WO2024026419A1 - Quinoxaline derivatives as pik3 alpha modulators - Google Patents

Quinoxaline derivatives as pik3 alpha modulators Download PDF

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Publication number
WO2024026419A1
WO2024026419A1 PCT/US2023/071136 US2023071136W WO2024026419A1 WO 2024026419 A1 WO2024026419 A1 WO 2024026419A1 US 2023071136 W US2023071136 W US 2023071136W WO 2024026419 A1 WO2024026419 A1 WO 2024026419A1
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alkyl
compound
cancer
independently
optionally substituted
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PCT/US2023/071136
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French (fr)
Inventor
Yelena ARNAUTOVA
Etienne DARDENNE
Iwona WRONA
Ivan JEWETT
Istvan J. Enyedy
Fernando Padilla
Matthew C. Lucas
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Black Diamond Therapeutics, Inc.
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Publication of WO2024026419A1 publication Critical patent/WO2024026419A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • Phosphatidylinositol 3-Kinases are a group of plasma membrane-associated lipid kinases that upon activation catalyze the transfer of phosphate to the D-3’ position of inositol of phosphoinositol-4,5-phosphate (PIP2) to produce the second messenger phosphoinositol-3,4,5-phosphate (PIP3).
  • PIP2 phosphoinositol-4,5-phosphate
  • PIP3Ks are known to control and regulate of a variety of different cellular activities, including transcription, translation, proliferation, survival, chemotaxis, motility, cellular trafficking and metabolism.
  • PI3K subunits Genetic alterations such as mutations, amplifications, deletions and translocations in genes encoding PI3K subunits have been implicated in several of different diseases and disorder, including, CLOVES syndrome, PIK3CA-related overgrowth syndrome, as well as a variety of cancers.
  • mutations in the gene PIK3CA which encodes the p110 ⁇ (also referred to as PI3K ⁇ ) catalytic subunit, have been linked to numerous cancers, including bladder cancer, brain cancer, breast cancer, colon cancer, endometrial cancer, ovarian cancer, skin cancer, stomach cancer, lung cancer and prostate cancer.
  • mutations include oncogenic gain-of-function mutations that occur within mutation hotspots, primarily within the kinase and helicase domains. Accordingly, p110 ⁇ has been identified as a potential therapeutic target in the treatment of various cancers and other PI3K-driven diseases.
  • multiple inhibitors of PI3Ks have been developed, including alpelisib, buparlisib, taselisib, and inavolisib.
  • the efficacy of these existing PI3K inhibitors has been hindered by on-target related toxicities, including hyperglycemia, rash, diarrhea, myelosuppression, and transaminitis.
  • the present disclosure provides a compound of Formula (I): an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 is halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R 2 is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R 3 is C 3 -C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more
  • the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound as described herein (e.g., a method comprising one or more steps described in Schemes 1-2).
  • a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in Examples 1-24).
  • the present disclosure provides a method of modulating PI3K ⁇ activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • a method of modulating PI3K ⁇ activity comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • 3 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
  • the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating PI3K ⁇ activity (e.g., in vitro or in vivo).
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating PI3K ⁇ activity (e.g., in vitro or in vivo).
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.
  • the present disclosure provides a method of preparing a compound of the present disclosure.
  • the present disclosure provides a method of preparing a compound, comprising one or more steps described herein.
  • the present disclosure relates to quinoxaline derivatives, prodrugs, and pharmaceutically acceptable salts thereof, which may modulate PI3K ⁇ activity and are accordingly useful in methods of treatment of the human or animal body.
  • the present disclosure also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them and to their use in the treatment of disorders in which PI3K ⁇ is implicated, such as cancer.
  • Definitions [0026] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below. [0027] Without wishing to be limited by this statement, it is understood that, while various options for variables are described herein, the disclosure intends to encompass operable embodiments having combinations of the options.
  • the disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options.
  • various options for variables X, L, and Y are described herein, the disclosure may be interpreted as excluding structures for non-operable compound caused by certain combinations of variables X, L, and Y (e.g., when each of X, L, and Y is -O-).
  • alkyl As used herein, “alkyl”, “C 1 , C 2 , C 3 , C 4 , C 5 or C 6 alkyl” or “C 1 -C 6 alkyl” is intended to include C1, C2, C3, C4, C5 or C6 straight chain (linear) saturated aliphatic hydrocarbon groups 5 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 and C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups.
  • C 1 -C 6 alkyl is intends to include C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkyl groups.
  • alkyl examples include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl.
  • a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C1-C6 for straight chain, C 3 -C 6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.
  • optionally substituted alkyl refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino), acylamino (including alky
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • alkenyl includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups.
  • a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain).
  • C 2 -C 6 includes alkenyl groups containing two to six carbon atoms.
  • C 3 -C 6 includes alkenyl groups containing three to six carbon atoms.
  • optionally substituted alkenyl refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including 6 289225266 v1 Attorney Docket No.
  • alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • alkynyl includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups.
  • a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
  • C2-C6 includes alkynyl groups containing two to six carbon atoms.
  • C3- C6 includes alkynyl groups containing three to six carbon atoms.
  • C2-C6 alkenylene linker” or “C 2 -C 6 alkynylene linker” is intended to include C 2 , C 3 , C 4 , C 5 or C 6 chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups.
  • C 2 - C 6 alkenylene linker is intended to include C2, C3, C4, C5 and C6 alkenylene linker groups.
  • optionally substituted alkynyl refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sul
  • optionally substituted moieties include both the unsubstituted moieties and the moieties having one or more of the designated substituents.
  • substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl- piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl. 7 289225266 v1 Attorney Docket No.
  • cycloalkyl refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C 3 -C 12 , C 3 -C 10 , or C 3 -C 8 ).
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl.
  • polycyclic cycloalkyl only one of the rings in the cycloalkyl needs to be non- aromatic.
  • heterocycloalkyl refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. ⁇ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise.
  • heteroatoms such as O, N, S, P, or Se
  • heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6- tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-
  • variable X cycloalkyl or heterocycloalkyl
  • variable X cycloalkyl or heterocycloalkyl
  • aryl includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure.
  • aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like.
  • heteroaryl is intended to include a stable 5-, 6-, or 7- membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. ⁇ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur.
  • the nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined).
  • heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.
  • Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).
  • the heteroaryl is thiophenyl or benzothiophenyl.
  • the heteroaryl is thiophenyl.
  • the heteroaryl benzothiophenyl.
  • aryl and heteroaryl include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.
  • the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, 9 289225266 v1 Attorney Docket No
  • ASET-039/001WO 325190-2191 amino including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
  • Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxole-5-yl).
  • substituted means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogen atoms on the atom are replaced.
  • Keto substituents are not present on aromatic moieties.
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. [0043] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring.
  • hydroxy or “hydroxyl” includes groups with an -OH or -O- .
  • halo or “halogen” refers to fluoro, chloro, bromo and iodo.
  • haloalkyl or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms. 10 289225266 v1 Attorney Docket No.
  • optionally substituted haloalkyl refers to unsubstituted haloalkyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sul
  • alkoxy or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom.
  • alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups.
  • substituted alkoxy groups include halogenated alkoxy groups.
  • the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, s
  • halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.
  • the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and/or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.
  • compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps.
  • any description of a method of treatment or prevention includes use of the compounds to provide such treatment or prevention as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to prepare a medicament to treat or prevent such condition.
  • the treatment or prevention includes treatment or prevention of human or non-human animals including rodents and other disease models.
  • any description of a method of treatment includes use of the compounds to provide such treatment as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment includes use of the compounds to prepare a medicament to treat such condition.
  • the treatment includes treatment of human or non-human animals including rodents and other disease models.
  • the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal.
  • the mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig.
  • the subject can also be a bird or fowl.
  • the subject is a human.
  • the term “subject in need thereof” refers to a subject having a disease or having an increased risk of developing the disease.
  • a subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein.
  • a subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein.
  • a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large).
  • a subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment.
  • the subject in need thereof received and failed all known effective 13 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 therapies for a disease or disorder disclosed herein.
  • the subject in need thereof received at least one prior therapy.
  • the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.
  • the term “treat” can also include treatment of a cell in vitro or an animal model. It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a condition.
  • Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • a compound of the present disclosure can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.
  • the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.
  • one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc.
  • compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.
  • pharmaceutical composition is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject.
  • the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial.
  • the quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • active ingredient e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof
  • the dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
  • the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable excipient means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the 15 289225266 v1 Attorney Docket No.
  • ASET-039/001WO 325190-2191 following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment.
  • a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches.
  • the dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects.
  • the state of the disease condition e.g., a disease or disorder disclosed herein
  • the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.
  • the term “therapeutically effective amount”, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect.
  • the effect can be detected by any assay method known in the art.
  • the precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration.
  • Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • the term “therapeutically effective amount” refers to an amount of a pharmaceutical agent to treat or ameliorate an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect.
  • the effect can be detected by any assay method known in the art.
  • the precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration.
  • Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, 16 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 usually rats, mice, rabbits, dogs, or pigs.
  • the animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
  • Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50 % of the population) and LD 50 (the dose lethal to 50 % of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50.
  • Pharmaceutical compositions that exhibit large therapeutic indices are preferred.
  • the dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
  • Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect.
  • Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy.
  • Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.
  • compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilising processes.
  • Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion 17 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), cyclodextrins and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilisation.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier.
  • compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, orange flavoring. 18 289225266 v1 Attorney Docket No.
  • the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebuliser.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebuliser.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays, powders or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • compositions can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No.4,522,811. [0081] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease or disorder disclosed herein and also preferably causing complete regression of the disease or disorder. Dosages can range from about 0.01 mg/kg per day to 19 289225266 v1 Attorney Docket No.
  • ASET-039/001WO 325190-2191 about 5000 mg/kg per day.
  • An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. Improvement in survival and growth indicates regression.
  • the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell.
  • the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral organic acid salts of basic residues such as amines, alkali organic salts of acidic residues such as carboxylic acids, and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic organic acids.
  • such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric,
  • the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.
  • compositions include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3- 20 289225266 v1 Attorney Docket No.
  • the present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.
  • all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.
  • the compounds, or pharmaceutically acceptable salts thereof are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally.
  • the dosage regimen utilising the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to counter or arrest the progress of the condition.
  • the compounds described herein, and the pharmaceutically acceptable salts thereof are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent.
  • suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous organic solutions.
  • the compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.
  • All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples.
  • the present disclosure provides a compound of Formula (I): an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 is halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R 2 is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R 3 is C 3 -C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with
  • each R 3a independently is halogen, C1-C6 alkyl, or C6-C10 aryl, wherein the C1-C6 alkyl or C6-C10 aryl is optionally substituted with one or more halogen;
  • the present disclosure provides a compound of Formula (I), wherein: R 1 is halogen, cyano, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 2 is H, or C1-C6 alkyl; R 3 is 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R 3a ; each R 3a independently is C6-C10 aryl optionally substituted with one or more halogen; T is -(C1-C6 alkyl)-*, or -(C1-C6 alkyl)-NR T -*, wherein * denotes attachment to A; 23 289225266 v1 Attorney Docket No.
  • the present disclosure provides a compound of Formula (I): an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 is halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 haloalkyl; R 2 is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R 3 is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C 3 -C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C 6 - C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one
  • variables R 1 , R 2 , R 3 , R 3a , T, R T , A, R A , and R A1 can each be, where applicable, selected from the groups described herein, and any group described herein for any of variables R 1 , R 2 , R 3 , R 3a , T, R T , A, R A , and R A1 can be combined, where applicable, with any group described herein for one or more of the remainder of variables R 1 , R 2 , R 3 , R 3a , T, R T , A, R A , and R A1 .
  • R 1 is halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C1-C6 haloalkyl.
  • R 1 is halogen, or cyano.
  • R 1 is halogen.
  • R 1 is F, Cl, Br, or I.
  • R 1 is F, Cl, or Br.
  • R 1 is F or Cl.
  • R 1 is F.
  • R 1 is Cl. In some embodiments, R 1 is Br. In some embodiments, R 1 is I. [0106] In some embodiments, R 1 is cyano. 25 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0107] In some embodiments, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl. [0108] In some embodiments, R 1 is C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. [0109] In some embodiments, R 1 is C1-C6 alkyl.
  • R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is propyl. In some embodiments, R 1 is butyl. In some embodiments, R 1 is pentyl. In some embodiments, R 1 is hexyl. In some embodiments, R 1 is isopropyl. In some embodiments, R 1 is isobutyl. In some embodiments, R 1 is isopentyl. In some embodiments, R 1 is isohexyl. In some embodiments, R 1 is secbutyl. In some embodiments, R 1 is secpentyl. In some embodiments, R 1 is sechexyl.
  • R 1 is tertbutyl. [0111] In some embodiments, R 1 is C1-C6 haloalkyl. [0112] In some embodiments, R 1 is halomethyl. In some embodiments, R 1 is haloethyl. In some embodiments, R 1 is halopropyl. In some embodiments, R 1 is halobutyl. In some embodiments, R 1 is halopentyl. In some embodiments, R 1 is halohexyl. [0113] In some embodiments, R 1 is CF3.
  • R 2 is H, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C1-C6 haloalkyl. [0115] In some embodiments, R 2 is H, halogen, or cyano. [0116] In some embodiments, R 2 is H. [0117] In some embodiments, R 2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl. [0118] In some embodiments, R 2 is C 1 -C 6 alkyl.
  • R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is propyl. In some embodiments, R 2 is butyl. In some embodiments, R 2 is pentyl. In some embodiments, R 2 is hexyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is isobutyl. In some embodiments, R 2 is isopentyl. In some embodiments, R 2 is isohexyl. In some embodiments, R 2 is secbutyl. In some embodiments, R 2 is secpentyl. In some embodiments, R 2 is sechexyl.
  • R 2 is tertbutyl. [0120] In some embodiments, R 2 is methyl. [0121] In some embodiments, R 3 is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12- membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R 3a . 26 289225266 v1 Attorney Docket No.
  • R 3 is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12- membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is substituted with one or more R 3a .
  • R 3 is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl.
  • R 3 is 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R 3a .
  • R 3 is 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is substituted with one or more R 3a .
  • R 3 is 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl.
  • R 3 is 3- to 12-membered heterocycloalkyl optionally substituted with one or more R 3a .
  • R 3 is 3- to 12-membered heterocycloalkyl substituted with one or more R 3a .
  • R 3 is 3- to 12-membered heterocycloalkyl.
  • R 3 is a bicyclic 3- to 12-membered heterocycloalkyl.
  • R 3 is a fused 3- to 12-membered heterocycloalkyl.
  • R 3 is a spiro 3- to 12-membered heterocycloalkyl.
  • R 3 is a bridged 3- to 12-membered heterocycloalkyl.
  • R 3 is morpholinyl optionally substituted with one or more R 3a .
  • R 3 is piperidinyl optionally substituted with one or more R 3a .
  • R 3 is piperazinyl optionally substituted with one or more R 3a .
  • R 3 is azetidinyl optionally substituted with one or more R 3a .
  • R 3 is pyrrolidinyl optionally substituted with one or more R 3a .
  • R 3 is 2-oxa-5-azabicyclo[2.2.1]heptanyl optionally substituted with one or more R 3a .
  • R 3 is morpholinyl substituted with one or more R 3a .
  • R 3 is piperidinyl substituted with one or more R 3a .
  • R 3 is piperazinyl substituted with one or more R 3a .
  • R 3 is azetidinyl substituted with one or more R 3a .
  • R 3 is pyrrolidinyl substituted with one or more 27 289225266 v1 Attorney Docket No.
  • R 3 is 2-oxa-5-azabicyclo[2.2.1]heptanyl substituted with one or more R 3a .
  • R 3 is morpholinyl.
  • R 3 is piperidinyl.
  • R 3 is piperazinyl.
  • R 3 is azetidinyl.
  • R 3 is pyrrolidinyl.
  • R 3 is 2-oxa-5- azabicyclo[2.2.1]heptanyl.
  • R 3 is 5- to 10-membered heteroaryl optionally substituted with one or more R 3a .
  • R 3 is 5- to 10-membered heteroaryl substituted with one or more R 3a .
  • R 3 is 5- to 10-membered heteroaryl.
  • R 3 is pyridinyl.
  • each R 3a independently is halogen, C 1 -C 6 alkyl, or C 6 -C 10 aryl, wherein the C1-C6 alkyl or C6-C10 aryl is optionally substituted with one or more halogen.
  • each R 3a independently is C6-C10 aryl optionally substituted with one or more halogen. [0143] In some embodiments, each R 3a independently is C6-C10 aryl substituted with one or more halogen. [0144] In some embodiments, each R 3a independently is C 6 -C 10 aryl. [0145] In some embodiments, each R 3a independently is phenyl optionally substituted with one or more halogen. [0146] In some embodiments, each R 3a independently is phenyl substituted with one or more halogen. [0147] In some embodiments, each R 3a independently is phenyl.
  • alkyl)-*, -(C1-C6 alkyl)-O-*, -O-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-NR T -*, -NR T -(C1-C6 alkyl)-*, 28 289225266 v1 Attorney Docket No.
  • T is -(C 1 -C 6 alkyl)-*, -(C 1 -C 6 alkyl)-O-*, or -(C 1 -C 6 alkyl)- NR T -*, wherein * denotes attachment to A.
  • T is -(C1-C6 alkyl)-*, or -(C1-C6 alkyl)-NR T -*, wherein * denotes attachment to A.
  • T is -(C 1 -C 6 alkyl)-*, wherein * denotes attachment to A.
  • T is branched -(C1-C6 alkyl)-*, wherein * denotes attachment to A.
  • T is -CH(CH 3 )-*, wherein * denotes attachment to A.
  • T is -(C1-C6 alkyl)-NR T -*, wherein * denotes attachment to A.
  • T is -CH(CH3)-NR T -*, wherein * denotes attachment to A.
  • T is -CH(CH 3 )-NH-*, wherein * denotes attachment to A.
  • each R T is H or C1-C6 alkyl. [0160] In some embodiments, R T is H or C1-C6 alkyl. [0161] In some embodiments, R T is H. [0162] In some embodiments, R T is C1-C6 alkyl.
  • A is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein the C 3 -C 12 cycloalkyl, 3- to 12- membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R A .
  • A is C 3 -C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein the C 3 -C 12 cycloalkyl, 3- to 12- membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is substituted with one or more R A .
  • A is 3- to 12-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R A .
  • A is 3- to 12-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is substituted with one or more R A .
  • A is 3- to 12-membered heterocycloalkyl optionally substituted with one or more R A .
  • A is 3- to 12-membered heterocycloalkyl substituted with one or more R A .
  • A is 3- to 12-membered heterocycloalkyl.
  • A is C 6 -C 10 aryl optionally substituted with one or more R A .
  • A is C 6 -C 10 aryl substituted with one or more R A .
  • A is pyridinyl optionally substituted with one or more R A .
  • A is [1,2,4]triazolo[4,3-a]pyridinyl optionally substituted with one or more R A .
  • A is thiophenyl optionally substituted with one or more R A .
  • A is 2,3-dihydrobenzo[b]thiophene substituted with one or more R A .
  • A is pyrazolyl substituted with one or more R A .
  • A is pyridinyl substituted with one or more R A .
  • A is [1,2,4]triazolo[4,3-a]pyridinyl substituted with one or more R A .
  • A is thiophenyl substituted with one or more R A .
  • A is 2,3-dihydrobenzo[b]thiophene.
  • A is pyrazolyl.
  • A is pyridinyl.
  • A is [1,2,4]triazolo[4,3-a]pyridinyl.
  • A is thiophenyl.
  • each R A independently is oxo, halogen, -OH, cyano, or -NH2. [0199] In some embodiments, each R A independently is oxo. [0200] In some embodiments, each R A independently is halogen. [0201] In some embodiments, each R A independently is F, Cl, Br, or I. In some embodiments, each R A independently is F, Cl, or Br. In some embodiments, each R A independently is F or Cl. 31 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0202] In some embodiments, each R A independently is F. In some embodiments, each R A independently is Cl.
  • each R A independently is Br. In some embodiments, each R A independently is I. [0203] In some embodiments, each R A independently is -OH. [0204] In some embodiments, each R A independently is cyano. [0205] In some embodiments, each R A independently is -NH 2 .
  • 32 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
  • each R A independently is methyl optionally substituted with one or more R A1 . In some embodiments, each R A independently is ethyl optionally substituted with one or more R A1 . In some embodiments, each R A independently is propyl optionally substituted with one or more R A1 . In some embodiments, each R A independently is butyl optionally substituted with one or more R A1 . In some embodiments, each R A independently is pentyl optionally substituted with one or more R A1 . In some embodiments, each R A independently is hexyl optionally substituted with one or more R A1 . In some embodiments, each R A independently is isopropyl optionally substituted with one or more R A1 .
  • each R A independently is isobutyl optionally substituted with one or more R A1 . In some embodiments, each R A independently is isopentyl optionally substituted with one or more R A1 . In some embodiments, each R A independently is isohexyl optionally substituted with one or more R A1 . In some embodiments, each R A independently is secbutyl optionally substituted with one or more R A1 . In some embodiments, each R A independently is secpentyl optionally substituted with one or more R A1 . In some embodiments, each R A independently is sechexyl optionally substituted with one or more R A1 .
  • each R A independently is tertbutyl optionally substituted with one or more R A1 .
  • each R A independently is methyl substituted with one or more R A1 .
  • each R A independently is ethyl substituted with one or more R A1 .
  • 34 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
  • each R A independently is propyl substituted with one or more R A1 .
  • each R A independently is butyl substituted with one or more R A1 .
  • each R A independently is pentyl substituted with one or more R A1 .
  • each R A independently is hexyl substituted with one or more R A1 . In some embodiments, each R A independently is isopropyl substituted with one or more R A1 . In some embodiments, each R A independently is isobutyl substituted with one or more R A1 . In some embodiments, each R A independently is isopentyl substituted with one or more R A1 . In some embodiments, each R A independently is isohexyl substituted with one or more R A1 . In some embodiments, each R A independently is secbutyl substituted with one or more R A1 . In some embodiments, each R A independently is secpentyl substituted with one or more R A1 .
  • each R A independently is sechexyl substituted with one or more R A1 . In some embodiments, each R A independently is tertbutyl substituted with one or more R A1 . [0223] In some embodiments, each R A independently is methyl. In some embodiments, each R A independently is ethyl. In some embodiments, each R A independently is propyl. In some embodiments, each R A independently is butyl. In some embodiments, each R A independently is pentyl. In some embodiments, each R A independently is hexyl. In some embodiments, each R A independently is isopropyl. In some embodiments, each R A independently is isobutyl.
  • each R A independently is isopentyl. In some embodiments, each R A independently is isohexyl. In some embodiments, each R A independently is secbutyl. In some embodiments, each R A independently is secpentyl. In some embodiments, each R A independently is sechexyl. In some embodiments, each R A independently is tertbutyl.
  • two R A1 together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C 3 -C 12 cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C 3 -C 12 cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH2.
  • each R A1 independently is H, halogen, -OH, or -NH 2 .
  • each R A1 independently is H.
  • each R A1 independently is halogen.
  • each R A1 independently is F, Cl, Br, or I. In some embodiments, each R A1 independently is F, Cl, or Br. In some embodiments, each R A1 independently is F or Cl. [0232] In some embodiments, each R A1 independently is F. In some embodiments, each R A1 independently is Cl. In some embodiments, each R A1 independently is Br. In some embodiments, each R A1 independently is I. [0233] In some embodiments, each R A1 independently is -OH. [0234] In some embodiments, each R A1 independently is -NH 2 .
  • each R A1 independently is C3-C12 cycloalkyl optionally substituted with -OH. [0239] In some embodiments, each R A1 independently is C3-C12 cycloalkyl substituted with - OH. [0240] In some embodiments, each R A1 independently is C 3 -C 12 cycloalkyl. [0241] In some embodiments, the compound is of Formula (I-a), (I-b), (I-c), (I-d), (I-e), or (I- f): 36 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the compound is of Formula (I-g): 37 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 (I-g) or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the compound is of Formula (I-h): ; (I-h) or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the compound is of Formula (I-i): (I-i) or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the compound is of Formula (I-j): (I-j) or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the compound is of Formula (I-k): ; 38 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 (I-k) or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the compound is a compound described in Table 1 or Table 2, or a prodrug or pharmaceutically acceptable salt thereof.
  • the compound is a compound described in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.
  • the compound is a prodrug of a compound described in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound described in Table 1 or Table 2. [0251] In some embodiments, the compound is a compound described in Table 1, or a prodrug or pharmaceutically acceptable salt thereof. [0252] In some embodiments, the compound is a compound described in Table 1, or a pharmaceutically acceptable salt thereof. [0253] In some embodiments, the compound is a prodrug of a compound described in Table 1, or a pharmaceutically acceptable salt thereof. [0254] In some embodiments, the compound is a compound described in Table 1. [0255] In some embodiments, the compound is a compound described in Table 2, or a prodrug or pharmaceutically acceptable salt thereof.
  • the compound is a compound described in Table 2, or a pharmaceutically acceptable salt thereof.
  • the compound is a prodrug of a compound described in Table 2, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound described in Table 2.
  • Table 1 39 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 40 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 41 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 42 289225266 v1 Attorney Docket No.
  • ASET-039/001WO 325190-2191 49 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 246 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 51 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 52 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 53 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 54 289225266 v1 Attorney Docket No.
  • the compound is a pharmaceutically acceptable salt of a compound described in Table 1.
  • the compound is a pharmaceutically acceptable salt of a compound described in Table 2.
  • the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.
  • the compound is an isotopic derivative of any one of the compounds described in Table 1, or a prodrug or pharmaceutically acceptable salt thereof.
  • the compound is an isotopic derivative of any one of the compounds described in Table 1 or a pharmaceutically acceptable salt thereof.
  • the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 1 or a pharmaceutically acceptable salt thereof.
  • the compound is an isotopic derivative of any one of the compounds described in Table 1.
  • the compound is an isotopic derivative of any one of the compounds described in Table 2, or a prodrug or pharmaceutically acceptable salt thereof.
  • the compound is an isotopic derivative of any one of the compounds described in Table 2 or a pharmaceutically acceptable salt thereof.
  • the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 2 or a pharmaceutically acceptable salt thereof.
  • the compound is an isotopic derivative of any one of the compounds described in Table 2. 55 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0270] It is understood that the isotopic derivative can be prepared using any of a variety of art-recognised techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. [0271] In some embodiments, the isotopic derivative is a deuterium labeled compound.
  • the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.
  • the term “isotopic derivative”, as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled.
  • an isotopic derivative of a compound of Formula (I) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (I).
  • the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from 2 H, 13 C, 14 C, 15 N, 18 O, 29 Si, 31 P, and 34 S.
  • the isotopic derivative is a deuterium labeled compound (i.e., being enriched with 2 H with regard to one or more atoms thereof).
  • the compound is a 18 F labeled compound.
  • the compound is a 123 I labeled compound, a 124 I labeled compound, a 125 I labeled compound, a 129 I labeled compound, a 131 I labeled compound, a 135 I labeled compound, or any combination thereof.
  • the compound is a 33 S labeled compound, a 34 S labeled compound, a 35 S labeled compound, a 36 S labeled compound, or any combination thereof.
  • the 35 36 S, and/or S labeled compound can be prepared using any of a variety of art-recognised techniques.
  • the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a 18 F, 123 I, 124 I, 34 35 36 S, S, and/or S labeled reagent for a non-isotope labeled reagent.
  • a compound of the invention or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned 18 F, 123 I, and 36 S atom(s) is within the scope of the invention. Further, substitution with isotope (e.g,, 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and/or 36 S) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.
  • the molecular weight is less than 600 and, for example, is 550 daltons or less.
  • a suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers.
  • racemic mixture A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”
  • chiral centre refers to a carbon atom bonded to four nonidentical substituents.
  • chiral isomer means a compound with at least one chiral centre. Compounds with more than one chiral centre may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral centre is present, a stereoisomer may be characterised by the absolute configuration (R or S) of that chiral centre.
  • Absolute configuration refers to the arrangement in space of the substituents attached to the chiral centre.
  • the substituents attached to the chiral centre under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).
  • the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules. [0286] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers.
  • atropic isomers are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.
  • tautomer is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another.
  • Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs.
  • Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.
  • -CHO aldehyde group
  • -OH hydroxy groups
  • ring-shaped cyclic (ring-shaped) form as exhibited by glucose.
  • isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can 59 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • the compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • Some of the compounds of the disclosure may have geometric isomeric centres (E- and Z- isomers).
  • the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that modulate PI3K ⁇ activity.
  • the present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.
  • the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable.
  • a salt for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein.
  • Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).
  • pharmaceutically acceptable anion refers to an anion suitable for forming a pharmaceutically acceptable salt.
  • a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein.
  • Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion.
  • the substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.
  • Nonlimiting examples of hydrates include monohydrates, dihydrates, etc.
  • Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc. 60 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0297]
  • the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate.
  • Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H 2 O.
  • an analog refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure origin to the reference compound.
  • derivative refers to compounds that have a common core structure and are substituted with various groups as described herein.
  • bioisostere refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms.
  • the objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound.
  • the bioisosteric replacement may be physicochemically or topologically based.
  • Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev.96, 3147-3176, 1996.
  • certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms.
  • a suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that modulate PI3K ⁇ activity.
  • certain compounds of any one of the Formulae disclosed herein may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof, which modulate PI3K ⁇ activity.
  • crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) 61 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis. [0303] Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compounds of Formula (I) include all such forms.
  • tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
  • keto enol enolate Compounds of any one of the Formulae disclosed herein containing an amine function may also form N-oxides.
  • a reference herein to a compound of Formula (I) that contains an amine function also includes the N-oxide.
  • N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen- containing heterocycle.
  • N-oxides can be formed by treatment of the corresponding amine with an oxidising agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W.
  • the compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure.
  • a prodrug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the disclosure.
  • a prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property- modifying group can be attached.
  • prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any one of the Formulae disclosed herein.
  • the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis 62 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 and when made available within the human or animal body by way of cleavage of a prodrug thereof.
  • the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K.
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include C1-C10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C 1 -C 10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C 1 -C 6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • Suitable pharmaceutically acceptable ether forming groups 63 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 for a hydroxy group include ⁇ -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C 1 -C 4 alkoxy-C 2 -C 4 alkylamine such as 2-methoxyethylamine, a phenyl-C 1 - C 4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a C1-4alkylamine such as methylamine
  • a (C1-C4 alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl,morpholinomethyl,piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1- ylmethyl.
  • the in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug).
  • the present disclosure excludes any individual compounds not possessing the biological activity defined herein.
  • Methods of Synthesis [0313] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure. [0314] In some aspects, the present disclosure provides a method of a compound, comprising one or more steps as described herein. [0315] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound as described herein. [0316] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein. 64 289225266 v1 Attorney Docket No.
  • the compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples. [0318] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art. [0319] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, 65 289225266 v1 Attorney Docket No.
  • ASET-039/001WO 325190-2191 for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia.
  • a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.
  • a base such as sodium hydroxide
  • a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.
  • the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound Formula (I) into another compound of Formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or (iv) forming a prodrug thereof.
  • the resultant compounds of Formula (I) can be isolated and purified using techniques well known in the art.
  • the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions.
  • suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2- dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, 66 2892252
  • ASET-039/001WO 325190-2191 such as acetone, methylisobutylketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the said solvents or mixtures with water.
  • MIBK methylisobutylketone
  • NMP N-methylpyrrolidinone
  • nitriles such as acetonitrile
  • sulfoxides such as dimethyl sulfoxide (DMSO)
  • nitro compounds such as nitromethane or nitrobenzene
  • esters such as ethyl a
  • reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used.
  • Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours.
  • additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
  • a substituted nitroaniline (1) can be reduced to provide aminoaniline (2).
  • Condensation between aniline (2) and ethyl 2-oxoacetate gives quinoxaline (3) which can be converted to the halo compound (4) with phosphrous oxychloride reagent.
  • Substitution of halide (4) with amines may afford substituted quinoxalines (5).
  • Palladium- catalyzed acylation of halide (5) may give acyl quinoxaline (6).
  • Reductive amination of ketone (6) to amine (7) may be effected with a reducing agent such as sodium cyanoborohydride.
  • This amine (7) can then be coupled with an aryl halide under palladium catalyst conditions to give racemic compound (8) of Formula (I). These racemates (8) can then be purified on a chiral column to give arbitrarily assigned pure enantiomers (9) and (10).
  • Reaction Scheme 1 [0333] In some embodiments, ketone (6) can be reduced to alcohol (7) with a reducing agent such as sodium borohydride. This alcohol (7) can be covereted to aryl amine (8) in the presence of copper bromide. Racemic amine (8) can then be purified on a chiral column to give arbitrarily assigned pure enantiomers (9) and (10).
  • Reaction Scheme 2 68 289225266 v1 Attorney Docket No.
  • ASET-039/001WO 325190-2191 Biological Assays Compounds designed, selected and/or optimised by methods described above, once produced, can be characterised using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity.
  • the molecules can be characterised by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.
  • high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art.
  • High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.
  • Various in vitro or in vivo biological assays are may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.
  • the biological assay is described in the Examples herein.
  • the biological activity of the compounds may be determined utilizing a p-AKT S473 assay.
  • cells e.g., MCF10A-PI3K ⁇ -WT, MCF10A- PI3K ⁇ -H1047R and MCF10A- PI3K ⁇ -E545K cells
  • cells may be 69 289225266 v1 Attorney Docket No.
  • p-AKT S473 may be measured using HTRF cellular kit by Cisbio (64AKSPET) according to manufacturer’s protocol. In some embodiments, p-AKT S473 levels may be measured using the kit. In some embodiments, the cells (e.g., MCF10A-PI3K ⁇ -WT, MCF10A- PI3K ⁇ -H1047R and MCF10A- PI3K ⁇ -E545K cells) may be lysed.
  • antibodies may be mixed with detection buffer and may be added to the lysate and may be incubated overnight.
  • luminescence may be read on a plate reader (e.g., Ensight plate reader). In some embodiments, luminescence may be read at 665 nm. In some embodiments, luminescence may be read at 620 nm wavelengths.
  • a decrease in p-AKT S473 levels indicate a downregulation of the PI3K ⁇ pathway. In some embodiments, a decrease in p-AKT S473 levels indicate a downregulation of cell proliferation.
  • the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.
  • the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 2. [0341]
  • the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.
  • the compounds of present disclosure can also be formulated for intravenous (bolus or in- fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • the formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle.
  • the aqueous vehicle component may comprise water and at 70 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 least one pharmaceutically acceptable excipient.
  • Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/suspending agent, buffer, and pH modifying agent, and a mixture thereof. [0344] Any suitable solubility enhancing agent can be used.
  • solubility enhancing agent examples include cyclodextrin, such as those selected from the group consisting of hydroxypropyl- ⁇ -cyclodextrin, methyl- ⁇ -cyclodextrin, randomly methylated- ⁇ -cyclodextrin, ethylated- ⁇ -cyclodextrin, triacetyl- ⁇ -cyclodextrin, peracetylated- ⁇ -cyclodextrin, carboxymethyl- ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, 2-hydroxy-3- (trimethylammonio)propyl- ⁇ -cyclodextrin, glucosyl- ⁇ -cyclodextrin, sulfated ⁇ -cyclodextrin (S- ⁇ -CD), maltosyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin sulfobutyl ether, branched- ⁇ -cyclodextrin, hydroxy
  • Any suitable chelating agent can be used.
  • a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.
  • Any suitable preservative can be used.
  • Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.
  • quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethon
  • the aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure).
  • the tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.
  • the aqueous vehicle may also contain a viscosity/suspending agent.
  • Suitable viscosity/suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as 71 289225266 v1 Attorney Docket No.
  • ASET-039/001WO 325190-2191 polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.
  • Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P
  • the formulation may contain a pH modifying agent.
  • the pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid.
  • These acidic and/or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.
  • the aqueous vehicle may also contain a buffering agent to stabilise the pH.
  • the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and ⁇ -aminocaproic acid, and mixtures thereof.
  • a phosphate buffer such as sodium dihydrogen phosphate and disodium hydrogen phosphate
  • a borate buffer such as boric acid, or salts thereof including disodium tetraborate
  • a citrate buffer such as citric acid, or salts thereof including sodium citrate
  • ⁇ -aminocaproic acid and mixtures thereof.
  • the formulation may further comprise a wetting agent.
  • Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.
  • Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules.
  • Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, 72 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavouring agent such as peppermint, methyl salicylate, orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, 72 289225266 v1 Attorney Docket No. ASET-039/
  • a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or
  • compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a PI3K ⁇ related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat a PI3K ⁇ related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • Phosphatidylinositol 3-Kinases are a group of plasma membrane-associated lipid kinases that upon activation catalyze the transfer of phosphate to the D-3’ position of inositol of phosphoinositol-4,5-phosphate (PIP2) to produce phosphoinositol-3,4,5-phosphate 73 289225266 v1 Attorney Docket No.
  • PIP3 ASET-039/001WO 325190-2191.
  • PIP3 is a second messenger that binds and recruits a subset of Pleckstrin-homology, FYVE, Phox, or other lipid-binding domains of downstream target to the cell membrane.
  • Signaling proteins e.g. AKT, PDK1
  • AKT, PDK1 can then bind to the lipid product of PI3K, localize to cell membrane and activate downstream cellular activity that includes transcription, translation, proliferation, survival, chemotaxis, motility, cellular trafficking and metabolism.
  • PI3Ks include a conserved family of 15 kinases that exhibit distinct substrate specificities, expression patterns and modes of regulation.
  • PI3Ks are divided into three classes (I, II and III) based on their structures and substrate specificities.
  • Class I PI3Ks encompass PI3Ks containing one of the p110 ⁇ , p110 ⁇ , p110 ⁇ and p110 ⁇ catalytic subunits, which are encoded by the PIK3CA, PIK3CB, PIK3CD and PIK3CG genes, respectively. These catalytic subunits are constitutively associated with regulatory subunits: p85 ⁇ , p55 ⁇ , p50 ⁇ , p85 ⁇ , p55 ⁇ , p101 or p84.
  • mutations in the gene PIK3CA which encodes the p110 ⁇ (also referred to as PI3K ⁇ ) catalytic subunit, have been linked to numerous cancers, including bladder cancer, brain cancer, breast cancer, colon cancer, endometrial cancer, ovarian cancer, skin cancer, stomach cancer, lung cancer and prostate cancer. Mutations in the PIK3CA gene are notably observed within several “mutation hotspots” that are located within the kinase and helicase domains. These mutations include the E542K mutation, the E545K mutation and the H1047R mutation. Moreover, many of these mutations have been shown to be oncogenic gain- of-function mutations.
  • PI3Ks Given the connection to various disease, including cancer, PI3Ks, and more specifically, PI3K ⁇ , have been a target for therapeutic intervention. To this end, multiple inhibitors of PI3Ks have been developed, including alpelisib, buparlisib, taselisib, and inavolisib. These inhibitors are active against one or multiple Class I PI3K isoforms. [0364] A major limitation of those agents in the clinic is their inability to reach the required level for target inhibition without on-target related toxicities.
  • PI3K ⁇ is known to play a central role in regulating glucose homeostasis. Consequently, pharmacologic inhibition of PI3K ⁇ often results in severe hyperglycemia and/or hyperinsulinemia.
  • high circulating insulin levels can reactivate the PI3K pathway in cancer cells and be potentially mitogenic. This creates a feedback regulation loop that minimizes the effect of PI3K inhibitors.
  • hyperglycemia and/or hyperinsulinemia are often managed with co-administration of a glucose lowering agent such at metformin.
  • a glucose lowering agent such at metformin.
  • the present disclosure provides a method of modulating PI3K ⁇ activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of modulating PI3K ⁇ activity (e.g., in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of modulating PI3K ⁇ activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of modulating PI3K ⁇ activity (e.g., in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the disease or disorder is associated with an implicated PI3K ⁇ activity.
  • the disease or disorder is a disease or disorder in which PI3K ⁇ activity is implicated.
  • the disease or disorder is associated with an implicated PI3K ⁇ activity.
  • the disease or disorder is a disease or disorder in which PI3K ⁇ activity is implicated.
  • the disease or disorder is congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal (CLOVES) syndrome.
  • the disease or disorder is PIK3CA-related overgrowth syndrome.
  • the disease or disorder is cancer.
  • the cancer is characterized by an amplification (i.e. increase) in the expression of the PIK3CA gene and/or an amplification (i.e. increase) in the expression of the PI3K ⁇ protein.
  • the cancer is characterized by a decrease in the expression of the PIK3CA gene and/or decrease in the expression of the PI3K ⁇ protein.
  • the cancer is characterized by at least one oncogenic mutation in the PIK3CA gene. It is understood that a cancer that is characterized by at least one oncogenic mutation in the PIK3CA gene is a cancer that is typically associated with at least one oncogenic mutation in the PIK3CA gene, including, but not limited to, cancers whose primary oncogenic activity is thought to be driven by the at least one oncogenic mutation in the PIK3CA gene.
  • the cancer is characterized by at least one oncogenic variant of the PI3K ⁇ protein.
  • a cancer that is characterized by least one oncogenic variant of the PI3K ⁇ protein is a cancer that is typically associated with at least one oncogenic variant of the PI3K ⁇ protein, including, but not limited to, cancers whose primary oncogenic activity is thought to be driven by the at least one oncogenic variant of the PI3K ⁇ protein.
  • an oncogenic variant of PI3K ⁇ protein is a PI3K ⁇ protein molecule that comprises at least one oncogenic mutation and that is produced as the result of the expression of a PIK3CA gene that comprises at least one oncogenic mutation.
  • the subject has at least one oncogenic mutation in the PIK3CA
  • the subject has at least one tumor and/or cancerous cell that expresses an oncogenic variant of the PI3K ⁇ protein.
  • an oncogenic mutation can include, but is not limited to a mutation that results in the substitution of one amino acid for another at a specific position within the protein product of the gene, a mutation that results in the substitution of one or more amino acids for one or more amino acids between two specific positions within the protein product of the gene, a mutation that results in an insertion of one or more amino acids between two positions within the protein product of the gene, a mutation that results in the deletion of one more amino acids between two positions within the protein product of the gene, and mutation that results in a fusion of the protein product of the gene, or portion thereof, with another protein, or portion thereof, or any combination thereof.
  • an oncogenic mutation can include, but is not limited to, a missense mutation, a nonsynonymous mutation, an insertion of one or more nucleotides, a deletion of one or more nucleotides, an inversion and a deletion-insertion.
  • the gene in the context of a gene (e.g. PIK3CA), can have one or more of the 77 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 aforementioned types of oncogenic mutations, including combinations of different types of oncogenic mutations.
  • an oncogenic mutation can include, but is not limited to, the substitution of one amino acid for another at a specific position within the protein, the substitution of one or more amino acids for one or more amino acids between two specific positions within the protein, an insertion of one or more amino acids between two positions within the protein, a deletion of one more amino acids between two positions within the protein, and a fusion of the protein, or portion thereof, with another protein, or portion thereof, or any combination thereof.
  • a protein e.g. the PI3K ⁇ protein
  • an oncogenic mutation of the PI3K ⁇ protein can be any one of E542K, E545K and H1047R (numbering corresponding to SEQ ID NO: 1).
  • a wild-type PI3K ⁇ protein sequence of the present disclosure may comprise, consist essentially of, or consist of the amino acid sequence of: 1 MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLITIKHELF 51 KEARKYPLHQ LLQDESSYIF VSVTQEAERE EFFDETRRLC DLRLFQPFLK 101 VIEPVGNREE KILNREIGFA IGMPVCEFDM VKDPEVQDFR RNILNVCKEA 151 VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IVVIWVIVSP 201 NNDKQKYTLK INHDCVPEQV IAEAIRKKTR SMLLSSEQLK LCVLEYQGKY 251 ILKVCGCDEY FLEKYPLSQY KYIRSCIMLG RMPNLMLMAK ESLYSQLPMD 301 CFTMPSYSRR ISTATPYMNG ETSTKSLWVI NSALRI
  • the cancer is a carcinoma, a lymphoma, a blastoma, a sarcoma, a leukemia, a brain cancer, a breast cancer, a blood cancer, a bone cancer, a lung cancer, a skin cancer, a liver cancer, an ovarian cancer, a bladder cancer, a renal cancer, a kidney cancer, a 78 289225266 v1 Attorney Docket No.
  • ASET-039/001WO 325190-2191 gastric cancer a thyroid cancer, a pancreatic cancer, an esophageal cancer, a prostate cancer, a cervical cancer, a uterine cancer, a stomach cancer, a soft tissue cancer, a laryngeal cancer, a small intestine cancer, a testicular cancer, an anal cancer, a vulvar cancer, a joint cancer, an oral cancer, a pharynx cancer or a colorectal cancer.
  • the cancer is adrenocortical carcinoma, bladder urothelial carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, cholangiocarcinoma, colon adenocarcinoma, lymphoid neoplasm diffuse large B-cell lymphoma, esophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, kidney chromophobe, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, acute myeloid leukemia, brain lower grade glioma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma, paraganglioma, prostate adenocarcinoma,
  • cancers include breast cancer, lung cancer, lymphoma, melanoma, liver cancer, colorectal cancer, ovarian cancer, bladder cancer, renal cancer or gastric cancer.
  • Further examples of cancer include neuroendocrine cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, thyroid cancer, endometrial cancer, biliary cancer, esophageal cancer, anal cancer, salivary, cancer, vulvar cancer, cervical cancer, Acute lymphoblastic leukemia (ALL), Acute myeloid leukemia (AML), Adrenal gland tumors, Anal cancer, Bile duct cancer, Bladder cancer, Bone cancer, Bowel cancer, Brain tumors, Breast cancer, Cancer of unknown primary (CUP), Cancer spread to bone, Cancer spread to brain, Cancer spread to liver, Cancer spread to lung, Carcinoid, Cervical cancer, Children's cancers, Chronic lymphocytic leukemia (CLL), Chrome myeloid leukemia (CML), Colorectal cancer, Ear cancer, Endo
  • Retinoblastoma Salivary gland cancer, Secondary' cancer, Signet cell cancer, Skin cancer, Small bowel cancer, Soft tissue sarcoma, Stomach cancer, T cell childhood non Hodgkin lymphoma (NHL), Testicular cancer, Thymus gland cancer, Thyroid cancer, Tongue cancer, Tonsil cancer, Tumors of the adrenal gland, Uterine cancer. Vaginal cancer, Vulval cancer, Wilms' tumor, Womb cancer and Gynaecological cancer.
  • cancer also include, but are not limited to, Hematologic malignancies, Lymphoma, Cutaneous T-cell lymphoma, Peripheral T-cell lymphoma, Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, Multiple myeloma, Chrome lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, Myelodysplastic syndromes, Myelofibrosis, Biliary tract cancer, Hepatocellular cancer, Colorectal cancer, Breast cancer, Lung cancer, Non-small cell lung cancer, Ovarian cancer, Thyroid Carcinoma, Renal Cell Carcinoma, Pancreatic cancer, Bladder cancer, skin cancer, malignant melanoma, merkel cell carcinoma, Uveal Melanoma or Glioblastoma multiforme.
  • the cancer is B-cell lymphoma, adrenocortical carcinoma, bladder urothelial carcinoma, breast cancer, cervical adenocarcinoma, cervical squamous-cell carcinoma, cholangiocarcinoma, colorectal adenocarcinoma, colorectal cancer, diffuse glioma, esophageal squamous-cell cancer, esophagogastric adenocarcinoma, esophagogastric cancer, fibrolamellar carcinoma, germ-cell carcinoma, glioblastoma, glioma, head and neck squamous- cell carcinoma, hepatocellular carcinoma, leukemia, melanoma, mesothelioma, miscellaneous neuroepithelial tumor, nerve-sheath tumor, non-small-cell lung cancer, ovarian cancer, pancreatic cancer, pheochromocytoma, prostate cancer, renal clear
  • the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a compound of the 80 289225266 v1 Attorney Docket No.
  • the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating PI3K ⁇ activity (e.g., in vitro or in vivo).
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating PI3K ⁇ activity (e.g., in vitro or in vivo).
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing cancer in a subject in need thereof.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject in need thereof.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating PI3K ⁇ activity (e.g., in vitro or in vivo).
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein. 81 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0407] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof. [0408] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a subject in need thereof.
  • the present disclosure provides compounds that function as modulators of PI3K ⁇ activity.
  • the compounds of the present disclosure are inhibitors of the PI3K ⁇ protein.
  • the compounds of the present disclosure specifically inhibit mutated PI3K ⁇ protein as compared to wild-type PI3K ⁇ protein.
  • the compounds of the present disclosure bind to the PI3K ⁇ protein in an allosteric pocket that is in proximity to the 1047 mutational hotspot.
  • Effectiveness of compounds of the disclosure can be determined by industry-accepted assays/ disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge.
  • the present disclosure also provides a method of treating a disease or disorder in which PI3K ⁇ activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.
  • Routes of Administration Compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be administered alone as a sole therapy or can be administered in addition with one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.
  • therapeutic effectiveness may be enhanced by administration of an adjuvant (i.e.
  • the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced).
  • the benefit experienced by an individual may be increased by administering the compound of Formula (I) with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • another therapeutic agent which also includes a therapeutic regimen
  • the compound of the disclosure need not be administered via the same route as other therapeutic agents, and may, because of different physical and chemical characteristics, be administered by a different route.
  • the compound of the disclosure may be administered orally to generate and maintain good blood levels thereof, while the other therapeutic agent may be administered intravenously.
  • the initial administration may be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
  • the particular choice of other therapeutic agent will depend upon the diagnosis of the attending physicians and their judgment of the condition of the individual and the appropriate treatment protocol. According to this aspect of the disclosure there is provided a combination for use in the treatment of a disease in which PI3K ⁇ activity is implicated comprising a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and another suitable agent.
  • a pharmaceutical composition which comprises a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in combination with a suitable, in association with a pharmaceutically acceptable diluent or carrier.
  • compounds of Formula (I) and pharmaceutically acceptable salts thereof are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of modulators of PI3K ⁇ activity in laboratory animals such as dogs, rabbits, monkeys, mini-pigs, rats and mice, as part of the search for new therapeutic agents.
  • any of the alternate embodiments of macromolecules of the present disclosure described herein also apply.
  • the compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g.
  • both neutral compounds and salts of the compounds of Formula (I) are synthesized and tested in the examples. It is understood that the neutral compounds of Formula (I) may be converted to the corresponding pharmaceutically acceptable salts of the compounds using routine techniques in the art (e.g., by saponification of an ester to the carboxylic acid salt, or by hydrolyzing an amide to form a corresponding carboxylic acid and then converting the carboxylic acid to a carboxylic acid salt).
  • salts e.g., formate salt
  • the salts of the compounds of Formula (I) may be converted to the corresponding neutral compounds using routine techniques in the art (e.g., pH adjustment and, optionally, extraction (e.g., into an aqueous phase)).
  • reaction mixture was quenched with water (20 mL) at 25 °C and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Racemate 2-[1-(7-methyl-3-morpholino-quinoxalin-5-yl)ethylamino]benzoic acid (0.18 g, 459 ⁇ mol) was separated by SFC (column: DAICEL CHIRALPAK AD (250 x 30 mm,10 ⁇ m); mobile phase: [0.1% ammonium hydroxide ethanol]; B%: 30%-30%, 4 min) to give (R)-2-((1-(7-methyl-3-morpholinoquinoxalin-5-yl)ethyl)amino)benzoic acid (50 mg, 127 ⁇ mol, 27%) as a yellow solid.
  • Step 2 Synthesis of 2-(4-(2-fluorophenyl)piperazin-1-yl)-6-methyl-8- vinylquinoxaline
  • Step 4 Synthesis of 2-((1-(3-(4-(2-fluorophenyl)piperazin-1-yl)-7-methylquinoxalin- 5-yl)ethyl)amino)benzoic acid [0472] A solution of methyl 2-((1-(3-(4-(2-fluorophenyl)piperazin-1-yl)-7-methylquinoxalin- 5-yl)ethyl)amino)benzoate (0.03 g, 60.0 ⁇ mol) and lithium hydroxide monohydrate (7.19 mg, 300 ⁇ mol) in tetrahydrofuran (1 mL) and water (1 mL) was stirred at 50 ⁇ for 12 h.
  • Example 4 Synthesis of methyl 2-((1-(7-methyl-3-morpholinoquinoxalin-5- yl)ethyl)amino)benzoate [0473] Step 1. Synthesis of 4-(8-bromo-6-methylquinoxalin-2-yl)morpholine [0474] A solution of 8-bromo-2-chloro-6-methyl-quinoxaline (2.50 g, 9.71 mmol), morpholine (1.69 g, 19.4 mmol) and diisopropylethylamine (3.76 g, 29.1 mmol) in 1-methyl- 2-pyrrolidone (10 mL) was stirred at 100 ⁇ for 12 h.
  • reaction mixture was quenched with water (20 mL) at 25 °C and extracted with ethyl acetate 95 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 (150 mL x 3).
  • the combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • ASET-039/001WO 325190-2191 A solution of 3-bromo-5-chlorobenzene-1,2-diamine (3.9 g, 17.6 mmol) and ethyl 2- oxoacetate (3.60 g, 17.6 mmol, 50% aq.) in ethanol (40 mL) was stirred at 60 °C for 3 h. The mixture was concentrated under reduced pressure. N,N-dimethylformamide (100 mL) was then added and the mixture was heated to 100 °C to fully dissolve the residue. Then the mixture was cooled to 25 °C and filtered.
  • Step 8 Synthesis of 2-(1-[7-chloro-3-(morpholin-4-yl)quinoxalin-5-yl]ethylamino)- benzoic acid [0512] To a solution of crude 1-(1-[7-chloro-3-(morpholin-4-yl)quinoxalin-5-yl]ethyl)-2,4- dihydro-1H-3,1-benzoxazine-2,4-dione in methanol (4 mL) was added sodium hydroxide (82.0 mg, 2.05 mmol).
  • Step 1 Synthesis of 8-bromo-6-methyl-2-(piperidin-1-yl)quinoxaline
  • An inseparable mixture of 8-bromo-2-chloro-6-methylquinoxaline (4.0 g, 15.5 mmol) and 5-bromo-2-chloro-7-methylquinoxaline were dissolved in acetonitrile. Piperidine (13.2 g, 155 mmol) was added and reaction mixture was heated to 70 °C overnight. After cooling to room temperature, the mixture was filtered to give a mixture of isomers.
  • Example 10 Preparation of 2-(1-[3-(azetidin-1-yl)-7-methylquinoxalin-5-yl]ethylamino)- benzoic acid [0522] Step 1. Synthesis of 2-(azetidin-1-yl)-8-bromo-6-methylquinoxaline [0523] An inseparable mixture of 8-bromo-2-chloro-6-methylquinoxaline (3.0 g, 11.7 mmol) and 5-bromo-2-chloro-7-methylquinoxaline was dissolved in acetonitrile.
  • Step 4 Synthesis of 8-bromo-2-chloro-6-(trifluoromethyl)quinoxaline
  • Step 5 Synthesis of 8-bromo-2-chloro-6-(trifluoromethyl)quinoxaline
  • Step 6 Synthesis of 1-[3-(morpholin-4-yl)-7-(trifluoromethyl)quinoxalin-5-yl]ethan- 1-one [0541] A round bottom flask was charged sequentially with 8-bromo-2-(morpholin-4-yl)-6- (trifluoromethyl)quinoxaline (3.0 g, 8.28 mmol), tetrakis(triphenylphosphine)palladium(0) (480 mg, 414 ⁇ mol) and cesium fluoride (7.55 g, 49.7 mmol).
  • reaction flask was flushed with argon for 5 minutes, then 1-(trimethylsilyl)ethan-1-one (2.89 g, 24.9 mmol) and 1,2- dichloroethane was added.
  • the reaction flask was flushed again with argon for another 5 106 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 minutes and left stirring overnight at 75 °C.
  • the reaction mixture was filtered and the filtrate was concentrated under vacuum and the residue was purified by flash chromatography to give 1-[3-(morpholin-4-yl)-7-(trifluoromethyl)quinoxalin-5-yl]ethan-1-one (1.6 g, 4.67 mmol, 56%).
  • Step 7 Synthesis of 1-[3-(morpholin-4-yl)-7-(trifluoromethyl)quinoxalin-5-yl]ethan- 1-ol
  • Example 14 and Example 15 Preparation of 2-[(1R)-1-[3-(morpholin-4-yl)-7- (trifluoromethyl)quinoxalin-5-yl]ethyl]aminobenzoic acid and 2-[(1R)-1-[3-(morpholin- 4-yl)-7-(trifluoromethyl)quinoxalin-5-yl]ethyl]aminobenzoic acid 107 289225266 v1 Attorney Docket No.
  • Example 16 Preparation of 2-(1-[7-methyl-2-(pyrrolidin-1-yl)quinoxalin-5- yl]ethylamino)-benzoic acid [0547] Step 1. Synthesis of 8-bromo-6-methyl-2-(pyrrolidin-1-yl)quinoxaline 108 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0548] An inseparable mixture of 8-bromo-2-chloro-6-methylquinoxaline (5.0 g, 19.4 mmol) and 5-bromo-2-chloro-7-methylquinoxaline was dissolved in acetonitrile.
  • ASET-039/001WO 325190-2191 [0560] A solution of 8-bromo-3,6-dimethyl-quinoxalin-2-ol (1 g, 3.95 mmol) in phosphorus oxychloride (33.0 g, 215 mmol) was stirred at 110 °C for 16 hr. On completion, the reaction mixture was poured into ice-water (60 mL) by dropwise, resulting the formation of much precipitate. The precipitate was filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5 um; mobile phase: [water(ammonium bicarbonate)- acetonitrile]; B%: 16%-46%, 9 min) to give 2-((1-(2,7-dimethyl-3-morpholinoquinoxalin-5-yl)ethyl)amino)benzoic acid (0.1 g, 246 ⁇ mol, 35%) as a white solid.
  • reaction mixture was quenched by addition water (30 mL) and then filtered.
  • the filtered cake was washed with ethyl acetate (50 mL).
  • the organic layer in the filtrate was separated and the aqueous layer was then extracted with ethyl acetate (20 mL ⁇ 2).
  • the combined organic layers were washed with brine (30 mL ⁇ dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step 5 Synthesis of (R)-1-(2,7-dimethyl-3-morpholinoquinoxalin-5-yl)ethan-1-amine [0579] To a solution of (R)-1-(2,7-dimethyl-3-morpholinoquinoxalin-5-yl)ethan-1-amine (40 mg, 102 ⁇ mol) in dioxane (4 mL) was added hydrogen chloride/dioxane (0.4 mL), the mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated under reduced pressure. The residue was diluted with saturation sodium bicarbonate (2.0 mL) and extracted with ethyl acetate (5 mL ⁇ 3).
  • Example 21 Preparation of (R)-2-((1-(2,7-dimethyl-3-(piperidin-1-yl)quinoxalin-5- yl)ethyl)amino)-5-fluorobenzoic acid (Compound 28) 115 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0582] Step 1.
  • reaction mixture was quenched by water (30 mL) and then filtered.
  • the filtered cake washed with ethyl acetate (50 mL).
  • the filtrate was then extracted with ethyl acetate (20 mL ⁇ 2).
  • the combined organic layers were washed with brine (30 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step 2 Synthesis of 2-(((1R)-1-(2,7-dimethyl-3-(methylsulfinyl)quinoxalin-5- yl)ethyl)amino)-5-fluorobenzoic acid 119 289225266 v1 Attorney Docket No.
  • Example 24 Preparation of (R)-2-((1-(3-(4,4-difluoropiperidin-1-yl)-7-fluoro-2- methylquinoxalin-5-yl)ethyl)amino)-5-fluorobenzoic acid (Compound 34) 120 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0602] Step 1.
  • Example 25 Synthesis and Characterization of Additional Exemplary Compounds [0622] Other exemplary compounds were further synthesized following the procedures described herein, and characterizations of these further synthesized exemplary compounds are shown in Table A below. 124 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 Table A 125 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 126 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 127 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 128 289225266 v1 Attorney Docket No.
  • Example 26 Biological Activity of Exemplary Compounds of the Present Disclosure 129 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
  • the biological activity of exemplary compounds of the present disclosure was determined utilizing a p-AKT S473 assay described herein. [0624] Briefly, MCF10A-PI3K ⁇ -WT, MCF10A- PI3K ⁇ -H1047R and MCF10A- PI3K ⁇ - E545K cells were grown in DMEM/F12 supplemented with Horse Serum, EGF, Hydrocortisone, Cholera toxin and Insulin.
  • the cells were dissociated with TryPLE, washed with media and plated in 384 wells plate. The next day, serial dilution of compounds were applied to the cell for 2 hours and p-AKT S473 was measured using HTRF cellular kit by Cisbio (64AKSPET) according to manufacturer’s protocol. To measure p-AKT S473 levels using the kit, the cells were lysed, antibodies mixed with detection buffer were then added to the lysate and incubated overnight in the dark. The next day luminescence was read on a Ensight plate reader at 665 nm and 620 nm wavelengths.
  • a decrease in p-AKT S473 levels indicate a downregulation of the PI3K ⁇ pathway and cell proliferation, thereby indicating inhibition of the PI3K ⁇ protein by the compounds of the present disclosure.
  • Table B and Table C assign each compound a code for potency in the assay described above: A, B, C, D, or E.
  • A represents an IC 50 value ⁇ 500 nM
  • B represents an IC50 value ⁇ 500 nM and ⁇ 1000 nM
  • C represents an IC50 value ⁇ 1000 nM and ⁇ 5000 nM
  • D represents an IC50 value ⁇ 5000 nM and ⁇ 10,000 nM
  • E represents an IC50 value ⁇ 10,000 nM.
  • Table B 130 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 Table C Example 27.
  • the biological activity of exemplary compounds of the present disclosure was determined utilizing a HCT-116 assay described herein.
  • HCT-116-PIK3Ca-WT and HCT-116-PIK3Ca-H1047R are grown in RPMI supplemented with 10% fetal bovine serum.
  • HCT-116-PIK3Ca-WT and HCT-116-PIK3Ca-H1047R cells are dissociated with TryPLE, wash with media and plated in 384 wells plate (density: WT & H1047R: 15K/well).
  • 131 289225266 v1 Attorney Docket No.
  • A represents an IC50 value ⁇ 100 nM
  • B represents an IC50 value ⁇ 100 nM and ⁇ 500 nM
  • C represents an IC50 value ⁇ 500 nM and ⁇ 1000 nM
  • D represents an IC50 value ⁇ 1000 nM and ⁇ 10,000 nM
  • E represents an IC50 value ⁇ 10,000 nM and ⁇ 30,000
  • F represents an IC50 value ⁇ 30,000 nM.
  • Embodiment 1 A compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 is halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 haloalkyl; R 2 is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; 132 289225266 v1 Attorney Docket No.
  • R 3 is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C 10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R 3a ; each R 3a independently is halogen, C1-C6 alkyl, or C6-C10 aryl, wherein the C1-C6 alkyl or C6-C10 aryl is optionally substituted with one or more halogen; alkyl)-*, -(C 1 -C 6 alkyl)-O-*, -O-(C 1 -C 6 alkyl)-*, -(C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl)--(C 1 -C 6 alkyl)
  • Embodiment 2 A compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 is halogen, cyano, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 2 is H, or C1-C6 alkyl; 133 289225266 v1 Attorney Docket No.
  • Embodiment 3 The compound of any one of the preceding embodiments, wherein R 1 is halogen or cyano.
  • Embodiment 4 The compound of any one of the preceding embodiments, wherein R 1 is C1-C6 alkyl or C1-C6 haloalkyl.
  • Embodiment 5 The compound of any one of the preceding embodiments, wherein R 2 is H.
  • Embodiment 6 The compound of any one of the preceding embodiments, wherein R 2 is C 1 -C 6 alkyl.
  • Embodiment 7 The compound of any one of the preceding embodiments, wherein R 3 is 3- to 12-membered heterocycloalkyl optionally substituted with one or more R 3a .
  • Embodiment 8 The compound of any one of the preceding embodiments, wherein R 3 is 5- to 10-membered heteroaryl optionally substituted with one or more R 3a .
  • Embodiment 9 The compound of any one of the preceding embodiments, wherein each R 3a independently is C 6 -C 10 aryl substituted with one or more halogen.
  • Embodiment 10 The compound of any one of the preceding embodiments, wherein T is -(C1-C6 alkyl)-*, wherein * denotes attachment to A.
  • Embodiment 11 The compound of any one of the preceding embodiments, wherein T is -(C 1 -C 6 alkyl)-NR T -*, wherein * denotes attachment to A.
  • Embodiment 12 The compound of any one of the preceding embodiments, wherein each R T is H.
  • Embodiment 13 The compound of any one of the preceding embodiments, wherein A is C6-C10 aryl optionally substituted with one or more R A .
  • Embodiment 14 The compound of any one of the preceding embodiments, wherein A is phenyl substituted with one or more R A .
  • Embodiment 15 The compound of any one of the preceding embodiments, wherein each R A independently is -NH2. 134 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
  • Embodiment 17 The compound of any one of the preceding embodiments, wherein each R A independently is 3- to 12-membered heterocycloalkyl.
  • Embodiment 18 The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-a), (I-b), (I-c), (I-d), (I-e), or (I-f), or a pharmaceutically acceptable salt or stereoisomer thereof.
  • Embodiment 19 The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-g), or a pharmaceutically acceptable salt or stereoisomer thereof.
  • Embodiment 20 The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-h), or a pharmaceutically acceptable salt or stereoisomer thereof.
  • Embodiment 21 The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-i), or a pharmaceutically acceptable salt or stereoisomer thereof.
  • Embodiment 22 The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-j), or a pharmaceutically acceptable salt or stereoisomer thereof.
  • Embodiment 23 The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-k), or a pharmaceutically acceptable salt or stereoisomer thereof.
  • Embodiment 24 The compound of any one of the preceding embodiments, wherein the compound is selected from a compound described in Table 1 or Table 2, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • Embodiment 25 A compound obtainable by, or obtained by, a method described herein; optionally, the method comprises one or more steps described in Schemes 1-2.
  • Embodiment 26 A pharmaceutical composition comprising the compound of any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. 135 289225266 v1 Attorney Docket No.
  • Embodiment 27 The pharmaceutical composition of any one of the preceding embodiments, wherein the compound is selected from a compound described in Table 1 or Table 2.
  • Embodiment 28 A method of modulating PI3K ⁇ activity, comprising contacting a cell with an effective amount of the compound of any one of the preceding embodiments; optionally the activity is in vitro or in vivo.
  • Embodiment 29 A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition of any one of the preceding embodiments.
  • Embodiment 30 The compound or pharmaceutical composition of any one of the preceding embodiments for use in modulating PI3K ⁇ activity; optionally, the activity is in vitro or in vivo.
  • Embodiment 31 The compound or pharmaceutical composition of any one of the preceding embodiments for use in treating or preventing a disease or disorder.
  • Embodiment 32 Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for modulating PI3K ⁇ activity; optionally, the activity is in vitro or in vivo.
  • Embodiment 33 Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for treating or preventing a disease or disorder.
  • Embodiment 34 The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is a disease or disorder in which PI3K ⁇ activity is implicated.
  • Embodiment 35 The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal (CLOVES) syndrome.
  • Embodiment 36 The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is PIK3CA-related overgrowth syndrome.
  • Embodiment 37 The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is cancer.
  • Embodiment 38 A method of treating or preventing cancer in a subject, the method comprising administering to the subject a compound of any one of the preceding embodiments. 136 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
  • Embodiment 39 A compound of any one of the preceding embodiments for treating or preventing cancer in a subject.
  • Embodiment 40 Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for treating or preventing cancer in a subject.
  • Embodiment 41 Use of the compound of any one of the preceding embodiments for treating or preventing cancer in a subject.
  • Embodiment 42 The method, compound, or use of any one of the preceding embodiments, wherein the cancer is characterized by at least one oncogenic mutation in the PIK3CA gene.
  • Embodiment 43 The method, compound, or use of any one of the preceding embodiments, wherein the cancer is characterized by at least one oncogenic variant of the PI3K ⁇ protein.
  • Embodiment 44 The method, compound, or use of any one of the preceding embodiments, wherein the subject has at least one oncogenic mutation in the PIK3CA gene.
  • Embodiment 45 The method, compound, or use of any one of the preceding embodiments, wherein the subject has at least one tumor and/or cancerous cell that expresses an oncogenic variant of PI3K ⁇ protein.
  • Embodiment 46 The method, compound, or use of any one of the preceding embodiments, wherein the oncogenic mutation of the PI3K ⁇ protein is any one of E542K, E545K and H1047R.
  • Embodiment 47 The method, compound, or use of any one of the preceding embodiments, wherein the cancer is a carcinoma, a lymphoma, a blastoma, a sarcoma, a leukemia, a brain cancer, a breast cancer, a blood cancer, a bone cancer, a lung cancer, a skin cancer, a liver cancer, an ovarian cancer, a bladder cancer, a renal cancer, a kidney cancer, a gastric cancer, a thyroid cancer, a pancreatic cancer, an esophageal cancer, a prostate cancer, a cervical cancer, a uterine cancer, a stomach cancer, a soft tissue cancer, a laryngeal cancer, a small intestine cancer, a testicular cancer, an anal cancer, a vulvar cancer, a joint cancer, an oral cancer, a pharynx cancer or a colorectal cancer.
  • the cancer is a carcinoma, a lymphoma, a blastoma
  • Embodiment 1A A compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 is halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 haloalkyl; R 2 is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; 137 289225266 v1 Attorney Docket No.
  • R 3 is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C 10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R 3a ; each R 3a independently is C6-C10 aryl optionally substituted with one or more halogen; alkyl)-*, -(C1-C6 alkyl)-O-*, -O-(C 1 -C 6 alkyl)-*, -(C 1 -C 6 alkyl)-NR T - -NR T -(C 1 -C 6 alkyl)-*, -(C 1 -C 6 haloalkyl)-*, -(C 1 -C 1 -C
  • Embodiment 2A A compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 is halogen, cyano, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 2 is H, or C1-C6 alkyl; R 3 is 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R 3a ; each R 3a independently is C6-C10 aryl optionally substituted with one or more halogen; T is -(C1-C6 alkyl)-*, or -(C1-C6 alkyl)-NR T -*, wherein * denotes attachment to A; 138 289225266 v1 Attorney Docket No.
  • Embodiment 3A The compound of any one of the preceding embodiments, wherein R 1 is halogen or cyano.
  • Embodiment 4A The compound of any one of the preceding embodiments, wherein R 1 is C1-C6 alkyl or C1-C6 haloalkyl.
  • Embodiment 5A The compound of any one of the preceding embodiments, wherein R 2 is H.
  • Embodiment 6A The compound of any one of the preceding embodiments, wherein R 2 is C1-C6 alkyl.
  • Embodiment 7A The compound of any one of the preceding embodiments, wherein R 3 is 3- to 12-membered heterocycloalkyl optionally substituted with one or more R 3a .
  • Embodiment 8A The compound of any one of the preceding embodiments, wherein R 3 is 5- to 10-membered heteroaryl optionally substituted with one or more R 3a .
  • Embodiment 9A The compound of any one of the preceding embodiments, wherein each R 3a independently is C6-C10 aryl substituted with one or more halogen.
  • Embodiment 10A The compound of any one of the preceding embodiments, wherein T is -(C1-C6 alkyl)-*, wherein * denotes attachment to A.
