WO2024026424A1 - Dérivés de quinazolinone et utilisations associées - Google Patents

Dérivés de quinazolinone et utilisations associées Download PDF

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WO2024026424A1
WO2024026424A1 PCT/US2023/071148 US2023071148W WO2024026424A1 WO 2024026424 A1 WO2024026424 A1 WO 2024026424A1 US 2023071148 W US2023071148 W US 2023071148W WO 2024026424 A1 WO2024026424 A1 WO 2024026424A1
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alkyl
compound
cancer
independently
cycloalkyl
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PCT/US2023/071148
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English (en)
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Etienne DARDENNE
Iwona WRONA
Ivan JEWETT
Istvan J. Enyedy
Fernando Padilla
Yelena ARNAUTOVA
Pui Yee Ng
Matthew C. Lucas
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Black Diamond Therapeutics, Inc.
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Publication of WO2024026424A1 publication Critical patent/WO2024026424A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • 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
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D401/14—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 three or more hetero rings
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    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D413/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems

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.
  • PI3K inhibitors including improved inhibitors of the PI3K ⁇ catalytic subunit.
  • PI3K inhibitors that specifically target mutated forms of PI3K ⁇ over wild-type PI3K ⁇ .
  • the present disclosure provides a compound of Formula (I): an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, or C 1 -C 6 haloalkyl; R 2 is H, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkyl, C 3 - C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl, wherein the C1-C6 alkyl, C 2 -C 6 alken
  • 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 1-4).
  • 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 1-320).
  • 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 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 quinazolinone 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 [0025] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below. [0026] 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 and C 3 , C 4 , C 5 or C 6 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., C 1 -C 6 for straight chain, C3-C6 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.
  • C3-C6 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 alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sul
  • 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., C2-C6 for straight chain, C3-C6 for branched chain).
  • C 2 -C 6 includes alkynyl groups containing two to six carbon atoms.
  • C 3 - C6 includes alkynyl groups containing three to six carbon atoms.
  • 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.
  • C 2 - C 6 alkenylene linker is intended to include C 2 , C 3 , C 4 , C 5 and C 6 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.
  • 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-
  • 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, amino (including alkylamino, dialkylamino
  • 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. [0042] 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.
  • 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. Further, it should be understood that the order of steps order for performing certain actions is immaterial so long as the invention remains operable.
  • 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, 5 th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M.
  • 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 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.
  • the present disclosure also provides pharmaceutical 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 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, 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. [0072] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect.
  • 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.
  • 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.
  • pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
  • the appropriate formulation is dependent upon the route of administration chosen.
  • 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.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
  • the carrier can be a solvent or dispersion 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.
  • 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
  • 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.
  • 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.
  • 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 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. [0080] 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 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 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- 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.
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • 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.
  • 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.
  • One skilled in the art will recognise the advantages of certain routes of administration.
  • 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.
  • Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19 th edition, Mack Publishing Co., Easton, PA (1995).
  • 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 provided examples illustrate different components and methodology useful in 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.
  • 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.
  • the present disclosure provides a compound of Formula (I): ; (I) an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, or C 1 -C 6 haloalkyl; R 2 is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkyl, C 3 - C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl, wherein the C1-
  • the present disclosure provides a compound of Formula (I), wherein: R 1 is H, halogen, C1-C6 alkyl, or C1-C6 alkoxyl; R 2 is H, halogen; R 3 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 12 cycloalkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more R 3a ; each R 3a independently is -OH, cyano, C 1 -C 6 alkoxyl, C 3 -C 12 cycloalkyl, or 3- to 12- membered heterocycloalkyl; R 4 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 4a ; each R 4a independently is
  • the present disclosure provides a compound of Formula (I): ; an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, or C 1 -C 6 haloalkyl; R 2 is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkyl, C 3 - C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl, wherein the C1-C6 alkyl, C2-C6
  • variables R 1 , R 2 , R 3 , R 3a , R 4 , R 4a , R 5 , 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 , R 4 , R 4a , R 5 , 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 , R 4 , R 4a , R 5 , T, R T , A, R A and R A1 .
  • R 1 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.
  • R 1 is H or halogen.
  • R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, or C1-C6 haloalkyl.
  • R 1 is H. [0104] In some embodiments, R 1 is halogen. [0105] In some embodiments, R 1 is F, Cl, Br, or I. In some embodiments, R 1 is F, Cl, or Br. In some embodiments, R 1 is F or Cl. [0106] In some embodiments, R 1 is F. In some embodiments, R 1 is Cl. In some embodiments, R 1 is Br. In some embodiments, R 1 is I. [0107] In some embodiments, R 1 is C 1 -C 6 alkyl or C 1 -C 6 alkoxyl. [0108] In some embodiments, R 1 is C 1 -C 6 alkyl. [0109] In some embodiments, R 1 is methyl.
  • 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. In some embodiments, R 1 is tertbutyl.
  • R 1 is C1-C6 alkoxyl. [0111] In some embodiments, R 1 is methoxy. In some embodiments, R 1 is ethoxy. In some embodiments, R 1 is propoxy. In some embodiments, R 1 is butoxy. In some embodiments, R 1 is pentoxy. In some embodiments, R 1 is hexoxy. [0112] In some embodiments, R 2 is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. [0113] In some embodiments, R 2 is H, halogen, or cyano.
  • R 2 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. [0115] In some embodiments, R 2 is H, or halogen. [0116] In some embodiments, R 2 is H. [0117] In some embodiments, R 2 is halogen. [0118] In some embodiments, R 2 is F, Cl, Br, or I. In some embodiments, R 2 is F, Cl, or Br. In some embodiments, R 2 is F or Cl. [0119] In some embodiments, R 2 is F. In some embodiments, R 2 is Cl. In some embodiments, R 2 is Br. In some embodiments, R 2 is I.
