WO2024064024A1 - Dérivés de ((4-oxo-3,4-dihydroquinazolin-8-yl)méthyl)amine utilisés en tant qu'inhibiteurs de p13k pour le traitement du cancer - Google Patents

Dérivés de ((4-oxo-3,4-dihydroquinazolin-8-yl)méthyl)amine utilisés en tant qu'inhibiteurs de p13k pour le traitement du cancer Download PDF

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WO2024064024A1
WO2024064024A1 PCT/US2023/032852 US2023032852W WO2024064024A1 WO 2024064024 A1 WO2024064024 A1 WO 2024064024A1 US 2023032852 W US2023032852 W US 2023032852W WO 2024064024 A1 WO2024064024 A1 WO 2024064024A1
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compound
enantiomer
cycloalkyl
heterocyclyl
heteroaryl
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PCT/US2023/032852
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English (en)
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James F. Blake
Mark Laurence Boys
David A. Mareska
Joshua Nathaniel Payette
Christie A. Schulte
Bryan Yestrepsky
Qian Zhao
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Onkure, Inc.
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Publication of WO2024064024A1 publication Critical patent/WO2024064024A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • 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
    • C07D401/08—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 carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/08—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 linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/08—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 carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Phosphatidylinositol lipids and their various phosphorylated subspecies are second messengers involved in a wide array of cellular vesicle trafficking and signal transduction processes.
  • Phosphoinositide 3' kinases are a family of enzymes responsible for phosphorylation of the 3' hydroxyl position of the inositol ring of Pls. PI3Ks are subdivided into 3 classes according to their structure and substrates.
  • Class II PI3Ks (PI3K-C2a, PI3K-C2P, PI3K- C2y) and Class III PI3Ks (vps34) are monomeric enzymes primarily associated with endocytosis and autophagy (Posor et al., Biochim Biophys Acta 2015, 1851, 794; Backer, Biochem J. 2016, 473, 2251).
  • the Class I PI3Ks are heterodimeric, consisting of a catalytic kinase subunit (pllOa, P, y, 6) and one of several regulatory subunits that determine binding partners and subcellular localization.
  • PI3Ks Class I PI3Ks are activated upon interaction with receptor tyrosine kinases (RTKs), Ras-related GTPases, G-protein coupled receptors, and/or related adaptor proteins, and in their active form convert phosphatidylinositol 4,5-diphosphate (PIP2) to phosphatidyl 3,4,5- triphosphate (PIP3) (Fruman et al., Cell 2017, 170, 605).
  • RTKs receptor tyrosine kinases
  • Ras-related GTPases Ras-related GTPases
  • G-protein coupled receptors G-protein coupled receptors
  • adaptor proteins phosphatidylinositol 3,4,5- triphosphate
  • AKT and mTOR Activation of the AKT/mTOR pathways are implicated in several growth-related roles and pathologies including glucose regulation, cell survival, angiogenesis, and proliferation (Porta et al., Front Oncol. 2014, 4, 1), indicating a role for Class I PI3Ks as a critical upstream regulator of these functions.
  • Class I PI3Ks are further subdivided into 4 isoforms (a, p, y, and 6) based on the identity of their catalytic (pllOa, pliop, pllOy, or p1108) and regulatory (p85a or its various splice variants, p85P, p55y, or plOl) subunits, giving rise to distinct roles in cellular physiology (Vanhaesebroeck et al., J Mol Med (Berl). 2016, 94, 5). PI3Ky and PI3K6 are mostly expressed in leukocytes and play an important role in pro-inflammatory pathways (Hawkins et.
  • PI3Ka and p are more ubiquitously expressed and share similar but not identical roles.
  • PI3Ka has a nonredundant role in angiogenesis (Soler et al., J Exp Med. 2013, 210, 1937), while PI3KfJ is known to serve a specific function in platelet aggregation (Liu et. al., Nat Rev Drug Discov. 2009, 8, 627; Jackson et al., Nat Med. 2005, 11, 507).
  • Elevation or constitutive activation of the PI3K pathway is one of the most frequent events in human cancers.
  • the PI3K pathway is overactivated through a variety of mechanisms, including activating mutation of PI3K isoforms, up-regulation of PI3K isoforms, loss or inactivation of the tumor suppressor PTEN, or hyperactivation of tyrosine kinase growth factor receptors or other upstream signaling partners (Yang et al., Mol Cancer 2019, 18, 1).
  • PIK3CA the gene encoding the pllOa subunit of PI3Ka, is frequently mutated or amplified in a variety of tumor types. Missense mutations occur in all domains of pllOa, but cluster in two 'hot spots', the most common being E542K and E545K in the helical domain, and H1047R in the kinase domain.
  • Tissue cellular response to insulin requires PI3K signaling through the ubiquitously expressed pllOa sub-unit.
  • pan-PI3K inhibition of the target disrupts glucose metabolism in tissues, leading to insulin resistance (Hopkins et al., Nature 2018, 560, 499).
  • selective PI3K isoform inhibitors were developed.
  • PI3Ka inhibitors are associated with hyperglycemia and rash due to the pllOa sub-unit role in insulin response (Rugo et al., The Breast 2022, 61, 156).
  • PI3K6 inhibitor a selective PI3K6 inhibitor (idelalisib), where the pll06 sub-unit is highly expressed in immune cells, causes severe diarrhea and colitis.
  • mutant PI3Ka isoform may suppress cancer signaling while having minimal effect on PI3K signaling in healthy cells bearing just wild type PI3Ka, leading to a reduction in the toxicities associated with nonselective PI3K inhibition (Castel et al., Nat Cancer 2021 2, 587).
  • An aspect of the invention is a compound of Formula (1) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein: Ri is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted;
  • R2 is H, C1-C4 alkyl, C3-C7 cycloalkyl, CF 3 , CH 2 F or CF2H, and where R2 is not H, the carbon atom attached to R2 is a chiral center and exists as a (R)- and (S)-racemic mixture or as either the (R)- or (S)- enantiomer;
  • R3 is H or C1-C4 alkyl
  • Rs is H, C1-C4 alkyl, C3-C7 cycloalkyl, heteroaryl, CF 3 , CH 2 F or CF2H;
  • R7 is independently H, C1-C4 alkyl, C3-C7 cycloalkyl, halogen, CN, CF 3 , OCF 3 , OCH3, CH 2 F or CF2H; each R7 is independently H, C1-C4 alkyl, C3-C7 cycloalkyl, halogen, CN, CF 3 , OCF 3 , OCH3, CH 2 F or CF 2 H;
  • R4 is L1-L 2 -L3-L4-L5-R8;
  • Ls is H, cycloalkyl, heterocyclyl, aryl, heteroaryl or a bond, where each of the cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, and the cycloalkyl and/or heterocyclyl is optionally part of a bridged, fused or spiro ring system;
  • the ring is 4- to 7- membered substituted or unsubstituted non-aromatic heterocyclic ring containing (in addition to the nitrogen atom) 0, 1 or 2 heteroatoms which may be N, O, S or Si, with the proviso that if the ring size is 4 or 5, the number of additional heteroatoms will be 0 or 1 and if the ring size is from 6 to 7, the number of additional heteroatoms will be 0, 1 or 2, where if the ring is substituted, the substituents include, but are not limited to, one or more of CH3, F, Cl, CF 3 , CF2H, CH 2 F, OCH3, cyclopropyl, CH 2 CF 3 , an oxetane ring, or COR a where R a is C1-C4 alkyl, O-C1-C4 alkyl, or NRbRc where Rb and R c are independently H or Ci-C4alkyl; with the proviso that for
  • each of Li, L3 and L4 is a bond and L 2 is not a bond.
  • each of Li, L3 and L4 is a bond and L 2 is cycloalkyl that is optionally part of a bridged, fused or spiro ring system.
  • each of Li, L3 and L4 is a bond and L 2 is cycloalkyl that is part of a bridged ring system.
  • each of Li, L 3 and L 4 is a bond and L 2 is cycloalkyl that is part of a fused ring system.
  • each of Li, L3 and L4 is a bond and L 2 is cycloalkyl that is part of a spiro ring system.
  • each of Li, L3 and L4 is a bond and L 2 is CEC.
  • each of Li, L 2 , L3 and L4 is a bond and Ls is cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted.
  • each of Li, L 2 , L3 and L4 is a bond and Ls is cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, and Rs is H.
  • each of Li, L 2 , L 3 and L 4 is a bond and L 5 is cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, and R 8 is cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the Ci-Cs alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted.
  • each of Li, L 2 , L 3 and L 4 is a bond and L 5 is cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, and Rs is -CRgR 10 Ru.
