors and L- asparaginase [00271] In some embodiments, the cancer is associated with low asparagine synthetase (ASNS) expression and low glutaminase (e.g. GLS1) expression. In some embodiments, the cancer is associated with low asparagine synthetase (ASNS) expression and low glutaminase (e.g. GLS1) expression and the chemotherapeutic agents are L- asparaginase (L-ASNase) and/or one or more glutaminase inhibitors. Accordingly, in some embodiments, the one or more compounds of the application or pharmaceutically acceptable salts, prodrugs and/or solvates thereof are administered or used in combination with L-asparaginase (L-ASNase) and/or one or more glutaminase inhibitors for improving the efficacy of L-ASNase and/or the one or more glutaminase inhibitors for treating a cancer associated with low asparagine synthetase (ASNS) expression and low glutaminase (e.g. GLS1) expression. In some embodiments, the glutaminase inhibitor is a GLS1 inhibitor. In some embodiments, the chemotherapeutic agents are L-asparaginase (L-ASNase) and one or more glutaminase inhibitors. [00272] In some embodiments, the cancer is associated with asparagine synthetase (ASNS) overexpression or dysregulation and glutaminase (e.g. GLS1) overexpression or dysregulation. In some embodiments, the cancer is associated with asparagine synthetase (ASNS) overexpression or dysregulation and glutaminase (e.g. GLS1) overexpression or dysregulation and the chemotherapeutic agents are L-asparaginase (L-ASNase), one or more glutaminase inhibitors and/or one or more asparagine synthetase (ASNS) inhibitors. Therefore, in some embodiments, the one or more compounds of the application or pharmaceutically acceptable salts, prodrugs and/or solvates thereof are administered or used in combination with L-asparaginase (L-ASNase) and/or one or more glutaminase inhibitors and/or one or more asparagine synthetase (ASNS) inhibitors for improving the efficacy of L-ASNase and/or the one or more glutaminase inhibitors and/or the one or more asparagine synthetase (ASNS) inhibitors for treating a cancer associated with asparagine synthetase (ASNS) overexpression or dysregulation and glutaminase (e.g. GLS1) overexpression or dysregulation. In some embodiments, the glutaminase inhibitors is a GLS1 inhibitor. In some embodiments, the chemotherapeutic agents are L-asparaginase (L-ASNase), one or more glutaminase inhibitors and one or more asparagine synthetase (ASNS) inhibitors. [00273] Compounds of the application are either used alone or in combination with other known agents useful for treating diseases, disorders or conditions treatable by inhibiting GCN2. When used in combination with other agents useful in treating diseases, disorders or conditions that are treatable by inhibiting GCN2, it is an embodiment that the compounds of the application are administered contemporaneously with those agents. As used herein, “contemporaneous administration” 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. The exact details of the administration will depend on the pharmacokinetics of the two substances in the presence of each other and can include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of administration of the other, if the pharmacokinetics are suitable. Design of suitable dosing regimens is routine for one skilled in the art. In particular embodiments, two substances will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition that contains both substances. It is a further embodiment of the present application that a combination of agents is administered to a subject in a non-contemporaneous fashion In some embodiments compounds of the present application are administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present application provides a single unit dosage form comprising one or more compounds of the application (e.g. a compound of Formula I), an additional therapeutic agent, and a pharmaceutically acceptable carrier. [00274] Treatment methods comprise administering to a subject a therapeutically effective amount of one or more of the compounds of the application and optionally consist of a single administration, or alternatively comprise a series of administrations, and optionally comprise concurrent administration or use of one or more other therapeutic agents. For example, in some embodiments, the compounds of the application may be administered at least once a week. In some embodiments, the compounds may be administered to the subject from about one time per two or three weeks, or about one time per week to about once daily for a given treatment. In another embodiment, the compounds are administered 2, 3, 4, 5 or 6 times daily. The length of the treatment period depends on a variety of factors, such as the severity of the disease, disorder or condition, the age of the subject, the concentration and/or the activity of the compounds of the application, and/or a combination thereof. It will also be appreciated that the effective dosage of the compound used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compounds are administered to the subject in an amount and for duration sufficient to treat the subject. In some embodiments treatment comprise prophylactic treatment. For example, a subject with early cancer can be treated to prevent progression, or alternatively a subject in remission can be treated with a compound or composition of the application to prevent recurrence. [00275] The dosage of compounds of the application varies depending on many factors such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate of the compound in the subject to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. Compounds of the application may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. Dosages will generally be selected to maintain a serum level of compounds of the application from about 0.01 µg/cc to about 1000 µg/cc or about 01 µg/cc to about 100 µg/cc As a representative example oral dosages of one or more compounds of the application will range between about 0.05 mg per day to about 1000 mg per day for an adult, suitably about 0.1 mg per day to about 500 mg per day, more suitably about 1 mg per day to about 200 mg per day. For parenteral administration, a representative amount is from about 0.001 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 1 mg/kg or about 0.1 mg/kg to about 1 mg/kg will be administered. For oral administration, a representative amount is from about 0.001 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 1 mg/kg or about 0.1 mg/kg to about 1 mg/kg. For administration in suppository form, a representative amount is from about 0.1 mg/kg to about 10 mg/kg or about 0.1 mg/kg to about 1 mg/kg. Compounds of the application may be administered in a single daily, weekly or monthly dose or the total daily dose may be divided into two, three or four daily doses. [00276] In an embodiment, effective amounts vary according to factors such as the disease state, age, sex and/or weight of the subject. In a further embodiment, the amount of a given compound or compounds that will correspond to an effective amount will vary depending upon factors, such as the given drug(s) or compound(s), the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. [00277] To be clear, in the above, the term “a compound” also includes embodiments wherein one or more compounds are referenced. Likewise, the term “compounds of the application” also includes embodiments wherein only one compound is referenced. V. Methods of Preparation of Compounds of the Application [00278] Compounds of the present application can be prepared by various synthetic processes. The choice of particular structural features and/or substituents may influence the selection of one process over another. The selection of a particular process to prepare a given compound of Formula I is within the purview of the person of skill in the art. Some starting materials for preparing compounds of the present application are available from commercial chemical sources. Other starting materials, for example as described below, are readily prepared from available precursors using straightforward transformations that are well known in the art. [00279] The compounds of Formula I generally can be prepared according to the processes illustrated in the Schemes below. In the structural formulae shown below the variables are as defined in Formula I unless otherwise stated. A person skilled in the art would appreciate that many of the reactions depicted in the Schemes below would be sensitive to oxygen and water and would know to perform the reaction under an anhydrous, inert atmosphere if needed. Reaction temperatures and times are presented for illustrative purposes only and may be varied to optimize yield as would be understood by a person skilled in the art. [00280] Accordingly, in some embodiments, the compounds of Formula I, are prepared as shown in Scheme 1. Scheme 1 Therefore, in some embodiments the compound of Formula B or a protected version thereof, is coupled with a 2-halo-substituted quinazoline compound of Formula A (wherein Y and Y' are each independently halogen, such as Br) in the presence of a suitable base such as K₂CO₃ or DBU and in a suitable solvent such as MeCN or DMF to afford intermediate compound of Formula C. The compound of Formula C is boronated, for example under standard borylation conditions such as in the presence of suitable reagents such a s bispinacolatodiboron, PdCl₂dppf:CH₂Cl₂ complex, and a base such as KOAc and in a suitable solvent such as dioxane at a suitable temperature, such as 100-110^oC to provide the boronated compound of Formula D wherein R^a and R^b 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. Subsequent treatment of the compound of Formula D with various halo-sulfonamides of Formula G wherein Y'' is halogen (prepared by coupling the corresponding sulfonyl halide compound of Formula E wherein Y''' is halogen with the aniline compound of Formula F for example under suitable coupling conditions) using suitable conditions such the Suzuki-Miyaura coupling conditions provide compounds of Formula I. Scheme 2 [00281] In an embodiment, as shown in Scheme 2, the intermediate compound of Formula C wherein Y is halogen is coupled with asubstituted-3-anilino-boronate compound of Formula H (prepared from commercially available or synthesized 3-halo-aniline compounds of Formula F wherein Y'' is halogen) under suitable coupling conditions such as under Suzuki-Miyaura coupling conditions to provide intermediate compounds of formula J. Sulfonylation of the compounds of Formula J with heterocyclic containing sulfonyl halide compounds of Formula E wherein Y''' is halogen, under for example basic conditions provides the compounds of Formula I. [00282] Generally, the reactions described above are performed in a suitable inert organic solvent and at temperatures and for times that will optimize the yield of the desired compounds. Examples of suitable inert organic solvents include, but are not limited to, 2- propanol, dimethylformamide (DMF), 1,4-dioxane, methylene chloride, chloroform, tetrahydrofuran (THF), toluene, and the like. [00283] 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. [00284] 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. [00285] The formation of solvates will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a “hydrate”. The formation of solvates of the compounds of the application will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art. [00286] Prodrugs of the compounds of the present application may be, for example, conventional esters formed with available hydroxy, thiol, amino or carboxyl groups. For example, available hydroxy or amino groups may be acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g. an acid chloride in pyridine). [00287] Throughout the processes described herein it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in “Protective Groups in Organic Synthesis”, T.W. Green, P.G.M. Wuts, Wiley-Interscience, New York, (1999). It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to one skilled in the art. Examples of transformations are given herein, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are given in “Comprehensive Organic Transformations – A Guide to Functional Group Preparations” R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “Advanced Organic Chemistry”, March, 4th ed. McGraw Hill (1992) or, “Organic Synthesis”, Smith, McGraw Hill, (1994). Techniques for purification of intermediates and final products include, for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by one skilled in the art. [00288] 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. [00289] One skilled in the art will recognize that where a reaction step of the present application is carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems EXAMPLES [00290] The following non-limiting examples are illustrative of the present application: Synthesis and Characterization of Exemplary Compounds of the Application General Method SNAR (SNAr ) [00291] 6-Bromo-2-chloroquinazoline (1 equiv), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (2 equiv) and a cyclohexanediamine (2 equiv) in MeCN were heated with stirring in a sealed vial at 120 ^oC in a microwave reactor. Either a precipitate was directly collected by filtration, rinsing the filter cake with MeCN or the reaction mixture was concentered under reduced pressure onto Celite and purified by flash chromatography on silica gel (using one of the cartridges: InnoFlash®, Biotage®, RediSep®Rf). General Method MB (Miyaura borylation) [00292] A degassed 1,4-dioxane mixture of N1-(6-bromoquinazolin-2-yl)- cyclohexyldiamine (1.0 equiv), B2pin2 (1.3 equiv), KOAc (3.5 equiv) and typically PdCl₂dppf^.CH₂Cl₂ (0.1 equiv) were heated sealed under argon in a microwave reactor (typically, 100 ^oC) or oil bath (typically, 100-110 ^oC). The crude mixture was then most often used in the following Suzuki-Miyaura cross coupling step without further purification. General Method SMC (Suzuki Miyaura Crosscoupling) [00293] A vial equipped with a stirring bar, filled with Ar or N₂, was charged with aryl boronic acid or aryl boronic ester (typically 1-1.5 equiv, in most instances aryl boronic esters were used as crude mixtures in 1,4-dioxane), base (Cs₂CO₃ typically 3 equiv), aryl halide (typically 1 equiv), catalyst/ligand (one of: PdCl₂dppf or PdCl₂dppf^.CH₂Cl₂; typically, 0.1 equiv). The vial was sealed, H₂O and organic solvent or a mixture of organic solvents (DME, 1,4-dioxane) were added. The reaction mixture was degassed with Ar or N₂ by repeated evacuation and refill with the inert gas and then heated, sealed in a microwave reactor or an oil bath for the time specified. After the reaction was deemed complete by LCMS analysis, the mixture was concentrated under reduced pressure, deposited on a plug of Celite or a SiO₂ samplet and purified by flash chromatography (typically using SiO₂ InnoFlash® cartridge or SiO₂ Biotage® cartridge or SiO₂ RediSep®Rf cartridge and hexanes-EtOAc or CH₂Cl₂–MeOH or CH₂Cl₂–MeOH-NH3) or preparative HPLC (typically using Biotage® SNAP KP-C₁₈-HS cartridge or RedisSep®Rբ C₁₈ and MeOH in H₂O + 0.05 % TFA or MeCN in H₂O + 0.1 % formic acid), optionally followed by a filtration through a Waters PoraPak™ CX column or an Isolute™ CSX-2 column, rinsing with MeOH and eluting the desired material with 2 M NH₃ in MeOH. General Method for NS (N-sulfonylation) [00294] A solution of substituted 3-bromoaniline (1 equiv) and anh pyridine (typically 1.5-2.0 equiv) in CH₂CI₂ (typically 0.06-0.19 M) was treated with one portion of solid 5- chloro-2-methoxypyridine-3-sulfonyl chloride (typically, 1 equiv) at 0 ^oC. The reaction was allowed slowly to reach rt and stirring was continued overnight. The reaction mixture was then concentrated under reduced pressure onto Celite or alternatively washed by extraction with H₂O, the organic extracts were concentrated under reduced pressure and depositing on Biotage® samplet or Celite and purified by flash chromatography on silica gel using one of the cartridges: InnoFlash®, Biotage®, RediSep®Rf. Example 1: Synthesis of 5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin- 6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (I-1) Step 1: N1-(6-bromoquinazolin-2-yl)-N4,N4-dimethylcyclohexane-1,4-diamine [00295] Prepared by General Method SNAR using 6-bromo-2-chloroquinazoline (200 mg, 0.82 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL, 1.6 mmol) and N1,N1- dimethylcyclohexane-1,4-diamine (cis/trans mixture, 234 mg, 1.64 mmol) in MeCN (5 mL); by heating at 120 ^oC for 1 h. N1-(6-bromoquinazolin-2-yl)-N4,N4-dimethylcyclohexane-1,4- diamine was isolated by filtration as a light yellow solid (80 mg, 28 % yield, 2.6:1.0 mixture of isomers). MS (ESI) m/z 349.1/351.1 [M+H]⁺. Step 2: N1,N1-dimethyl-N4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2- yl)cyclohexane-1,4-diamine [00296] Prepared by General Method MB using N1-(6-bromoquinazolin-2-yl)-N4,N4- dimethylcyclohexane-1,4-diamine (80 mg, 0.23 mmol, mixture of cis/trans isomers), B2pin2 (76 mg, 0.30 mmol), KOAc (79 mg, 0.80 mmol) and PdCl₂dppf^.CH₂Cl₂ (18 mg, 0.023 mmol) in 1,4-dioxane (8 mL); by heating in an oil bath at 110 ^oC for 2 h. The crude mixture was used directly in the following Suzuki-Miyaura cross coupling step. MS (ESI) m/z 397.57 [M+H]⁺. Step 3: N-(3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide [00297] Prepared by General Method NS using 3-bromo-2,4-difluoroaniline (400 mg, 1.92 mmol), pyridine (0.23 mL, 2.9 mmol) and 5-chloro-2-methoxypyridine-3-sulfonyl chloride (466 mg, 1.92 mmol) in CH₂CI₂ (10 mL). The reaction mixture was concentrated under reduced pressure, deposited on a plug of SiO₂ and purified by flash chromatography (using CH₂CI₂) to afford N-(3-bromo-2,4-difluorophenyl)-2-chloro-5-methoxypyridine-3- sulfonamide as a tan solid (758 mg, 95 % yield). MS (ESI) 411.2/413.2 [M-H]-. Step 4: 5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4- difluorophenyl)-2-methoxypyridine-3-sulfonamide [00298] Prepared by General Method SMC using a crude solution of N1,N1- dimethyl-N4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)cyclohexane- 1,4-diamine (80 mg, 0.20 mmol, mixture of cis/trans isomers), 1,4-dioxane (5 mL), H₂O (2.5 mL), Cs₂CO₃ (132 mg, 0.40 mmol), N-(3-bromo-2,4-difluorophenyl)-5-chloro-2- methoxypyridine-3-sulfonamide (88 mg, 0.20 mmol) and PdCl₂dppf^.CH₂Cl₂ (16 mg, 0.020 mmol); by heating in a microwave reactor at 90 °C for 1.5 h. Purified by flash chromatography using MeOH in CH₂CI₂ followed by a filtration through a Waters PoraPak CX column and later a preparative HPLC using MeOH in H₂O to afford 5-chloro-N-(3-(2- ((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-2- methoxypyridine-3-sulfonamide as a white solid (25 mg, 21 % yield, ratio for the two geometric isomers: 97:3).¹H NMR (500 MHz, DMSO-d6) δ ppm 9.14 (br. s., 1 H), 8.32 (d, J=2.57 Hz, 1 H), 8.02 (d, J=2.57 Hz, 1 H), 7.74 - 7.83 (m, 1 H), 7.62 (d, J=8.68 Hz, 1 H), 7.39 - 7.55 (m, 2 H), 7.21 (td, J=9.11, 6.11 Hz, 1 H), 6.90 - 7.05 (m, 1 H), 3.84 (s, 5 H), 2.70 (br. s., 1 H), 2.49 (s, 6 H), 2.08 (br. s., 2 H), 1.94 (d, J=11.62 Hz, 2 H), 1.48 (q, J=11.49 Hz, 2 H), 1.29 - 1.40 (m, 2 H). MS (ESI) m/z 603.6 [M+H]⁺. [00299] NB: The pure trans-isomer (I-1 trans, (I-2)) or pure cis isomer (I- cis, I-3) are prepared from the corresponding cis- or trans- N1,N1-dimethylcyclohexane-1,4-diamine. [00300] A synthesis of I-2 is provided in example 14. Example 2: Synthesis of cis-5-chloro-N-(3-(2-((4- (dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)pyridine-3- sulfonamide, trifluoroacetic acid) (Trifluoroacetic acid salt of I-5, I-5.CF₃CO₂H) Step 1 N-(3-bromo-2,4-difluorophenyl)-5-chloropyridine-3-sulfonamide [00301] Prepared following Method NS using CH₂CI₂ (20 mL), 5-chloropyridine-3- sulfonyl chloride (250 mg, 1.18 mmol), 3-bromo-2,4-difluoroaniline (245 mg, 1.18 mmol) and pyridine (0.19 mL, 2.36 mmol). The reaction mixture was partitioned between H₂O and CH₂CI₂. The organic phase was washed with H₂O. The combined organic layers were concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (using EtOAc in hexanes) to afford N-(3-bromo-2,4-difluorophenyl)-5- chloropyridine-3-sulfonamide as a tan solid (323.0 mg, 71 % ). MS (ESI)₃83.03/385.16 [M+H]⁺. Step 2: N1-(6-bromoquinazolin-2-yl)-N4,N4-dimethylcyclohexane-1,4-diamine [00302] Following General Method SNAR using N1,N1-dimethylcyclohexane-1,4- diamine (351 mg, 2.464 mmol, mixture of cis isomers), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.74 mL, 4.9 mmol), MeCN (20 mL) and 6-bromo-2-chloroquinazoline (600 mg, 2.46 mmol); by heating in a microwave reactor at 120 ºC for 2 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (using CH₂CI₂/MeOH/ conc aq NH₄OH 89/10/1 in CH₂CI₂) to afford N1-(6-bromoquinazolin-2-yl)-N4,N4-dimethylcyclohexane-1,4-diaminex as a pale yellow solid (634.0 mg, 74 % yield, the two isomers in the ratio of 1.0:1.9 ). MS (ESI) 349.1/351.1 [M+H]⁺. Step 3: N1,N1-dimethyl-N4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2- yl)cyclohexane-1,4-diamine [00303] Prepared following General Method MB using N1-(6-bromoquinazolin-2-yl)- N4,N4-dimethylcyclohexane-1,4-diamine (634 mg, 1.815 mmol), B₂pin₂ (599 mg, 2.360 mmol), KOAc (624 mg, 6.35 mmol), PdCl₂dppf^.CH₂Cl₂ (148 mg, 0.182 mmol) in 1,4-dioxane (20 mL); by heating an oil bath at 110 ^oC for 2 h. MS (ESI) 397.38 [M+H]⁺. The crude mixture of cis and trans isomers was used in the following Suzuki-Miyaura cross coupling step. Step 3: 5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4- difluorophenyl)pyridine-3-sulfonamide, trifluoroacetic acid [00304] Prepared following General Method SMC using N-(3-bromo-2,4- difluorophenyl)-5-chloropyridine-3-sulfonamide (70 mg, 0.18 mmol), Cs₂CO₃ (119 mg, 0.36 mmol), PdCl₂dppf^.CH₂Cl₂ (15 mg, 0.018 mmol), crude N1,N1-dimethyl-N4-(6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)cyclohexane-1,4-diamine (2.0 mL, 0.18 mmol, 0.091 M) and H₂O (1.0 mL); by heating sealed in a microwave reactor at 90 ºC for 90 min. The reaction mixture was purified by flash chromatography (using CH₂CI₂/MeOH/conc aq NH₄OH 89/10/1 in CH₂CI₂) followed by preparative HPLC to afford cis-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4- difluorophenyl)pyridine-3-sulfonamide, trifluoroacetic acid as a pale yellow solid (19.0 mg, 17 % yield, 97:3 ratio of isomers).¹H NMR (500 MHz, CD₃OD) δ ppm 8.91 - 9.27 (m, 1 H), 8.61 - 8.74 (m, 2 H), 7.99 - 8.11 (m, 1 H), 7.71 (br. s., 1 H), 7.52 - 7.59 (m, 1 H), 7.36 - 7.44 (m, 1 H), 7.17 - 7.31 (m, 1 H), 6.99 - 7.11 (m, 1 H), 4.30 (br. s., 1 H), 3.98 (br. s., 1 H), 2.73 - 2.88 (m, 6 H), 1.62 - 2.20 (m, 8 H). MS (ESI) found 573.21 [M+H]⁺. [00305] The pure trans-isomer (trans, I-4) and trifluoroacetic acid salt (I-4.CF₃CO₂H) is prepared from the corresponding trans- N1,N1-dimethylcyclohexane-1,4-diamine. Example 3: Synthesis of rac-5-chloro-N-(3-(2-(((1R,3S)-3- (dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-2-methoxypyridine- 3-sulfonamide (I-6) Step 1: rac-(1R,3S)-N1-(6-bromoquinazolin-2-yl)cyclohexane-1,3-diamine. [00306] Prepared by General Method SNAR using 6-bromo-2-chloroquinazoline (600 mg, 2.46 mmol), cis-cyclohexane-1,3-diamine dihydrochloride (461 mg, 2.46 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.5 mL, 9.9 mmol) in MeCN (20 mL); by heating in a microwave reactor at 120 ºC for 2 h. Purified by flash chromatography to afford (rac- (1R,3S)-N1-(6-bromoquinazolin-2-yl)cyclohexane-1,3-diamine as a grey waxy solid (897.0 mg, quant yield based on purity of 92 %). MS (ESI) 321.12/323.08 [M+H]⁺. Step 2: rac-(1R,3S)-N1-(6-bromoquinazolin-2-yl)-N3,N3-dimethylcyclohexane-1,3-diamine [00307] Rac-(1R,3S)-N1-(6-bromoquinazolin-2-yl)cyclohexane-1,3-diamine (120 mg, 0.34 mmol, 92 %) in THF (15 mL) was treated with a formaldehyde solution,( 37% wt in H₂O, 0.28 mL, 3.8 mmol) at rt. After 1 h 40 min of stirring at rt NaBH(OAc)₃ (299 mg, 1.41 mmol) was added in one portion and stirring was continued for 1 d. Another portion of NaBH(OAc)₃ (153 mg, 0.72 mmol) was then added. After additional day of stirring at rt, EtOH and H₂O were added and the reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography on silica gel using CH₂CI₂/MeOH/conc aq NH₄OH 89/10/1 in CH₂CI₂ to afford rac-(1R,3S)-N1-(6- bromoquinazolin-2-yl)-N3,N3-dimethylcyclohexane-1,3-diamine as a pale yellow solid ( 26.0 mg, 19 % yield). MS (ESI) 349.18 [M+H]⁺. Step 3: rac-(1R,3S)-N1,N1-dimethyl-N3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinazolin-2-yl)cyclohexane-1,3-diamine [00308] Prepared by General Method MB using rac-(1R,3S)-N1-(6- bromoquinazolin-2-yl)-N3,N3-dimethylcyclohexane-1,3-diamine (42 mg, 0.11 mmol), B₂pin₂ (36.9 mg, 0.145 mmol), KOAc (38.4 mg, 0.391 mmol), PdCl₂dppf^.CH₂Cl₂(9.1 mg, 0.011 mmol) and 1,4-dioxane (3 mL); by heating an oil bath at 110 °C for 1.5 h. The crude mixture of rac-(1R,3S)-N1,N1-dimethyl-N3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinazolin-2-yl)cyclohexane-1,3-diamine was used directly in the following Suzuki- Miyaura cross coupling step. Step 4: rac-5-chloro-N-(3-(2-(((1R,3S)-3-(dimethylamino)cyclohexyl)amino)quinazolin-6- yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide [00309] Prepared by General Method SMC using N-(3-bromo-2,4-difluorophenyl)-5- chloro-2-methoxypyridine-3-sulfonamide (46.3 mg, 0.112 mmol), Cs₂CO₃ (73.0 mg, 0.224 mmol), PdCl₂dppf^.CH₂Cl₂(9.1 mg, 0.011 mmol), rac-(1R,3S)-N1,N1-dimethyl-N3-(6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)cyclohexane-1,3-diamine (44.3 mg, 0.112 mmol, 3 mL in 1,4-dioxane, crude) and H₂O (1.5 mL); by heating in a microwave reactor at 90 ºC for 90 min. Purified by flash chromatography on silica gel followed by preparative HPLC and filtration through a Waters PoraPak CX column to afford rac-5-chloro-N-(3-(2-(((1R,3S)-3-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4- difluorophenyl)-2-methoxypyridine-3-sulfonamide as a an off white solid (10.2 mg, 15% yield).¹H NMR (500 MHz, CD₃OD) δ ppm 10.39 (br. s., 1 H), 9.65 (br. s., 1 H), 9.18 (br. s., 1 H), 9.09 (s, 1 H), 8.51 (d, J=2.08 Hz, 1 H), 8.07 (d,J=2.08 Hz, 1 H), 7.77 - 7.91 (m, 1 H), 7.68 - 7.76 (m, 3 H), 7.51 - 7.65 (m, 2 H), 7.27 - 7.37 (m, 1 H), 7.18 - 7.26 (m, 1 H), 4.01 (br. s., 1 H), 3.91 (s, 3 H), 2.75 (br. s., 6 H), 1.78 - 2.13 (m, 3 H), 1.19 - 1.54 (m, 4 H), 1.05 (t, J=6.97 Hz, 1 H). MS (ESI) found 603.3 [M+H]⁺. Example 4: Synthesis of N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)- 2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (I-7) Step 1: N-(3-bromo-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide [00310] Prepared by General Method NS using CH₂CI₂ (20 mL), 2-methoxypyridine- 3-sulfonyl chloride (250 mg, 1.20 mmol), 3-bromo-2,4-difluoroaniline (250 mg, 1.20 mmol), pyridine (0.24 mL, 3.0 mmol). After the completion, the reaction was partitioned between H₂O and CH₂CI₂. The organic phase was washed with H₂O. The combined organic layers were concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (using EtOAc in hexanes) to afford N-(3-bromo-2,4-difluorophenyl)-2- methoxypyridine-3-sulfonamide as a beige solid (387.0 mg, 81 %). MS (ESI) 379.08/381.15 [M+H]⁺. Step 2: N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)- 2-methoxypyridine-3-sulfonamide [00311] Prepared by General Method SMC using N-(3-bromo-2,4-difluorophenyl)-2- methoxypyridine-3-sulfonamide (70 mg, 0.18 mmol)), Cs₂CO₃ (119 mg, 0.364 mmol), PdCl₂dppf^.CH₂Cl₂(14.9 mg, 0.018 mmol), N1,N1-dimethyl-N4-(6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazolin-2-yl)cyclohexane-1,4-diamine (2.0 mL, 0.18 mmol in 1,4- dioxane 2 mL, crude 0.091 M) and H₂O (1.0 mL); by heating in a microwave reactor at 90 ºC for 90 min. Purified by flash chromatography and later by preparative HPLC followed by a filtration through a Waters PoraPak CX column to afford N-(3-(2-((4- (dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-2-methoxypyridine- 3-sulfonamide as an off white solid (7.0 mg, 7 % yield, 98.5:1.5 ratio of isomers).¹H NMR (500 MHz, DMSO-d6) δ ppm 10.18 (s, 1 H), 9.39 (br. s., 1 H), 9.21 (br. s., 1 H), 8.41 (dd, J=4.89, 1.71 Hz, 1 H), 8.06 (dd, J=7.58, 1.71 Hz, 1 H), 7.81 (br. s., 2 H), 7.49 - 7.65 (m, 2 H), 7.26 - 7.34 (m, 1 H), 7.20 (t, J=8.93 Hz, 1 H), 7.13 (dd, J=7.58, 5.01 Hz, 1 H), 4.28 (br. s., 1 H), 3.92 (s, 4 H), 3.24 (dd, J=11.49, 8.56 Hz, 1 H), 2.76 (d, J=4.89 Hz, 6 H), 2.02 (d, J=11.00 Hz, 2 H), 1.74 - 1.92 (m, 4 H), 1.67 (t, J=13.33 Hz, 2 H). MS (ESI) 569.43 [M+H]⁺. Example 5: Synthesis of rac-5-chloro-N-(3-(2-(((1R,3R)-3- (dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-2-methoxypyridine- 3-sulfonamide (I-8) Step 1: Rac-(1R,3R)-N1-(6-bromoquinazolin-2-yl)cyclohexane-1,3-diamine [00312] Prepared by General Method SNAR using 1,8-diazabicyclo[5.4.0]undec-7- ene (0.19 mL, 1.3 mmol), 6-bromo-2-chloroquinazoline (153 mg, 0.63 mmol) and trans-1,3- cyclohexanediamine (79 mg, 0.69 mmol) in MeCN (15 mL); by heating in a microwave reactor at 120 ºC for 2 h. Purified by flash chromatography to afford rac-(6- bromoquinazolin-2-yl)cyclohexane-1,3-diamine as a brown gum (146.0 mg, 72 % yield). MS (ESI) 321.22/323.23 [M+H]⁺. Step 2: rac-(1R,3R)-N1-(6-bromoquinazolin-2-yl)-N3,N3-dimethylcyclohexane-1,3-diamine [00313] Rac-(1R,3R)-N1-(6-bromoquinazolin-2-yl)cyclohexane-1,3-diamine (146 mg, 0.45 mmol) in formic acid (4.0 mL, 107 mmol) was treated with formaldehyde solution (37% wt in H₂O, 0.34 mL, 4.5 mmol) at rt. The vial was sealed and heated in an oil at 100 ^oC for 2 h, later the reaction mixture was left standing at rt overnight. The reaction was then concentrated under reduced pressure, xs 7 M NH₃ in MeOH was added and the material was concentrated again while being deposited on Celite. Purified by flash chromatography (using CH₂CI₂/MeOH/NH₄OH 89:10:1 in CH₂CI₂) to afford rac-(1R,3R)-N1-(6- bromoquinazolin-2-yl)-N3,N3-dimethylcyclohexane-1,3-diamine as a pale yellow solid (48.0 mg, 26 % yield based on purity of 87 %). MS (ESI) 349.2/351.1 [M+H]⁺. Step 3: rac-(1R,3R)-N1,N1-dimethyl-N3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinazolin-2-yl)cyclohexane-1,3-diamine [00314] Prepared by General Method MB using 1,4-dioxane (5 mL), rac-(1R,3R)- N1-(6-bromoquinazolin-2-yl)-N3,N3-dimethylcyclohexane-1,3-diamine (48 mg, 0.12 mmol, 87 %), B₂pin₂ (39.5 mg, 0.155 mmol), KOAc (41 mg, 0.42 mmol) and PdCl₂dppf^.CH₂Cl₂(9.8 mg, 0.012 mmol); by heating in an oil bath at 105 °C for 1.5 h. The crude mixture was used directly in the following Suzuki-Miyaura cross coupling step. MS (ESI) 397.5 [M+H]⁺. Step 4: Rac-5-chloro-N-(3-(2-(((1R,3R)-3-(dimethylamino)cyclohexyl)amino)quinazolin-6- yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide [00315] Prepared by General Method SMC using N-(3-bromo-2,4-difluorophenyl)-5- chloro-2-methoxypyridine-3-sulfonamide (0.055 g, 0.13 mmol), Cs₂CO₃ (0.087 g, 0.27 mmol), PdCl₂dppf^.CH₂Cl₂ (10.9 mg, 0.013 mmol), rac-(1R,3R)-N1,N1-dimethyl-N3-(6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)cyclohexane-1,3-diamine (0.047 g, 0.12 mmol, in 1,4-dioxane 5 mL, crude) and H₂O (2.5 mL); by heating in an oil bath at 95 ºC for 1. 5 h. The reaction was cooled to rt and another batch of PdCl₂dppf^.CH₂Cl₂(11 mg, 0.013 mmol) was added. The reaction mixture that was then heated in an oil bath at 95 ^oC for 2.5 h. Purified by flash chromatography followed by preparative HPLC and a filtration through a Waters PoraPak CX column to afford rac-5- chloro N(3(2(((1R3R) 3 (dimethylamino)cyclohexyl)amino)quinazolin6yl) 24 difluorophenyl)-2-methoxypyridine-3-sulfonamide as a beige solid ( 16.3 mg, 20 % yield). ¹H NMR (500 MHz, DMSO-d6) δ ppm 9.10 (br. s., 1 H), 8.30 (br. s., 1 H), 7.96 (d, J=2.08 Hz, 1 H), 7.74 (s, 1 H), 7.56 (d, J=8.68 Hz, 1 H), 7.44 (d,J=8.56 Hz, 2 H), 7.12 - 7.25 (m, 1 H), 6.98 (d, J=8.31 Hz, 1 H), 4.27 (br. s., 1 H), 3.79 (s, 3 H), 1.35 - 1.96 (m, 10 H). MS (ESI) 603.33 [M+H]⁺. Example 6: Synthesis of N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)- 2,4-difluorophenyl)-2-(trifluoromethyl)pyridine-3-sulfonamide (I-9)

