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WO2024211346A1 - Inhibiteurs de pi3k-alpha mutants et leur utilisation en tant que produits pharmaceutiques - Google Patents

Inhibiteurs de pi3k-alpha mutants et leur utilisation en tant que produits pharmaceutiques Download PDF

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WO2024211346A1
WO2024211346A1 PCT/US2024/022742 US2024022742W WO2024211346A1 WO 2024211346 A1 WO2024211346 A1 WO 2024211346A1 US 2024022742 W US2024022742 W US 2024022742W WO 2024211346 A1 WO2024211346 A1 WO 2024211346A1
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ethyl
amino
chloro
oxo
dimethyl
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Chun Chen
Ryan Holmes
Soham Maity
Andrew P. Combs
Andrew W. Buesking
Sarah PAWLEY
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Prelude Therapeutics Inc
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Prelude Therapeutics 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
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • PI3Ks consist of a p85 regulatory subunit in complex with a p110 catalytic subunit (p110 ⁇ , ⁇ , ⁇ or ⁇ ) (1).
  • p110 ⁇ coded by the PIK3CA gene shows a broad tissue distribution and the binding of a phosphorylated receptor tyrosine kinase (RTK) activates p110a through the release of a subset of inhibitory contacts with p85.
  • RTK phosphorylated receptor tyrosine kinase
  • P110 ⁇ generate phosphatidylinositol3,4,5-trisphosphate (PtdIns(3,4,5)P3; also known as PIP3), which interact with 3-phosphoinositide-binding Pleckstrin homology (PH) domains found in diverse proteins, including protein kinases such as AKT resulting in its phosphorylation at Thr308 and Ser473 triggering a cascade of mitogenic signaling (2).
  • This signaling results in a multitude of cellular effects including proliferation, survival, chemotaxis, cellular trafficking, motility, metabolism, inflammatory and allergic responses, transcription and translation (3).
  • PIK3CA hotspot mutations are one of the most frequent oncogenic mutations in cancer.
  • PIK3CA helical (E542K, E545K) and kinase (H1047R) domains function by perturbing local interfaces between p85 and p110 ⁇ and increasing dynamic events required for catalysis on membranes (1,4).
  • Oncogenic mutations in the PIK3CA gene increase lipid kinase activity and transform cells and are the drivers of the pathology. These mutations are observed in a broad range of cancers including breast, colon, uterine, bladder, cervical, and lung cancer (5,6,7). [0004] Given its key role in cancer PI3Ks have been the focus of extensive drug development.
  • pan-class I PI3K inhibitor copanlisib (Aliqopa/BAY 80-6946; Bayer) was approved for follicular lymphoma and in 2019, the PI3K ⁇ inhibitor alpelisib (Piqray/NVP-BYL719; Novartis) was approved for the treatment of advanced breast cancer, in combination with the estrogen receptor (ER) downregulator fulvestrant (1,8).
  • ER estrogen receptor
  • pan-class I PI3K and dual PI3K ⁇ /PI3K ⁇ , or even PI3K ⁇ selective inhibitors have impacted the realization of full clinical utility of these compounds.
  • the toxicity of PI3K inhibitors is dependent on their isoform 105807.005004– PCT Application selectivity profile. Inhibition of PI3K ⁇ is associated with hyperglycemia and rash, whereas inhibition of PI3K ⁇ or PI3K ⁇ is associated with diarrhea, myelosuppression, and transaminitis (1).
  • a recent study reported that while progression of disease is the largest contributor to alpelisib discontinuation, adverse events are the leading cause for early drug cessation (10). Shorter alpelisib exposure is associated with greater cancer progression.
  • ring A is: W is a 5-10 membered heteroaryl ring comprising 1-4 heteroatoms selected from N, O, and S, or a 5-12 membered heterocyclic group comprising 1-4 heteroatoms selected from N, O, and S, C1-C8 alkyl, haloalkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, aryl, heteroaryl, cycloalkyl, - 3 - 4877-0794-3771.1 105807.005004– PCT Application cycloalkenyl, heterocycloalkenyl, NR c R d , OR b , or SR b ; wherein each group is optionally substituted by 1-6 R f groups; Y is CR 2 or N; n is
  • R e is C 3 -C 8 cycloalkyl, heterocycloalkyl wherein the heterocycloalkyl is attached to (C 1 - C6-alkyl) through a carbon atom or a sulfur atom of the heterocycloalkyl group, cycloalkenyl, heterocycloalkenyl wherein the heterocycloalkenyl is attached to (C1-C6-alkyl) through a carbon atom or a sulfur atom of the heterocycloalkenyl group, aryl, or heteroaryl, and each C 3 -C 8 cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted by 1-6 R f groups; each R f is independently H, D, oxo, halogen, C1-C8 alkoxide, C1-C8 alkyl, haloalkyl, -OH, -CN, -
  • substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • C1-C6 alkyl is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
  • C0 alkyl refers to a covalent bond. - 5 - 4877-0794-3771.1 105807.005004– PCT Application [0021] It is further intended that the compounds of the invention are stable.
  • stable refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.
  • alkyl when used alone or as part of a substituent group, refers to a straight- or branched-chain hydrocarbon group having from 1 to 12 carbon atoms (“C1-C12”), preferably 1 to 6 carbons atoms (“C 1 -C 6 ”), in the group.
  • alkyl groups include methyl (Me, C 1 alkyl), ethyl (Et, C 2 alkyl), n-propyl (C 3 alkyl), isopropyl (C 3 alkyl), butyl (C 4 alkyl), isobutyl (C4alkyl), sec-butyl (C4alkyl), tert-butyl (C4alkyl), pentyl (C5alkyl), isopentyl (C5alkyl), tert- pentyl (C5alkyl), hexyl (C6alkyl), isohexyl (C6alkyl), and the like. Alkyl groups of the are optionally substituted.
  • the alkyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1- C 6 haloalkoxy, -C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkyl) 2 , -OC(O)NH(C 1 -C 6 alkyl), - OC(O)N(C 1 -C 6 alkyl) 2 , -S(O) 2 NH(C 1 -C 6 alkyl), and -S(O) 2 N(C 1 -C 6 alkyl) 2 .
  • substituents independently selected from -OH, -CN, amino, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1- C
  • the alkyl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d , or NR c R d ; or the alkyl group is optionally substituted by 1-6 R f groups.
  • halo or halogen refers to chloro, fluoro, bromo, or iodo.
  • cycloalkyl when used alone or as part of a substituent group refers to cyclic- containing, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms (“C3-C10”), preferably from 3 to 6 carbon atoms (“C 3- C 6 ”).
  • Cycloalkyl groups of the disclosure include monocyclic groups, as well as multicyclic groups such as bicyclic and tricyclic groups. In those embodiments having at least one multicyclic cycloalkyl group, the cyclic groups can share one common atom (i.e., spirocyclic).
  • the cyclic groups share two common atoms (e.g., fused or bridged).
  • cycloalkyl groups include, for example, cyclopropyl (C3), cyclobutyl (C4), cyclopropylmethyl (C4), cyclopentyl (C5), cyclohexyl (C6), 1-methylcyclopropyl (C4), 2-methylcyclopentyl (C4), adamantanyl (C 10 ), spiro[3.3]heptanyl, bicyclo[3.3.0]octanyl, and the like.
  • the cycloalkyl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d , or NR c R d ; or the cycloalkyl group is optionally substituted by 1-6 R f groups.
  • cycloalkenyl when used alone or as part of a substituent group refers to monocyclic or multicyclic, partially saturated ring structure having from 3 to 10 carbon atoms (“C3-C10”), preferably from 3 to 6 carbon atoms (“C3-C6”).
  • Cycloalkenyl groups of the disclosure include monocyclic groups, as well as multicyclic groups such as bicyclic and tricyclic groups. In those embodiments having at least one multicyclic cycloalkenyl group, the cyclic groups can share one common atom (i.e., spirocyclic). In other embodiments having at least one multicyclic cycloalkenyl group, the cyclic groups share two common atoms (e.g., fused or bridged).
  • the term -C 3 -C 6 cycloalkenyl refers to a cycloalkenyl group having between three and six carbon atoms.
  • the cycloalkenyl group may be attached at any carbon atom of the partially saturated ring such that the result is a stable structure.
  • Cycloalkenyl groups include groups in which the partially saturated ring is fused to an aryl group. Examples of cycloalkenyl groups include, for example, cyclopropenyl (C 3 ), cyclobutenyl (C 4 ), cyclopropenylmethyl (C 4 ), cyclopentenyl (C5), cyclohexenyl (C6), 1-methylcyclopropenyl (C4), 2-methylcyclopentenyl (C4), adamantenyl (C10), spiro[3.3]heptenyl, bicyclo[3.3.0]octenyl, indanyl, and the like.
  • Cycloalkenyl groups of the disclosure are optionally substituted. Unless otherwise specified, in those embodiments wherein the cycloalkenyl group is substituted, the cycloalkenyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1- C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy, -C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 - C 6 alkyl) 2 , -OC(O)NH(C 1 -C 6 alkyl), -OC(O)N(C 1 -C 6 alkyl) 2 , -S(O) 2 NH(C 1 -C 6 alkyl), and - S(O)2N(C1-C6alkyl)2.
  • the cycloalkenyl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d , or NR c R d ; or the cycloalkenyl group is optionally substituted by 1-6 R f groups.
  • 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d , or NR c R d ; or the cycloalkenyl group is optionally substituted by 1-6 R f groups.
  • heterocycloalkyl when used alone or as part of a substituent group refers to any three to twelve membered monocyclic or multicyclic, saturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S.
  • Heterocycloalkyl groups - 7 - 4877-0794-3771.1 105807.005004– PCT Application of the disclosure include monocyclic groups, as well as multicyclic groups such as bicyclic and tricyclic groups.
  • the cyclic groups can share one common atom (i.e., spirocyclic).
  • the cyclic groups share two common atoms (e.g., fused or bridged).
  • the term -C3-C6 heterocycloalkyl refers to a heterocycloalkyl group having between three and six carbon ring atoms.
  • heterocycloalkyl group may be attached at any heteroatom or carbon atom of the group such that the result is a stable structure.
  • heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, azepanyl, diazepanyl, oxepanyl, dioxepanyl, azocanyl diazocanyl, oxocanyl, dioxocanyl, di
  • Heteroycloalkyl groups of the disclosure are optionally substituted. Unless otherwise specified, in those embodiments wherein the heterocycloalkyl group is substituted, the heterocycloalkyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy, - C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -OC(O)NH(C1-C6alkyl), -OC(O)N(C1-C6alkyl)2, - S(O) 2 NH(C 1 -C 6 alkyl), and -S(O) 2 N(C 1 -C 6 alkyl) 2 .
  • substituents independently selected from -OH, -CN,
  • the heterocycloalkyl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , - SR a , -NR a R d , or NR c R d ; or the heterocycloalkyl group is optionally substituted by 1-6 R f groups.
  • 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , - SR a , -NR a R d , or NR c R d ; or the heterocycloalkyl group is optionally substituted by 1-6 R f groups.
  • heterocycloalkenyl when used alone or as part of a substituent group refers to any three to twelve membered monocyclic or multicyclic, partially saturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S.