  • each of Li, L 2 , L 3 and L 4 is a bond and Ls is cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, and Rs is -OR 10 or -ORn.
  • each of Li, L 2 , L 3 and L 4 is a bond and Ls is cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, and Rs is -SRn.
  • each of Li, L 2 , L 3 and L 4 is a bond and Ls is cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, and Rs is -NR 10 Rn.
  • R 2 is CH 3 or CH 2 F.
  • R 3 is H.
  • R 5 is CH 3 .
  • R? is H.
  • R 2 , Rs and Rs are CH 3 .
  • Ri is heterocyclyl, aryl or heteroaryl, where each of the heterocyclyl, aryl or heteroaryl is unsubstituted or substituted.
  • Ri is heterocyclyl, where the heterocyclyl is unsubstituted or substituted.
  • Ri is aryl, where the aryl is unsubstituted or substituted.
  • Ri is heteroaryl, where the heteroaryl is unsubstituted or substituted.
  • Ri is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 and R 3 is H.
  • Ri is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 and R 3 is H.
  • Ri is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 and R 3 is H.
  • Ri is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 , R 3 is H and R 7 is H.
  • Ri is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 , R 3 is H and R 7 is H.
  • Ri is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 , R 3 is H and R 7 is H.
  • Ri is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 , R 3 is H, R 7 is H and Rs is CH 3 .
  • Ri is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 , R 3 is H, R 7 is H and R 5 is CH 3 .
  • Ri is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 , R 3 is H, R 7 is H and Rs is CH 3 .
  • the compound of Formula (1) is a compound of Formula (2) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 4 are defined as in the compound of Formula (1) and the carbon marked with * is a chiral center and exists as a (R)- and (S)-racemic mixture or as either the (R)- or (S)- enantiomer.
  • the listing of substituents within brackets indicates individual compounds containing one of each of the substituents.
  • the compound of Formula (1) is a compound of Formula (3) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein: each of Xi, X 2 and X 3 is independently N, CH or substituted C, where at least one of Xi, X 2 and X 3 is N;
  • R 4 and R 7 are defined as in the compound of Formula (1), the carbon marked with * is a chiral center and exists as a (R)- and (S)-racemic mixture or as either the (R)- or (S)- enantiomer, and the listing of substituents within brackets indicates individual compounds containing one of each of the substituents.
  • Xi is N
  • X 2 is CH or substituted C
  • X 3 is CH or substituted C.
  • X 2 is N, Xi is CH or substituted C, and X 3 is CH or substituted C.
  • X 3 is N, Xi is CH or substituted C, and X 2 is CH or substituted C.
  • Xi and X 3 are N, and X 2 is CH or substituted C.
  • Xi, X 2 and X 3 are N.
  • the compound of Formula (1) is a compound of Formula (4) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein: each of Xi, X 2 and X 3 is independently N, CH or substituted C;
  • R 7 is defined as in the compound of Formula (1), the carbon marked with * is a chiral center and exists as a (R)- and (S)-racemic mixture or as either the (R)- or (S)- enantiomer, the listing of substituents within brackets indicates individual compounds containing one of each of the substituents, and
  • R4 is selected from the group consisting of: wherein L 3 , L 4 , Ls and Rs is defined as in the compound of Formula (1).
  • Xi is N
  • X2 is CH or substituted C
  • X 3 is CH or substituted C.
  • X2 is N
  • Xi is CH or substituted C
  • X 3 is CH or substituted C.
  • X 3 is N
  • Xi is CH or substituted C
  • X 2 is CH or substituted C.
  • Xi and X 3 are N, and X 2 is CH or substituted C.
  • Xi, X 2 and X 3 are N.
  • Xi, X2 and X 3 are CH or substituted C.
  • the compound of Formula (1) is a compound of Formula (5) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein: the carbon marked with * is a chiral center and exists as a (R)- and (S)-racemic mixture or as either the (R)- or (S)- enantiomer, the listing of substituents within brackets indicates individual compounds containing one of each of the substituents, and the heteroaryl or heterocyclyl rings linked to the bicyclo[l.l.l]pentane moiety are unsubstituted or substituted.
  • the fluoroalkyl linked to the bicyclo[l.l.l]pentane moiety is CF 3 , CHF 2 , CH 2 F, CF 2 CH 3 , CFHCH 3 , CH 2 CF 3 , OCF 3 , OCHF 2 , OCH 2 F, OCF 2 CH 3 , OCFHCH 3 or OCH 2 CF 3 .
  • the heteroaryl linked to the bicyclo[l.l.l]pentane moiety is furan, benzofuran, thiophene, benzothiophene, pyrrole, indole, isoindole, 7-azaindole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindazole, pyridine, quinoline, isoquinoline, oxazole, isoxazole, benzoxazole, pyrazole, imidazole, benzimidazole, thiazole, benzothiazole, isothiazole, 1,2,4-triazole, 1,2,3-triazole, tetrazole, 1,2,5-oxadiazole, 1,2,3-oxadiazole, 1,3,4-thiadiazole, pyridazine, pyrimidine, pyrazine, 1,2,4-tria
  • the heterocyclyl linked to the bicyclo[l.l.l]pentane moiety is azirine, aziridine, azetidine, 2,3-dihydroazete, 1,3-diazetidine, 2H-oxete, thietane, 2H-thiete, azetidin-2-one, morpholine, thiomorpholine, pyrrolidinone, pyrrolidinine, 2-pyrroline, 3-pyrroline, pyrazolidine, 2-pyrazoline, 2-imidazoline, imidazolidine, piperidine, piperazine, pyridin-2-ones, oxirane, thiirane, oxetane, propylene oxide, 1,3- dioxolane, 1,2-oxathiolane, 1,3-oxathiolane, sulfolane, 2,4-thiazolidinedione, succinimi
  • the compound of Formula (1) is a compound of Formula (6) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound, or a pharmaceutically acceptable salt thereof, wherein:
  • Ri is a substituted or unsubstituted heterocyclyl, aryl or heteroaryl, wherein the heterocyclyl, aryl or heteroaryl ring directly attached to the nitrogen atom linked to the asymmetric center attached to the isoquinoline moiety contains a carboxylic acid substituent at the ortho position to the point of attachment,
  • R4 and R7 are defined as in the compound of Formula (1), the carbon marked with * is a chiral center and exists as a (R)- and (S)-racemic mixture or as either the (R)- or (S)- enantiomer, and the listing of substituents within brackets indicates individual compounds containing one of each of the substituents.
  • Ri is heteroaryl
  • Ri is aryl
  • An aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising any compound of the invention as described herein (such as any one of Formula (1), (2), (3), (4), (5) or (6)) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprising any compound of the invention as described herein or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof further comprises one or more anti-cancer agents.
  • Another aspect of the invention is a method of treating a disease in which PI3K activity is implicated in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of any compound of the invention as described herein (such as any one of Formula (1), (2), (3), (4), (5) or (6)) or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof.
  • any compound of the invention as described herein such as any one of Formula (1), (2), (3), (4), (5) or (6)
  • a solvate enantiomer, diastereomer, tautomer, polymorph or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof.
  • the disease to be treated is cancer.
  • the disease is a cancer bearing a PI3Ka H1047 mutation (such as H1047R).
  • the term "at risk for” as used herein, refers to a medical condition or set of medical conditions exhibited by a patient which may predispose the patient to a particular disease or affliction.
  • these conditions may result from influences that include, but are not limited to, behavioral, emotional, chemical, biochemical, or environmental influences.
  • the term "effective amount" as used herein, refers to a particular amount of a pharmaceutical composition comprising a therapeutic agent that achieves a clinically beneficial result (/.e., for example, a reduction of symptoms). Toxicity and therapeutic efficacy of such compositions can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50/ ED50- Compounds that exhibit large therapeutic indices are preferred.
  • the data obtained from these cell culture assays and additional animal studies can be used in formulating a range of dosages for human use.
  • the dosages of such compounds lie preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage varies within this range depending upon the dosage form employed, the sensitivity of the patient, and the route of administration.
  • the term "symptom" as used herein, refers to any subjective or objective evidence of disease or physical disturbance observed by the patient.
  • subjective evidence is usually based upon patient self-reporting and may include, but is not limited to, pain, headache, visual disturbances, nausea and/or vomiting.
  • objective evidence is usually a result of medical testing including, but not limited to, body temperature, complete blood count, lipid panels, thyroid panels, blood pressure, heart rate, electrocardiogram, tissue body imaging scans and other medical testing results.
