WO2024081345A1 - Benzopyrimidin-4(3h)-ones utilisées en tant qu'inhibiteurs de pi3k - Google Patents

Benzopyrimidin-4(3h)-ones utilisées en tant qu'inhibiteurs de pi3k Download PDF

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WO2024081345A1
WO2024081345A1 PCT/US2023/034999 US2023034999W WO2024081345A1 WO 2024081345 A1 WO2024081345 A1 WO 2024081345A1 US 2023034999 W US2023034999 W US 2023034999W WO 2024081345 A1 WO2024081345 A1 WO 2024081345A1
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compound
enantiomer
substituted
unsubstituted
pharmaceutically acceptable
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PCT/US2023/034999
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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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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • Phosphoinositide 3’ kinases are a family of enzymes responsible for phosphorylation of the 3’ hydroxyl position of the inositol ring of PIs. PI3Ks are subdivided into 3 classes according to their structure and substrates. Class II PI3Ks (PI3K ⁇ C2 ⁇ , PI3K ⁇ C2 ⁇ , PI3K ⁇ C2 ⁇ ) 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 (p110 ⁇ , ⁇ , ⁇ , ⁇ ) and one of several regulatory subunits that determine binding partners and subcellular localization.
  • 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 4,5 ⁇ diphosphate
  • PIP3 phosphatid
  • 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 ( ⁇ , ⁇ , ⁇ , and ⁇ ) based on the identity of their catalytic (p110 ⁇ , p110 ⁇ , p110 ⁇ , or p110 ⁇ ) and regulatory (p85 ⁇ or its various splice variants, p85 ⁇ , p55 ⁇ , or p101) subunits, giving rise to distinct roles in cellular physiology (Vanhaesebroeck et al., J Mol Med (Berl). 2016, 94, 5). PI3K ⁇ and PI3K ⁇ are mostly expressed in leukocytes and play an important role in pro ⁇ inflammatory pathways (Hawkins et.
  • PI3K ⁇ and ⁇ are more ubiquitously expressed and share similar
  • PI3K ⁇ has a nonredundant role in angiogenesis (Soler et al., J Exp Med. 2013, 210, 1937), while PI3K ⁇ 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). Mutations in the gene coding for PI3K ⁇ or mutations which lead to upregulation of PI3K ⁇ have been found to occur in many human cancers such as lung, stomach, endometrial, ovarian, bladder, breast, colon, brain, prostate, and skin cancers (Goncalves et al., N Eng J Med. 2018, 379,2052).
  • PIK3CA the gene encoding the p110 ⁇ subunit of PI3K ⁇
  • PIK3CA is frequently mutated or amplified in a variety of tumor types. Missense mutations occur in all domains of p110 ⁇ , but cluster in two ‘hot spots’, the most common being E542K and E545K in the helical domain, and H1047R in the kinase domain.
  • Helical domain mutations reduce inhibition of p110 ⁇ by p85 or facilitate direct interaction of p110 ⁇ with insulin receptor substrate 1 (IRS1)37, whereas kinase domain mutations increase interaction of p110 ⁇ with lipid membranes, concomitantly upregulating signaling events.
  • IRS1 insulin receptor substrate 1
  • Tissue cellular response to insulin requires PI3K signaling through the ubiquitously expressed p110 ⁇ 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.
  • PI3K ⁇ inhibitors are associated with hyperglycemia and rash due to the p110 ⁇ sub ⁇ unit role in insulin response (Rugo et al., The Breast 2022, 61, 156).
  • PI3K ⁇ inhibitors are associated with hyperglycemia and rash due to the p110 ⁇ sub ⁇ unit role in insulin response (Rugo et al., The Breast 2022, 61, 156).
  • use of a selective PI3K ⁇ inhibitor (idelalisib), where the p110 ⁇ sub ⁇ unit is highly expressed in immune cells, causes severe diarrhea and colitis.
  • 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: R 1 is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted, with the proviso that R 1 is not R 2 is H, C 1 ⁇ C 4 alkyl, C 3 ⁇ C 7 cycloalkyl, CF 3 , CH 2 F or CF 2 H, and where R 2 is not H, the carbon atom attached to R 2 is a chiral center and exists as
  • 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 CH 3 , F, Cl, CF 3 , CF 2 H, CH 2 F, OCH 3 , cyclopropyl, CH 2 CF 3 , an oxetan
  • 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 CH 3 , F, Cl, CF 3 , CF 2 H, CH 2 F, OCH 3 , cyclopropyl, CH 2 CF 3 , an oxetane ring, or COR a where R a is C 1 ⁇ C 4 alkyl, O ⁇ C 1 ⁇ C 4 alkyl, or NR b R c where R b and R c are independently H or C 1 ⁇ C
  • the N ⁇ linked heterocyclyl ring is a substituted or unsubstituted aziridine, azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2 ⁇ oxa ⁇ 7 ⁇ azaspiro[3.5]nonane, 1, 4 ⁇ dioxa ⁇ 7 ⁇ azaspiro[4.4]nonane or 2 ⁇ azaadamantane.
  • R 4 is ⁇ NR 9 ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 , where L 1 to L 7 , R 8 and R 9 are as defined.
  • R 4 is ⁇ O ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 , where L 1 to L 7 and R 8 are as defined.
  • R 4 is ⁇ S ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; ⁇ S(O) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; or ⁇ S(O) 2 ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 , where L 1 to L 7 and R 8 are as defined.