  • R 3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkyl, C 3 -C 12 cycloalkyl, or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R 3a .
  • R 3 is H. [0122] In some embodiments, R 3 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl, wherein the C1-C6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkyl, C 3 -C 12 cycloalkyl, or 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R 3a .
  • R 3 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C 1 -C 6 haloalkyl, C 3 -C 12 cycloalkyl, or 3- to 12-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkyl, C 3 -C 12 cycloalkyl, or 3- to 12-membered heterocycloalkyl, is substituted with one or more R 3a .
  • R 3 is C1-C6 alkyl optionally substituted with one or more R 3a .
  • R 3 is C 1 -C 6 alkyl substituted with one or more R 3a .
  • R 3 is methyl optionally substituted with one or more R 3a .
  • R 3 is ethyl optionally substituted with one or more R 3a .
  • R 3 is propyl optionally substituted with one or more R 3a .
  • R 3 is butyl optionally substituted with one or more R 3a .
  • R 3 is pentyl optionally substituted with one or more R 3a .
  • R 3 is hexyl optionally substituted with one or more R 3a .
  • R 3 is isopropyl optionally substituted with one or more R 3a .
  • R 3 is isobutyl optionally substituted with one or more R 3a .
  • R 3 is isopentyl optionally substituted with one or more R 3a .
  • R 3 is isohexyl optionally substituted with one or more R 3a .
  • R 3 is secbutyl optionally substituted with one or more R 3a .
  • R 3 is secpentyl optionally substituted with one or more R 3a .
  • R 3 is sechexyl optionally substituted with one or more R 3a . In some embodiments, R 3 is tertbutyl optionally substituted with one or more R 3a . [0127] In some embodiments, R 3 is methyl substituted with one or more R 3a . In some embodiments, R 3 is ethyl substituted with one or more R 3a . In some embodiments, R 3 is propyl substituted with one or more R 3a . In some embodiments, R 3 is butyl substituted with one or more R 3a . In some embodiments, R 3 is pentyl substituted with one or more R 3a .
  • R 3 is hexyl substituted with one or more R 3a . In some embodiments, R 3 is isopropyl substituted with one or more R 3a . In some embodiments, R 3 is isobutyl substituted with one or more R 3a . In some embodiments, R 3 is isopentyl substituted with one or more R 3a . In some embodiments, R 3 is isohexyl substituted with one or more R 3a . In some embodiments, R 3 is secbutyl substituted with one or more R 3a . In some embodiments, R 3 is secpentyl substituted with one or more R 3a . In some embodiments, R 3 is sechexyl substituted with one or more R 3a .
  • R 3 is tertbutyl substituted with one or more R 3a .
  • R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl.
  • R 3 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 12 cycloalkyl.
  • R 3 is C 1 -C 6 alkyl.
  • R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is propyl. In some embodiments, R 3 is butyl. In some embodiments, R 3 is pentyl. In some embodiments, R 3 is hexyl. In some embodiments, R 3 is isopropyl. In some embodiments, R 3 is isobutyl. In some embodiments, R 3 is isopentyl. In some embodiments, R 3 is isohexyl. In some embodiments, R 3 is secbutyl. In some embodiments, R 3 is secpentyl. In some embodiments, R 3 is sechexyl.
  • R 3 is tertbutyl. [0132] In some embodiments, R 3 is C1-C6 haloalkyl. [0133] In some embodiments, R 3 is halomethyl. In some embodiments, R 3 is haloethyl. In some embodiments, R 3 is halopropyl. In some embodiments, R 3 is halobutyl. In some embodiments, R 3 is halopentyl. In some embodiments, R 3 is halohexyl. [0134] In some embodiments, R 3 is C3-C12 cycloalkyl.
  • each R 3a independently is halogen, -OH, cyano, C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl.
  • each R 3a independently is -OH, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C 3 -C 12 cycloalkyl, or 3- to 12-membered heterocycloalkyl.
  • each R 3a independently is halogen. [0138] In some embodiments, each R 3a independently is -OH or cyano. [0139] In some embodiments, each R 3a independently is -OH. [0140] In some embodiments, each R 3a independently is cyano. [0141] In some embodiments, each R 3a independently is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C1-C6 alkoxyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl.
  • each R 3a independently is C1-C6 alkoxyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocycloalkyl. [0143] In some embodiments, each R 3a independently is C 1 -C 6 alkoxyl. [0144] In some embodiments, each R 3a independently is C3-C12 cycloalkyl. [0145] In some embodiments, each R 3a independently is 3- to 12-membered heterocycloalkyl. [0146] In some embodiments, two R 3a , together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl or C 3 -C 12 cycloalkyl.
  • two R 3a together with the atoms they are attached, form a 3- to 12-membered heterocycloalkyl.
  • two R 3a together with the atoms they are attached, form a C 3 - C12 cycloalkyl.
  • R 4 is –(C 1 -C 6 alkyl)-(3- to 12-membered heterocycloalkyl), 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 R 4a .
  • R 4 is C 3 -C 12 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 R 4a .
  • R 4 is –(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl).
  • R 4 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, C6-C10 aryl, or 5- to 10-membered heteroaryl is substituted with one or more R 4a .
  • R 4 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 4a .
  • R 4 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 4a .
  • R 4 is 3- to 12-membered heterocycloalkyl optionally substituted with one or more R 4a .
  • R 4 is 3- to 12-membered heterocycloalkyl substituted with one or more R 4a .
  • R 4 is a bicyclic 3- to 12-membered heterocycloalkyl.