  • disease refers to any impairment of the normal state of the living animal or one of its parts that interrupts or modifies the performance of the vital functions. Typically manifested by distinguishing signs and symptoms, a disease is usually a response to i) environmental factors (such as malnutrition, industrial hazards, or climate); ii) specific infective agents (such as worms, bacteria, or viruses); iii) inherent defects of the organism (such as genetic anomalies); and/or iv) combinations of these factors.
  • environmental factors such as malnutrition, industrial hazards, or climate
  • specific infective agents such as worms, bacteria, or viruses
  • iii) inherent defects of the organism such as genetic anomalies
  • the terms “reduce”, “inhibit”, “diminish”, “suppress”, “decrease”, “prevent” and grammatical equivalents thereof when used in reference to the expression of any symptom in an untreated subject relative to a treated subject, indicate that the quantity and/or magnitude of the symptoms in the treated subject is lower than in the untreated subject by any amount that is recognized as clinically relevant by any medically trained personnel.
  • the quantity and/or magnitude of the symptoms in the treated subject is at least 10% lower than, at least 25% lower than, at least 50% lower than, at least 75% lower than, and/or at least 90% lower than the quantity and/or magnitude of the symptoms in the untreated subject.
  • inhibitory compound refers to any compound capable of interacting with (/.e., for example, attaching, binding, etc.) to a binding partner under conditions such that the binding partner becomes unresponsive to its natural ligands.
  • Inhibitory compounds may include, but are not limited to, small organic molecules, antibodies, and proteins/peptides.
  • the term "attached” as used herein, refers to any interaction between a medium (or carrier) and a drug. Attachment may be reversible or irreversible. Such attachment includes, but is not limited to, covalent bonding, ionic bonding, Van der Waals forces or friction, and the like.
  • a drug is attached to a medium (or carrier) if it is impregnated, incorporated, coated, in suspension with, in solution with, mixed with, etc.
  • drug or “compound” as used herein, refers to any pharmacologically active substance capable of being administered which achieves a desired effect. Drugs or compounds can be synthetic or naturally occurring, non-peptide, proteins or peptides, oligonucleotides or nucleotides, polysaccharides, or sugars.
  • administered refers to any method of providing a composition to a patient such that the composition has its intended effect on the patient.
  • An exemplary method of administering is by a direct mechanism such as, local tissue administration (/.e., for example, extravascular administration, such as subcutaneous, intramuscular, or intraperitoneal), intravenous, oral ingestion, transdermal patch, topical, inhalation, suppository, etc.
  • patient is a human or animal and needs not be hospitalized. For example, out-patients and persons in nursing homes are "patients.”
  • a patient may be a human or non-human animal of any age and therefore includes both adults and juveniles (/.e., children). It is not intended that the term "patient” connote a need for medical treatment. Therefore, a patient may voluntarily be subject to experimentation, whether clinical or in support of basic science studies.
  • subject refers to, but is not limited to, humans (e.g., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., monkeys); non-human mammals, such as cows, pigs, horses, sheep, mice, goats, cats, dogs; and/or birds, such as chickens, ducks and/or geese.
  • humans e.g., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., monkeys); non-human mammals, such as cows, pigs, horses, sheep, mice, goats, cats, dogs; and/or birds, such as
  • affinity refers to any attractive force between substances or particles that causes them to enter into and remain in chemical combination.
  • an inhibitor compound that has a high affinity for a receptor will provide greater efficacy in preventing the receptor from interacting with its natural ligands, than an inhibitor with a low affinity.
  • test compound refers to any compound or molecule considered a candidate as an inhibitory compound.
  • combination therapy refers to refers to a dosing regimen of two or more different therapeutically active agents during a period of time, wherein the therapeutically active agents are administered together or separately.
  • combination therapy is a non-fixed combination.
  • non-fixed combination refers to two or more different therapeutic agents that are formulated as separate compositions or dosages such that they may be administered separately to a subject in need thereof either simultaneously or sequentially with variable intervening time limits.
  • in vivo refers to an event that takes place in a subject's body.
  • in vitro refers to an event that takes places outside of a subject's body.
  • protein refers to any of numerous naturally occurring extremely complex substances (such as an enzyme or antibody) that contain amino acid residues joined by peptide bonds, and which include carbon, hydrogen, nitrogen, oxygen, and typically sulfur.
  • a protein comprises amino acids having an order of magnitude within the hundreds.
  • peptide refers to any of various amides that are derived from two or more amino acids by combination of the amino group of one acid with the carboxyl group of another and are usually obtained by partial hydrolysis of proteins.
  • a peptide comprises amino acids having an order of magnitude with the tens.
  • pharmaceutically acceptable refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human.
  • pharmaceutically acceptable carrier includes any and all solvents, or a dispersion medium including, but not limited to, water, ethanol, a polyol (such as, for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, vegetable oils, coatings, isotonic and absorption delaying agents, liposome, commercially available cleansers, and the like. Supplementary bioactive ingredients also can be incorporated into such carriers.
  • pharmaceutically acceptable salt refers to a salt that does not adversely impact the biological activity and properties of the compound and is suitable for use in contact with the tissues of subjects without undue toxicity, irritation and/or allergic response and the like.
  • Pharmaceutically acceptable salts include those derived from suitable inorganic acids, organic acids and bases, and include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, naphthalene sulfonic acid, lactic acid, succinic acid, oxalic acid, stearic acid, and the like.
  • pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt (e.g., a sodium or a potassium salt), an alkaline earth metal salt (e.g., a calcium or a magnesium salt), a salt formed from an organic base, and an amino acid salt.
  • a salt such as an ammonium salt, an alkali metal salt (e.g., a sodium or a potassium salt), an alkaline earth metal salt (e.g., a calcium or a magnesium salt), a salt formed from an organic base, and an amino acid salt.
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metals, alkaline earth metals, and ammonium and quaternary ammonium compounds. Specific metals include, but are not limited to, sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Organic bases from which salts may be prepared include, for example, primary, secondary, and tertiary amines.
  • prodrug refers to a compound that is transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound.
  • a prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound.
  • a prodrug has improved physicochemical properties (such as bioavailability) and/or delivery properties over the parent compound.
  • Prodrugs are typically designed to enhance pharmaceutically and/or pharmacokinetically based properties associated with the parent compound. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in subject.
  • Prodrugs include compounds wherein a hydroxy, amino, or mercapto group is bonded to any group that, when the prodrug is administered to a subject, cleaves to form a free hydroxy, free amino, or free mercapto group, respectively.
  • Prodrugs are well known to be prepared from carboxylic acids in the form of, for example, carboxylate esters or thioesters.
  • purified or isolated as used herein, may refer to a composition (such as, for example, a peptide composition) that has been subjected to treatment (e.g., fractionation) to remove various other components, and which composition substantially retains its expressed biological activity.
  • treatment e.g., fractionation
  • sample includes, for example, environmental and biological samples.
  • Environmental samples include material from the environment such as soil and water.
  • Biological samples include animal (e.g., human), fluids (e.g., blood, plasma, and serum), solids (e.g., stool), tissue, liquid foods (e.g., milk), and solid foods (e.g., vegetables).
  • a pulmonary sample may be collected by bronchoalveolar lavage (BAL) which comprises fluid and cells derived from lung tissues.
  • BAL bronchoalveolar lavage
  • a biological sample may comprise a cell, tissue extract, body fluid, chromosomes or extrachromosomal elements isolated from a cell, genomic DNA (in solution or bound to a solid support such as for Southern blot analysis), RNA (in solution or bound to a solid support such as for Northern blot analysis), cDNA (in solution or bound to a solid support) and the like.
  • biological activity refers to any molecule having structural, regulatory or biochemical functions.
  • biological activity may be determined, for example, by restoration of wild-type growth in cells lacking protein activity.
  • Cells lacking protein activity may be produced by many methods (i.e., for example, point mutation and frame-shift mutation). Complementation is achieved by transfecting cells which lack protein activity with an expression vector which expresses the protein, a derivative thereof, or a portion thereof.
  • label refers to any composition detectable by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical or chemical means.
  • labels include biotin for staining with labeled streptavidin conjugate, magnetic beads (e.g., Dynabeads’), fluorescent dyes (e.g., fluorescein, Texas Red’, rhodamine, green fluorescent protein, and the like), radiolabels (e.g., 3 H, 125 l, 35 S, 14 C, or 32 P), enzymes (e.g., horse radish peroxidase, alkaline phosphatase and others commonly used in an ELISA), and calorimetric labels such as colloidal gold or colored glass or plastic (e.g., polystyrene, polypropylene, latex, etc.) beads.
  • fluorescent dyes e.g., fluorescein, Texas Red’, rhodamine, green fluorescent protein, and the like
  • radiolabels e.g., 3 H
  • Patents teaching the use of such labels include, but are not limited to, U.S. Patent Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149; and 4,366,241 (all herein incorporated by reference in their entireties).