  • R 8 is a 6 ⁇ membered aryl ring; or is a 5 ⁇ to 6 ⁇ membered heteroaryl ring containing from 1 ⁇ 3 nitrogen atoms; or is a non ⁇ aromatic 3 ⁇ to 7 ⁇ membered carbocycle; or is a non ⁇ aromatic 3 ⁇ to 7 ⁇ membered heterocycle containing from 1 to 3 heteroatoms selected from N, O, S and Si with the proviso that if the ring size is 4 or 5 then the number of heteroatoms will be 1 or 2 and if the ring size is 6 or 7 the number heteroatoms will be 1, 2 or 3; or is a C 1 ⁇ C 6 alkyl group, where the aryl ring, the heteroaryl ring, the carbocycle, the heterocycle and the C 1 ⁇ C 6 alkyl group are unsubstituted or substituted with one or more of CH 3 , F, Cl, CF 3 , CF 2 H, CH 2 F, OCH 3 ,
  • R 4 is [00014] where R d is H or CH 3 and R e is CH 3 , C 3 ⁇ C 6 cycloalkyl, a six ⁇ membered aromatic or heteroaromatic ring containing from 0, 1 or 2 nitrogen atoms which may be optionally substituted with CH 3 , F, Cl, CF 3 , CF 2 H, CH 2 F, OCH 3 , cyclopropyl, CN or N(CH 3 ) 2 , or R d and R e together with the attached nitrogen atom may form a 4 ⁇ to 7 ⁇ membered non ⁇ aromatic heterocycle containing from 1 to 2 heteroatoms which may be either N or O, with the proviso that if the ring size is 4 or 5 the number of heteroatoms will be 1 and if the ring size is from 6 to 7, the number of heteroatoms will be 1 or 2, where the ring is unsubstituted or is substituted
  • R a is C 1 ⁇ C 4 alkyl, O ⁇ C 1 ⁇ C 4 alkyl, or NR b R c where R b and R c are independently H or C 1 ⁇ C 4 alkyl.
  • R 4 is a N ⁇ linked non ⁇ aromatic heterocyclyl ring , where the heterocyclyl ring is substituted or unsubstituted, optionally contains one or more additional atoms selected from N, O, Si and S, and is optionally part of a bridged, fused or spiro ring system.
  • the N ⁇ linked heterocyclyl ring is azetidine, pyrrolidine, imidazoline, imidazolidine, piperazine, morpholine, thiomorpholine, piperidine, indoline, tetrahydroquinoline, decahydroquinoline, 2 ⁇ oxa ⁇ 7 ⁇ azaspiro[3.5]nonane, 1,3,8 ⁇ triazaspiro[4.5] ⁇ decan ⁇ 4 ⁇ one, 1, 4 ⁇ dioxa ⁇ 7 ⁇ azaspiro[4.4]nonane.
  • the N ⁇ linked non ⁇ aromatic heterocyclyl ring is substituted or unsubstituted, optionally contains one or more additional atoms selected from N, O, Si and S, and is not part of a bridged, fused or spiro ring system.
  • the N ⁇ linked non ⁇ aromatic heterocyclyl ring is substituted or unsubstituted, optionally contains one or more additional atoms selected from N, O, Si and S, and is part of a bridged, fused or spiro ring system.
  • the N ⁇ linked non ⁇ aromatic heterocyclyl ring is substituted or unsubstituted, does not contain additional atoms selected from N, O, Si and S, and is not part of a bridged, fused or spiro ring system.
  • the N ⁇ linked non ⁇ aromatic heterocyclyl ring is substituted or unsubstituted, does not contain additional atoms selected from N, O, Si and S, and is part of a bridged, fused or spiro ring system.
  • the N ⁇ linked non ⁇ aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one sulfur ring atom, and is not part of a bridged, fused or spiro ring system.
  • the N ⁇ linked non ⁇ aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one sulfur ring atom, and is part of a bridged, fused or spiro ring system.
  • the N ⁇ linked non ⁇ aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one oxygen ring atom, and is not part of a bridged, fused or spiro ring system.
  • the N ⁇ linked non ⁇ aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one oxygen ring atom, and is part of a bridged, fused or spiro ring system.
  • the N ⁇ linked non ⁇ aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one additional nitrogen ring atom, and is not part of a bridged, fused or spiro ring system.
  • the N ⁇ linked non ⁇ aromatic heterocyclyl ring is substituted or unsubstituted, contains at least one additional nitrogen ring atom, and is part of a bridged, fused or spiro ring system.
  • R 2 is CH 3 or CH 2 F.
  • R 3 is H.
  • R 5 is CH 3 .
  • R 6 is CH 3 .
  • each R 7 is independently H or F.
  • R 2 , R 5 and R 6 are CH 3 .
  • R 1 is heterocyclyl, aryl or heteroaryl, where each of the heterocyclyl, aryl or heteroaryl is unsubstituted or substituted.
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted.
  • R 1 is aryl, where the aryl is unsubstituted or substituted.
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted.
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; and R 3 is H.
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; and R 3 is H.
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; and R 3 is H.
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; and each R 7 is independently H or F.
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; and each R 7 is independently H or F.
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; and each R 7 is independently H or F.
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; each R 7 is independently H or F; and R 5 is CH 3 .
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; each R 7 is independently H or F; and R 5 is CH 3 .
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; each R 7 is independently H or F; and R 5 is CH 3 .
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; and R 4 is ⁇ O ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 .
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; and R 4 is ⁇ S ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 .
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; and R 4 is ⁇ S(O) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 .
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; and R 4 is ⁇ S(O) 2 ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 .
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; and R 4 is ⁇ (NR 9 ) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 .
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; and R 4 is ⁇ O ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 .
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; and R 4 is ⁇ S ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 .
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; and R 4 is ⁇ S(O) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 .
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; and R 4 is ⁇ S(O) 2 ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 .
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; and R 4 is ⁇ (NR 9 ) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 .
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; and R 4 is ⁇ O ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 .
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; and R 4 is ⁇ S ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 .
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; and R 4 is ⁇ S(O) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 .
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; and R 4 is ⁇ S(O) 2 ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 .
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; and R 4 is ⁇ (NR 9 ) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 .
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ O ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; and each R 7 is independently H or F.
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H, R 4 is ⁇ S ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 and each R 7 is independently H or F.
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S(O) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; and each R 7 is independently H or F.
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S(O) 2 ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; and each R 7 is independently H or F.
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ (NR 9 ) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; and each R 7 is independently H or F.
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ O ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; and each R 7 is independently H or F.
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; and each R 7 is independently H or F.
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S(O) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; and each R 7 is independently H or F.
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S(O) 2 ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; and each R 7 is independently H or F.
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ (NR 9 ) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; and each R 7 is independently H or F.
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ O ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; and each R 7 is independently H or F.