  • Heterocycloalkenyl groups of the disclosure include monocyclic groups, as well as multicyclic groups such as bicyclic and tricyclic groups.
  • the cyclic groups can share one common atom (i.e., spirocyclic).
  • the cyclic groups share two common atoms (e.g., fused or bridged).
  • the term -C3-C6 heterocycloalkenyl refers to a heterocycloalkenyl group having between three and six carbon atoms.
  • heterocycloalkenyl group may be attached at any heteroatom or carbon atom of the - 8 - 4877-0794-3771.1 105807.005004– PCT Application partially saturated ring such that the result is a stable structure.
  • Heterocycloalkenyl groups include groups in which the partially saturated ring is fused to an aryl group, such as, for example isoindoline, , or in which the partially saturated ring is fused to a heteroaryl group, such as, for example, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, .
  • Heteroycloalkenyl groups of the disclosure are optionally substituted.
  • the heterocycloalkenyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy, - C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -OC(O)NH(C1-C6alkyl), -OC(O)N(C1-C6alkyl)2, - S(O) 2 NH(C 1 -C 6 alkyl), and -S(O) 2 N(C 1 -C 6 alkyl) 2 .
  • substituents independently selected from -OH, -CN, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and
  • the heterocycloalkenyl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , - SR a , -NR a R d , or NR c R d ; or the heterocycloalkenyl group is optionally substituted by 1-6 R f groups.
  • 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , - SR a , -NR a R d , or NR c R d ; or the heterocycloalkenyl group is optionally substituted by 1-6 R f groups.
  • heteroaryl when used alone or as part of a substituent group refers to a mono- or bicyclic- aromatic ring structure including carbon atoms as well as up to five heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl rings can include a total of 5, 6, 7, 8, 9, or 10 ring atoms.
  • heteroaryl groups include but are not limited to, pyrrolyl, furyl, thiophenyl (thienyl), oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, and the like.
  • Heteroaryl groups of the disclosure are optionally substituted.
  • the heteroaryl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 - C6haloalkoxy, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -OC(O)NH(C1-C6alkyl), - OC(O)N(C 1 -C 6 alkyl) 2 , -S(O) 2 NH(C 1 -C 6 alkyl), and -S(O) 2 N(C 1 -C 6 alkyl) 2 .
  • substituents independently selected from -OH, -CN, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C
  • the heteroaryl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d , or NR c R d ; or the heteroaryl group is optionally substituted by 1-6 R f groups.
  • 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d , or NR c R d ; or the heteroaryl group is optionally substituted by 1-6 R f groups.
  • aryl when used alone or as part of a substituent group refers to a mono- or bicyclic- aromatic carbon ring structure.
  • Aryl rings can include a total of 5, 6, 7, 8, 9, or 10 ring atoms.
  • aryl groups include but are not limited to, phenyl, napthyl, and the like.
  • Aryl groups of the disclosure are optionally substituted. Unless otherwise specified, in those embodiments wherein the aryl group is substituted, the aryl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 - C6haloalkyl, and C1-C6haloalkoxy, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -OC(O)NH(C1- C6alkyl), -OC(O)N(C1-C6alkyl)2, -S(O)2NH(C1-C6alkyl), and -S(O)2N(C1-C6alkyl)2.
  • the aryl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d , or NR c R d ; or the aryl group is optionally substituted by 1-6 R f groups.
  • 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d , or NR c R d ; or the aryl group is optionally substituted by 1-6 R f groups.
  • C1-6alk refers to an aliphatic linker having 1, 2, 3, 4, 5, or 6 carbon atoms and includes, for example, –CH2-, –CH(CH3)-, -CH(CH3)-CH2-, and –C(CH3)2-.
  • -C 0 alk- refers to a bond.
  • C 0 -C 6 alk when used alone or as part of a substituent group refers to an aliphatic linker having 0, 1, 2, 3, 4, 5 or 6 carbon atoms.
  • -C1alk- for example, refers to a -CH 2 -.
  • -C 0 alk- refers to a bond.
  • the -C 1 -C 6 alkyl, -C 1 - C 10 alkyl, -C 1 -C 8 alkoxide, -C 2 -C 6 alkenyl, -C 2 -C 10 alkenyl, -C 2 -C 6 alkynyl, -C 2 -C 10 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, and heterocycloalkyl groups are optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , - NR a R d , or NR c R d ; or the -C 1 -C 6 alkyl, -C 1 -C 10 alkyl, -C 1 -C 8 alkoxide, -C 2 -C 6 alkenyl, -C 2
  • alkoxy refers to an –O-alkyl group.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
  • hydroxylalkyl refers to an alkyl group substituted by OH.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • the compounds of the present invention may exist as rotational isomers. In some embodiments, the compounds of the present invention exist as mixtures of rotational isomers in any proportion. In other embodiments, the compounds of the present invention exist as particular rotational isomers, substantially free of other rotational isomers.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.
  • the compounds of the invention, and salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compound of the invention.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or - 11 - 4877-0794-3771.1 105807.005004– PCT Application base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • a “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • a “solvate” refers to a physical association of a compound of Formula I with one or more solvent molecules.
  • Subject includes humans.
  • Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • “treating” or “treatment” refers to modulating the disease or - 12 - 4877-0794-3771.1 105807.005004– PCT Application disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • “treating” or “treatment” refers to delaying the onset of the disease or disorder.
  • “Compounds of the present disclosure,” and equivalent expressions, are meant to embrace compounds of Formula I as described herein, as well as its subgenera, which expression includes the stereoisomers (e.g., entaniomers, diastereomers) and constitutional isomers (e.g., tautomers) of compounds of Formula I as well as the pharmaceutically acceptable salts, where the context so permits.
  • the term “isotopic variant” refers to a compound that contains proportions of isotopes at one or more of the atoms that constitute such compound that is greater than natural abundance.
  • an “isotopic variant” of a compound can be radiolabeled, that is, contain one or more radioactive isotopes, or can be labeled with non-radioactive isotopes such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • non-radioactive isotopes such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • the following atoms, where present may vary, so that for example, any hydrogen may be 2 H/D, any carbon may be 13 C, or any nitrogen may be 15 N, and that the presence and placement of such atoms may be determined within the skill of the art.
  • stereomers compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers,” for example, diastereomers, enantiomers, and atropisomers.
  • the compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers at each asymmetric center, or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include all stereoisomers and mixtures, racemic or otherwise, thereof.
  • the disclosure is directed to compounds of Formula I: - 13 - 4877-0794-3771.1 105807.005004– PCT Application or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof, wherein ring A is: W is a 5-10 membered heteroaryl ring comprising 1-4 heteroatoms selected from N, O, and S, a 5-12 membered heterocyclic group comprising 1-4 heteroatoms selected from N, O, and S, C 1 -C 8 alkyl, haloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, NR c R d , OR b , or SR b ; wherein each group is optionally substituted by 1-6 R f groups; Y is CR 2 or N; n is 1, 2, or 3; m is 1, 2 or 3;
  • R e is C 3 -C 8 cycloalkyl, heterocycloalkyl wherein the heterocycloalkyl is attached to (C 1 - C6-alkyl) through a carbon atom or a sulfur atom of the heterocycloalkyl group, cycloalkenyl, heterocycloalkenyl wherein the heterocycloalkenyl is attached to (C 1 -C 6 -alkyl) through a carbon atom or a sulfur atom of the heterocycloalkenyl group, aryl, or heteroaryl, and each C 3 -C 8 cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted by 1-6 R f groups; each R f is independently H, D, oxo, halogen, C 1 -C 8 alkoxide, C 1 -C 8 alkyl, haloalkyl, -OH, -
  • ring A in Formula - 15 - 4877-0794-3771.1 105807.005004– PCT Application
  • ring A in Formula [0054] ring A in Formula [0055]
  • R 6 in Formula (I) is -F.
  • R 6 in Formula (I) is -Cl.
  • R 6 in Formula (I) is -Br.
  • R 6 in Formula (I) is -I.
  • R 6 in Formula (I) is -CN.
  • W in Formula (I) is a 5-10 membered heteroaryl ring comprising 1-4 heteroatoms selected from N, O, and S, a 5-12 membered heterocyclic group comprising 1-4 heteroatoms selected from N, O, and S, C1-C8 alkyl, haloalkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, NR c R d , OR b , or SR b , wherein each group is optionally substituted by 1-6 R f groups.
  • W in Formula (I) is a 5-12 membered heterocyclic group comprising 1-4 heteroatoms selected from N, O, and S.
  • the 5-12 membered heterocyclic group is an isoindoline group or a piperidine group.
  • the 5-12 membered heterocyclic group is an isoindoline group.
  • the 5-12 membered heterocyclic group is a piperidine group.
  • the 5-12 membered heterocyclic group is a 3-azabicyclo[3.1.0]hexane, pyrrolidine, azetidine, piperazine, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine or 1,4,5,6- tetrahydropyrrolo[3,4-c]pyrazole group.
  • the 5-12 membered heterocyclic group is a 3-azabicyclo[3.1.0]hexane.
  • the 5-12 membered heterocyclic group is a pyrrolidine group.
  • the 5-12 membered heterocyclic group is an azetidine group.
  • the 5-12 membered heterocyclic group is a piperazine group. In some embodiments, the 5-12 membered heterocyclic group is 6,7-dihydro-5H- pyrrolo[3,4-b]pyridine group. In some embodiments, the 5-12 membered heterocyclic group is a 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole group. In some embodiments, W in Formula (I) is NR c R d . In some embodiments, W in Formula (I) is substituted by 1-6 R f groups. [0058] In other embodiments, W in Formula (I) is a 5-10 membered heteroaryl ring comprising 1-4 heteroatoms selected from N, O, and S.
  • W in Formula (I) is C 1 -C 8 alkyl. In other embodiments, W in Formula (I) is haloalkyl. In other embodiments, W in - 16 - 4877-0794-3771.1 105807.005004– PCT Application Formula (I) is -C 2 -C 6 alkenyl. In other embodiments, W in Formula (I) is -C 2 -C 6 alkynyl. In other embodiments, W in Formula (I) is aryl. In other embodiments, W in Formula (I) is heteroaryl. In other embodiments, W in Formula (I) is cycloalkyl. In other embodiments, W in Formula (I) is cycloalkenyl.
  • W in Formula (I) is heterocycloalkenyl. In other embodiments, W in Formula (I) is NR c R d . In other embodiments, W in Formula (I) is NR c R d . In other embodiments, W in Formula (I) is OR b . In other embodiments, W in Formula (I) is SR b . In some embodiments, W in Formula (I) is substituted by 1 or 2 R f groups. [0059] In some embodiments, Y in Formula (I) is CR 2 or N. In some embodiments, Y in Formula (I) is N. In other embodiments, Y in Formula (I) is CR 2 . In other embodiments, Y in Formula (I) is CH.
  • n in Formula (I) is 1, 2, or 3. In some embodiments, n in Formula (I) is 1. In other embodiments, n in Formula (I) is 2. In yet other embodiments, n in Formula (I) is 3. [0061] In some embodiments, m in Formula (I) is 1, 2 or 3. In some embodiments, m in Formula (I) is 1. In other embodiments, m in Formula (I) is 2. In yet other embodiments, m in Formula (I) is 3.