  • the labels contemplated in the present invention may be detected by conventional methods. For example, radiolabels may be detected using photographic film or scintillation counters, fluorescent markers may be detected using a photodetector to detect emitted light.
  • Enzymatic labels are typically detected by providing the enzyme with a substrate and detecting, the reaction product produced by the action of the enzyme on the substrate, and calorimetric labels are detected by simply visualizing the colored label.
  • conjugate refers to any compound that has been formed by the joining of two or more moieties.
  • a "moiety" or “group” as used herein, is any type of molecular arrangement designated by formula, chemical name, or structure.
  • a conjugate comprises one or more moieties or chemical groups. This means that the formula of the moiety is substituted at some position in order to be joined and be a part of the molecular arrangement of the conjugate.
  • moieties may be directly covalently joined, it is not intended that the joining of two or more moieties must be directly to each other.
  • a linking group, a crosslinking group, or a joining group refers to any molecular arrangement that will connect moieties by covalent bonds such as, but not limited to, one or more amide group(s).
  • the conjugate may be unsubstituted, the conjugate may have a variety of additional substituents connected to the linking groups and/or connected to the moieties.
  • a "monomeric polymer” or “homopolymer” is a polymer that contains the same repeating, asymmetric subunit.
  • a “copolymer” is a polymer derived from two or more types of monomeric species (/.e., two or more different chemical asymmetric subunits).
  • “Block copolymers” are polymers comprised of two or more species of polymer subunits linked by covalent bonds.
  • substituted refers to at least one hydrogen atom of a molecular arrangement that is replaced with a non-hydrogen substituent.
  • the number of substituents present depends on the number of hydrogen atoms available for replacement and includes replacement of more than one hydrogen atom bound to a single atom (such as in the case of a carbon atom or a silicon atom which may be available for mono-, di- or tri- substitution or in the case of a nitrogen atom which may be available for mono-, di- or trisubstitution or in the case of an oxygen atom or a sulfur atom which may be available for mono-substitution).
  • Substituents include, but are not limited to, halogen (e.g., F, Cl, Br, I), hydroxy (OH), oxo, cyano (CN), nitro (NO2), amino, alkylamino, dialkylamino, branched or unbranched alkyl (e.g., methyl, ethyl, propyl, isopropyl, sec-butyl, etc.), cycloalkyl (e.g., cyclopropyl), fluoroalkyl (e.g., CF 3 , CF 2 H, CH 2 F, CH 2 CF 3 , CH 2 CF2H, CHFCHF2, CF2CH 2 F, CF2CF 3 , CF2CH3, CF(CH 3 ) 2 , CH 2 CH 2 CF 3 , CF2CH 2 CF 3 , CF2CF2CF 3 , etc.) or
  • substituents may be further substituted with one or more substituents as defined above, such that a substituent may constitute, for example, a substituted alkyl, a substituted aryl, a substituted arylalkyl, a substituted heterocyclyl, or a substituted heterocycloalkyl.
  • unsubstituted refers to any compound that does not contain extra substituents attached to the compound.
  • an unsubstituted compound refers to the chemical makeup of the compound without added substituents (e.g., no non-hydrogen substituents).
  • unsubstituted proline is a proline amino acid even though the amino group of proline may be considered as disubstituted with alkyl groups.
  • bond refers to the absence of that substituent. For example, in the 4-atom sequence A-B-C-D, when B and C are both listed as being bonds, the result is the 2-atom sequence A-D. If only B is listed as being a bond, the result is the 3-atom sequence A-C-D.
  • alkyl refers to any straight chain or branched, non-cyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10 carbon atoms, while the term “lower alkyl” has the same meaning as alkyl but contains from 1 to 3 carbon atoms.
  • the term “higher alkyl” has the same meaning as alkyl but contains from 4 to 10 carbon atoms.
  • saturated straight chain alkyls include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and the like, while saturated branched alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tertbutyl, isopentyl, and the like.
  • a methyl substituent may be depicted as "CH3" or "Me" or as a terminal bond with no indication of specific atoms.
  • cycloalkyl refers to saturated and unsaturated cyclic alkyls.
  • Representative saturated cyclic alkyls include, but are not limited to, C 3 -C 14 (such as C 3 - C7) cycloalkyls, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl, and the like; while unsaturated cyclic alkyls include, but are not limited to, cyclobutenyl, cyclopentenyl and cyclohexenyl, cyclohexadiene, and the like. Cyclic alkyls are also referred to herein as "homocycles" or "homocyclic rings”.
  • bicyclic compounds as used herein, encompasses “bridged” compounds, “fused” compounds and “spiro” compounds as described.
  • spiro or “spirocyclic” as used herein, refers to chemical structures having at least two rings sharing one common atom.
  • the rings may be cycloalkyl, heterocyclyl or a combination thereof, and may include one or more aryl or heteroaryl rings.
  • Examples include, but are not limited to, spirocyclic cyclopropanes, spirocyclic aziridines, spirocyclic cyclobutanes, spirocyclic azetidines, spirocyclic oxetanes, spirocyclic cyclopentanes, spirocyclic pyrrolidines, spirocyclic 1,3-dioxolanes, spirocyclic dioxanes, spirocyclic oxathiolanes, spirocyclic thiazolidines, spirocyclic cyclohexanes, spirocyclic piperidines and spirocyclic piperizines, where the other ring is cycloalkyl (e.g., cyclobutane, cyclopentane or cyclohexane) or heterocyclyl (e.g., piperidine, tetrahydropyran, te
  • Exemplary embodiments include, but are not limited to, l,4-dioxaspiro[4.5]decane, 1,4-dioxa- 8-azaspiro[4.5]decane, 2-azaspiro[4.4]nonane, 2-azaspiro[4.4]nonane, 2,7- diazaspiro[4.4]nonane, 3-azaspiro[5.5]undecane, 3,9-diazaspiro[5.5]undecane, 6- azaspiro[3.4]octane, 6-azaspiro[2.5]octane, l,3-dihydrospiro[indene-2,3'-pyrrolidine] and 3,4- dihydro-2H-spiro[naphthalene-l,4'-piperidine],
  • bridged refers to a compound containing two nonadjacent atoms common to two rings.
  • exemplary embodiments include, but are not limited to, norbornane, bicyclo[l.l.l]pentane, bicyclo[2.2.1]heptane, l,4-diazabicyclo[2.2.2]octane, 3,8-diazabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, bicyclo[3.2.1]octane, 3,6- diazabicyclo[3.1.1]heptane, 3,6-diazabicyclo[2.2.1]heptane, and other bridged piperazines and bridged piperidines.
  • fused refers to polycyclic ring systems in which any two adjacent rings have two, and only two, adjacent atoms in common (ortho-fused) and polycyclic ring systems in which a ring contains two, and only two, adjacent atoms in common with each of two or more rings of a contiguous series of ortho-fused rings (ortho- and peri-fused).
  • An exemplary embodiment is pentalene and dibenzoxepine (ortho-fused) and pyrene (ortho- and peri-fused).
  • Ortho-fused systems have "n” common sides and “2n” common atoms while perifused systems have “n” common sides and less than “2n” atoms in common.
  • Other exemplary fused systems include, but are not limited to, fused cyclopropyl rings, fused aziridine rings, fused cyclobutane rings, fused azetidine rings, fused cyclopentane rings, fused pyrrolidine rings, fused cyclohexane rings, fused piperidine rings, fused tetrahydropyran rings and fused piperazine rings, where each of these rings may be fused to an identical or different ring, such a pyrrolidine ring fused to another pyrrolidine ring (e.g., octahydropyrrolo[3,4-c]pyrrole) or to a cyclohexane ring (e.g., octahydro-lH-indole or octahydr
  • fused aryl or heteroaryl rings such as a pyridine ring fused with a cycloalkyl ring (e.g., cyclopentane or cyclohexane) or with a heterocyclyl ring (e.g., tetrahydrofuran or tetrahydropyran).
  • a cycloalkyl ring e.g., cyclopentane or cyclohexane
  • heterocyclyl ring e.g., tetrahydrofuran or tetrahydropyran
  • aromatic refers to any aromatic carbocyclic (i.e., all of the ring atoms are carbon) substituent such as, but not limited to, phenyl (from benzene), tolyl (from toluene), xylyl (from xylene) or multi-ring systems (e.g., naphthyl (from naphthalene) and anthracenyl (from anthracene).