  • R 4 is a fused 3- to 12-membered heterocycloalkyl.
  • R 4 is a spiro 3- to 12-membered heterocycloalkyl.
  • R 4 is a bridged 3- to 12-membered heterocycloalkyl.
  • R 4 is morpholinyl optionally substituted with one or more R 4a .
  • R 4 is piperidinyl optionally substituted with one or more R 4a . In some embodiments, R 4 is piperazinyl optionally substituted with one or more R 4a . In some embodiments, R 4 is azetidinyl optionally substituted with one or more R 4a . In some embodiments, R 4 is 1,4-oxazepanyl optionally substituted with one or more R 4a . In some embodiments, R 4 is 2-oxa-6-azaspiro[3.4]octanyl optionally substituted with one or more R 4a . In some embodiments, R 4 is 2-oxa-7-azaspiro[3.5]nonanyl optionally substituted with one or more R 4a .
  • R 4 is 6-azaspiro[3.4]octanyl optionally substituted with one or more R 4a .
  • R 4 is 2-oxa-6-azaspiro[3.5]nonanyl optionally substituted with one or more R 4a .
  • R 4 is 2-oxa-6-azaspiro[3.3]heptanyl optionally substituted with one or more R 4a .
  • R 4 is 3-azabicyclo[3.1.0]hexanyl optionally substituted with one or more R 4a .
  • R 4 is 2- azaspiro[3.5]nonanyl optionally substituted with one or more R 4a .
  • R 4 is hexahydro-1H-furo[3,4-c]pyrrolyl optionally substituted with one or more R 4a .
  • R 4 is pyrrolidinyl optionally substituted with one or more R 4a .
  • R 4 is octahydropyrrolo[1,2-a]pyrazinyl optionally substituted with one or more R 4a .
  • R 4 is tetrahydropyranyl optionally substituted with one or more R 4a .
  • R 4 is 2-oxa-5-azabicyclo[2.2.1]heptanyl optionally substituted with one or more R 4a .
  • R 4 is 7-oxa-2-azaspiro[3.5]nonanyl optionally substituted with one or more R 4a .
  • R 4 is morpholinyl substituted with one or more R 4a .
  • R 4 is piperidinyl substituted with one or more R 4a .
  • R 4 is piperazinyl substituted with one or more R 4a .
  • R 4 is azetidinyl substituted with one or more R 4a .
  • R 4 is 1,4-oxazepanyl substituted with one or more R 4a .
  • R 4 is 2-oxa-6-azaspiro[3.4]octanyl substituted with one or more R 4a . In some embodiments, R 4 is 2-oxa-7-azaspiro[3.5]nonanyl substituted with one or more R 4a . In some embodiments, R 4 is 6-azaspiro[3.4]octanyl substituted with one or more R 4a . In some embodiments, R 4 is 2-oxa-6-azaspiro[3.5]nonanyl substituted with one or more R 4a . In some embodiments, R 4 is 2-oxa-6-azaspiro[3.3]heptanyl substituted with one or more R 4a .
  • R 4 is 3-azabicyclo[3.1.0]hexanyl substituted with one or more R 4a . In some embodiments, R 4 is 2-azaspiro[3.5]nonanyl substituted with one or more R 4a . In some embodiments, R 4 is hexahydro-1H-furo[3,4-c]pyrrolyl substituted with one or more R 4a . In some embodiments, R 4 is pyrrolidinyl substituted with one or more R 4a . In some embodiments, R 4 is octahydropyrrolo[1,2-a]pyrazinyl substituted with one or more R 4a .
  • R 4 is tetrahydropyranyl substituted with one or more R 4a .
  • R 4 is 2-oxa-5-azabicyclo[2.2.1]heptanyl substituted with one or more R 4a .
  • R 4 is 7-oxa-2-azaspiro[3.5]nonanyl substituted with one or more R 4a .
  • R 4 is C 3 -C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl.
  • R 4 is 3- to 12-membered heterocycloalkyl, or 5- to 10- membered heteroaryl. [0164] In some embodiments, R 4 is 3- to 12-membered heterocycloalkyl. [0165] In some embodiments, R 4 is morpholinyl. In some embodiments, R 4 is piperidinyl. In some embodiments, R 4 is piperazinyl. In some embodiments, R 4 is azetidinyl. In some embodiments, R 4 is 1,4-oxazepanyl. In some embodiments, R 4 is 2-oxa-6-azaspiro[3.4]octanyl.
  • R 4 is 2-oxa-7-azaspiro[3.5]nonanyl. In some embodiments, R 4 is 6- azaspiro[3.4]octanyl. In some embodiments, R 4 is 2-oxa-6-azaspiro[3.5]nonanyl. In some embodiments, R 4 is 2-oxa-6-azaspiro[3.3]heptanyl. In some embodiments, R 4 is 3- azabicyclo[3.1.0]hexanyl. In some embodiments, R 4 is 2-azaspiro[3.5]nonanyl. In some embodiments, R 4 is hexahydro-1H-furo[3,4-c]pyrrolyl. In some embodiments, R 4 is pyrrolidinyl.
  • R 4 is octahydropyrrolo[1,2-a]pyrazinyl. In some embodiments, R 4 is tetrahydropyranyl. In some embodiments, R 4 is 2-oxa-5- azabicyclo[2.2.1]heptanyl. In some embodiments, R 4 is 7-oxa-2-azaspiro[3.5]nonanyl. [0166] In some embodiments, R 4 is 5- to 10-membered heteroaryl. [0167] In some embodiments, R 4 is pyridinyl.
  • each R 4a independently is halogen, C1-C6 alkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl.
  • each R 4a independently is halogen.