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; and each R 7 is independently H or F.
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S(O) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; and each R 7 is independently H or F.
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S(O) 2 ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; and each R 7 is independently H or F.
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ (NR 9 ) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; and each R 7 is independently H or F.
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ O ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; and R 5 is CH 3 .
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; and R 5 is CH 3 .
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S(O) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; and R 5 is CH 3 .
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S(O) 2 ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; and R 5 is CH 3 .
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ (NR 9 ) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; and R 5 is CH 3 .
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ O ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; and R 5 is CH 3 .
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; and R 5 is CH 3 .
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S(O) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; and R 5 is CH 3 .
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S(O) 2 ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; and R 5 is CH 3 .
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ (NR 9 ) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; and R 5 is CH 3 .
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ O ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; and R 5 is CH 3 .
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; and R 5 is CH 3 .
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S(O) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; and R 5 is CH 3 .
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S(O) 2 ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; and R 5 is CH 3 .
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ (NR 9 ) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; and R 5 is CH 3 .
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ O ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; R 7 is H; R 5 is CH 3 ; and R 6 is CH 3 .
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; R 5 is CH 3 ; and R 6 is CH 3 .
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S(O) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; R 5 is CH 3 ; and R 6 is CH 3 .
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S(O) 2 ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; R 5 is CH 3 ; and R 6 is CH 3 .
  • R 1 is heterocyclyl, where the heterocyclyl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ (NR 9 ) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; R 5 is CH 3 ; and R 6 is CH 3 .
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ O ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; R 5 is CH 3 ; and R 6 is CH 3 .
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; R 5 is CH 3 ; and R 6 is CH 3 .
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S(O) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; R 5 is CH 3 ; and R 6 is CH 3 .
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S(O) 2 ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; R 5 is CH 3 ; and R 6 is CH 3 .
  • R 1 is aryl, where the aryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ (NR 9 ) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 , each R 7 is independently H or F, R 5 is CH 3 and R 6 is CH 3 .
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ O ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; R 5 is CH 3 ; and R 6 is CH 3 .
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; R 5 is CH 3 ; and R 6 is CH 3 .
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S(O) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; R 5 is CH 3 ; and R 6 is CH 3 .
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ S(O) 2 ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; R 5 is CH 3 ; and R 6 is CH 3 .
  • R 1 is heteroaryl, where the heteroaryl is unsubstituted or substituted, R 2 is CH 3 or CH 2 F; R 3 is H; R 4 is ⁇ (NR 9 ) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 ; each R 7 is independently H or F; R 5 is CH 3 ; and R 6 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: each of X 1 , X 2 and X 3 is independently N, CH or substituted C, where at least one of X 1 , X 2 and X 3 is N; R 4 is ⁇ NR 9 ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 , where L 1 to L 7 , R 8 and R 9 are as defined in the compound of Formula (1); R 7 is as defined 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 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 X 1 , X 2 and X 3 is independently N, CH or substituted C, where at least one of X 1 , X 2 and X 3 is N; R 4 is ⁇ NR 9 ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 , where L 1 to L 7 , R 8 and R 9 are as defined 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 for a given compound indicates individual compounds containing one of each of the substituents
  • 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: R 1 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 benzopyrimidin ⁇ 4(3H) ⁇ one moiety contains a carboxylic acid substituent at the ortho position to the point of attachment; R 4 and R 7 are as defined 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 compound of Formula (1) is a compound of Formula (5)
  • R 1 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 benzopyrimidin ⁇ 4(3H) ⁇ one moiety contains a carboxylic acid substituent at the ortho position to the point of attachment;
  • R 4 is as defined 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 for a given compound indicates individual compounds containing one of each of the substituents.
  • the compound of Formula (1) is a compound of Formula (1)
  • R 4 is selected from [000110]
  • R 1 is substituted or unsubstituted heteroaryl.
  • R 1 is substituted or unsubstituted heteroaryl and R 4 is ⁇ O ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 .
  • R 1 is substituted or unsubstituted heteroaryl and R 4 is ⁇ (NR 9 ) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 .
  • R 1 is substituted or unsubstituted aryl.
  • R 1 is substituted or unsubstituted aryl and R 4 is ⁇ O ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 .
  • R 1 is substituted or unsubstituted aryl and R 4 is ⁇ (NR 9 ) ⁇ L 1 ⁇ L 2 ⁇ L 3 ⁇ L 4 ⁇ L 5 ⁇ L 6 ⁇ L 7 ⁇ R 8 .
  • An aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising any compound of the invention as described herein (such as a compound of Formula (1), (2), (3), (4), (5), (6), (7) or (8)) 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 a compound of Formula (1), (2), (3), (4), (5), (6), (7) or (8)) or 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 PI3K ⁇ H1047 mutation (such as H1047R).
  • DETAILED DESCRIPTION OF THE INVENTION refers to a medical condition or set of medical conditions exhibited by a patient which may predispose the patient to a particular
  • 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 (i.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 LD 50 / ED 50 .
  • 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. For example, 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.
  • 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.
  • the term "inhibitory compound” as used herein, refers to any compound capable of interacting with (i.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.
  • attachment 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 (i.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 (i.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.
  • infant e.g., infant, child, adolescent
  • adult subject e.g., young adult, middle ⁇ aged adult or senior adult
  • other primates e.g., monkeys
  • non ⁇ human mammals such as cows, pigs, horses, sheep, mice, goats, cats, dogs
  • birds such as chickens, ducks and/or geese.
  • affinity refers to any attractive force between substances or particles that causes them to enter into
  • 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.
  • the term "derived from” as used herein, refers to the source of a compound or sequence. In one respect, a compound or sequence may be derived from an organism or particular species. In another respect, a compound or sequence may be derived from a larger complex or sequence.
  • the term "test compound” as used herein, 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.
  • the 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.
  • the term “synergy” or “synergistic” as used herein refers to the phenomenon where the combination of two therapeutic agents of a combination therapy is greater in terms of measured results than the sum of the effect of each agent when administered alone.
  • the term “in vivo” as used herein 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. In general, 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. In general, 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
  • 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. In various instances, 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.
  • 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.
  • 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.