  • arylalkyl or “aralkyl” as used herein, refers to any alkyl having at least one alkyl hydrogen atom replaced with an aryl moiety such as, but not limited to, benzyl, - (CH 2 ) 2 phenyl, -(CH 2 ) 3 phenyl, -CH(phenyl)2, and the like.
  • halogen refers to any fluoro, chloro, bromo, or iodo moiety.
  • haloalkyl refers to any alkyl where at least one hydrogen atom (and including all hydrogen atoms) has been replaced with a halogen atom, such as, for example, trifluoromethyl, dichloromethyl, difluoromethyl, monofluoromethyl, monobromomethyl, 1,1,1-trifluoroethyl and the like.
  • heteroaryl refers to any aromatic heterocyclic ring of 5 to 10 or more members and having at least one heteroatom selected from nitrogen, oxygen or sulfur, and containing at least 1 carbon atom, including, but not limited to, both mono- and bicyclic- ring systems.
  • the heteroaryl ring may be attached as a substituent via a ring heteroatom or a carbon atom.
  • heteroaromatics include, but are not limited to, furan, benzofuran, thiophene, benzothiophene, pyrrole, indole, isoindole, 7-azaindole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindazole, pyridine, quinoline, isoquinoline, oxazole, isoxazole, benzoxazole, pyrazole, imidazole, benzimidazole, thiazole, benzothiazole, isothiazole, 1,2,4-triazole, 1,2,3-triazole, tetrazole, 1,2,5-oxadiazole, 1,2,3-oxadiazole, 1,3,4-thiadiazole, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5- triazine, cinnoline, phthalazine
  • heteroarylalkyl means any alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl moiety, such as -CH 2 bpyridinyl, -CH 2 hpyrim idinyl, and the like.
  • heterocycle or “heterocyclyl” or “heterocyclic ring” as used herein, refers to a nonaromatic ring which is either saturated or unsaturated and which contains 1 or more heteroatoms independently selected from nitrogen, oxygen, sulfur and silicon, wherein each of the nitrogen and sulfur heteroatoms may be in an oxidized state, and each of the nitrogen and silicon heteroatoms is substituted or unsubstituted and the nitrogen heteroatoms may be optionally quaternized, and includes bicyclic rings in which any of the above heterocycles are fused to an aryl or heteroaryl ring.
  • the heterocyclic ring may be attached as a substituent via a ring heteroatom or a carbon atom.
  • heterocycles may contain 3 to 14 or more ring atoms (such as 3- to 7-membered monocyclic rings or 7- to 10- membered bicyclic rings) and include, but are not limited to, 2H-azirine, azetidine, 2,3- dihydroazete, 1,3-diazetidine, 2H-oxete, thietane, 2H-thiete, azetidin-2-one, morpholine, thiomorpholine, pyrrolidinone, pyrrolidinine, 2-pyrroline, 3-pyrroline, pyrazolidine, 2- pyrazoline, 2-imidazoline, imidazolidine, piperidine, piperazine, pyridin-2-ones (such as 2- pyridone and l-methyl-2-pyridone), ethylene oxide (oxirane), ethylene imine (aziridine), ethylene sulfide (thiirane), oxet
  • heterocycloalkyl refers to any alkyl having at least one alkyl hydrogen atom replaced with a heterocycle, such as -Cl- morpholinyl, and the like.
  • alkyloxy or "alkoxy”, as used herein, means any alkyl moiety attached through an oxygen bridge (/.e., -O-alkyl) such as, but not limited to, methoxy, ethoxy, and the like.
  • thioalkyl as used herein, means any alkyl moiety attached through a sulfur bridge (/.e., -S-alkyl) such as, but not limited to, methylthio, ethylthio, and the like.
  • alkenyl refers to an unbranched or branched hydrocarbon chain having one or more carbon-carbon double bonds therein and may also be referred to as an "unsaturated alkyl".
  • the double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkenyl groups include, but are not limited to vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl.
  • An alkenyl group can be unsubstituted or substituted with one or two suitable substituents.
  • alkynyl refers to unbranched or branched hydrocarbon chain having one or more carbon-carbon triple bonds therein and may also be referred to as an "unsaturated alkyl".
  • the triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkynyl groups include, but are not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-l-butynyl, 4-propyl-2- pentynyl-, and 4-butyl-2-hexynyl.
  • An alkynyl group can be unsubstituted or substituted with one or two suitable substituents.
  • reactive groups refer to nucleophiles, electrophiles, or radically active groups, i.e., groups that react in the presence of radicals.
  • a nucleophile is a moiety that forms a chemical bond to its reaction partner (the electrophile) by donating both bonding electrons. Electrophiles accept these electrons. Nucleophiles may take part in nucleophilic substitution, whereby a nucleophile becomes attracted to a full or partial positive charge on an element and displaces the group it is bonded to. Alternatively, nucleophiles may take part in substitution of carbonyl group.
  • Carboxylic acids are often made electrophilic by creating succinyl esters and reacting these esters with aminoalkyls to form amides.
  • Other common nucleophilic groups are thiolalkyls, hydroxylalkyls, primary and secondary amines, and carbon nucleophiles such as enols and alkyl metal complexes.
  • Other preferred methods of ligating proteins, oligosaccharides and cells using reactive groups are disclosed (Lemieux et al., Trends in Biotechnology 1998, 16, 506, incorporated herein by reference in its entirety).
  • one provides reactive groups for the Staudinger ligation, i.e., "click chemistry" with an azide comprising moiety and alkynyl reactive groups to form triazoles.
  • Michael additions of a carbon nucleophile enolate with an electrophilic carbonyl, or the Schiff base formation of a nucleophilic primary or secondary amine with an aldehyde or ketone may also be utilized.
  • Other methods of bioconjugation are provided (Hang et al. Accounts of Chemical Research 2001, 34, 7 27 and Kiick et al. Proc Natl Acad Sci US. A. 2002, 99, 19, both of which are incorporated by reference in its entirety).
  • biocompatible refers to any material that does not illicit a substantial detrimental response in the host. There is always concern when a foreign object is introduced into a living body that the object will induce an immune reaction, such as an inflammatory response that will have negative effects on the host.
  • biocompatibility is evaluated according to the application for which it was designed: for example, a bandage is regarded as biocompatible with the skin, whereas an implanted medical device is regarded as biocompatible with the internal tissues of the body.
  • biocompatible materials include, but are not limited to, biodegradable and biostable materials.
  • a substantial detrimental response has not occurred if an implant comprising the material is in close association to its implant site within the host animal and the response is better than a tissue response recognized and established as suitable from materials provided in an ASTM.
  • ASTM subcommittee F04.16 on Biocompatibility Test Methods has developed biocompatibility standards for medical and surgical materials and devices which includes E1262-88, F612-20, F719-20el, F720-17, F748-16, F749-20, F750-20, F756-17; F763-04, F813-20, F895-11, F981-04, F1027-86, F1408-20a, F1439-03, F1877-16, F1903-18, F1904-14, F1983-14, F1984-99, F2147- 01, F2148-18, F2382-18, F2808-17, F1288-19 and F2909-19, each of which is incorporated herein by reference.
  • materials that are to be used in contact with the blood stream must be composed of materials that meet hemocompatibility standards.
  • One of these tests is for damage to red blood cells, which can result in hemolysis that is, rupturing of the cells, as described in F756-17 Standard Practice for Assessment of Hemolytic Properties of Materials.
  • a "bioactive substance” refers to any of a variety of chemical moieties and that binds with a biomolecule such as, but not limited to, peptides, proteins, enzymes, receptors, substrates, lipids, antibodies, antigens, and nucleic acids.
  • the bioactive substance is a biomolecule but it is not intended that the bioactive substance be limited to biomolecules.
  • the bioactive substances provide hydrophobic, hydrophilic, or electrostatic interactions, such as polycarboxylic acids that are anionic at physiological pH.
  • the alkaline growth factors (with isoelectric point above 7) are retained via favorable electrostatic interactions by the polycarboxylates, and subsequently released in a controlled and sustained manner.
  • Cancer is a term used for a physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, leukemia, blastoma, and sarcoma.
  • cancers include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer (NSCLC), glioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia (AML), multiple myeloma, gastrointestinal cancer, renal cell carcinoma, renal cancer (e.g., advanced renal cell carcinoma), ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, brain cancer, stomach cancer, urothelial carcinoma (including local advanced or metastatic urothelial carcinoma), bladder cancer, hepatoma, breast cancer and head and neck cancer.
  • NSCLC non-small cell lung cancer
  • glioma Hodgkin's lymphoma,
  • stereoisomer refers to compounds that have the same atomic connectivity but different atomic arrangement in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, diastereomers and atropisomers. In the context of the present invention, the term “enantiomerically pure” is understood to mean that the compound in question with respect to the absolute configuration of the chiral center is present in an enantiomeric excess of more than 95%, preferably more than 97%.