  • each R 4a independently is F, Cl, Br, or I.
  • each R 4a independently is F, Cl, or Br.
  • each R 4a independently is F or Cl.
  • each R 4a independently is F.
  • each R 4a independently is C 6 -C 10 aryl optionally substituted with one or more halogen or cyano.
  • each R 4a independently is 3- to 12-membered heterocycloalkyl optionally substituted with one or more halogen or cyano.
  • each R 4a independently is 5- to 10-membered heteroaryl optionally substituted with one or more halogen or cyano.
  • each R 4a independently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl. [0179] In some embodiments, each R 4a independently is C1-C6 alkyl, C1-C6 haloalkyl, or C1- C6 alkoxyl. [0180] In some embodiments, each R 4a independently is C 1 -C 6 alkyl. [0181] In some embodiments, each R 4a independently is methyl.
  • each R 4a independently is ethyl. In some embodiments, each R 4a independently is propyl. In some embodiments, each R 4a independently is butyl. In some embodiments, each R 4a independently is pentyl. In some embodiments, each R 4a independently is hexyl. In some embodiments, each R 4a independently is isopropyl. In some embodiments, each R 4a independently is isobutyl. In some embodiments, each R 4a independently is isopentyl. In some embodiments, each R 4a independently is isohexyl. In some embodiments, each R 4a independently is secbutyl. In some embodiments, each R 4a independently is secpentyl.
  • each R 4a independently is sechexyl. In some embodiments, each R 4a independently is tertbutyl. [0182] In some embodiments, each R 4a independently is C 1 -C 6 haloalkyl. [0183] In some embodiments, each R 4a independently is halomethyl. In some embodiments, each R 4a independently is haloethyl. In some embodiments, each R 4a independently is halopropyl. In some embodiments, each R 4a independently is halobutyl. In some embodiments, each R 4a independently is halopentyl. In some embodiments, each R 4a independently is halohexyl.
  • each R 4a independently is C1-C6 alkoxyl. [0185] In some embodiments, each R 4a independently is methoxy. In some embodiments, each R 4a independently is ethoxy. In some embodiments, each R 4a independently is propoxy. In some embodiments, each R 4a independently is butoxy. In some embodiments, each R 4a independently is pentoxy. In some embodiments, each R 4a independently is hexoxy. [0186] In some embodiments, R 5 is H, halogen, cyano, C 1 -C 6 alkyl, or C 1 -C 6 alkoxyl.
  • R 5 is H, halogen, cyano, or C 1 -C 6 alkoxyl. [0188] In some embodiments, R 5 is H, halogen, or cyano. [0189] In some embodiments, R 5 is H. [0190] In some embodiments, R 5 is C 1 -C 6 alkyl. [0191] In some embodiments, R 5 is C1-C6 alkoxyl. [0192] In some embodiments, R 5 is methoxy. In some embodiments, R 5 is ethoxy. In some embodiments, R 5 is propoxy. In some embodiments, R 5 is butoxy. In some embodiments, R 5 is pentoxy. In some embodiments, R 5 is hexoxy.
  • 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)-*, wherein * denotes attachment to A.
  • T is -(C3-C12 cycloalkyl)-*, wherein * denotes attachment to A.
  • T is branched -(C1-C6 alkyl)-*, wherein * denotes attachment to A.
  • T is -CH(CH3)-*, wherein * denotes attachment to A.
  • T is -(C1-C6 alkyl)-O-*, wherein * denotes attachment to A.
  • T is -CH(CH 3 )-O-*, wherein * denotes attachment to A.
  • T is -(C 1 -C 6 alkyl)-NR T -*, wherein * denotes attachment to A.
  • T is -(C1-C6 alkyl)-NR T -(C1-C6 alkyl)-*, 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 C 1 -C 6 alkyl.
  • R T is H or C1-C6 alkyl.
  • R T is H.
  • R T is C 1 -C 6 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, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R A .
  • 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, 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, C 6 -C 10 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, C 6 -C 10 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 C6-C10 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 C6-C10 aryl.
  • A is phenyl optionally substituted with one or more R A .
  • A is phenyl substituted with one or more R A .
  • A is phenyl.
  • A is 5- to 10-membered heteroaryl optionally substituted with one or more R A .
  • A is 5- to 10-membered heteroaryl substituted with one or more R A .
  • A is 5- to 10-membered heteroaryl.
  • A is 2,3-dihydrobenzo[b]thiophene optionally substituted with one or more R A .
  • A is pyrazolyl optionally 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 . [0229] In some embodiments, A is 2,3-dihydrobenzo[b]thiophene substituted with one or more R A . In some embodiments, 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 -NH 2 .
  • each R A independently is oxo.
  • each R A independently is halogen.
  • each R A independently is F, Cl, Br, or I.
  • each R A independently is F, Cl, or Br.
  • each R A independently is F or Cl.
  • each R A independently is F.
  • each R A independently is Cl.
  • each R A independently independently is Br.
  • each R A independently independently is I.
  • each R A independently is C1-C6 alkyl optionally substituted with one or more R A1 .
  • each R A independently is C 1 -C 6 alkyl substituted with one or more R A1 .
  • each R A independently is C1-C6 alkyl.
  • each R A independently is methyl optionally substituted with one or more R A1 .
  • each R A independently is ethyl optionally substituted with one or more R A1 .
  • each R A independently independently is propyl optionally substituted with one or more R A1 .
  • 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 . In some embodiments, 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 .
  • 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 . In some embodiments, each R A independently is tertbutyl optionally substituted with one or more R A1 . [0262] In some embodiments, 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 . In some embodiments, each R A independently is propyl substituted with one or more R A1 . In some embodiments, each R A independently is butyl substituted with one or more R A1 . In some embodiments, each R A independently is pentyl substituted with one or more R A1 . In some embodiments, 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 .