  • 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
  • label refers to any composition detectable by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical or chemical means.
  • Such 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 I, 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, 125 I, 35 S, 14 C, or 32 P
  • enzymes e.g., horse
  • 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). Additionally, although the conjugate may be unsubstituted, the
  • 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 (i.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 tri ⁇ substitution 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 (NO 2 ), 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 CF 2 H, CHFCHF 2 , CF 2 CH 2 F, CF 2 CF 3 , CF 2 CH 3 , CF(CH 3 ) 2 , CH 2 CH 2 CF 3 , CF 2 CH 2 CF 3 , CF 2 CF 2 CF 2 , CF 2 CF 2 , CF 2 CF 2
  • each R f and R g may be the same or different and are independently, hydrogen, alkyl (e.g., CH 3 ), substituted alkyl, haloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, where each R f and R g may be the same or different and are independently, hydrogen, alkyl (e.g., CH 3 ), substituted alkyl, haloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, where each R f and R g may be the same or different and are independently, hydrogen, alkyl (e.g., CH 3 ), substituted alkyl, haloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, where each R f and R g may be the same or different and are independently, hydrogen, alkyl (e.g., CH 3 ), substituted
  • 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.
  • 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, tert ⁇ butyl, isopentyl, and the like.
  • a methyl substituent may be depicted as “CH 3 ” 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 ⁇ C 7 ) cycloalkyls, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl, and the like; while unsaturated cyclic alkyls include, but are not limited to,
  • Cyclic alkyls are also referred to herein as “homocycles” or “homocyclic 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, 1,4 ⁇ 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, 1,3 ⁇ dihydrospiro[indene ⁇ 2,3' ⁇ pyrrolidine] and 3,4 ⁇ dihydro ⁇ 2H ⁇ spiro[naphthalene ⁇ 1,4' ⁇ piperidine].
  • bridged refers to a compound containing two nonadjacent atoms common to two rings.
  • exemplary embodiments include, but are not limited to, norbornane, bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, 1,4 ⁇ 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 peri ⁇ fused 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 ⁇ 1H ⁇ indole or octahydro ⁇ 1H ⁇ isoindole).
  • 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.
  • 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.
  • heteroaryl ring may be attached as a substituent via a ring heteroatom or a carbon atom.
  • Representative 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, pyra
  • heteroarylalkyl means any alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl moiety, such as ⁇ CH 2 pyridinyl, ⁇ CH 2 pyrimidinyl, 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 1 ⁇ methyl ⁇ 2 ⁇ pyridone), ethylene oxide (oxirane), ethylene imine (aziridine), ethylene sulfide (thi
  • heterocycloalkyl refers to any alkyl having at least one alkyl hydrogen atom replaced with a heterocycle, such as ⁇ CH 2 morpholinyl, and the like.
  • alkyloxy or “alkoxy”, as used herein, means any alkyl moiety attached through an oxygen bridge (i.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 (i.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.
  • 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 ⁇ 1 ⁇ 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.
  • 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
  • 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, 727, 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 ⁇ 20e1, 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.
  • 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 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) ⁇
  • optically active compounds 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.
  • the synthesis of 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.
  • 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.
  • agents to treat or inhibit cancer 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 examples 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, thalidomide analogs such as lenalidomide, and proteasome inhibitors such as Velcade.
  • 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.
  • 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 I), carbon ⁇ 14 ( 14 C), nitrogen ⁇ 15 ( 15 N), sulfur ⁇ 35 ( 35 S) and chlorine ⁇ 36 ( 36 Cl).
  • 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 I), 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), (6), (7) or (8)) 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 Formula I) or a pharmaceutically ⁇ acceptable salt thereof, where the compound exists as a single enantiomer being in an enantiomeric excess (% ee) of ⁇ 95%, such as ⁇ 98%, such as ⁇ 99%.
  • 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. 2015, 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 of the invention are typically PI3K ⁇ 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 PI3K ⁇ 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 Formula (1) through Formula (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 a compound of any one of Formula (1), (2), (3), (4), (5), (6), (7) or (8)) 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.
  • Compounds of Formula (1) of the present invention were generally prepared according to the synthetic route identified in Scheme 1:
  • chlorination was achieved by refluxing 2 in POCl 3 followed by neutralization with aqueous base.
  • Intermediates of general structure 4 were then generated by S N Ar substitutions upon chlorobenzopyrimidinones 3.
  • treatment of intermediates 3 with an amine, an amine hydrochloride salt, an alcohol, or a thiol (depending on whether R 4 is desired to be an N ⁇ link, O ⁇ link, or S ⁇ link, respectively), in some embodiments with the addition of an appropriate base (e.g., but not limited to, DIEA, K 2 CO 3 , or NaH), in an appropriate solvent (e.g., but not limited to, ACN, NMP, or DMF) at room temperature or, in some embodiments,
  • an appropriate base e.g., but not limited to, DIEA, K 2 CO 3 , or NaH
  • an appropriate solvent e.g., but not limited to, ACN, NMP, or DMF
  • Ketone derivatives of the general structure 5 were generated from 4 by carbonylation utilizing the halogen functional group of 4.
  • the bromine substituent of 4 was replaced with an acetyl group by treatment with tributyl(1 ⁇ ethoxyvinyl)tin and a catalytic palladium species (e.g., but not limited to, Pd(PPh 3 ) 4 or PdCl 2 (PPh 3 ) 2 ) at elevated temperature, followed by hydrolysis with aqueous HCl, to yield ketones 5.
  • Intermediates 5 served as a platform for further expansion into diverse R 2 substitutions (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, alkyls, etc.) through a variety of known techniques (including, but not limited to, the methods described in Prakash, et al., J. Am. Chem. Soc.
  • alcohols 6 were converted first to the corresponding methanesulfonates via treatment with Ms 2 O or MsCl and an amine base (e.g., but not limited to, Et 3 N or DIEA), or the corresponding bromides via treatment with PBr 3 , followed by treatment with amines 7, to furnish benzyl amines 9.
  • Sulfonamides of general structure 8 were converted to secondary amines 9 via known desulfonylation protocols.