  • R 1 in Formula I is H, D, OR a , C 1 -C 8 alkoxide, C 1 -C 8 alkyl, haloalkyl, -C3-C8 cycloalkyl, -C3-C8 cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, or (C 1 -C 6 -alkyl)-R e ; wherein said C 1 -C 8 alkoxide, C 1 -C 8 alkyl, haloalkyl, C 3 - C 8 cycloalkyl, -C 3 -C 10 cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, and (C1-C6-alkyl)-R e are optionally substituted by 1-6 R f groups.
  • R 1 in Formula I is H. In some embodiments, R 1 in Formula I is D. In some embodiments, R 1 in Formula I is OR a . In some embodiments, R 1 in Formula I is C 1 - C8 alkoxide. In some embodiments, R 1 in Formula I is C1-C8 alkyl. In some embodiments, R 1 in Formula I is haloalkyl. In some embodiments, R 1 in Formula I is C3-C8 cycloalkyl. In some embodiments, R 1 in Formula I is C 3 -C 8 cycloalkenyl. In some embodiments, R 1 in Formula I is aryl. In some embodiments, R 1 in Formula I is heteroaryl.
  • the C 1 -C 8 alkoxide, C1-C8 alkyl, haloalkyl, C3-C8 cycloalkyl, -C3-C10 cycloalkenyl, aryl, and heteroaryl are optionally substituted by 1-6 R f groups.
  • R 1 in Formula I is H.
  • R 1 in Formula I is C1-C8alkyl.
  • R 1 in Formula I is methyl.
  • R 1 in Formula I is heterocycloalkyl optionally substituted by 1-6 R f groups.
  • R 1 in Formula I is tetrahydro-2H-pyran optionally substituted - 17 - 4877-0794-3771.1 105807.005004– PCT Application by 1-6 R f groups.
  • R 1 in Formula I is tetrahydrothiophene optionally substituted by 1-6 R f groups.
  • R 1 in Formula I is tetrahydrothiophene-1,1- dioxide optionally substituted by 1-6 R f groups.
  • R 1 in Formula I is tetrahydrofuran optionally substituted by 1-6 R f groups.
  • R 1 in Formula I is oxetane optionally substituted by 1-6 R f groups.
  • R 1 in Formula I is pyrrolidine optionally substituted by 1-6 R f groups.
  • R 1 in Formula I is heterocycloalkenyl optionally substituted by 1-6 R f groups.
  • R 1 in Formula I is (C1-C6-alkyl)-R e optionally substituted by 1-6 R f groups.
  • R e is azetidine optionally substituted by 1-6 R f groups, pyrazole optionally substituted by 1-6 R f groups, p-methoxybenzene or propyl.
  • R e is pyrazole optionally substituted by 1-6 R f groups.
  • each R 2 in Formula I is independently H, D, halogen, C1-C8 alkoxide, C1-C8 alkyl, haloalkyl, -OH, -CN, -NO 2 , -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b , -C(O)OR b , -C(O)NR c R d , -S(O)R b ,
  • At least one R 2 in Formula I is H. In some embodiments, at least one R 2 in Formula I is D. In some embodiments, at least one R 2 in Formula I is halogen. In some embodiments, at least one R 2 in Formula I is C 1 -C 8 alkoxide. In some embodiments, at least one R 2 in Formula I is C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d , or NR c R d .
  • At least one R 2 in Formula I is haloalkyl. In other embodiments, at least one R 2 in Formula I is -OH. In other embodiments, at least one R 2 in Formula I is -CN. In other embodiments, at least one R 2 in Formula I is -NO 2 . In other embodiments, at least one R 2 in Formula I is -C2-C6 alkenyl. In other embodiments, at least one R 2 in Formula I is -C2-C6 alkynyl. In other embodiments, at least one R 2 in Formula I is aryl. In other embodiments, at least one R 2 in Formula I is hetereoaryl.
  • At least one R 2 in Formula I is cycloalkyl. In other embodiments, at least one R 2 in Formula I is cycloalkenyl. In other - 18 - 4877-0794-3771.1 105807.005004– PCT Application embodiments, at least one R 2 in Formula I is heterocycloalkyl. In some embodiments, at least one R 2 in Formula I is heterocycloalkenyl. In other embodiments, at least one R 2 in Formula I is -OR a . In other embodiments, at least one R 2 in Formula I is -SR a . In other embodiments, at least one R 2 in Formula I is -NR c R d .
  • At least one R 2 in Formula I is -NR a R c . In other embodiments, at least one R 2 in Formula I is -C(O)R b . In other embodiments, at least one R 2 in Formula I is -OC(O)R b . In other embodiments, at least one R 2 in Formula I is -C(O)OR b . In other embodiments, at least one R 2 in Formula I is -C(O)NR c R d . In other embodiments, at least one R 2 in Formula I is -S(O)R b . In other embodiments, at least one R 2 in Formula I is - S(O) 2 NR c R d .
  • At least one R 2 in Formula I is - C(O)NR b OR b . In other embodiments, at least one R 2 in Formula I is -S(O)2OR b . In other embodiments, at least one R 2 in Formula I is -OS(O)2OR b . In other embodiments, at least one R 2 in Formula I is -OPO(OR b )(OR b ). [0071] In some embodiments, at least one R 2 in Formula I is H, C 1 -C 8 alkyl, CF 3 , Br, F, CN or CHF2. In some embodiments, at least one R 2 in Formula I is H.
  • At least one R 2 in Formula I is C 1 -C 8 alkyl. In some embodiments, at least one R 2 in Formula I is methyl. In some embodiments, at least one R 2 in Formula I is CF 3 . In some embodiments, at least one R 2 in Formula I is Br. In some embodiments, at least one R 2 in Formula I is F. In some embodiments, at least one R 2 in Formula I is CN. In some embodiments, at least one R 2 in Formula I is CHF 2 .
  • R 3 in Formula I is H, D, C1-C8 alkyl, haloalkyl, or CN; wherein said C1-C8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, - CN, -OR a , -SR a , -NR a R d , or NR c R d .
  • R 3 in Formula I is H.
  • R 3 in Formula I is D.
  • R 3 in Formula I is C1-C8 alkyl.
  • the C1-C8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , - NR a R d , or NR c R d .
  • R 3 in Formula I is haloalkyl.
  • R 3 in Formula I is CN. - 19 - 4877-0794-3771.1 105807.005004– PCT Application [0074]
  • R 3 in Formula I is H or C1-C8 alkyl.
  • R 3 in Formula I is H.
  • R 3 in Formula I is C1-C8alkyl.
  • R 3 in Formula I is methyl.
  • R 4 in Formula I is H, D, C1-C8 alkyl, haloalkyl, or CN; wherein said C1-C8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, - CN, -OR a , -SR a , -NR a R d , or NR c R d .
  • R 4 in Formula I is H.
  • R 4 in Formula I is D.
  • R 4 in Formula I is C1-C8 alkyl.
  • the C1-C8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , - NR a R d , or NR c R d .
  • R 4 in Formula I is haloalkyl.
  • R 4 in Formula I is CN.
  • R 4 in Formula I is H or C 1 -C 8 alkyl.
  • R 4 in Formula I is H.
  • R 4 in Formula I is C 1 -C 8 alkyl.
  • R 4 in Formula I is methyl.
  • R 3 and R 4 in Formula I together with the atom to which they are attached are combined to form a C 3 -C 7 cycloalkyl or C 4 -C 8 heterocycloalkyl. In some embodiments, R 3 and R 4 in Formula I together with the atom to which they are attached are combined to form a C3-C7 cycloalkyl. In some embodiments, R 3 and R 4 in Formula I together with the atom to which they are attached are combined to form a C 4 -C 8 heterocycloalkyl.
  • At least one R 5 in Formula I is H. In some embodiments, at least one R 5 in Formula I is D. In some embodiments, at least one R 5 in Formula I is halogen. In some embodiments, at least one R 5 in Formula I is C1-C8 alkoxide. In some embodiments, at least one R 5 in Formula I is C 1 -C 8 alkyl. In some embodiments, the C 1 -C 8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d , or NR c R d .
  • At least one R 5 in Formula I is haloalkyl. In other embodiments, at least one R 5 in Formula I is -OH. In other embodiments, at least one R 5 in Formula I is -CN. In other embodiments, at least one R 5 in Formula I is -NO2. In other embodiments, at least one R 5 in Formula I is -C 2 -C 6 alkenyl. In other embodiments, at least one R 5 in Formula I is -C 2 -C 6 alkynyl. In other embodiments, at least one R 5 in Formula I is aryl.
  • At least one R 5 in Formula I is hetereoaryl. In other embodiments, at least one R 5 in Formula I is cycloalkyl. In other embodiments, at least one R 5 in Formula I is cycloalkenyl. In other embodiments, at least one R 5 in Formula I is heterocycloalkyl. In some embodiments, at least one R 5 in Formula I is heterocycloalkenyl. In other embodiments, at least one R 5 in Formula I is -OR a . In other embodiments, at least one R 5 in Formula I is -SR a . In other embodiments, at least one R 5 in Formula I is -NR c R d .
  • At least one R 5 in Formula I is -NR a R c . In other embodiments, at least one R 5 in Formula I is -C(O)R b . In other embodiments, at least one R 5 in Formula I is -OC(O)R b . In other embodiments, at least one R 5 in Formula I is -C(O)OR b . In other embodiments, at least one R 5 in Formula I is -C(O)NR c R d . In other embodiments, at least one R 5 in Formula I is -S(O)R b . In other embodiments, at least one R 5 in Formula I is - S(O)2NR c R d .
  • At least one R 5 in Formula I is - C(O)NR b OR b . In other embodiments, at least one R 5 in Formula I is -S(O)2OR b . In other embodiments, at least one R 5 in Formula I is -OS(O)2OR b . In other embodiments, at least one R 5 in Formula I is -OPO(OR b )(OR b ). [0082] In some embodiments, at least one R 5 in Formula I is a carboxylic acid group or isostere thereof. In some embodiments, at least one R 5 in Formula I is a carboxylic acid group. In some embodiments, at least one R 5 in Formula I is -CO 2 H.
  • each R a in Formula I is independently H, D, -C(O)R b , - 2, - C 10 alkyl, - C2-C10 alkenyl, -C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl.
  • R a in Formula I is H.
  • R a in Formula I is D.
  • R a in Formula I is -P(OR c ) 2 , -P(O)R c R b , -P(O)OR c OR b , -S(O)R b , -S(O)NR c R d , -S(O)2R b , -S(O)2NR c R d , SiR b 3, and the like.
  • R a in Formula I is -C1-C10alkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, and the like.
  • each R b in Formula I is independently H, D, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl.
  • R b in Formula I is H. In some embodiments, R b in Formula I is D. In some embodiments, R b in Formula I is -C1-C6 alkyl. In some embodiments, R b in Formula I is -C2-C6 alkenyl. In some embodiments, R b in Formula I is -C2-C6 alkynyl. In other embodiments, R b in Formula I is aryl. In other embodiments, R b in Formula I is cycloalkyl. In other embodiments, R b in Formula I is cycloalkenyl. In other embodiments, R b in Formula I is heteroaryl. In other embodiments, R b in Formula I is heterocycloalkyl.