  • 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 . In some embodiments, 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 . [0263] In some embodiments, each R A independently is methyl. In some embodiments, each R A independently is ethyl.
  • 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. In some embodiments, 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, oxo, halogen, -OH, or -NH 2 .
  • each R A1 independently is H, halogen, -OH, or -NH 2 .
  • each R A1 independently is H. [0272] In some embodiments, each R A1 independently is oxo. [0273] In some embodiments, each R A1 independently is halogen. [0274] In some embodiments, 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. [0275] 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. [0276] In some embodiments, each R A1 independently is -OH.
  • each R A1 independently is -NH2.
  • each R A1 independently is C1-C6 alkyl.
  • each R A1 independently is C 1 -C 6 alkyl optionally substituted with one or more R A2 .
  • each R A1 independently is C3-C12 cycloalkyl optionally substituted with one or more R A2 .
  • each R A1 independently is C3-C12 cycloalkyl optionally substituted with -OH.
  • each R A1 independently is C 3 -C 12 cycloalkyl substituted with - OH.
  • each R A1 independently is C3-C12 cycloalkyl.
  • each R A2 independently is -OH, cyano, C 1 -C 6 alkoxyl, C 3 -C 12 cycloalkyl, or C 3 -C 12 heterocycloalkyl, wherein the C 3 -C 12 cycloalkyl or C 3 -C 12 heterocycloalkyl is optionally substituted with one or more halogen or C1-C6 alkyl.
  • each R A2 independently is -OH.
  • each R A2 independently is cyano. [0298] In some embodiments, each R A2 independently is C1-C6 alkoxyl. [0299] In some embodiments, each R A2 independently is C 3 -C 12 cycloalkyl. [0300] In some embodiments, each R A2 independently is C 3 -C 12 cycloalkyl optionally substituted with one or more halogen or C1-C6 alkyl. [0301] In some embodiments, each R A2 independently is C3-C12 heterocycloalkyl.
  • each R A2 independently is C3-C12 heterocycloalkyl optionally substituted with one or more halogen or C1-C6 alkyl.
  • the compound is of Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), or (I-i): (I-e)
  • the compound is of Formula (I-j): (I-j) or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the compound is of Formula (I-k): (I-k) or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the compound is of Formula (I-l), or Formula (I-m): ; ; (I-m) or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the compound is of Formula (I-n): (I-n) or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the compound is of Formula (I-o): 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.
  • the compound is a compound described in Table 1, or a prodrug or pharmaceutically acceptable salt thereof.
  • the compound is a compound described in Table 1, or a pharmaceutically acceptable salt thereof.
  • the compound is a prodrug of a compound described in Table 1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound described in Table 1.
  • 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 Compo N o. 182 183 184 185 Table 2
  • 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.
  • the isotopic derivative can be prepared using any of a variety of art-recognised techniques.
  • 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.
  • 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 isotopic derivative is a compound described in Table 3, an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • Table 3 [0336]
  • 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 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and/or 36 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, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and/or 36 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, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and 36 S atom(s) is within the scope of the invention.
  • substitution with isotope may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.
  • 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
  • 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
  • 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
  • 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
  • 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.
  • stereoisomers 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.” [0346] As used herein, the term “chiral centre” refers to a carbon atom bonded to four nonidentical substituents. [0347] As used herein, the term “chiral isomer” means a compound with at least one chiral centre.
  • 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.
  • 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).
  • 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. 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.
  • 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
  • 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 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.
  • the present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.
  • 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.
  • 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.
  • 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.
  • 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) spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy.
  • DRIFT Diffuse Reflectance Infrared Fourier Transform
  • NIR Near Infrared
  • solution and/or solid state nuclear magnetic resonance spectroscopy The water content of such crystalline materials may be determined by Karl Fischer analysis.
  • 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 illustrated below
  • imine/enamine amide/imino alcohol
  • amidine/amidine nitroso/oxime
  • thioketone/enethiol nitro/aci-nitro.
  • 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 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. 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.
  • 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 C 1 -C 10 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.
  • Suitable pharmaceutically acceptable ether forming groups 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 C 1-4 alkylamine such as methylamine, a (C 1 -C 4 alkyl) 2 amine 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.
  • an amine such as ammonia
  • a C 1-4 alkylamine such as methylamine
  • a (C 1 -C 4 alkyl) 2 amine such as dimethylamine, N-ethyl-N-methylamine or diethy
  • 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-(C 1 -C 4 alkyl)piperazin-1- ylmethyl.
  • the present disclosure excludes any individual compounds not possessing the biological activity defined herein.
  • Methods of Synthesis [0376] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure. [0377] In some aspects, the present disclosure provides a method of a compound, comprising one or more steps as described herein. [0378] 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.
  • the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein.
  • 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.
  • 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.
  • 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.
  • 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, 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.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • 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.
  • 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.
  • 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, such as acetone,
  • 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.
  • an appropriately substituted anthranilic acid (1) may be reacted with a variety amines utilizing a peptide coupling reagent (e.g.
  • amide derivatives (2) Condensation of amide (2) with a phosgene reagent may provide quinazolinones (3). Substitution of halogen (3) with a variety of amines may afford intermediate (4). Palladium-catalyzed acylation of halide (4) affords keto quinazolinone (5) which then may be undergo reductive amination in the presence of a reducing agent such as sodium cyanoborohydride to afford amine (6). Subsequent alkylation of amine (6) under mild base conditions or coupling with an aryl halide under palladium catalyst may give racemic mixture (7) of Formula (I).
