US20110190323A1 - Cortistatin analogues and syntheses thereof - Google Patents

Cortistatin analogues and syntheses thereof Download PDF

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US20110190323A1
US20110190323A1 US13/061,318 US200913061318A US2011190323A1 US 20110190323 A1 US20110190323 A1 US 20110190323A1 US 200913061318 A US200913061318 A US 200913061318A US 2011190323 A1 US2011190323 A1 US 2011190323A1
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Alec Nathanson Flyer
Hong Myung Lee
Andrew G. Myers
Cristina Montserrat Nieto-Oberhuber
Matthew D. Shair
Chong Si
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Harvard College
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Angiogenesis is the process of generating new capillary blood vessels from the pre-existing vasculature. After birth, angiogenesis contributes to organ growth, but in adulthood it is strictly regulated and occurs only during wound healing and in the female reproductive cycle. See Klagsbrun et al., Molecular angiogenesis. Chemistry & Biology 1999, 6 (8), R217-R224. Under normal physiological conditions, angiogenesis is tightly controlled by a series of pro-angiogenic and anti-angiogenic factors, which allow vascular growth for controlled periods of time. Ferrara, Vascular Endothelial Growth Factor as a Target for Anticancer Therapy. The Oncologist 2004, 9:2-10.
  • Persistent, unregulated angiogenesis has been implicated in a wide range of diseases, including rheumatoid arthritis, macular degeneration, atherosclerosis, obesity, benign neoplasms, and cancers. See Moulton et al., Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Circulation 1999, 99, (13), 1726-1732; and Manahan et al., The hallmarks of cancer. Cell 2000, 100, (1), 57-70.
  • Tumor growth depends heavily on neovascularization—tumors are marked by a state of constant hypoxia, and in order to grow beyond 1-2 mm in size they require new capillaries to supply nutrients, remove metabolic waste, and also to metastasize. See Hanahan et al., Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996, 86, (3), 353-364.
  • VEGF vascular endothelial growth factor
  • bFGF basic fibroblast growth factor
  • ANGPT2 angiopoietin 2
  • PDGF platelet-derived growth factor
  • VEGF has been shown to induce endothelial cell proliferation; furthermore, activation of the receptor VEGF2 has been associated with the production of matrix metalloproteinases (MMPs) which degrade the extracellular matrix (ECM), thus allowing migration of cells and further mobilizing pro-angiogenic proteins from the stroma.
  • MMPs matrix metalloproteinases
  • ECM extracellular matrix
  • Ferrara Vascular Endothelial Growth Factor as a Target for Anticancer Therapy. The Oncologist 2004, 9, 2-10; and Moses, The regulation of neovascularization by matrix metalloproteinases and their inhibitors. Stem Cells 1997, 15, (3), 180-189.
  • pro-angiogenic proteins upregulate endothelial integrins and are thought to sustain endothelial cell viability during the detachments that are required as the cell migrates towards the tumor.
  • Tumors also promote blood vessel growth by down-regulating endogenous angiogenesis inhibitors such as thrombospondin. Rastinejad et al., Regulation of the activity of a new inhibitor of angiogenesis by a cancer suppressor gene. Cell 1989, 56, (3), 345-355.
  • Direct inhibitors of angiogenesis either neutralize VEGF in the blood plasma, such as the antibody Bevacizumab (AVASTIN) or prevent endothelial cell growth in response to VEGF or other angiogenic factor stimulation, such as the kinase inhibitor sunitinib malate (SUTENT).
  • Indirect inhibitors such as the small molecule gefitinib (IRESSA), block tumor cell production of VEGF or other pro-angiogenic factors.
  • Direct angiogenesis inhibitors are less likely to induce acquired resistance because they target genetically stable endothelial cells instead of mutating tumor cells. Kerbel, Inhibition of tumor angiogenesis as a strategy to circumvent acquired-resistance to anticancer therapeutic agents. Bioessays 1991, 13, (1), 31-36.
  • tumor vasculature is “leaky”, being characterized by aberrant morphology, absent or loosely attached pericytes, an abnormal basement membrane, and high interstitial pressure.
  • Jain Normalizing tumor vasculature with anti-angiogenic therapy: A New Paradigm for Combination Therapy. Nature Medicine 2001, 7, (9), 987-989. Synergistic effects in combination therapy have been observed, supporting the predictions of Teicher that simultaneous targeting of both cancer cells and their supporting vasculature would provide maximal benefit.
  • Jain Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nature Medicine 2001, 7, (9), 987-989.
  • genotypically normal cells may also have tissue mass regulated by the endothelial microvasculature.
  • Gerber et al. The role of VEGF in normal and neoplastic hematopoiesis. Journal of Molecular Medicine 2003, 81, (1), 20-31. Rats that have undergone hepatectomy to remove 70% of their liver regenerate the lost mass in approximately 10 days. If an angiogenic protein, such as VEGF, is administered systemically, the liver continues to grow beyond its normal size. In contrast, if an angiogenesis inhibitor is administered, liver regeneration is prevented; discontinuation of the inhibitor is followed by immediate liver regeneration. Folkman, Opinion-Angiogenesis: an organizing principle for drug discovery?