  • R b in Formula I is heterocycloalkenyl.
  • each R c or R d in Formula I is independently H, D, -C 1 -C 6 alkyl, - C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl.
  • R c or R d in Formula I is H.
  • R c or R d in Formula I is D.
  • R c or R d in Formula I is -C1-C10 alkyl.
  • R c or R d in Formula I is -C2-C6 alkenyl. In some embodiments, R c or R d in Formula I is -C 2 -C 6 alkynyl. In other embodiments, R c or R d in Formula I is -OC 1 -C 6 alkyl. In other embodiments, R c or R d in Formula I is -O-cycloalkyl. In other embodiments, R c or R d in Formula I is aryl. In other embodiments, R c or R d in Formula I is cycloalkyl. In other embodiments, R c or R d in Formula I is cycloalkenyl.
  • R c or R d in Formula I is heteroaryl. In other embodiments, R c or R d in Formula I is heterocycloalkyl. In other embodiments, R c or R d in Formula I is heterocycloalkenyl. [0090] In yet other embodiments, R c and R d in Formula I, together with the atom to which they are both attached, form a monocyclic or multicyclic heterocycloalkyl, or a monocyclic or - 22 - 4877-0794-3771.1 105807.005004– PCT Application multicyclic heterocyclo-alkenyl group. In yet other embodiments, R c and R d in Formula I form a monocyclic heterocycloalkyl.
  • R c and R d in Formula I form a multicyclic heterocycloalkyl. In yet other embodiments, R c and R d in Formula I form a monocyclic heterocyclo-alkenyl group. In yet other embodiments, R c and R d in Formula I form a multicyclic heterocyclo-alkenyl group.
  • R e in Formula I is C 3 -C 8 cycloalkyl, heterocycloalkyl wherein the heterocycloalkyl is attached to (C1-C6-alkyl) through a carbon atom or a sulfur atom of the heterocycloalkyl group, cycloalkenyl, heterocycloalkenyl wherein the heterocycloalkenyl is attached to (C1-C6-alkyl) through a carbon atom or a sulfur atom of the heterocycloalkenyl group, aryl, or heteroaryl, and each C 3 -C 8 cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted by 1-6 R f groups.
  • R e in Formula I is C 3 -C 8 cycloalkyl optionally substituted by 1-6 R f groups. In some embodiments, R e in Formula I is heterocycloalkyl optionally substituted by 1-6 R f groups. In some embodiments, the heterocycloalkyl is attached to (C1-C6-alkyl) through a carbon atom of the heterocycloalkyl group. In some embodiments, the heterocycloalkyl is attached to (C 1 -C 6 -alkyl) through a sulfur atom of the heterocycloalkyl group. In other embodiments, R e in Formula I is cycloalkenyl optionally substituted by 1-6 R f groups.
  • R e in Formula I is heterocycloalkenyl optionally substituted by 1-6 R f groups.
  • the heterocycloalkenyl is attached to (C 1 -C 6 -alkyl) through a carbon atom of the heterocycloalkenyl group.
  • the heterocycloalkenyl is attached to (C 1 - C6-alkyl) through a sulfur atom of the heterocycloalkenyl group.
  • R e in Formula I is aryl optionally substituted by 1-6 R f groups.
  • R e in Formula I is heteroaryl optionally substituted by 1-6 R f groups.
  • R e in Formula I is azetidine or piperidine optionally substituted by 1-6 R f groups, pyrazole optionally substituted by 1-6 R f groups, phenyl optionally substituted by 1-6 R f groups or cycloalkyl optionally substituted by 1-6 R f groups.
  • R e in Formula I is azetidine optionally substituted by 1-6 R f groups.
  • R e in Formula I is piperidine optionally substituted by 1-6 R f groups.
  • R e in Formula I is phenyl optionally substituted by 1-6 R f groups.
  • R e in Formula I is cycloalkyl optionally substituted by 1-6 R f groups.
  • each R f in Formula I is independently H, D, oxo, halogen, C1-C8 alkoxide, C1-C8 alkyl, haloalkyl, -OH, -CN, -NO 2 , -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -OR a , -SR a , -NR c R d , - 23 - 4877-0794-3771.1 105807.005004– PCT Application -NR a R c , -C(O)R b , -OC(O)R b , -C(O)OR b
  • R f in Formula I is H. In some embodiments, R f in Formula I is D. In some embodiments, R f in Formula I is oxo. In some embodiments, R f in Formula I is halogen. In some embodiments, R f in Formula I is C1-C8 alkoxide. In some embodiments, R f in Formula I is C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -OR a , -SR a , -NR a R d , or NR c R d .
  • R f in Formula I is haloalkyl. In some embodiments, R f in Formula I is -OH. In some embodiments, R f in Formula I is -CN. In some embodiments, R f in Formula I is -NO 2 . In some embodiments, R f in Formula I is -C2-C6 alkenyl. In some embodiments, R f in Formula I is - C2-C6 alkynyl. In some embodiments, R f in Formula I is aryl. In some embodiments, R f in Formula I is heteroaryl. In some embodiments, R f in Formula I is cycloalkyl. In other embodiments, R f in Formula I is cycloalkenyl.
  • R f in Formula I is heterocycloalkyl. In other embodiments, R f in Formula I is heterocycloalkenyl. In other embodiments, R f in Formula I is -OR a . In other embodiments, R f in Formula I is -SR a . In other embodiments, R f in Formula I is -NR c R d . In other embodiments, R f in Formula I is -NR a R c . In other embodiments, R f in Formula I is -C(O)R b . In other embodiments, R f in Formula I is - OC(O)R b . In other embodiments, R f in Formula I is -C(O)OR b .
  • R f in Formula I is -B(OR c )(OR d ). In yet other embodiments, R f in Formula I is -S(O)2R b . In yet other embodiments, R f in Formula I is -C(O)NR b OR b . In yet other embodiments, R f in Formula I is -S(O) 2 OR b . In yet other embodiments, R f in Formula I is - OS(O)2OR b . In yet other embodiments, R f in Formula I is -OPO(OR b )(OR b ). [0096] In some embodiments, the compounds of Formula (I) are the pharmaceutically acceptable salts.
  • the compounds of Formula (I) are solvates. In some embodiments, the compounds of Formula (I) are N-oxides. In some embodiments, the compounds of Formula (I) are stereoisomers. - 24 - 4877-0794-3771.1 105807.005004– PCT Application [0097] In some embodiments, the compounds of Formula (I) are represented by compounds of Formula II or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof; wherein each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n, W, and Y are as defined with respect to Formula (I).
  • the compounds of Formula (I) are represented by compounds of Formula III or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof; wherein each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, W and Y are as defined with respect to Formula (I).
  • each R 5 is H.
  • R 6 is -F.
  • R 6 is -Cl.
  • R 6 is -Br.
  • R 6 is -I.
  • R 6 is -CN.
  • the compounds of Formula (I) are represented by compounds of Formula IV - 25 - 4877-0794-3771.1 105807.005004– PCT Application or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof; wherein each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R c , R d ,m, and Y are defined with respect to Formula (I).
  • each R 5 is H.
  • R 6 is -F.
  • R 6 is -Cl.
  • R 6 is -Br.
  • R 6 is -I.
  • R 6 is -CN.
  • the compounds of Formula (I) are represented by compounds of Formula IV-1, Formula IV-2, Formula IV-3, or Formula IV-4: or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof; wherein each R 2 , R c , R d , and m are defined with respect to Formula (I).
  • the compounds of Formula (I) are represented by compounds of Formula V or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof; wherein each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and m are as defined with respect to Formula (I), and W a is a 5-10 membered - 26 - 4877-0794-3771.1 105807.005004– PCT Application heteroaryl group comprising 1-4 heteroatoms selected from N, O, and S, or an aryl group, wherein each group is optionally substituted by 1-6 R f groups.
  • each R 5 is H.
  • R 6 is -F.
  • R 6 is -Cl.
  • R 6 is -Br.
  • R 6 is -I.
  • R 6 is -CN.
  • the compounds of Formula (I) are represented by compounds of Formula V-1, Formula V-2, Formula V-3, or Formula V-4: or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof; wherein each R 2 and m are as defined with respect to Formula (I), and W a is a 5-10 membered heteroaryl group comprising 1-4 heteroatoms selected from N, O, and S, or an aryl group, wherein each group is optionally substituted by 1-6 R f groups.
  • the compounds of Formula (I) are represented by compounds of Formula VI - 27 - 4877-0794-3771.1 105807.005004– PCT Application or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof; wherein each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, are defined with respect to Formula (I), and W b is a 5-12 membered heterocyclic group comprising 1-4 heteroatoms selected from N, O, and S, or a cycloalkyl group, wherein each group is optionally substituted by 1-6 R f groups.
  • each R 5 is H.
  • R 6 is -F.
  • R 6 is -Cl.
  • R 6 is -Br.
  • R 6 is -I.
  • R 6 is -CN.
  • the compounds of Formula (I) are represented by compounds of Formula VI-1, Formula VI-2, Formula VI-3, or Formula VI-4: or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof; wherein each R 2 and m are as defined with respect to Formula (I), and W b is a 5-12 membered heterocyclic group comprising 1-4 heteroatoms selected from N, O, and S, or a cycloalkyl group, wherein each group is optionally substituted by 1-6 R f groups.
  • the compounds of Formula (I) are: 3-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)-6-chloropicolinic acid; 6-Chloro-3-((1-(2-((1R,5S,6s)-6-((methoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-3- yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid; - 28 - 4877-0794-3771.1 105807.005004– PCT Application 6-Chloro-3-((1-(2-(4,4-difluoropiperidin-1-yl)-6-fluoro-3-methyl
  • the compounds of Formula (I) are: 6-chloro-3-(((R)-1-(2-((1R,5S,6S)-6-((methoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid; 6-chloro-3-(((S)-1-(2-((1R,5S,6S)-6-((methoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)- 3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid; (R)-6-chloro-3-(((R)-1-(2-((1R,5S,6S)-6-((methoxycarbony
  • the compounds of the disclosure are pharmaceutically acceptable salts of the compounds of Formula I (including all subgenera described herein). In other embodiments, the compounds of the disclosure are not salts. In some embodiments, the compounds of the disclosure are N-oxides of the compounds of Formula I (including all subgenera described herein). In other embodiments, the compounds of the disclosure are not N-oxides of the compounds of Formula I (including all subgenera described herein). In some embodiments, the compounds of the disclosure are solvates of the compounds of Formula I (including all subgenera described herein).
  • the compounds - 44 - 4877-0794-3771.1 105807.005004– PCT Application of the disclosure are not solvates of the compounds of Formula I (including all subgenera described herein).
  • Isotopic variants of the compounds of Formula I are also contemplated by the present disclosure.
  • the compounds of the disclosure include a carboxylic acid moiety. In some aspects, the present disclosure also encompasses carboxylic acid prodrugs of these embodiments.