  • Reaction Scheme 1 In some embodiments, racemic mixtures of appropriately substituted quinazolinone (7) may be purified on a chiral column to give arbitrarily assigned pure enantiomers (8) and (9) of Formula (I).
  • Reaction Scheme 2 [0397]
  • quinazolinone ketone (5) may be condensed with tert- butanesulfinamide in the presence of a Lewis acid (e.g. titanium ethoxide) to afford sulfinimine (10). Reduction of sulfinimine (10) with a reducing agent such as borane-THF may yield chiral sulfinamide (11) which can be hydrolyzed to amine (12) under acidic conditions.
  • a Lewis acid e.g. titanium ethoxide
  • Reduction of sulfinimine (10) with a reducing agent such as borane-THF may yield chiral sulfinamide (11) which can be hydrolyzed to amine (12) under acidic conditions.
  • Bio 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 dissociated with TryPLE, washed with media and plated in wells plate.
  • serial dilution of compounds were applied to the cell.
  • p-AKT S473 may be measured using HTRF cellular kit by Cisbio (64AKSPET) according to manufacturer’s protocol.
  • p-AKT S473 levels may be measured using the kit.
  • the cells e.g., MCF10A-PI3K ⁇ -WT, MCF10A- PI3K ⁇ -H1047R and MCF10A- PI3K ⁇ -E545K cells
  • the cells e.g., MCF10A-PI3K ⁇ -WT, MCF10A- PI3K ⁇ -H1047R and MCF10A- PI3K ⁇ -E545K cells
  • 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. In some embodiments, 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.
  • Pharmaceutical Compositions [0405] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient.
  • 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. [0406]
  • 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 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. [0409] 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 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.
  • cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose
  • polyethylene glycols such as polyethylene glycol 300, polyethylene glycol 400
  • carboxymethyl cellulose such as polyethylene glycol 300, polyethylene glycol 400
  • carboxymethyl cellulose such as polyethylene
  • 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.
  • 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.
  • 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, 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, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent
  • 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 (PIP 3 ).
  • PIP 3 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. [0429] 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), the gene can have one or more of the aforementioned types of oncogenic mutations, including combinations of different types of oncogenic mutations.
  • a protein e.g.
  • 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.
  • the protein in the context of a protein (e.g. the PI3K ⁇ protein), the protein can have one or more of the aforementioned types of oncogenic mutations, including combinations of different types of oncogenic mutations.
  • 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
  • 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 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 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.
  • 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.
  • 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. In some embodiments, the compounds of the present disclosure specifically inhibit mutated PI3K ⁇ protein as compared to wild-type PI3K ⁇ protein. [0476] In some embodiments, the compounds of the present disclosure bind to the PI3K ⁇ protein in an allosteric pocket that is in proximity to the 1047 mutational hotspot. [0477] 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.
  • the compound of the present 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.
  • 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 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
  • 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 adjusted the pH to 4 ⁇ 5 with hydrochloric acid (1 M). The mixture was stirred at 25 °C for 0.5 hr, then adjusted to pH 8 ⁇ 9 with saturated sodium bicarbonate solution. Then the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (400 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step 3 Synthesis of 8-(1-aminoethyl)-3,6-dimethyl-2-(piperidin-1-yl)quinazolin- 4(3H)-one
  • 8-acetyl-3,6-dimethyl-2-(1-piperidyl)quinazolin-4-one (0.33 g, 1.10 mmol) in methanol (5 mL) was added ammonium acetate (1.70 g, 22.1 mmol) and sodium cyanoborohydride (69.3 mg, 1.10 mmol). The mixture was stirred at 60 °C for 1 hr.
  • reaction mixture was quenched by saturated ammonium chloride solution (50 mL) at 0 °C, and then diluted with water (30 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (60 mL x 2), dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was poured into water (300 mL) at 25 °C, and then filtered through celite. The filtrate was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step 10 Synthesis of (R)-8-(1-((4-fluoro-2-(piperidin-4-yl)phenyl)amino)ethyl)-3,6- dimethyl-2-(4-methyltetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one [0655] To a solution of tert-butyl (R)-4-(2-((1-(3,6-dimethyl-2-(4-methyltetrahydro-2H- pyran-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)-5-fluorophenyl)piperidine-1- carboxylate (25.0 mg, 42.2 ⁇ mol) in dichloromethane (1 mL) was added trifluoroacetic acid (384 mg, 3.37 mmol).
  • the mixture was stirred at 110 °C for 12 hr under nitrogen atmosphere.
  • the reaction mixture was adjusted to pH 7 ⁇ 8 with saturated sodium bicarbonate solution and then extracted with ethyl acetate (250 mL ⁇ 3).
  • the combined organic layers were washed with brine (250 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was dissolved in dichloromethane (10 mL) and formic acid (10 mL) was stirred at 25 °C for 0.5 hr.
  • the crude product was purified by prep-HPLC (column: Kromasil Eternity XT 250x80mmx10um;mobile phase: [water (ammonia hydroxide v/v)- acetonitrile];gradient:35%-65% B over 20 min) to give (R)-N-((1R)-1-(3-cyclopropyl-6- fluoro-4-oxo-2-(tetrahydro-2H-pyran-3-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2- methylpropane-2-sulfinamide (1.30 g, 2.98 mmol, 56%) as a yellow solid.