  • Embodiment 11A The compound of any one of the preceding embodiments, wherein T is -(C 1 -C 6 alkyl)-NR T -*, wherein * denotes attachment to A.
  • Embodiment 12A The compound of any one of the preceding embodiments, wherein each R T is H.
  • Embodiment 13A The compound of any one of the preceding embodiments, wherein A is C 6 -C 10 aryl optionally substituted with one or more R A .
  • Embodiment 14A The compound of any one of the preceding embodiments, wherein A is phenyl substituted with one or more R A .
  • Embodiment 15A The compound of any one of the preceding embodiments, wherein each R A independently is -NH2.
  • Embodiment 17A The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-a), (I-b), (I-c), (I-d), (I-e), or (I-f), or a pharmaceutically acceptable salt or stereoisomer thereof.
  • Embodiment 18A The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-g), or a pharmaceutically acceptable salt or stereoisomer thereof.
  • Embodiment 19A The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-i), or a pharmaceutically acceptable salt or stereoisomer thereof.
  • Embodiment 20A The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-j), or a pharmaceutically acceptable salt or stereoisomer thereof.
  • Embodiment 21A The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-k), or a pharmaceutically acceptable salt or stereoisomer thereof.
  • Embodiment 22A The compound of any one of the preceding embodiments, wherein the compound is selected from a compound described in Table 1, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • Embodiment 23A A compound obtainable by, or obtained by, a method described herein; optionally, the method comprises one or more steps described in Schemes 1-2.
  • Embodiment 24A A pharmaceutical composition comprising the compound of any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • Embodiment 25A The pharmaceutical composition of any one of the preceding embodiments, wherein the compound is selected from a compound described in Table 1.
  • Embodiment 26A A method of modulating PI3K ⁇ activity, comprising contacting a cell with an effective amount of the compound of any one of the preceding embodiments; optionally the activity is in vitro or in vivo.
  • Embodiment 27A A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition of any one of the preceding embodiments. 140 289225266 v1 Attorney Docket No.
  • Embodiment 28A The compound or pharmaceutical composition of any one of the preceding embodiments for use in modulating PI3K ⁇ activity; optionally, the activity is in vitro or in vivo.
  • Embodiment 29A The compound or pharmaceutical composition of any one of the preceding embodiments for use in treating or preventing a disease or disorder.
  • Embodiment 30A Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for modulating PI3K ⁇ activity; optionally, the activity is in vitro or in vivo.
  • Embodiment 31A Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for treating or preventing a disease or disorder.
  • Embodiment 32A The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is a disease or disorder in which PI3K ⁇ activity is implicated.
  • Embodiment 33A The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal (CLOVES) syndrome.
  • Embodiment 34A The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is PIK3CA-related overgrowth syndrome.
  • Embodiment 35A The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is cancer.
  • Embodiment 36A A method of treating or preventing cancer in a subject, the method comprising administering to the subject a compound of any one of the preceding embodiments.
  • Embodiment 37A A compound of any one of the preceding embodiments for treating or preventing cancer in a subject.
  • Embodiment 38A Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for treating or preventing cancer in a subject.
  • Embodiment 39A Use of the compound of any one of the preceding embodiments for treating or preventing cancer in a subject.
  • Embodiment 40A The method, compound, or use of any one of the preceding embodiments, wherein the cancer is characterized by at least one oncogenic mutation in the PIK3CA gene. 141 289225266 v1 Attorney Docket No.
  • Embodiment 41A The method, compound, or use of any one of the preceding embodiments, wherein the cancer is characterized by at least one oncogenic variant of the PI3K ⁇ protein.
  • Embodiment 42A The method, compound, or use of any one of the preceding embodiments, wherein the subject has at least one oncogenic mutation in the PIK3CA gene.
  • Embodiment 43A The method, compound, or use of any one of the preceding embodiments, wherein the subject has at least one tumor and/or cancerous cell that expresses an oncogenic variant of PI3K ⁇ protein.
  • Embodiment 44A The method, compound, or use of any one of the preceding embodiments, wherein the oncogenic mutation of the PI3K ⁇ protein is any one of E542K, E545K and H1047R.
  • Embodiment 45A The method, compound, or use of any one of the preceding embodiments, wherein the cancer is a carcinoma, a lymphoma, a blastoma, a sarcoma, a leukemia, a brain cancer, a breast cancer, a blood cancer, a bone cancer, a lung cancer, a skin cancer, a liver cancer, an ovarian cancer, a bladder cancer, a renal cancer, a kidney cancer, a gastric cancer, a thyroid cancer, a pancreatic cancer, an esophageal cancer, a prostate cancer, a cervical cancer, a uterine cancer, a stomach cancer, a soft tissue cancer, a laryngeal cancer, a small intestine cancer,

Abstract

The present disclosure relates to compounds of Formula (I) and to their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for modulating PI3Kα activity and may be used in the treatment of diseases or disorders in which PI3Kα activity is implicated, such as cancer.

Description

Attorney Docket No. ASET-039/001WO 325190-2191 QUINOXALINE DERIVATIVES AND RELATED USES CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63/369,620, filed on July 27, 2022, which is incorporated by reference herein in their entirety for all purposes. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING [0002] The contents of the electronic sequence listing (ASET_039_001WO_SeqList_ST26.xml; Size: 3,004 bytes; and Date of Creation: July 19, 2023) are herein incorporated by reference in its entirety. BACKGROUND [0003] Phosphatidylinositol 3-Kinases (PI3Ks) are a group of plasma membrane-associated lipid kinases that upon activation catalyze the transfer of phosphate to the D-3’ position of inositol of phosphoinositol-4,5-phosphate (PIP2) to produce the second messenger phosphoinositol-3,4,5-phosphate (PIP3). PI3Ks are known to control and regulate of a variety of different cellular activities, including transcription, translation, proliferation, survival, chemotaxis, motility, cellular trafficking and metabolism. Genetic alterations such as mutations, amplifications, deletions and translocations in genes encoding PI3K subunits have been implicated in several of different diseases and disorder, including, CLOVES syndrome, PIK3CA-related overgrowth syndrome, as well as a variety of cancers. [0004] More specifically, mutations in the gene PIK3CA, which encodes the p110Į (also referred to as PI3KĮ) catalytic subunit, have been linked to numerous cancers, including bladder cancer, brain cancer, breast cancer, colon cancer, endometrial cancer, ovarian cancer, skin cancer, stomach cancer, lung cancer and prostate cancer. These mutations include oncogenic gain-of-function mutations that occur within mutation hotspots, primarily within the kinase and helicase domains. Accordingly, p110Į has been identified as a potential therapeutic target in the treatment of various cancers and other PI3K-driven diseases. [0005] To this end, multiple inhibitors of PI3Ks have been developed, including alpelisib, buparlisib, taselisib, and inavolisib. However, the efficacy of these existing PI3K inhibitors has been hindered by on-target related toxicities, including hyperglycemia, rash, diarrhea, myelosuppression, and transaminitis. 1 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0006] Accordingly, there is a need in the art for improved PI3K inhibitors, including improved inhibitors of the PI3KĮ catalytic subunit. In particular, there is a need in the art for PI3K inhibitors that specifically target mutated forms of PI3KĮ over wild-type PI3KĮ. SUMMARY [0007] In some aspects, the present disclosure provides a compound of Formula (I):
Figure imgf000003_0001
an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R2 is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R3 is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R3a; each R3a independently is halogen, C1-C6 alkyl, or C6-C10 aryl, wherein the C1-C6 alkyl or C6-C10 aryl is optionally substituted with one or more halogen; T is -O-*, -NRT-*, -C(=O)NRT-*, -NRTC(=O)-*, -(C1-C6 alkyl)-*, -(C1-C6 alkyl)-O-*, -O-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-O-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-NRT-*, -NRT-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-NRT-(C1-C6 alkyl)-*, -(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-O-*, - O-(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-NRT-*, or -NRT-(C1-C6 haloalkyl)-*, wherein * denotes attachment to A; each RT is H or C1-C6 alkyl; A is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RA; each RA independently is oxo, halogen, -OH, cyano, -NH2, -C(=O)OH, -C(=O)O(C1- C6 alkyl), -C(=O)N(RA1)2, -C(=O)N(ORA1)RA1, -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, - S(=O)(=NRA1)RA1, -S(=O)2N(RA1)2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl, wherein the -C(=O)O(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1- 2 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RA1; and each RA1 independently is oxo, H, halogen, -OH, -NH2, -C(=O)OH, -C(=O)(C1-C6 alkyl), -C(=O)((C1-C6 alkyl)-OH), -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C3-C12 cycloalkyl, wherein the C3-C12 cycloalkyl is optionally substituted with -OH; or two RA1, together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C3- C12 cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH2. [0008] In some aspects, the present disclosure provides a compound of Formula (I), wherein: R1 is halogen, cyano, C1-C6 alkyl, or C1-C6 haloalkyl; R2 is H, or C1-C6 alkyl; R3 is 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R3a; each R3a independently is C6-C10 aryl optionally substituted with one or more halogen; T is -(C1-C6 alkyl)-*, or -(C1-C6 alkyl)-NRT-*, wherein * denotes attachment to A; each RT is H; A is C6-C10 aryl optionally substituted with one or more RA; each RA independently is -NH2, -C(=O)OH, -C(=O)O(C1-C6 alkyl), or -S(=O)2(C1-C6 alkyl). [0009] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound as described herein (e.g., a method comprising one or more steps described in Schemes 1-2). [0010] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. [0011] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in Examples 1-24). [0012] In some aspects, the present disclosure provides a method of modulating PI3KĮ activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. 3 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0013] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0014] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0015] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating PI3KĮ activity (e.g., in vitro or in vivo). [0016] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein. [0017] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein. [0018] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating PI3KĮ activity (e.g., in vitro or in vivo). [0019] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [0020] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein. [0021] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure. [0022] In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps described herein. [0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure 4 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control. [0024] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION [0025] The present disclosure relates to quinoxaline derivatives, prodrugs, and pharmaceutically acceptable salts thereof, which may modulate PI3KĮ activity and are accordingly useful in methods of treatment of the human or animal body. The present disclosure also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them and to their use in the treatment of disorders in which PI3KĮ is implicated, such as cancer. Definitions [0026] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below. [0027] Without wishing to be limited by this statement, it is understood that, while various options for variables are described herein, the disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options. For example, while various options for variables X, L, and Y are described herein, the disclosure may be interpreted as excluding structures for non-operable compound caused by certain combinations of variables X, L, and Y (e.g., when each of X, L, and Y is -O-). [0028] As used herein, “alkyl”, “C1, C2, C3, C4, C5 or C6 alkyl” or “C1-C 6 alkyl” is intended to include C1, C2, C3, C4, C5 or C6 straight chain (linear) saturated aliphatic hydrocarbon groups 5 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 and C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intends to include C1, C2, C3, C4, C5 and C6 alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms. [0029] As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. [0030] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms. [0031] As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including 6 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. [0032] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “C3- C6” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6 alkenylene linker” or “C2-C6 alkynylene linker” is intended to include C2, C3, C4, C5 or C6 chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C2- C6 alkenylene linker is intended to include C2, C3, C4, C5 and C6 alkenylene linker groups. [0033] As used herein, the term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. [0034] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl- piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl. 7 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0035] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non- aromatic. [0036] As used herein, the term “heterocycloalkyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.¸ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6- tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1- azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane- 1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3- azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4- c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H- pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2- azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2- azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa- azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, 5,6-dihydro-4H- cyclopenta[b]thiophenyl, and the like. In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic (e.g., 4,5,6,7- tetrahydrobenzo[c]isoxazolyl). [0037] It is understood that when a variable has two attachments to the rest of the formula of the compound, the two attachments could be at the same atom or different atoms of the variable. For example, when a variable (e.g., variable X) is cycloalkyl or heterocycloalkyl, and has two 8 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 attachments to the rest of the formula of the compound, the two attachments could be at the same atom or different atoms of the cycloalkyl or heterocycloalkyl. [0038] As used herein, the term “aryl” includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. [0039] As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7- membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.¸ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidised (i.e., N→O and S(O)p, where p = 1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl). In some embodiments, the heteroaryl is thiophenyl or benzothiophenyl. In some embodiments, the heteroaryl is thiophenyl. In some embodiments, the heteroaryl benzothiophenyl. [0040] Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine. [0041] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, 9 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxole-5-yl). [0042] As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. [0043] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds. [0044] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds. [0045] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O- . [0046] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo. [0047] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms. 10 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0048] As used herein, the term “optionally substituted haloalkyl” refers to unsubstituted haloalkyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. [0049] As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy. [0050] As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and/or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise. [0051] It is to be understood that the present disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein. The present disclosure also provides 11 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples. [0052] It is to be understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously. [0053] It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof. [0054] It is to be understood that compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognised reference textbooks of organic synthesis known to those in the art [0055] One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognise 12 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999. [0056] It is to be understood that, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to provide such treatment or prevention as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to prepare a medicament to treat or prevent such condition. The treatment or prevention includes treatment or prevention of human or non-human animals including rodents and other disease models. [0057] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment includes use of the compounds to prepare a medicament to treat such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models. [0058] As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the subject is a human. [0059] As used herein, the term “subject in need thereof” refers to a subject having a disease or having an increased risk of developing the disease. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective 13 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy. [0060] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model. It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. [0061] It is to be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes. [0062] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder. [0063] It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th edition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure. 14 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0064] It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier. [0065] As used herein, the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required. [0066] As used herein, the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0067] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient. [0068] It is to be understood that a pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the 15 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. [0069] It is to be understood that a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., a disease or disorder disclosed herein) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment. [0070] As used herein, the term “therapeutically effective amount”, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician. [0071] As used herein, the term “therapeutically effective amount”, refers to an amount of a pharmaceutical agent to treat or ameliorate an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician. [0072] It is to be understood that, for any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, 16 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50 % of the population) and LD50 (the dose lethal to 50 % of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. [0073] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation. [0074] The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilising processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen. [0075] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion 17 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), cyclodextrins and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. [0076] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilisation. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. [0077] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, capsules or sachets. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, orange flavoring. 18 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0078] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebuliser. [0079] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays, powders or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. [0080] The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No.4,522,811. [0081] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved. [0082] In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease or disorder disclosed herein and also preferably causing complete regression of the disease or disorder. Dosages can range from about 0.01 mg/kg per day to 19 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 about 5000 mg/kg per day. An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. Improvement in survival and growth indicates regression. As used herein, the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell. [0083] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. [0084] It is to be understood that, for the compounds of the present disclosure being capable of further forming salts, all of these forms are also contemplated within the scope of the claimed disclosure. [0085] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral organic acid salts of basic residues such as amines, alkali organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc. [0086] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt. [0087] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3- 20 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3. [0088] It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt. [0089] The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognise the advantages of certain routes of administration. [0090] The dosage regimen utilising the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to counter or arrest the progress of the condition. [0091] Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. [0092] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in 21 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure. [0093] In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer. [0094] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow. [0095] As use herein, the phrase “compound of the disclosure” refers to those compounds which are disclosed herein, both generically and specifically. Compounds of the Present Disclosure [0096] In some aspects, the present disclosure provides a compound of Formula (I):
Figure imgf000023_0001
an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R2 is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R3 is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R3a; 22 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 each R3a independently is halogen, C1-C6 alkyl, or C6-C10 aryl, wherein the C1-C6 alkyl or C6-C10 aryl is optionally substituted with one or more halogen; T is -O-*, -NRT-*, -C(=O)NRT-*, -NRTC(=O)-*, -(C1-C6 alkyl)-*, -(C1-C6 alkyl)-O-*, -O-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-O-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-NRT-*, -NRT-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-NRT-(C1-C6 alkyl)-*, -(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-O-*, - O-(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-NRT-*, or -NRT-(C1-C6 haloalkyl)-*, wherein * denotes attachment to A; each RT is H or C1-C6 alkyl; A is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RA; each RA independently is oxo, halogen, -OH, cyano, -NH2, -C(=O)OH, -C(=O)O(C1- C6 alkyl),
Figure imgf000024_0001
alkyl), -P(=O)(C1-C6 alkyl)2, - S(=O)(=NRA1)RA1, -S(=O)2N(RA1)2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl, wherein the -C(=O)O(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1- C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RA1; and each RA1 independently is oxo, H, halogen, -OH, -NH2, -C(=O)OH, -C(=O)(C1-C6 alkyl), -C(=O)((C1-C6 alkyl)-OH), -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C3-C12 cycloalkyl, wherein the C3-C12 cycloalkyl is optionally substituted with -OH; or two RA1, together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C3- C12 cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH2. [0097] In some aspects, the present disclosure provides a compound of Formula (I), wherein: R1 is halogen, cyano, C1-C6 alkyl, or C1-C6 haloalkyl; R2 is H, or C1-C6 alkyl; R3 is 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R3a; each R3a independently is C6-C10 aryl optionally substituted with one or more halogen; T is -(C1-C6 alkyl)-*, or -(C1-C6 alkyl)-NRT-*, wherein * denotes attachment to A; 23 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 each RT is H; A is C6-C10 aryl optionally substituted with one or more RA; each RA independently is -NH2, -C(=O)OH, -C(=O)O(C1-C6 alkyl), or -S(=O)2(C1-C6 alkyl). [0098] In some aspects, the present disclosure provides a compound of Formula (I):
Figure imgf000025_0001
an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R2 is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R3 is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R3a; each R3a independently is C6-C10 aryl optionally substituted with one or more halogen;
Figure imgf000025_0002
alkyl)-*, -(C1-C6 alkyl)-O-*, -O-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-NRT-*, -NRT-(C1-C6 alkyl)-*, -(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-O-*, -O-(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-NRT-*, or -NRT-(C1-C6 haloalkyl)- *, wherein * denotes attachment to A; each RT is H or C1-C6 alkyl; A is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RA; each RA independently is oxo, halogen, -OH, cyano, -NH2, -C(=O)OH, -C(=O)O(C1- C6 alkyl), -C(=O)N(RA1)2, -C(=O)N(ORA1)RA1, -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, - S(=O)(=NRA1)RA1, -S(=O)2N(RA1)2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl, wherein the -C(=O)O(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1- C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RA1; and 24 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 each RA1 independently is H, halogen, -OH, -NH2, -C(=O)OH, -C(=O)(C1-C6 alkyl), - S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C3-C12 cycloalkyl, wherein the C3-C12 cycloalkyl is optionally substituted with -OH; or two RA1, together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C3- C12 cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH2. [0099] In some aspects, the present disclosure provides a compound of Formula (I), wherein: R1 is halogen, cyano, C1-C6 alkyl, or C1-C6 haloalkyl; R2 is H, or C1-C6 alkyl; R3 is 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R3a; each R3a independently is C6-C10 aryl optionally substituted with one or more halogen; T is -(C1-C6 alkyl)-*, or -(C1-C6 alkyl)-NRT-*, wherein * denotes attachment to A; each RT is H; A is C6-C10 aryl optionally substituted with one or more RA; each RA independently is -NH2, -C(=O)OH, -C(=O)O(C1-C6 alkyl), or -S(=O)2(C1-C6 alkyl). [0100] It is understood that, for a compound of the present disclosure, variables R1, R2, R3, R3a, T, RT, A, RA, and RA1 can each be, where applicable, selected from the groups described herein, and any group described herein for any of variables R1, R2, R3, R3a, T, RT, A, RA, and RA1 can be combined, where applicable, with any group described herein for one or more of the remainder of variables R1, R2, R3, R3a, T, RT, A, RA, and RA1. Variables R1, R2, R3, R3a [0101] In some embodiments, R1 is halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl. [0102] In some embodiments, R1 is halogen, or cyano. [0103] In some embodiments, R1 is halogen. [0104] In some embodiments, R1 is F, Cl, Br, or I. In some embodiments, R1 is F, Cl, or Br. In some embodiments, R1 is F or Cl. [0105] In some embodiments, R1 is F. In some embodiments, R1 is Cl. In some embodiments, R1 is Br. In some embodiments, R1 is I. [0106] In some embodiments, R1 is cyano. 25 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0107] In some embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl. [0108] In some embodiments, R1 is C1-C6 alkyl, or C1-C6 haloalkyl. [0109] In some embodiments, R1 is C1-C6 alkyl. [0110] In some embodiments, R1 is methyl. In some embodiments, R1 is ethyl. In some embodiments, R1 is propyl. In some embodiments, R1 is butyl. In some embodiments, R1 is pentyl. In some embodiments, R1 is hexyl. In some embodiments, R1 is isopropyl. In some embodiments, R1 is isobutyl. In some embodiments, R1 is isopentyl. In some embodiments, R1 is isohexyl. In some embodiments, R1 is secbutyl. In some embodiments, R1 is secpentyl. In some embodiments, R1 is sechexyl. In some embodiments, R1 is tertbutyl. [0111] In some embodiments, R1 is C1-C6 haloalkyl. [0112] In some embodiments, R1 is halomethyl. In some embodiments, R1 is haloethyl. In some embodiments, R1 is halopropyl. In some embodiments, R1 is halobutyl. In some embodiments, R1 is halopentyl. In some embodiments, R1 is halohexyl. [0113] In some embodiments, R1 is CF3. [0114] In some embodiments, R2 is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl. [0115] In some embodiments, R2 is H, halogen, or cyano. [0116] In some embodiments, R2 is H. [0117] In some embodiments, R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl. [0118] In some embodiments, R2 is C1-C6 alkyl. [0119] In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is propyl. In some embodiments, R2 is butyl. In some embodiments, R2 is pentyl. In some embodiments, R2 is hexyl. In some embodiments, R2 is isopropyl. In some embodiments, R2 is isobutyl. In some embodiments, R2 is isopentyl. In some embodiments, R2 is isohexyl. In some embodiments, R2 is secbutyl. In some embodiments, R2 is secpentyl. In some embodiments, R2 is sechexyl. In some embodiments, R2 is tertbutyl. [0120] In some embodiments, R2 is methyl. [0121] In some embodiments, R3 is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12- membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R3a. 26 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0122] In some embodiments, R3 is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12- membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is substituted with one or more R3a. [0123] In some embodiments, R3 is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl. [0124] In some embodiments, R3 is 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R3a. [0125] In some embodiments, R3 is 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is substituted with one or more R3a. [0126] In some embodiments, R3 is 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl. [0127] In some embodiments, R3 is 3- to 12-membered heterocycloalkyl optionally substituted with one or more R3a. [0128] In some embodiments, R3 is 3- to 12-membered heterocycloalkyl substituted with one or more R3a. [0129] In some embodiments, R3 is 3- to 12-membered heterocycloalkyl. [0130] In some embodiments, R3 is a bicyclic 3- to 12-membered heterocycloalkyl. [0131] In some embodiments, R3 is a fused 3- to 12-membered heterocycloalkyl. [0132] In some embodiments, R3 is a spiro 3- to 12-membered heterocycloalkyl. [0133] In some embodiments, R3 is a bridged 3- to 12-membered heterocycloalkyl. [0134] In some embodiments, R3 is morpholinyl optionally substituted with one or more R3a. In some embodiments, R3 is piperidinyl optionally substituted with one or more R3a. In some embodiments, R3 is piperazinyl optionally substituted with one or more R3a. In some embodiments, R3 is azetidinyl optionally substituted with one or more R3a. In some embodiments, R3 is pyrrolidinyl optionally substituted with one or more R3a. In some embodiments, R3 is 2-oxa-5-azabicyclo[2.2.1]heptanyl optionally substituted with one or more R3a. [0135] In some embodiments, R3 is morpholinyl substituted with one or more R3a. In some embodiments, R3 is piperidinyl substituted with one or more R3a. In some embodiments, R3 is piperazinyl substituted with one or more R3a. In some embodiments, R3 is azetidinyl substituted with one or more R3a. In some embodiments, R3 is pyrrolidinyl substituted with one or more 27 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 R3a. In some embodiments, R3 is 2-oxa-5-azabicyclo[2.2.1]heptanyl substituted with one or more R3a. [0136] In some embodiments, R3 is morpholinyl. In some embodiments, R3 is piperidinyl. In some embodiments, R3 is piperazinyl. In some embodiments, R3 is azetidinyl. In some embodiments, R3 is pyrrolidinyl. In some embodiments, R3 is 2-oxa-5- azabicyclo[2.2.1]heptanyl. [0137] In some embodiments, R3 is 5- to 10-membered heteroaryl optionally substituted with one or more R3a. [0138] In some embodiments, R3 is 5- to 10-membered heteroaryl substituted with one or more R3a. [0139] In some embodiments, R3 is 5- to 10-membered heteroaryl. [0140] In some embodiments, R3 is pyridinyl. [0141] In some embodiments, each R3a independently is halogen, C1-C6 alkyl, or C6-C10 aryl, wherein the C1-C6 alkyl or C6-C10 aryl is optionally substituted with one or more halogen. [0142] In some embodiments, each R3a independently is C6-C10 aryl optionally substituted with one or more halogen. [0143] In some embodiments, each R3a independently is C6-C10 aryl substituted with one or more halogen. [0144] In some embodiments, each R3a independently is C6-C10 aryl. [0145] In some embodiments, each R3a independently is phenyl optionally substituted with one or more halogen. [0146] In some embodiments, each R3a independently is phenyl substituted with one or more halogen. [0147] In some embodiments, each R3a independently is phenyl. Variables T, RT, A, RA, RA1 [0148] In some embodiments,
Figure imgf000029_0001
alkyl)-*, -(C1-C6 alkyl)-O-*, -O-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-O-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-NRT-*, -NRT-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-NRT-(C1-C6 alkyl)-*, -(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-O-*, -O-(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-NRT-*, or -NRT-(C1-C6 haloalkyl)-*, wherein * denotes attachment to A. [0149] In some embodiments,
Figure imgf000029_0002