  • Carboxylic acid prodrugs include, but are not limited to, C1-C6 alkyl esters (e.g., methyl, ethyl, isopropyl, butyl, and isoamyl), 2-aminoethyl esters (e.g., 2- morpholinoethyl), C6-C10 aryl esters (e.g. phenyl, indanyl, and guaiacol), (acyloxy)alkyl esters, [(alkoxycarbonyl)oxy]alkyl esters, and (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esters. See, e.g., Maag, H. (2007).
  • compositions and Methods of Administration [00135]
  • the disclosure is directed to pharmaceutical compositions comprising compounds of Formula I, or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof.
  • the subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present disclosure as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
  • the pharmaceutical compositions contain pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • the subject pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions.
  • the one or more compounds of the invention and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time.
  • the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, - 45 - 4877-0794-3771.1 105807.005004– PCT Application 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%
  • the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 5%,
  • the concentration of one or more compounds of the invention is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v.
  • the concentration of one or more compounds of the invention is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to - 46 - 4877-0794-3771.1 105807.005004– PCT Application approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v.
  • the amount of one or more compounds of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009
  • the amount of one or more compounds of the invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g,
  • the amount of one or more compounds of the invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.
  • the compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. An exemplary dosage is 10 to 30 mg per day.
  • a pharmaceutical composition of the invention typically contains an active ingredient (i.e., a compound of the disclosure) of the present invention or a pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, - 47 - 4877-0794-3771.1 105807.005004– PCT Application carriers, including but not limited to inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • the invention provides a pharmaceutical composition for oral administration containing a compound of the invention, and a pharmaceutical excipient suitable for oral administration.
  • the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a compound of the invention; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration.
  • the composition further contains: (iv) an effective amount of a third agent.
  • the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption.
  • compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in- water emulsion, or a water-in-oil liquid emulsion.
  • dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients.
  • compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some - 48 - 4877-0794-3771.1 105807.005004– PCT Application compounds.
  • water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf- life or the stability of formulations over time.
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.
  • An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending on the form of preparation desired for administration.
  • any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro- crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose.
  • suitable carriers include powders, capsules, and tablets, with the solid oral preparations.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxy-propyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.
  • natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyr
  • suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or - 49 - 4877-0794-3771.1 105807.005004– PCT Application powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle.
  • Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form.
  • a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein.
  • the amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition.
  • Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
  • Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof.
  • a lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.
  • the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • the tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can also be presented as hard gelatin capsules - 50 - 4877-0794-3771.1 105807.005004– PCT Application wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • Surfactant which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.
  • a suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10.
  • HLB hydrophilic-lipophilic balance
  • Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.
  • Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.
  • lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10.
  • Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-
  • ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and - 51 - 4877-0794-3771.1 105807.005004– PCT Application di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di- glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
  • Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP -phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, capry
  • Hydrophilic non-ionic surfactants may include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene stea,
  • the polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.
  • Other hydrophilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG- 12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 gly
  • Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof.
  • preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.
  • the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use, e.g., compositions for injection.
  • a solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.
  • suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin - 53 - 4877-0794-3771.1 105807.005004– PCT Application derivatives; ethers of polyethylene
  • solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxy-ethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide.
  • solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • the amount of solubilizer that can be included is not particularly limited.
  • the amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art.
  • the solubilizer can be in a weight ratio of 10%, 25%o, 50%), 100%o, or up to about 200%> by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%>, 2%>, 1%) or even less. Typically, the solubilizer may be present in an amount of about 1%> to about 100%, more typically about 5%> to about 25%> by weight.
  • the composition can further include one or more pharmaceutically acceptable additives and excipients.
  • additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • detackifiers anti-foaming agents
  • buffering agents buffering agents
  • polymers antioxidants
  • preservatives chelating agents
  • viscomodulators tonicifiers
  • flavorants colorants
  • odorants opacifiers
  • suspending agents binders
  • fillers fillers
  • plasticizers plasticizers
  • lubricants and mixtures thereof.
  • an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons.
  • Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)-aminomethane (TRIS) and the like.
  • amino acids amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)
  • bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like.
  • a pharmaceutically acceptable acid such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids
  • Salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used.
  • the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like.
  • Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.
  • Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like.
  • suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p- toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like.
  • compositions for Injection [00175]
  • the invention provides a pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection.
  • Components and amounts of agents in the compositions are as described herein. - 55 - 4877-0794-3771.1 105807.005004– PCT Application
  • the forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
  • Aqueous solutions in saline are also conventionally used for injection.
  • Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • certain desirable methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.
  • Pharmaceutical Compositions for Topical (e.g., Transdermal) Delivery are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • certain desirable methods of preparation are vacuum-dry
  • the invention provides a pharmaceutical composition for transdermal delivery containing a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.
  • Compositions of the present invention can be formulated into preparations in solid, semisolid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions.
  • DMSO dimethylsulfoxide
  • carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients.
  • a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.
  • the pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration- enhancing molecules known to those trained in the art of topical formulation.
  • humectants e.g., urea
  • glycols e.g., propylene glycol
  • alcohols e.g., ethanol
  • fatty acids e.g., oleic acid
  • surfactants e.g., isopropyl myristate and sodium lauryl sulfate
  • pyrrolidones e.g., isopropyl myristate and sodium lauryl sulfate
  • pyrrolidones e.glycerol monolaurate, sulfoxides, terpenes (e.g., menthol)
  • amines amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present invention in controlled amounts, either with or without another agent.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos.5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Pharmaceutical Compositions for Inhalation are well known in the art.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • Other Pharmaceutical Compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art.
  • Administration of the compounds or pharmaceutical composition of the present invention can be affected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. Compounds can also be administered intraadiposally or intrathecally. [00188] The amount of the compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician.
  • an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g., by dividing such larger doses into several small doses for administration throughout the day. [00189] In some embodiments, a compound of the invention is administered in a single dose.
  • a compound of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six - 58 - 4877-0794-3771.1 105807.005004– PCT Application times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day.
  • a compound of the invention and another agent are administered together about once per day to about 6 times per day.
  • the administration of a compound of the invention and an agent continues for less than about 7 days.
  • the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.
  • Administration of the compounds of the invention may continue as long as necessary.
  • a compound of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days.
  • a compound of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day.
  • a compound of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.
  • An effective amount of a compound of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • the compositions of the invention may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
  • Such a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty.
  • compounds of the invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis.
  • a compound of the invention may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent.
  • a compound of the invention is admixed with a matrix.
  • a matrix may be a polymeric matrix and may serve to bond the compound to the stent.
  • Polymeric matrices suitable for such use include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g. polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters.
  • lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copo
  • Suitable matrices may be nondegrading or may degrade with time, releasing the compound or compounds.
  • Application of the invention may be applied to the surface of the stent by various methods such as dip/spin coating, spray coating, dip-coating, and/or brush-coating.
  • the compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent.
  • the compound may be located in the body of the stent or graft, for example in microchannels or micropores. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall.
  • Such stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the invention in a suitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent may be removed via an additional brief solvent wash.
  • compounds of the invention may be covalently linked to a stent or graft.
  • a covalent linker may be used which degrades in vivo, leading to the release of the compound of the invention. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages.
  • Compounds of the invention may additionally be administered intravascularly from a balloon used during angioplasty.
  • Extravascular administration of the compounds via the pericard or via advential application of formulations of the invention may also be performed to decrease restenosis.
  • a variety of stent devices which may be used as described are disclosed, for example, in the following references, all of which are hereby incorporated by reference: U.S. Pat. No. 5451233; U.S. Pat. No.5040548; U.S. Pat. No.5061273; U.S. Pat. No.5496346; U.S. Pat. No. 5292331; U.S. Pat. No.5674278; U.S. Pat. No.3657744; U.S. Pat. No.4739762; U.S. Pat. No. 5195984; U.S.
  • the compounds of the invention may be administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the invention may be found by routine experimentation in light of the instant disclosure.
  • a compound of the invention is administered in a composition that comprises one or more agents, and the agent has a shorter half- life than the compound of the invention unit dose forms of the agent and the compound of the invention may be adjusted accordingly.
  • the subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of - 60 - 4877-0794-3771.1 105807.005004– PCT Application precise dosages.
  • the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
  • Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
  • Methods of Use The method typically comprises administering to a subject a therapeutically effective amount of a compound of the invention.
  • the therapeutically effective amount of the subject combination of compounds may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • IC 50 refers to the half maximal inhibitory concentration of an inhibitor in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is needed to inhibit a given biological process (or component of a process, i.e., an enzyme, cell, cell receptor or microorganism) by half.
  • the present disclosure provides a method of modulating PI3K (e.g., PI3K ⁇ ) activity (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt, N- oxide, or stereoisomer thereof.
  • PI3K e.g., PI3K ⁇
  • a method of modulating PI3K activity e.g., PI3K ⁇ activity (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt, N- oxide, or stereoisomer thereof.
  • the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a - 61 - 4877-0794-3771.1 105807.005004– PCT Application pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof, or a pharmaceutical composition of the present disclosure.
  • the disease or disorder is associated with an implicated PI3K activity.
  • the disease or disorder is a disease or disorder in which PI3K activity is implicated.
  • the disease or disorder is a cancer.
  • the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, aids-related cancers, aids- related lymphoma, anal cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, cancer of unknown primary, cardiac (heart) tumors, atypical teratoid/rhabdoid tumor, primary CNS lymphoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colorectal cancer, craniopharyngioma, cutaneous t-cell lymphoma, mycosis fungoides, Sezary syndrome
  • ALL acute lymphoblastic
  • the cancer is Endometrial cancer, Breast cancer, oesophageal squamous-cell cancer, Cervical squamous-cell carcinoma, Cervical adenocarcinoma, Colorectal adenocarcinoma, Bladder Urothelial Carcinoma, Glioblastoma, Ovarian cancer, Non-small-cell Lung cancer, Esophagogastric cancer, Nerve-sheath tumor, Head and neck squamous-cell carcinoma, Melanoma, Esophagogastric adenocarcinoma, Soft-tissue sarcoma, Prostate cancer, Fibrolamellar carcinoma, Hepatocellular carcinoma, Diffuse glioma, Colorectal cancer, Pancreatic cancer, Cholangiocarcinoma, B-cell lymphoma, Mesothelioma, Adrenocortical carcinoma, Renal non-clear-cell carcinoma, Renal clear-cell carcinoma,
  • the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, cervical cancer, bladder cancer, esophageal cancer, pancreatic cancer, bone cancer, hepatobiliary cancer, medulloblastoma, kidney cancer or prostate cancer.
  • the cancer is a breast cancer, a prostate cancer, or a brain cancer.
  • the cancer is a breast cancer.
  • the cancer is a prostate cancer.
  • the cancer is a brain cancer.
  • the breast cancer is metastatic breast cancer.
  • the breast cancer is ductal carcinoma in situ (DCIS).
  • the breast cancer is invasive ductal carcinoma.
  • the breast cancer is triple - 63 - 4877-0794-3771.1 105807.005004– PCT Application negative breast cancer.
  • the breast cancer is medullary carcinoma.
  • the breast cancer is tubular carcinoma.
  • the breast cancer is mucinous carcinoma.