  • Step 7 Synthesis of 8-((R)-1-aminoethyl)-3-cyclopropyl-6-fluoro-2-(tetrahydro-2H- pyran-3-yl)quinazolin-4(3H)-one [0672] To a solution of (R)-N-((1R)-1-(3-cyclopropyl-6-fluoro-4-oxo-2-(tetrahydro-2H- pyran-3-yl)-3,4-dihydroquinazolin-8-yl)ethyl)-2-methylpropane-2-sulfinamide (1.30 g, 2.98 mmol) in dichloromethane (6 mL) was added hydrochloric acid/dioxane (4 M, 13.0 mL).
  • reaction mixture was raised to 25 °C and stirred at 25 °C for 1.5 hr to form a diazonium salt. Then a suspension of sodium bromide (812 mg, 7.90 mmol) and cuprous bromide (283 mg, 1.97 mmol) in water (2.5 mL) was added and the mixture was stirred at 80 °C for 3 hr under nitrogen atmosphere. On completion, the reaction mixture was filtered and washed with ethyl acetate (30 mL x 3).
  • 1-(2-amino-5-fluoro-phenyl)piperidin-4-ol (7 g, 33.2 mmol) was added slowly into the system and stirred.
  • sodium nitrite (2.53 g, 36.6 mmol) was added into water (12 mL), stirred until clarification, and then slowly dropped into the raw material system while controlling the temperature to 0 to 10 ° C. After the completion of dropping, the reaction system was raised to 25 °C, and stirred for 1.5 hr to form a diazonium salt system.
  • reaction mixture was partitioned between water (200 mL) and ethyl acetate (500 mL), the organic phase was separated, washed with brine 500 mL (250 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step 2 Synthesis of 8-acetyl-3,6-dimethyl-2-tetrahydropyran-4-yl-quinazolin-4-one
  • 1-vinyloxybutane 9.18 g, 91.63 mmol
  • [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenylphosphane 11.8 g, 91.6 mmol
  • palladium (II) acetate 343 mg, 1.53 mmol
  • reaction mixture was concentrated under reduced pressure and dissolved in n-butyl alcohol (100 mL) and formic acid (8.76 g, 182 mmol) was added, then the mixture was stirred at 25 °C for 0.5 hr.
  • the reaction mixture was poured into water (500 mL), extracted with ethyl acetate (100 mL ⁇ 3). The combined organic layers were dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue.
  • reaction mixture was quenched with saturated sodium sulfite solution (30 mL) and extracted with ethyl acetate (80 mL ⁇ 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue.
  • reaction mixture was quenched by addition potassium fluoride (30 mL) at 25 °C, and then extracted with ethyl acetate 30 mL, then added hydrochloric acid (2 M, 21.8 mL), the mixture was stirred at 25 °C for 2 hr.
  • the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • the reaction mixture was quenched by addition potassium fluoride (50 mL) at 25 °C, and then extracted with ethyl acetate (50 mL).
  • the organic layer was then added hydrochloric acid (2 M, 30 mL) and stirred at 25 °C for 2 hr.
  • the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step 4 Synthesis of 8-bromo-3,6,7-trimethyl-2-morpholino-quinazolin-4-one [0849] To a solution of 8-bromo-2-chloro-3,6,7-trimethyl-quinazolin-4-one (3.20 g, 10.6 mmol) in dichloromethane (30 mL) was added morpholine (4.62 g, 53.0 mmol) and diisopropylethylamine (6.86 g, 53.0 mmol). The mixture was stirred at 40 °C for 12 hr.
  • reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 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.
  • Step 7 Synthesis of 8-ethanimidoyl-3,6,7-trimethyl-2-morpholino-quinazolin-4-one [0855] To a solution of 8-[(Z)-N-hydroxy-C-methyl-carbonimidoyl]-3,6,7-trimethyl-2- morpholino-quinazolin-4-one (1.00 g, 3.03 mmol) in methanol (30 mL) and ammonium hydroxide (3 mL) was added Raney Nickel (249 mg, 291 ⁇ mol) under nitrogen atmosphere.
  • reaction mixture added hydrogen chloride (1 M, 61.8 mL) at 25 °C and stirred at 25 °C for 0.5 hr.
  • Step 8 Synthesis of (NE,R)-N-[1-(5-fluoro-3,6-dimethyl-2-morpholino-4-oxo- quinazolin-8-yl)ethylidene]-2-methyl-propane-2-sulfinamide [0875] To a solution of 8-acetyl-5-fluoro-3,6-dimethyl-2-morpholino-quinazolin-4-one (1.1 g, 3.44 mmol) and (R)-2-methylpropane-2-sulfinamide (2.09 g, 17.2 mmol) in anhydrous tetrahydrofuran (16.5 mL) was added tetraethoxytitanium (3.93 g, 17.2 mmol).
  • the mixture was stirred at 75 °C for 12 hr.
  • the reaction mixture was diluted with anhydrous tetrahydrofuran (30 mL) and poured into water (100 mL), filtered and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was quenched by saturated potassium fluoride solution 300 mL, and then diluted with water (100 mL), and extracted with ethyl acetate (400 mL x 2).
  • reaction mixture was quenched by water (10 mL), then filtered and washed with ethyl acetate (10 mL), the filtrate was extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step 8 Synthesis of (R)-8-(1-aminoethyl)-3-(difluoromethyl)-6-fluoro-2- morpholinoquinazolin-4(3H)-one [0911] To a solution of (R)-N-[(1R)-1-[3-(difluoromethyl)-6-fluoro-2-morpholino-4-oxo- quinazolin-8-yl]eth-yl]-2-methyl-propane-2-sulfinamide (50 mg, 112 ⁇ mol) in dichloromethane (2 mL) at 0 °C was added hydrochloric acid / dioxane (4 M, 2 mL).
  • reaction mixture was diluted with water (10 mL) and filtered to remove the undissolved solid.
  • the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo to give a residue.