alkyl)-*, -(C1-C6 alkyl)-O-*, -O-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-NRT-*, -NRT-(C1-C6 alkyl)-*, 28 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 -(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-O-*, -O-(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-NRT- *, or -NRT- (C1-C6 haloalkyl)-*, wherein * denotes attachment to A. [0150] In some embodiments, T is -O-*, -NRT-*, -C(=O)NRT-*, -(C1-C6 alkyl)-*, -(C1-C6 alkyl)-O-*, -(C1-C6 alkyl)-NRT-*, -(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-O-*, or -(C1-C6 haloalkyl)-NRT-*, wherein * denotes attachment to A. [0151] In some embodiments, T is -(C1-C6 alkyl)-*, -(C1-C6 alkyl)-O-*, or -(C1-C6 alkyl)- NRT-*, wherein * denotes attachment to A. [0152] In some embodiments, T is -(C1-C6 alkyl)-*, or -(C1-C6 alkyl)-NRT-*, wherein * denotes attachment to A. [0153] In some embodiments, T is -(C1-C6 alkyl)-*, wherein * denotes attachment to A. [0154] In some embodiments, T is branched -(C1-C6 alkyl)-*, wherein * denotes attachment to A. [0155] In some embodiments, T is -CH(CH3)-*, wherein * denotes attachment to A. [0156] In some embodiments, T is -(C1-C6 alkyl)-NRT-*, wherein * denotes attachment to A. [0157] In some embodiments, T is -CH(CH3)-NRT-*, wherein * denotes attachment to A. [0158] In some embodiments, T is -CH(CH3)-NH-*, wherein * denotes attachment to A. [0159] In some embodiments, each RT is H or C1-C6 alkyl. [0160] In some embodiments, RT is H or C1-C6 alkyl. [0161] In some embodiments, RT is H. [0162] In some embodiments, RT is C1-C6 alkyl. [0163] In some embodiments, A is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12- membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RA. [0164] In some embodiments, A is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12- membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is substituted with one or more RA. [0165] In some embodiments, A is 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RA. [0166] In some embodiments, A is 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is substituted with one or more RA. 29 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0167] In some embodiments, A is 3- to 12-membered heterocycloalkyl optionally substituted with one or more RA. [0168] In some embodiments, A is 3- to 12-membered heterocycloalkyl substituted with one or more RA. [0169] In some embodiments, A is 3- to 12-membered heterocycloalkyl. [0170] In some embodiments, A is C6-C10 aryl optionally substituted with one or more RA. [0171] In some embodiments, A is C6-C10 aryl substituted with one or more RA. [0172] In some embodiments, A is C6-C10 aryl. [0173] In some embodiments, A is phenyl optionally substituted with one or more RA. [0174] In some embodiments, A is phenyl substituted with one or more RA. [0175] In some embodiments, A is phenyl. [0176] In some embodiments, A is phenyl optionally substituted with -NH2. [0177] In some embodiments, A is phenyl optionally substituted with -NH2 and -C(=O)OH. [0178] In some embodiments, A is phenyl optionally substituted with -C(=O)OH. [0179] In some embodiments, A is phenyl optionally substituted with -C(=O)O(C1-C6 alkyl). [0180] In some embodiments, A is phenyl optionally substituted with -C(=O)O(CH3). [0181] In some embodiments, A is phenyl optionally substituted with -S(=O)2(C1-C6 alkyl). [0182] In some embodiments, A is phenyl optionally substituted with -S(=O)2(CH3). [0183] In some embodiments, A is phenyl substituted with -NH2. [0184] In some embodiments, A is phenyl substituted with -NH2 and -C(=O)OH. [0185] In some embodiments, A is phenyl substituted with -C(=O)OH. [0186] In some embodiments, A is phenyl substituted with -C(=O)O(C1-C6 alkyl). [0187] In some embodiments, A is phenyl substituted with -C(=O)O(CH3). [0188] In some embodiments, A is phenyl substituted with -S(=O)2(C1-C6 alkyl). [0189] In some embodiments, A is phenyl substituted with -S(=O)2(CH3). [0190] In some embodiments, A is 5- to 10-membered heteroaryl optionally substituted with one or more RA. [0191] In some embodiments, A is 5- to 10-membered heteroaryl substituted with one or more RA. [0192] In some embodiments, A is 5- to 10-membered heteroaryl. [0193] In some embodiments, A is 2,3-dihydrobenzo[b]thiophene optionally substituted with one or more RA. In some embodiments, A is pyrazolyl optionally substituted with one or more RA. In some embodiments, A is pyridinyl optionally substituted with one or more RA. In some 30 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 embodiments, A is [1,2,4]triazolo[4,3-a]pyridinyl optionally substituted with one or more RA. In some embodiments, A is thiophenyl optionally substituted with one or more RA. [0194] In some embodiments, A is 2,3-dihydrobenzo[b]thiophene substituted with one or more RA. In some embodiments, A is pyrazolyl substituted with one or more RA. In some embodiments, A is pyridinyl substituted with one or more RA. In some embodiments, A is [1,2,4]triazolo[4,3-a]pyridinyl substituted with one or more RA. In some embodiments, A is thiophenyl substituted with one or more RA. [0195] In some embodiments, A is 2,3-dihydrobenzo[b]thiophene. In some embodiments, A is pyrazolyl. In some embodiments, A is pyridinyl. In some embodiments, A is [1,2,4]triazolo[4,3-a]pyridinyl. In some embodiments, A is thiophenyl. [0196] In some embodiments, each RA independently is oxo, halogen, -OH, cyano, -NH2, - C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)N(RA1)2, -C(=O)N(ORA1)RA1, -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)
Figure imgf000032_0001
alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the -C(=O)O(C1-C6 alkyl), - C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RA1. [0197] In some embodiments, each RA independently is oxo, halogen, -OH, cyano, -NH2, - C(=O)OH, -C(=O)O(C1-C6 alkyl), -C(=O)N(RA1)2, -C(=O)N(ORA1)RA1, -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6
Figure imgf000032_0002
alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the -C(=O)O(C1-C6 alkyl), - C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is substituted with one or more RA1. [0198] In some embodiments, each RA independently is oxo, halogen, -OH, cyano, or -NH2. [0199] In some embodiments, each RA independently is oxo. [0200] In some embodiments, each RA independently is halogen. [0201] In some embodiments, each RA independently is F, Cl, Br, or I. In some embodiments, each RA independently is F, Cl, or Br. In some embodiments, each RA independently is F or Cl. 31 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0202] In some embodiments, each RA independently is F. In some embodiments, each RA independently is Cl. In some embodiments, each RA independently is Br. In some embodiments, each RA independently is I. [0203] In some embodiments, each RA independently is -OH. [0204] In some embodiments, each RA independently is cyano. [0205] In some embodiments, each RA independently is -NH2. [0206] In some embodiments, each RA independently is -C(=O)OH, -C(=O)O(C1-C6 alkyl), - C(=O)N(RA1)2, -C(=O)N(ORA1)RA1, -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, - S(=O)(=NRA1)RA1, -S(=O)2N(RA1)2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl, wherein the -C(=O)O(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1- C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RA1. [0207] In some embodiments, each RA independently is -C(=O)OH, -C(=O)O(C1-C6 alkyl), - C(=O)N(RA1)2, -C(=O)N(ORA1)RA1, -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, - S(=O)(=NRA1)RA1, -S(=O)2N(RA1)2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl, wherein the -C(=O)O(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1- C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is substituted with one or more RA1. [0208] In some embodiments, each RA independently is -C(=O)OH. [0209] In some embodiments, each RA independently is -C(=O)O(C1-C6 alkyl). [0210] In some embodiments, each RA independently is -C(=O)O(C1-C6 alkyl), wherein the alkyl is optionally substituted with one or more RA1. [0211] In some embodiments, each RA independently is -C(=O)O(C1-C6 alkyl), wherein the alkyl is substituted with one or more RA1. [0212] In some embodiments, each RA independently is -S(=O)2(C1-C6 alkyl). [0213] In some embodiments, each RA independently is -S(=O)2(C1-C6 alkyl), wherein the alkyl is optionally substituted with one or more RA1. [0214] In some embodiments, each RA independently is -S(=O)2(C1-C6 alkyl), wherein the alkyl is substituted with one or more RA1. 32 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0215] In some embodiments, each RA independently is -S(=O)2(methyl) optionally substituted with one or more RA1. In some embodiments, each RA independently is - S(=O)2(ethyl) optionally substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(propyl) optionally substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(butyl) optionally substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(pentyl) optionally substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(hexyl) optionally substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(isopropyl) optionally substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(isobutyl) optionally substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(isopentyl) optionally substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(isohexyl) optionally substituted with one or more RA1. In some embodiments, each RA independently is - S(=O)2(secbutyl) optionally substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(secpentyl) optionally substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(sechexyl) optionally substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(tertbutyl) optionally substituted with one or more RA1. [0216] In some embodiments, each RA independently is -S(=O)2(methyl) substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(ethyl) substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(propyl) substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(butyl) substituted with one or more RA1. In some embodiments, each RA independently is - S(=O)2(pentyl) substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(hexyl) substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(isopropyl) substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(isobutyl) substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(isopentyl) substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(isohexyl) substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(secbutyl) substituted with one or more RA1. In some embodiments, each RA independently is - S(=O)2(secpentyl) substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(sechexyl) substituted with one or more RA1. In some embodiments, each RA independently is -S(=O)2(tertbutyl) substituted with one or more RA1. 33 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0217] In some embodiments, each RA independently is -S(=O)2(methyl). In some embodiments, each RA independently is -S(=O)2(ethyl). In some embodiments, each RA independently is -S(=O)2(propyl). In some embodiments, each RA independently is - S(=O)2(butyl). In some embodiments, each RA independently is -S(=O)2(pentyl). In some embodiments, each RA independently is -S(=O)2(hexyl). In some embodiments, each RA independently is -S(=O)2(isopropyl). In some embodiments, each RA independently is - S(=O)2(isobutyl). In some embodiments, each RA independently is -S(=O)2(isopentyl). In some embodiments, each RA independently is -S(=O)2(isohexyl). In some embodiments, each RA independently is -S(=O)2(secbutyl). In some embodiments, each RA independently is - S(=O)2(secpentyl). In some embodiments, each RA independently is -S(=O)2(sechexyl). In some embodiments, each RA independently is -S(=O)2(tertbutyl). [0218] In some embodiments, each RA independently is C1-C6 alkyl optionally substituted with one or more RA1. [0219] In some embodiments, each RA independently is C1-C6 alkyl substituted with one or more RA1. [0220] In some embodiments, each RA independently is C1-C6 alkyl. [0221] In some embodiments, each RA independently is methyl optionally substituted with one or more RA1. In some embodiments, each RA independently is ethyl optionally substituted with one or more RA1. In some embodiments, each RA independently is propyl optionally substituted with one or more RA1. In some embodiments, each RA independently is butyl optionally substituted with one or more RA1. In some embodiments, each RA independently is pentyl optionally substituted with one or more RA1. In some embodiments, each RA independently is hexyl optionally substituted with one or more RA1. In some embodiments, each RA independently is isopropyl optionally substituted with one or more RA1. In some embodiments, each RA independently is isobutyl optionally substituted with one or more RA1. In some embodiments, each RA independently is isopentyl optionally substituted with one or more RA1. In some embodiments, each RA independently is isohexyl optionally substituted with one or more RA1. In some embodiments, each RA independently is secbutyl optionally substituted with one or more RA1. In some embodiments, each RA independently is secpentyl optionally substituted with one or more RA1. In some embodiments, each RA independently is sechexyl optionally substituted with one or more RA1. In some embodiments, each RA independently is tertbutyl optionally substituted with one or more RA1. [0222] In some embodiments, each RA independently is methyl substituted with one or more RA1. In some embodiments, each RA independently is ethyl substituted with one or more RA1. 34 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 In some embodiments, each RA independently is propyl substituted with one or more RA1. In some embodiments, each RA independently is butyl substituted with one or more RA1. In some embodiments, each RA independently is pentyl substituted with one or more RA1. In some embodiments, each RA independently is hexyl substituted with one or more RA1. In some embodiments, each RA independently is isopropyl substituted with one or more RA1. In some embodiments, each RA independently is isobutyl substituted with one or more RA1. In some embodiments, each RA independently is isopentyl substituted with one or more RA1. In some embodiments, each RA independently is isohexyl substituted with one or more RA1. In some embodiments, each RA independently is secbutyl substituted with one or more RA1. In some embodiments, each RA independently is secpentyl substituted with one or more RA1. In some embodiments, each RA independently is sechexyl substituted with one or more RA1. In some embodiments, each RA independently is tertbutyl substituted with one or more RA1. [0223] In some embodiments, each RA independently is methyl. In some embodiments, each RA independently is ethyl. In some embodiments, each RA independently is propyl. In some embodiments, each RA independently is butyl. In some embodiments, each RA independently is pentyl. In some embodiments, each RA independently is hexyl. In some embodiments, each RA independently is isopropyl. In some embodiments, each RA independently is isobutyl. In some embodiments, each RA independently is isopentyl. In some embodiments, each RA independently is isohexyl. In some embodiments, each RA independently is secbutyl. In some embodiments, each RA independently is secpentyl. In some embodiments, each RA independently is sechexyl. In some embodiments, each RA independently is tertbutyl. [0224] In some embodiments, each RA1 independently is oxo, H, halogen, -OH, -NH2, - C(=O)OH, -C(=O)(C1-C6 alkyl), -C(=O)((C1-C6 alkyl)-OH), -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C3-C12 cycloalkyl, wherein the C3-C12 cycloalkyl is optionally substituted with -OH; or two RA1, together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH2. [0225] In some embodiments, each RA1 independently is H, halogen, -OH, -NH2, -C(=O)OH, -C(=O)(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C3-C12 cycloalkyl, wherein the C3-C12 cycloalkyl is optionally substituted with - OH; or two RA1, together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C3- C12 cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH2. 35 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0226] In some embodiments, each RA1 independently is H, halogen, -OH, -NH2, -C(=O)OH, -C(=O)(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C3-C12 cycloalkyl, wherein the C3-C12 cycloalkyl is optionally substituted with - OH. [0227] In some embodiments, two RA1, together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH2. [0228] In some embodiments, each RA1 independently is H, halogen, -OH, or -NH2. [0229] In some embodiments, each RA1 independently is H. [0230] In some embodiments, each RA1 independently is halogen. [0231] In some embodiments, each RA1 independently is F, Cl, Br, or I. In some embodiments, each RA1 independently is F, Cl, or Br. In some embodiments, each RA1 independently is F or Cl. [0232] In some embodiments, each RA1 independently is F. In some embodiments, each RA1 independently is Cl. In some embodiments, each RA1 independently is Br. In some embodiments, each RA1 independently is I. [0233] In some embodiments, each RA1 independently is -OH. [0234] In some embodiments, each RA1 independently is -NH2. [0235] In some embodiments, each RA1 independently is -C(=O)OH, -C(=O)(C1-C6 alkyl), - S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C3-C12 cycloalkyl, wherein the C3-C12 cycloalkyl is optionally substituted with -OH. [0236] In some embodiments, each RA1 independently is -C(=O)OH, -C(=O)(C1-C6 alkyl), - S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C3-C12 cycloalkyl. [0237] In some embodiments, each RA1 independently is -C(=O)OH, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C12 cycloalkyl. [0238] In some embodiments, each RA1 independently is C3-C12 cycloalkyl optionally substituted with -OH. [0239] In some embodiments, each RA1 independently is C3-C12 cycloalkyl substituted with - OH. [0240] In some embodiments, each RA1 independently is C3-C12 cycloalkyl. [0241] In some embodiments, the compound is of Formula (I-a), (I-b), (I-c), (I-d), (I-e), or (I- f): 36 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000038_0001
or a pharmaceutically acceptable salt or stereoisomer thereof. [0242] In some embodiments, the compound is of Formula (I-g): 37 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000039_0001
(I-g) or a pharmaceutically acceptable salt or stereoisomer thereof. [0243] In some embodiments, the compound is of Formula (I-h):
Figure imgf000039_0002
; (I-h) or a pharmaceutically acceptable salt or stereoisomer thereof. [0244] In some embodiments, the compound is of Formula (I-i):
Figure imgf000039_0003
(I-i) or a pharmaceutically acceptable salt or stereoisomer thereof. [0245] In some embodiments, the compound is of Formula (I-j):
Figure imgf000039_0004
(I-j) or a pharmaceutically acceptable salt or stereoisomer thereof. [0246] In some embodiments, the compound is of Formula (I-k):
Figure imgf000039_0005
; 38 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 (I-k) or a pharmaceutically acceptable salt or stereoisomer thereof. [0247] In some embodiments, the compound is a compound described in Table 1 or Table 2, or a prodrug or pharmaceutically acceptable salt thereof. [0248] In some embodiments, the compound is a compound described in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. [0249] In some embodiments, the compound is a prodrug of a compound described in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. [0250] In some embodiments, the compound is a compound described in Table 1 or Table 2. [0251] In some embodiments, the compound is a compound described in Table 1, or a prodrug or pharmaceutically acceptable salt thereof. [0252] In some embodiments, the compound is a compound described in Table 1, or a pharmaceutically acceptable salt thereof. [0253] In some embodiments, the compound is a prodrug of a compound described in Table 1, or a pharmaceutically acceptable salt thereof. [0254] In some embodiments, the compound is a compound described in Table 1. [0255] In some embodiments, the compound is a compound described in Table 2, or a prodrug or pharmaceutically acceptable salt thereof. [0256] In some embodiments, the compound is a compound described in Table 2, or a pharmaceutically acceptable salt thereof. [0257] In some embodiments, the compound is a prodrug of a compound described in Table 2, or a pharmaceutically acceptable salt thereof. [0258] In some embodiments, the compound is a compound described in Table 2. Table 1
Figure imgf000040_0001
39 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000041_0001
40 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000042_0001
41 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000043_0001
42 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000044_0001
43 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000045_0001
44 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000046_0001
45 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 Table 2
Figure imgf000047_0001
46 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000048_0001
47 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000049_0001
48 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000050_0001
49 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000051_0001
246 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000052_0001
51 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000053_0001
52 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000054_0001
53 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000055_0001
54 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000056_0001
[0259] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound described in Table 1. [0260] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound described in Table 2. [0261] In some aspects, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein. [0262] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1, or a prodrug or pharmaceutically acceptable salt thereof. [0263] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 or a pharmaceutically acceptable salt thereof. [0264] In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 1 or a pharmaceutically acceptable salt thereof. [0265] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1. [0266] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2, or a prodrug or pharmaceutically acceptable salt thereof. [0267] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2 or a pharmaceutically acceptable salt thereof. [0268] In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 2 or a pharmaceutically acceptable salt thereof. [0269] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2. 55 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0270] It is understood that the isotopic derivative can be prepared using any of a variety of art-recognised techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. [0271] In some embodiments, the isotopic derivative is a deuterium labeled compound. [0272] In some embodiments, the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein. [0273] The term “isotopic derivative”, as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled. For example, an isotopic derivative of a compound of Formula (I) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (I). In some embodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from 2H, 13C, 14C, 15N, 18O, 29Si, 31P, and 34S. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with 2H with regard to one or more atoms thereof). In some embodiments, the compound is a 18F labeled compound. In some embodiments, the compound is a 123I labeled compound, a 124I labeled compound, a 125I labeled compound, a 129I labeled compound, a 131I labeled compound, a 135I labeled compound, or any combination thereof. In some embodiments, the compound is a 33S labeled compound, a 34S labeled compound, a 35S labeled compound, a 36S labeled compound, or any combination thereof. [0274] It is understood that the 35 36
Figure imgf000057_0001
S, and/or S labeled compound, can be prepared using any of a variety of art-recognised techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a 18F, 123I, 124I, 34 35 36
Figure imgf000057_0002
S, S, and/or S labeled reagent for a non-isotope labeled reagent. [0275] A compound of the invention or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned 18F, 123I,
Figure imgf000057_0003
and 36S atom(s) is within the scope of the invention. Further, substitution with isotope (e.g,, 18F, 123I, 124I, 125I, 129I, 131I, 135I, 3S, 34S, 35S, and/or 36S) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. [0276] For the avoidance of doubt it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group. 56 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0277] The various functional groups and substituents making up the compounds of the Formula (I) are typically chosen such that the molecular weight of the compound does not exceed 1000 daltons. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 daltons. In some embodiments, the molecular weight is less than 600 and, for example, is 550 daltons or less. [0278] A suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. [0279] It will be understood that the compounds of any one of the Formulae disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds. [0280] It will be understood that while compounds disclosed herein may be presented in one particular configuration. Such particular configuration is not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers. In some embodiments, the presentation of a compound herein in a particular configuration intends to encompass, and to refer to, each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof; while the presentation further intends to refer to the specific configuration of the compound. [0281] It will be understood that while compounds disclosed herein may be presented without specified configuration (e.g., without specified stereochemistry). Such presentation intends to encompass all available isomers, tautomers, regioisomers, and stereoisomers of the compound. In some embodiments, the presentation of a compound herein without specified configuration intends to refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof. 57 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0282] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.” [0283] As used herein, the term “chiral centre” refers to a carbon atom bonded to four nonidentical substituents. [0284] As used herein, the term “chiral isomer” means a compound with at least one chiral centre. Compounds with more than one chiral centre may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral centre is present, a stereoisomer may be characterised by the absolute configuration (R or S) of that chiral centre. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral centre. The substituents attached to the chiral centre under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116). [0285] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules. [0286] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity. [0287] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity. 58 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0288] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases. [0289] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose. [0290] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others. [0291] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can 59 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. [0292] The compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that modulate PI3KĮ activity. [0293] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions. [0294] It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate). [0295] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms. [0296] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc. 60 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0297] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O. [0298] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure origin to the reference compound. [0299] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein. [0300] As used herein, the term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev.96, 3147-3176, 1996. [0301] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that modulate PI3KĮ activity. [0302] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof, which modulate PI3KĮ activity. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) 61 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis. [0303] Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compounds of Formula (I) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
Figure imgf000063_0001
keto enol enolate [0304] Compounds of any one of the Formulae disclosed herein containing an amine function may also form N-oxides. A reference herein to a compound of Formula (I) that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen- containing heterocycle. N-oxides can be formed by treatment of the corresponding amine with an oxidising agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane. [0305] The compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property- modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any one of the Formulae disclosed herein. [0306] Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis 62 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically-produced compound or a metabolically-produced compound. [0307] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987. [0308] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-C10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4- (C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups 63 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 for a hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups. [0309] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxyethylamine, a phenyl-C1- C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof. [0310] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl,morpholinomethyl,piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1- ylmethyl. [0311] The in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug). [0312] Suitably, the present disclosure excludes any individual compounds not possessing the biological activity defined herein. Methods of Synthesis [0313] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure. [0314] In some aspects, the present disclosure provides a method of a compound, comprising one or more steps as described herein. [0315] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound as described herein. [0316] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein. 64 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0317] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples. [0318] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art. [0319] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised. [0320] It will be appreciated that during the synthesis of the compounds of the disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. [0321] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, 65 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. [0322] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon. [0323] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon. [0324] Once a compound of Formula (I) has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound Formula (I) into another compound of Formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or (iv) forming a prodrug thereof. [0325] The resultant compounds of Formula (I) can be isolated and purified using techniques well known in the art. [0326] In some embodiments, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2- dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, 66 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 such as acetone, methylisobutylketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the said solvents or mixtures with water. [0327] The reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used. [0328] Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours. [0329] Moreover, by utilising the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. [0330] As will be understood by the person skilled in the art of organic synthesis, compounds of the present disclosure are readily accessible by various synthetic routes, some of which are exemplified in the accompanying examples. The skilled person will easily recognise which kind of reagents and reactions conditions are to be used and how they are to be applied and adapted in any particular instance – wherever necessary or useful – in order to obtain the compounds of the present disclosure. Furthermore, some of the compounds of the present disclosure can readily be synthesised by reacting other compounds of the present disclosure under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present disclosure, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person. Likewise, the skilled person will apply – whenever necessary or useful – synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well- known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons). [0331] General routes for the preparation of a compound of the application are described in Schemes 1-2 herein. 67 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0332] In some embodiments, a substituted nitroaniline (1) can be reduced to provide aminoaniline (2). Condensation between aniline (2) and ethyl 2-oxoacetate gives quinoxaline (3) which can be converted to the halo compound (4) with phosphrous oxychloride reagent. Substitution of halide (4) with amines may afford substituted quinoxalines (5). Palladium- catalyzed acylation of halide (5) may give acyl quinoxaline (6). Reductive amination of ketone (6) to amine (7) may be effected with a reducing agent such as sodium cyanoborohydride. This amine (7) can then be coupled with an aryl halide under palladium catalyst conditions to give racemic compound (8) of Formula (I). These racemates (8) can then be purified on a chiral column to give arbitrarily assigned pure enantiomers (9) and (10). Reaction Scheme 1
Figure imgf000069_0001
[0333] In some embodiments, ketone (6) can be reduced to alcohol (7) with a reducing agent such as sodium borohydride. This alcohol (7) can be covereted to aryl amine (8) in the presence of copper bromide. Racemic amine (8) can then be purified on a chiral column to give arbitrarily assigned pure enantiomers (9) and (10). Reaction Scheme 2 68 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000070_0001