Step 1: N-(3-bromo-2,4-difluorophenyl)-2-(trifluoromethyl)pyridine-3-sulfonamide

[00316] Prepared by General Method NS using CH₂CI₂(12 mL), 2- (trifluoromethyl)pyridine-3-sulfonyl chloride (0.27 g, 1.1 mmol), 3-bromo-2,4-difluoroaniline (0.23 g, 1.1 mmol), pyridine (0.27 mL, 3.3 mmol). After the completion, the reaction was partitioned between H₂O and CH₂CI₂. The organic phase was washed with H₂O. The combined organic layers were concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (using CH₂CI₂/MeOH/aq NH4OH 89:10:1 in CH₂CI₂) to afford N-(3-bromo-2,4-difluorophenyl)-2-(trifluoromethyl)pyridine-3-sulfonamide as a beige solid (301 mg, 64 % based on the purity of 98%). MS (ESI) found 417.19/419.13 [M+H]⁺. Step 2: N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)- 2-(trifluoromethyl)pyridine-3-sulfonamide

[00317] Prepared by General Method SMC using N-(3-bromo-2,4-difluorophenyl)-2- (trifluoromethyl)pyridine-3-sulfonamide (0.080 g, 0.19 mmol), Cs₂CO₃ (0.128 g, 0.39 mmol), PdCl₂dppf^.CH₂Cl₂(0.016 g, 0.020 mmol), N1,N1-dimethyl-N4-(6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazolin-2-yl)cyclohexane-1,4-diamine (2.16 mL, 0.20 mmol, in 1,4- dioxane, crude) and H₂O (1.0 mL); by heating in a microwave reactor at 90 ºC for 90 min. Purified by flash chromatography (using CH₂CI₂/MeOH/conc aq NH₄OH 89/10/1) followed by preparative HPLC (MeCN/H₂O + 0.1 % HCO₂H) and a filtration through a Waters PoraPak CX column to afford N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6- yl)-2,4-difluorophenyl)-2-(trifluoromethyl)pyridine-3-sulfonamide as an off white solid (10.0 mg, 8 % yield, 91:9 ratio of isomers).¹H NMR (500 MHz, CD₃OD) δ ppm 8.96 (s, 1 H), 8.64 (d, J=4.40 Hz, 1 H), 8.37 (d, J=8.07 Hz, 1 H), 7.65 (s, 1 H), 7.60 (dd, J=8.01, 4.71 Hz, 1 H), 7.51 - 7.56 (m, 1 H), 7.44 - 7.49 (m, 1 H), 7.14 - 7.22 (m, 1 H), 6.83 (t, J=9.11 Hz, 1 H), 4.18 (br. s., 1 H), 2.88 - 2.99 (m, 1 H), 2.64 (s, 6 H), 2.09 (d, J=12.59 Hz, 2 H), 1.59 - 1.88 (m, 6 H). MS (ESI) found 607.3 [M+H]⁺. Example 7: Synthesis of 2-(difluoromethoxy)-N-(3-(2-((4- (dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)pyridine-3- sulfonamide dihydrochloride) (DiHydrochloride salt of I-10, I-10.2HCl) Step 1: N-(3-bromo-2,4-difluorophenyl)-2-(difluoromethoxy)pyridine-3-sulfonamide [00318] Prepared by General Method NS using CH₂CI₂ (12 mL), 2- (difluoromethoxy)pyridine-3-sulfonyl chloride (0.26 g, 1.05 mmol), 3-bromo-2,4- difluoroaniline (0.22 g, 1.0 mmol), pyridine (0.25 mL, 3.2 mmol). After the completion the reaction was partitioned between H₂O and CH₂CI₂. The organic phase was washed with H₂O. The combined organic layers were concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (using CH₂CI₂/MeOH/aq NH₄OH 89:10:1 in CH₂CI₂) to afford N-(3-bromo-2,4-difluorophenyl)-2-(difluoromethoxy)pyridine-3- sulfonamide as an off white solid (254 mg, 55 % based on the purity of 95 %). MS (ESI) found 415.06/417.13 [M+H]⁺. Step 2: 2-(difluoromethoxy)-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)- 2,4-difluorophenyl)pyridine-3-sulfonamide [00319] Prepared by General Method SMC using N-(3-bromo-2,4-difluorophenyl)-2- (difluoromethoxy)pyridine-3-sulfonamide (0.080 g, 0.19 mmol, 95 %), Cs₂CO₃ (0.128 g, 0.39 mmol), PdCl₂dppf^.CH₂Cl₂(0.016 g, 0.020 mmol), N1,N1-dimethyl-N4-(6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)cyclohexane-1,4-diamine (2.16 mL, 0.20 mmol, in 1,4-dioxane, crude) and H₂O (1.0 mL); by heating in a microwave reactor at 90 ºC for 90 min. Purified by flash chromatography (using CH₂CI₂/MeOH/conc aq NH₄OH 89/10/1 in CH₂CI₂) followed by preparative HPLC (MeCN/H₂O + 0.1 % HCO₂H) and a filtration through a Waters PoraPak CX column to afford 2-(difluoromethoxy)-N-(3-(2-((4- (dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)pyridine-3- sulfonamide as an off white solid (10.0 mg, 8 % yield).¹H NMR (500 MHz, CD₃OD) δ ppm 8.88 - 9.01 (m, 1 H), 8.26 (dd, J=4.83, 1.53 Hz, 1 H), 8.18 (dd, J=7.70, 1.59 Hz, 1 H), 7.64 (s, 1 H), 7.54 (t, J= 71.8 Hz, 1 H), 7.45 - 7.53 (m, 2 H), 7.32 (td, J=8.77, 5.81 Hz, 1 H), 7.19 (dd, J=7.70, 4.89 Hz, 1 H), 6.90 (t, J=9.11 Hz, 1 H), 4.16 (br. s., 1 H), 2.77 (br. s., 1 H), 2.50 - 2.58 (m, 6 H), 2.06 (d, J=10.76 Hz, 2 H), 1.60 - 1.85 (m, 6 H). MS (ESI) 605.3 [M+H]⁺. Step 3: 2-(difluoromethoxy)-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)- 2,4-difluorophenyl)pyridine-3-sulfonamide, 2Hydrochloride [00320] 2-(difluoromethoxy)-N-(3-(2-((4- (dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)pyridine-3- sulfonamide (10 mg) was taken into MeOH (5 mL) and treated with HCl (0.05 mL, 4 M, 1,4- dioxane) at rt. The reaction was shaken and sonicated then filtered and concentrated under reduced pressure to obtain 2-(difluoromethoxy)-N-(3-(2-((4- (dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)pyridine-3- sulfonamide, 2Hydrochloride as a yellow solid (12.0 mg, 9 %) MS (ESI) 605.3 [M+H]⁺. Example 8: Synthesis of trans-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6- yl)-2,4-difluorophenyl)-5-fluoropyridine-3-sulfonamide (1-11) [00321] A vial containing Cesium carbonate (177 mg, 0.545 mmol), N-(3-bromo-2,4- difluorophenyl)-5-fluoropyridine-3-sulfonamide (100 mg, 0.272 mmol)(RSL-4023-) trans- N1,N1-dimethyl-N4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)quinazolin-2- yl)cyclohexane-1,4-diamine (202 mg, 0.327 mmol) and PdCl₂dppf^.CH₂Cl₂ (22.24 mg, 0.027 mmol) in water (2 mL) and 1,2-Dimethoxyethane (DME) (4 mL) was added. Degassed, heated, sealed in a microwave reactor at 90 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (25 g SiO₂ Innoflash® Cartridge, using MeOH in CH₂CI₂ eluting at 16 % of the more polar phase, pooled fractions:2-5. Repurification by preparative HPLC (30 g Biotage® C₁₈, MeCN in H₂O + 0.1 % FA eluting at 21 % MeCN, pooled fractions:16-21, freeze dried to afford trans-N-(3-(2-((4 dimethylamino)cyclohexyl)amino)quinazolin-6-yl)- 2,4-difluorophenyl)-5 (fluoropyridine-3-sulfonamide as a white solid (6.0 mg, 4 % yield). [00322] LC-MS calcd. for [C₂₇H₂₇F₃N₆O₂S + H]⁺ 557.19; found 557.26 1H NMR (500 MHz, DMSO-d6) δ ppm 9.05 (br. s., 1 H), 8.62 (br. s., 1 H), 8.49 (br. s., 1 H), 8.14 (br. s., 1 H), 7.68 - 7.78 (m, 2 H), 7.55 (d, J=7.70 Hz, 1 H), 7.42 (br. s., 1 H), 7.34 (d, J=6.24 Hz, 1 H), 7.08 (d, J=6.36 Hz, 1 H), 6.73 (t, J=8.74 Hz, 1 H), 6.50 (br. s., 1 H), 3.78 (br. s., 1 H), 2.33 (br. s., 6 H), 2.00 (br. s., 2 H), 1.84 (d, J=8.07 Hz, 2 H), 1.22 - 1.50 (m, 4 H) observed: 27 H, required: 27 H + 119F NMR (471 MHz, DMSO-d6) δ ppm -126.64 (br. s., 1 F), -128.22 (br. s., 1 F), -130.17 (br. s., 1 F) Example 9: Synthesis of cis-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)- 2,4-difluorophenyl)-5-fluoropyridine-3-sulfonamide dihydrochloride (Dihydrochloride salt of I-12, I-12.2HCl) Step 1: N-(3-bromo-2,4-difluorophenyl)-5-fluoropyridine-3-sulfonamide [00323] Prepared by General Method NS using CH₂CI₂ (12 mL), 5-fluoropyridine-3- sulfonyl chloride (0.25 g, 1.29 mmol), 3-bromo-2,4-difluoroaniline (0.269 g, 1.29 mmol) and pyridine (0.31 mL, 3.9 mmol). The reaction was partitioned between H₂O and CH₂CI₂. The organic phase was washed with H₂O. The combined organic layers were concentrated under reduced pressure, deposited on Celite and purified by flash chromatography to afford N-(3-bromo-2,4-difluorophenyl)-5-fluoropyridine-3-sulfonamide as an off white solid with purple tinge (297 mg, 63 % ). MS (ESI) 367.11/369.11 [M+H]⁺. Step 2: cis-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4- difluorophenyl)-5-fluoropyridine-3-sulfonamide [00324] Prepared by General Method SMC using N-(3-bromo-2,4-difluorophenyl)-5- fluoropyridine-3-sulfonamide (0.080 g, 0.22 mmol), Cs₂CO₃ (0.128 g, 0.39 mmol), PdCl₂dppf^.CH₂Cl₂ (0.016 g, 0.020 mmol), cis-N1,N1-dimethyl-N4-(6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)cyclohexane-1,4-diamine (2.16 mL, 0.20 mmol, in 1,4-dioxane, crude) and H₂O (1.0 mL); by heating in a microwave reactor at 90 ºC for 90 min. Purified by flash chromatography followed by preparative HPLC and a filtration through a Waters PoraPak CX column to afford cis-N-(3-(2-((4- (dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-5-fluoropyridine-3- sulfonamide as a light orange solid (13.0 mg, 12 % yield, isomers ratio= 96:4). ¹H NMR (500 MHz, CD₃OD) δ ppm 9.04 (s, 1 H), 8.74 (s, 1 H), 8.59 (d, J=2.69 Hz, 1 H), 7.95 (dt, J=8.07, 2.14 Hz, 1 H), 7.73 (s, 1 H), 7.60 - 7.65 (m, 1 H), 7.53 - 7.58 (m, 1 H), 7.35 (td, J=8.99, 5.87 Hz, 1 H), 6.96 (t, J=9.17 Hz, 1 H), 4.26 (t, J=3.12 Hz, 1 H), 3.00 - 3.08 (m, 1 H), 2.69 - 2.77 (m, 6 H), 2.14 - 2.20 (m, 2 H), 1.71 - 1.96 (m,6 H). MS (ESI) 557.5 [M+H]⁺. Step 3: cis-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4- difluorophenyl)-5-fluoropyridine-3-sulfonamide, 2Hydrochloride [00325] cis-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4- difluorophenyl) 5fluoropyridine 3sulfonamide (13 mg) was taken into MeOH (5 mL) and treated with HCl (0.05 mL, 4 M in dioxane) at rt. The reaction was shaken and sonicated then filtered and concentrated to obtain cis-N-(3-(2-((4- (dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-5-fluoropyridine-3- sulfonamide, 2Hydrochloride as a yellow solid (16.0 mg, 100%). MS (ESI) found 557.5 [M+H]⁺. Example 10: Synthesis of cis-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6- yl)-2,4-difluorophenyl)-5-(trifluoromethyl)pyridine-3-sulfonamide, formic acid (Formic acid salt of I-13, I-13.HCO₂H) Step 1: N-(3-bromo-2,4-difluorophenyl)-5-(trifluoromethyl)pyridine-3-sulfonamide [00326] A CH₂CI₂ (12 mL) solution of 5-(trifluoromethyl)pyridine-3-sulfonyl fluoride (0.255 g, 1.11 mmol) and 3-bromo-2,4-difluoroaniline (0.232 g, 1.11 mmol) was treated with pyridine (0.27 mL, 3.3 mmol) in one portion at 0 ^oC. The reaction was allowed to warm slowly to rt. After 7 d of stirring at rt, CH₂CI₂ was removed under reduced pressure. The liquid residue was diluted with anh DMSO (2 mL) and treated with HOBt (1.5 mg, 0.011 mmol), 1,1,3,3-tetramethyldisiloxane (0.39 mL, 2.2 mmol) and N,N-diisopropylethylamine (0.39 mL, 2.2 mmol). After 8 d of stirring at rt the reaction was concentrated, deposited on Celite and purified by preparative HPLC (using MeCN/H₂O + 0.1 % HCO₂H) to afford N-(3- bromo-2,4-difluorophenyl)-5-(trifluoromethyl)pyridine-3-sulfonamide as an off white solid (162.0 mg, 33 % yield based on purity of 95 %). MS (ESI) 417.1/419.2 [M+H]⁺. Step 2. Cis-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4- difluorophenyl)-5-(trifluoromethyl)pyridine-3-sulfonamide, formic acid [00327] Prepared by General Method SMC using N-(3-bromo-2,4-difluorophenyl)-5- (trifluoromethyl)pyridine-3-sulfonamide (0.087 g, 0.20 mmol, 95 %), Cs₂CO₃ (0.129 g, 0.396 mmol), PdCl₂dppf^.CH₂Cl₂(0.016 g, 0.020 mmol), cis-N1,N1-dimethyl-N4-(6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)cyclohexane-1,4-diamine (2.2 mL, 0.20 mmol, in 1,4-dioxane, crude) and H₂O (1.0 mL); by heating in a microwave reactor at 90 ºC for 90 min. Purified by purified by flash chromatography followed by preparative HPLC (using MeCN/H₂O + 0.1 % HCO₂H) to afford cis-N-(3-(2-((4- (dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-5- (trifluoromethyl)pyridine-3-sulfonamide, formic acid as a pale yellow solid (12.4 mg, 10 % yield, 93:7 mix of isomers).¹H NMR (500 MHz, CD₃OD) δ ppm 9.00 - 9.20 (m, 3 H), 8.40 (s, 1 H), 7.71 (s, 1 H), 7.56 - 7.62 (m, 2 H), 7.43 - 7.53 (m, 1 H), 7.11 (t, J=8.99 Hz, 1 H), 4.31 (br. s., 1 H), 3.19 - 3.31 (m, 1 H), 2.88 (s, 6 H), 2.13 - 2.33 (m, 2 H), 1.68 - 2.02 (m, 6 H). MS (ESI) 607.3 [M+H]⁺. Example 11: Synthesis of cis-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6- yl)-2,4-difluorophenyl)-5-methylpyridine-3-sulfonamide, formic acid (Formic acid salt of I- 14, I-14.HCO₂H) Step 1: N-(3-bromo-2,4-difluorophenyl)-5-methylpyridine-3-sulfonamide [00328] A CH₂CI₂(5 mL) solution of 5-methylpyridine-3-sulfonyl chloride (0.252 g, 1.31 mmol) and 3-bromo-2,4-difluoroaniline (0.274 g, 1.31 mmol) was treated with pyridine (0.32 mL, 3.9 mmol) in one portion at 0 ^oC. The reaction was allowed to warm slowly to rt and then stirred at the temperature for 7 d. Later 1,4-diazabicyclo[2.2.2]octane (0.295 g, 2.63 mmol) was added followed by anh MeCN (20 mL). The reaction was stirred at rt for another 7 d. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography to afford cis-N-(3-bromo-2,4-difluorophenyl)- 5-methylpyridine-3-sulfonamide as a tan solid (146.0 mg, 31 %). MS (ESI) 363.16/365.16 [M+H]⁺. Step 2: cis-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4- difluorophenyl)-5-methylpyridine-3-sulfonamide, formic acid [00329] Prepared by General Method SMC using N-(3-bromo-2,4-difluorophenyl)-5- methylpyridine-3-sulfonamide (0.080 g, 0.22 mmol), Cs₂CO₃ (0.143 g, 0.440 mmol), PdCl₂dppf^.CH₂Cl₂ (0.018 g, 0.022 mmol), cis-N1,N1-dimethyl-N4-(6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)cyclohexane-1,4-diamine (2.42 mL, 0.22 mmol, in 1,4-dioxane, crude) and H₂O (1.0 mL); by heating in a microwave reactor at 90 ºC for 90 min. Purified by flash chromatography followed by preparative HPLC to afford cis-N-(3-(2- ((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-5- methylpyridine-3-sulfonamide, formic acid as a pale yellow solid (15 mg, 11 % yield, 95:5 mixture of isomers).¹H NMR (500 MHz, CD₃OD) δ ppm 9.09 (br. s., 1 H), 8.64 (d, J=14.18 Hz, 2 H), 8.22 - 8.54 (m, 1 H), 8.01 (br. s., 1 H), 7.73 (br. s., 1 H), 7.60 (br. s., 2 H), 7.44 - 7.55 (m, 1 H), 7.14 (t, J=8.80 Hz, 1 H), 4.32 (br. s., 1 H), 2.90 (s, 6 H), 2.42 (s, 3 H), 2.20 - 2.32 (m, 2 H), 1.64 - 2.04 (m, 6H). MS (ESI) 553.4 [M+H]⁺. Example 12: Synthesis of N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)- 2,4-difluorophenyl)-2-methylpyridine-3-sulfonamide, 2*formic acid (Formic acid salt of I-15, I-15.2HCO₂H) Step 1: N-(3-bromo-2,4-difluorophenyl)-2-methylpyridine-3-sulfonamide [00330] To 3-bromo-2,4-difluoroaniline (271 mg, 1.305 mmol), 1,4- diazabicyclo[2.2.2]octane (293 mg, 2.61 mmol) in anh MeCN (12 mL) at 0 ^oC was added 2-methylpyridine-3-sulfonyl chloride (250 mg, 1.30 mmol) in MeCN (9 mL). After stirring for 10 min at the temperature, the suspension was stirred at rt for 21 h. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography to afford N-(3-bromo-2,4-difluorophenyl)-2-methylpyridine-3-sulfonamide as an off white solid (427.0 mg, 90 % yield). MS (ESI) 363.28/365.23 [M+H]⁺. Step 2: N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)- 2-methylpyridine-3-sulfonamide, 2*formic acid