  • treatment of compounds of the general structure 8 with potassium thiophenolate and K 2 CO 3 afforded amines 9.
  • Ester intermediates 9 were converted to the corresponding carboxylic acids of general structure 10 via known de ⁇ esterification protocols.
  • each R h and each R i are independently selected from H, CH 3 , c ⁇ Pr, c ⁇ Bu, CF 3 and OH; and each “A” is selected from O, S, S(O) and S(O) 2 . All chiral centers in the below R 4 structures that are not specified, exist as a (R) ⁇ and (S) ⁇ racemic mixture or as either (R) ⁇ or (S) ⁇ enantiomer.
  • R 4 is selected from: or R 4 is selected from the following:
  • each X is independently N or CH; each X a is independently O or CH 2 ; each X b is independently O, CH 2 or N k N m ; each R h and each R i are independently selected from H, CH 3 , c ⁇ Pr, c ⁇ Bu, CF 3 and OH; each R j is independently selected from CF 3 , CH 2 CF 3 , CH 2 CF 2 H, OCH 3 , OCF 3 , OCH 2 CF 3, Oc ⁇ Pr, aryl, heteroaryl, COCH 3 and CO 2 CH 3 ; each R k and R m is CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 OH, CH 2 CH 2 N(CH 3 ) 2 , COCH 3 ; and each “A” is selected from O, S, S(O) and S(O) 2 .
  • R 4 All chiral centers in the below R 4 structures that are not specified, exist as a (R) ⁇ and (S) ⁇ racemic mixture or as either (R) ⁇ or (S) ⁇ enantiomer. or a solvate, enantiomer, diastereomer, tautomer, polymorph or isotope ⁇ labeled compound, or a pharmaceutically acceptable salt thereof, where R 4 is selected from:
  • R 1 is selected from Experimental [000199] All commercially available solvents and reagents were used as received. All 1 H 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.
  • NaBH 4 sodium borohydride
  • N 2 nitrogen
  • Na 2 CO 3 sodium carbonate
  • Na 2 SO 4 sodium sulfate
  • NaCl sodium chloride
  • NaHCO 3 sodium bicarbonate
  • NaH 2 PO 4 monosodium phosphate
  • NMP N ⁇ methylpyrrolidone Oxetane: 4 ⁇ membered ring containing 3 carbon ring atoms and 1 oxygen ring atom.
  • PBr 3 phosphorous tribromide
  • PCl 5 phosphorous pentachloride
  • Pd ⁇ PEPPSI ⁇ IHeptCl 3 ⁇ chloropyridine dichloro[1,3 ⁇ bis(2,6 ⁇ di ⁇ 4 ⁇ heptylphenyl)imidazol ⁇ 2 ⁇ ylidene](3 ⁇ chloropyridyl)palladium(II)
  • Pd(dppf)Cl 2 (1,1' ⁇ bis(diphenylphosphino)ferrocene)palladium(II) dichloride
  • Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium(0)
  • Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium(0)
  • PdCl 2 (PPh 3 ) 2 bis(triphenylphosphine)palladium(II) dichloridePE: petroleum ether
  • POCl 3 phospho
  • the resulting mixture was stirred for 48 h at 100 °C.
  • the resulting mixture was diluted with H 2 O, filtered, and the filter cake was washed with DCM.
  • the filtrate was extracted with CH 2 Cl 2 (2 x 50 mL). The combined organics were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure.
  • Step 2 Preparation of N ⁇ (1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl) ⁇ 2 ⁇ methylpropane ⁇ 2 ⁇ sulfinamide
  • N ⁇ [(1) ⁇ 1 ⁇ [2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxoquinazolin ⁇ 8 ⁇ yl]ethylidene] ⁇ 2 ⁇ methylpropane ⁇ 2 ⁇ sulfinamide (300 mg, 0.70 mmol) and CeCl 3 •7H 2 O (130 mg, 0.35 mmol) in methanol was added NaBH 4 (53 mg, 1.4 mmol) portion wise at 78 °C under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature, then diluted with H 2 O. The resulting
  • Step 3 Preparation of 8 ⁇ (1 ⁇ aminoethyl) ⁇ 2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethylquinazolin ⁇ 4 ⁇ one [000204] To a stirred solution of N ⁇ (1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl) ⁇ 2 ⁇ methylpropane ⁇ 2 ⁇ sulfinamide (1.1 g, 2.54 mmol) and in 1,4 ⁇ dioxane was added 4 M HCl in 1,4 ⁇ dioxane (11 mL, 44 mmol) dropwise at room temperature.
  • Compound 1 6 ⁇ chloro ⁇ 3 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)picolinic acid (Enantiomer 1)
  • Compound 2 6 ⁇ chloro ⁇ 3 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)picolinic acid (Enantiomer 2)
  • Step 1 Preparation of 2 ⁇ amino ⁇ 3 ⁇ bromo ⁇ N,5 ⁇ dimethylbenzamide
  • HATU 165 g, 434 mmol
  • methylamine hydrochloride 66 g, 978 mmol
  • Step 2 Preparation of 8 ⁇ bromo ⁇ 3,6 ⁇ dimethyl ⁇ 1H ⁇ quinazoline ⁇ 2,4 ⁇ dione [000208] A mixture of 2 ⁇ amino ⁇ 3 ⁇ bromo ⁇ N,5 ⁇ dimethylbenzamide (19.2 g, 79.0 mmol), triphosgene (23.4 g, 79.0 mmol), and DIEA (13.8 mL, 79.0 mmol) in DCM (250 mL) was
  • Step 3 Preparation of 8 ⁇ bromo ⁇ 2 ⁇ chloro ⁇ 3,6 ⁇ dimethylquinazolin ⁇ 4 ⁇ one [000209] A mixture of 8 ⁇ bromo ⁇ 3,6 ⁇ dimethyl ⁇ 1H ⁇ quinazoline ⁇ 2,4 ⁇ dione (18 g, 66.9 mmol), DIEA (47 mL, 268 mmol) in POCl 3 (200 mL, 878 mmol) was stirred overnight at 100 °C under a nitrogen atmosphere and then concentrated under reduced pressure. Residual POCl 3 was quenched with H 2 O at 0 °C. The mixture was adjusted to pH 7 with NaHCO 3 and then was extracted with DCM (3 x 300 mL).