  • the present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)- isomers, (L)-isomers, atropisomers, tautomers and racemic and other mixtures thereof, such as enantiomers or diastereomeric enriched mixtures, all of which are within the scope of the present disclosure.
  • compounds of the invention as defined herein may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form.
  • optically active compounds may be carried out by standard techniques of organic chemistry well known in the art such as, for example, by synthesis from optically active starting materials or by resolution of a racemic compound. Similarly, the enantiomeric or diastereomeric purity of a compound may be evaluated using standard laboratory techniques.
  • compositions of the invention can take any suitable form for the desired route of administration.
  • any suitable orally deliverable dosage form can be used, including without limitation water, glycols, oils, alcohols, and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents, and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms.
  • Injectable compositions or intravenous infusions are also provided in the form of solutions, suspensions, and emulsions.
  • the carrier usually comprises sterile water and possibly other ingredients to aid solubility.
  • Injectable solutions may be prepared in which the carrier comprises a saline solution, a glucose solution, or a mixture of a saline and a glucose solution.
  • Suitable oils include, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids, and mixtures of these and other oils.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives as needed, where the additives may facilitate administration of the composition to the skin and/or may facilitate preparation of the compositions to be delivered.
  • suitable additives may facilitate administration of the composition to the skin and/or may facilitate preparation of the compositions to be delivered.
  • These compositions may be administered in various ways, e.g., as a transdermal patch or as an ointment.
  • Acid or base addition salts of the compounds of the invention are typically more suitable in the preparation of aqueous compositions due to their increased water solubility over the corresponding neutral form of the compounds.
  • compositions of the invention may comprise one or more of a filler, diluent, adjuvant, vehicle, or other excipient to facilitate storage and/or administration of the active ingredients contained therein.
  • a pharmaceutical composition according to the present invention may contain one or more additional therapeutic agents, for example, to increase efficacy or to decrease undesired side effects.
  • the pharmaceutical composition further contains one or more additional therapeutic agents useful to treat or inhibit a disease mediated directly or indirectly by PI3K.
  • additional therapeutic agents include, without limitation, agents to treat or inhibit cancer, Huntington's disease, cystic fibrosis, liver fibrosis, renal fibrosis, pulmonary fibrosis, skin fibrosis, rheumatoid arthritis, diabetes, or heart failure.
  • the additional therapeutic agent to be included is an anti-cancer agent.
  • an anti-cancer agent include, but are not limited to, DNA- damaging cytotoxic drugs, alkylating agents such as cyclophosphamide, dacarbazine, and cisplatin; anti-metabolites such as methotrexate, mercaptopurine, thioguanine, fluorouracil, and cytarabine; plant alkaloids such as vinblastine and paclitaxel; antitumor antibiotics such as doxorubicin, bleomycin and mitomycin; hormones/antihormones such as prednisone, tamoxifen, and flutamide; other types of anticancer agents such as asparaginase, rituximab, trastuzumab, imatinib, retinoic acid, and derivatives, colony stimulating factors, amifostine, camptothecin, topotecan, thal
  • the present invention provides a method of inhibiting or treating diseases arising from abnormal cell proliferation and/or differentiation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds according to the present invention.
  • the method of inhibiting or treating disease comprises administering to a subject in need thereof, a composition comprising an effective amount of one or more compounds of the invention and a pharmaceutically acceptable carrier.
  • the composition to be administered may further contain a therapeutic agent such as an anti-cancer agent.
  • the compounds of the invention are defined herein by their chemical structures and/or chemical names and are generally listed according to the IUPAC or CAS nomenclature system. Abbreviations that are well known to one of ordinary skill in the art may be used. When a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is intended to be determinative of the compound's identity.
  • the present invention includes compounds labeled with various radioactive or nonradioactive isotopes.
  • atomic isotopes may include, but are not limited to, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 l), carbon-14 ( 14 C), nitrogen-15 ( 15 N), sulfur-35 ( 35 S) and chlorine-36 ( 36 CI).
  • one or more hydrogen atoms in a compound of the invention can be replaced by deuterium.
  • a compound of the invention includes at least one deuterium atom, or two or more deuterium atoms, or three or more deuterium atoms, etc.
  • compounds of the invention may also be radiolabeled with a radioactive isotope such as tritium ( 3 H), iodine-125 ( 125 l), and carbon-14 ( 14 C).
  • a radioactive isotope such as tritium ( 3 H), iodine-125 ( 125 l), and carbon-14 ( 14 C).
  • a radiolabeled compound is useful as a therapeutic or prophylactic agent, provides a reagent for research such as for an assay, and/or provides a diagnostic agent for techniques such as in vivo imaging. Synthetic methods for incorporating isotopes into organic compounds are well known in the art.
  • a compound of the invention as defined herein (such as a compound of any one of Formula (1), (2), (3), (4), (5) or (6)) or a pharmaceutically- acceptable salt thereof, exists as a single enantiomer being in an enantiomeric excess (% ee) of > 95%, such as > 98%, such as > 99%.
  • a pharmaceutical composition comprises a compound of the invention as defined herein (such as a compound of any one of Formula (1),
  • the disease or disorder to be treated by the compounds of the invention is selected from congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome (CLOVES), mosaic tissue overgrowth syndromes, venous malformations and brain malformations associated with severe epilepsy or PIK3CA-related overgrowth syndrome (PROS) (Keppler- Noreuil et al., Am J Med Genet A. 201S, 167A, 287; Kurek et al. Am. J. Hum. Genet. 2012, 90, 1108).
  • the cancer to be treated is a cancer bearing a PI3K H1047 mutation (such as H1047R) (Thorpe et al., Nat Rev Cancer 2015, 15, 7).
  • the compounds are typically PI3Ka H1047R mutant-selective inhibitors that exhibit greater selectivity for the H1047R mutation over the wild-type.
  • the compounds may decrease the amount of phosphorylated AKT (pAKT) and decrease proliferation selectively in PI3Ka H1047R mutant cell lines, preferably across several tumor types.
  • pAKT phosphorylated AKT
  • a PI3K H1047R mutant selective inhibitor of the invention (such as defined by a compound of any one of Formula (1), (2), (3), (4), (5) or (6)) dosed in combination with a selective estrogen receptor degrader (SERD) such as, but not limited to, fulvestrant, elacestrant, camizestrant or vepdegestrant may exhibit a combination benefit leading to tumor regression in ER+ / PI3K H1047R mutant tumors such as, but not limited to, the breast cancer xenograft model T47D, at doses where little or no regression would be observed with either single agent.
  • SESD selective estrogen receptor degrader
  • a PI3K H1047R mutant selective inhibitor of the invention (such as defined by a compound of any one of Formula (1), (2), (3), (4), (5) or (6)) dosed in combination with a HER2 inhibitor such as, but not limited to, tucatinib or trastuzumab may exhibit a combination benefit leading to tumor regression in ER- / HER2+ / PI3K H1047R mutant tumors such as, but not limited to, the breast cancer xenograft model HCC1954, at doses where little or no regression would be observed with either single agent.
  • a HER2 inhibitor such as, but not limited to, tucatinib or trastuzumab
  • intermediate bromoquinazolin-4-ones 4 can be generated by various cyclization methods.
  • cyclization of 1 may be effected by treatment with T 3 P and Hunig's base or pyridine, followed by K 2 CO 3 (Scheme 1).
  • R 4 is a substituted [l,l,l]-bicyclopentane
  • a number of methods are known for their preparation (Org. Lett. 2020, 1648-1654; Organic Process Research & Development 2021, 642-647; Angew. Chemie Int. Ed.
  • cyclization with 1 can be achieved by condensation mediated by MgSO 4 and PTSA followed by oxidation with DDQ.
  • Acetylquinazolinones 5 may be created by carbonylations of 4.
  • the bromine substituent of 4 may be replaced with an acetyl group by treatment with tributyl(l-ethoxyvinyl)tin and a catalytic palladium species (e.g., but not limited to, Pd(PPh 3 )4 or PdCI 2 (PPh 3 ) 2 ) at elevated temperature, followed by hydrolysis with aqueous HCI, to yield ketones 5.
  • a catalytic palladium species e.g., but not limited to, Pd(PPh 3 )4 or PdCI 2 (PPh 3 ) 2
  • intermediates 5 can serve as a platform for further expansion into diverse R 3 substitutions (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, alkyls, etc.) through a variety of known techniques (including, but not limited, to Prakash, et al., J. Am. Chem. Soc. 1989, 111, 393; Zhao, et al., Org. Lett. 2011, 13, 5342; Reichel, et al., Angew. Chem. Int. Ed. 2020, 59, 12268; etc.).