[00331] Prepared by General Method SMC using Cs₂CO₃ (162 mg, 0.496 mmol), N- (3-bromo-2,4-difluorophenyl)-2-methylpyridine-3-sulfonamide (90 mg, 0.248 mmol), PdCl₂dppf^.CH₂Cl₂ (20 mg, 0.025 mmol), H₂O (1.8 mL), N1,N1-dimethyl-N4-(6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)cyclohexane-1,4-diamine (3.6 mL, 0.25 mmol, in 1,4-dioxane); by heating in a microwave reactor at 90 °C for 90 min. Purified by flash chromatography followed by preparative HPLC (MeCN/H₂O + 0.1 % HCO₂H) to afford N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-2- methylpyridine-3-sulfonamide, formic acid as a pale yellow solid ( 38.0 mg, 18 % yield, isomer ratio 96:4).¹H NMR (500 MHz, CD₃OD) δ ppm 9.00 - 9.14 (m, 1 H), 8.60 (d, J=4.16 Hz, 1 H), 8.21 - 8.52 (m, 2 H), 8.15 (d, J=7.46 Hz, 1 H), 7.68 (s, 1 H), 7.52 - 7.59 (m, 2 H), 7.41 - 7.50 (m, 1 H), 7.36 (dd, J=7.83, 4.89 Hz, 1 H), 7.08 (t, J=8.93 Hz, 1 H), 4.30 (br. s., 1 H), 2.88 (s, 6 H), 2.86 (s, 3H), 2.17 - 2.32 (m, 2 H), 1.75 - 2.06 (m, 6 H). MS (ESI) 553.4 [M+H]⁺. Example 13: Synthesis of 5-cyano-N-(3-(2-(((1r,4r)-4- (dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)pyridine-3- sulfonamide, formic acid (Formic acid salt of I-16, I-16.HCO₂H)