Biological Assays [0334] Compounds designed, selected and/or optimised by methods described above, once produced, can be characterised using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterised by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity. [0335] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high- throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below. [0336] Various in vitro or in vivo biological assays are may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein. [0337] In some embodiments, the biological assay is described in the Examples herein. [0338] In some embodiments, the biological activity of the compounds may be determined utilizing a p-AKT S473 assay. [0339] In some embodiments, cells (e.g., MCF10A-PI3KĮ-WT, MCF10A- PI3KĮ-H1047R and MCF10A- PI3KĮ-E545K cells) may be grown in DMEM/F12 supplemented with Horse Serum, EGF, Hydrocortisone, Cholera toxin and Insulin. In some embodiments, cells may be 69 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 dissociated with TryPLE, washed with media and plated in wells plate. In some embodiments, serial dilution of compounds were applied to the cell. In some embodiments, p-AKT S473 may be measured using HTRF cellular kit by Cisbio (64AKSPET) according to manufacturer’s protocol. In some embodiments, p-AKT S473 levels may be measured using the kit. In some embodiments, the cells (e.g., MCF10A-PI3KĮ-WT, MCF10A- PI3KĮ-H1047R and MCF10A- PI3KĮ-E545K cells) may be lysed. In some embodiments, antibodies may be mixed with detection buffer and may be added to the lysate and may be incubated overnight. In some embodiments, luminescence may be read on a plate reader (e.g., Ensight plate reader). In some embodiments, luminescence may be read at 665 nm. In some embodiments, luminescence may be read at 620 nm wavelengths. In some embodiments, a decrease in p-AKT S473 levels indicate a downregulation of the PI3KĮ pathway. In some embodiments, a decrease in p-AKT S473 levels indicate a downregulation of cell proliferation. Pharmaceutical Compositions [0340] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 2. [0341] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. [0342] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in- fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts. [0343] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at 70 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/suspending agent, buffer, and pH modifying agent, and a mixture thereof. [0344] Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-ȕ-cyclodextrin, methyl-ȕ-cyclodextrin, randomly methylated-ȕ-cyclodextrin, ethylated-ȕ-cyclodextrin, triacetyl-ȕ-cyclodextrin, peracetylated-ȕ-cyclodextrin, carboxymethyl-ȕ-cyclodextrin, hydroxyethyl-ȕ-cyclodextrin, 2-hydroxy-3- (trimethylammonio)propyl-ȕ-cyclodextrin, glucosyl-ȕ-cyclodextrin, sulfated ȕ-cyclodextrin (S-ȕ-CD), maltosyl-ȕ-cyclodextrin, ȕ-cyclodextrin sulfobutyl ether, branched-ȕ-cyclodextrin, hydroxypropyl-Ȗ-cyclodextrin, randomly methylated-Ȗ-cyclodextrin, and trimethyl-Ȗ- cyclodextrin, and mixtures thereof. [0345] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof. [0346] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof. [0347] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof. [0348] The aqueous vehicle may also contain a viscosity/suspending agent. Suitable viscosity/suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as 71 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof. [0349] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid. These acidic and/or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range. [0350] The aqueous vehicle may also contain a buffering agent to stabilise the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and İ-aminocaproic acid, and mixtures thereof. [0351] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof. [0352] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, 72 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavouring agent such as peppermint, methyl salicylate, orange flavoring. [0353] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier. [0354] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing). [0355] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents. [0356] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a PI3KĮ related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition. [0357] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat a PI3KĮ related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition. [0358] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine. Methods of Use [0359] Phosphatidylinositol 3-Kinases (PI3Ks) are a group of plasma membrane-associated lipid kinases that upon activation catalyze the transfer of phosphate to the D-3’ position of inositol of phosphoinositol-4,5-phosphate (PIP2) to produce phosphoinositol-3,4,5-phosphate 73 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 (PIP3). PIP3 is a second messenger that binds and recruits a subset of Pleckstrin-homology, FYVE, Phox, or other lipid-binding domains of downstream target to the cell membrane. Signaling proteins (e.g. AKT, PDK1) can then bind to the lipid product of PI3K, localize to cell membrane and activate downstream cellular activity that includes transcription, translation, proliferation, survival, chemotaxis, motility, cellular trafficking and metabolism. PI3Ks include a conserved family of 15 kinases that exhibit distinct substrate specificities, expression patterns and modes of regulation. PI3Ks are divided into three classes (I, II and III) based on their structures and substrate specificities. [0360] Class I PI3Ks encompass PI3Ks containing one of the p110Į, p110ȕ, p110į and p110Ȗ catalytic subunits, which are encoded by the PIK3CA, PIK3CB, PIK3CD and PIK3CG genes, respectively. These catalytic subunits are constitutively associated with regulatory subunits: p85Į, p55Į, p50Į, p85ȕ, p55Ȗ, p101 or p84. [0361] Genetic alterations such as mutation, amplification, deletion or translocation in genes in PI3K signaling are believed to be implicated in several diseases or disorders e.g., CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS) as well as human cancers (e.g. B-cell lymphoma, adrenocortical carcinoma, bladder urothelial carcinoma, breast cancer, cervical adenocarcinoma, cervical squamous-cell carcinoma, cholangiocarcinoma, colorectal adenocarcinoma, colorectal cancer, diffuse glioma, esophageal squamous-cell cancer, esophagogastric adenocarcinoma, esophagogastric cancer, fibrolamellar carcinoma, germ-cell carcinoma, glioblastoma, glioma, head and neck squamous-cell carcinoma, hepatocellular carcinoma, leukemia, melanoma, mesothelioma, miscellaneous neuroepithelial tumor, nerve-sheath tumor, non-small-cell lung cancer, ovarian cancer, pancreatic cancer, pheochromocytoma, prostate cancer, renal clear-cell carcinoma, renal nonclear-cell carcinoma, soft-tissue sarcoma, thymic tumor, thyroid cancer and endometrial cancer). [0362] More specifically, mutations in the gene PIK3CA, which encodes the p110Į (also referred to as PI3KĮ) catalytic subunit, have been linked to numerous cancers, including bladder cancer, brain cancer, breast cancer, colon cancer, endometrial cancer, ovarian cancer, skin cancer, stomach cancer, lung cancer and prostate cancer. Mutations in the PIK3CA gene are notably observed within several “mutation hotspots” that are located within the kinase and helicase domains. These mutations include the E542K mutation, the E545K mutation and the H1047R mutation. Moreover, many of these mutations have been shown to be oncogenic gain- of-function mutations. 74 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0363] Given the connection to various disease, including cancer, PI3Ks, and more specifically, PI3KĮ, have been a target for therapeutic intervention. To this end, multiple inhibitors of PI3Ks have been developed, including alpelisib, buparlisib, taselisib, and inavolisib. These inhibitors are active against one or multiple Class I PI3K isoforms. [0364] A major limitation of those agents in the clinic is their inability to reach the required level for target inhibition without on-target related toxicities. Those inhibitors suffer from on target toxicities such as hyperglycemia and rash (associated with PI3KĮ inhibition); diarrhea, myelosuppression and transaminitis (associated with inhibition of PI3Kį and PI3KȖ). More specifically, PI3KĮ is known to play a central role in regulating glucose homeostasis. Consequently, pharmacologic inhibition of PI3KĮ often results in severe hyperglycemia and/or hyperinsulinemia. In addition to the toxicities associated with high blood glucose, high circulating insulin levels can reactivate the PI3K pathway in cancer cells and be potentially mitogenic. This creates a feedback regulation loop that minimizes the effect of PI3K inhibitors. In the clinic, hyperglycemia and/or hyperinsulinemia are often managed with co-administration of a glucose lowering agent such at metformin. [0365] Without wishing to be bound by theory, in the context of cancer driven by mutated PI3KĮ, selective inhibition of the mutated form of PI3KĮ over the wild-type form of PI3KĮ in tumor cells of host tissues that control glucose metabolism could potentially overcome the limitation of the current generation of PI3KĮ inhibitors. Such specificity could allow for an improvement in the therapeutic window for drug dosing by limiting toxicities and allow higher doses for more complete on-target inhibition. Given that high circulating insulin levels can reactivate the PI3K pathway in cancer cells and be potentially mitogenic as mentioned above, selective inhibition of mutated PI3KĮ will avoid the creation of the feedback regulation loop that minimizes the effect of PI3K inhibitors. [0366] In some aspects, the present disclosure provides a method of modulating PI3KĮ activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. [0367] In some aspects, the present disclosure provides a method of modulating PI3KĮ activity (e.g., in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof. [0368] In some aspects, the present disclosure provides a method of modulating PI3KĮ activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. 75 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0369] In some aspects, the present disclosure provides a method of modulating PI3KĮ activity (e.g., in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof. [0370] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. [0371] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0372] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof. [0373] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0374] In some embodiments, the disease or disorder is associated with an implicated PI3KĮ activity. In some embodiments, the disease or disorder is a disease or disorder in which PI3KĮ activity is implicated. [0375] In some embodiments, the disease or disorder is associated with an implicated PI3KĮ activity. In some embodiments, the disease or disorder is a disease or disorder in which PI3KĮ activity is implicated. [0376] In some embodiments, the disease or disorder is congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal (CLOVES) syndrome. [0377] In some embodiments, the disease or disorder is PIK3CA-related overgrowth syndrome. [0378] In some embodiments, the disease or disorder is cancer. [0379] In some embodiments, the cancer is characterized by an amplification (i.e. increase) in the expression of the PIK3CA gene and/or an amplification (i.e. increase) in the expression of the PI3KĮ protein. 76 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0380] In some embodiments, the cancer is characterized by a decrease in the expression of the PIK3CA gene and/or decrease in the expression of the PI3KĮ protein. [0381] In some embodiments, the cancer is characterized by at least one oncogenic mutation in the PIK3CA gene. It is understood that a cancer that is characterized by at least one oncogenic mutation in the PIK3CA gene is a cancer that is typically associated with at least one oncogenic mutation in the PIK3CA gene, including, but not limited to, cancers whose primary oncogenic activity is thought to be driven by the at least one oncogenic mutation in the PIK3CA gene. [0382] In some embodiments, the cancer is characterized by at least one oncogenic variant of the PI3KĮ protein. [0383] It is understood that a cancer that is characterized by least one oncogenic variant of the PI3KĮ protein is a cancer that is typically associated with at least one oncogenic variant of the PI3KĮ protein, including, but not limited to, cancers whose primary oncogenic activity is thought to be driven by the at least one oncogenic variant of the PI3KĮ protein. [0384] It is understood that an oncogenic variant of PI3KĮ protein is a PI3KĮ protein molecule that comprises at least one oncogenic mutation and that is produced as the result of the expression of a PIK3CA gene that comprises at least one oncogenic mutation. [0385] In some embodiments, the subject has at least one oncogenic mutation in the PIK3CA [0386] In some embodiments, the subject has at least one tumor and/or cancerous cell that expresses an oncogenic variant of the PI3KĮ protein. [0387] As would be appreciated by the skilled artisan, in the context of a gene (e.g. PIK3CA), an oncogenic mutation can include, but is not limited to a mutation that results in the substitution of one amino acid for another at a specific position within the protein product of the gene, a mutation that results in the substitution of one or more amino acids for one or more amino acids between two specific positions within the protein product of the gene, a mutation that results in an insertion of one or more amino acids between two positions within the protein product of the gene, a mutation that results in the deletion of one more amino acids between two positions within the protein product of the gene, and mutation that results in a fusion of the protein product of the gene, or portion thereof, with another protein, or portion thereof, or any combination thereof. As would be appreciated by the skilled artisan, in the context of a gene, an oncogenic mutation can include, but is not limited to, a missense mutation, a nonsynonymous mutation, an insertion of one or more nucleotides, a deletion of one or more nucleotides, an inversion and a deletion-insertion. As would be appreciated by the skilled artisan, in the context of a gene (e.g. PIK3CA), the gene can have one or more of the 77 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 aforementioned types of oncogenic mutations, including combinations of different types of oncogenic mutations. [0388] As would be appreciated by the skilled artisan, in the context of a protein (e.g. the PI3KĮ protein), an oncogenic mutation can include, but is not limited to, the substitution of one amino acid for another at a specific position within the protein, the substitution of one or more amino acids for one or more amino acids between two specific positions within the protein, an insertion of one or more amino acids between two positions within the protein, a deletion of one more amino acids between two positions within the protein, and a fusion of the protein, or portion thereof, with another protein, or portion thereof, or any combination thereof. As would be appreciated by the skilled artisan, in the context of a protein (e.g. the PI3KĮ protein), the protein can have one or more of the aforementioned types of oncogenic mutations, including combinations of different types of oncogenic mutations. [0389] In some embodiments, an oncogenic mutation of the PI3KĮ protein can be any one of E542K, E545K and H1047R (numbering corresponding to SEQ ID NO: 1). [0390] A wild-type PI3KĮ protein sequence of the present disclosure may comprise, consist essentially of, or consist of the amino acid sequence of: 1 MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLITIKHELF 51 KEARKYPLHQ LLQDESSYIF VSVTQEAERE EFFDETRRLC DLRLFQPFLK 101 VIEPVGNREE KILNREIGFA IGMPVCEFDM VKDPEVQDFR RNILNVCKEA 151 VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IVVIWVIVSP 201 NNDKQKYTLK INHDCVPEQV IAEAIRKKTR SMLLSSEQLK LCVLEYQGKY 251 ILKVCGCDEY FLEKYPLSQY KYIRSCIMLG RMPNLMLMAK ESLYSQLPMD 301 CFTMPSYSRR ISTATPYMNG ETSTKSLWVI NSALRIKILC ATYVNVNIRD 351 IDKIYVRTGI YHGGEPLCDN VNTQRVPCSN PRWNEWLNYD IYIPDLPRAA 401 RLCLSICSVK GRKGAKEEHC PLAWGNINLF DYTDTLVSGK MALNLWPVPH 451 GLEDLLNPIG VTGSNPNKET PCLELEFDWF SSVVKFPDMS VIEEHANWSV 501 SREAGFSYSH AGLSNRLARD NELRENDKEQ LKAISTRDPL SEITEQEKDF 551 LWSHRHYCVT IPEILPKLLL SVKWNSRDEV AQMYCLVKDW PPIKPEQAME 601 LLDCNYPDPM VRGFAVRCLE KYLTDDKLSQ YLIQLVQVLK YEQYLDNLLV 651 RFLLKKALTN QRIGHFFFWH LKSEMHNKTV SQRFGLLLES YCRACGMYLK 701 HLNRQVEAME KLINLTDILK QEKKDETQKV QMKFLVEQMR RPDFMDALQG 751 FLSPLNPAHQ LGNLRLEECR IMSSAKRPLW LNWENPDIMS ELLFQNNEII 801 FKNGDDLRQD MLTLQIIRIM ENIWQNQGLD LRMLPYGCLS IGDCVGLIEV 851 VRNSHTIMQI QCKGGLKGAL QFNSHTLHQW LKDKNKGEIY DAAIDLFTRS 901 CAGYCVATFI LGIGDRHNSN IMVKDDGQLF HIDFGHFLDH KKKKFGYKRE 951 RVPFVLTQDF LIVISKGAQE CTKTREFERF QEMCYKAYLA IRQHANLFIN 1001 LFSMMLGSGM PELQSFDDIA YIRKTLALDK TEQEALEYFM KQMNDAHHGG 1051 WTTKMDWIFH TIKQHALN (SEQ ID NO: 1). [0391] In some embodiments, the cancer is a carcinoma, a lymphoma, a blastoma, a sarcoma, a leukemia, a brain cancer, a breast cancer, a blood cancer, a bone cancer, a lung cancer, a skin cancer, a liver cancer, an ovarian cancer, a bladder cancer, a renal cancer, a kidney cancer, a 78 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 gastric cancer, a thyroid cancer, a pancreatic cancer, an esophageal cancer, a prostate cancer, a cervical cancer, a uterine cancer, a stomach cancer, a soft tissue cancer, a laryngeal cancer, a small intestine cancer, a testicular cancer, an anal cancer, a vulvar cancer, a joint cancer, an oral cancer, a pharynx cancer or a colorectal cancer. [0392] In some embodiments, the cancer is adrenocortical carcinoma, bladder urothelial carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, cholangiocarcinoma, colon adenocarcinoma, lymphoid neoplasm diffuse large B-cell lymphoma, esophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, kidney chromophobe, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, acute myeloid leukemia, brain lower grade glioma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma, paraganglioma, prostate adenocarcinoma, rectum adenocarcinoma, sarcoma, skin cutaneous melanoma, stomach adenocarcinoma, testicular germ cell tumors, thyroid carcinoma, thymoma, uterine carcinosarcoma, uveal melanoma. Other examples include breast cancer, lung cancer, lymphoma, melanoma, liver cancer, colorectal cancer, ovarian cancer, bladder cancer, renal cancer or gastric cancer. Further examples of cancer include neuroendocrine cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, thyroid cancer, endometrial cancer, biliary cancer, esophageal cancer, anal cancer, salivary, cancer, vulvar cancer, cervical cancer, Acute lymphoblastic leukemia (ALL), Acute myeloid leukemia (AML), Adrenal gland tumors, Anal cancer, Bile duct cancer, Bladder cancer, Bone cancer, Bowel cancer, Brain tumors, Breast cancer, Cancer of unknown primary (CUP), Cancer spread to bone, Cancer spread to brain, Cancer spread to liver, Cancer spread to lung, Carcinoid, Cervical cancer, Children's cancers, Chronic lymphocytic leukemia (CLL), Chrome myeloid leukemia (CML), Colorectal cancer, Ear cancer, Endometrial cancer, Eye cancer, Follicular dendritic cell sarcoma, Gallbladder cancer, Gastric cancer, Gastro esophageal junction cancers, Germ cell tumors, Gestational trophoblastic disease (GIT), Hairy cell leukemia, Head and neck cancer, Hodgkin lymphoma, Kaposi’s sarcoma, Kidney cancer, Laryngeal cancer, Leukemia, Gastric linitis plastica, Liver cancer, Lung cancer, Lymphoma, Malignant schwannoma, Mediastinal germ cell tumors, Melanoma skin cancer, Men's cancer, Merkel cell skin cancer, Mesothelioma, Molar pregnancy, Mouth and oropharyngeal cancer, Myeloma, Nasal and paranasal sinus cancer, Nasopharyngeal cancer, Neuroblastoma, Neuroendocrine tumors, Non-Hodgkin lymphoma (NHL), Esophageal cancer, Ovarian cancer, Pancreatic cancer, Penile cancer, Persistent trophoblastic disease and choriocarcinoma, 79 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 Pheochromocytoma, Prostate cancer, Pseudomyxoma peritonei, Rectal cancer. Retinoblastoma, Salivary gland cancer, Secondary' cancer, Signet cell cancer, Skin cancer, Small bowel cancer, Soft tissue sarcoma, Stomach cancer, T cell childhood non Hodgkin lymphoma (NHL), Testicular cancer, Thymus gland cancer, Thyroid cancer, Tongue cancer, Tonsil cancer, Tumors of the adrenal gland, Uterine cancer. Vaginal cancer, Vulval cancer, Wilms' tumor, Womb cancer and Gynaecological cancer. Examples of cancer also include, but are not limited to, Hematologic malignancies, Lymphoma, Cutaneous T-cell lymphoma, Peripheral T-cell lymphoma, Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, Multiple myeloma, Chrome lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, Myelodysplastic syndromes, Myelofibrosis, Biliary tract cancer, Hepatocellular cancer, Colorectal cancer, Breast cancer, Lung cancer, Non-small cell lung cancer, Ovarian cancer, Thyroid Carcinoma, Renal Cell Carcinoma, Pancreatic cancer, Bladder cancer, skin cancer, malignant melanoma, merkel cell carcinoma, Uveal Melanoma or Glioblastoma multiforme. [0393] In some embodiments, the cancer is B-cell lymphoma, adrenocortical carcinoma, bladder urothelial carcinoma, breast cancer, cervical adenocarcinoma, cervical squamous-cell carcinoma, cholangiocarcinoma, colorectal adenocarcinoma, colorectal cancer, diffuse glioma, esophageal squamous-cell cancer, esophagogastric adenocarcinoma, esophagogastric cancer, fibrolamellar carcinoma, germ-cell carcinoma, glioblastoma, glioma, head and neck squamous- cell carcinoma, hepatocellular carcinoma, leukemia, melanoma, mesothelioma, miscellaneous neuroepithelial tumor, nerve-sheath tumor, non-small-cell lung cancer, ovarian cancer, pancreatic cancer, pheochromocytoma, prostate cancer, renal clear-cell carcinoma, renal nonclear-cell carcinoma, soft-tissue sarcoma, thymic tumor, thyroid cancer or endometrial cancer. [0394] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0395] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0396] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a compound of the 80 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0397] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. [0398] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating PI3KĮ activity (e.g., in vitro or in vivo). [0399] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating PI3KĮ activity (e.g., in vitro or in vivo). [0400] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein. [0401] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein. [0402] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing cancer in a subject in need thereof. [0403] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject in need thereof. [0404] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating PI3KĮ activity (e.g., in vitro or in vivo). [0405] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [0406] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein. 81 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0407] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof. [0408] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a subject in need thereof. [0409] The present disclosure provides compounds that function as modulators of PI3KĮ activity. [0410] In some embodiments, the compounds of the present disclosure are inhibitors of the PI3KĮ protein. In some embodiments, the compounds of the present disclosure specifically inhibit mutated PI3KĮ protein as compared to wild-type PI3KĮ protein. [0411] In some embodiments, the compounds of the present disclosure bind to the PI3KĮ protein in an allosteric pocket that is in proximity to the 1047 mutational hotspot. [0412] Effectiveness of compounds of the disclosure can be determined by industry-accepted assays/ disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge. [0413] The present disclosure also provides a method of treating a disease or disorder in which PI3KĮ activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. Routes of Administration [0414] Compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be administered alone as a sole therapy or can be administered in addition with one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. [0415] For example, therapeutic effectiveness may be enhanced by administration of an adjuvant (i.e. by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, by way of example only, the benefit experienced by an individual may be increased by administering the compound of Formula (I) with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. 82 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0416] In the instances where the compound of the present disclosure is administered in combination with other therapeutic agents, the compound of the disclosure need not be administered via the same route as other therapeutic agents, and may, because of different physical and chemical characteristics, be administered by a different route. For example, the compound of the disclosure may be administered orally to generate and maintain good blood levels thereof, while the other therapeutic agent may be administered intravenously. The initial administration may be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician. [0417] The particular choice of other therapeutic agent will depend upon the diagnosis of the attending physicians and their judgment of the condition of the individual and the appropriate treatment protocol. According to this aspect of the disclosure there is provided a combination for use in the treatment of a disease in which PI3KĮ activity is implicated comprising a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and another suitable agent. [0418] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in combination with a suitable, in association with a pharmaceutically acceptable diluent or carrier. [0419] In addition to its use in therapeutic medicine, compounds of Formula (I) and pharmaceutically acceptable salts thereof are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of modulators of PI3KĮ activity in laboratory animals such as dogs, rabbits, monkeys, mini-pigs, rats and mice, as part of the search for new therapeutic agents. [0420] In any of the above-mentioned pharmaceutical composition, process, method, use, medicament, and manufacturing features of the instant disclosure, any of the alternate embodiments of macromolecules of the present disclosure described herein also apply. [0421] The compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e., at the site of desired action). [0422] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray or powder); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through 83 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. EXAMPLES [0423] For exemplary purpose, both neutral compounds and salts of the compounds of Formula (I) are synthesized and tested in the examples. It is understood that the neutral compounds of Formula (I) may be converted to the corresponding pharmaceutically acceptable salts of the compounds using routine techniques in the art (e.g., by saponification of an ester to the carboxylic acid salt, or by hydrolyzing an amide to form a corresponding carboxylic acid and then converting the carboxylic acid to a carboxylic acid salt). Further, it is understood that the salts (e.g., formate salt) of the compounds of Formula (I) may be converted to the corresponding neutral compounds using routine techniques in the art (e.g., pH adjustment and, optionally, extraction (e.g., into an aqueous phase)). Abbreviations: DMSO Dimethylsulfoxide ES / ESI electrospray ionisation HPLC high-performance liquid chromatography IPA Isopropylalcohol LC liquid chromatography MS mass spectrometry NMR nuclear magnetic resonance SFC supercritical fluid chromatography TBDPS tert-butyldiphenylsilyl TBS tert-butyldimethylsilyl TFA trifluoroacetic acid TLC thin layer chromatography Preparation of Common Intermediate Preparation of Intermediate-A: 8-bromo-2-chloro-6-methylquinoxaline (Int-A)
Figure imgf000085_0001
[0424] Step 1. Synthesis of 3-bromo-5-methylbenzene-1,2-diamine 84 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0425] To a solution of 2-bromo-4-methyl-6-nitro-aniline (20 g, 86.5 mmol), ammonium chloride (92.6 g, 1.73 mol) in tetrahydrofuran (50 mL) and methanol (400 mL) was added zinc powder (56.6 g, 865 mmol). The mixture was stirred at 40 °C for 3 h. On completion, the mixture was quenched with water (200 mL). Then the mixture was filtered and the filtrate was concentrated in vacuo to give 3-bromo-5-methylbenzene-1,2-diamine (17 g, 84.5 mmol, 95%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) į 6.48 (d, J = 1.2 Hz, 1 H) 6.33 (d, J = 1.2 Hz, 1 H) 4.76 (s, 2 H) 4.38 (s, 2 H) 2.06 (s, 3 H); m/z ES+ [M+H]+ 200.8. [0426] Step 2. Synthesis of 8-bromo-6-methylquinoxalin-2-ol [0427] A solution of 3-bromo-5-methyl-benzene-1,2-diamine (9.5 g, 47.3 mmol), ethyl 2- oxoacetate (9.65 g, 47.5 mmol) in ethanol (100 mL) was stirred at 90 °C for 12 h. On completion, the reaction mixture was diluted with water (100 mL) and ethyl acetate (300 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 20/1 to 0/1) to give 8-bromo- 6-methylquinoxalin-2-ol (2.5 g, 10.4 mmol, 22%) as a yellow solid. m/z ES+ [M+H]+ 240.7. [0428] Step 3. Synthesis of 8-bromo-2-chloro-6-methylquinoxaline [0429] A solution of 8-bromo-6-methyl-quinoxalin-2-ol (4.5 g, 18.8 mmol) in phosphorus oxychloride (82.5 g, 538 mmol) was stirred at 120 °C for 12 h. On completion, the reaction mixture was slowly poured into ice-water (200 mL). The resulting precipitate was filtered and the filter cake was collected. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 10/1 to 0/1) to give 8-bromo-2-chloro-6-methylquinoxaline (2.5 g, 9.71 mmol, 51%) as a yellow solid; m/z ES+ [M+H]+ 259.0. Preparation of Intermediate-B: 5-bromo-3-chloro-2,7-dimethylquinoxaline (Int-B)
Figure imgf000086_0001
[0430] Step 1. Synthesis of 3-bromo-5-methylbenzene-1,2-diamine [0431] To a solution of 2-bromo-4-methyl-6-nitro-aniline (5.00 g, 21.6 mmol) in ethanol (50 mL) was added iron powder (4.83 g, 86.6 mmol) and aqueous ammonium chloride solution (7 M, 30.92 mL). The mixture was stirred at 80 °C for 5 hours. On completion, the mixture was filtered and the filtered cake was washed with ethyl acetate (100 mL x 3). Then the filtrate was adjusted to pH ~ 8 with solid potassium carbonate. The organic phase was 85 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 separated and washed with brine (30 mL), which was further dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-bromo-5-methyl-benzene- 1,2-diamine (4.30 g, crude) as a brown solid. 1H NMR (400 MHz, CDCl3) į = 6.81 (s, 1H), 6.47 (s, 1H), 2.19 (s, 3H); m/z ES+ [M+H]+ 200.9. [0432] Step 2. Synthesis of 8-bromo-3,6-dimethylquinoxalin-2-ol [0433] A solution of 3-bromo-5-methyl-benzene-1,2-diamine (10 g, 49.7 mmol), methyl 2- oxopropanoate (5.59 g, 54.7 mmol) in methanol (100 mL) was stirred at 25 °C for 16 hr. On completion, the mixture was filtered and the filtered cake was concentrated in vacuo. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 20/1 to 0/1) to give compound 8-bromo-3,6-dimethylquinoxalin-2-ol (8 g, 31.6 mmol, 64%) as a brown solid.1H NMR (400 MHz, DMSO-d6) į 11.50 (s, 1H), 7.62 (s, 1H), 7.53 (s, 1H), 2.42 (s, 3H), 2.37 (s, 3H); m/z ES + [M+H]+ 253.0. [0434] Step 3. Synthesis of 5-bromo-3-chloro-2,7-dimethylquinoxaline [0435] A solution of 8-bromo-3,6-dimethyl-quinoxalin-2-ol (1 g, 3.95 mmol) in phosphorus oxychloride (33.0 g, 215 mmol) was stirred at 110 °C for 16 hr. On completion, the reaction mixture was slowly poured into ice-water (60 mL), resulting in the formation of much precipitate. The precipitate was then filtered and the filtered cake was collected, which was further purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=20/1 to 0/1) to give compound 5-bromo-3-chloro-2,7-dimethylquinoxaline (1 g, 3.68 mmol, 93%) as a brown solid.1H NMR (400 MHz, DMSO-d6) į 7.99 (s, 1H), 7.77 (s, 1H), 2.73 (s, 3H), 1.89 (s, 3H). Preparation of Intermediate C: (R)-1-(2,7-dimethyl-3-(methylthio)quinoxalin-5- yl)ethan-1-amine (Int-C)
Figure imgf000087_0001
[0436] Step 1. Synthesis of 5-dromo-2,7-dimethyl-3-(methylthio)quinoxaline 86 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0437] To a solution of 5-bromo-3-chloro-2,7-dimethyl-quinoxaline (500 mg, 1.84 mmol) in dimethyl acetamide (5 mL) was added sodium methyl mercaptide (284 mg, 4.05 mmol) portionwise at 0 °C, the mixture was stirred at 0 °C for 1 hour. On completion, the mixture was poured into water (15.0 mL) and then filtered. The filtered cake was concentrated under reduced pressure to give 5-bromo-2,7-dimethyl-3-methylsulfanyl-quinoxaline (350 mg, crude) as a brown solid. m/z ES+ [M+H]+ 282.9. [0438] Step 2. Synthesis of 1-(2,7-dimethyl-3-(methylthio)quinoxalin-5-yl)ethan-1-one [0439] A mixture of 5-bromo-2,7-dimethyl-3-methylsulfanyl-quinoxaline (200 mg, 706 ^mol), 1-vinyloxybutane (212 mg, 2.12 mmol), diisopropylethylamine (274 mg, 2.12 mmol) , palladium acetate (15.8 mg, 70.6 ^mol) and [2-(2-diphenylphosphanylphenoxy)phenyl]- diphenyl-phosphane (38.0 mg, 70.6 ^mol) in n-butanol (3 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 12 hour under nitrogen atmosphere. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was dispersed in ethyl acetate (1 mL) and then aqueous hydrochloric acid (1 M, 1 mL) was added. The mixture was stirred at 25 °C for 0.5 hour. On completion, the mixture was adjusted to pH ~ 8 with solid sodium carbonate, which was then diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The reidue wa purified by prep-TLC (petroleum ether/ethyl acetate=6/1) to give 1-(2,7-dimethyl-3-(methylthio)quinoxalin-5-yl)ethan-1-one (101 mg, 410 ^mol, 62%) as a white solid. NMR (400 MHz, CDCl3) į 7.88 (s, 1H), 7.84 (d, J = 1.6 Hz, 1H), 2.96 (s, 3H), 2.69 (s, 6H), 2.56 (s, 3H). [0440] Step 3. Synthesis of (R)-N-(1-(2,7-dimethyl-3-(methylthio)quinoxalin-5- yl)ethylidene)-2-methylpropane-2-sulfinamide [0441] To a solution of 1-(2,7-dimethyl-3-methylsulfanyl-quinoxalin-5-yl)ethanone (100 mg, 406 ^mol) in anhydrous tetrahydrofuran (3 mL) was added tetraisopropyl titanate (346 mg, 1.22 mmol) and (R)-2-methylpropane-2-sulfinamide (147 mg, 1.22 mmol). The mixture was stirred at 75 °C for 12 hour. On completion, the reaction mixture was quenched by water (10 mL) and then filtered. The filtered cake was washed with ethyl acetate (50 mL), and the combined filtrate was then extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R)-N-(1-(2,7-dimethyl-3- (methylthio)quinoxalin-5-yl)ethylidene)-2-methylpropane-2-sulfinamide (84 mg, crude) as a yellow oil. 87 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0442] m/z ES+ [M+H]+ 350.1. [0443] Step 4. Synthesis of (R)-N-((R)-1-(2,7-dimethyl-3-(methylthio)-1,4- dihydroquinoxalin-5-yl)ethyl)-2-methylpropane-2-sulfinamide [0444] To a solution of (R)-N-(1-(2,7-dimethyl-3-(methylthio)quinoxalin-5-yl)ethylidene)-2- methylpropane-2-sulfinamide (84 mg, 240 ^mol) in anhydrous tetrahydrofuran (3 mL) was added borane-dimethyl sulfide complex (10 M, 120 ^L) dropwise at -50 °C under nitrogen, the mixture was then stirred at 0 °C for 2 hours. On completion, the reaction mixture was quenched by methanol (1 mL) at 0 °C and then concentrated under reduced pressure to give (R)-N-((R)-1-(2,7-dimethyl-3-(methylthio)-1,4-dihydroquinoxalin-5-yl)ethyl)-2- methylpropane-2-sulfinamide (84 mg, crude) as a yellow oil. m/z ES+ [M+H]+ 354.1. [0445] Step 5. Synthesis of (R)-N-((R)-1-(2,7-dimethyl-3-(methylthio)quinoxalin-5- yl)ethyl)-2-methylpropane-2-sulfinamide [0446] To a mixture of (R)-N-((R)-1-(2,7-dimethyl-3-(methylthio)-1,4-dihydroquinoxalin-5- yl)ethyl)-2-methylpropane-2-sulfinamide (84 mg, 237 ^mol) in ethyl acetate (10 mL) was added manganese dioxide (206 mg, 2.38 mmol). The mixture was stirred at 25 °C for 2 hour. On completion, the mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water (ammonia hydroxide v/v)-ACN];B%: 50%-80%,9min) to give (R)- N-((R)-1-(2,7-dimethyl-3-(methylthio)quinoxalin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (60 mg, 131 ^mol, 55%) as a white solid. m/z ES+ [M+H]+ 352.1. [0447] Step 6. Synthesis of (R)-1-(2,7-dimethyl-3-(methylthio)quinoxalin-5-yl)ethan-1- amine [0448] To a solution of (R)-N-((R)-1-(2,7-dimethyl-3-(methylthio)quinoxalin-5-yl)ethyl)-2- methylpropane-2-sulfinamide (60 mg, 170 ^mol) in dichloromethane (2 mL) was added hydrochloric acid/dioxane (0.5 mL), the mixture was stirred at 25 °C for 0.5 hour. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1875*30mm*3um;mobile phase: [water(FA)- ACN];B%: 5%-35%,7min) to give (R)-1-(2,7-dimethyl-3-(methylthio)quinoxalin-5-yl)ethan- 1-amine (35 mg, 141 ^mol, 83%) as a white solid. m/z ES+ [M+H]+ 248.1. Preparation of Intermediate D: N-((1R)-1-(2,7-dimethyl-3-(methylsulfinyl)quinoxalin-5- yl)ethyl)-4-fluoro-2-(methylsulfonyl)aniline (Int-D) 88 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000090_0002
[0449] Step 1. Synthesis of (R)-N-(1-(2,7-dimethyl-3-(methylthio)quinoxalin-5-yl)ethyl)-4- fluoro-2-(methylsulfonyl)aniline [0450] A suspension of (R)-1-(2,7-dimethyl-3-(methylthio)quinoxalin-5-yl)ethan-1-amine (35 mg, 141 ^mol), 1,4-difluoro-2-methylsulfonyl-benzene (108 mg, 565 ^mol) and cesium carbonate (138 mg, 424 ^mol) in dimethyl acetamide (0.5 mL) was stirred at 120 °C for 36 hours. On completion, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether/ethyl acetate=1/1) to give (R)-N-(1-(2,7- dimethyl-3-(methylthio)quinoxalin-5-yl)ethyl)-4-fluoro-2-(methylsulfonyl)aniline (30 mg, 68.3 ^mol, 48%) as a yellow oil. m/z ES+ [M+H]+ 420.1. [0451] Step 2. Synthesis of N-((1R)-1-(2,7-dimethyl-3-(methylsulfinyl)quinoxalin-5- yl)ethyl)-4-fluoro-2-(methylsulfonyl)aniline [0452] To a solution of (R)-N-(1-(2,7-dimethyl-3-(methylthio)quinoxalin-5-yl)ethyl)-4- fluoro-2-(methylsulfonyl)aniline (25 mg, 59.6 ^mol) in anhydrous tetrahydrofuran (5 mL) was added Oxone (47.6 mg, 77.4 ^mol) in water (0.3 mL) at 25 °C, the mixture was stirred at 25 °C for 0.5 hours. On completion, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give
Figure imgf000090_0001
1-(2,7-dimethyl-3-(methylsulfinyl)quinoxalin-5-yl)ethyl)-4-fluoro-2-(methylsulfonyl)aniline (25 mg, crude) as a white solid. m/z ES+ [M+H]+ 436.1. Synthesis of Examples Example 1 and Example 2. Preparation of (R)-2-((1-(7-methyl-3-morpholinoquinoxalin- 5-yl)ethyl)amino)benzoic acid and (S)-2-((1-(7-methyl-3-morpholinoquinoxalin-5- yl)ethyl)amino)benzoic acid 89 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000091_0001