  • Step 4 Preparation of 8 ⁇ bromo ⁇ 2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethylquinazolin ⁇ 4 ⁇ one
  • 8 ⁇ bromo ⁇ 2 ⁇ chloro ⁇ 3,6 ⁇ dimethylquinazolin ⁇ 4 ⁇ one (1 g, 3.48 mmol) and 4,4 ⁇ dimethylpiperidine (1.56 g, 10.4 mmol) in acetonitrile (10 mL) was added DIEA (3.0 mL, 17.4 mmol).
  • DIEA 3.0 mL, 17.4 mmol
  • Step 6 Preparation of 2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 8 ⁇ (1 ⁇ hydroxyethyl) ⁇ 3,6 ⁇ dimethylquinazolin ⁇ 4 ⁇ one
  • 8 ⁇ acetyl ⁇ 2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethylquinazolin ⁇ 4 ⁇ one 900 mg, 2.75 mmol
  • MeOH MeOH
  • NaBH 4 (2.08 g, 55.0 mmol
  • Step 7 Preparation of methyl 6 ⁇ chloro ⁇ 3 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)picolinate
  • Methanesulfonic anhydride (634 mg, 3.64 mmol) was added in portions to a stirred solution of 2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 8 ⁇ (1 ⁇ hydroxyethyl) ⁇ 3,6 ⁇ dimethylquinazolin ⁇ 4 ⁇ one (300 mg, 0.911 mmol) and TEA (553 mg, 5.47 mmol) in DCM (3 mL) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C and then methyl 3 ⁇ amino ⁇ 6 ⁇ chloropyridine ⁇ 2 ⁇ carboxylate (203 mg, 1.09 mmol) was added.
  • Step 8 Preparation of 6 ⁇ chloro ⁇ 3 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)picolinic acid (Enantiomers 1 and 2) [000214] To a stirred solution of methyl 6 ⁇ chloro ⁇ 3 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)picolinate (290 mg, 0.58 mmol) in MeOH (6 mL) and H 2 O (3 mL) was added NaOH (326 mg, 8.15 mmol).
  • Compound 3 6 ⁇ chloro ⁇ 3 ⁇ ((1 ⁇ (2 ⁇ (5 ⁇ fluoroisoindolin ⁇ 2 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)picolinic acid (Enantiomer 1)
  • Compound 4 6 ⁇ chloro ⁇ 3 ⁇ ((1 ⁇ (2 ⁇ (5 ⁇ fluoroisoindolin ⁇ 2 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)picolinic acid (Enantiomer 2) [000219] Prepared in a manner similar to Compounds 1 and 2 using 5 ⁇ fluoroisoindoline in place of 4,4 ⁇ dimethylpiperidine in Step 4.
  • Example 1 4 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino) ⁇ 1 ⁇ methyl ⁇ 1H ⁇ pyrazole ⁇ 3 ⁇ carboxylic acid (Enantiomer 1) [000223]
  • Example 2 4 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino) ⁇ 1 ⁇ methyl ⁇ 1H ⁇ pyrazole ⁇ 3 ⁇ carboxylic acid (Enantiomer 2) Step 1: Preparation of methyl 4 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇
  • Step 2 Preparation of 4 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino) ⁇ 1 ⁇ methyl ⁇ 1H ⁇ pyrazole ⁇ 3 ⁇ carboxylic acid (Enantiomers 1 and 2) [000225] A solution of NaOH (171 mg, 4.29 mmol) in H 2 O (5 mL) was added to a mixture of methyl 4 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino) ⁇ 1 ⁇ methyl ⁇ 1H ⁇ pyrazole ⁇ 3 ⁇ carboxylate (200 mg, 0.43 mmol) in MeOH (5 mL).
  • the crude product was purified by prep ⁇ HPLC (column: XBridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: 10 mmol NH 4 HCO 3 + 0.05% NH 3 ⁇ H 2 O, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 22% B to 52% B in 9 min, 52% B; Wave Length: 254 nm; RT1(min): 7) to afford 4 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino) ⁇ 1 ⁇ methyl ⁇ 1H ⁇ pyrazole ⁇ 3 ⁇ carboxylic acid as a white solid (80 mg, 41% yield).
  • Example 3 4 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino) ⁇ 1 ⁇ methyl ⁇ 2 ⁇ oxo ⁇ 1,2 ⁇ dihydropyridine ⁇ 3 ⁇ carboxylic acid (Enantiomer 1)
  • Example 4 4 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino) ⁇ 1 ⁇ methyl ⁇ 2 ⁇ oxo ⁇ 1,2 ⁇ dihydropyridine ⁇ 3 ⁇ carboxylic acid (Enantiomer 2)
  • Step 1 Preparation of methyl 4 ⁇ chloro ⁇ 2 ⁇ hydroxypyridine ⁇ 3 ⁇ carboxylate
  • BBr 3 5 mL, 53.0 mmol
  • Step 2 Preparation of methyl 4 ⁇ chloro ⁇ 1 ⁇ methyl ⁇ 2 ⁇ oxopyridine ⁇ 3 ⁇ carboxylate [000237]
  • a solution of methyl 4 ⁇ chloro ⁇ 2 ⁇ hydroxypyridine ⁇ 3 ⁇ carboxylate (1.3 g, 6.93 mmol), Cs 2 CO 3 (4.52 g, 13.9 mmol) and CH 3 I (0.98 g, 6.93 mmol) in DMF (10 mL) was stirred 1 h at room temperature.
  • the resulting mixture was diluted with water (100 mL) and extracted with EA (3 x 50 mL).
  • the combined organics were washed with brine (2 x 30 mL), dried over anhydrous MgSO 4 , and concentrated under reduced pressure.