Step 1: N-(3-bromo-2,4-difluorophenyl)-5-cyanopyridine-3-sulfonamide and N-(3-bromo- 2,4-difluorophenyl)-5-cyano-N-((5-cyanopyridin-3-yl)sulfonyl)pyridine-3-sulfonamide [00332] Prepared by General Method NS using CH₂CI₂ (20 mL), 5-cyanopyridine-3- sulfonyl chloride (0.256 g, 1.26 mmol), pyridine (0.51 mL, 6.3 mmol) and 3-bromo-2,4- difluoroaniline (0.263 g, 1.26 mmol). After stirring for 1 d 18 h the reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography to afford a mixture of N-(3-bromo-2,4-difluorophenyl)-5-cyanopyridine-3- sulfonamide and N-(3-bromo-2,4-difluorophenyl)-5-cyano-N-((5-cyanopyridin-3- yl)sulfonyl)pyridine-3-sulfonamide an off white solid with purple tinge (339.0 mg, 58 %, ratio of the two products: 1.0: 0.6). MS (ESI) 374.25/376.20 [M+H]⁺ and MS (ESI) 540.22/542.16 [M+H]⁺. Step 2: 5-cyano-N-(3-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4- difluorophenyl)pyridine-3-sulfonamide, formic acid [00333] Prepared by General Method SMC using Cs₂CO₃ (163 mg, 0.500 mmol), PdCl₂dppf^.CH₂Cl₂(13.62 mg, 0.017 mmol), a mixture (total of 80 mg, ratio=1.0:0.6) of N-(3- bromo-2,4-difluorophenyl)-5-cyanopyridine-3-sulfonamide (49 mg, 0.13 mmol) and N-(3- bromo-2,4-difluorophenyl)-5-cyano-N-((5-cyanopyridin-3-yl)sulfonyl)pyridine-3- sulfonamide (31 mg, 0.058 mmol), trans-N1,N1-dimethyl-N4-(6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazolin-2-yl)cyclohexane-1,4-diamine (83 mg, 0.13 mmol, 64 % ), H₂O (2.0 mL) and DME (4 mL); by heating in a microwave reactor at 90 °C for 1.5 h. Purified by preparative HPLC (30 g Biotage® C₁₈, MeCN in H₂O + 0.1 % HCO₂H to afford 5-cyano- N-(3-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4- difluorophenyl)pyridine-3-sulfonamide, formic acid as a pale yellow solid (16.0 mg, 19 % yield).1H NMR (500 MHz, DMSO-d6) δ ppm 9.14 (br. s., 1 H), 9.03 (d, J=15.65 Hz, 2 H), 8.42 (s, 1 H), 7.90 - 8.27 (m, 1 H), 7.74 - 7.81 (m, 1 H), 7.63 (d,J=8.56 Hz, 1 H), 7.48 (t, J=831 Hz 2 H) 716 (td J=914 630 Hz 1 H) 685 (t J=923 Hz 1 H) 388 (d J=746 Hz, 1 H), 3.01 (br. s., 1 H), 2.66 (s, 6 H), 2.11 (br. s., 2 H), 2.00 (d, J=11.25 Hz, 2 H), 1.57 (q, J=11.45 Hz, 2 H), 1.32 - 1.43 (m, 2 H). MS (ESI) 564.5 [M+H]⁺. Example 14: Synthesis of 5-chloro-N-(3-(2-(((1r,4r)-4- (dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-2-methoxypyridine- 3-sulfonamide (I-2) Step 1 Synthesis of (1r,4r)-N1,N1-dimethyl-N4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)quinazolin-2-yl)cyclohexane-1,4-diamine (Intermediate C) [00334] To a solution of (1r,4r)-N1-(6-bromoquinazolin-2-yl)-N4,N4- dimethylcyclohexane-1,4-diamine (2.5 g, 7.15 mmol) in 1,4 dioxane (62.5 mL), Bis(pinacolato)diboron (2.18 g, 8.58 mmol) and potassium acetate (2.4 g, 21.47 mmol) were added and the reaction mass was degassed using nitrogen. To this, PdCl₂(dppf) (0.53 g, 0.715 mmol) was added under nitrogen atmosphere and reaction mass was stirred at 110 °C for 6 h. After completion of reaction, the reaction mass was diluted with EtOAc filtered through celite bed and concentrate to get crude. The crude was treated with hexane, pure compound came out in hexanes and was concentrated to afford the title compound Intermediate C (2.7 g,7.32 mmol, 98.05%) as yellow sticky solid of (1r,4r)-N1,N1-dimethyl- N4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)cyclohexane-1,4- diamine. LCMS: [M+H]+=397.5. Step 2: 5-chloro-N-(3-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4- difluorophenyl)-2-methoxypyridine-3-sulfonamide (I-2) [00335] Prepared by General Method SMC using Cs₂CO₃ (158 mg, 0.484 mmol), N- (3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (100 mg, 0.242 mmol), trans-N1,N1-dimethyl-N4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinazolin-2-yl)cyclohexane-1,4-diamine (180 mg, 0.290 mmol, 64 % purity) and PdCl₂dppf^.CH₂Cl₂ (19.74 mg, 0.024 mmol), Water (2 mL), DME (4 mL); by heating in a microwave reactor at 90 °C for 1.5 h. Purified by preparative HPLC (using MeCN in H₂O + ^{0.1 % HCO}2^{H) followed by a filtration through a Waters PoraPak CX column to afford 5-} chloro-N-(3-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4- difluorophenyl)-2-methoxypyridine-3-sulfonamide as a white solid ( 11 mg, 7 % yield based on purity of 97 %).¹H NMR (500 MHz, DMSO-d6) δ ppm 9.13 (br. s., 1 H), 8.33 (d, J=2.08 Hz, 1 H), 8.02 (d, J=2.57 Hz, 1 H), 7.79 (s, 1 H), 7.61 (d, J=8.44 Hz, 1 H), 7.48 (dd, J=14.37, 8.25 Hz, 2 H), 7.21 (td, J=8.99, 6.24 Hz, 1 H), 6.99 (t, J=9.11 Hz, 1 H), 3.84 (s, 3 H), 2.69 - 2.84 (m, 1 H), 2.01 - 2.15 (m, 2 H), 1.88 - 1.97 (m, 2 H), 1.41 - 1.55 (m, 2 H), 1.31 - 1.40 (m, 2H). MS (ESI) 603.4 [M+H]⁺. Example 15: Preparation of hydrochloride salt of I-2 ((trans)-5-Chloro-N-(3-(2-((4- (dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4difluorophenyl)-2-methoxypyridine- 3-sulfonamide hydrochloride salt) (I-2.HCl) HCl [00336] (trans)-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6- yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (100 mg, 0.166 mmol) was mixed with H₂O (10 mL) and MeCN (3 mL) at rt. Then aq HCl (0.1 M, 3.32 mL, 0.332 mmol) was added, the reaction mixture became a clear solution. The solution was freeze dried to give (trans)-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4- difluorophenyl)-2-methoxypyridine-3-sulfonamide hydrochloride salt as an off-white solid (96.2 mg, 89 %). ¹H NMR (500 MHz, DMSO-d6) δ = 9.14 (br d, J = 2.7 Hz, 1 H), 8.39 (br s, 1 H), 8.03 (d, J = 2.6 Hz, 1 H), 7.79 (s, 1 H), 7.61 (br d, J = 8.3 Hz, 1 H),7.51 (br s, 2 H), 7.29 - 7.20 (m, 1 H), 7.13 - 7.00 (m, 1 H), 3.87 (s, 3 H), 3.95 - 3.81 (m, 1 H), 2.99 - 2.88 (m, 1 H), 2.61 (br s, 6 H), 2.19 - 2.04 (m, 2 H), 1.98 (br d, J = 11.1 Hz, 2 H), 1.62 - 1.47 (m, 2 H), 1.45 - 1.32 (m, 2 H). MS (ESI) 603.46 [M+H]⁺. Example 16: Preparation of methanesulfonic acid salt of I-2 ((trans)-5-Chloro-N-(3-(2-((4- (dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-2-methoxypyridine- 3-sulfonamide methanesulfonic acid salt) (I-2.CH₃SO₃CO₂H) MeSO3H [00337] (trans)-5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6- yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (100 mg, 0.166 mmol) was mixed with H₂O (10 mL) and MeCN (3 mL) at rt. Then MeSO3H (15.9 mg, 0.166 mmol) was added, the reaction mixture became a clear solution. The solution was freeze dried to give (trans)- 5-chloro-N-(3-(2-((4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4- difluorophenyl)-2-methoxypyridine-3-sulfonamide methanesulfonic acid salt as a beige solid (112.6 mg, 95 %). ¹H NMR (500 MHz, DMSO-d6) δ = 10.39 (s, 1 H), 9.35 (br d, J = 2.6 Hz, 1 H), 9.15 (br s, 1 H), 8.51 (d, J = 2.4 Hz, 1 H), 8.07 (d, J = 2.4 Hz, 1 H),7.80 (s, 1 H), 7.60 (br d, J = 8.3 Hz, 2 H), 7.52 (br d, J = 8.2 Hz, 1 H), 7.36 - 7.29 (m, 1 H), 7.25 - 7.18 (m, 1 H), 3.91 (s.1 H), 3.97 - 3.84 (m, 1 H), 2.76(d, J = 4.8 Hz, 6 H), 2.30 (s,3 H), 2.19 - 2.08 (m, 2 H), 2.03 (br d, J = 11.7 Hz, 2 H), 1.69 - 1.54 (m, 2 H), 1.48 - 1.34 (m, 2 H). MS (ESI) 603.46 [M+H]⁺. Example 17: Synthesis of N-(3-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin- 6-yl)-4-fluorophenyl)-3-methoxypyrazine-2-sulfonamide (I-17) Step 1. N-(3-bromo-4-fluorophenyl)-3-methoxypyrazine-2-sulfonamide [00338] An anhydrous (anh) DMSO (1.2 mL) solution of 3-methoxypyrazine-2- sulfonyl fluoride (0.200 g, 1.041 mmol), 3-bromo-4-fluoroaniline (0.593 g, 3.12 mmol) and HOBt (2.81 mg, 0.021 mmol) was treated with 1,1,3,3-tetramethyldisiloxane (0.368 mL, 2.080 mmol) and DIPEA (0.362 mL, 2.08 mmol). The reaction mixture was stirred at rt for 45 min and then heated in an oil bath at 40 ^oC for 1 d. After cooling to rt, the reaction mixture was diluted with EtOAc and extracted in sequence with H₂O and then 0.1 M aq HCl. The organic layer was concentrated under reduced pressure, deposited on Celite, and purified by flash chromatography (using MeOH in CH₂CI₂) to afford N-(3-bromo-4- fluorophenyl)-3-methoxypyrazine-2-sulfonamide as a beige-yellow, sticky solid (251 mg, 67 %). MS (ESI) 362.16/364.16 [M+H]⁺. Step 2. N-(3-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-4- fluorophenyl)-3-methoxypyrazine-2-sulfonamide [00339] Prepared by General Method SMC using Cs₂CO₃ (162 mg, 0.497 mmol), N- (3-bromo-4-fluorophenyl)-3-methoxypyrazine-2-sulfonamide (90 mg, 0.25 mmol), trans- N1,N1-dimethyl-N4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2- yl)cyclohexane-1,4-diamine (118 mg, 0.298 mmol, Intermediate C) PdCl₂dppf^.CH₂Cl₂ (20.3 mg, 0.025 mmol), H₂O (2 mL) and DME (4 mL); by heating sealed in a microwave reactor at 90 °C for 1 h. Purified by flash chromatography (using MeOH in CH₂CI₂) followed by preparative HPLC (using MeCN in H₂O + 0.1 % HCO₂H) and a filtration through a Waters PoraPak CX column, rinsing with MeOH and eluting with 2 M NH₃ in MeOH to afford N-(3- (2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-4-fluorophenyl)-3- methoxypyrazine-2-sulfonamide as a pale yellow solid (14 mg, 10 % yield based on purity of 99 %). ¹H NMR(500 MHz, DMSO-d6) δ ppm 9.10 (br.s., 1 H), 8.44 (s, 1 H), 8.27 (d, J=1.34 Hz, 1 H), 8.14 (s, 1 H), 7.77 (s, 1 H), 7.65 (d, J=8.68 Hz, 1 H), 7.34 - 7.52 (m, 2 H), 7.26 - 7.32 (m, 1 H), 7.12 - 7.20 (m, 1 H), 7.04 - 7.11 (m, 1 H), 3.96 (s, 3 H), 3.73 - 3.85 (m, 1 H),2.47 - 2.57 (m, 1 H), 2.28 - 2.39 (m, 6 H), 2.00 (br.s., 2 H), 1.80-1.90 (m, 2 H), 1.19 - 1.47 (m, 4 H). MS (ESI) 552.55 [M+H]⁺. Example 18: Synthesis of N-(3-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin- 6-yl)-2,4-difluorophenyl)-5-(trifluoromethyl)pyridine-3-sulfonamide (I-18) [00340] Prepared by General Method SMC using Cs₂CO₃ (156 mg, 0.479 mmol), N- (3-bromo-2,4-difluorophenyl)-5-(trifluoromethyl)pyridine-3-sulfonamide (100 mg, 0.240 mmol), trans-N1,N1-dimethyl-N4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinazolin-2-yl)cyclohexane-1,4-diamine (114 mg, 0.288 mmol, Intermediate C), PdCl₂dppf^.CH₂Cl₂ (19.6 mg, 0.024 mmol) in H₂O (2 mL) and DME (4 mL); by heating, sealed in a microwave reactor at 90 °C for 1.5 h. Purified by flash chromatography (using MeOH in CH₂CI₂) followed by preparative HPLC (using MeCN in H₂O + 0.1 % HCO₂H) and filtration through a Waters PoraPak CX column, rinsing with MeOH and eluting with 2 M NH₃ in MeOH to afford N-(3-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6- yl)-2,4-difluorophenyl)-5-(trifluoromethyl)pyridine-3-sulfonamide as a white solid (15.0 mg, 10 % yield based on purity of 93 %). ¹H NMR(500 MHz, DMSO-d6) δ ppm 9.12 (br.s., 1 H), 9.08 (s, 1 H), 9.01 (s, 1 H), 8.24 (s, 1 H), 7.77 (s, 1 H), 7.60 (d, J=8.68 Hz, 1 H), 7.42 - 7.54 (m, 2 H), 7.08 - 7.27 (m, 1 H), 6.88 (t, J=9.23 Hz, 1 H), 3.87 (br.s., 1 H), 3.09 (br.s., 1 H), 2.70 (br.s., 6 H), 2.04 - 2.17 (m, 2 H), 2.00 (d, J=11.25 Hz, 2 H), 1.59 (q, J=11.37 Hz, 2 H), 1.33 - 1.43 (m, 2 H). MS (ESI) 607.29 [M+H]⁺. Example 19: Synthesis of N-(3-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin- 6-yl)-2,4-difluorophenyl)-5-methylpyridine-3-sulfonamide formic acid (Formic acid salt of I- 19, I-19.HCO₂H) [00341] Prepared by General Method SMC using Cs₂CO₃ (144 mg, 0.44 mmol), N- (3-bromo-2,4-difluorophenyl)-5-methylpyridine-3-sulfonamide (80 mg, 0.22 mmol), trans- N1,N1-dimethyl-N4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2- yl)cyclohexane-1,4-diamine (164 mg, 0.264 mmol, Intermediate C), PdCl₂dppf^.CH₂Cl₂ (18 mg, 0.022 mmol) in H₂O (2 mL) and DME (4 mL); by heating, sealed in a microwave reactor at 90 °C for 2 h. Purified by flash chromatography (using CH₂CI₂/MeOH/conc aq NH₄OH 89/10/1 in CH₂CI₂0 to 100 % than MeOH in CH₂CI₂) followed by preparative HPLC (using MeCN in H₂O + 0.1 % HCO₂H) to afford N-(3-(2-(((1r,4r)-4- (dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-5-methylpyridine-3- sulfonamide formic acid salt, as a white solid (23.0 mg, 17 % yield based on purity of 96 %). ¹H NMR(500 MHz, DMSO-d6) δ ppm 9.06 (br.s., 1 H), 8.57 (s, 1 H), 8.42 (s, 1 H), 8.14 (s, 1 H), 7.80 (s, 1 H), 7.70 (s, 1 H), 7.53 (d, J=8.56 Hz, 1 H), 7.41 (dd, J=16.63, 8.07 Hz, 2 H), 7.04 - 7.17 (m, 1 H), 6.86 (t, J=9.23 Hz, 1 H), 3.78 (br.s., 1 H), 2.65 (br.s., 1 H), 2.26 (s, 3 H), 2.01 (br.s., 2 H), 1.87 (d, J=11.13 Hz, 2 H), 1.41 (q, J=11.45 Hz, 2 H), 1.29 (q, J=11.86 Hz, 2 H). MS (ESI) 553.45 [M+H]⁺. Example 20: Synthesis of 5-chloro-N-(2,4-difluoro-3-(2-(((1r,4r)-4- morpholinocyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide, formic acid (Formic acid salt of I-20, I-20.HCO₂H) Step 1. 2-(methylthio)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline and (2- (methylthio)quinazolin-6-yl)boronic acid [00342] Prepared by General Method MB using 6-bromo-2-(methylthio)quinazoline (2 g, 7.8 mmol), B₂pin₂ (3 g, 12 mmol), KOAc (2.3 g, 23 mmol), 1,4-dioxane (20 mL), Pd₂(dba)₃ (0.72 g, 0.78 mmol) and XPhos (0.37 g, 0.78 mmol); by heating in an oil bath at 80°C for 2 h. After completion, the reaction mass poured into H₂O (100 mL) and extracted with EtOAc (3 x 50 mL), dried (anh Na₂SO₄), concentrated under reduced pressure, suspended in hexanes (200 mL) and stirred at rt for 30 min. Later, the suspension was filtered and the filtrate was evaporated under reduced pressure to afford a mixture of 2- (methylthio)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline and (2- (methylthio)quinazolin-6-yl)boronic acid as a light yellow solid (2.2 g, 88 %). MS (ESI) 303.0 [M+H]⁺ and 221.0 [M+H]⁺. Step 2.2,4-difluoro-3-(2-(methylthio)quinazolin-6-yl)aniline [00343] Prepared by General Method SMC using a mixture of 2-(methylthio)-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline and (2-(methylthio)quinazolin-6- yl)boronic acid (1.85 g, 6.1 mmol), 3-bromo-2,4-difluoroaniline (0.65 g, 3.1 mmol), 1,4- dioxane:THF (1:1, 20 mL), PdCl₂(PPh3)₂ (0.427 g, 0.610 mmol), Cs₂CO₃ (2.97 g, 9.15 mmol) and H₂O (5 mL); by heating at 80 °C for 2 h. Later, the reaction mixture was poured into H₂O (80 mL) and extracted with EtOAc (3x 40 mL). The combined organic extracts were dried (anh Na₂SO₄) and evaporated under reduced pressure. Purified by column chromatography eluting with 19 % EtOAc in hexanes to afford 2,4-difluoro-3-(2- (methylthio)quinazolin-6-yl)aniline (0.9 g, 97 %) as a light yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 9.49 (d, J = 7.6 Hz, 1 H), 8.17 (s, 1 H), 8.04 – 7.90 (m, 2 H), 6.97 (q, J = 10.7, 10.1 Hz, 1 H), 6.85 (td, J = 9.4, 5.6 Hz, 1 H), 5.17 (s, 2 H), 2.65 (s, 3 H). MS (ESI) 304.28 [M+H]⁺. Step 3. 5-chloro-N-(2,4-difluoro-3-(2-(methylthio)quinazolin-6-yl)phenyl)-2- methoxypyridine-3-sulfonamide [00344] Prepared by General Method NS using 2,4-difluoro-3-(2- (methylthio)quinazolin-6-yl)aniline (400 mg, 1.32 mmol), 5-chloro-2-methoxypyridine-3- sulfonyl chloride (319 mg, 1.32 mmol), CH₂Cl₂ (24 mL) and pyridine (0.532 mL, 6.59 mmol); by slowly warming from -30 ^oC to rt and then stirring at rt for the total of 1 d 19 h. The reaction mixture was washed with H₂O (2x), concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (using EtOAc in CH₂Cl₂) to afford 5-chloro-N-(2,4-difluoro-3-(2-(methylthio)quinazolin-6-yl)phenyl)-2-methoxypyridine-3- sulfonamide as a beige solid (114 mg, 16 % based on purity of 96 %). MS ESI 509.22 [M+H]⁺. Step 4. 5-chloro-N-(2,4-difluoro-3-(2-(((1r,4r)-4-morpholinocyclohexyl)amino)quinazolin- 6-yl)phenyl)-2-methoxypyridine-3-sulfonamide. [00345] A CH₂Cl₂ (10 mL) solution of 5-chloro-N-(2,4-difluoro-3-(2- (methylthio)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (72 mg, 0.136 mmol, 96 %) at -25 ^oC was treated with 3-chloroperbenzoic acid (35 mg, 0.14 mmol, approx.70 %) suspended in CH₂Cl₂ (1.5 mL). The reaction mixture was stirred with cooling for 10 min and then at rt for the total of 70 min. After removal of CH₂Cl₂ by rotatory evaporation, to the cream beige solid residue was added (1r,4r)-4-morpholinocyclohexan-1-amine*2HCl (70 mg, 0.27 mmol) followed by DIPEA (0.24 mL, 1.36 mmol) and i-PrOH (16 mL). The material was suspended using sonication. Subsequently it was stirred at rt for 2 h and then at 50 ^oC for 18 h. DIPEA (0.24 mL, 1.4 mmol) was added again and heating with stirring was continued at 80 °C for 1 d 18 h and finally at 100 °C for 3 h. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by preparative HPLC (using MeCN in H₂O + 0.1 % HCO₂H) to afford 5-chloro-N-(2,4-difluoro-3-(2-(((1r,4r)- 4-morpholinocyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3- sulfonamide*HCO₂H as a pale yellow solid (18.5 mg, 18 % yield based on purity of 93 %). ¹H NMR(500 MHz, DMSO-d₆) δ 9.12 (br.s., 1 H), 8.46 (d, J=2.45 Hz, 1 H), 8.14 (s, 1 H), 8.01-8.09 (m, 1 H), 7.77 (s, 1 H), 7.56-7.61 (m, 1 H), 7.52 (br.s., 1 H), 7.45 (d, J=7.46 Hz, 1 H), 7.29 (dt, J=5.99, 8.80 Hz, 1 H), 7.10-7.22 (m, 1 H), 3.89 (s, 3 H), 3.75-3.86 (m, 1 H), 3.55-3.63 (m, 4 H), 2.25 (br.s., 1 H), 1.83-2.13 (m, 4 H), 1.27-1.48 (m, 4 H). MS (ESI) 645.47 [M+H]⁺. Example 21: Synthesis of 5-chloro-N-(2,4-difluoro-3-(2-(((1r,4r)-4- (methylamino)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide formic acid (Formic acid salt of I-21, I-21.HCO₂H) Step 1. tert-Butyl ((1r,4r)-4-((6-bromoquinazolin-2-yl)amino)cyclohexyl)carbamate [00346] A DMF (24 mL) mixture of N-Boc-trans-1,4-cyclohexanediamine (3.30 g, 15.4 mmol), 6-bromo-2-chloroquinazoline (2.5 g, 10.27 mmol) and K₂CO₃(2.84 g, 20.53 mmol) was heated at in an oil bath at 100 °C for 1 h. After cooling to rt, H₂O (40 mL) was added. The product was filtered, rinsed with H₂O (40 mL) to afford tert-butyl ((1r,4r)-4-((6- bromoquinazolin-2-yl)amino)cyclohexyl)carbamate as a light yellow solid (4.6 g, quant, contaminated by a small amount of N-Boc-trans-1,4-cyclohexanediamine). MS (ESI) 421.40/423.28 [M+H]⁺. Step 2. (1r,4r)-N1-(6-bromo-3,4-dihydroquinazolin-2-yl)-N4-methylcyclohexane-1,4- diamine [00347] To tert-butyl ((1r,4r)-4-((6-bromoquinazolin-2- yl)amino)cyclohexyl)carbamate (500 mg, 1.19 mmol) in anh THF (20 mL) under Ar was added dropwise LiAlH₄ (1.0 M in THF, 2.4 mL, 2.4 mmol) at -5 °C. The reaction mixture was briefly stirred outside of the cooling bath and the heated in an oil bath at 65-75 °C overnight. Later, the reaction was cooled to 0 ^oC, quenched with EtOAc and then 10 % aq NaOH. The mixture was filtered, rinsing the collected solid with xs EtOAc. The filtrate combined with the washings was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (using 2 M NH₃ in MeOH and CH₂CI₂ to afford a pale-yellow gum solidifying slowly to an off white solid (318 mg, 77 % based on the purity of 97 %). The material with the partially reduced quinazoline ring has been tentatively assigned as (1r,4r)-N1-(6-bromo-3,4-dihydroquinazolin-2-yl)-N4-methylcyclohexane-1,4- diamine. MS (ESI) 337.40/339.34 [M+H]⁺. Step 3. (1r,4r)-N1-methyl-N4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4- dihydroquinazolin-2-yl)cyclohexane-1,4-diamine [00348] Prepared by General Method MB using (1r,4r)-N1-(6-bromo-3,4- dihydroquinazolin-2-yl)-N4-methylcyclohexane-1,4-diamine (100 mg, 0.297 mmol), B2pin2 (98 mg, 0.38 mmol), KOAc (87 mg, 0.89 mmol) in anh 1,4-dioxane (4 mL); after a period of sonication at rt, by heating sealed in a microwave reactor at 100 °C for 90 min. The crude mixture was used directly in the following step. MS ESI 385.55 [M+H]⁺. Step 4. 