[0453] Step 1. Synthesis of 4-(8-bromo-6-methylquinoxalin-2-yl)morpholine [0454] A solution of 8-bromo-2-chloro-6-methyl-quinoxaline (2.5 g, 9.71 mmol), morpholine (1.69 g, 19.4 mmol) and diisopropylethylamine (3.76 g, 29.1 mmol) in 1-methyl-2-pyrrolidone (10 mL) was stirred at 100 ^ for 12 h. On completion, the reaction mixture was quenched with water (30 mL) and then extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 20/1 to 0/1) to give 4-(8-bromo-6-methylquinoxalin-2- yl)morpholine (2.3 g, 7.46 mmol, 76%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) į 6.48 (d, J = 1.2 Hz, 1 H), 6.33 (d, J = 1.2 Hz, 1 H), 4.76 (s, 2 H), 4.38 (s, 2 H), 2.06 (s, 3 H); m/z ES+ [M+H]+ 310.0. [0455] Step 2. Synthesis of 1-(7-methyl-3-morpholinoquinoxalin-5-yl)ethan-1-one [0456] To a solution of 4-(8-bromo-6-methyl-quinoxalin-2-yl)morpholine (2 g, 6.49 mmol) and palladium(II)bis(triphenylphosphine) dichloride (455 mg, 648 μmol) in toluene (20 mL) was added tributyl(1-ethoxyvinyl)stannane (7.03 g, 19.4 mmol). The mixture was stirred at 110 °C for 16 h. On completion, the reaction mixture was adjusted to pH 4~5 with hydrochloric acid solution (1 M). The mixture was stirred at 25 ^ for 0.5 h and then adjusted to pH 8~9 with 10% sodium bicarbonate solution. Then the reaction mixture was extracted with ethyl acetate (150 mL x 2). The combined organic layers were washed with brine 60 mL (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (0.1% formic acid conditions) to give 1-(7- 90 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 methyl-3-morpholinoquinoxalin-5-yl)ethan-1-one (1 g, 3.69 mmol, 55%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) į 8.79 (s, 1 H), 7.76 (s, 1 H), 7.67 (s, 1 H), 3.67 - 3.81 (m, 8 H), 2.77 (s, 3 H), 2.43 (s, 3 H); m/z ES+ [M+H]+ 271.9. [0457] Step 3. Synthesis of 1-(7-methyl-3-morpholinoquinoxalin-5-yl)ethan-1-amine [0458] To a solution of 1-(7-methyl-3-morpholino-quinoxalin-5-yl)ethanone (0.8 g, 2.95 mmol) and ammonium acetate (4.55 g, 58.9 mmol) in methanol (3 mL) was added sodium cyanoborohydride (185 mg, 2.95 mmol). The mixture was stirred at 60 ^ for 12 h. On completion, the mixture was concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% formic acid conditions) to give 1-(7-methyl-3- morpholinoquinoxalin-5-yl)ethan-1-amine (0.8 g, 2.94 mmol, 99%) as a white solid.1H NMR (400 MHz, DMSO-d6) į 8.82 (s, 1 H), 7.79 (s, 1 H), 7.68 (d, J = 1.6 Hz, 1 H), 3.74 - 3.77 (m, 4 H), 3.73 (s, 4 H), 2.78 (s, 3 H), 2.44 (s, 3 H); m/z ES+ [M+H]+ 273.1. [0459] Step 4. Synthesis of methyl 2-((1-(7-methyl-3-morpholinoquinoxalin-5- yl)ethyl)amino)benzoate [0460] A solution of 1-(7-methyl-3-morpholino-quinoxalin-5-yl)ethanamine (0.7 g, 2.57 mmol), methyl 2-oxocyclohexanecarboxylate (2.01 g, 12.8 mmol), Ir(ppy)2(dtbbpy)PF6 (234 mg, 257 μmol), Co(dmgH)2Cl2 (89.1 mg, 257 μmol), 1,4-diazabicyclo[2.2.2]octane (576 mg, 5.14 mmol) and acetic acid (7.72 mg, 128 μmol) in acetonitrile (6 mL) was degassed by bubbling nitrogen stream, then irradiated with two 34 W blue LED lamps (at approximately 7 cm away) as the light source to keep the reaction temperature at 25 ^ for 14 h. On completion, the reaction mixture was quenched with water (20 mL) at 25 °C and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150 x 25 mm, 10um; mobile phase: [water (FA)-acetonitrile]; B%: 62%-92%, 10 min) to give methyl 2-((1-(7-methyl-3- morpholinoquinoxalin-5-yl)ethyl)amino)benzoate (0.2 g, 492 μmol, 19%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) į 8.81 (s, 1H), 8.35 (d, J = 7.2 Hz, 1H), 7.78 (dd, J = 1.2, 8.0 Hz, 1H), 7.53 (s, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.27 - 7.16 (m, 1H), 6.61 - 6.41 (m, 2H), 5.55 - 5.46 (m, 1H), 3.88 - 3.73 (m, 11H), 2.37 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H]+ 407.2. [0461] Step 5. Synthesis of 2-((1-(7-methyl-3-morpholinoquinoxalin-5- yl)ethyl)amino)benzoic acid [0462] To a solution of methyl 2-[1-(7-methyl-3-morpholino-quinoxalin-5- yl)ethylamino]benzoate (0.2 g, 492 μmol) in tetrahydrofuran (4 mL), methanol (2 mL) and water (2 mL) was added lithium hydroxide monohydrate (103 mg, 2.46 mmol). The mixture 91 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 was stirred at 40 ^ for 16 h. On completion, the mixture was adjusted to pH 5~6 with 2 N hydrochloric acid solution. The resulting precipitate was filtered, collected and dried in vacuo to give 2-((1-(7-methyl-3-morpholinoquinoxalin-5-yl)ethyl)amino)benzoic acid (0.18 g, 458 μmol, 90%) as a yellow solid. m/z ES+ [M+H]+ 393.2. [0463] Step 6. Chiral purification [0464] Racemate 2-[1-(7-methyl-3-morpholino-quinoxalin-5-yl)ethylamino]benzoic acid (0.18 g, 459 μmol) was separated by SFC (column: DAICEL CHIRALPAK AD (250 x 30 mm,10 μm); mobile phase: [0.1% ammonium hydroxide ethanol]; B%: 30%-30%, 4 min) to give (R)-2-((1-(7-methyl-3-morpholinoquinoxalin-5-yl)ethyl)amino)benzoic acid (50 mg, 127 μmol, 27%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) į 8.81 (s, 1 H), 8.70 - 8.54 (m, 1 H), 7.77 (d, J = 7.6 Hz, 1 H), 7.52 (s, 1 H), 7.40 (s, 1 H), 7.12 (t, J = 7.2 Hz, 1 H), 6.51 - 6.32 (m, 2 H), 5.50 (d, J = 5.6 Hz, 1 H), 3.77 (s, 8 H), 2.37 (s, 3 H), 1.59 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H]+ 393.2 and (S)-2-((1-(7-methyl-3-morpholinoquinoxalin-5- yl)ethyl)amino)benzoic acid (0.03 g, 76.4 μmol, 16%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) į 8.82 (s, 1 H), 8.70 - 8.50 (m, 1 H), 7.87 - 7.73 (m, 1 H), 7.53 (s, 1 H), 7.41 (d, J = 1.6 Hz, 1 H), 7.17 - 7.08 (m, 1 H), 6.51 - 6.39 (m, 2 H), 5.59 - 5.42 (m, 1 H), 3.81 - 3.74 (m, 8 H), 2.38 (s, 3 H), 1.60 (d, J = 6.7 Hz, 3 H); m/z ES+ [M+H]+ 393.2. Example 3. Preparation of 2-((1-(3-(4-(2-fluorophenyl)piperazin-1-yl)-7- methylquinoxalin-5-yl)ethyl)amino)benzoic acid
Figure imgf000093_0001
[0465] Step 1. Synthesis of 8-bromo-2-(4-(2-fluorophenyl)piperazin-1-yl)-6- methylquinoxaline [0466] A solution of 8-bromo-2-chloro-6-methyl-quinoxaline (0.9 g, 3.49 mmol), 1-(2- fluorophenyl)piperazine (629 mg, 3.49 mmol) and diisopropylethylamine (1.36 g, 10.5 mmol) in 1-methyl-2-pyrrolidone (10 mL) was stirred at 100 ^ for 16 h. On completion, the reaction 92 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 mixture was quenched with water (30 mL) and then extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=10/1 to 0/1) to give 8-bromo-2- (4-(2-fluorophenyl)piperazin-1-yl)-6-methylquinoxaline (1.1 g, 2.74 mmol, 78%) as a yellow solid. m/z ES+ [M+H]+ 403.0. [0467] Step 2. Synthesis of 2-(4-(2-fluorophenyl)piperazin-1-yl)-6-methyl-8- vinylquinoxaline [0468] A solution of 8-bromo-2-[4-(2-fluorophenyl)piperazin-1-yl]-6-methyl-quinoxaline (0.5 g, 1.25 mmol), potassium trifluoro(vinyl)borate (500 mg, 3.74 mmol), cesium carbonate (1 M, 2.5 mL) and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (101 mg, 124 μmol) in 1,4-dioxane (20 mL) was stirred at 85 ^ under nitrogen for 16 h. On completion, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (0.1% formic acid conditions) to give 2-(4-(2- fluorophenyl)piperazin-1-yl)-6-methyl-8-vinylquinoxaline (0.4 g, 1.15 mmol, 90%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) į 8.85 (s, 1 H), 7.75 (d, J = 1.6 Hz, 1 H), 7.68 (dd, J = 17.6, 11.2 Hz, 1 H), 7.59 (s, 1 H), 7.20 - 7.06 (m, 3 H), 7.04 - 6.98 (m, 1 H), 6.05 (dd, J = 17.6, 1.2 Hz, 1 H), 5.52 - 5.31 (m, 1 H), 3.94 - 3.89 (m, 4 H), 3.19- 3.14 (m, 4 H), 2.46 (s, 3 H), 1.05 (t, J = 7.2 Hz, 1 H); m/z ES+ [M+H]+ 349.2. [0469] Step 3. Synthesis of methyl 2-((1-(3-(4-(2-fluorophenyl)piperazin-1-yl)-7- methylquinoxalin-5-yl)ethyl)amino)benzoate [0470] A solution of 2-[4-(2-fluorophenyl)piperazin-1-yl]-6-methyl-8-vinyl-quinoxaline (0.15 g, 430 μmol), methyl 2-aminobenzoate (97.6 mg, 645 μmol), p-toluenesulfonic acid (6.46 mg, 43.0 μmol) and tetrakis(triphenylphosphine)palladium(0) (99.5 mg, 86.1 μmol) in toluene (4 mL) was stirred at 100 ^ for 16 h. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150 x 25, 10 um; mobile phase: [water (FA) - acetonitrile]; B%: 80%-100%, 10 min) to give methyl 2-[1-[3-[4- (2-fluorophenyl)piperazin-1-yl]-7-methyl-quinoxalin-5-yl]ethylamino]benzoate (30.0 mg, 60.0 μmol, 13%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) į 8.88 (s, 1 H), 8.35 (d, J = 7.2 Hz, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.54 (s, 1 H), 7.43 (s, 1 H), 7.23 - 7.08 (m, 4 H), 7.05 – 6.96 (m, 1 H), 6.60 - 6.40 (m, 2 H), 5.70 - 5.28 (m, 1 H), 3.96 (d, J = 5.2 Hz, 4 H), 3.82 (s, 3 H), 3.19 (s, 4 H), 2.38 (s, 3 H), 1.63 (d, J = 6.8 Hz, 3 H); m/z ES+ [M+H]+ 500.4. 93 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0471] Step 4. Synthesis of 2-((1-(3-(4-(2-fluorophenyl)piperazin-1-yl)-7-methylquinoxalin- 5-yl)ethyl)amino)benzoic acid [0472] A solution of methyl 2-((1-(3-(4-(2-fluorophenyl)piperazin-1-yl)-7-methylquinoxalin- 5-yl)ethyl)amino)benzoate (0.03 g, 60.0 μmol) and lithium hydroxide monohydrate (7.19 mg, 300 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was stirred at 50 ^ for 12 h. On completion, the mixture was acidified with aqueous hydrochloric acid (1 M) to adjust pH = 3~4 and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150 x 25 mm, 10 μm; mobile phase: [water(FA)-acetonitrile]; B%: 65%-95%, 10 min) to give 2-((1-(3-(4-(2-fluorophenyl)piperazin-1-yl)-7-methylquinoxalin-5- yl)ethyl)amino)benzoic acid (18.0 mg, 37.0 μmol, 61%) as a yellow
Figure imgf000095_0001
MHz, DMSO-d6) į 8.88 (s, 1 H), 8.73 - 8.55 (m, 1 H), 7.79 (d, J = 7.2 Hz, 1 H), 7.52 (s, 1 H), 7.41 (d, J = 1.6 Hz, 1 H), 7.22 - 7.07 (m, 4 H), 7.05 - 6.98 (m, 1 H), 6.53 - 6.35 (m, 2 H), 5.53 (d, J = 5.6 Hz, 1 H), 3.96 (d, J = 2.4 Hz, 4 H), 3.19 (t, J = 4.8 Hz, 4 H), 2.37 (s, 3 H), 1.60 (d, J = 6.8 Hz, 3 H); m/z ES+ [M+H]+ 486.0. Example 4. Synthesis of methyl 2-((1-(7-methyl-3-morpholinoquinoxalin-5- yl)ethyl)amino)benzoate
Figure imgf000095_0002
[0473] Step 1. Synthesis of 4-(8-bromo-6-methylquinoxalin-2-yl)morpholine [0474] A solution of 8-bromo-2-chloro-6-methyl-quinoxaline (2.50 g, 9.71 mmol), morpholine (1.69 g, 19.4 mmol) and diisopropylethylamine (3.76 g, 29.1 mmol) in 1-methyl- 2-pyrrolidone (10 mL) was stirred at 100 ^ for 12 h. On completion, the reaction mixture was quenched with water (30 mL) and then extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 20/1 to 0/1) to give 4-(8-bromo-6- 94 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 methylquinoxalin-2-yl)morpholine (2.30 g, 7.46 mmol, 76%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) į 6.48 (d, J = 1.2 Hz, 1H), 6.33 (d, J = 1.2 Hz, 1H), 4.76 (s, 2H), 4.38 (s, 2H), 2.06 (s, 3H); m/z ES+ [M+H]+ 310.0. [0475] Step 2. Synthesis of 1-(7-methyl-3-morpholinoquinoxalin-5-yl)ethan-1-one [0476] To a solution of 4-(8-bromo-6-methyl-quinoxalin-2-yl)morpholine (2 g, 6.49 mmol), palladium(II)bis(triphenylphosphine) dichloride (455 mg, 648 ^mol) in toluene (20 mL) was added tributyl(1-ethoxyvinyl)stannane (7.03 g, 19.4 mmol). The mixture was stirred at 110 °C for 16 h under nitrogen. The reaction mixture was adjusted to pH = 4~5 with aqueous hydrochloric acid (1 N). The mixture was stirred at 25 ^ for 0.5 h. Then the mixture was adjusted to pH = 8~9 with saturated sodium bicarbonate. Then the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (150 mL x 2). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (0.1% formic acid conditions) to give 1-(7-methyl-3-morpholinoquinoxalin-5-yl)ethan-1-one (1.00 g, 3.69 mmol, 55%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) į 8.79 (s, 1H) 7.76 (s, 1H) 7.67 (s, 1H), 3.67 - 3.81 (m, 8H), 2.77 (s, 3H), 2.43 (s, 3H); m/z ES+ [M+H]+ 271.9. [0477] Step 3. Synthesis of 1-(7-methyl-3-morpholinoquinoxalin-5-yl)ethan-1-amine [0478] A solution of 1-(7-methyl-3-morpholino-quinoxalin-5-yl)ethanone (0.8 g, 2.95 mmol), ammonium acetate (4.55 g, 58.9 mmol) and sodium cyanoborohydride (185 mg, 2.95 mmol) in methanol (3 mL) was stirred at 60 ^ for 12 h. On completion, the mixture was concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% formic acid conditions) to give 1-(7-methyl-3-morpholinoquinoxalin-5-yl)ethan-1-amine (0.800 g, 2.94 mmol, 99%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) į 8.82 (s, 1H) 7.79 (s, 1H), 7.68 (d, J = 1.6 Hz, 1H), 3.74 - 3.77 (m, 4H), 3.73 (s, 4H), 2.78 (s, 3H), 2.44 (s, 3H); m/z ES+ [M+H]+ 273.1 [0479] Step 4. Synthesis of methyl 2-((1-(7-methyl-3-morpholinoquinoxalin-5- yl)ethyl)amino)benzoate [0480] A solution of 1-(7-methyl-3-morpholino-quinoxalin-5-yl)ethanamine (700 mg, 2.57 mmol), methyl 2-oxocyclohexanecarboxylate (2.01 g, 12.8 mmol), Ir(ppy)2(dtbbpy)PF6 (234 mg, 257 ^mol), Co(dmgH)2pyCl (89.1 mg, 257 ^mol), 1,4-diazabicyclo [2.2.2]octane (576 mg, 5.14 mmol), acetic acid (7.72 mg, 128 ^mol) in acetonitrile (6 mL) was degassed by bubbling nitrogen stream, then irradiated with two 34 W blue LED lamps (at approximately 7 cm away) as the light source to keep the reaction temperature at 25 ^ for 14 h. On completion, the reaction mixture was quenched with water (20 mL) at 25 °C and extracted with ethyl acetate 95 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 (150 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150 x 25 mm, 10 um; mobile phase: [water (FA)-acetonitrile]; B%: 62%-92%, 10 min) to give methyl 2-((1-(7-methyl-3- morpholinoquinoxalin-5-yl)ethyl)amino)benzoate (200 mg, 492 ^mol, 19%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) į 8.81 (s, 1H), 8.35 (d, J = 7.2 Hz, 1H), 7.78 (dd, J = 1.2, 8.0 Hz, 1H), 7.53 (s, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.27 - 7.16 (m, 1H), 6.61 - 6.41 (m, 2H), 5.55 - 5.46 (m, 1H), 3.88 - 3.73 (m, 11H), 2.37 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H]+ 407.2. Example 5. Preparation of 2-((1-(7-chloro-3-(pyridin-4-yl)quinoxalin-5- yl)ethyl)amino)benzoic acid
Figure imgf000097_0001
[0481] Step 1. Synthesis of 3-bromo-5-chlorobenzene-1,2-diamine [0482] A suspension of 2-bromo-4-chloro-6-nitroaniline (5 g, 19.8 mmol), iron powder (5.55 g, 99.4 mmol) and ammonium chloride (5.32 g, 99.4 mmol) in ethanol (50 mL) and water (10 mL) was stirred at 60 °C for 16 h. On completion, the mixture was filtered and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3-bromo-5-chlorobenzene-1,2-diamine (3.9 g, 17.6 mmol, 88%) as yellow solid.1H NMR (400 MHz, CDCl3) į 6.97 (d, J = 2.4 Hz, 1H), 8.65 (d, J = 2.4 Hz, 1H), 3.65 (s, 4H). [0483] Step 2. Synthesis of 8-bromo-6-chloroquinoxalin-2-ol 96 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0484] A solution of 3-bromo-5-chlorobenzene-1,2-diamine (3.9 g, 17.6 mmol) and ethyl 2- oxoacetate (3.60 g, 17.6 mmol, 50% aq.) in ethanol (40 mL) was stirred at 60 °C for 3 h. The mixture was concentrated under reduced pressure. N,N-dimethylformamide (100 mL) was then added and the mixture was heated to 100 °C to fully dissolve the residue. Then the mixture was cooled to 25 °C and filtered. The filter cake was collected to give 8-bromo-6-chloroquinoxalin- 2-ol (1 g, 3.85 mmol, 21%) as a yellow solid. 1H NMR (400 MHz, CDCl3) į 12.06 - 11.63 (m, 1H), 8.68 (s, 1H), 8.04 (s, 1H), 7.94 (s, 1H). [0485] Step 3. Synthesis of 8-bromo-2,6-dichloroquinoxaline [0486] A solution of 8-bromo-6-chloroquinoxalin-2-ol (0.9 g, 3.47 mmol) in phosphorus oxychloride (5.5 mL) was stirred at 100 °C for 0.5 h. On completion, the mixture was concentrated under reduced pressure. The residue was diluted with saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 10/1 to 5/1) to give 8-bromo-2,6-dichloroquinoxaline (960 mg, 3.45 mmol, 99%) as a yellow solid. m/z ES+ [M+H]+ 278.8. [0487] Step 4. Synthesis of 8-bromo-6-chloro-2-(pyridin-4-yl)quinoxaline [0488] To a solution 8-bromo-2,6-dichloroquinoxaline (450 mg, 1.62 mmol) and pyridin-4- ylboronic acid (199 mg, 1.62 mmol) in 1,4-dioxane (10 mL) water (1 mL) was added (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride (118 mg, 161 μmol) and potassium carbonate (335 mg, 2.43 mmol). The mixture was stirred at 80 °C for 2 h under nitrogen. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate= 3/1 to 1/1) to give 8-bromo-6-chloro-2-(pyridin-4-yl)quinoxaline (300 mg, 935 μmol, 57%) as a yellow solid. m/z ES+ [M+H]+ 322.2. [0489] Step 5. Synthesis of 1-(7-chloro-3-(pyridin-4-yl)quinoxalin-5-yl)ethan-1-one [0490] A solution of 8-bromo-6-chloro-2-(pyridin-4-yl)quinoxaline (300 mg, 935 μmol), tributyl(1-ethoxyvinyl)stannane (0.732 g, 2.03 mmol) and palladium(II)bis(triphenylphosphine) dichloride (65.6 mg, 93.5 μmol) in toluene (5 mL) was stirred at 110 °C for 16 h under nitrogen. On completion, the mixture was quenched with aqueous hydrochloric acid (1 N, 2.8 mL) and stirred at 25 °C for 1 h. Saturated potassium fluoride solution (10 mL) was added. The mixture was stirred at 25 °C for 1 h and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. 97 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 3/1 to 1/1) to give 1-(7-chloro-3-(pyridin-4-yl)quinoxalin-5-yl)ethan-1-one (250 mg, 881 μmol, 94%) as a yellow solid. m/z ES+ [M+H]+ 284.1. [0491] Step 6. Synthesis of 1-(7-chloro-3-(pyridin-4-yl)quinoxalin-5-yl)ethan-1-amine [0492] To a solution of 1-(7-chloro-3-(pyridin-4-yl)quinoxalin-5-yl)ethan-1-one (250 mg, 881 μmol) in methanol (5 mL) was added ammonium acetate (679 mg, 8.81 mmol) and sodium cyanoborohydride (83.0 mg, 1.32 mmol). The mixture was stirred at 60 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% ammonium hydroxide conditions) to give 1-(7-chloro-3-(pyridin-4-yl)quinoxalin-5-yl)ethan- 1-amine (50 mg, 175 μmol, 20%) as a yellow solid. m/z ES+ [M+H]+ 285.1. [0493] Step 7. Synthesis of tert-butyl 2-((1-(7-chloro-3-(pyridin-4-yl)quinoxalin-5- yl)ethyl)amino)benzoate [0494] To a solution of 1-(7-chloro-3-(pyridin-4-yl)quinoxalin-5-yl)ethan-1-amine (50 mg, 175 μmol), tert-butyl 2-bromobenzoate (90.3 mg, 351 μmol) in toluene (1 mL) was added tris- (dibenzylideneacetone)dipalladium(0) (16.0 mg, 17.5 μmol), dicyclohexyl-[2-[2,6-di(propan- 2-yloxy)phenyl]phenyl]phosphane (8.19 mg, 17.5 μmol) and cesium carbonate (171 mg, 526 μmol). The mixture was stirred at 110 °C for 3 h under nitrogen. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=3/1) to give tert-butyl 2-((1-(7-chloro-3-(pyridin-4- yl)quinoxalin-5-yl)ethyl)amino)benzoate (50 mg, 108 μmol, 61%) as a yellow solid. m/z ES+ [M+H]+ 461.1. [0495] Step 8. Synthesis of 2-((1-(7-Chloro-3-(pyridin-4-yl)quinoxalin-5- yl)ethyl)amino)benzoic acid [0496] A solution of tert-butyl 2-((1-(7-chloro-3-(pyridin-4-yl)quinoxalin-5- yl)ethyl)amino)benzoate (50 mg, 108 μmol) in trifluoroacetic acid (1 mL) was stirred at 25 °C for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex C18 75 x 30 mm, 3 um; mobile phase: [water(FA)- acetonitrile]; B%: 35%-65%, 7 min) to give 2-((1-(7-chloro-3-(pyridin-4-yl)quinoxalin-5- yl)ethyl)amino)benzoic acid (20.31 mg, 46.1 μmol, 43%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) į 9.84 (s, 1H), 8.97 (d, J = 6.4 Hz, 2H), 8.61 (d, J = 6.4 Hz, 2H), 8.18 (d, J = 2.4 Hz, 1H), 7.88 - 7.76 (m, 2H), 7.67 - 7.56 (m, 1H), 7.25 - 7.03 (m, 1H), 6.62 - 6.45 (m, 2H), 5.88 (d, J = 6.8 Hz, 1H), 1.75 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H]+ 405.1. 98 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 Example 6. Preparation of 2-(1-[7-chloro-3-(morpholin-4-yl)quinoxalin-5- yl]ethylamino)-benzoic acid
Figure imgf000100_0001
[0497] Step 1. Synthesis of 8-bromo-6-chloroquinoxalin-2-ol [0498] A mixture of 3-bromo-5-chlorobenzene-1,2-diamine (1.0 g, 4.52 mmol) and ethyl 2- oxoacetate (461 mg, 4.52 mmol) in ethanol (20 mL) was heated to 40 °C overnight. After cooling to room temperature, the reaction was evaporated to give 8-bromo-6-chloroquinoxalin- 2-ol (1.1 g, 4.03 mmol, 89.2%) as a mixture of both isomers. LC/MS [M+H]+ 258.8. [0499] Step 2. Synthesis of 8-bromo-2,6-dichloroquinoxaline [0500] A mixture of pyridazin-3-ol (1.9 g, 19.8 mmol) in phosphorus oxychloride (19 mL) was heated to 60 °C for 90 minutes. After cooling to room temperature, the reaction was quenched in ice/water and neutralized with solid sodium bicarbonate. The product was extracted with ethyl acetate, the organic phase was washed with brine, dried (sodium sulfate) and evaporated to give 2.1 g of 8-bromo-2,6-dichloroquinoxaline. LC/MS [M+H]+ 278.8. [0501] Step 3. Synthesis of 8-bromo-6-chloro-2-(morpholin-4-yl)quinoxaline [0502] A mixture of 8-bromo-2,6-dichloroquinoxaline (15.0 g, 54.0 mmol), morpholine (5.64 g, 64.8 mmol), ethylbis(propan-2-yl)amine (14.0 g, 108 mmol) in acetonitrile was heated to 100 °C overnight. After cooling to room temperature, the mixture was filtered. The precipitate solid was washed with ethyl acetate and filtrate was evaporated to give 8-bromo-6-chloro-2- (morpholin-4-yl)quinoxaline (1.8 g, 5.2 mmol, 9.6%). LC/MS [M+H]+ 328. [0503] Step 4. Synthesis of 6-chloro-8-(1-ethoxyethenyl)-2-(morpholin-4-yl)quinoxaline [0504] To a degassed solution of 8-bromo-6-chloro-2-(morpholin-4-yl)quinoxaline (1.1 g, 3.35 mmol) and tributyl(1-ethoxyethenyl)stannane (1.33 g, 3.68 mmol) in toluene was added dichloropalladium bis(triphenylphosphane) (235 mg, 335 μmol). The reaction mixture was heated at 65 °C overnight. The mixture was extracted with ethyl acetate / brine. The organic phase was washed with saturated potassium fluoride, dried over sodium sulfate and 99 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 concentrated in vacuo to give 6-chloro-8-(1-ethoxyethenyl)-2-(morpholin-4-yl)quinoxaline (900 mg, 1.69 mmol, 50%) [0505] Step 5. Synthesis of 1-[7-chloro-3-(morpholin-4-yl)quinoxalin-5-yl]ethan-1-one [0506] A solution of 6-chloro-8-(1-ethoxyethenyl)-2-(morpholin-4-yl)quinoxaline (900 mg, 2.81 mmol) in tetrahydrofuran/1 N HCl is stirred for 1 h at 25 °C. The mixture is diluted with ethyl acetate, washed three times with brine, dried over sodium sulfate and concentrated by rotary evaporation. Purification by flash chromatography affords 1-[7-chloro-3-(morpholin-4- yl)quinoxalin-5-yl]ethan-1-one (200 mg, 651 μmol, 23%). LC/MS [M+H]+ 292.0. [0507] Step 6. Synthesis of 1-[7-chloro-3-(morpholin-4-yl)quinoxalin-5-yl]ethan-1-ol [0508] To a solution of 1-[7-chloro-3-(morpholin-4-yl)quinoxalin-5-yl]ethan-1-one (200 mg, 686 μmol) in methanol and dichloromethane (3/1) was added sodium borohydride (28.5 mg, 753 μmol). The mixture was stirred at 10 °C for 2 h. Then, dichloromethane and water were added. The layers were separated. The aqueous layer was extracted with dichloromethane (2x) and the combined organic layers were dried over sodium sulfate, filtered and evaporated in vacuo. The crude product was purified by silica gel chromatography to give 1-[7-chloro-3- (morpholin-4-yl)quinoxalin-5-yl]ethan-1-ol (60.0 mg, 194 μmol, 28%). LC/MS [M+H]+ 294.2. [0509] Step 7. Synthesis of 1-(1-[7-chloro-3-(morpholin-4-yl)quinoxalin-5-yl]ethyl)-2,4- dihydro-1H-3,1-benzoxazine-2,4-dione [0510] To a solution of 1-[7-chloro-3-(morpholin-4-yl)quinoxalin-5-yl]ethan-1-ol (60.5 mg, 206 μmol), 2,4-dihydro-1H-3,1-benzoxazine-2,4-dione (67.2 mg, 412 μmol), and triphenylphosphine (70.2 mg, 268 μmol) in tetrahydrofuran at 0 °C was added (E)-N-[(propan- 2-yloxy)carbonyl]imino(propan-2-yloxy)formamide (54.2 mg, 268 μmol). The resulting mixture was stirred at +4 °C overnight and then subsequently used in the next step without additional purification. LC/MS [M+H]+ 439.2. [0511] Step 8. Synthesis of 2-(1-[7-chloro-3-(morpholin-4-yl)quinoxalin-5-yl]ethylamino)- benzoic acid [0512] To a solution of crude 1-(1-[7-chloro-3-(morpholin-4-yl)quinoxalin-5-yl]ethyl)-2,4- dihydro-1H-3,1-benzoxazine-2,4-dione in methanol (4 mL) was added sodium hydroxide (82.0 mg, 2.05 mmol). The reaction mixture was refluxed for 1 h. The resulting mixture was concentrated and purified by HPLC to provide 2-(1-[7-chloro-3-(morpholin-4-yl)quinoxalin- 5-yl]ethylamino)benzoic acid (50.0 mg, 115 μmol, 56%).
Figure imgf000101_0001
NMR (400 MHz, DMSO-d6) į 8.90 (s, 1H), 7.78 (dd, J = 8.6, 2.0 Hz, 2H), 7.50 (d, J = 2.4 Hz, 1H), 7.16 (t, J = 8.2 Hz, 1H), 6.50 (t, J = 7.5 Hz, 1H), 6.39 (d, J = 8.5 Hz, 1H), 5.49 (d, J = 6.8 Hz, 1H), 1.61 (d, J = 6.6 Hz, 3H); LC/MS [M+H]+ 413.0. 100 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 Example 7. Preparation of 2-(1-[7-methyl-3-(piperidin-1-yl)quinoxalin-5-yl]ethyl amino)- benzoic acid
Figure imgf000102_0001
[0513] Step 1. Synthesis of 8-bromo-6-methyl-2-(piperidin-1-yl)quinoxaline [0514] An inseparable mixture of 8-bromo-2-chloro-6-methylquinoxaline (4.0 g, 15.5 mmol) and 5-bromo-2-chloro-7-methylquinoxaline were dissolved in acetonitrile. Piperidine (13.2 g, 155 mmol) was added and reaction mixture was heated to 70 °C overnight. After cooling to room temperature, the mixture was filtered to give a mixture of isomers. A mixture was purified by column flash chromatography (Hexane/MTBE 95/5) to give 8-bromo-6-methyl-2- (piperidin-1-yl)quinoxaline (1.0 g, 3.1 mmol, 20%). LC/MS [M+H]+ 306.2. [0515] Step 2. Synthesis of 1-[7-methyl-3-(piperidin-1-yl)quinoxalin-5-yl]ethan-1-one [0516] The flask was charged sequentially with 8-bromo-6-methyl-2-(piperidin-1- yl)quinoxaline (801 mg, 2.62 mmol), tetrakis(triphenylphosphine)palladium(0) (152 mg, 131 μmol) and cesium fluoride (1.59 g, 10.5 mmol) and flushed with Ar for 5 minutes. Then 1- (trimethylsilyl)ethan-1-one (608 mg, 5.23 mmol, 750 μL) and 1,2-dichloroethane were added. The reaction mixture was flushed with Ar for another 5 minutes and left stirring overnight at 75 °C. The reaction mixture was filtered, the filtrate was concentrated under vacuum to give a crude residue that was purified by flash chromatography to afford 1-[7-methyl-3-(piperidin-1- yl)quinoxalin-5-yl]ethan-1-one (400 mg, 1.41 mmol, 54%). LC/MS [M+H]+ 270.2. [0517] Step 3. Synthesis of 1-[7-methyl-3-(piperidin-1-yl)quinoxalin-5-yl]ethan-1-ol [0518] To a solution of 1-[7-methyl-3-(piperidin-1-yl)quinoxalin-5-yl]ethan-1-one (600 mg, 2.23 mmol) in toluene/iso-propanol (1/1) mixture was added tris(propan-2-yloxy)alumina (546 mg, 2.67 mmol). The reaction mixture was heated to 50 °C overnight. After cooling to room temperature, the mixture was quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with 101 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 brine, dried sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography to give 1-[7-methyl-3-(piperidin-1-yl)quinoxalin-5- yl]ethan-1-ol (500 mg, 1.75 mmol, 79%). LC/MS [M+H]+ 272.2. [0519] Step 4. Synthesis of 2-(1-[7-methyl-3-(piperidin-1-yl)quinoxalin-5-yl]ethyl amino)- benzoic acid [0520] A mixture of 1-[7-methyl-3-(piperidin-1-yl)quinoxalin-5-yl]ethan-1-ol (500 mg, 1.84 mmol) , 2-aminobenzoic acid (252 mg, 1.84 mmol), copper(II) bromide (20.6 mg, 92.1 μmol) and diphenylphosphinobenzene-3-sulfonic acid sodium salt (67.1 mg, 184 μmol) in water was heated at 100 °C for 16 h in a sealed tube. After cooling to room temperature, the mixture was quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried sodium sulfate, and filtered. The filtrate was concentrated in vacuo. Residue was purified by HPLC 2-10 min 40- 60% water/acetonitrile flow rate 30 mL/min, on column SunFire 19 x 100 mm.1H NMR (500 MHz, DMSO-d6) į 12.58 (s, 1H), 8.79 (s, 1H), 8.43 (s, 1H), 7.75 (dd, J = 7.9, 1.7 Hz, 1H), 7.46 (s, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.21 – 7.07 (m, 1H), 6.54 – 6.34 (m, 2H), 5.50 (s, 1H), 4.31 (d, J = 4.2 Hz, 1H), 3.99 – 3.61 (m, 4H), 2.34 (s, 3H), 1.73 – 1.43 (m, 8H), 1.02 (d, J = 6.1 Hz, 3H). Example 8 and Example 9. Preparation of 2-[(1R)-1-[7-methyl-3-(piperidin-1- yl)quinoxalin-5-yl]ethyl]aminobenzoic acid and 2-[(1R)-1-[7-methyl-3-(piperidin-1- yl)quinoxalin-5-yl]ethyl]aminobenzoic acid
Figure imgf000103_0001
[0521] The racemic mixture 2-(1-[7-methyl-3-(piperidin-1-yl)quinoxalin-5- yl]ethylamino)benzoic acid (50.0 mg, 128 μmol) have been further separated into individual enantiomers by chiral HPLC (Chiralpak IA (250 x 4.6 mm, 5 μm), hexanes (0.1% TFA)-IPA, 70-30, 0.6 mL/min) to afford 2-[(1R)-1-[7-methyl-3-(piperidin-1-yl)quinoxalin-5- yl]ethyl]aminobenzoic acid (12.0 mg, 4.87 μmol, 8%). 1H NMR (400 MHz, Acetonitrile-d3) į 8.69 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.44 (s, 1H), 7.11 (t, J = 7.7 Hz, 1H), 6.59 – 6.41 (m, 2H), 5.69 (d, J = 6.6 Hz, 1H), 3.83 (d, J = 4.5 Hz, 4H), 2.40 (s, 4H), 2.19 (s, 1H), 102 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 1.79 – 1.67 (m, 6H), 1.64 (d, J = 6.7 Hz, 3H); LC/MS [M+H]+ 391.20; and 2-[(1R)-1-[7- methyl-3-(piperidin-1-yl)quinoxalin-5-yl]ethyl]aminobenzoic acid (13.0 mg, 4.87 μmol, 8%). NMR (500 MHz, DMSO-d6) į 12.59 (s, 1H), 8.79 (s, 1H), 8.43 (s, 1H), 7.75 (dd, J = 7.9, 1.7 Hz, 1H), 7.46 (d, J = 1.7 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.13 (ddd, J = 8.6, 7.1, 1.8 Hz, 1H), 6.56 – 6.38 (m, 2H), 5.50 (s, 1H), 3.78 (d, J = 5.9 Hz, 4H), 2.34 (s, 3H), 1.64 (d, J = 15.8 Hz, 6H), 1.57 (d, J = 6.6 Hz, 3H); LC/MS [M+H]+ 391.2. Example 10. Preparation of 2-(1-[3-(azetidin-1-yl)-7-methylquinoxalin-5-yl]ethylamino)- benzoic acid
Figure imgf000104_0001
[0522] Step 1. Synthesis of 2-(azetidin-1-yl)-8-bromo-6-methylquinoxaline [0523] An inseparable mixture of 8-bromo-2-chloro-6-methylquinoxaline (3.0 g, 11.7 mmol) and 5-bromo-2-chloro-7-methylquinoxaline was dissolved in acetonitrile. Azetidine hydrochloride (3.27 g, 35.0 mmol) and 2H,3H,4H,6H,7H,8H,9H,10H-pyrimido[1,2-a]azepine (10.6 g, 69.9 mmol) was added and reaction mixture was heated to 70 °C overnight. After cooling to room temperature, the mixture was filtered to give a mixture of isomers. A mixture was purified by column flash chromatography to give 2-(azetidin-1-yl)-8-bromo-6- methylquinoxaline (1.1 g, 3.76 mmol, 32%). LCMS [M+H]+ 280.0. [0524] Step 2. Synthesis of 1-[3-(azetidin-1-yl)-7-methylquinoxalin-5-yl]ethan-1-one [0525] The flask was charged sequentially with 2-(azetidin-1-yl)-8-bromo-6- methylquinoxaline (1.1 g, 3.95 mmol), tetrakis(triphenylphosphine)palladium(0) (229 mg, 198 μmol) and cesium fluoride (2.4 g, 15.8 mmol) and flushed with Ar for 5 minutes, then 1- (trimethylsilyl)ethan-1-one (919 mg, 7.91 mmol) and 1,2-dichloroethane was added, flushed with Ar for another 5 minutes and left stirring overnight at 75 °C. The reaction mixture was filtered, the filtrate was concentrated under vacuum and the residue was purified by flash 103 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 chromatography to give 1-[3-(azetidin-1-yl)-7-methylquinoxalin-5-yl]ethan-1-one (500 mg, 1.97 mmol, 50%). LCMS [M+H]+ 242.2. [0526] Step 3. Synthesis of 1-[3-(azetidin-1-yl)-7-methylquinoxalin-5-yl]ethan-1-ol [0527] To a solution of 1-[3-(azetidin-1-yl)-7-methylquinoxalin-5-yl]ethan-1-one (500 mg, 2.07 mmol) in toluene/isopropanol(1/1) was added tris(propan-2-yloxy)aluminium (508 mg, 2.49 mmol). The reaction mixture was heated to 50 °C overnight. After cooling to room temperature, the mixture was quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography to give 1-[3-(azetidin-1-yl)-7-methylquinoxalin- 5-yl]ethan-1-ol (200 mg, 781 μmol, 38%). LCMS [M+H]+ 244.2. [0528] Step 4. Synthesis of 2-({1-[3-(azetidin-1-yl)-7-methylquinoxalin-5-yl]ethyl}amino)- benzoic acid [0529] A mixture of 1-[3-(azetidin-1-yl)-7-methylquinoxalin-5-yl]ethan-1-ol (200 mg, 822 μmol), 2-aminobenzoic acid (113 mg, 822 μmol), copper(ll) bromide (9.2 mg, 41.1 μmol) and diphenylphosphinobenzene-3-sulfonic acid sodium salt (30.0 mg, 82.2 μmol) in water (4 mL) was heated at 100 °C overnight in a sealed tube under air. After cooling to room temperature, the precipitate was separated from reaction mixture and was purified by HPLC to give 2-(1-[3- (azetidin-1-yl)-7-methylquinoxalin-5-yl]ethylamino)benzoic acid (100 mg, 262 μmol, 31.9%). 1H NMR (600 MHz, DMSO-d6) į 12.58 (s, 1H), 8.46 (s, 1H), 8.28 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 7.13 (q, J = 11.5, 9.6 Hz, 1H), 6.45 (t, J = 8.0 Hz, 2H), 5.48 (q, J = 6.6 Hz, 1H), 4.23 (dq, J = 24.3, 8.0 Hz, 4H), 2.42 (d, J = 7.6 Hz, 1H), 2.34 (s, 3H), 1.63 – 1.37 (m, 3H); LCMS [M+H]+ 363.2. Example 11 and Example 12. Preparation of 2-[(1R)-1-[3-(azetidin-1-yl)-7- methylquinoxalin-5-yl]ethyl]aminobenzoic acid and 2-[(1S)-1-[3-(azetidin-1-yl)-7- methylquinoxalin-5-yl]ethyl]aminobenzoic acid
Figure imgf000105_0001
[0530] Enantiomers of racemic 2-(1-[3-(azetidin-1-yl)-7-methylquinoxalin-5- yl]ethylamino)benzoic acid (100 mg, 276 μmol) have been separated by chiral HPLC 104 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 (Column: Chiralpak AD (250 x 30 mm, 10 μm); Mobile phase: hexanes-IPA-TFA, 90-10-0.05 Flow Rate: 30 mL/min; Column Temperature: 24 °C; Wavelength: 215 nm, 268 nm, 368 nm), RetTime (isomer A) = 13.35 min; RetTime (isomer B) = 17.11 min) to afford: 2-[(1R)-1-[3- (azetidin-1-yl)-7-methylquinoxalin-5-yl]ethyl]aminobenzoic acid (4.0 mg, 2.62 μmol) as an off-white solid. 1H NMR (600 MHz, DMSO-d6) į 12.58 (s, 1H), 8.46 (s, 1H), 8.28 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 7.13 (q, J = 11.5, 9.6 Hz, 1H), 6.45 (t, J = 8.0 Hz, 2H), 5.48 (q, J = 6.6 Hz, 1H), 4.23 (dq, J = 24.3, 8.0 Hz, 4H), 2.42 (d, J = 7.6 Hz, 1H), 2.34 (s, 3H), 1.63 – 1.37 (m, 3H); LCMS [M+H]+ 363.0. and 2-[(1S)-1-[3-(azetidin-1-yl)-7-methylquinoxalin-5-yl]ethyl]aminobenzoic acid (5.0 mg, 2.62 μmol) as an off-white solid.1H NMR (600 MHz, DMSO-d6) į 12.60 (s, 1H), 8.47 (s, 1H), 8.28 (s, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 7.13 (q, J = 10.2, 9.0 Hz, 1H), 6.45 (t, J = 7.9 Hz, 2H), 5.48 (q, J = 6.8 Hz, 1H), 4.23 (dq, J = 24.3, 8.0 Hz, 4H), 2.33 (d, J = 17.7 Hz, 3H), 1.57 (d, J = 6.6 Hz, 3H); LCMS [M+H]+ 363.0. Example 13. Preparation of 2-(1-[3-(morpholin-4-yl)-7-(trifluoromethyl)quinoxalin-5- yl]ethylamino)benzoic acid
Figure imgf000106_0001
[0531] Step 1. Synthesis of 2-bromo-6-nitro-4-(trifluoromethyl)aniline [0532] To a solution of 4-amino-3-nitrobenzotrifluoride (50.0 g, 242 mmol) in 500 mL of acetic acid was added bromine (46.5 g, 291 mmol) at room temperature. The reaction solution was stirred at 50 °C for 24 h. The mixture was allowed to cool to room temperature and concentrated in vacuo to give 2-bromo-6-nitro-4-(trifluoromethyl)aniline (68.0 g, 219 mmol, 91%). LC/MS [M-H]+ 285.0. 105 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0533] Step 2. Synthesis of 3-bromo-5-(trifluoromethyl)benzene-1,2-diamine [0534] To the solution of 2-bromo-6-nitro-4-(trifluoromethyl)aniline (55.0 g, 193 mmol) in ethyl acetate was added dichlorostannane dihydrate (218 g, 965 mmol) and resulting mixture was left stirring overnight at 75 °C. The reaction mixture was poured on the water, filtered, organic phase was separated, water extracted with ethyl acetate. The combined organic layers were washed with water, dried and concentrated under vacuum. The residue was used in the next stage without further purification. LC/MS [M+H]+ 256.8. [0535] Step 3. Synthesis of 8-bromo-6-(trifluoromethyl)quinoxalin-2-ol [0536] To a solution of 3-bromo-5-(trifluoromethyl)benzene-1,2-diamine (32.0 g, 125 mmol) in ethanol was added ethyl 2-oxoacetate (12.8 g, 126 mmol), which was then stirred at room temperature for 1 h and left stirring overnight at 75 °C. The mixture was filtered while it is still hot and the filtrate was left cooling for 6 h. The formed precipitate was filtered and washed with ethanol to give 8-bromo-6-(trifluoromethyl)quinoxalin-2-ol. LC/MS [M+H]+ 292.8. [0537] Step 4. Synthesis of 8-bromo-2-chloro-6-(trifluoromethyl)quinoxaline The mixture of 8-bromo-6-(trifluoromethyl)quinoxalin-2-ol (5.5 g, 18.8 mmol) in 20 mL of phosphoryl trichloride was left stirring overnight at 80 °C. After that reaction mixture was concentrated under vacuum, treated with 60 mL of saturated sodium bicarbonate solution in water and extracted with ethyl acetate (3 x 30 mL), organic phase was dried and concentrated under vacuum to give 8-bromo-2-chloro-6-(trifluoromethyl)quinoxaline (5.0 g, 15.3 mmol, 81%). [0538] Step 5. Synthesis of 8-bromo-2-(morpholin-4-yl)-6-(trifluoromethyl)quinoxaline [0539] To a solution of 8-bromo-2-chloro-6-(trifluoromethyl)quinoxaline (5.0 g, 16.1 mmol) in acetonitrile was added morpholine (5.59 g, 64.2 mmol). The reaction mixture was heated to 70 °C overnight. After cooling to room temperature, the mixture was filtered and the crude residue was purified by column flash chromatography to give 8-bromo-2-(morpholin-4-yl)-6- (trifluoromethyl)quinoxaline (5.0 g, 13.1 mmol, 82%). LC/MS [M+H]+ 362.0. [0540] Step 6. Synthesis of 1-[3-(morpholin-4-yl)-7-(trifluoromethyl)quinoxalin-5-yl]ethan- 1-one [0541] A round bottom flask was charged sequentially with 8-bromo-2-(morpholin-4-yl)-6- (trifluoromethyl)quinoxaline (3.0 g, 8.28 mmol), tetrakis(triphenylphosphine)palladium(0) (480 mg, 414 μmol) and cesium fluoride (7.55 g, 49.7 mmol). The reaction flask was flushed with argon for 5 minutes, then 1-(trimethylsilyl)ethan-1-one (2.89 g, 24.9 mmol) and 1,2- dichloroethane was added. The reaction flask was flushed again with argon for another 5 106 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 minutes and left stirring overnight at 75 °C. The reaction mixture was filtered and the filtrate was concentrated under vacuum and the residue was purified by flash chromatography to give 1-[3-(morpholin-4-yl)-7-(trifluoromethyl)quinoxalin-5-yl]ethan-1-one (1.6 g, 4.67 mmol, 56%). LC/MS [M+H]+ 326.2. [0542] Step 7. Synthesis of 1-[3-(morpholin-4-yl)-7-(trifluoromethyl)quinoxalin-5-yl]ethan- 1-ol [0543] To a solution of 1-[3-(morpholin-4-yl)-7-(trifluoromethyl)quinoxalin-5-yl]ethan-1- one (200 mg, 614 μmol) in toluene/isopropanol (1/1) was added tris(propan-2-yloxy)aluminum (188 mg, 921 μmol). The reaction mixture was heated to 50 °C overnight. After cooling to room temperature, the mixture was quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give 1- [3-(morpholin-4-yl)-7-(trifluoromethyl)quinoxalin-5-yl]ethan-1-ol (150 mg, 435 μmol, 71%). LC/MS [M+H]+ 328.0. [0544] Step 8. Synthesis of 2-(1-[3-(morpholin-4-yl)-7-(trifluoromethyl)quinoxalin-5- yl]ethylamino)benzoic acid [0545] A mixture of 1-[3-(morpholin-4-yl)-7-(trifluoromethyl)quinoxalin-5-yl]ethan-1-ol (500 mg, 1.53 mmol), 2-aminobenzoic acid (210 mg, 1.53 mmol), copper(II) bromide (17.1 mg, 76.4 μmol) and diphenylphosphinobenzene-3-sulfonic acid sodium salt (55.7 mg, 153 μmol) in water (4 mL) was heated at 100 °C overnight in a sealed tube under air. After cooling, the precipitate was separated from reaction mixture and was purified by HPLC to give 2-(1-[3- (morpholin-4-yl)-7-(trifluoromethyl)quinoxalin-5-yl]ethylamino)benzoic acid (50.0 mg, 106 μmol, 7%). 1H NMR (500 MHz, DMSO-d6) į 12.66 (s, 1H), 8.96 (s, 1H), 8.49 (d, J = 7.1 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.77 (dd, J = 7.9, 1.7 Hz, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.16 (ddd, J = 8.7, 7.0, 1.8 Hz, 1H), 6.49 (t, J = 7.5 Hz, 1H), 6.43 (d, J = 8.5 Hz, 1H), 5.58 – 5.44 (m, 1H), 3.87 (q, J = 4.7 Hz, 5H), 3.77 (t, J = 4.9 Hz, 4H), 1.62 (d, J = 6.6 Hz, 3H); LC/MS [M+H]+ 447.2. Example 14 and Example 15. Preparation of 2-[(1R)-1-[3-(morpholin-4-yl)-7- (trifluoromethyl)quinoxalin-5-yl]ethyl]aminobenzoic acid and 2-[(1R)-1-[3-(morpholin- 4-yl)-7-(trifluoromethyl)quinoxalin-5-yl]ethyl]aminobenzoic acid 107 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000109_0001