  • Step 3 Preparation of methyl 4 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino) ⁇ 1 ⁇ methyl ⁇ 2 ⁇ oxo ⁇ 1,2 ⁇ dihydropyridine ⁇ 3 ⁇ carboxylate [000238] A solution of methyl 4 ⁇ chloro ⁇ 1 ⁇ methyl ⁇ 2 ⁇ oxopyridine ⁇ 3 ⁇ carboxylate (100 mg, 0.50 mmol) in EtOH (5 mL) was treated with Et 3 N (251 mg, 2.48 mmol) and 8 ⁇ (1 ⁇ aminoethyl) ⁇ 2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethylquinazolin ⁇ 4 ⁇ one (179 mg, 0.55 mmol) for 48 h at 80 °C.
  • Step 4 Preparation of 4 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino) ⁇ 1 ⁇ methyl ⁇ 2 ⁇ oxo ⁇ 1,2 ⁇ dihydropyridine ⁇ 3 ⁇ carboxylic acid (Enantiomers 1 and 2) [000239] A solution of methyl 4 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino) ⁇ 1 ⁇ methyl ⁇ 2 ⁇ oxo ⁇ 1,2 ⁇ dihydropyridine ⁇ 3 ⁇ carboxylate (100 mg, 0.20 mmol) and NaOH (41 mg, 1.02 mmol) in MeOH (2 mL) and H 2 O (0.5 mL) was stirred overnight
  • Compound 7 3 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)picolinic acid (Enantiomer 1)
  • Compound 8 3 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)picolinic acid (Enantiomer 2) [000245] Prepared in a manner similar to Compounds 1 and 2 using methyl 3 ⁇ aminopicolinate in place of methyl 3 ⁇ amino ⁇ 6 ⁇ chloropicolinate in Step 7.
  • Example 5 3 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino) ⁇ 6 ⁇ methylpicolinic acid (Enantiomer 1) [000249]
  • Example 6 3 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino) ⁇ 6 ⁇ methylpicolinic acid (Enantiomer 2) [000250] Prepared in a manner similar to Compounds 1 and 2 using methyl 3 ⁇ amino ⁇ 6 ⁇ methylpicolinate in place of methyl 3 ⁇ amino ⁇ 6 ⁇ chloropicolinate in Step 7.
  • Example 7 4 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)isothiazole ⁇ 3 ⁇ carboxylic acid (Enantiomer 1)
  • Example 8 4 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)isothiazole ⁇ 3 ⁇ carboxylic acid (Enantiomer 2)
  • Example 9 2 ⁇ chloro ⁇ 5 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)thiazole ⁇ 4 ⁇ carboxylic acid (Enantiomer 1) [000259]
  • Example 10 2 ⁇ chloro ⁇ 5 ⁇ ((1 ⁇ (2 ⁇ (4,4 ⁇ dimethylpiperidin ⁇ 1 ⁇ yl) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)thiazole ⁇ 4 ⁇ carboxylic acid (Enantiomer 2) [000260] Prepared in a manner similar to Compounds 1 and 2 using methyl 5 ⁇ amino ⁇ 2 ⁇ chlorothiazole ⁇ 4 ⁇ carboxylate in place of methyl 3 ⁇ amino ⁇ 6 ⁇ chloropicolinate in Step 7.
  • Example 11 6 ⁇ chloro ⁇ 3 ⁇ ((1 ⁇ (2 ⁇ ((4 ⁇ chloro ⁇ 3 ⁇ (trifluoromethoxy)benzyl)thio) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)picolinic acid (Enantiomer 1) [000264]
  • Example 12 6 ⁇ chloro ⁇ 3 ⁇ ((1 ⁇ (2 ⁇ ((4 ⁇ chloro ⁇ 3 ⁇ (trifluoromethoxy)benzyl)thio) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)picolinic acid (Enantiomer 2) Step 1: Preparation of 8 ⁇ bromo ⁇ 3,6 ⁇ dimethyl ⁇ 2 ⁇ sulfanylidene ⁇ 1H ⁇ quinazolin ⁇ 4 ⁇ one [000265] Into a 1000 mL round ⁇ bottom flas
  • Step 2 Preparation of 8 ⁇ acetyl ⁇ 3,6 ⁇ dimethyl ⁇ 2 ⁇ sulfanylidene ⁇ 1H ⁇ quinazolin ⁇ 4 ⁇ one [000266] Under an argon atmosphere at room temperature, Pd(PPh 3 ) 4 (8.1 g, 7.02 mmol) was added in portions to a solution of 8 ⁇ bromo ⁇ 3,6 ⁇ dimethyl ⁇ 2 ⁇ sulfanylidene ⁇ 1H ⁇ quinazolin ⁇ 4 ⁇ one (10 g, 35.1 mmol) and tributyl(1 ⁇ ethoxyethenyl)stannane (25.4 g, 70.1 mmol) in dioxane (100 mL).
  • Step 3 Preparation of 8 ⁇ acetyl ⁇ 2 ⁇ ((4 ⁇ chloro ⁇ 3 ⁇ (trifluoromethoxy)benzyl)thio) ⁇ 3,6 ⁇ dimethylquinazolin ⁇ 4(3H) ⁇ one
  • a solution of 8 ⁇ acetyl ⁇ 3,6 ⁇ dimethyl ⁇ 2 ⁇ sulfanylidene ⁇ 1H ⁇ quinazolin ⁇ 4 ⁇ one (2 g, 8.05 mmol) in THF (100 mL) was treated with 4 ⁇ (bromomethyl) ⁇ 1 ⁇ chloro ⁇ 2 ⁇ (trifluoromethoxy)benzene (2.45 g, 8.45 mmol) at room temperature under argon atmosphere followed by the addition of Cs 2 CO 3 (5.27 g, 16.1 mmol) in portions at room temperature.