5-chloro-N-(2,4-difluoro-3-(2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)-3,4- dihydroquinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide. [00349] Prepared by General Method SMC using the entire material from the previous step (1r,4r)-N1-methyl-N4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4- dihydroquinazolin-2-yl)cyclohexane-1,4-diamine (crude in 1,4-dioxane, 4 mL), N-(3-bromo- 2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (159 mg, 0.385 mmol), Cs₂CO₃ (338 mg, 1.04 mmol), PdCl₂dppf^.CH₂Cl₂ (24 mg, 0.030 mmol) and H₂O (2 mL); by heating in a microwave reactor at 90 °C for 80 min. Purified by flash chromatography (using MeOH in CH₂CI₂ to afford 5-chloro-N-(2,4-difluoro-3-(2-(((1r,4r)-4- (methylamino)cyclohexyl)amino)-3,4-dihydroquinazolin-6-yl)phenyl)-2-methoxypyridine-3- sulfonamide as a tan solid (132 mg, 75 %). MS (ESI) 591.51 [M+H]⁺. Step 5. 5-chloro-N-(2,4-difluoro-3-(2-(((1r,4r)-4-(methylamino)cyclohexyl)amino) quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [00350] 5-chloro-N-(2,4-difluoro-3-(2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)- 3,4-dihydroquinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (132 mg from the previous step) was suspended in CHCl3 (10 mL) with sonication and vortex mixing. The suspension was degassed with a stream of Ar before 2,3-dichloro-5,6-dicyano-p- benzoquinone (87 mg, 0.38 mmol) was added in one portion at rt. The degassing was repeated, and the mixture was stirred at rt for 1.7 h and then with heating in an oil bath at 50 °C for 3 d and finally at 80 °C for 1 h. The reaction was cooled to rt, treated with satd aq NaHCO₃. The phases were separated. The aq phase was extracted with 20 % MeOH in CH₂Cl₂(3x). The combined organic layers were concentrated under reduced pressure, deposited on Celite and purified by preparative HPLC (MeCN in H₂O + 0.1 % HCO₂H) to afford 5-chloro-N-(2,4-difluoro-3-(2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin- 6-yl)phenyl)-2-methoxypyridine-3-sulfonamide*HCO₂H as a pale yellow powder (6.3 mg, 3.3 % yield based on purity of 99 %). ¹H NMR(500 MHz, DMSO-d₆) δ 9.07 (br.s., 1 H), 8.16 (br.s., 3 H), 7.91 (d, J=2.57 Hz, 1 H), 7.73 (s, 1 H), 7.57 (d, J=8.93 Hz, 1H 2 H), 7.07 (dt, J=6.36, 9.23 Hz, 1 H), 6.78 (t, J=9.35 Hz, 1 H), 3.78 (br.s., 1 H), 3.73 (s, 3 H),, 2.73- 2.92 (m, 1 H), 2.48 (br.s., 3 H), 1.94-2.08 (m, 4 H), 1.20-1.46 (m, 4 H). MS (ESI) 589.38 [M+H]⁺. Example 22: Synthesis of 5-chloro-N-(2,4-difluoro-3-(2-(((1r,4r)-4-((2- methoxyethyl)(methyl)amino)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2- methoxypyridine-3-sulfonamide (I-22) Step 1. (1r,4r)-N1-(2-methoxyethyl)-N1-methylcyclohexane-1,4-diamine*2TFA [00351] To tert-butyl N-[trans-4-(methylamino)cyclohexyl]carbamate (150 mg, 0.66 mmol), DIPEA (0.34 mL, 2.0 mmol) in anh MeCN (4.9 mL) was added BrCH₂CH₂OMe (0.074 mL, 0.79 mmol) and the reaction mixture was heated at 85 °C in an oil bath overnight. The reaction was concentrated under reduced pressure and then briefly under high vacuum to leave light tan gum (MS (ESI) [M+H]⁺ 287.12) that was later taken into CH₂Cl₂ (3 mL) and treated with TFA (0.50 mL, 6.6 mmol) at rt. Stirring was continued for 1.5 h before volatiles were removed by rotatory evaporation and the residue was dried under high vacuum leaving a gum that was used in the following step without further purification. MS (ESI) 187.35 [M+H]⁺. Step 2. (1r,4r)-N1-(6-bromoquinazolin-2-yl)-N4-(2-methoxyethyl)-N4-methylcyclohexane- 1,4-diamine [00352] Crude (1r,4r)-N1-(2-methoxyethyl)-N1-methylcyclohexane-1,4- diamine*2TFA from the previous step (136 mg, 0.33 mmol), K₂CO₃ (908 mg, 6.6 mmol) in anh DMF (5 mL) was stirred for several min at rt before 6-bromo-2-chloroquinazoline (112 mg, 0.46 mmol) was added in one portion at rt. The reaction mixture was then heated with stirring in an oil bath at 100 °C for 20 min and then at 50 ^oC for 2 d. After cooling to rt, the reaction mixture was diluted with xs H₂O and filtered, dried to afford (1r,4r)-N1-(6- bromoquinazolin-2-yl)-N4-(2-methoxyethyl)-N4-methylcyclohexane-1,4-diamine as a light yellow solid (243 mg, 95 % pure by UV but containing some DIPEA). The material was used with further purification in the following step. MS (ESI) 393.38|395.33 [M+H]⁺. Step 3. (1r,4r)-N1-(2-methoxyethyl)-N1-methyl-N4-(6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazolin-2-yl)cyclohexane-1,4-diamine [00353] Prepared by General Method MB using (1r,4r)-N1-(6-bromoquinazolin-2-yl)- N4-(2-methoxyethyl)-N4-methylcyclohexane-1,4-diamine (crude 243 mg, 0.33 mmol), KOAc (0.097 g, 0.98 mmol) and PdCl₂dppf^.CH₂Cl₂ (0.027 g, 0.033 mmol) in anh 1,4- dioxane (10 mL); by heating in an oil bath at 100 °C for 2.2 h. The material was used crude directly in the subsequent Suzuki-Miyaura step. MS (ESI) 441.59 [M+H]⁺. Step 4. 5-chloro-N-(2,4-difluoro-3-(2-(((1r,4r)-4-((2- methoxyethyl)(methyl)amino)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2- methoxypyridine-3-sulfonamide [00354] Prepared by General Method SMC using N-(3-bromo-2,4-difluorophenyl)- 5-chloro-2-methoxypyridine-3-sulfonamide (65 mg, 0.16 mmol), PdCl₂dppf^.CH₂Cl₂ (12.8 mg, 0.016 mmol), Cs₂CO₃ (256 mg, 0.79 mmol), H₂O (2.3 mL) and (1r,4r)-N1-(2- methoxyethyl)-N1-methyl-N4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2- yl)cyclohexane-1,4-diamine (crude in 1,4-dioxane 0.033 M, 4.8 mL, 0.16 mmol); by heating sealed in a microwave reactor at 90 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure, deposited on Celite and purified by flash chromatography (using MeOH in CH₂CI₂) followed by preparative HPLC (using MeCN in H₂O + 0.1 % HCO₂H) and a filtration through a 3-propylsulfonic acid-functionalized silica gel column, rinsing with MeOH and eluting with 2 M NH₃ in MeOH to afford 5-chloro-N-(2,4-difluoro-3-(2-(((1r,4r)- 4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2- methoxypyridine-3-sulfonamide as sticky tan solid (8.0 mg, 7 % based on the purity of 92 %). ¹H NMR(500 MHz, CD₃OD) δ 9.04 (s, 1 H), 8.33 (d, J=2.57 Hz, 1 H), 8.07 (d, J=2.57 Hz, 1 H), 7.75 (s, 1 H), 7.61-7.65 (m, 1 H), 7.56-7.60 (m, 1 H), 7.45 (dt, J=5.69, 8.83 Hz, 1 H), 7.06 (t, J=9.11 Hz, 1 H), 4.57 (br.s., 1 H), 4.00 (s, 3 H), 3.65-3.71 (m, 2 H), 3.41-3.44 (m, 3 H), 3.22 (t,J=4.52 Hz, 2 H), 3.11-3.19 (m, 1 H), 2.75 (s, 3 H), 2.29 (d, J=11.98 Hz, 2 H), 2.05-2.14 (m, 2 H),, 1.65-1.78 (m, 2 H), 1.43-1.56 (m,2 H). MS (ESI) 647.49 [M+H]⁺ Example 23: Synthesis of 5-chloro-N-(2,4-difluoro-3-(2-(((1R,4r)-4-((R)-3-fluoropyrrolidin- 1-yl)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-23) Step 1. tert-butyl ((1R,4r)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)carbamate and tert-butyl ((1S,4s)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)carbamate [00355] To a solution of (R)-3-fluoropyrrolidine HCl (0.56 g, 6.3 mmol) and tert-butyl (4-oxocyclohexyl)carbamate (1 g, 4.7 mmol) in MeOH:CH₂Cl₂ (1:9) was added AcOH (1 mL) and the reaction mixture was stirred at rt for 10 min. NaBH(OAc)₃ (1.99 g, 9.38 mmol) was then added and the reaction mixture was stirred at rt for 16 h. After completion, the reaction mixture was diluted with satd aq NaHCO₃ (50 mL) and extracted with EtOAc (3 x 50mL). The combined organic layers were dried (anh Na₂SO₄) and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with EtOAc to afford tert-butyl ((1S,4s)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)carbamate as a yellow solid (400 mg 60 %%) and tert-butyl ((1R,4r)-4-((R)-3-fluoropyrrolidin-1- yl)cyclohexyl)carbamate as a yellow solid (350 mg, 52 %). MS (ESI) 287.3 [M+H]⁺. Step 2. (1R,4r)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexan-1-amine 2HCl [00356] To a solution of tert-butyl ((1R,4r)-4-((R)-3-fluoropyrrolidin-1- yl)cyclohexyl)carbamate (0.35 g, 1.2 mmol) in CH₂Cl₂ (3.5 mL) was added HCl (4 M in 1,4- dioxane, 3.5 mL) and reaction was stirred at rt for 3 h. After completion, the reaction mixture was concentrated under reduced pressure to afford (1R,4r)-4-((R)-3-fluoropyrrolidin-1- yl)cyclohexan-1-amine 2HCl as a brown solid (0.34 g). MS (ESI) 187.1 [M+H]⁺. Step 3.6-bromo-N-((1R,4r)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)quinazolin-2-amine [00357] To a solution of (1R,4r)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexan-1-amine 2HCl (0.34 g, 1.8 mmol) in DMF (4 mL), K₂CO₃ (0.79 mg, 5.75 mmol) was added and reaction mixture was stirred at rt for 15 min. 6-Bromo-2-chloroquinazoline (0.4 g, 1.6 mmol) was then added and the reaction mixture was stirred at rt for 16 h. After completion, the reaction mixture was diluted with EtOAc (50 mL), washed with ice cooled H₂O (2x 50 mL) and later brine (2x 50 mL). The organic layer was dried (anh Na₂SO₄), concentrated under reduced pressure. and purified by column chromatography eluting with 5% MeOH in CH₂Cl₂ to afford 6-bromo-N-((1R,4r)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)quinazolin-2-amine as a yellow solid (0.4 g, 48 %). MS (ESI) 393.1/395.1 [M+H]⁺. Step 4. N-((1R,4r)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazolin-2-amine [00358] Prepared by General Method MB using 6-bromo-N-((1R,4r)-4-((R)-3- fluoropyrrolidin-1-yl)cyclohexyl)quinazolin-2-amine (0.4 g, 1.0 mmol), 1,4-dioxane (5 mL), KOAc (0.3 g, 3.05 mmol), B2pin2 (0.516 g, 2.03 mmol) and Pd(dppf)Cl₂ (0.075 g, 0.01 mmol); by heating under N2 at 80 °C for 16 h. After completion, the reaction mixture was diluted with EtOAc (50 mL) and filtered through Celite, The volatiles were removed under reduced pressure to give crude N-((1R,4r)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine as dark brown solid (0.4 g) which was used as such in next step without further purification. MS (ESI) 441.4 [M+H]⁺. Step 5. 5-chloro-N-(2,4-difluoro-3-(2-(((1R,4r)-4-((R)-3-fluoropyrrolidinyl) cyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [00359] Prepared by General Method SMC using crude N-((1R,4r)-4-((R)-3- fluoropyrrolidin-1-yl)cyclohexyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin- 2-amine (0.4 g, 0.9 mmol), 1,4-dioxane (4 mL), K₂CO₃ (0.39 g, 3.4 mmol), N-(3-bromo-2,4- difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (0.38 g, 0.9 mmol) and Pd(dppf)Cl₂*CH₂Cl₂ (0.074 g, 0.09 mmol); by heating under N₂ at 80 °C for 16 h. After completion, the reaction mixture was diluted with satd aq NaHCO₃ (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried (anh Na₂SO₄)_, concentrated under reduced pressure and purified by column chromatography eluting with 5 % MeOH in CH₂Cl₂ to afford 5-chloro-N-(2,4-difluoro-3-(2-(((1R,4r)-4-((R)-3- fluoropyrrolidin-1-yl)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3- sulfonamide as a yellowish solid (0.022 g, 3.5 %). ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (br. s., 1 H), 8.45 (br. s., 1 H), 8.14 (s, 1 H), 8.05 (d, J=1.96 Hz, 1 H), 7.77 (s, 1 H), 7.40 - 7.64 (m, 3 H), 7.28 (m, J=6.80 Hz, 1 H), 7.04 - 7.19 (m, 1 H), 5.20 (d, J=55.76 Hz, 1 H), 3.88 (s, 4 H), 3.76 - 3.86 (m, 1 H), 2.82 - 3.03 (m, 2 H), 2.07 - 2.20 (m, 5 H), 1.88 - 2.07 (m, 10 H), 1.22 - 1.41 (m, 8 H). MS (ESI) 646.8 [M+H]⁺. Example 24: Synthesis of 5-chloro-N-(2,4-difluoro-3-(2-(((1S,4s)-4-((R)-3-fluoropyrrolidin- 1-yl)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I-24) Step 1. (1S,4s)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexan-1-amine (R)-4-(3-fluoropyrrolidin- 1-yl)cyclohexan-1-amine*2HCl [00360] To a solution of tert-butyl ((1S,4s)-4-((R)-3-fluoropyrrolidin-1- yl)cyclohexyl)carbamate (0.4 g, 1.4 mmol) in CH₂Cl₂ (4 mL) was added HCl (4 M in 1,4- dioxane, 4 mL) and the reaction mixture was stirred at rt for 3 h. After completion, the reaction mixture was concentrated under reduced pressure to afford (1S,4s)-4-((R)-3- fluoropyrrolidin-1-yl)cyclohexan-1-amine*2HCl as brown solid (0.4 g). MS (ESI) 187.1 [M+H]⁺. Step 2.6-bromo-N-((1S,4s)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)quinazolin-2-amine [00361] To a DMF (5 mL) solution of (1S,4s)-4-((R)-3-fluoropyrrolidin-1- yl)cyclohexan-1-amine 2HCl (0.4 g, 2.1 mmol) K₂CO₃ (0.99 mg, 7.2 mmol) was added and reaction mixture was stirred at rt for 15 min. Later, 6-bromo-2-chloroquinazoline (0.5 g, 2 mmol) was added and the reaction mixture was stirred at rt for 16 h. After completion, the reaction mixture was diluted with EtOAc (50 mL) and washed with ice cold H₂O (2x 50 mL) and brine (2x 50 mL). The organic layer was dried (anh Na₂SO₄) and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with 5 % MeOH in CH₂Cl₂ to afford 6-bromo-N-((1S,4s)-4-((R)-3-fluoropyrrolidin-1- yl)cyclohexyl)quinazolin-2-amine as a yellow solid (0.51 g, 48 %). MS (ESI) 393.1 [M+H]⁺. Step 3. N-((1S,4s)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazolin-2-amine [00362] Prepared by General Method MB using 6-bromo-N-((1S,4s)-4-((R)-3- fluoropyrrolidin-1-yl)cyclohexyl)quinazolin-2-amine (0.5 g, 1.4 mmol), 1,4-dioxane (5 mL), KOAc (0.37g, 3.81 mmol), B₂pin₂ (0.485 g, 1.91 mmol) and Pd(dppf)Cl₂ (0.093 g, 0.13 mmol); by heating under N₂ at 80 °C for 16 h. After completion, the reaction mixture was diluted with EtOAc (50 mL), filtered through Celite and concentrated under reduced pressure to give crude N-((1S,4s)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine as dark brown solid (0.5 g) which was used in the next step without further purification. MS (ESI) 441.3 [M+H]⁺ and 359.2 [M+H]⁺ for the corresponding boronic acid. Step 4. 5-chloro-N-(2,4-difluoro-3-(2-(((1S,4s)-4-((R)-3-fluoropyrrolidin-1- yl)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [00363] Prepared by General Method SMC using crude N-((1S,4s)-4-((R)-3- fluoropyrrolidin-1-yl)cyclohexyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin- 2-amine (0.5 g, 1.1 mmol), 1,4-dioxane (5 mL), K₂CO₃ (0.47 g, 3.4 mmol), N-(3-bromo-2,4- difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (0.46 g, 1.1 mmol) and Pd(dppf)Cl₂*CH₂Cl₂ (0.093 g, 0.11mmol); by heating under N2 at 80 °C for 16 h. After completion, the reaction mixture was diluted with satd aq NaHCO₃ (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried (anh Na₂SO₄) and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with 5 % MeOH in CH₂Cl₂ to afford 5-chloro-N-(2,4-difluoro-3-(2- (((1S,4s)-4-((R)-3-fluoropyrrolidin-1-yl)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2- methoxypyridine-3-sulfonamide as a yellowish solid (60 mg, 8.2%). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.38 (br. s., 1 H), 9.14 (br. s., 1 H), 8.49 (br. s., 1 H), 8.07 (br. s., 1 H), 7.77 (br. s., 1 H), 7.56-7.49 (m, 3 H), 7.12 - 7.39 (m, 2 H), 5.23 (d, J=54.79 Hz, 1 H), 3.94 - 4.06 (m, 1 H), 3.90 (br. s., 3 H), 3.10-2.70 (m, 2 H), 2.40-2.00 (m, 2 H), 1.90-1.50 (m, 11 H). MS (ESI) 647.2 [M+H]⁺. Example 25: Synthesis of 5-chloro-N-(2,4-difluoro-3-(2-(((1R,4r)-4-((R)-3- methoxypyrrolidin-1-yl)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3- sulfonamide (I-25) Step1 (1R,4r)-4-((R)-3-methoxypyrrolidin-1-yl)cyclohexan-1-amine 2HCl and (1S,4s)-4- ((R)-3-methoxypyrrolidin-1-yl)cyclohexan-1-amine 2HCl [00364] To a solution of (R)-3-methoxypyrrolidine HCl (0.86 g, 0.19 mmol) and tert- butyl (4-oxocyclohexyl)carbamate (1.22 g, 0.175 mmol) in MeOH:CH₂Cl₂ (1:9) was added Et₃N (0.24 mL) and the reaction mixture was stirred at rt for 10 min. Later, NaBH(OAc)₃ (2.97 g, 0.44 mmol) was added, and the reaction mixture was stirred at rt for 16 h. After completion, the reaction mixture was diluted with satd aq NaHCO₃ (50 mL) and extracted with EtOAc (3 x 50mL). The combined organic layers were dried (anh Na₂SO₄), concentrated under reduced pressure and purified by column chromatography eluting with EtOAc to afford a mixture of tert-butyl ((1R,4r)-4-((R)-3-methoxypyrrolidin-1- yl)cyclohexyl)carbamate and tert-butyl ((1S,4s)-4-((R)-3-methoxypyrrolidin-1- yl)cyclohexyl)carbamate as a yellow solid (1.3 g, 76 %). The material was taken into CH₂Cl₂ (15 mL) and xs HCl (4 M in 1,4-dioxane, 13 mL) was added before stirring was continued at rt for 3 h. After completion, the reaction mixture was concentrated under reduced pressure.to afford a mixture of (1R,4r)-4-((R)-3-methoxypyrrolidin-1-yl)cyclohexan-1-amine 2HCl and (1S,4s)-4-((R)-3-methoxypyrrolidin-1-yl)cyclohexan-1-amine 2HCl as brown solid (1 g). MS (ESI) 199.2 [M+H]⁺. Step 2. 6-bromo-N-((1R,4r)-4-((R)-3-methoxypyrrolidin-1-yl)cyclohexyl)quinazolin-2- amine and 6-bromo-N-((1S,4s)-4-((R)-3-methoxypyrrolidin-1-yl)cyclohexyl)quinazolin-2- amine [00365] To a DMF (20 mL) solution of a mixture of (1R,4r)-4-((R)-3- methoxypyrrolidin-1-yl)cyclohexan-1-amine 2HCl and (1S,4s)-4-((R)-3-methoxypyrrolidin- 1-yl)cyclohexan-1-amine 2HCl (2 g, 10 mmol), K₂CO₃ (4.17 g, 30.3 mmol) was added and the reaction mixture was stirred at rt for 15 min before 6-bromo-2-chloroquinazoline (2.46 g, 10.1 mmol) was added, later the stirring was continued at rt for 16 h. After completion, the reaction mixture was diluted with EtOAc (100 mL) and washed with ice cold water (3x 100 mL) and brine (2x 100 mL). The organic layer was dried (anh Na₂SO₄), concentrated under reduced pressure and purified by column chromatography eluting with 5 % MeOH in CH₂Cl₂ to afford 6-bromo-N-((1S,4s)-4-((R)-3-methoxypyrrolidin-1- yl)cyclohexyl)quinazolin-2-amine as a yellow solid (0.3 g, 15 %) followed by 6-bromo-N- ((1R,4r)-4-((R)-3-methoxypyrrolidin-1-yl)cyclohexyl)quinazolin-2-amine as a yellow solid (0.22 g, 11 %). MS (ESI) 405.3/407.3 [M+H]⁺. Step 3. N-((1R,4r)-4-((R)-3-methoxypyrrolidin-1-yl)cyclohexyl)-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinazolin-2-amine [00366] Prepared by General Method MB using 1,4-dioxane (5 mL), 6-bromo-N- ((1R,4r)-4-((R)-3-methoxypyrrolidin-1-yl)cyclohexyl)quinazolin-2-amine (0.22 g, 0.54 mmol), KOAc(0.16 g, 1.6 mmol), B₂pin₂ (0.207 g, 0.81 mmol), and Pd(dppf)Cl₂ (0.04 g, 0.054 mmol); by heating under N₂ at 80 °C for 16 h. After completion, the reaction mixture was diluted with EtOAc (30 mL) and filtered through Celite, The volatiles were removed under reduced pressure to give crude N-((1R,4r)-4-((R)-3-methoxypyrrolidin-1- yl)cyclohexyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine as dark brown solid (0.2 g) which was used in next step without further purification. MS (ESI) 453.2 [M+H]⁺. Step 4. 5-chloro-N-(2,4-difluoro-3-(2-(((1R,4r)-4-((R)-3-methoxypyrrolidin-1- yl)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [00367] Prepared by General Method SMC using 1,4-dioxane (2 mL), crude N- ((1R,4r)-4-((R)-3-methoxypyrrolidin-1-yl)cyclohexyl)-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazolin-2-amine (0.2 g, 0.44 mmol), K₂CO₃ (0.18 g, 1.32 mmol), N-(3- bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (0.18 g, 0.44 mmol) and Pd(dppf)Cl_2*CH₂Cl₂ (0.035 g, 0.04 mmol); by heating under N₂ at 80 °C for 16 h. After completion, the reaction mixture was diluted with satd aq NaHCO₃ (20 mL) and extracted with EtOAc (3x 15 mL). The combined organic layers were dried (anh Na₂SO₄), concentrated under reduced pressure and purified by column chromatography, eluting with 5 % MeOH in CH₂Cl₂ to afford 5-chloro-N-(2,4-difluoro-3-(2-(((1R,4r)-4-((R)-3- methoxypyrrolidin-1-yl)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3- sulfonamide as an off white solid (0.022 g, 7.6 %).¹H NMR (400 MHz, DMSO-d6) δ ppm 10.73 (br.s., 1 H), 9.13 (br. s., 1 H), 8.31 (br. s., 1 H), 8.01 (d, J=3.05 Hz, 1 H), 7.78 (s, 1 H), 7.41 - 7.66 (m, 3 H), 7.11 - 7.26 (m, 1 H), 6.89 - 7.03 (m, 1 H), 3.89 - 3.97 (m, 1 H), 3.83 (s, 3 H), 3.20 (s, 3 H), 2.91 - 3.06 (m, 1 H), 2.70 - 2.90 (m, 4 H), 1.88 -2.09 (m, 6 H), 1.70 - 1.84 (m, 1 H), 1.26 - 1.48 (m, 4 H). MS (ESI) 659.25 [M+H]⁺. Example 26: Synthesis of 5-chloro-N-(2,4-difluoro-3-(2-(((1S,4s)-4-((R)-3- methoxypyrrolidin-1-yl)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3- sulfonamide (I-26) Step 1. N-((1S,4s)-4-((R)-3-methoxypyrrolidin-1-yl)cyclohexyl)-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinazolin-2-amine