  • Step 3 Synthesis of 8-bromo-6-fluoro-2-(tetrahydro-2H-pyran-4-yl)quinazolin- 4(3H)-one [0935] To a mixture of N-(2-bromo-6-carbamoyl-4-fluoro-phenyl)tetrahydropyran-4- carboxamide (160 g, 463 mmol) in methyl alcohol (700 mL) was added sodium methoxide (834 g, 4.64 mol), the reaction mixture was stirred at 40 °C for 2 hr.
  • reaction mixture was poured into water (300 mL), filtered and the filtered cake in ethyl acetate (400 mL) stirred for 5 min then filtered, the filtered liquor was partitioned between ethyl acetate (400 mL) and water (300 mL). The organic phase was separated, washed with brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was added hydrochloric acid (1 M, 30 mL) and stirred at 25 °C for 0.5 hr. On completion, the mixture was neutralized with solid sodium hydroxide. The mixture was diluted with water (100 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 8-acetyl-6-methyl-2-morpholino-3H-quinazolin-4-one (4.28 g, crude) as an off-white solid; m/z ES+ [M+H] + 288.1.
  • Step 3 Synthesis of 8-bromo-2-chloro-6-iodo-3-methyl-quinazolin-4-one [0963] To a solution of 2-amino-3-bromo-5-iodo-N-methyl-benzamide (18 g, 50.7 mmol) in dioxane (200 mL) was added thiocarbonyl dichloride (11.7 g, 101 mmol). The mixture was stirred at 25 °C for 0.5 hr.
  • reaction mixture was quenched with sodium sulfite solution 100 mL, then the mixture was added water (500 mL) and extracted with ethyl acetate (300 mL x 3), the combined organic layers was dried over anhydrous sodium sulfate.
  • Step 10 Synthesis of 8-(1-aminoethyl)-6-(difluoromethyl)-3-methyl-2-morpholino- quinazolin-4-one
  • 8-acetyl-6-(difluoromethyl)-3-methyl-2-morpholino-quinazolin-4- one (30.0 mg, 88.9 ⁇ mol) and ammonium acetate (137 mg, 1.78 mmol) in methanol (10 mL) and dichloromethane (5 mL) was added sodium cyanoborohydride (8.38 mg, 133 ⁇ mol). The mixture was stirred at 60 °C for 1 hr.
  • reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (50 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 to give a residue.
  • Step 4 Synthesis of [(3S)-1-(2-bromo-5-fluoro-phenyl)-3-piperidyl]oxy-tert-butyl- dimethyl-silane [1021] To a solution of (3S)-1-(2-bromo-5-fluoro-phenyl)piperidin-3-ol (460 mg, 1.68 mmol) in N,N-dimethylformamide (5 mL) was added imidazole (342. mg, 5.03 mmol) and tert-butylchlorodimethylsilane (505 mg, 3.36 mmol). The mixture was stirred at 25 °C for 2 hr.
  • reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), the combined organic layers were washed with sodium bicarbonate (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step 1 Synthesis of 2-amino-3-bromo-N-isopropyl-5-methylbenzamide
  • 2-amino-3-bromo-5-methyl-benzoic acid 5 g, 21.7 mmol
  • propan-2-amine 2.57 g, 43.5 mmol
  • N,N-dimethylformamide 50 mL
  • Example 6 and Example 7 Preparation of (R)-2-((1-(3-(cyclobutylmethyl)-6-methyl-2- morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid and S)-2-((1-(3- (cyclobutylmethyl)-6-methyl-2-morpholino-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (stereochemistry arbitrarily assigned for both enantiomers) [1076] Racemate 2-((1-(3-(Cyclobutylmethyl)-6-methyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (35 mg, 73.4 ⁇ mol) was purified by SFC (column: Daicel CHIRALCEL OD (
  • the mixture was stirred at 130 °C for 12 hr under nitrogen.
  • the reaction mixture was then added hydrogen chloride (1 M, 0.5 mL) at 25 °C and stirred for 30 min.
  • the reaction mixture was quenched with water (100 mL) at 20 °C, and then extracted with ethyl acetate (100 mL x 3).
  • the combined organic layers were washed with water (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Example 11 Preparation of 3-((1-(3,6-dimethyl-2-morpholino-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzonitrile [1092] To a solution of 8-(1-aminoethyl)-3,6-dimethyl-2-morpholino-quinazolin-4-one (80 mg, 265 ⁇ mol) in toluene (1 mL) was added 3-bromobenzonitrile (144 mg, 794 ⁇ mol), tris(dibenzylideneacetone)dipalladium (24 mg, 26.5 ⁇ mol), cesium carbonate (259 mg, 794 ⁇ mol) and dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (12.4 mg, 26.5 ⁇ mol).
  • the resudue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm, 5 um; mobile phase: [water (ammonium bicarbonate)- acetonitrile]; B%: 49%-79%, 10 min) to give 8-(1-((2-fluorophenyl)amino)ethyl)-3,6- dimethyl-2-morpholinoquinazolin-4(3H)-one (26.6 mg, 66.5 ⁇ mol, 20%) as a white solid.

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Abstract

La présente invention concerne des composés de formule (I) et leurs promédicaments, sels pharmaceutiquement acceptables, compositions pharmaceutiques et procédés d'utilisation et des procédés pour leur préparation. Les composés de l'invention sont utiles pour moduler l'activité de PI3Kα et peuvent être utilisés dans le traitement de maladies ou de troubles dans lesquels l'activité de PI3Kα est impliquée, tels que le cancer.
PCT/US2023/071148 2022-07-27 2023-07-27 Dérivés de quinazolinone et utilisations associées WO2024026424A1 (fr)

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