  • Alcohol-substituted quinazolinones of general structure 6 may be prepared by the reduction of 5.
  • the reduction may be achieved by treatment of 5 with NaBFU in MeOH to yield 6.
  • the bromine substituent of aminobenzamides 1 may be replaced with an acetyl group to give acetylbenzamides 7, of which the ketone may be reduced and protected (such as with protecting groups like tert-butyldimethylsilyl) to give intermediates 8.
  • Cyclization in manners similar to that from 1 to 4 may be effected to provide quinazolinones 9 from aminobenzamides 8.
  • deprotections of the secondary alcohol groups within intermediates 9 can of course yield compounds 6.
  • alcohols 6 can be converted to anthranilic acid derivatives 11 via a number of different methodologies.
  • the alcohol functionality of 6 may first be converted to a leaving group such as a bromide or a mesylate utilizing commonly known methods.
  • Nucleophilic displacement of the benzylic reactive groups of 10 by an anthranilic acid ester can give compounds 11.
  • An alternate approach to the preparations of compounds 11 is to use a Mitsunobu type of reaction of the anthranilic acid ester with alcohols 6 to give 11 directly.
  • the transient use of an activating group (such as a 2,4-dinitrobenzenesulfonyl group) on the anthranilic acid amine functionality can facilitate the Mitsunobu reaction.
  • DDQ 2,3- dichloro-5,6-dicyanobenzoquinone
  • triphenylphosphine may also be employed in the direct reaction of the alcohol 6 with the anthranilic acid ester (Shalit, T.; et al., Tetrahedron Lett. 2010, 51, 5988-5991; Iranpoor, N.; et al., Tetrahedron 2009, 65, 3893-3899; Panday, S. K., Mini-Rev. Org. Chem. 2019, 16(2), 127-140; Fukuyama, Tohru; et al., Tetrahedron Lett. 1997, 38(33), 5831-5834).
  • Ester intermediates 11 can be converted to the corresponding carboxylic acids.
  • de-esterification of intermediates 11 can be achieved via treatment with metal hydroxides (e.g., but not limited to, LiOH or NaOH).
  • an appropriate acid e.g., but not limited to, TFA, or HCI in 1,4-dioxane or water.
  • the major isomer may be separated from the other minor isomer via standard chromatographic means.
  • a judicious choice of the antipode of the sulfinyl-imine and the reducing agent may give access to either antipode of the sulfinyl-amine.
  • Sulfinyl-amines 15 can be cleaved to the single enantiomer of chiral amines 16 using standard conditions (such as hydrogen chloride on dioxane).
  • Standard coupling reactions of amines 16 with aryl iodides 17 may then give the resulting anthranilic acid derivatives 18 (Yang et al., Org. Process Res. & Dev. 2022, 26(6), 1690-1750; Surry and Buchwald, Chem. Sci. 2011, 2(1), 27-50). Ester hydrolysis may then provide carboxylic acids 19.
  • NMR spectra were recorded using a Bruker Avance III HD 300 MHz or Bruker Avance III HD 400 MHz.
  • MS samples were analyzed on a Shimadzu LCMS-2020 mass spectrometer with electrospray ionization operating in positive and negative ion mode. Samples were introduced into the mass spectrometer using chromatography. All final products had a purity of > 90 %, unless specified otherwise in the experimental details. HPLC purity was measured on a Shimadzu Acquity HPLC system.
  • DIBAL diisobutylaluminum hydride
  • HATU l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
  • K 2 CO 3 potassium carbonate
  • KOAc potassium acetate
  • LiOH lithium hydroxide
  • mCPBA meto-chloroperoxybenzoic acid
  • NaH 2 PO4 monosodium phosphate
  • NMP N -methylpyrrolidone
  • Oxetane 4-membered ring containing 3 carbon ring atoms and 1 oxygen ring atom.
  • PCI5 phosphorous pentachloride
  • Pd-PEPPSI-IHeptCI 3-chloropyridine dichloro[l,3-bis(2,6-di-4-heptylphenyl)imidazol-2- ylidene](3-chloropyridyl)palladium(ll)
  • Pd(dppf)Ck (l,l'-bis(diphenylphosphino)ferrocene)palladium(ll) dichloride
  • Pd(PPhs)4 tetrakis(triphenylphosphine)palladium(0)
  • Pd2(dba)s tris(dibenzylideneacetone)dipalladium(0)
  • PdCLfPPhsh bis(triphenylphosphine)palladium(ll) dichloridePE: petroleum ether
  • Example 1 2-((l-(2-(5-fluoro-lH-indol-2-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Enantiomer 1)
  • Step 1 Preparation of 8-bromo-2-(5-fluoro-lH-indol-2-yl)-3,6-dimethyl-2,3-dihydroquinazolin- 4(lH)-one.
  • Step 3 Preparation of 8-acetyl-2-(5-fluoro-lH-indol-2-yl)-3,6-dimethylquinazolin-4(3H)-one.
  • Step 4 Preparation of 2-(5-fluoro-lH-indol-2-yl)-8-(l-hydroxyethyl)-3,6-dimethylquinazolin-
  • Step 5 Preparation of tert-butyl 2-((N-(l-(2-(5-fluoro-lH-indol-2-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2-nitrophenyl)sulfonamido)benzoate.
  • Step 6 Preparation of tert-butyl 2-((l-(2-(5-fluoro-lH-indol-2-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate.
  • Step 7 Preparation of 2-((l-(2-(5-fluoro-lH-indol-2-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid.
  • Step 8 Preparation of 2-((l-(2-(5-fluoro-lH-indol-2-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Enantiomers 1 and 2).
  • Racemic 2-((l-(2-(5-fluoro-lH-indol-2-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid 50 mg was separated by chiral prep-HPLC with the following conditions: Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.1% FA)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 10% B to 10% B in 26 min; Wavelengths: 220/254 nm; RTl(min): 19.695; RT2(min): 22.84; Sample Solvent: EtOH-HPLC; Injection Volume: 0.5 mL.
  • Step 1 Preparation of methyl 2-((l-(2-isopentyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoate.
  • Step 2 Preparation of 2-((l-(2-isopentyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (Enantiomers 1 and 2).
  • Racemic 2-((l-(2-isopentyl-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid 200 mg was separated by chiral prep-HPLC with the following conditions: Column: (R, R)-WHELK-Ol-Kromasil, 2.11*25 cm, 5 pm; Mobile Phase A: EtOH- HPLC, Mobile Phase B: Hex(0.1% FA)-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 37 min; Wavelengths: 220/254 nm; RTl(min): 23.848; RT2(min): 30.603; Sample Solvent: EtOH- HPLC; Injection Volume: 0.9 mL.
  • Step 1 Preparation of 8-(l-bromoethyl)-2-(4-chlorophenyl)-3,6-dimethylquinazolin-4(3H)-one.
  • Step 2 Preparation of methyl 2-((l-(2-(4-chlorophenyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate.
  • Step 3 Preparation of 2-((l-(2-(4-chlorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (Enantiomers 1 and 2).
  • Racemic 2-((l-(2-(4-chlorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid 150 mg was separated by chiral prep HPLC with the following conditions: Column: CHIRALPAK ID, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.1% FA)-HPLC, Mobile Phase B: IPA-HPLC; Flow rate: 20 mL/min; Gradient: 7% B to 7% B in 23 min; Wavelengths: 220/254 nm; RTl(min): 13.609; RT2(min): 17.646; Sample Solvent: EtOH-HPLC; Injection Volume: 0.5 mL.
  • Example 7 2-((l-(2-(3-chlorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (Enantiomer 1)
  • Example 8 2-((l-(2-(3-chlorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (Enantiomer 2)
  • Step 1 Preparation of N-(2-bromo-4-methyl-6-(methylcarbamoyl)phenyl)-2,3-dihydro-lH- indene-2-carboxamide.
  • Step 2 Preparation of 8-bromo-2-(2,3-dihydro-lH-inden-2-yl)-3,6-dimethylquinazolin-4(3H)- one.
  • Step 3 Preparation of 8-acetyl-2-(2,3-dihydro-lH-inden-2-yl)-3,6-dimethylquinazolin-4(3H)- one.
  • Step 4 Preparation of 2-(2,3-dihydro-lH-inden-2-yl)-8-(l-hydroxyethyl)-3,6- dimethylquinazolin-4(3H)-one.
  • Step 5 Preparation of tert-butyl 2-((l-(2-(2,3-dihydro-lH-inden-2-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate.