[00368] Prepared by General Method MB using 6-bromo-N-((1R,4r)-4-((R)-3- methoxypyrrolidin-1-yl)cyclohexyl)quinazolin-2-amine (0.1 g, 0.25 mmol) in 1,4-dioxane (3 mL), KOAc(0.073 g, 0.74 mmol), B₂pin₂ (0.094 g, 0.37 mmol) and Pd(dppf)Cl₂ (0.018 g, 0.025 mmol); by heating at 80 °C for 16 h. After completion, the reaction mixture was diluted with EtOAc (25 mL), filtered through Celite. The volatiles were removed under reduced pressure to give crude N-((1S,4s)-4-((R)-3-methoxypyrrolidin-1-yl)cyclohexyl)-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine as dark brown solid (0.1 g) which was used as such in next step without further purification. MS (ESI) 453.2 [M+H]⁺ and 372.1 [M+H]⁺ for the corresponding boronic acid. Step 2: 5-chloro-N-(2,4-difluoro-3-(2-(((1S,4s)-4-((R)-3-methoxypyrrolidin-1- yl)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [00369] Prepared by General Method SMC using crude N-((1S,4s)-4-((R)-3- methoxypyrrolidin-1-yl)cyclohexyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinazolin-2-amine (0.1 g, 0.22 mmol), 1,4-dioxane (1 mL), K₂CO₃ (0.09 g, 0.66 mmol), N-(3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (0.092 g, 0.22 mmol) and Pd(dppf)Cl₂*CH₂Cl₂ (0.018 g, 0.022 mmol); by heating at 80 °C for 16 h. Later, the reaction mixture was diluted with satd aq NaHCO₃ solution (10 mL), extracted with EtOAc (3 x 10 mL). The combined organic layers were dried (anh Na₂SO₄), concentrated under reduced pressure. Purified by column chromatography, eluting with 5 % MeOH in CH₂Cl₂ to afford 5-chloro-N-(2,4-difluoro-3-(2-(((1S,4s)-4-((R)-3-methoxypyrrolidin-1- yl)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide as an off white solid (0.031 g, 21 %). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.27 (br. s., 1 H), 9.15 (br. s., 1 H), 8.45 (br. s., 1 H), 8.05 (d, J=2.93 Hz, 1 H), 7.79 (s, 1 H), 7.45 - 7.66 (m, 3 H), 7.32-7.21 (m, 1 H), 7.09 - 7.18 (m, 1 H), 3.91 - 4.09 (m, 2 H), 3.88 (s, 3 H), 3.21 (s, 3 H), 1.94 - 2.08 (m, 2 H), 1.74 - 1.93 (m, 6 H), 1.55 - 1.71 (m, 6 H). MS (ESI) 659.2 [M+H]⁺. Example 27: Synthesis of 5-chloro-N-(2,4-difluoro-3-(2-(((1r,4r)-4-(methyl(oxetan-3- yl)amino)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (I- 27)