  • the breast cancer is Paget disease of the breast or nipple.
  • the breast cancer is inflammatory breast cancer (IBC).
  • the prostate cancer is an adenocarcinoma. In some embodiments, the prostate cancer is a small cell carcinoma. In some embodiments, the prostate cancer is a neuroendocrine tumor. In some embodiments, the prostate cancer is a transitional cell carcinoma. In some embodiments, the prostate cancer is a sarcoma. [00213] In some embodiments, the brain cancer is an acoustic neuroma. In some embodiments, the brain cancer is an astrocytoma. In some embodiments, the brain cancer is a brain metastasis. In some embodiments, the brain cancer is choroid plexus carcinoma. In some embodiments, the brain cancer is craniopharyngioma.
  • the brain cancer is an embryonal tumor. In some embodiments, the brain cancer is an ependymoma. In some embodiments, the brain cancer is a glioblastoma. In some embodiments, the brain cancer is a glioma. In some embodiments, the brain cancer is a medulloblastoma. In some embodiments, the brain cancer is a meningioma. In some embodiments, the brain cancer is an oligodendroglioma. In some embodiments, the brain cancer is a pediatric brain tumor. In some embodiments, the brain cancer is a pineoblastoma. In some embodiments, the brain cancer is a pituitary tumor.
  • the disease or disorder associated with PI3K includes, but is not limited to, CLOVES syndrome (congenial lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS), breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.
  • CLOVES syndrome congenial lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome
  • PROS PIK3CA-related overgrowth syndrome
  • the diseases or disorder associated with PI3K is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome).
  • CLOVES syndrome congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome.
  • the disease or disorder associated with PI3K is PIK3CA-related overgrowth syndrome (PROS).
  • the disease or disorder associated with PI3K is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.
  • the disease or disorder associated with PI3K is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.
  • the disease or disorder associated with PI3K is leukemia, lymphoma, or sarcoma.
  • the cancer is endometrial cancer, head and neck cancer, or a sarcoma.
  • the cancer is endometrial cancer. In some embodiments the cancer is head and neck cancer.
  • the cancer is a sarcoma.
  • the sarcoma is soft tissue sarcoma, osteosarcoma, chondrosarcoma, Ewing sarcoma, hemangioendothelioma, angiosarcoma, fibrosarcoma, myofibrosarcoma, chordoma, adamantinoma, liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, or malignant solitary fibrous tumor.
  • the sarcoma is soft tissue sarcoma.
  • the soft tissue sarcoma is liposarcoma, atypical lipomatous tumor, dermatofibrosarcoma protuberans, malignant solitary fibrous tumor, inflammatory myofibroblastic tumor, low-grade myofibroblastic sarcoma, fibrosarcoma, myxofibrosarcoma, low-grade fibromyxoid sarcoma, giant cell tumor of soft tissues, leiomyosarcoma, malignant glomus tumor, rhabdomyosarcoma, hemangioendothelioma, angiosarcoma of soft tissue, extraskeletal osteosarcoma, gastrointestinal stromal tumor, malignant gastrointestinal stromal tumor (GIST), malignant peripheral nerve sheath tumor, malignant Triton tumor, malignant granular cell tumor, malignant ossifying fibromyxoid tumor, stromal sarcoma, myoepithelial carcinoma, malignant phosphaturic mesenchy
  • the present disclosure provides a method of treating or preventing a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt, N- oxide, or stereoisomer thereof, or a pharmaceutical composition of the present disclosure.
  • a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating or preventing a breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating or preventing a prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating or preventing a brain cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a brain cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof thereof for use in modulating PI3K (e.g., PI3K ⁇ ) activity (e.g., in vitro or in vivo).
  • PI3K e.g., PI3K ⁇
  • the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof for use in treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof for use in treating a disease or disorder disclosed herein.
  • the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof for use in treating or preventing a cancer in a subject in need thereof.
  • the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof for use in treating a cancer in a subject in need thereof.
  • the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof for use in treating or preventing a breast cancer in a subject in need thereof.
  • the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof for use in treating a breast cancer in a subject in need thereof.
  • the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof for use in treating or preventing a prostate cancer in a subject in need thereof.
  • the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof for use in treating a prostate cancer in a subject in need thereof.
  • the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof for use in treating or preventing a brain cancer in a subject in need thereof.
  • the present disclosure provides a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof for use in treating a brain cancer in a subject in need thereof.
  • the present disclosure provides use of a compound as described oerein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof in the manufacture of a medicament for modulating PI3K (e.g., PI3K ⁇ ) activity (e.g., in vitro or in vivo).
  • PI3K e.g., PI3K ⁇
  • the present disclosure provides use of a compound as described oerein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof in the manufacture of a medicament for treating or preventing a cancer in a subject in need thereof.
  • the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof in the manufacture of a medicament for treating a cancer in a subject in need thereof.
  • the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof in the manufacture of a medicament for treating or preventing a breast cancer in a subject in need thereof.
  • the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof in the manufacture of a medicament for treating a breast cancer in a subject in need thereof.
  • the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof in the manufacture of a medicament for treating or preventing a prostate cancer in a subject in need thereof.
  • the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof in the manufacture of a medicament for treating a prostate cancer in a subject in need thereof.
  • the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof in the manufacture of a medicament for treating or preventing a brain cancer in a subject in need thereof.
  • the present disclosure provides use of a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof in the manufacture of a medicament for treating a brain cancer in a subject in need thereof.
  • the present disclosure provides compounds that function as modulators of PI3K activity.
  • the present disclosure therefore provides a method of modulating PI3K activity in vitro or in vivo, said method comprising contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof, as defined herein.
  • PI3K is modulation is inhibition of PI3K.
  • the PI3K inhibitor is a compound as described herein or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof.
  • the PI3K inhibitor is a PI3K ⁇ inhibitor. In some embodiments, the PI3K inhibitor is a PI3K ⁇ H1047R mutant inhibitor. In some embodiments, the PI3K inhibitor is alpha/beta non-selective. In some embodiments, the PI3K inhibitor is alpha selective. In some embodiments, the PI3K inhibitor is beta selective. [00257] Effectiveness of compounds of the disclosure can be determined by industry-accepted assays/disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge.
  • the present disclosure also provides a method of treating a disease or disorder in which PI3K activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, N-oxide, or stereoisomer thereof, or a pharmaceutical composition as defined herein.
  • the disclosure provides a method of modulating the activity of the PI3K ⁇ allosteric active site, wherein the modulation is induced through peripheral site targeting.
  • the peripheral site is targeted with an agent selected from a small molecule, a peptide, a peptidomimetic, a protein, a protein mimetic, a nucleic acid, an antibody, an antibody- drug conjugate, a nucleoprotein complex, an immunotherapy, or a combination thereof.
  • an agent selected from a small molecule, a peptide, a peptidomimetic, a protein, a protein mimetic, a nucleic acid, an antibody, an antibody- drug conjugate, a nucleoprotein complex, an immunotherapy, or a combination thereof.
  • Suitable solvents can be substantially nonreactive with the starting materials (reactants), the - 69 - 4877-0794-3771.1 105807.005004– PCT Application intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), or mass spectrometry
  • HPLC high performance liquid chromatography
  • Lg is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf, OTs, or OMs)
  • halogen e.g., Cl, Br, or I
  • pseudohalogen e.g., OTf, OTs, or OMs
  • palladium(0) catalyst such as bis(triphenylphosphine)palladium(II) dichloride and an appropriate stannane, such as tributyl(1-ethoxyvinyl)tin
  • Heck conditions e.g., palladium catalyst, such as palladium(II) acetate, a ligand, such as 1,3-bis(diphenylphosphino)propane, and an appropriate olefin, such as butyl vinyl ether
  • carbonylation coupling conditions e.g., palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0),
  • Compounds 1-2 can be converted to compounds 1-4 under either reductive conditions (e.g., in the presence of a suitable reducing agent, such as sodium borohydride) or nucleophilic addition conditions with nucleophiles 1-3 where M 1 is a metal (e.g., Li, MgCl, MgBr, ZnCl, or ZnBr).
  • a suitable reducing agent such as sodium borohydride
  • nucleophiles 1-3 where M 1 is a metal e.g., Li, MgCl, MgBr, ZnCl, or ZnBr.
  • Alcohols 1-4 can be transformed to compounds 1-5 where Lg 1 is halogen (e.g., Cl, Br, or I) under standard deoxygenative halogenation conditions (e.g., thionyl chloride, phosphorous tribromide, or triphenylphosphine and iodine) or a pseudohalogen (e.g., OTf, OTs, or OMs) under standard sulfonylation conditions (e.g., in the presence of a sulfonylating agent, such as methanesulfonyl chloride, p-toluenesulfonyl chloride, or trifluoromethanesulfonic anhydride, and a base, such as triethylamine).
  • halogen e.g., Cl, Br, or I
  • deoxygenative halogenation conditions e.g., thionyl chloride, phosphorous tribromide, or triphenylpho
  • Compounds 2-1 where Lg 3 is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be coupled with an amine 2-2 under standard amide bond formation conditions such as in the presence of an amide coupling reagent (e.g., N,N’-cabonyldiimidazole or HATU) and a base (e.g., diisopropylethylamine) to provide compounds 2-3.
  • an amide coupling reagent e.g., N,N’-cabonyldiimidazole or HATU
  • a base e.g., diisopropylethylamine
  • Anilines 2-3 can be converted to heterocycles 2-4 under standard acylation conditions (e.g., in the presence of N,N’- cabonyldiimidazole or triphosgene and a suitable base, such as 1,8-diazabicyclo[5.4.0]undec-7- ene).
  • Diones 2-4 can be halogenated with suitable reagents, such as phosphoryl chloride or phosphoryl bromide, to provide compounds 2-5 where X 2 is halogen (e.g., Cl or Br).
  • Reaction of heterocycles 2-4 with amines 2-6 in the presence of an amide coupling reagent e.g., (benzotriazol-1-yl-oxy)tri-pyrrolidinophosphonium hexafluorophosphate or bromotripyrrolidinophosphonium hexafluorophosphate
  • an amide coupling reagent e.g., (benzotriazol-1-yl-oxy)tri-pyrrolidinophosphonium hexafluorophosphate or bromotripyrrolidinophosphonium hexafluorophosphate
  • a base e.g., 1,8- diazabicyclo[5.4.0] undec-7-ene or triethylamine
  • reaction of heterocycles 3-1 with amines 2-6 in the presence of an amide coupling reagent e.g., (benzotriazol-1-yl-oxy)tri-pyrrolidino-phosphonium hexafluorophosphate or bromotripyrrolidinophosphonium hexafluorophosphate
  • an amide coupling reagent e.g., (benzotriazol-1-yl-oxy)tri-pyrrolidino-phosphonium hexafluorophosphate or bromotripyrrolidinophosphonium hexafluorophosphate
  • a base e.g., 1,8-diazabicyclo[5.4.0] undec-7-ene or triethylamine
  • Compounds 2-4 can be transformed into compounds 3-1 under standard Stille conditions (e.g., palladium(0) catalyst, such as bis(triphenylphosphine)palladium(II) dichloride and an appropriate stannane, such as tri-n-butyl(1-ethoxyvinyl)tin), or Heck conditions (e.g., palladium catalyst, such as palladium(II) acetate, a ligand, such as 1,3-bis(diphenylphosphino)propane, and an appropriate olefin, such as butyl vinyl ether), or carbonylation coupling conditions (e.g., palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), a carbonyl source, such as carbon monoxide, and suitable boronic acid, such as phenylboronic acid).