[0546] The racemic mixture, 2-(1-[3-(morpholin-4-yl)-7-(trifluoromethyl)quinoxalin-5- yl]ethylamino)benzoic acid was separated into individual enantiomers by chiral HPLC on column Chiralpak AD-H (250 x 4.6 mm, 5 μm), hexanes (0.1 %TFA)-IPA, 70-30, 0.6 mL/min, to afford 2-[(1R)-1-[3-(morpholin-4-yl)-7-(trifluoromethyl)quinoxalin-5- yl]ethyl]aminobenzoic acid (50.0 mg, 106 μmol). 1H NMR (500 MHz, DMSO-d6) į 12.65 (s, 1H), 8.96 (s, 1H), 8.50 (d, J = 6.9 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.77 (dd, J = 7.9, 1.7 Hz, 1H), 7.72 (d, J = 2.1 Hz, 1H), 7.16 (ddd, J = 8.7, 7.0, 1.7 Hz, 1H), 6.49 (t, J = 7.5 Hz, 1H), 6.43 (d, J = 8.5 Hz, 1H), 5.52 (t, J = 6.6 Hz, 1H), 3.87 (q, J = 4.7 Hz, 4H), 3.77 (t, J = 4.8 Hz, 4H), 1.62 (d, J = 6.6 Hz, 3H); LC/MS [M-H]+ 445.0. and 2-[(1S)-1-[3-(morpholin-4-yl)-7-(trifluoromethyl)quinoxalin-5-yl]ethyl]aminobenzoic acid (50.0 mg, 106 μmol). 1H NMR (500 MHz, DMSO-d6) į 12.66 (s, 1H), 8.96 (s, 1H), 8.49 (d, J = 7.1 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.77 (dd, J = 7.9, 1.7 Hz, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.16 (ddd, J = 8.7, 7.0, 1.8 Hz, 1H), 6.49 (t, J = 7.5 Hz, 1H), 6.43 (d, J = 8.5 Hz, 1H), 5.58 – 5.44 (m, 1H), 3.87 (q, J = 4.7 Hz, 5H), 3.77 (t, J = 4.9 Hz, 4H), 1.62 (d, J = 6.6 Hz, 3H); LC/MS [M-H]+ 445.0. Example 16. Preparation of 2-(1-[7-methyl-2-(pyrrolidin-1-yl)quinoxalin-5- yl]ethylamino)-benzoic acid
Figure imgf000109_0002
[0547] Step 1. Synthesis of 8-bromo-6-methyl-2-(pyrrolidin-1-yl)quinoxaline 108 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0548] An inseparable mixture of 8-bromo-2-chloro-6-methylquinoxaline (5.0 g, 19.4 mmol) and 5-bromo-2-chloro-7-methylquinoxaline was dissolved in acetonitrile. Pyrrolidine (13.8 g, 194 mmol) was added and the reaction mixture was heated to 70 °C overnight. After cooling to room temperature, the mixture was filtered to give a mixture of isomers. A mixture was purified by column flash chromatography to give 8-bromo-6-methyl-2-(pyrrolidin-1- yl)quinoxaline (400 mg, 1.3 mmol, 6.7%). LC/MS [M+H]+ 294.0. [0549] Step 2. Synthesis of 1-[7-methyl-2-(pyrrolidin-1-yl)quinoxalin-5-yl]ethan-1-one [0550] The flask was charged sequentially with 5-bromo-7-methyl-2-(pyrrolidin-1- yl)quinoxaline (450 mg, 1.54 mmol), tetrakis(triphenylphosphine)palladium(0) (89.3 mg, 80.0 μmol) and cesium fluoride (935 mg, 6.16 mmol) and flushed with Ar for 5 minutes. Then 1- (trimethylsilyl)ethan-1-one (358 mg, 3.08 mmol) and 1,2-dichloroethane was added, flushed with Ar for another 5 minutes and left stirring overnight at 75 °C. The reaction mixture was filtered, the filtrate was concentrated under vacuum and the residue was purified by flash chromatography to give 1-[7-methyl-2-(pyrrolidin-1-yl)quinoxalin-5-yl]ethan-1-one (300 mg, 1.12 mmol, 73%). LC/MS [M+H]+ 256.2. [0551] Step 3. Synthesis of 1-[7-methyl-2-(pyrrolidin-1-yl)quinoxalin-5-yl]ethan-1-ol [0552] 1-[7-Methyl-2-(pyrrolidin-1-yl)quinoxalin-5-yl]ethan-1-one (300 mg, 1.18 mmol) was dissolved in toluene/isopropanol(1/1). Tris(propan-2-yloxy)aluminum (360 mg, 1.76 mmol) was added and reaction mixture was heated to 50 °C overnight. After cooling to room temperature, the mixture was quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography to give 1-[7-methyl-2-(pyrrolidin-1-yl)quinoxalin-5- yl]ethan-1-ol (150 mg, 554 μmol, 47%). LC/MS [M+H]+ 258.2. [0553] Step 4. Synthesis of 2-(1-[7-methyl-2-(pyrrolidin-1-yl)quinoxalin-5- yl]ethylamino)benzoic acid [0554] A mixture of 1-[7-methyl-2-(pyrrolidin-1-yl)quinoxalin-5-yl]ethan-1-ol (150 mg, 583 μmol), 2-aminobenzoic acid (79.8 mg, 582 μmol), copper(II) bromide (6.5 mg, 29.1 μmol) and diphenylphosphinobenzene-3-sulfonic acid sodium salt (21.2 mg, 58.2 μmol) in water (4 mL) was heated at 100 °C overnight in a sealed tube under air. After cooling the precipitate was separated from reaction mixture and was purified by HPLC to give 2-(1-[7-methyl-2- (pyrrolidin-1-yl)quinoxalin-5-yl]ethylamino)benzoic acid (30.0 mg, 75.7 μmol, 13%). 1H NMR (400 MHz, DMSO-d6) į 8.73 (s, 1H), 8.47 (s, 1H), 7.83 – 7.67 (m, 1H), 7.47 (s, 1H), 109 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 7.35 (d, J = 2.0 Hz, 1H), 7.10 (t, J = 7.7 Hz, 1H), 6.48 – 6.26 (m, 2H), 5.52 (d, J = 7.1 Hz, 1H), 3.82 – 3.49 (m, 4H), 2.35 (s, 3H), 2.09 (d, J = 14.3 Hz, 1H), 2.03 (d, J = 6.2 Hz, 4H), 1.59 (d, J = 6.6 Hz, 3H); LC/MS [M+H]+ 377.2. Example 17. Preparation of 2-((1-(2,7-dimethyl-3-morpholinoquinoxalin-5- yl)ethyl)amino)-benzoic acid
Figure imgf000111_0001
[0555] Step 1. Synthesis of 3-bromo-5-methylbenzene-1,2-diamine [0556] To a solution of 2-bromo-4-methyl-6-nitro-aniline (30 g, 129 mmol), ammonium chloride (138 g, 2.60 mol) in anhydrous tetrahydrofuran (50 mL) and methanol (400 mL) was added zinc powder (84.9 g, 1.30 mol). The mixture was stirred at 40 °C for 3 hr. On completion, the mixture was quenched by water (300 mL). Then the mixture was filtered. The filtered cake was collected and quenched by hydrochloric acid (1N, 600 mL), which was further adjusted to pH ~7 by sat. sodium bicarbonate. The resulting precipitate was filtered and concentrated in vacuo to give 3-bromo-5-methylbenzene-1,2-diamine (22 g, 109 mmol, 81%) as a brown solid. [0557] Step 2. Synthesis of 8-bromo-3,6-dimethylquinoxalin-2-ol [0558] A solution of 3-bromo-5-methyl-benzene-1,2-diamine (10 g, 49.7 mmol), methyl 2- oxopropanoate (5.59 g, 54.7 mmol) in methanol (100 mL) was stirred at 25 °C for 16 hr. On completion, the mixture was filtered and the filtered cake was dried in vacuo. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 20/1 to 0/1) to give 8-bromo-3,6-dimethylquinoxalin-2-ol (8 g, 31.6 mmol, 64%) as a brown solid.1H NMR (400 MHz, DMSO-d6) į 11.91 - 11.05 (m, 1H), 7.71 - 7.47 (m, 2H), 2.44 - 2.35 (m, 6H). [0559] Step 3. Synthesis of 5-bromo-3-chloro-2,7-dimethylquinoxaline 110 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0560] A solution of 8-bromo-3,6-dimethyl-quinoxalin-2-ol (1 g, 3.95 mmol) in phosphorus oxychloride (33.0 g, 215 mmol) was stirred at 110 °C for 16 hr. On completion, the reaction mixture was poured into ice-water (60 mL) by dropwise, resulting the formation of much precipitate. The precipitate was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 20/1 to 0/1) to give 5-bromo-3-chloro-2,7-dimethylquinoxaline (1 g, 3.68 mmol, 93%) as a brown solid.1H NMR (400 MHz, DMSO-d6) į 7.99 (s, 1H), 7.77 (s, 1H), 2.73 (s, 3H), 1.89 (s, 3H). [0561] Step 4. Synthesis of 4-(8-bromo-3,6-dimethylquinoxalin-2-yl)morpholine [0562] A solution of 5-bromo-3-chloro-2,7-dimethyl-quinoxaline (5 g, 18.4 mmol), morpholine (1.60 g, 18.4 mmol) and diisopropylethylamine (7.14 g, 55.2 mmol) in 1- methylpyrrolidin-2-one (100 mL) was stirred at 110 °C for 16 hr. On completion, the mixture was quenched by water (200 mL). The resulting precipitate was filtered and the filtered cake was concentrated in vacuo to give 4-(8-bromo-3,6-dimethylquinoxalin-2-yl)morpholine (6 g, crude) as a brown solid. m/z ES+ [M+H]+ 324.0. [0563] Step 5. Synthesis of 1-(2,7-dimethyl-3-morpholinoquinoxalin-5-yl)ethan-1-one [0564] A solution of 4-(8-bromo-3,6-dimethyl-quinoxalin-2-yl)morpholine (4 g, 12.41 mmol), 1-vinyloxybutane (3.73 g, 37.2mmol), [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl- phosphane (668 mg, 1.24 mmol), palladium acetate (557 mg, 2.48 mmol) and diisopropylethylamine (4.81 g, 37.2 mmol) in n-butanol (40 mL) was stirred at 100 °C for 16 hr under nitrogen atmosphere. On completion, the reaction mixture was quenched by water (100 mL) at 25 °C, and extracted with ethyl acetate (250 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 10/1 to 0/1) to give 1-(2,7- dimethyl-3-morpholinoquinoxalin-5-yl)ethan-1-one (3 g, 10.5 mmol, 86%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) į 7.79 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 0.8 Hz, 1H), 3.82 - 3.76 (m, 4H), 3.42 - 3.35 (m, 2H), 3.32 - 3.29 (m, 4H), 3.08 - 3.00 (m, 2H), 2.61 (s, 3H), 2.46 (s, 3H), 1.86 (s, 3H), 1.50 - 1.40 (m, 4H), 1.37 - 1.27 (m, 4H), 0.80 (t, J = 7.2 Hz, 6H); m/z ES+ [M+H]+ 286.1. [0565] Step 6. Synthesis of 1-(2,7-dimethyl-3-morpholinoquinoxalin-5-yl)ethan-1-amine [0566] To a solution of 1-(2,7-dimethyl-3-morpholino-quinoxalin-5-yl)ethanone (1 g, 3.50 mmol), ammonium acetate (4.05 g, 52.5 mmol) in methanol (20 mL) was added sodium cyanoborohydride (220 mg, 3.50 mmol). The mixture was stirred at 60 °C for 3 hr. On 111 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 completion, the mixture was concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% ammonium hydroxide) to give 1-(2,7-dimethyl-3- morpholinoquinoxalin-5-yl)ethan-1-amine (0.6 g, 2.10 mmol, 60%) as a brown solid. m/z ES+ [M+H]+ 287.1. [0567] Step 7. Synthesis of 2-((1-(2,7-dimethyl-3-morpholinoquinoxalin-5- yl)ethyl)amino)benzoic acid [0568] A suspension of 1-(2,7-dimethyl-3-morpholino-quinoxalin-5-yl)ethanamine (0.2 g, 698 ^mol), 2-iodobenzoic acid (519 mg, 2.10 mmol), copper powder (88.7 mg, 1.40 mmol) and triethylamine (212 mg, 2.10 mmol) in dimethyl acetamide (10 mL) was stirred at 110 °C for 16 hr under nitrogen atmosphere. On completion, the mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5 um; mobile phase: [water(ammonium bicarbonate)- acetonitrile]; B%: 16%-46%, 9 min) to give 2-((1-(2,7-dimethyl-3-morpholinoquinoxalin-5-yl)ethyl)amino)benzoic acid (0.1 g, 246 ^mol, 35%) as a white solid. 1H NMR (400 MHz, CD3OD) į 7.98 - 7.34 (m, 4H), 7.07 - 6.96 (m, 1H), 6.64 - 6.47 (m, 1H), 5.88 - 5.57 (m, 1H), 3.92 (d, J = 1.2 Hz, 4H), 3.42 (s, 4H), 2.70 (s, 3H), 2.41 (d, J = 1.2 Hz, 3H), 1.73 - 1.61 (m, 3H); m/z ES+ [M+H]+ 407.1. Example 18 and Example 19. Preparation of (R)-2-((1-(2,7-dimethyl-3- morpholinoquinoxalin-5-yl)ethyl)amino)benzoic acid and (S)-2-((1-(2,7-dimethyl-3- morpholinoquinoxalin-5-yl)ethyl)amino)benzoic acid
Figure imgf000113_0001
[0569] The racemic mixture 2-[1-(2,7-dimethyl-3-morpholino-quinoxalin-5- yl)ethylamino]benzoic acid (90.0 mg, 221 ^mol) was separated by SFC (column: DAICEL CHIRALCEL OD (250 x 30 mm, 10 um); mobile phase: [0.1% ammonium hydroxide methanol]; B%: 45%-45%, 3.3 min) to give (R)-2-((1-(2,7-dimethyl-3-morpholinoquinoxalin- 5-yl)ethyl)amino)benzoic acid (20.0 mg, 49.2 ^mol, 22%) as a white solid.1H NMR (400 MHz, CD3OD) į 7.98 - 7.34 (m, 4H), 7.07 - 6.96 (m, 1H), 6.64 - 6.47 (m, 1H), 5.88 - 5.57 (m, 1H), 3.92 (d, J = 1.2 Hz, 4H), 3.42 (s, 4H), 2.70 (s, 3H), 2.41 (d, J = 1.2 Hz, 3H), 1.73 - 1.61 (m, 3H); m/z ES+ [M+H]+ 407.1; and (S)-2-((1-(2,7-dimethyl-3-morpholinoquinoxalin-5- yl)ethyl)amino)benzoic acid (20.0 mg, 49.2 ^mol, 22%) as a white NMR (400 MHz, 112 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 DMSO-d6) į 12.63 (br. s, 1H), 8.68 - 8.42 (m, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.53 (s, 1H), 7.43 (s, 1H), 7.15 (t, J = 7.6 Hz, 1H), 6.57 - 6.38 (m, 2H), 5.55 (s, 1H), 3.85 - 3.80 (m, 4H), 3.41 - 3.35 (m, 4H), 2.65 (s, 3H), 2.40 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H]+ 407.1. Example 20. Preparation of (R)-N-(1-(2,7-dimethyl-3-morpholinoquinoxalin-5-yl)ethyl)- 2-(methylsulfonyl)aniline (Compound 26)
Figure imgf000114_0001
[0570] Step 1. Synthesis of 4-(8-bromo-3,6-dimethylquinoxalin-2-yl)morpholine [0571] To a solution of 5-bromo-3-chloro-2,7-dimethyl-quinoxaline (500 mg, 1.84 mmol) in N-methyl-pyrrolidone (5 mL) was added diisopropylethylamine (714 mg, 5.52 mmol) and morpholine (176 mg, 2.03 mmol). The mixture was stirred at 100 °C for 12 h. On completion, the mixture was poured into water (15.0 mL) and then filtered. The filtered cake was concentrated under reduced pressure to give 4-(8-bromo-3,6-dimethyl-quinoxalin-2- yl)morpholine (500 mg, crude) as a brown solid. m/z ES+ [M+H]+ 321.9. [0572] Step 2. Synthesis of 1-(2,7-dimethyl-3-morpholinoquinoxalin-5-yl)ethan-1-one [0573] A mixture of 4-(8-bromo-3,6-dimethyl-quinoxalin-2-yl)morpholine (500 mg, 1.55 mmol), 1-vinyloxybutane (777 mg, 7.76 mmol), [2-(2-diphenylphosphanylphenoxy)phenyl]- diphenyl-phosphane (83.6 mg, 155 ^mol), palladium acetate (34.8 mg, 155 ^mol) and diisopropylethylamine (601 mg, 4.66 mmol) in n-butanol (5 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 12 hours under nitrogen atmosphere. On completion, the mixture was concentrated under reduced pressure to give a 113 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 residue. The residue was dispersed in ethyl acetate (5 mL) and then aquoues hydrochloric acid (1 M, 5 mL) was added. The mixture was stirred at 25 °C for 1 hour. The mixture was then basified with solid potassium carbonate to pH ~ 8, then diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chouromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 0/1) to give 1-(2,7-dimethyl-3-morpholino-quinoxalin-5-yl)ethanone (260 mg, 911 ^mol, 59%) as a brown solid. 1H NMR (400 MHz, CDCl3) į 7.86 (br d, J = 5.2 Hz, 2H), 3.93 (t, J = 4.6 Hz, 4H), 3.40 (t, J = 4.6 Hz, 4H), 2.94 (s, 3H), 2.73 (s, 3H), 2.55 (s, 3H); m/z ES+ [M+H]+ 286.0. [0574] Step 3. Synthesis of (R)-N-(1-(2,7-dimethyl-3-morpholinoquinoxalin-5- yl)ethylidene)-2-methylpropane-2-sulfinamide [0575] To a solution of 1-(2,7-dimethyl-3-morpholino-quinoxalin-5-yl)ethanone (900 mg, 3.15 mmol) and (R)-2-methylpropane-2-sulfinamide (1.53 g, 12.6 mmol) in anhydrous tetrahydrofuran (10 mL) was added tetraethoxytitanium (3.60 g, 15.8 mmol), the mixture was stirred at 80 °C for 12 hours under nitrogen. On completion, the reaction mixture was quenched by addition water (30 mL) and then filtered. The filtered cake was washed with ethyl acetate (50 mL). The organic layer in the filtrate was separated and the aqueous layer was then extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (30 mL × dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chouromatography (silicon dioxide, petroleum ether/ethyl acetate=0/1 to 1/0) to give (R)-N-[1-(2,7-dimethyl-3- morpholino-quinoxalin-5-yl)ethylidene]-2-methyl-propane-2-sulfinamide (E/Z ratio ~2/1, 900 mg, 2.28 mmol, 72.4%) as a yellow solid. 1H NMR (400 MHz, CDCl3) į 7.77 - 7.68 (m, 1H), 7.60 - 7.28 (m, 1H), 3.98 - 3.82 (m, 4H), 3.45 - 3.25 (m, 4H), 2.95 (s, 2H), 2.70 (s, 3H), 2.62 (s, 1H), 2.54 (s, 3H), 1.34 (s, 6H), 1.17 (s, 3H); m/z ES+ [M+H]+ 389.2. [0576] Step 4. Synthesis of (R)-N-((R)-1-(2,7-dimethyl-3-morpholinoquinoxalin-5-yl)ethyl)- 2-methylpropane-2-sulfinamide [0577] To a solution of (R)-N-[1-(2,7-dimethyl-3-morpholino-quinoxalin-5-yl)ethylidene]-2- methyl-propane-2-sulfinamide (800 mg, 2.06 mmol) in anhydrous tetrahydrofuran (10 mL) was added borane-dimethyl sulfide complex (10 M, 1.03 mL) dropwise at -50 °C under nitrogen, the mixture was then stirred at -20 °C for 2 hours under nitrogen. On completion, the mixture was quenched by addition methanol (5 mL) at 0 °C, then concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum 114 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 ether/ethyl acetate=0/1, Rf = 0.19) to give (R)-N-((R)-1-(2,7-dimethyl-3- morpholinoquinoxalin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (250 mg, 620 ^mol, 30%) as a yellow oil. m/z ES+ [M+H]+ 391.1. [0578] Step 5. Synthesis of (R)-1-(2,7-dimethyl-3-morpholinoquinoxalin-5-yl)ethan-1-amine [0579] To a solution of (R)-1-(2,7-dimethyl-3-morpholinoquinoxalin-5-yl)ethan-1-amine (40 mg, 102 ^mol) in dioxane (4 mL) was added hydrogen chloride/dioxane (0.4 mL), the mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated under reduced pressure. The residue was diluted with saturation sodium bicarbonate (2.0 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R)-1-(2,7-dimethyl-3- morpholinoquinoxalin-5-yl)ethan-1-amine (25.0 mg, crude) as a yellow oil. 1H NMR (400 MHz, CDCl3) į 7.58 (s, 1H), 7.43 (d, J = 1.6 Hz, 1H), 4.89 (dd, J = 6.8, 13.2 Hz, 1H), 3.96 - 3.91 (m, 4H), 3.38 - 3.33 (m, 4H), 2.69 (s, 3H), 2.52 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H]+ 287.1. [0580] Step 6. Synthesis of (R)-N-(1-(2,7-dimethyl-3-morpholinoquinoxalin-5-yl)ethyl)-2- (methylsulfonyl)aniline [0581] To a solution of (R)-1-(2,7-dimethyl-3-morpholinoquinoxalin-5-yl)ethan-1-amine (25.0 mg, 87.3 ^mol), 1-fluoro-2-methylsulfonyl-benzene (60.8 mg, 349 ^mol) and cesium carbonate (85.3 mg, 262 ^mol) in dimethyl acetamide (0.2 mL) was stirred at 140 °C for 12 hours. On completion, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon dioxide, petroleum ether: ethyl acetate = 1:1, Rf = 0.49) and then re-purified by prep-HPLC (column: Phenomenex C18 75×30mm×3um;mobile phase: [water(FA)- ACN];B%: 52%-82%,7min) to give (R)-N-(1-(2,7-dimethyl-3-morpholinoquinoxalin-5- yl)ethyl)-2-(methylsulfonyl)aniline (5.37 mg, 12.2 ^mol, 14%) as a yellow solid.1H NMR (400 MHz, CDCl3) į 7.75 (dd, J = 1.2, 8.0 Hz, 1H), 7.59 (s, 1H), 7.40 (s, 1H), 7.19 (t, J = 7.2 Hz, 1H), 6.81 (d, J = 6.4 Hz, 1H), 6.69 (t, J = 7.6 Hz, 1H), 6.53 (d, J = 8.4 Hz, 1H), 5.70 – 5.60 (m, 1H), 3.94 (t, J = 4.8 Hz, 4H), 3.41 (br d, J = 2.8 Hz, 4H), 3.12 (s, 3H), 2.73 (s, 3H), 2.46 (s, 3H), 1.68 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H]+ 441.1. Example 21. Preparation of (R)-2-((1-(2,7-dimethyl-3-(piperidin-1-yl)quinoxalin-5- yl)ethyl)amino)-5-fluorobenzoic acid (Compound 28) 115 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000117_0001
[0582] Step 1. Synthesis of 5-bromo-2,7-dimethyl-3-(piperidin-1-yl)quinoxaline [0583] A solution of 5-bromo-3-chloro-2,7-dimethyl-quinoxaline (1.60 g, 5.89 mmol) and piperidine (552 mg, 6.48 mmol) and diisopropylethylamine (2.28 g, 17.7 mmol) in N-methyl- pyrrolidone (20 mL) was stirred at 110 °C for 16 hours. On completion, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chouromatography (silicon dioxide, petroleum ether/ethyl acetate=0/1 to 1/0 ^ to give 5- bromo-2,7-dimethyl-3-(1-piperidyl)quinoxaline (1.80 g, 5.62 mmol, 95%) as a brown solid.
Figure imgf000117_0002
319.9. [0584] Step 2. Synthesis of 1-(2,7-dimethyl-3-(piperidin-1-yl)quinoxalin-5-yl)ethan-1-one [0585] A mixture of 5-bromo-2,7-dimethyl-3-(1-piperidyl)quinoxaline (1.70 g, 5.31 mmol), 1-vinyloxybutane (1.60 g, 15.9 mmol), diisopropylethylamine (2.06 g, 15.9 mmol), palladium acetate (119 mg, 531 ^mol) and [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl- phosphane (286 mg, 531 ^mol) in n-butanol (18 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 95 °C for 12 hours under nitrogen atmosphere. On completion, the mixture was quenched by aqueous hydrochloric acid (1 mL, 1 M) and then stirred at 25 °C for 1 h. The mixture was adjusted to pH ~ 8 with solid sodium carbonate, then diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chouromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 0/1) to give 1-[2,7-dimethyl-3-(1- piperidyl)quinoxalin-5-yl]ethanone (1.10 g, 3.88 mmol, 73%) as a brown solid. 1H NMR (400 MHz, CDCl3) į 7.84 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H), 3.37 - 3.27 (m, 4H), 2.96 (s, 3H), 2.70 (s, 3H), 2.53 (s, 3H), 1.82 - 1.75 (m, 4H), 1.74 - 1.67 (m, 2H); m/z ES+ [M+H]+ 284.1. 116 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0586] Step 3. Synthesis of (R)-N-(1-(2,7-dimethyl-3-(piperidin-1-yl)quinoxalin-5- yl)ethylidene)-2-methylpropane-2-sulfinamide [0587] To a solution of 1-[2,7-dimethyl-3-(1-piperidyl)quinoxalin-5-yl]ethanone (1.00 g, 3.53 mmol) in anhydrous tetrahydrofuran (15 mL) was added tetraisopropoxytitanium (5.01 g, 17.6 mmol) and (R)-2-methylpropane-2-sulfinamide (1.71 g, 14.1 mmol), the mixture was stirred at 75 °C for 12 hrs. On completion, the reaction mixture was quenched by water (30 mL) and then filtered. The filtered cake washed with ethyl acetate (50 mL). The filtrate was then extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate = 1/0 to 0/1) to give (R)-N-(1-(2,7-dimethyl-3-(piperidin-1- yl)quinoxalin-5-yl)ethylidene)-2-methylpropane-2-sulfinamide (E/Z ratio ~ 5/2, 1.20 g, 3.10 mmol, 88%) as a brown solid. 1H NMR (400 MHz, CDCl3) į 7.76 - 7.66 (m, 1H), 7.59 - 7.32 (m, 1H), 3.27 (br d, J = 5.2 Hz, 4H), 2.98 (s, 2H), 2.70 (s, 3H), 2.64 (s, 1H), 2.54 (s, 3H), 1.77 (br d, J = 4.0 Hz, 4H), 1.73 - 1.67 (m, 2H), 1.36 (s, 6H), 1.18 (s, 3H). [0588] Step 4. Synthesis of (R)-N-((R)-1-(2,7-dimethyl-3-(piperidin-1-yl)quinoxalin-5- yl)ethyl)-2-methylpropane-2-sulfinamide [0589] To a solution of (R)-N-(1-(2,7-dimethyl-3-(piperidin-1-yl)quinoxalin-5- yl)ethylidene)-2-methylpropane-2-sulfinamide (500 mg, 1.29 mmol) in anhydrous tetrahydrofuran (10 mL) was added borane-dimethyl sulfide complex (10 M, 646 ^L) dropwise at -50 °C under nitrogen, the mixture was then stirred at 0 °C for 2 hrs. On completion, the reaction mixture was carefully quenched by methanol (10 mL) at 0 °C and then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150×25mm× 5um;mobile phase: [water (ammonia hydroxide v/v)-ACN];B%: 55%-85%,9min) to give (R)-N-((R)-1-(2,7-dimethyl-3-(piperidin-1-yl)quinoxalin-5-yl)ethyl)- 2-methylpropane-2-sulfinamide (250 mg, 643 ^mol, 50%) as a yellow oil. m/z ES+ [M+H]+ 389.3. [0590] Step 5. Synthesis of (R)-1-(2,7-dimethyl-3-(piperidin-1-yl)quinoxalin-5-yl)ethan-1- amine [0591] To a solution of (R)-N-((R)-1-(2,7-dimethyl-3-(piperidin-1-yl)quinoxalin-5-yl)ethyl)- 2-methylpropane-2-sulfinamide (60.0 mg, 154 ^mol) in dioxane (6 mL) was added hydrogen chloride/dioxane (0.6 mL), the mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was diluted with saturated sodium bicarbonate solution (5.0 mL) and extracted with ethyl acetate (10 mL × 3). 117 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R)-1-(2,7-dimethyl-3-(piperidin-1-yl)quinoxalin- 5-yl)ethan-1-amine (40.0 mg, crude) as a yellow oil. m/z ES+ [M+H]+ 285.1. [0592] Step 6. Synthesis of (R)-2-((1-(2,7-dimethyl-3-(piperidin-1-yl)quinoxalin-5- yl)ethyl)amino)-5-fluorobenzoic acid [0593] A mixture of (R)-1-(2,7-dimethyl-3-(piperidin-1-yl)quinoxalin-5-yl)ethan-1-amine (60.0 mg, 211 ^mol), 5-fluoro-2-iodo-benzoic acid (168 mg, 633 ^mol), triethylamine (427 mg, 4.22 mmol), copper powder (13.4 mg, 211 ^mol) in dimethyl acetamide (0.5 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 110 °C for 2 hour under nitrogen atmosphere. The residue was directly purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 64%- 94%,10min) and then re-purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 64%-94%,10min) to give (R)-2-((1-(2,7- dimethyl-3-(piperidin-1-yl)quinoxalin-5-yl)ethyl)amino)-5-fluorobenzoic acid (10.0 mg, 23.8 ^mol, 11.3%) as a yellow solid. 1H NMR (400 MHz, CDCl3) į 7.66 (dd, J = 3.2, 9.6 Hz, 1H), 7.57 (s, 1H), 7.37 (s, 1H), 6.97 - 6.86 (m, 1H), 6.41 (dd, J = 4.4, 9.6 Hz, 1H), 5.63 (q, J = 6.4 Hz, 1H), 3.40 - 3.26 (m, 4H), 2.72 (s, 3H), 2.44 (s, 3H), 1.85 – 1.75 (m, 4H), 1.75 – 1.69 (m, 2H), 1.68 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H]+ 423.2. Example 22. Preparation of (R)-N-(1-(3-(4,4-difluoropiperidin-1-yl)-2,7- dimethylquinoxalin-5-yl)ethyl)-4-fluoro-2-(methylsulfonyl)aniline (Compound 35)
Figure imgf000119_0001
[0594] Step 1. Synthesis of (R)-N-(1-(3-(4,4-difluoropiperidin-1-yl)-2,7-dimethylquinoxalin- 5-yl)ethyl)-4-fluoro-2-(methylsulfonyl)aniline [0595] To a solution of 4,4-difluoropiperidine (162 mg, 1.03 mmol, hydrochloric acid) in diisopropylethylamine (0.2 mL) was added N-((1R)-1-(2,7-dimethyl-3- (methylsulfinyl)quinoxalin-5-yl)ethyl)-4-fluoro-2-(methylsulfonyl)aniline (90 mg, 206 ^mol), the mixture was stirred at 110 °C for 12 hours. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silicon 118 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 dioxide, petroleum ether / ethyl acetate = 1/1) to give (R)-N-(1-(3-(4,4-difluoropiperidin-1-yl)- 2,7-dimethylquinoxalin-5-yl)ethyl)-4-fluoro-2-(methylsulfonyl)aniline (12.2 mg, 24.4 ^mol, 11.8%) as a yellow
Figure imgf000120_0001
(400 MHz, CDCl3) į 7.61 (s, 1H), 7.51 (dd, J = 3.2, 8.4 Hz, 1H), 7.38 (d, J = 1.2 Hz, 1H), 6.93 (ddd, J = 3.2, 8.0, 9.2 Hz, 1H), 6.60 (br d, J = 6.8 Hz, 1H), 6.44 (dd, J = 4.0, 9.2 Hz, 1H), 5.56 (t, J = 6.8 Hz, 1H), 3.53 (br t, J = 5.6 Hz, 4H), 3.15 (s, 3H), 2.74 (s, 3H), 2.46 (s, 3H), 2.30 - 2.15 (m, 4H), 1.67 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H]+ 493.2. Example 23. Preparation of (R)-2-((1-(3-(3-(difluoromethyl)azetidin-1-yl)-2,7- dimethylquinoxalin-5-yl)ethyl)amino)-5-fluorobenzoic acid (Compound 44)
Figure imgf000120_0002
[0596] Step 1. Synthesis of (R)-2-((1-(2,7-dimethyl-3-(methylthio)quinoxalin-5- yl)ethyl)amino)-5-fluorobenzoic acid [0597] A mixture of (1R)-1-(2,7-dimethyl-3-methylsulfanyl-quinoxalin-5-yl)ethanamine (600 mg, 2.43 mmol), 5-fluoro-2-iodo-benzoic acid (3.23 g, 12.1 mmol), copper powder (462 mg, 7.28 mmol), triethylamine (4.91 g, 48.5 mmol) in dimethyl acetamide (6 mL) was degassed and purged with nitrogen atmosphere for 3 times, and then the mixture was stirred at 110 °C for 2 hours under nitrogen atmosphere. On completion, the reaction mixture was filtered. Then the filtrate was diluted with sat. ammonium chloride 5 mL and extracted with ethyl acetate (5 mL× 3). The combined organic layers were washed with brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 1/1) to give compound 2-[[(1R)-1-(2,7-dimethyl-3-methylsulfanyl-quinoxalin-5- yl)ethyl]amino]-5-fluoro-benzoic acid (450 mg, 946 ^mol, 39%) as a brown oil. 1H NMR (400 MHz, CDCl3) į 7.94 (d, J = 7.6 Hz, 1H), 7.82 (dd, J = 2.0, 10.4 Hz, 1H), 7.69 (dd, J = 3.2, 9.6 Hz, 1H), 7.53 - 7.47 (m, 1H), 7.35 (dt, J = 2.4, 8.3 Hz, 1H), 6.99 - 6.89 (m, 1H), 6.35 (dd, J = 4.4, 9.2 Hz, 1H), 5.75 (q, J = 6.4 Hz, 1H), 2.74 (s, 6H), 2.49 (s, 3H), 1.73 (d, J = 6.4 Hz, 3H); m/z ES+ [M+H]+ 386.1. [0598] Step 2. Synthesis of 2-(((1R)-1-(2,7-dimethyl-3-(methylsulfinyl)quinoxalin-5- yl)ethyl)amino)-5-fluorobenzoic acid 119 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0599] To a solution of 2-[[(1R)-1-(2,7-dimethyl-3-methylsulfanyl-quinoxalin-5- yl)ethyl]amino]-5-fluoro-benzoic acid (50.0 mg, 129 ^mol) in anhydrous tetrahydrofuran (5 mL) was added potassium peroxomonosulfate (103 mg, 168 ^mol) in water (1 mL). The mixture was stirred at 0 °C for 0.5 hours. On completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL× 3). The combined organic layers were washed with brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 2-[[(1R)-1-(2,7-dimethyl-3-methylsulfinyl- quinoxalin-5-yl)ethyl]amino]-5-fluoro-benzoic acid (40.0 mg, crude) as a brown oil. [0600] Step 3. Synthesis of (R)-2-((1-(3-(3-(difluoromethyl)azetidin-1-yl)-2,7- dimethylquinoxalin-5-yl)ethyl)amino)-5-fluorobenzoic acid [0601] To a solution of 3-(difluoromethyl)azetidine (213 mg, 1.99 mmol) in diisopropylethylamine (0.4 mL) was added 4Å molecular sieves (40.0 mg, 99.6 ^mol) and 2- [[(1R)-1-(2,7-dimethyl-3-methylsulfinyl-quinoxalin-5-yl)ethyl]amino]-5-fluoro-benzoic acid (40.0 mg, 99.6 ^mol). The mixture was stirred at 60 °C for 12 hours. On completion, the reaction mixture was directly concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 46%-76%,10min) to give compound 2-[[(1R)-1- [3-[3-(difluoromethyl)azetidin-1-yl]-2,7-dimethyl-quinoxalin-5-yl]ethyl]amino]-5-fluoro- benzoic acid (11.4 mg, 25.5 ^mol, 26%) as a white solid. 1H NMR (400 MHz, CDCl3) į 7.59 (dd, J = 3.2, 9.6 Hz, 1H), 7.49 (s, 1H), 7.30 (s, 1H), 6.91 - 6.80 (m, 1H), 6.32 (dd, J = 4.4, 9.2 Hz, 1H), 6.04 (td, J = 56.4, 4.8 Hz, 1H), 5.49 (q, J = 6.8 Hz, 1H), 4.42 - 4.29 (m, 2H), 4.23 (td, J = 4.8, 8.8 Hz, 2H), 3.20 - 3.02 (m, 1H), 2.59 (s, 3H), 2.36 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H]+ 445.2. Example 24. Preparation of (R)-2-((1-(3-(4,4-difluoropiperidin-1-yl)-7-fluoro-2- methylquinoxalin-5-yl)ethyl)amino)-5-fluorobenzoic acid (Compound 34) 120 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000122_0001
[0602] Step 1. Synthesis of 3-bromo-5-fluorobenzene-1,2-diamine [0603] To a solution of 2-bromo-4-fluoro-6-nitro-aniline (5 g, 21.2 mmol) in ethanol (50 mL) was added Fe powder (4.75 g, 85.1 mmol) and aqueous ammonium chloride (7 M, 30.39 mL), the mixture was stirred at 80 °C for 3 hours. On completion, the mixture was filtered and the filtered cake was washed with ethyl acetate (100 mL x 3). Then the filtrate was adjusted to pH ~ 8 with solid potassium carbonate. The organic phase was separated, then washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-bromo-5-fluoro-benzene-1,2-diamine (4.3 g, crude) as a brown solid. m/z ES+ [M+H]+ 204.9. [0604] Step 2. Synthesis of 8-bromo-6-fluoro-3-methylquinoxalin-2-ol [0605] To a solution of 3-bromo-5-fluoro-benzene-1,2-diamine (4.3 g, 20.9 mmol) in methanol (50 mL) was added methyl 2-oxopropanoate (2.36 g, 23.0 mmol). The mixture was stirred at 25 °C for 12 h. On completion, the mixture was filtered and the filtered cake was concentrated under reduced pressure to give 8-bromo-6-fluoro-3-methyl-quinoxalin-2-ol (4 g, crude, mixture of regio-isomers) as a white solid. m/z ES+ [M+H]+ 256.9. [0606] Step 3. Synthesis of 5-bromo-3-chloro-7-fluoro-2-methylquinoxaline 121 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0607] A solution of 8-bromo-6-fluoro-3-methyl-quinoxalin-2-ol (4.00 g, 15.5 mmol) in phosphorus oxychloride (20 mL) was stirred at 110 °C for 2 h under nitrogen. On completion, the reaction mixture was carefully poured into water (100 mL) at 25 - 30 °C and then filtered. The filtered cake was concentrated under reduced pressure to give 5-bromo-3-chloro-7-fluoro- 2-methyl-quinoxaline (2.6 g, crude, mixture of regio-isomers) as a yellow solid. [0608] Step 4. Synthesis of 5-bromo-3-(4,4-difluoropiperidin-1-yl)-7-fluoro-2- methylquinoxaline [0609] To a solution of 5-bromo-3-chloro-7-fluoro-2-methyl-quinoxaline (2.1 g, 7.62 mmol), 4,4-difluoropiperidine (1.32 g, 8.38 mmol, hydrogen chloride) in N-methyl pyrrolidone (21 mL) was added diisopropylethylamine (3.94 g, 30.4 mmol). The mixture was stirred at 100 °C for 12 hour. On completion, the mixture was diluted with water (80 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chouromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 0/1) to give 5-bromo-3-(4,4-difluoro-1-piperidyl)-7-fluoro-2-methyl-quinoxaline (1.7 g, 4.72 mmol, 62%) as a yellow solid (Note: The minor regio-isomer was removed at this stage and the desired product was confirmed by 2D NMR). 1H NMR (400MHz, CDCl3) į = 7.72 (dd, J = 2.8, 8.4 Hz, 1H), 7.54 (dd, J = 2.8, 8.8 Hz, 1H), 3.68 - 3.56 (m, 4H), 2.74 (s, 3H), 2.30 - 2.17 (m, 4H); m/z ES+ [M+H]+ 360.0. [0610] Step 5. Synthesis of 1-(3-(4,4-difluoropiperidin-1-yl)-7-fluoro-2-methylquinoxalin-5- yl)ethan-1-one [0611] A mixture of 5-bromo-3-(4,4-difluoro-1-piperidyl)-7-fluoro-2-methyl-quinoxaline (1.5 g, 4.16 mmol) , 1-vinyloxybutane (1.25 g, 12.4 mmol), diisopropylethylamine (1.61 g, 12.4 mmol), [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (224 mg, 416 ^mol) and palladium acetate (93.5 mg, 416 ^mol) in n-butanol (15 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 95 °C for 12 hour under nitrogen atmosphere. On completion, the mixture was quenched by aqueous hydrochloric acid (1 M, 10 mL) and then stirred at 25 °C for 1 hour. The mixture was adjusted to pH ~ 8 by solid sodium carbonate, then diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chouromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 0/1) to give 1-[3-(4,4- difluoro-1-piperidyl)-7-fluoro-2-methyl-quinoxalin-5-yl]ethanone (670 mg, 2.00 mmol, 48%) as a yellow solid. m/z ES+ [M+H]+ 324.4. 122 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0612] Step 6. Synthesis of (R)-N-(1-(3-(4,4-difluoropiperidin-1-yl)-7-fluoro-2- methylquinoxalin-5-yl)ethylidene)-2-methylpropane-2-sulfinamide [0613] To a solution of 1-[3-(4,4-difluoro-1-piperidyl)-7-fluoro-2-methyl-quinoxalin-5- yl]ethanone (670 mg, 2.07 mmol) in anhydrous tetrahydrofuran (10 mL) was added tetraisopropyl titanate (1.77 g, 6.22 mmol) and (R)-2-methylpropane-2-sulfinamide (879 mg, 7.25 mmol). The mixture was stirred at 75 °C for 12 hour. On completion, the reaction mixture was quenched by water (30 mL) and then filtered. The filtered cake was washed with ethyl acetate (50 mL). And the filtrate was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chouromatography (silicon dioxide, petroleum ether/ethyl acetate=1/0 to 0/1) to give (R)-N-(1-(3-(4,4-difluoropiperidin-1-yl)-7-fluoro-2-methylquinoxalin-5-yl)ethylidene)-2- methylpropane-2-sulfinamide (E/Z ratio ~2/1, 700 mg, 1.64 mmol, 79%) as a yellow solid. 1H NMR (400 MHz, CDCl3) į 7.62 (dd, J = 2.8, 8.8 Hz, 1H), 7.54 (dd, J = 2.4, 8.8 Hz, 1H), 3.48 (br t, J = 5.6 Hz, 4H), 2.96 (s, 2H), 2.72 (s, 3H), 2.60 (s, 1H), 2.28 - 2.12 (m, 4H), 1.34 (s, 6H), 1.19 (s, 3H); m/z ES+ [M+H]+ 427.2. [0614] Step 7. Synthesis of (R)-N-((R)-1-(3-(4,4-difluoropiperidin-1-yl)-7-fluoro-2-methyl- 1,4-dihydroquinoxalin-5-yl)ethyl)-2-methylpropane-2-sulfinamide [0615] To a solution of (R)-N-(1-(3-(4,4-difluoropiperidin-1-yl)-7-fluoro-2- methylquinoxalin-5-yl)ethylidene)-2-methylpropane-2-sulfinamide (500 mg, 1.17 mmol) in anhydrous tetrahydrofuran (10 mL) was added borane-dimethyl sulfide complex (10 M, 586 ^L) dropwise at -50 °C under nitrogen, the mixture was then stirred at 0 °C for 2 hours under nitrogen. On completion, the reaction mixture was carefully quenched by methanol (10 mL) at 0 °C and then concentrated under reduced pressure to give
Figure imgf000124_0001
1-(3-(4,4- difluoropiperidin-1-yl)-7-fluoro-2-methyl-1,4-dihydroquinoxalin-5-yl)ethyl)-2- methylpropane-2-sulfinamide (500 mg, crude) as a black oil. m/z ES+ [M+H]+ 431.2. [0616] Step 8. Synthesis of (R)-N-((R)-1-(3-(4,4-difluoropiperidin-1-yl)-7-fluoro-2- methylquinoxalin-5-yl)ethyl)-2-methylpropane-2-sulfinamide [0617] To a solution of (R)-N-((R)-1-(3-(4,4-difluoropiperidin-1-yl)-7-fluoro-2-methyl-1,4- dihydroquinoxalin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (600 mg, 1.39 mmol) in ethyl acetate (20 mL) was added manganese dioxide (1.21 g, 13.9 mmol), the mixture was stirred at 25 °C for 2 hours. On completion, the mixture was filtered and the filtered cake was concentrated under reduced pressure to give (R)-N-((R)-1-(3-(4,4-difluoropiperidin-1-yl)-7- 123 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 fluoro-2-methylquinoxalin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, crude) as a yellow oil. m/z ES+ [M+H]+ 429.3. [0618] Step 9. Synthesis of (R)-1-(3-(4,4-difluoropiperidin-1-yl)-7-fluoro-2- methylquinoxalin-5-yl)ethan-1-amine [0619] To a solution of (R)-N-((R)-1-(3-(4,4-difluoropiperidin-1-yl)-7-fluoro-2- methylquinoxalin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 280 ^mol) in dichloromethane (10 mL) was added hydrogen chloride/dioxane (1 mL), the mixture was stirred at 25 °C for 0.5 hour. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 75*30mm*3um;mobile phase: [water(FA)-ACN];B%: 8%-38%,7min) to give (R)-1-(3-(4,4- difluoropiperidin-1-yl)-7-fluoro-2-methylquinoxalin-5-yl)ethan-1-amine (65 mg, 197 ^mol, 70%) as a yellow solid. m/z ES+ [M+H]+ 325.1. [0620] Step 10. Synthesis of (R)-2-((1-(3-(4,4-difluoropiperidin-1-yl)-7-fluoro-2- methylquinoxalin-5-yl)ethyl)amino)-5-fluorobenzoic acid [0621] A mixture of (R)-1-(3-(4,4-difluoropiperidin-1-yl)-7-fluoro-2-methylquinoxalin-5- yl)ethan-1-amine (45 mg, 139 ^mol), 5-fluoro-2-iodo-benzoic acid (147 mg, 555 ^mol), triethylamine (140 mg, 1.39 mmol), copper powder (8.82 mg, 139 ^mol) in dimethyl acetamide (0.3 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 110 °C for 2 hour under nitrogen atmosphere. On completion, the residue was filtered and the filtrate was directly purified by prep-HPLC (column: Phenomenex C18 75*30mm*3um;mobile phase: [water(FA)-ACN];B%: 55%-85%,10min) to give (R)-2-((1-(3- (4,4-difluoropiperidin-1-yl)-7-fluoro-2-methylquinoxalin-5-yl)ethyl)amino)-5-fluorobenzoic acid (25.4 mg, 54.1 ^mol, 39%) as a yellow solid.