  • Step 4 Preparation of 2 ⁇ ((4 ⁇ chloro ⁇ 3 ⁇ (trifluoromethoxy)benzyl)thio) ⁇ 8 ⁇ (1 ⁇ hydroxyethyl) ⁇ 3,6 ⁇ dimethylquinazolin ⁇ 4(3H) ⁇ one [000268] To a mixture of 8 ⁇ acetyl ⁇ 2 ⁇ ((4 ⁇ chloro ⁇ 3 ⁇ (trifluoromethoxy)benzyl)thio) ⁇ 3,6 ⁇ dimethylquinazolin ⁇ 4(3H) ⁇ one (848 mg, 1.86 mmol,) and CH 3 OH (50 mL) was added NaBH 4 (351 mg, 9.29 mmol) in portions at room temperature. The resulting mixture was stirred for 1 h and
  • Step 5 Preparation of methyl 6 ⁇ chloro ⁇ 3 ⁇ ((1 ⁇ (2 ⁇ ((4 ⁇ chloro ⁇ 3 ⁇ (trifluoromethoxy)benzyl)thio) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)picolinate [000269] Into a 100 mL round ⁇ bottom flask were added 2 ⁇ ((4 ⁇ chloro ⁇ 3 ⁇ (trifluoromethoxy)benzyl)thio) ⁇ 8 ⁇ (1 ⁇ hydroxyethyl) ⁇ 3,6 ⁇ dimethylquinazolin ⁇ 4(3H) ⁇ one (400 mg, 0.872 mmol) and DCM (5 mL).
  • PBr 3 (354 mg, 1.31 mmol) was added in portions at 0 °C. The resulting solution was stirred at room temperature for 1 h and then was quenched with H 2 O (10 mL). The mixture was adjusted to pH 8 with saturated aqueous NaHCO 3 and then was extracted with DCM (3 x 50 mL). The combined organic layers were washed with saturated aqueous NaHCO 3 (2 x 10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 6 Preparation of 6 ⁇ chloro ⁇ 3 ⁇ ((1 ⁇ (2 ⁇ ((4 ⁇ chloro ⁇ 3 ⁇ (trifluoromethoxy)benzyl)thio) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)picolinic acid (Enantiomers 1 and 2) [000270] Into a 40 mL vial were added methyl 6 ⁇ chloro ⁇ 3 ⁇ ((1 ⁇ (2 ⁇ ((4 ⁇ chloro ⁇ 3 ⁇ (trifluoromethoxy)benzyl)thio) ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)picolinate (210 mg, 0.335 mmol), THF (3 mL), and potassium trimethylsilanolate (429 mg, 3.35 mmol) at room temperature.
  • Example 13 6 ⁇ chloro ⁇ 3 ⁇ ((1 ⁇ (2 ⁇ isobutoxy ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)picolinic acid (Enantiomer 1)
  • Example 14 6 ⁇ chloro ⁇ 3 ⁇ ((1 ⁇ (2 ⁇ isobutoxy ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)picolinic acid (Enantiomer 2) Step 1: Preparation of 8 ⁇ bromo ⁇ 3,6 ⁇ dimethyl ⁇ 2 ⁇ (2 ⁇ methylpropoxy)quinazolin ⁇ 4 ⁇ one
  • Step 2 Preparation of 6 ⁇ chloro ⁇ 3 ⁇ ((1 ⁇ (2 ⁇ isobutoxy ⁇ 3,6 ⁇ dimethyl ⁇ 4 ⁇ oxo ⁇ 3,4 ⁇ dihydroquinazolin ⁇ 8 ⁇ yl)ethyl)amino)picolinic acid (Enantiomers 1 and 2) [000277] Prepared in a manner similar to Steps 5 to 8 in Examples 1 and 2.
  • Examples 15 to 33 were prepared in a manner similar to that described for Examples 1 to 14 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.
  • 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 ⁇ L 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. Cells were grown for 72 hours at 37 ° Celsius and 5% CO 2 . After 72 hours, cells were equilibrated at room temperature for 15 minutes. 30 ⁇ L of CellTiter ⁇ Glo reagent is added to the plate, which is then shaken for 30 minutes at temperature at 300 ⁇ 500 rpm. Cells are then read on an Envision plate reader. The percentage of inhibition of proliferation was
  • %Inhibition 100 x (Lum D – Lum Sample ) / (Lum D –Lum Inh ), where D is obtained from cells treated with 0.1% DMSO only; Inh is obtained from cells treated with 10 ⁇ M 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.
  • Lysis buffer reagent ⁇ L was added to the plate, which was then centrifuged for 1 minute at 1000 rpm. Then the plate was incubated at room temperature for 30 minutes. After 30 minutes, 4 ⁇ L of antibody mix containing Eu Cryptate, d2 Cryptate, and detection buffer, was added to the plate. The plate was centrifuged for 1 minute at 1000 rpm and then incubated overnight at room temperature. The plate was read on an Envision plate reader using the HTRF protocol.
  • Reagent table [000285] For EC50 values shown in Table 2, “A” refers to 1 nM ⁇ EC50 ⁇ 500 nM; “B” refers to 500 nM ⁇ EC50 ⁇ 2 ⁇ M; “C” refers to 2 ⁇ M ⁇ EC50 ⁇ 15 ⁇ M; and “D” refers to an EC50 > 15 ⁇ M.
  • 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.10 ⁇ L of working solutions (0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng/mL) were added to 10 ⁇ L of the blank Female CD1 Mouse plasma to achieve calibration standards of 0.5 ⁇ 1000 ng/mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng/mL) in a total volume of 20 ⁇ L.
  • PI3K in cancer divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer 15(1): 7 ⁇ 24. [000313] Vanhaesebroeck, B., Whitehead M. A., and Pi ⁇ eiro, R. 2016. Molecules in medicine mini ⁇ review: isoforms of PI3K in biology and disease. J Mol Med (Berl). 94(1): 5 ⁇ 11. [000314] Yang, J., Nie, J., Ma, X., Wei, Y., Peng, Y., and Wei, X. 2019. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol Cancer 18(26): 1 ⁇ 28.

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Abstract

L'invention concerne de nouveaux inhibiteurs de PI3K de formule générale (1) ainsi que leurs procédés de préparation et leur utilisation dans le traitement de maladies associées à l'élévation ou à l'activation de la voie PI3K, formule (1), dans laquelle R1 à R7 sont tels que définis.
PCT/US2023/034999 2022-10-14 2023-10-12 Benzopyrimidin-4(3h)-ones utilisées en tant qu'inhibiteurs de pi3k WO2024081345A1 (fr)

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