  • palladium(0) catalyst such as bis(triphenylphosphine)palladium(II) dich
  • Compounds 3-1 can be converted to compounds 4-1 under reductive conditions (e.g., in the presence of a suitable reducing agent, such as sodium borohydride).
  • Alcohols 4-1 can be transformed to compounds 4-2 where Lg 2 is halogen (e.g., Cl, Br, or I) under standard deoxygenative halogenation conditions (e.g., thionyl chloride, phosphorous tribromide, or triphenylphosphine and iodine) or a pseudohalogen (e.g., OTf, OTs, or OMs) under standard sulfonylation conditions (e.g., in the presence of a sulfonylating agent, such as methanesulfonyl chloride, p-toluenesulfonyl chloride, or trifluoromethanesulfonic anhydride, and a base, such as triethylamine).
  • halogen e.g., Cl
  • Scheme IV - 73 - 4877-0794-3771.1 105807.005004– PCT Application [00271]
  • Compounds of Formula (I) can be prepared from as shown in Scheme V. Annulation of amino acids 5-1 where Z is CR 5 or N can afford bicycles 5-2. Reaction of compounds 5-2 with alcohols 5-3, which can be prepared as described in Scheme I, under standard Mitsunobu conditions, such as in the presence of an azodicarboxylate (e.g., diisopropyl azodicarboxylate) and a phosphine (e.g., triphenylphosphine) can afford compounds 5-4.
  • an azodicarboxylate e.g., diisopropyl azodicarboxylate
  • a phosphine e.g., triphenylphosphine
  • a Lewis acid and an oxidant e.g., FeCl3 or TFA and air
  • amide coupling of anilines 2-3 with carboxylic acids 7-3 where W 1 is W and wherein this group is connected to the carboxylic acid functional group through a carbon atom of the W group under standard conditions, such as in the presence of an amide coupling reagent (e.g., EDC or HATU) and a base (e.g., 4- dimethylaminopyridine or triethylamine) can provide amides 7-4.
  • an amide coupling reagent e.g., EDC or HATU
  • a base e.g., 4- dimethylaminopyridine or triethylamine
  • Cyclization of compounds 7-4 under various conditions such as in the presence of an acid (e.g., p-toluenesulfonic acid or sulfuric acid), in the presence of a base (e.g., cesium carbonate or sodium hydroxide), in the presence of a dehydrating agent (e.g., acetic anhydride), or in the presence of I 2 and hexamethyldisilazane, can provide quinazolin-4(3H)-ones 7-2.
  • an acid e.g., p-toluenesulfonic acid or sulfuric acid
  • a base e.g., cesium carbonate or sodium hydroxide
  • a dehydrating agent e.g., acetic anhydride
  • I 2 and hexamethyldisilazane can provide quinazolin-4(3H)-ones 7-2.
  • Step 1.2-Amino-3-bromo-N,5-dimethylbenzamide To a solution of 2-amino-3-bromo-5-methylbenzoic acid (2.00 g, 8.69 mmol) in THF (20.0 mL) was added 1,1'-carbonyldiimidazole (1.55 g, 9.56 mmol), and the resulting reaction mixture was stirred at room temperature for 12 h.
  • Step 3.8-Bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one N,N-Diisopropylethylamine (0.64 mL, 3.68 mmol) was added dropwise to a mixture of 8-bromo-3,6-dimethylquinazoline-2,4(1H,3H)-dione (495 mg, 1.84 mmol) in phosphorous oxychloride (12.4 mL, 132 mmol) at room temperature. The heterogeneous mixture was heated at 95 °C for 16 h. The reaction was cooled to room temperature and then concentrated.
  • 3-Azabicyclo[3.1.0]hexane hydrochloride 620 mg, 5.2 mmol
  • 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one 750 mg, 2.6 mmol
  • triethylamine - 78 - 4877-0794-3771.1 105807.005004– PCT Application (1.1 mL, 7.8 mmol) in THF (26 mL) and the reaction mixture was heated to 70 oC for 18 h.
  • Sodium borohydride 200 mg, 5.2 mmol
  • 8-acetyl-2-(3- azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethylquinazolin-4(3H)-one 780 mg, 2.6 mmol
  • the mixture was diluted with DCM and water.
  • Phosphorous tribromide (0.35 mL, 3.8 mmol) was added to a solution of crude 2-(3- azabicyclo[3.1.0]hexan-3-yl)-8-(1-hydroxyethyl)-3,6-dimethylquinazolin-4(3H)-one (450 mg) in DCM (7.5 mL), and the solution was stirred for 1 h.
  • the reaction mixture was cooled to room temperature, diluted with MeCN, and filtered.
  • the crude solution was purified by prep-HPLC on a CSH-FP column (60-80% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (32 mg, 36 ⁇ mol, 16% yield).
  • reaction mixture was diluted with MeCN, filtered, and purified by prep-HPLC on a C18 column (60-80% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (8.2 mg, 12 ⁇ mol, 40% yield).
  • tert-butyl N-[rac-(1R,5S)-3-(8-acetyl-3,6-dimethyl-4-oxoquinazolin- 2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]carbamate 140 mg, 0.339 mmol
  • DCM 3 mL
  • TFA 0.519 mL, 6.79 mmol
  • 6-chloro-1H-pyrido[3,2-d][1,3]oxazine-2,4-dione (21.3 mg, 0.107 mmol) in THF (0.5 mL) was added triphenylphosphine (28.2 mg, 0.107 mmol) and diisopropyl azodicarboxylate (21.1 ⁇ L, 0.107 mmol).
  • the title compound was synthesized by procedures analogous to those outlined in Example 1, Step 6.
  • LC-MS calc. for C16H17F3N3O2 [M+H] + : m/z 340.1; Found: 340.0.
  • the title compound was synthesized by procedures analogous to those outlined in Example 1, Step 7.
  • LC-MS calc. for C22H22F3N5O3 [M+H] + : m/z 497.1; Found: 496.9.
  • Example 5 Example 5
  • tert-butyl dimethylchlorosilane 208 mg, 1.38 mmol
  • Step 4.8-Acetyl-6-fluoro-2-((1R,5S,6s)-6-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl)-3- methylquinazolin-4(3H)-one [00321] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 5. LC-MS calc. for C16H17FN3O3 [M+H] + : m/z 318.1; Found: 318.0.
  • the title compound was synthesized by procedures analogous to those outlined in Example 3, Step 5.
  • the reaction mixture was bubbled with nitrogen for 1 min and stirred at 100 °C overnight.
  • the reaction was quenched with KF solution and stirred at room temperature for 1 h.
  • the solid was removed by filtration.
  • the solution was diluted with DCM (10 mL), washed with water (10 mL) and brine (10 mL), dried over Na 2 SO 4 , filtered, and concentrated.
  • the residue was dissolved in THF (10 mL) and HCl (1 N, 5.0 mL, 5.0 mmol) was added.
  • the resulting mixture was stirred for 0.5 h.
  • the reaction was diluted with water (2 mL) and extracted with DCM (2 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated.
  • the title compound was synthesized by procedures analogous to those outlined in Example 1, Step 6.
  • LC-MS calc. for C 23 H 36 N 3 O 3 Si [M+H] + m/z 430.3; found 430.4.
  • the title compound was synthesized by procedures analogous to those outlined in Example 8, Step 2.
  • LC-MS calc. for C16H17ClN3O2 [M+H]+ m/z 318.1; Found 318.3.
  • Step 4 2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-chloro-8-(1-hydroxyethyl)-3- methylquinazolin-4(3H)-one [00351]
  • the title compound was synthesized by procedures analogous to those outlined in Example 1, Step 6.
  • LC-MS calc. for C16H19ClN3O2 [M+H] + : m/z 320.1; Found 320.3.
  • Step 5 3-((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-chloro-3-methyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)-6-chloropicolinic acid [00353]
  • the title compound was synthesized by procedures analogous to those outlined in Example 1, Step 7.
  • the title compound was synthesized by procedures analogous to those outlined in Example 8, Step 2 and Example 1, Step 6.
  • LC-MS calc. for C18H24N3O3 [M+H] + m/z 330.2; Found 330.4.
  • the title compound was synthesized by procedures analogous to those outlined in Example 8, Step 5.
  • Step 3.2,3-Bis(bromomethyl)pyrazine A mixture of 2,3-dimethylpyrazine (3.00 g, 27.7 mmol), N-bromosuccinimide (9.38 g, 52.7 mmol) and azobisisobutyronitrile (0.460 g, 2.77 mmol) in benzotrifluoride (30 mL) was stirred at 90 °C for 2 h. The mixture was filtered, and the organic layer was concentrated. The residue was purified by silica gel chromatography (0–5% EtOAc/hexane) to afford the title compound (400 mg, 1.3 mmol, 5.0% yield), a brown oil. LC-MS calc.
  • Step 4.6-Trityl-5,7-dihydropyrrolo[3,4-b]pyrazine A mixture of 2,3-bis(bromomethyl)pyrazine (400 mg, 1.5 mmol), triphenylmethanamine (351 mg, 1.35 mmol) and N,N-diisopropylethylamine (583 mg, 4.51 mmol) in DMF (5 mL) was stirred at 60 °C for 12 h. The mixture was cooled to room temperature, and water (30 mL) was added.
  • the title compound was synthesized by procedures analogous to those outlined in Example 2, Step 3.
  • the title compound was synthesized by procedures analogous to those outlined in Example 2, Step 3.
  • Step 2 Methyl (1R,5S,6r)-3-(8-(1-hydroxyethyl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate [00389] The title compound was synthesized by procedures analogous to those outlined in Example 8, Step 2, and Example 1, Step 6.
  • Step 3 6-Chloro-3-((1-(2-((1R,5S,6r)-6-(methoxycarbonyl)-3-azabicyclo[3.1.0] hexan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid [00391]
  • the title compound was synthesized by procedures analogous to those outlined in Example 1, Step 7.
  • LC-MS calc. for C 25 H 27 ClN 5 O 5 [M+H] + m/z 512.1; Found 512.3.
  • Step 4 Methyl (1R,5S,6r)-3-(8-(1-((2-(tert-butoxycarbonyl)-6-chloropyridin-3- yl)amino)ethyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxylate [00393] To a solution of 6-chloro-3-((1-(2-((1R,5S,6r)-6-(methoxycarbonyl)-3- azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid (260 mg, 0.51 mmol) in toluene (3 mL) was added 1,1-di-tert- butoxytriamino)pic
  • Step 5 (1R,5S,6r)-3-(8-(1-((2-(tert-Butoxycarbonyl)-6-chloropyridin-3- yl)amino)ethyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxylic acid [00395] To a solution of methyl (1R,5S,6r)-3-(8-(1-((2-(tert-butoxycarbonyl)-6-chloropyridin- 3-yl)amino)ethyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-3-azabicyclo [3.1.0]hexane- 6-carboxylate (180 mg, 0.32 mmol) in THF (2 mL) was added aq.