Figure imgf000125_0001
NMR (400 MHz, CDCl3) į 8.05 (br s, 1H), 7.70 (dd, J = 2.8, 9.6 Hz, 1H), 7.46 (dd, J = 2.8, 8.8 Hz, 1H), 7.40 (dd, J = 2.4, 9.2 Hz, 1H), 6.98 - 6.87 (m, 1H), 6.26 (dd, J = 4.4, 9.2 Hz, 1H), 5.68 - 5.57 (m, 1H), 3.55 (br t, J = 5.6 Hz, 4H), 2.77 (s, 3H), 2.31 - 2.18 (m, 4H), 1.70 (d, J = 6.8 Hz, 3H); m/z ES+ [M+H]+ 463.2. Example 25. Synthesis and Characterization of Additional Exemplary Compounds [0622] Other exemplary compounds were further synthesized following the procedures described herein, and characterizations of these further synthesized exemplary compounds are shown in Table A below. 124 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 Table A
Figure imgf000126_0001
125 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000127_0001
126 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000128_0001
127 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000129_0001
128 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000130_0001
Example 26. Biological Activity of Exemplary Compounds of the Present Disclosure 129 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0623] The biological activity of exemplary compounds of the present disclosure was determined utilizing a p-AKT S473 assay described herein. [0624] Briefly, MCF10A-PI3KĮ-WT, MCF10A- PI3KĮ-H1047R and MCF10A- PI3KĮ- E545K cells were grown in DMEM/F12 supplemented with Horse Serum, EGF, Hydrocortisone, Cholera toxin and Insulin. The cells were dissociated with TryPLE, washed with media and plated in 384 wells plate. The next day, serial dilution of compounds were applied to the cell for 2 hours and p-AKT S473 was measured using HTRF cellular kit by Cisbio (64AKSPET) according to manufacturer’s protocol. To measure p-AKT S473 levels using the kit, the cells were lysed, antibodies mixed with detection buffer were then added to the lysate and incubated overnight in the dark. The next day luminescence was read on a Ensight plate reader at 665 nm and 620 nm wavelengths. Without wishing to be bound by theory, a decrease in p-AKT S473 levels indicate a downregulation of the PI3KĮ pathway and cell proliferation, thereby indicating inhibition of the PI3KĮ protein by the compounds of the present disclosure. [0625] Table B and Table C assign each compound a code for potency in the assay described above: A, B, C, D, or E. According to the code, A represents an IC50 value <500 nM; B represents an IC50 value ^500 nM and <1000 nM; C represents an IC50 value ^1000 nM and <5000 nM; D represents an IC50 value ^5000 nM and <10,000 nM; and E represents an IC50 value ^10,000 nM. Table B
Figure imgf000131_0001
130 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000132_0001
Table C
Figure imgf000132_0002
Example 27. Biological Activity of Exemplary Compounds of the Present Disclosure [0626] The biological activity of exemplary compounds of the present disclosure was determined utilizing a HCT-116 assay described herein. [0627] HCT-116-PIK3Ca-WT and HCT-116-PIK3Ca-H1047R are grown in RPMI supplemented with 10% fetal bovine serum. [0628] HCT-116-PIK3Ca-WT and HCT-116-PIK3Ca-H1047R cells are dissociated with TryPLE, wash with media and plated in 384 wells plate (density: WT & H1047R: 15K/well). 131 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0629] The next day, serial dilution of compounds is applied to the cell for 2 hours and p- AKT S473 is measured using HTRF cellular kit by Cisbio (64AKSPET) according to manufacturer’s protocol. Briefly, cells are lysed, antibodies mix with detection buffer is then added to the lysate and incubate overnight in the dark. The next day luminescence is read on a Ensight plate reader at 665 nm and 620 nm wavelengths. [0630] Table D assigns each compound a code for potency in the assay described above: A, B, C, D, E, or F. According to the code, A represents an IC50 value <100 nM; B represents an IC50 value ^100 nM and <500 nM; C represents an IC50 value ^500 nM and <1000 nM; D represents an IC50 value ^1000 nM and <10,000 nM; E represents an IC50 value ^10,000 nM and <30,000; F represents an IC50 value ^30,000 nM. Table D
Figure imgf000133_0001
EXEMPLARY EMBODIMENTS [0631] Embodiment 1: A compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R2 is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; 132 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 R3 is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R3a; each R3a independently is halogen, C1-C6 alkyl, or C6-C10 aryl, wherein the C1-C6 alkyl or C6-C10 aryl is optionally substituted with one or more halogen;
Figure imgf000134_0001
alkyl)-*, -(C1-C6 alkyl)-O-*, -O-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-O-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-NRT-*, -NRT-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-NRT-(C1-C6 alkyl)-*, -(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-O-*, - O-(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-NRT-*, or -NRT-(C1-C6 haloalkyl)-*, wherein * denotes attachment to A; each RT is H or C1-C6 alkyl; A is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RA; each RA independently is oxo, halogen, -OH, cyano, -NH2, -C(=O)OH, -C(=O)O(C1- C6 alkyl), -C(=O)N(RA1)2, -C(=O)N(ORA1)RA1, -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, - S(=O)(=NRA1)RA1, -S(=O)2N(RA1)2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl, wherein the -C(=O)O(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1- C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RA1; and each RA1 independently is oxo, H, halogen, -OH, -NH2, -C(=O)OH, -C(=O)(C1-C6 alkyl), -C(=O)((C1-C6 alkyl)-OH), -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C3-C12 cycloalkyl, wherein the C3-C12 cycloalkyl is optionally substituted with -OH; or two RA1, together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C3- C12 cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH2. [0632] Embodiment 2: A compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is halogen, cyano, C1-C6 alkyl, or C1-C6 haloalkyl; R2 is H, or C1-C6 alkyl; 133 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 R3 is 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R3a; each R3a independently is C6-C10 aryl optionally substituted with one or more halogen; T is -(C1-C6 alkyl)-*, or -(C1-C6 alkyl)-NRT-*, wherein * denotes attachment to A; each RT is H; A is C6-C10 aryl optionally substituted with one or more RA; each RA independently is halogen, -NH2, -C(=O)OH, -C(=O)O(C1-C6 alkyl), - S(=O)2(C1-C6 alkyl), or 3- to 12-membered heterocycloalkyl. [0633] Embodiment 3: The compound of any one of the preceding embodiments, wherein R1 is halogen or cyano. [0634] Embodiment 4: The compound of any one of the preceding embodiments, wherein R1 is C1-C6 alkyl or C1-C6 haloalkyl. [0635] Embodiment 5: The compound of any one of the preceding embodiments, wherein R2 is H. [0636] Embodiment 6: The compound of any one of the preceding embodiments, wherein R2 is C1-C6 alkyl. [0637] Embodiment 7: The compound of any one of the preceding embodiments, wherein R3 is 3- to 12-membered heterocycloalkyl optionally substituted with one or more R3a. [0638] Embodiment 8: The compound of any one of the preceding embodiments, wherein R3 is 5- to 10-membered heteroaryl optionally substituted with one or more R3a. [0639] Embodiment 9: The compound of any one of the preceding embodiments, wherein each R3a independently is C6-C10 aryl substituted with one or more halogen. [0640] Embodiment 10: The compound of any one of the preceding embodiments, wherein T is -(C1-C6 alkyl)-*, wherein * denotes attachment to A. [0641] Embodiment 11: The compound of any one of the preceding embodiments, wherein T is -(C1-C6 alkyl)-NRT-*, wherein * denotes attachment to A. [0642] Embodiment 12: The compound of any one of the preceding embodiments, wherein each RT is H. [0643] Embodiment 13: The compound of any one of the preceding embodiments, wherein A is C6-C10 aryl optionally substituted with one or more RA. [0644] Embodiment 14: The compound of any one of the preceding embodiments, wherein A is phenyl substituted with one or more RA. [0645] Embodiment 15: The compound of any one of the preceding embodiments, wherein each RA independently is -NH2. 134 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0646] Embodiment 16: The compound of any one of the preceding embodiments, wherein each RA independently is -C(=O)OH, -C(=O)O(C1-C6 alkyl), or -S(=O)2(C1-C6 alkyl). [0647] Embodiment 17: The compound of any one of the preceding embodiments, wherein each RA independently is 3- to 12-membered heterocycloalkyl. [0648] Embodiment 18: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-a), (I-b), (I-c), (I-d), (I-e), or (I-f), or a pharmaceutically acceptable salt or stereoisomer thereof. [0649] Embodiment 19: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-g), or a pharmaceutically acceptable salt or stereoisomer thereof. [0650] Embodiment 20: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-h), or a pharmaceutically acceptable salt or stereoisomer thereof. [0651] Embodiment 21: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-i), or a pharmaceutically acceptable salt or stereoisomer thereof. [0652] Embodiment 22: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-j), or a pharmaceutically acceptable salt or stereoisomer thereof. [0653] Embodiment 23: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-k), or a pharmaceutically acceptable salt or stereoisomer thereof. [0654] Embodiment 24: The compound of any one of the preceding embodiments, wherein the compound is selected from a compound described in Table 1 or Table 2, or a pharmaceutically acceptable salt or stereoisomer thereof. [0655] Embodiment 25: A compound obtainable by, or obtained by, a method described herein; optionally, the method comprises one or more steps described in Schemes 1-2. [0656] Embodiment 26: A pharmaceutical composition comprising the compound of any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. 135 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0657] Embodiment 27: The pharmaceutical composition of any one of the preceding embodiments, wherein the compound is selected from a compound described in Table 1 or Table 2. [0658] Embodiment 28: A method of modulating PI3KĮ activity, comprising contacting a cell with an effective amount of the compound of any one of the preceding embodiments; optionally the activity is in vitro or in vivo. [0659] Embodiment 29: A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition of any one of the preceding embodiments. [0660] Embodiment 30: The compound or pharmaceutical composition of any one of the preceding embodiments for use in modulating PI3KĮ activity; optionally, the activity is in vitro or in vivo. [0661] Embodiment 31: The compound or pharmaceutical composition of any one of the preceding embodiments for use in treating or preventing a disease or disorder. [0662] Embodiment 32: Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for modulating PI3KĮ activity; optionally, the activity is in vitro or in vivo. [0663] Embodiment 33: Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for treating or preventing a disease or disorder. [0664] Embodiment 34: The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is a disease or disorder in which PI3KĮ activity is implicated. [0665] Embodiment 35: The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal (CLOVES) syndrome. [0666] Embodiment 36: The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is PIK3CA-related overgrowth syndrome. [0667] Embodiment 37: The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is cancer. [0668] Embodiment 38: A method of treating or preventing cancer in a subject, the method comprising administering to the subject a compound of any one of the preceding embodiments. 136 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0669] Embodiment 39: A compound of any one of the preceding embodiments for treating or preventing cancer in a subject. [0670] Embodiment 40: Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for treating or preventing cancer in a subject. [0671] Embodiment 41: Use of the compound of any one of the preceding embodiments for treating or preventing cancer in a subject. [0672] Embodiment 42: The method, compound, or use of any one of the preceding embodiments, wherein the cancer is characterized by at least one oncogenic mutation in the PIK3CA gene. [0673] Embodiment 43: The method, compound, or use of any one of the preceding embodiments, wherein the cancer is characterized by at least one oncogenic variant of the PI3KĮ protein. [0674] Embodiment 44: The method, compound, or use of any one of the preceding embodiments, wherein the subject has at least one oncogenic mutation in the PIK3CA gene. [0675] Embodiment 45: The method, compound, or use of any one of the preceding embodiments, wherein the subject has at least one tumor and/or cancerous cell that expresses an oncogenic variant of PI3KĮ protein. [0676] Embodiment 46: The method, compound, or use of any one of the preceding embodiments, wherein the oncogenic mutation of the PI3KĮ protein is any one of E542K, E545K and H1047R. [0677] Embodiment 47: The method, compound, or use of any one of the preceding embodiments, wherein the cancer is a carcinoma, a lymphoma, a blastoma, a sarcoma, a leukemia, a brain cancer, a breast cancer, a blood cancer, a bone cancer, a lung cancer, a skin cancer, a liver cancer, an ovarian cancer, a bladder cancer, a renal cancer, a kidney cancer, a gastric cancer, a thyroid cancer, a pancreatic cancer, an esophageal cancer, a prostate cancer, a cervical cancer, a uterine cancer, a stomach cancer, a soft tissue cancer, a laryngeal cancer, a small intestine cancer, a testicular cancer, an anal cancer, a vulvar cancer, a joint cancer, an oral cancer, a pharynx cancer or a colorectal cancer. [0678] Embodiment 1A: A compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R2 is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; 137 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 R3 is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R3a; each R3a independently is C6-C10 aryl optionally substituted with one or more halogen;
Figure imgf000139_0001
alkyl)-*, -(C1-C6 alkyl)-O-*, -O-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-NRT-
Figure imgf000139_0002
-NRT-(C1-C6 alkyl)-*, -(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-O-*, -O-(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-NRT-*, or -NRT-(C1-C6 haloalkyl)- *, wherein * denotes attachment to A; each RT is H or C1-C6 alkyl; A is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RA; each RA independently is oxo, halogen, -OH, cyano, -NH2, -C(=O)OH, -C(=O)O(C1-
Figure imgf000139_0003
C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RA1; and each RA1 independently is H, halogen, -OH, -NH2, -C(=O)OH, -C(=O)(C1-C6 alkyl), - S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C3-C12 cycloalkyl, wherein the C3-C12 cycloalkyl is optionally substituted with -OH; or two RA1, together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C3- C12 cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH2. [0679] Embodiment 2A: A compound of Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is halogen, cyano, C1-C6 alkyl, or C1-C6 haloalkyl; R2 is H, or C1-C6 alkyl; R3 is 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R3a; each R3a independently is C6-C10 aryl optionally substituted with one or more halogen; T is -(C1-C6 alkyl)-*, or -(C1-C6 alkyl)-NRT-*, wherein * denotes attachment to A; 138 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 each RT is H; A is C6-C10 aryl optionally substituted with one or more RA; each RA independently is -NH2, -C(=O)OH, -C(=O)O(C1-C6 alkyl), or -S(=O)2(C1-C6 alkyl). [0680] Embodiment 3A: The compound of any one of the preceding embodiments, wherein R1 is halogen or cyano. [0681] Embodiment 4A: The compound of any one of the preceding embodiments, wherein R1 is C1-C6 alkyl or C1-C6 haloalkyl. [0682] Embodiment 5A: The compound of any one of the preceding embodiments, wherein R2 is H. [0683] Embodiment 6A: The compound of any one of the preceding embodiments, wherein R2 is C1-C6 alkyl. [0684] Embodiment 7A: The compound of any one of the preceding embodiments, wherein R3 is 3- to 12-membered heterocycloalkyl optionally substituted with one or more R3a. [0685] Embodiment 8A: The compound of any one of the preceding embodiments, wherein R3 is 5- to 10-membered heteroaryl optionally substituted with one or more R3a. [0686] Embodiment 9A: The compound of any one of the preceding embodiments, wherein each R3a independently is C6-C10 aryl substituted with one or more halogen. [0687] Embodiment 10A: The compound of any one of the preceding embodiments, wherein T is -(C1-C6 alkyl)-*, wherein * denotes attachment to A. [0688] Embodiment 11A: The compound of any one of the preceding embodiments, wherein T is -(C1-C6 alkyl)-NRT-*, wherein * denotes attachment to A. [0689] Embodiment 12A: The compound of any one of the preceding embodiments, wherein each RT is H. [0690] Embodiment 13A: The compound of any one of the preceding embodiments, wherein A is C6-C10 aryl optionally substituted with one or more RA. [0691] Embodiment 14A: The compound of any one of the preceding embodiments, wherein A is phenyl substituted with one or more RA. [0692] Embodiment 15A: The compound of any one of the preceding embodiments, wherein each RA independently is -NH2. [0693] Embodiment 16A: The compound of any one of the preceding embodiments, wherein each RA independently is -C(=O)OH, -C(=O)O(C1-C6 alkyl),
Figure imgf000140_0001
alkyl). 139 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0694] Embodiment 17A: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-a), (I-b), (I-c), (I-d), (I-e), or (I-f), or a pharmaceutically acceptable salt or stereoisomer thereof. [0695] Embodiment 18A: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-g), or a pharmaceutically acceptable salt or stereoisomer thereof. [0696] Embodiment 19A: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-i), or a pharmaceutically acceptable salt or stereoisomer thereof. [0697] Embodiment 20A: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-j), or a pharmaceutically acceptable salt or stereoisomer thereof. [0698] Embodiment 21A: The compound of any one of the preceding embodiments, wherein the compound is of Formula (I-k), or a pharmaceutically acceptable salt or stereoisomer thereof. [0699] Embodiment 22A: The compound of any one of the preceding embodiments, wherein the compound is selected from a compound described in Table 1, or a pharmaceutically acceptable salt or stereoisomer thereof. [0700] Embodiment 23A: A compound obtainable by, or obtained by, a method described herein; optionally, the method comprises one or more steps described in Schemes 1-2. [0701] Embodiment 24A: A pharmaceutical composition comprising the compound of any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. [0702] Embodiment 25A: The pharmaceutical composition of any one of the preceding embodiments, wherein the compound is selected from a compound described in Table 1. [0703] Embodiment 26A: A method of modulating PI3KĮ activity, comprising contacting a cell with an effective amount of the compound of any one of the preceding embodiments; optionally the activity is in vitro or in vivo. [0704] Embodiment 27A: A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition of any one of the preceding embodiments. 140 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0705] Embodiment 28A: The compound or pharmaceutical composition of any one of the preceding embodiments for use in modulating PI3KĮ activity; optionally, the activity is in vitro or in vivo. [0706] Embodiment 29A: The compound or pharmaceutical composition of any one of the preceding embodiments for use in treating or preventing a disease or disorder. [0707] Embodiment 30A: Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for modulating PI3KĮ activity; optionally, the activity is in vitro or in vivo. [0708] Embodiment 31A: Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for treating or preventing a disease or disorder. [0709] Embodiment 32A: The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is a disease or disorder in which PI3KĮ activity is implicated. [0710] Embodiment 33A: The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal (CLOVES) syndrome. [0711] Embodiment 34A: The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is PIK3CA-related overgrowth syndrome. [0712] Embodiment 35A: The method, compound, pharmaceutical composition, or use of any one of the preceding embodiments, wherein the disease or disorder is cancer. [0713] Embodiment 36A: A method of treating or preventing cancer in a subject, the method comprising administering to the subject a compound of any one of the preceding embodiments. [0714] Embodiment 37A: A compound of any one of the preceding embodiments for treating or preventing cancer in a subject. [0715] Embodiment 38A: Use of the compound of any one of the preceding embodiments in the manufacture of a medicament for treating or preventing cancer in a subject. [0716] Embodiment 39A: Use of the compound of any one of the preceding embodiments for treating or preventing cancer in a subject. [0717] Embodiment 40A: The method, compound, or use of any one of the preceding embodiments, wherein the cancer is characterized by at least one oncogenic mutation in the PIK3CA gene. 141 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 [0718] Embodiment 41A: The method, compound, or use of any one of the preceding embodiments, wherein the cancer is characterized by at least one oncogenic variant of the PI3KĮ protein. [0719] Embodiment 42A: The method, compound, or use of any one of the preceding embodiments, wherein the subject has at least one oncogenic mutation in the PIK3CA gene. [0720] Embodiment 43A: The method, compound, or use of any one of the preceding embodiments, wherein the subject has at least one tumor and/or cancerous cell that expresses an oncogenic variant of PI3KĮ protein. [0721] Embodiment 44A: The method, compound, or use of any one of the preceding embodiments, wherein the oncogenic mutation of the PI3KĮ protein is any one of E542K, E545K and H1047R. [0722] Embodiment 45A: The method, compound, or use of any one of the preceding embodiments, wherein the cancer is a carcinoma, a lymphoma, a blastoma, a sarcoma, a leukemia, a brain cancer, a breast cancer, a blood cancer, a bone cancer, a lung cancer, a skin cancer, a liver cancer, an ovarian cancer, a bladder cancer, a renal cancer, a kidney cancer, a gastric cancer, a thyroid cancer, a pancreatic cancer, an esophageal cancer, a prostate cancer, a cervical cancer, a uterine cancer, a stomach cancer, a soft tissue cancer, a laryngeal cancer, a small intestine cancer, a testicular cancer, an anal cancer, a vulvar cancer, a joint cancer, an oral cancer, a pharynx cancer or a colorectal cancer. EQUIVALENTS [0723] The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference. [0724] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto. 142 289225266 v1

Claims

Attorney Docket No. ASET-039/001WO 325190-2191 CLAIMS: 1. A compound of Formula (I):
Figure imgf000144_0001
an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R2 is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R3 is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R3a; each R3a independently is halogen, C1-C6 alkyl, or C6-C10 aryl, wherein the C1-C6 alkyl or C6-C10 aryl is optionally substituted with one or more halogen; T is -O-*, -NRT-*, -C(=O)NRT-*, -NRTC(=O)-*, -(C1-C6 alkyl)-*, -(C1-C6 alkyl)-O-*, -O-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-O-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-NRT-*, -NRT-(C1-C6 alkyl)-*, -(C1-C6 alkyl)-NRT-(C1-C6 alkyl)-*, -(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-O-*, - O-(C1-C6 haloalkyl)-*, -(C1-C6 haloalkyl)-NRT-*, or -NRT-(C1-C6 haloalkyl)-*, wherein * denotes attachment to A; each RT is H or C1-C6 alkyl; A is C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6- C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RA; each RA independently is oxo, halogen, -OH, cyano, -NH2, -C(=O)OH, -C(=O)O(C1- C6 alkyl), -C(=O)N(RA1)2, -C(=O)N(ORA1)RA1, -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, - S(=O)(=NRA1)RA1, -S(=O)2N(RA1)2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl, wherein the -C(=O)O(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -P(=O)(C1-C6 alkyl)2, -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1- C6 alkoxyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RA1; and each RA1 independently is oxo, H, halogen, -OH, -NH2, -C(=O)OH, -C(=O)(C1-C6 alkyl), -C(=O)((C1-C6 alkyl)-OH), -S(=O)2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 143 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 alkynyl, C1-C6 alkoxyl, or C3-C12 cycloalkyl, wherein the C3-C12 cycloalkyl is optionally substituted with -OH; or two RA1, together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C3-C12 cycloalkyl, wherein the 3- to 12-membered heterocycloalkyl or C3- C12 cycloalkyl is optionally substituted with one or more oxo, halogen, cyano, -OH, or -NH2. 2. A compound of Formula (I): ;
Figure imgf000145_0001
an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is halogen, cyano, C1-C6 alkyl, or C1-C6 haloalkyl; R2 is H, or C1-C6 alkyl; R3 is 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R3a; each R3a independently is C6-C10 aryl optionally substituted with one or more halogen; T is -(C1-C6 alkyl)-*, or -(C1-C6 alkyl)-NRT-*, wherein * denotes attachment to A; each RT is H; A is C6-C10 aryl optionally substituted with one or more RA; each RA independently is halogen, -NH2, -C(=O)OH, -C(=O)O(C1-C6 alkyl), - S(=O)2(C1-C6 alkyl), or 3- to 12-membered heterocycloalkyl. 3. The compound of any one of the preceding claims, wherein: R1 is halogen or cyano; or R1 is C1-C6 alkyl or C1-C6 haloalkyl. 4. The compound of any one of the preceding claims, wherein: R2 is H; or R2 is C1-C6 alkyl. 5. The compound of any one of the preceding claims, wherein: 144 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 R3 is 3- to 12-membered heterocycloalkyl optionally substituted with one or more R3a; or R3 is 5- to 10-membered heteroaryl optionally substituted with one or more R3a. 6. The compound of any one of the preceding claims, wherein each R3a independently is C6-C10 aryl substituted with one or more halogen. 7. The compound of any one of the preceding claims, wherein: T is -(C1-C6 alkyl)-*, wherein * denotes attachment to A; or T is -(C1-C6 alkyl)-NRT-*, wherein * denotes attachment to A. 8. The compound of any one of the preceding claims, wherein each RT is H. 9. The compound of any one of the preceding claims, wherein A is C6-C10 aryl optionally substituted with one or more RA. 10. The compound of any one of the preceding claims, wherein A is phenyl substituted with one or more RA. 11. The compound of any one of the preceding claims, wherein: each RA independently is -NH2; each RA independently is -C(=O)OH, -C(=O)O(C1-C6 alkyl), or -S(=O)2(C1-C6 alkyl); or each RA independently is 3- to 12-membered heterocycloalkyl. 12. The compound of any one of the preceding claims, wherein the compound is of Formula (I-a), (I-b), (I-c), (I-d), (I-e), or (I-f):
Figure imgf000146_0001
145 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000147_0001
or a pharmaceutically acceptable salt or stereoisomer thereof. 13. The compound of any one of the preceding claims, wherein the compound is of Formula (I-g), (I-h), (I-i), (I-j), or (I-k):
Figure imgf000147_0002
146 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191
Figure imgf000148_0001
(I-k) or a pharmaceutically acceptable salt or stereoisomer thereof. 14. The compound of any one of the preceding claims, wherein the compound is selected from a compound described in Table 1 or Table 2, or a pharmaceutically acceptable salt or stereoisomer thereof. 15. A compound obtainable by, or obtained by, a method described herein; optionally, the method comprises one or more steps described in Schemes 1-2. 16. A pharmaceutical composition comprising the compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. 147 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 17. The pharmaceutical composition of any one of the preceding claims, wherein the compound is selected from a compound described in Table 1 or Table 2. 18. A method of modulating PI3KĮ activity, comprising contacting a cell with an effective amount of the compound of any one of the preceding claims; optionally the activity is in vitro or in vivo. 19. A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition of any one of the preceding claims. 20. The compound or pharmaceutical composition of any one of the preceding claims for use in modulating PI3KĮ activity; optionally, the activity is in vitro or in vivo. 21. The compound or pharmaceutical composition of any one of the preceding claims for use in treating or preventing a disease or disorder. 22. Use of the compound of any one of the preceding claims in the manufacture of a medicament for modulating PI3KĮ activity; optionally, the activity is in vitro or in vivo. 23. Use of the compound of any one of the preceding claims in the manufacture of a medicament for treating or preventing a disease or disorder. 24. The method, compound, pharmaceutical composition, or use of any one of the preceding claims, wherein the disease or disorder is a disease or disorder in which PI3KĮ activity is implicated. 25. The method, compound, pharmaceutical composition, or use of any one of the preceding claims, wherein the disease or disorder is congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal (CLOVES) syndrome. 26. The method, compound, pharmaceutical composition, or use of any one of the preceding claims, wherein the disease or disorder is PIK3CA-related overgrowth syndrome. 148 289225266 v1 Attorney Docket No. ASET-039/001WO 325190-2191 27. The method, compound, pharmaceutical composition, or use of any one of the preceding claims, wherein the disease or disorder is cancer. 28. The method, compound, or use of any one of the preceding claims, wherein the cancer is a carcinoma, a lymphoma, a blastoma, a sarcoma, a leukemia, a brain cancer, a breast cancer, a blood cancer, a bone cancer, a lung cancer, a skin cancer, a liver cancer, an ovarian cancer, a bladder cancer, a renal cancer, a kidney cancer, a gastric cancer, a thyroid cancer, a pancreatic cancer, an esophageal cancer, a prostate cancer, a cervical cancer, a uterine cancer, a stomach cancer, a soft tissue cancer, a laryngeal cancer, a small intestine cancer, a testicular cancer, an anal cancer, a vulvar cancer, a joint cancer, an oral cancer, a pharynx cancer or a colorectal cancer. 149 289225266 v1
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