Step 1. tert-butyl ((1r,4r)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2- yl)amino)cyclohexyl)carbamate [00370] Prepared by General Method MB using 1,4-dioxane (5 mL), tert-butyl ((1r,4r)-4-((6-bromoquinazolin-2-yl)amino)cyclohexyl)carbamate (0.5 g, 1.2 mmol), KOAc(0.35 g, 3.6 mmol), B2pin2 (0.3 g, 1.2 mmol) and Pd(dppf)Cl₂. CH₂Cl₂ (0.097 g, 0.11 mmol); by heating under N2 at 90 °C for 16 h. After completion, the reaction mixture was diluted with EtOAc, filtered through Celite, The filtrate was concentrated under reduced pressure to afford tert-butyl ((1r,4r)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinazolin-2-yl)amino)cyclohexyl)carbamate as a brown sticky solid (0.5 g, 90 %) which was used directly in the next step. MS (ESI) 469.3 [M+H]⁺. Step 2. tert-butyl ((1r,4r)-4-((6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2,6- difluorophenyl)quinazolin-2-yl)amino)cyclohexyl)carbamate [00371] Prepared by General Method SMC using N-(3-bromo-2,4-difluorophenyl)-5- chloro-2-methoxypyridine-3-sulfonamide (0.8 g, 2.1 mmol), 1,4-dioxane:H₂O (9:1, 10 mL), tert-butyl ((1r,4r)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2- yl)amino)cyclohexyl)carbamate (1 g, 2.1 mmol), K₂CO₃ (0.8 g, 6.4 mmol) and PdCl₂(dppf)*CH₂Cl₂ (0.17 g, 0.21 mmol); by heating at 80 °C for 4 h. After completion, the reaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried (anh Na₂SO₄) and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with 60 % EtOAc in hexanes to afford tert-butyl ((1r,4r)-4-((6-(3-((5-chloro-2-methoxypyridine)-3- sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)amino) cyclohexyl)carbamate as a yellow solid (1 g, 69 %). MS (ESI) 675.17 [M+H]⁺. Step 3. N-(3-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-5- chloro-2-methoxypyridine-3-sulfonamide [00372] To a stirred solution of tert-butyl ((1r,4r)-4-((6-(3-((5-chloro-2- methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)quinazolin-2- yl)amino)cyclohexyl)carbamate (0.6 g, 0.9 mmol) in CH₂Cl₂ (6 mL), HCl (4 M in 1,4-dioxane, 6 mL) was added at 0 °C. The reaction mixture was then stirred at rt for 6 h. After completion, the reaction mixture was basified with satd aq NaHCO₃ (15 mL) and reaction mixture was stirred at rt for 5 min before the solid was filtered, dried to afford N-(3-(2- (((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-2- methoxypyridine-3-sulfonamide as a yellow solid (0.5 g, 98 %). MS (ESI) 575.3 [M+H]⁺. Step 4. 5-chloro-N-(2,4-difluoro-3-(2-(((1r,4r)-4-(oxetan-3- ylamino)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [00373] A MeOH (5 mL) solution of N-(3-(2-(((1r,4r)-4- aminocyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine- 3-sulfonamide (0.5 g, 0.9 mmol), oxetan-3-one (0.625 g, 8.69 mmol) was stirred at rt for 30 min. Later NaBH3CN (0.163 g, 2.60 mmol) was added, and the reaction mixture was further stirred at 35 °C for 16 h. After completion, the reaction mixture was concentrated and purified by column chromatography eluting with 11 % MeOH in CH₂Cl₂ to afford 5-chloro- N-(2,4-difluoro-3-(2-(((1r,4r)-4-(oxetan-3-ylamino)cyclohexyl)amino)quinazolin-6- yl)phenyl)-2-methoxypyridine-3-sulfonamide as a yellow sticky solid (0.15 g, 27 %). MS (ESI) 631.2 [M+H]⁺. Step 5. 5-chloro-N-(2,4-difluoro-3-(2-(((1r,4r)-4-(methyl(oxetan-3- yl)amino)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide [00374] A solution of 5-chloro-N-(2,4-difluoro-3-(2-(((1r,4r)-4-(oxetan-3- ylamino)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide (0.15 g, 0.23 mmol), paraformaldehyde (0.072 g, 2.4 mmol) in MeOH (2 mL) was stirred at rt for 30 min. Later NaBH₃CN (0.045 g, 0.71 mmol) was added, and the reaction mixture was further stirred at 35 °C for 16 h. After completion, the reaction mixture was concentrated. The crude material was purified by reverse phase column chromatography eluting with 45% of aq NH₄OH (0.1%) in MeCN to afford 5-chloro-N-(2,4-difluoro-3-(2-(((1r,4r)-4- (methyl(oxetan-3-yl)amino)cyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine- 3-sulfonamide as an off white solid (20 mg, 16 %). ¹H NMR (400 MHz, DMSO-d₆): δ 10.39 (br.s., 1 H), 9.12 (br.s., 1 H), 8.48 (br.s., 1 H), 8.07 (br.s., 1 H), 7.77 (br.s., 1 H), 7.49-7.57 (m, 3 H), 7.22-7.33 (m, 2 H), 4.50 (br.s., 4 H), 4.10-3.65 (m, 4 H), 2.15 (br.s., 3 H), 2.02 (br.s., 3 H), 1.65 (br.s., 2 H), 1.45-1.10 (m, 4 H). MS (ESI) 645.0 [M+H]⁺. [00375] Below are the structures, yields and ¹H NMR and MS for the exemplary compounds that have been synthesized:

Biological Assays GCN2 Enzymatic Assay [00376] To identify small molecule GCN2 inhibitors, a biochemical GCN2 enzymatic assay was outsourced to Eurofins. This assay was done radiometrically which utilizes full- length, GST-tagged GCN2 (E556G) produced in insect cells. The kinase concentration is 18.5 nM with 70 uM ATP (Km=77 uM) and [g-33P]-ATP in a Tris buffer containing 300 uM of an optimized peptide substrate (RSRSRSRSRSRSRSR). The reaction was initiated by the addition of the Mg/ATP mix. After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of phosphoric acid to a concentration of 0.5%.10 μL of the reaction was then spotted onto a P30 filtermat and washed four times for 4 minutes in 0.425% phosphoric acid and once in methanol prior to drying and scintillation counting. The results are shown in Table 1 where IC₅₀’s is reported in the following ranges: A: 0.1- 100 nM; B: 100-1000 nM; C: 1000-10000 nM; D: >10000 nM for the compounds of Formula (I) Table 1: IC₅₀’s(nM) for exemplary compounds of the application for inhibition of GCN2

Cell-based phosho- eIF2α Assay: [00377] To confirm target engagement in cells, an AlphaLISA assay (Perkin Elmer #TGREIR2S10K) was optimized to monitor eIF2α phosphorylation on Serine-51. This event is specifically catalyzed by GCN2 induced with halofuginone (an inhibitor of glutamyl-prolyl tRNA synthetase), borrelidin (an inhibitor of threonyl-tRNA synthetase) or L-asparaginase which activates GCN2 kinase activity by triggering the amino acid starvation response. SKOV3 or U2OS cells (seeded at 40,000 cell per well) are pretreated with exemplary GCN2 inhibitor compounds of the application (1 nM to 1 µM) for 1 hour, stimulated with borrelidin (10 µM) for 1 hour, then lysed and analyzed with the AlphaScreen SureFire kit, which utilizes an antibody based method to quantitatively detect phospho-eIF2α in an HTS format. Tumor Cell Growth Inhibition Assay: [00378] SKOV3 cells were seeded into a 384-well plate at 1,000 cells/well in 50ul medium (Alpha-MEM containing 10% FBS, 100 mg/ml Normocin, Invivogen and 50 mg/ml Gentamycin, Invitrogen). Plates were then incubated overnight for the cells to attach. An HP D300 digital dispenser was used to dose cells with ASNase, DMSO or test compounds across a 16-point range of concentrations (high dose of 10uM to low dose of 5nM). Plates were incubated in a humidified 5% CO₂ incubator at 37oC. After 3-5 days, plates were removed from the incubator and equilibrated to room temperature An equal volume of ATPlite assay reagent was then added to each well, and samples processed according to manufacturer’s instructions (Perkin Elmer). Luminescent signals were then measured using an Envision plate reader equipped with a US-Luminescence detector. Solubility assay [00379] The stock solutions of test compound were prepared in DMSO at the concentration of 30 mM, and the stock solution of control compound was prepared in DMSO at the concentration of 30 mM. Progesterone was used as positive control in the assay.10 µL stock solution of each compound was placed in order into their proper 96-well rack, followed by adding 990 µL of PBS at pH 7.4 into each vial of the cap-less Solubility Sample plate. This study was performed in duplicate. One stir stick was added to each vial and then vials were sealed using a molded PTDE/SIL 96-Well Plate Cover. The Solubility Sample plate was transferred to the Thermomixer Comfort plate shaker and incubated at RT for 2 hours with shaking at 1100 rpm. After 2 hours incubation, stir sticks were removed using a big magnet and all samples from the Solubility Sample plate were transferred into the filter plate. All the samples were filtered by using the Vacuum Manifold. An aliquot of 10 µL of the filtered samples were diluted with 980 µL of methanol and 10 µL of DMSO. The dilution factor might be changed according to the solubility value and the LC/MS signal response. The solution filtered was analyzed and quantified against a standard of known concentration in DMSO using LC coupled with Mass spectral peak identification and quantitation. The solubility values of the test compounds were calculated as follows:

DF means the dilution factor Microsomal stability Assays Liver microsomal metabolic stability [00380] In Phase I analysis, test compounds were incubated at a final concentration of 1 µM (this concentration was assumed to be well below the Km values to ensure linear reaction conditions i.e. to avoid saturation). Working stocks were initially diluted to a concentration of 40.0 µM in 0.1 M potassium phosphate buffer (pH 7.4) before addition to the reaction vials. Pooled human liver microsomes (Corning Gentest) were utilized at a final concentration of 0.5 mg/mL (protein). Duplicate wells were used for each time point (0 and 60 minutes). Reactions were carried out at 37°C in an orbital shaker at 175 rpm, and the final DMSO concentration was kept constant at 0.1%. The final volume for each reaction was 100 µL, which includes the addition of an NADPH-Regeneration Solution (NRS) mix. This NRS mix is comprised of glucose 6-phosphate dehydrogenase, NADP+, MgCl2, and glucose 6-phosphate. Upon completion of the 60-minute time point, reactions were terminated by the addition of 2-volumes (200 µL) of ice-cold, acetonitrile containing 0.5% formic acid and internal standard. Samples were then centrifuged at 4,000 rpm for 10 minutes to remove debris and precipitated protein. Approximately 150 µL of supernatant was subsequently transferred to a new 96 well microplate for LC/MS analysis: [00381] Narrow-window mass extraction LC-MS analysis was performed for all samples in this study using a Waters Xevo quadrupole time-of-flight (QTof) mass spectrometer to determine relative peak areas of test compounds. The percent remaining values are calculated using the following equations: % remaining = (A )/A0 ×100 where A is area response after incubation A0 is area response at initial time point [00382] The human microsomal metabolic stability and solubility properties of exemplary compounds of the application showing significantly improved metabolic stability and solubility profiles relative to a comparative compound from International Patent application publication No.2021/165346 (C-1) are presented in Table 2. Table 2: Human Microsomal Metabolic Stability and Solubility of representative compounds of the application

[00383] Table 3 provides the structure of comparative compounds from WO2021165346 (Black Belt TX Ltd) Table 3: Comparative compound structures

[00384] While the present application has been described with reference to what are presently considered to be the preferred examples, it is to be understood that the application is not limited to the disclosed examples. To the contrary, the present application is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims. [00385] All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.

Claims

CLAIMS: 1. A compound of Formula I, or a pharmaceutically acceptable salt, solvate and/or prodrug thereof: (I) R¹ is selected from C_3-10cycloalkyl substituted with one or two R⁹, C_3-10heteroycloalkyl substituted with one or two R¹⁰, C_1-6alkyleneC_3-10cycloalkyl optionally substituted with one or two R¹¹, and C_1-6alkyleneC_3-10heterocycloalkyl optionally substituted with one or two R¹²; R² and R³ are independently selected from H, halo, CN and C_1-6alkyl; R⁴, R⁵ and R⁶ are independently selected from H, halo, CN and C_1-6alkyl; R⁷ is selected from H, C_1-6alkyl and OC_1-6alkyl, the latter two groups being optionally substituted with one or more substituents selected from OH and halo; R⁸ is selected from H, halo, CN, C_1-6alkyl and OC_1-6alkyl, the latter two groups being optionally substituted with one or more substituents selected from OH and halo; each R⁹ is independently selected from NR¹³R¹⁴, C_1-6alkyleneNR¹³R¹⁴, C_1-6alkyl, C_2- 6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, the latter two groups being optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1- ₆alkyl; each R¹⁰ is independently selected from NR¹⁵R¹⁶, C_1-6alkyleneNR¹⁵R¹⁶, C_1-6alkyl, C_2- 6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, the latter two groups being optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1- ₆alkyl; each R¹¹ is independently selected from OH, NR¹⁷R¹⁸, C_1-6alkyl, C_2-6alkenyl, C_2-6alkyny, C_3- ₁₀cycloalkyl and C_3-10heterocycloalkyl, wherein all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR¹⁹, NR¹⁹R²⁰ and C_1-6alkyl; each R¹² is independently selected from OH, NR²¹R²², C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, wherein all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR²³, NR²³R²⁴ and C_1-6alkyl; R^13, R¹⁵, R¹⁷ and R²¹ are independently selected from H, C_1-6alkyl, C_3-10cycloalkyl and C_3- ₁₀heterocycloalkyl, the latter three groups being optionally substituted with one or two substituents selected from halo, OH and OC_1-6alkyl; R¹⁴, R¹⁶, R¹⁸, R¹⁹, R²⁰, R²², R²³ and R²⁴ are independently selected from H and C_1-6alkyl; and X is CH or N.

2. The compound of claim 1, wherein R¹ is selected from C_3-10cycloalkyl substituted with one or two R⁹, C_3-10heteroycloalkyl substituted with one or two R¹⁰, C_1-4alkyleneC_3- ₁₀cycloalkyl optionally substituted with one or two R¹¹, and C_1-4alkyleneC_3-10heterocycloalkyl optionally substituted with one or two R¹².

3. The compound of claim 2, wherein R¹ is C_3-10cycloalkyl substituted with one or two R⁹.

4. The compound of claim 3, wherein R¹ is a monocyclic C_3-10cycloalkyl or a bicyclic C_5- ₁₀cycloalkyl, each of which is substituted with one or two R⁹.

5. The compound of claim 4, wherein R¹ is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, a spirofused C_5-10cycloalkyl and a bridged C_5- ₁₀cycloalkyl, each of which is substituted with one or two R⁹.

6. The compound of claim 5, wherein R¹ is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each of which is substituted with one or two R⁹.

7. The compound of claim 6, wherein R¹ is cyclohexyl substituted with one R⁹.

8. The compound of claim 5, wherein R¹ is the spirofused C_5-10cycloalkyl 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 substituted with one or two R⁹.

9. The compound of claim 5, wherein R¹ is the bridged C_5-10cycloalkyl substituted with one or two R⁹ and the bridged C_5-10cycloalkyl is selected from a bicyclopentanyl, a bicycloheptanyl and a bicyclooctanyl each of which substituted with one or two R⁹.