  • Step 6 6-Chloro-3-((1-(3,6-dimethyl-4-oxo-2-((1R,5S,6r)-6-((2,2,2- trifluoroacetoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3,4-dihydroquinazolin-8-yl)ethyl) amino)picolinic acid [00397] To a solution of (1R,5S,6r)-3-(8-(1-((2-(tert-butoxycarbonyl)-6-chloropyridin-3- yl)amino)ethyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxylic acid (25.3 mg, 0.0457 mmol) in THF (1 mL) was added borane dimethyl sulfide - 102
  • Step 7 6-Chloro-3-((1-(2-((1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo [3.1.0]hexan- 3-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)picolinic acid [00399] To a solution of 6-chloro-3-((1-(3,6-dimethyl-4-oxo-2-((1R,5S,6r)-6-((2,2,2- trifluoroacetoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3,4-dihydroquinazolin-8- yl)ethyl)amino)picolinic acid (10.0 mg, 0.0172 mmol) in methanol (1 mL) was added potassium carbonate (7.15 mg, 0.0517 mmol).
  • Step 3 6-Chloro-3-[1-[3,6-dimethyl-2-[1-[(2-methylpropan-2- yl)oxycarbonyl]pyrrolidin-3-yl]-4-oxoquinazolin-8-yl]ethylamino]pyridine-2-carboxylic acid [00405]
  • the title compound was synthesized by procedures analogous to those outlined in Example 8, Step 5.
  • Step 3 Tert-Butyl (1R,5S,6s)-6-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate
  • Step 3 5-Bromo-7-methyl-3-phenyl-2H-isoquinolin-1-one - 108 - 4877-0794-3771.1 105807.005004– PCT Application [00426] To a solution of [(3-bromo-5-methylbenzoyl)amino] 2,2-dimethylpropanoate (388 mg, 1.23 mmol) in methanol (4 mL) was added phenylacetylene (0.176 mL, 1.61 mmol), bis[(pentamethylcyclopentadienyl)dichloro-rhodium] (153 mg, 0.247 mmol), and cesium acetate (593 mg, 3.09 mmol).
  • Step 4 5-Bromo-2,7-dimethyl-3-phenylisoquinolin-1-one
  • CMF cesium carbonate
  • iodomethane 0.0594 mL, 0.955 mmol
  • Step 5 5-(1-Hydroxyethyl)-2,7-dimethyl-3-phenylisoquinolin-1-one - 109 - 4877-0794-3771.1 105807.005004– PCT Application [00430]
  • the title compound was synthesized by procedures analogous to those outlined in Example 8, Step 1 and Example 1, Step 6.
  • Step 6 6-Chloro-3-[1-(2,7-dimethyl-1-oxo-3-phenylisoquinolin-5-yl)ethyl- amino]pyridine-2-carboxylic acid and 1-(2,7-dimethyl-1-oxo-3-phenylisoquinolin-5-yl)ethyl 3- amino-6-chloropyridine-2-carboxylate [00432]
  • the title compound was synthesized by procedures analogous to those outlined in Example 1, Step 7.
  • Step 2 8-(1-Hydroxyethyl)-3,6-dimethyl-2-(1-methylpyrazol-4-yl)quinazolin-4-one
  • the title compound was synthesized by procedures analogous to those outlined in Example 8, Step 2 and Example 1, Step 6.
  • Step 3 6-Chloro-3-[1-[3,6-dimethyl-2-(1-methylpyrazol-4-yl)-4-oxoquinazolin-8- yl]ethylamino]pyridine-2-carboxylic acid [00438] The title compound was synthesized by procedures analogous to those outlined in Example 1, Step 7.
  • the title compound was synthesized by procedures analogous to those outlined in Example 3, Step 5.
  • the crude reaction mixture was purified by prep-HPLC on a C18 column (15–20% MeCN/0.1% NH3 (aq.)) to afford the title compound as an ammonium salt.
  • the reaction mixture was quenched with ice-cold water (10 mL) and diluted with DCM (10 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered, and concentrated. The concentrated crude material was redissolved in DCM (3 mL), and to this were added tert-butyl 3- amino-6-chloropyridine-2-carboxylate (138 mg, 0.604 mmol), N,N-diisopropylethylamine (351 ⁇ L, 2.01 mmol). The reaction mixture was stirred at 40 °C overnight and then cooled to room temperature.
  • reaction mixture was concentrated, diluted with MeCN and water, and purified by prep-HPLC on a C18 column (5–17% MeCN/0.1% NH3 (aq.)) to afford the title compound as an ammonium salt (1.81 mg, 0.004 mmol, 9.90% yield), a white solid.
  • the title compound was synthesized by procedures analogous to those outlined in Example 24, Step 2.
  • the crude material was purified by prep-HPLC on a fluoro-phenyl column (24–36% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt.
  • the title compound was synthesized by procedures analogous to those outlined in Example 3, Step 5.
  • the crude reaction mixture was purified by prep-HPLC on a C18 column (12.3–32.3% MeCN/0.15% NH3 (aq.)) to afford the title compound as an ammonium salt.
  • Examples 27 – 29 [00474] Examples 27 – 29 listed in Tables 1 and 2 were synthesized according to procedures analogous to Example 26. All examples in this table were prepared as ammonium salts. Table 1. Examples 27 – 29 Table 2. Examples 27 – 29 - 119 - 4877-0794-3771.1 105807.005004– PCT Application Example 30.
  • LiOH 22 ⁇ L, 22 ⁇ mol, 1M (aq.)
  • TFA salt 2.0 mg, 3.5 ⁇ mol
  • Ethyl 3-amino-6-fluoropicolinate [00485] 6-Fluoro-2-iodopyridin-3-amine (200 mg, 0.84 mmol), palladium(II) acetate (38 mg, 0.17 mmol), and 1,1’-ferrocenediyl-bis(diphenylphosphine) (140 mg, 0.25 mmol) were dissolved in EtOH (2.1 mL) and sealed in a Schlenk flask. The flask was degassed with CO and cooled to -78 oC under an atmosphere of CO. The flask was sealed and heated to 100 oC for 72 h. The reaction was cooled to room temperature and diluted with DCM and water.
  • Step 3.3 ((1-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-3,6-dimethyl-4-oxo-3,4- dihydroquinazolin-8-yl)ethyl)amino)-6-fluoropicolinic acid [00489]
  • the title compound was synthesized by procedures analogous to those outlined in Example 38, Step 3.
  • Bromotripyrrolidinophosphonium hexafluorophosphate (240 mg, 0.51 mmol) (CAS: 132705-51-2), 8-(1-hydroxyethyl)-3,6-dimethylquinazoline-2,4(1H,3H)-dione (Isomer 1; Example 40, Step 2) (100 mg, 0.43 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL, 1.3 mmol) were dissolved in MeCN (2.1 mL) and the resulting mixture was stirred at room temperature for 1 hr.
  • Example 41 6-Chloro-3-((1-(2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-3,4- dihydro-quinazolin-8-yl)ethyl)amino)picolinic acid [00498] Step 1.2-(4,4-Dimethylpiperidin-1-yl)-8-(1-hydroxyethyl)-3,6-dimethylquinazolin- 4(3H)-one [00499] The title compound was synthesized from rac-8-(1-hydroxyethyl)-3,6- dimethylquinazoline-2,4(1H,3H)-dione (Example 40, Step 2) by procedure analogous to those outlined in Example 40, Step 3.
  • the reaction was diluted with water (2.0 mL) and DCM (1.0 mL) and the resulting two phases were separated. The aqueous layer was extracted with DCM (2 x 2 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by prep-HPLC on a C18 column (54.6-74.6% MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (2.4 mg, 4.2 ⁇ mol, 50% yield).
  • Step 2.8-Acetyl-3-methoxy-6-methylquinazoline-2,4(1H,3H)-dione [00510] To a solution of 2-amino-3-bromo-N-ethyl-5-methylbenzamide (500 mg, 1.94 mmol) in THF (10.0 mL) was added 1,1’-carbonyldiimidazole (631 mg, 3.89 mmol) and 1,8- diazabicyclo [5.4.0]undec-7-ene (0.871 mL, 5.83 mmol). The mixture was refluxed for 16 h. The reaction mixture was cooled to room temperature and poured into a mixture of ice water (5.0 mL) and sat.
  • the title compound was synthesized by procedures analogous to those outlined in Example 1, Steps 3-7.
  • the title compound was synthesized by procedures analogous to those outlined in Example 1, Steps 6-7.
  • LC-MS calc. for C23H25ClN5O4 [M+H] + : m/z 470.2; Found: 470.1.
  • Example 52 Example 52.
  • Examples 53 - 70 listed in Tables 7 and 8 were synthesized according to procedures analogous to Example 9, [Step 1-3] (Method A), Example 13, [Step 9-10] (Method B), Example 3, Steps 4–5 (method C), or Example 40 (Method D).
  • the appropriate starting materials for Methods A and B can be prepared according to procedures analogous to those reported herein. All examples in this table were prepared as the TFA salt unless otherwise noted.
  • Examples 80 – 83 Table 12. Examples 80 – 83 - 145 - 4877-0794-3771.1 105807.005004– PCT Application Example 84.6-Chloro-3-[1-(2,4,7-trimethyl-1-oxo-3-phenylisoquinolin-5-yl)ethylamino] pyridine-2-carboxylic acid - 146 - 4877-0794-3771.1 105807.005004– PCT Application [00526] The title compound was synthesized by procedures analogous to those outlined in Example 19, Steps 1–6.
  • PI3K Pathway Activation Assay [00527] The inhibitory activity of compounds was evaluated by measuring phosphorylation of AKT on Ser473 as a readout of the PI3K pathway using HTRF (CisBio catalog number: 64AKSPE). These studies were conducted in the T-47D (heterozygous PIK3CA H1047R) and SKBR3 (PIK3CA WT) cell lines.
  • T-47D RPMI 1640, ATCC ⁇ Modification (Gibco, A10491-01) supplemented with 10% v/v FBS (Gibco, 26140-079), 1% penicillin streptomycin (Gibco, 15140-122), and 7.4 ug/mL insulin (MilliporeSigma, I9278); SKBR3: McCoy’s 5a (Modified) Medium (Gibco, 16600-082) supplemented with 10% v/v FBS (Gibco, 26140-079). Cells were seeded in 384- well plates at a density of 4,000 cells/well.
  • a “+” denotes an IC50 value of > 10000 nM
  • a “++” denotes an IC50 value of 500 nM ⁇ IC50 ⁇ 10000 nM
  • a “+++” denotes an IC50 value of ⁇ 500 nM.

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Abstract

L'invention concerne des composés de formule I. Des compositions pharmaceutiques comprenant des composés de formule I, ainsi que leurs procédés d'utilisation et de préparation sont également décrits.
PCT/US2024/022742 2023-04-03 2024-04-03 Inhibiteurs de pi3k-alpha mutants et leur utilisation en tant que produits pharmaceutiques Pending WO2024211346A1 (fr)

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