  • Step 6 Preparation of 2-((l-(2-(2,3-dihydro-lH-inden-2-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid.
  • Step 7 Preparation of 2-((l-(2-(2,3-dihydro-lH-inden-2-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Enantiomers 1 and 2).
  • Example 12 2-((l-(2-(2,3-dihydro-lH-inden-2-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Enantiomer 2)
  • Example 13 2-((l-(2-(4-cyanophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (Enantiomer 1)
  • Example 14 2-((l-(2-(4-cyanophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (Enantiomer 2)
  • Step 1 Preparation of 3-acetyl-2-amino-N,5-dimethylbenzamide.
  • Step 2 Preparation of 2-amino-3-(l-hydroxyethyl)-N,5-dimethylbenzamide.
  • Step 3 Preparation of 2-amino-3-(l-((tert-butyldimethylsilyl)oxy)ethyl)-N,5- dimethylbenzamide. 5.0 eq TBSCI, 15 eq 1 H-lmidazole, DMF, 0 °C ⁇ rt, overnight
  • Step 4 Preparation of 4-(8-(l-((tert-butyldimethylsilyl)oxy)ethyl)-3,6-dimethyl-4-oxo-l,2,3,4- tetrahydroquinazolin-2-yl)benzonitrile.
  • Step 5 Preparation of 4-(8-(l-((tert-butyldimethylsilyl)oxy)ethyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-2-yl)benzonitrile.
  • Step 6 Preparation of 4-(8-(l-hydroxyethyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2- yl)benzonitrile.
  • Step 7 Preparation of tert-butyl 2-((l-(2-(4-cyanophenyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate.
  • Step 8 Preparation of 2-((l-(2-(4-cyanophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid.
  • Step 9 Preparation of 2-((l-(2-(4-cyanophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)benzoic acid (Enantiomers 1 and 2).
  • Example 15 2-((l-(2-(4-chloro-2-fluorophenyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid
  • Step 1 Preparation of 8-(l-((tert-butyldimethylsilyl)oxy)ethyl)-2-(4-chloro-2-fluorophenyl)-3,6- dimethyl-2,3-dihydroquinazolin-4(lH)-one.
  • Step 2 Preparation of 2-(4-chloro-2-fluorophenyl)-8-(l-hydroxyethyl)-3,6-dimethylquinazolin- 4(3H)-one.
  • Step 3 Preparation of 8-(l-bromoethyl)-2-(4-chloro-2-fluorophenyl)-3,6-dimethylquinazolin-
  • Step 4 Preparation of methyl 2-((l-(2-(4-chloro-2-fluorophenyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate.
  • Step 5 Preparation of 2-((l-(2-(4-chloro-2-fluorophenyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid.
  • Example 17 2-((l-(2-(4,4-dimethylcyclohexyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Enantiomer 2)
  • Step 1 Preparation of 3-(l-((tert-butyldimethylsilyl)oxy)ethyl)-2-(4,4-dimethylcyclohexane-l- carboxamido)-N,5-dimethylbenzamide.
  • Step 2 Preparation of 8-(l-((tert-butyldimethylsilyl)oxy)ethyl)-2-(4,4-dimethylcyclohexyl)-3,6- dimethylquinazolin-4(3H)-one.
  • Step 3 Preparation of tert-butyl 2-((N-(l-(2-(4,4-dimethylcyclohexyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)-2,4-dinitrophenyl)sulfonamido)benzoate.
  • Step 4 Preparation of tert-butyl 2-((l-(2-(4,4-dimethylcyclohexyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoate.
  • Step 5 Preparation of 2-((l-(2-(4,4-dimethylcyclohexyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Enantiomers 1 and 2).
  • Example 18 2-((l-(2-(3-(4-fluorophenyl)bicyclo[l.l.l]pentan-l-yl)-3,6-dimethyl-4- oxo-3, 4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Enantiomer 1)
  • Example 19 2-((l-(2-(3-(4-fluorophenyl)bicyclo[l.l.l]pentan-l-yl)-3,6-dimethyl-4- oxo-3, 4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Enantiomer 2)
  • Example 20 2-((l-(2-(4-chloro-3-methoxyphenethyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Enantiomer 1)
  • Example 24 2-((l-(3,6-dimethyl-4-oxo-2-((lR,5S,6r)-3-(2,2,2-trifluoroethyl)-3- azabicyclo[3.1.0]hexan-6-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Enantiomer 1)
  • Example 25 2-((l-(3,6-dimethyl-4-oxo-2-((lR,5S,6r)-3-(2,2,2-trifluoroethyl)-3- azabicyclo[3.1.0]hexan-6-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Enantiomer 2)
  • Step 1 Preparation of tert-butyl (lR,5S,6r)-6-(8-(l-((2-(methoxycarbonyl)phenyl)amino)ethyl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate.
  • Step 2 Preparation of methyl 2-((l-(2-((lR,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)-3,6-dimethyl- 4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate.
  • Step 3 Preparation of methyl 2-((l-(3,6-dimethyl-4-oxo-2-((lR,5S,6r)-3-(2,2,2-trifluoroethyl)-3- azabicyclo[3.1.0]hexan-6-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate.
  • Step 4 Preparation of 2-((l-(3,6-dimethyl-4-oxo-2-((lR,5S,6r)-3-(2,2,2-trifluoroethyl)-3- azabicyclo[3.1.0]hexan-6-yl)-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (Enantiomers 1 and 2).
  • Examples 26 to 377 were prepared in a manner similar to that described in Schemes 1 to 3 or Examples 1 to 25 and are identified and characterized in Table 1 below. If not specified otherwise, all depicted chiral centers exist as a (R)- and (S)-racemic mixture or as either (R)- or (S)- enantiomer. Table 1. Examples 26 to 377
  • T47D or SKBR3 cells were trypsinized, resuspended in culture media and seeded onto assay ready plates.
  • T47D culture media consisted of RPMI, 10% FBS and insulin (0.2 units/mL).
  • SKBR3 culture media consisted of McCoys 5a and 10% FBS.
  • Cells were seeded at a density of 1,500 cells/well and dispensed in 50 pL onto 384 well assay ready plates (Corning, 89089-790). Assay ready plates had previously been stamped with 10-point dilutions of compounds of interest, as well as controls.
  • the Echo655 is used to stamp plates at 40 nL of compound or DMSO.
  • %ln hibition 100 x (LurmiD - Lumsampie) / (LurriD -Luminh), where D is obtained from cells treated with 0.1% DMSO only; Inh is obtained from cells treated with lOuM Alpelisib.
  • T47D or SKBR3 cells were trypsinized, resuspended in culture media and seeded onto assay ready plates.
  • T47D culture media consisted of RPMI, 10% FBS and insulin (0.2 units/mL).
  • SKBR3 culture media consisted of McCoy's 5a and 10% FBS.
  • Cells were seeded at a density of 5000 cells/well and dispensed in 12.5 pL onto 384 well assay ready plates (Perkin Elmer, 6008238)). Assay ready plates had previously been stamped with 10-point dilutions of compounds of interest, as well as controls.
  • the Echo655 is used to stamp plates at 12.5 nL of compound or DMSO.
  • Reagent table [000255] For EC50 values shown in Table 2, "A” refers to 1 nM ⁇ EC50 ⁇ 500 nM; “B” refers to 500 nM ⁇ EC50 ⁇ 2 pM; “C” refers to 2 pM ⁇ EC50 ⁇ 15 pM; and “D” refers to an EC50 > 15 pM.
  • CD1 mice were dosed with a single IV or PO dose, followed by serial sampling of plasma at 0.0833 (IV only), 0.25, 0.5, 1, 2, 4, 8, 24 hours post dose. Desired serial concentrations of working solutions were achieved by diluting stock solution of analyte with 50% acetonitrile in water solution. Ten microliters of working solutions (0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng/mL) were added to 10 pL of the blank Female CD1 Mouse plasma to achieve calibration standards of 0.5 to approximately 1000 ng/mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng/mL) in a total volume of 20 pL.
  • PI 3-kinase pllObeta a new target for antithrombotic therapy. Nat Med. 11(5): 507-514.

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Abstract

La présente invention concerne des dérivés de ((4-oxo-3,4-dihydroquinazolin-8-yl)éthyl)amine de formule (I), ainsi que l'utilisation desdits composés en tant qu'inhibiteurs de P13K dans des méthodes de traitement du cancer.
PCT/US2023/032852 2022-09-19 2023-09-15 Dérivés de ((4-oxo-3,4-dihydroquinazolin-8-yl)méthyl)amine utilisés en tant qu'inhibiteurs de p13k pour le traitement du cancer WO2024064024A1 (fr)

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