10. The compound of any one of claims 1 to 9, wherein each R⁹ is independently selected from NR¹³R¹⁴ _, C_1-4alkyleneNR¹³R¹⁴, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-10cycloalkyl and C_3- ₁₀heterocycloalkyl, the latter two groups being optionally substituted with one or two substituents independently selected halo, C_1-4alkyl and OC_1-4alkyl.

11. The compound of claim 10, wherein each R⁹ is independently selected from NR¹³R¹⁴, C_1-4alkyleneNR¹³R¹⁴ and C_3-10heterocycloalkyl, the latter group being optionally substituted with one or two substituents selected from halo, C_1-4alkyl and OC_1-4alkyl.

12. The compound of claim 11, wherein each R⁹ is independently selected from NR¹³R¹⁴ and C_1-4alkyleneNR¹³R¹⁴.

13. The compound of claim 12, wherein each R⁹ is independently NR¹³R¹⁴.

14. The compound of any one of claims 10 to 13, wherein R¹³ is selected from H, C_1-4alkyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, the latter three groups being optionally substituted with one or two substituents selected from OH and OC_1-4alkyl.

15. The compound of claim 14, wherein R¹³ is selected from H and C_1-4alkyl optionally substituted with one or two substituents selected from OH and OC_1-4alkyl.

16. The compound of claim 15, wherein R¹³ is C_1-4alkyl optionally substituted with one or two substituents selected from OH and OC_1-4alkyl.

17. The compound of claim 15, wherein R¹³ is selected from H and CH₃.

18. The compound of any one of claims 10 to 17, wherein R¹⁴ is selected from H and C_1- ₄alkyl.

19. The compound of claim 18, wherein R¹⁴ is selected from H and CH₃.

20. The compound of claim 11, wherein each R⁹ is independently C_3-6heterocycloalkyl optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1- ₆alkyl.

21. The compound of claim 20, wherein each R⁹ is independently a C_3-6heterocycloalkyl including at least one ring heteromoiety selected from NH and N(C_1-4alkyl) and optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1-6alkyl.

22. The compound of claim 21, wherein each R⁹ is independently selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl, each of which is optionally substituted with one or two substituents selected from F, Cl, C_1-4alkyl and OC_1-4alkyl.

23. The compound of claim 2, wherein R¹ is C_3-10heterocycloalkyl substituted with one or two R¹⁰.

24. The compound of claim 23, wherein R¹ is a monocyclic C_3-10heterocycloalkyl or a bicyclic C_5-10heterocycloalkyl substituted with one or two R¹⁰.

25. The compound of claim 24, wherein R¹ is monocyclic C_3-6heterocycloalkyl including at least one ring heteromoiety selected from NH and N(C_1-6alkyl), and substituted with one or two R¹⁰.

26. The compound of claim 24, wherein R¹ is bicyclic C_5-10heterocycloalkyl substituted with one or two R¹⁰, and the bicyclic C_5-10heterocycloalkyl is a spirofused C_5-10heterocycloalkyl, a fused C₅-₁₀heterocycloalkyl or a bridged C_5-10heterocycloalkyl each of which is substituted with one or two R¹⁰.

27. The compound of claim 26, wherein the spirofused C_5-10heterocycloalkyl is selected from an azaspiro[4.4]nonane, an azaspiro[3.5]nonane, an azaspiro[5.4]decane and an azaspiro[5.2]octane each of which is substituted with one or two R¹⁰.

28. The compound of claim 26, wherein the fused C_5-10heterocycloalkyl is selected from an octahydroindolyl, an octahydroisoindolyl, a decahydroquinolyl and a decahydroisoquinolyl each of which is substituted with one or two R¹⁰.

29. The compound of claim 28, wherein the fused C_5-10heterocycloalkyl is selected from .

30. The compound of claim 26, wherein R¹ is the bridged C_5-10heterocycloalkyl selected from an azabicyclohexanyl, an azabicycloheptanyl a diazabicycloheptanyl, an azabicyclooctanyl and a diazabicyclooctanyl each of which is substituted with one or two R¹⁰.

31. The compound of any one of claims 23 to 30, wherein each R¹⁰ is independently selected from NR¹⁵R¹⁶, C_1-4alkyleneNR¹⁵R¹⁶, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_3- ₁₀cycloalkyl and C_3-10heterocycloalkyl, the latter two groups being optionally substituted with one or two substituents selected from halo, C_1-6alkyl and OC_1-6alkyl.

32. The compound of claim 31, wherein each R¹⁰ is independently selected from NR¹⁵R¹⁶ and C_1-4alkyleneNR¹⁵R¹⁶.

33. The compound of claim 31 or claim 32, wherein R¹⁵ is selected from H, C_1-4alkyl, C_3- ₁₀cycloalkyl and C_3-10heterocycloalkyl, the latter three groups being optionally substituted with one or two substituents selected from OH and OC_1-4alkyl.

34. The compound of claim 33 wherein R¹⁵ is selected from H and C_1-4alkyl optionally substituted with one or two substituents independently selected from OH and OC_1-4alkyl.

35. The compound of claim 34, wherein R¹⁵ is selected from H and CH₃.

36. The compound of any one of claims 31 to 35, wherein R¹⁶ is selected from H and C_1- ₄alkyl.

37. The compound of claim 31, wherein each R¹⁰ is independently C_3-6heterocycloalkyl including at least one ring heteromoiety selected from NH and N(C_1-4alkyl) optionally substituted with C_1-4alkyl.

38. The compound of claim 2, wherein R¹ is selected from C_1-4alkyleneC_3-10cycloalkyl optionally substituted with one or two R¹¹.

39. The compound of claim 38, wherein the cycloalkyl in the C_1-4alkyleneC_3-10cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spirofused C_5- ₁₀cycloalkyl and bridged C_5-10cycloalkyl, each of which is substituted with one or two R¹¹.

40. The compound of claim 39, wherein the cycloalkyl in the C_1-4alkyleneC_3-10cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl each of which is substituted with one or two R¹¹.

41. The compound of claim 39, wherein the cycloalkyl in the C_1-4alkyleneC_3-10cycloalkyl is the spirofused C_5-10cycloalkyl and the spirofused C_5-10cycloalkyl is selected from spiro[3.3]heptane, spiro[4.4]nonane, spiro[5.4]decane, spiro[4.5]octane and spiro[5.2]octane each of which is optionally substituted with one or two R¹¹.

42. The compound of claim 39, wherein the cycloalkyl in the C_1-4alkyleneC_3-10cycloalkyl is the bridged C_5-10cycloalkyl and the bridged C_5-10cycloalkyl is selected from a bicyclopentanyl, a bicycloheptanyl and a bicyclooctanyl each of which is optionally substituted with one or two R¹¹.

43. The compound of claim 38, wherein R¹ is CH₂C_{3- 8}cycloalkyl or CH₂CH₂C_{3- 8}cycloalkyl optionally substituted with one or two R¹¹.

44. The compound of any one of claims 38 to 43, wherein each R¹¹ is independently selected from OH, NR¹⁷R¹⁸, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl and C₃- ₁₀heterocycloalkyl, wherein all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR¹⁹, NR¹⁹R²⁰ and C_1-6alkyl.

45. The compound of claim 44, wherein each R¹¹ is independently selected from OH, NR¹⁷R¹⁸, C_1-4alkyl, C_3-8cycloalkyl and C_3-10heterocycloalkyl, wherein all alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR¹⁹, NR¹⁹R²⁰ and C_1-4alkyl.

46. The compound of claim 44, wherein each R¹¹ is independently NR¹⁷R¹⁸.

47. The compound of claim 45 or claim 46, wherein R¹⁷ is selected from H, C_1-4alkyl, C_3- ₁₀cycloalkyl and C_3-10heterocycloalkyl, the latter three groups being optionally substituted with one or two substituents selected from OH and OC_1-4alkyl.

48. The compound of claim 47, wherein R¹⁷ is selected from H and C_1-4alkyl optionally substituted with one or two substituents selected from OH and OC_1-4alkyl.

49. The compound of claim 48, wherein R¹⁷ is selected from H and CH₃.

50. The compound of any one of claims 44 to 49, wherein R¹⁸ is selected from H and C_1- ₄alkyl.

51. The compound of claim 44, wherein each R¹¹ is independently C_1-4alkyl optionally substituted with one or more substituents selected from halo, OR¹⁹ and NR¹⁹R²⁰.

52. The compound of claim 44, wherein each R¹¹ is independently a C_3-6heterocycloalkyl including at least one ring heteromoiety selected from NH and N(C_1-4alkyl) optionally substituted with one to three substituents selected from F, Cl, OR¹⁹, NR¹⁹R²⁰ and C_1-4alkyl.

53. The compound of claim 44, wherein each R¹¹ is independently C_{3- 8}cycloalkyl, optionally substituted with one or more substituents selected from F, Cl, OR¹⁹ and NR¹⁹R²⁰.

54. The compound of any one of claims 44 to 53, wherein R¹⁹ and R²⁰ are independently selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃.

55. The compound of claim 2, wherein R¹ is selected from C_1-4alkyleneC_3-10heterocycloalkyl optionally substituted with one or two R¹².

56. The compound of claim 55, wherein the heterocycloalkyl in the C_1-4alkyleneC_3- ₁₀heterocycloalkyl is selected from a monocyclic C_3-10heterocycloalkyl or bicyclic C_5- ₁₀heterocycloalkyl optionally substituted with one or two R¹².

57. The compound of claim 56, wherein the heterocycloalkyl in the C_1-4alkyleneC₃- ₁₀heterocycloalkyl is C_3-6heterocycloalkyl including at least one ring heteromoiety selected from NH and N(C_1-6alkyl), and optionally substituted with one or two R¹².

58. The compound of claim 57, wherein the C_3-6heterocycloalkyl including at least one ring heteromoiety selected from NH and N(C_1-6alkyl) in the C_1-4alkyleneC_3-8heterocycloalkyl is selected from azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl, each of which is optionally substituted with one R¹².

59. The compound of claim 56, wherein the heterocycloalkyl in the C_1-4alkyleneC₃- ₁₀heterocycloalkyl of R¹ is a bicyclic C_5-10heterocycloalkyl optionally substituted with one or two R¹² and the bicyclic C_5-10heterocycloalkyl is a spirofused C_5-10heterocycloalkyl, a fused C_5-10heterocycloalkyl or a bridged C_5-10heterocycloalkyl each of which is optionally substituted with one or two R¹².

60. The compound of claim 55, wherein R¹ is CH₂C_{3- 8}heterocycloalkyl or CH₂CH₂C_3- ₈heterocycloalkyl optionally substituted with one or two R¹².

61. The compound of any one of claims 55 to 60, wherein each R¹² is independently selected from OH, NR²¹R²², C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_{3- 8}cycloalkyl and C_3- ₈heterocycloalkyl, wherein all alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halo, OR²³, NR²³R²⁴ and C_1-6alkyl.

62. The compound of claim 61, wherein each R¹² is independently NR²¹R²².

63. The compound of claim 62, wherein R²¹ is selected from H, C_1-4alkyl, C_3-10cycloalkyl and C_3-10heterocycloalkyl, the latter three groups being optionally substituted with one or two substituents selected from OH and OC_1-4alkyl.

64. The compound of claim 63, wherein R²¹ is selected from H and C_1-4alkyl optionally substituted with one or two substituents selected from OH and OC_1-4alkyl.

65. The compound of claim 64, wherein R²¹ is selected from H and CH₃.

66. The compound of any one of claims 61 to 65, wherein R²² is selected from H and C_1- ₄alkyl.

67. The compound of claim 61, wherein each R¹² is independently C_1-4alkyl optionally substituted with one or more substituents selected from F, Cl, OR²³ and NR²³R²⁴.

68. The compound of claim 61, wherein each R¹² is independently C_3-6heterocycloalkyl including at least one ring heteromoiety selected from NH and N(C_1-4alkyl) optionally substituted with one to three substituents selected from F, Cl, OR²³, NR²³R²⁴ and C_1-4alkyl.

69. The compound of claim 67 or claim 68, wherein each R²³ and R²⁴ are independently selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)CH₂CH₃, and CH(CH₃)₃.

70. The compound of claim 1, wherein R¹ is selected from

.

71. The compound of any one of claims 1 to 70, wherein R² and R³ are independently selected from H, halo, CN and C_1-4alkyl.

72. The compound of claim 71, wherein R² and R³ are independently selected from H, and CH₃ or R² and R³ are both H.

73. The compound of any one of claims 1 to 72, wherein, R⁴, R⁵ and R⁶ are independently selected from H, F, Cl, CN and C_1-4alkyl.

74. The compound of claim 73, wherein one of R⁴ and R⁵ is F and the other is H or R⁴ and R⁵ are both H.

75. The compound of claim 73, wherein R⁶ is selected from H, F and Cl.

76. The compound of claim 75, wherein R⁶ is F.

77. The compound of any one of claims 1 to 76, wherein R⁷ is selected from H, C_1-4alkyl and OC_1-4alkyl, the latter two groups being optionally substituted with one or more of OH and halo.

78. The compound of claim 77, wherein R⁷ is selected from H, OCF₂H, OCH₃, and OCF₃.

79. The compound of any one of claims 1 to 78, wherein R⁸ is selected from H, halo, CN, C_1-4alkyl and OC_1-4alkyl, the latter two groups being optionally substituted with one or more of OH and halo.

80. The compound of claim 79, wherein R⁸ is selected from H, F, Cl, CN and CF₃.

81. The compound of claim 80, wherein R⁸ is Cl.

82. The compound of any one of claims 1 to 81, wherein X is N.

83. The compound of any one of claims 1 to 81, wherein X is CH.

84. The compound of claim 1, wherein the compound of Formula I is selected from:

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

85. A pharmaceutical composition comprising one or more compounds of any one of claims 1 to 84 and a pharmaceutically acceptable carrier.

86. A method of inhibiting general control nonderepressible 2 (GCN2) in a cell, either in a biological sample or in a patient, comprising administering an effective amount of one or more compounds of any one of claims 1 to 84 or pharmaceutically acceptable salts, prodrugs and/or solvates thereof to the cell.

87. A method of treating a disease, disorder or condition that is treatable by inhibiting GCN2, comprising administering a therapeutically effective amount of one or more compounds of any one of claims 1 to 84 or pharmaceutically acceptable salts, prodrugs and/or solvates thereof to a subject in need thereof.

88. The method of claim 87, wherein the disease, disorder or condition that is treatable by inhibiting GCN2 is a neoplastic disorder.

89. The method of claim 87, wherein disease, disorder or condition that is treatable by inhibiting GCN2, is cancer.

90. The method of claim 89, wherein the cancer is selected from one or more of solid tumors, breast cancer, colon cancer, bladder cancer, skin cancer, head and neck cancer, liver cancer, lung cancer, pancreatic cancer, ovarian cancer, prostate cancer, bone cancer and glioblastoma.

91. The method of claim 87, wherein the disease, disorder or condition that is treatable by inhibiting GCN2 is a peripheral neuropathy.

92. The method of claim 91, wherein the peripheral neuropathy is Charcot-Marie-Tooth (CMT) peripheral neuropathy.

93. A method of treating a disease, disorder or condition that is treatable by inhibiting GCN2 comprising administering a therapeutically effective amount of one or more compounds of any one of claims 1 to 84 or pharmaceutically acceptable salts, prodrugs and/or solvates thereof in combination with another known agent useful for treatment of a disease, disorder or condition treatable by inhibiting GCN2 to a subject in need thereof.

94. The method of claim 93, wherein the disease, disorder or condition treatable by inhibiting GCN2 is cancer and/or peripheral neuropathy.

95. The method of claim 94, wherein the disease, disorder or condition that is treatable by inhibiting GCN2, is cancer and the one or more compounds of the application are administered or used in combination with one or more additional cancer treatments.

96. The method of claim 95, wherein the one or more additional cancer treatments is a chemotherapeutic agent and the chemotherapeutic agent is cisplatin.

97. The method of claim 95, wherein the one or more additional cancer treatments is a chemotherapeutic agent and the chemotherapeutic agent is L-asparaginase (L-ASNase).

98. The method of claim 95, wherein the one or more additional cancer treatments is small molecule therapy and the small molecule therapy is a glutaminase inhibitor or an asparagine synthetase (ASNS) inhibitor.

99. A method of improving the efficacy of one or more additional cancer treatments for treating cancer comprising administering an effective amount of one or more compounds of any one of claims 1 to 84 or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with an effective amount of the one or more additional cancer treatments.

100. The method of claim 99, wherein the one or more additional cancer treatments is a chemotherapeutic agent and the chemotherapeutic agent is cisplatin.

101. The method of claim 98, wherein the one or more additional cancer treatments is a chemotherapeutic agent and the chemotherapeutic agent is L-asparaginase (L-ASNase).

102. The method of claim 98, wherein the one or more additional cancer treatments is small molecule therapy and the small molecule therapy is a glutaminase inhibitor or an asparagine synthetase (ASNS) inhibitor.

103. The method of claim 99, wherein the cancer is associated with low asparagine synthetase (ASNS) expression and the one or more additional cancer treatments is L- asparaginase (L-ASNase).

104. The method of claim 99, wherein the cancer is associated with asparagine synthetase (ASNS) overexpression or dysregulation and the one or more additional cancer treatments are one or more asparagine synthetase (ASNS) inhibitors and/or L-asparaginase.

105. The method of claim 99, wherein the cancer is associated with low asparagine synthetase (ASNS) expression and low glutaminase expression and the one or more additional cancer treatments are L-asparaginase (L-ASNase) and/or one or more glutaminase inhibitors.

106. The method of claim 99, wherein cancer is associated with asparagine synthetase (ASNS) overexpression or dysregulation and glutaminase overexpression or dysregulation and the one or more additional cancer treatments are L-asparaginase (L-ASNase), one or more glutaminase inhibitors and/or one or more asparagine synthetase (ASNS) inhibitors.