  • Ranibizumab a fragment of the monoclonal antibody therapy Bevacizumab (approved in 2004 for colorectal cancer), was approved for direct injection into the eye to treat age-related macular degeneration.
  • Ranieri et al. Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: From the biology to the clinic.
  • angiogenesis is a highly complex process regulated by a host of factors, and it is believed that inhibition of multiple factors in combination may lead to enhanced patient outcome. See Folkman, Antiangiogenesis in cancer therapy—endostatin and its mechanisms of action. Experimental Cell Research 2006, 312, (5), 594-607.
  • several of the currently available drugs are biologics and suffer the drawbacks of high production costs and required parenteral administration.
  • cortistatins Several members of a new family of anti-angiogenic alkaloids known as the cortistatins have been isolated from the marine sponge Corticium simplex (See FIG. 1 ).
  • the structure of cortistatin A is unusual among natural products and includes a rearranged steroid in the form of a 9(10-19)-abeo-androstane skeleton, an ether bridge connecting C5 and C8, and a C17 isoquinoline substituent.
  • the structure of cortistatin A was confirmed by X-ray crystallography, while its absolute configuration was determined using circular dichroism.
  • cortistatins exhibit extremely potent (2-40 nM) and selective cytostatic activity against human umbilical vein endothelial cells (HUVECs) with markedly less potency against a panel of human cancer cell lines (including KB3-1, Neuro2A, K562, and NHDF).
  • Cortistatin A exhibits a selectivity index ranging from 3,000 to 4,000 for the endothelial cell line, making it a valuable lead in the development of novel anti-angiogenic agents.
  • cortistatin A and several other members of the cortistatin family are direct and highly selective angiogenesis inhibitors. They have presented evidence for a cytostatic, and not cytotoxic, mechanism of action, and they have demonstrated that cortistatin A inhibits tubular formation in HUVECs and also inhibits HUVEC cellular migration.
  • Aoki and coworkers postulate that cortistatin A acts by inhibiting the phosphorylation of an unidentified 110 kDa protein that is normally phosphorylated upon VEGF stimulation, and they further propose that this protein may be involved in the PI3 kinase/AKT pathway for angiogenic factor-induced signal transduction.
  • Aoki et al Structure-activity relationship and biological property of cortistatins, anti-angiogenic spongean steroidal alkaloids. Bioorganic & Medicinal Chemistry 2007, 15, (21), 6758-6762.
  • the present invention provides synthetic methology for preparing cortitatins A, J, K, L, and various analogs thereof.
  • the inventive methology allows for the preparation of analogs of cortistatin that were previously not available from natural sources or semi-synthetic approaches. Certain of these analogs may be useful in the treatment of diseases associated with aberrant angiogenesis (e.g., cancer, benign neoplasms, obesity, macular degeneration, rheumatoid arthritis, diabetic retinopathy).
  • the present invention provides a novel synthetic approach to cortistatins A, J, K, and L, and analogs thereof, via an aza-Prins cyclization with a transannular cyclization reaction as shown below.
  • the present invention provides several novel synthetic approaches to cortistatin A, J, K, and L, and analogs thereof, as described herein.
  • the invention provides a synthetic approach that involves an oxidative dearomatization reaction with intramolecular hydroxyl trapping to form the C5-C8 oxa-bridge in preparing Intermediate 2 as depicted below.
  • the present invention provides a novel synthetic approach to intermediate 2 and to cortistatins A, J, K, and L and analogs thereof, via intramolecular oxidative coupling and the formation of cyclohexyldieneone derivatives as shown below.
  • the present invention provides further synthetic approach to precursors of cortistatins A, J, K, and L, and analogs thereof, from intermediate 2, via a multistep sequence comprising reductive ⁇ -halogenation, allylic epoxidation, azide formation, protecting group manipulations, and reductive amination as shown below.
  • the present invention provides synthetic approaches by which cortistatins A, J, K, and L, and analogs thereof, may be derivatized with biological probes or labels such as biotin or biotin derivatives via a multistep sequence comprising the reduction of an azide to a primary amine, which can be protected and/or converted to the corresponding biotinylated amide derivative as shown below.
  • the present invention provides novel cortistatin analogs.
  • the compounds provided by the inventive synthetic approached described herein may be useful as anti-angiogenic agents for use in treatment of cancer, benign tumors, diabetic retinopathy, rheumatoid arthritis, macular degeneration, obesity, atherosclerosis, and other diseases associated with aberrant angiogenesis.
  • the invention provides compounds of the general formula:
  • the invention provides compound of the formula:
  • the invention provides compound of the formula:
  • the invention provides compounds of the general formula:
  • the invention provides compounds of the general formula:
  • the invention provides compounds of the general formula:
  • the invention provides truncated cortistatin analogs of the formula:
  • the invention provides truncated cortistatin analogs of the formula:
  • the invention also provides compounds with a modified carbon skeleton of the formula:
  • the diseases, disorders, and conditions associated with undesired angiogensis include many types of cancer, benign tumors, diabetic retinopathy, rheumatoid arthritis, macular degeneration, obesity, and atherosclerosis.
  • the invention provides a method of treating a proliferative disease by administering an effective amount of an inventive compound to a subject.
  • the invention provides a method of inhibiting angiogenesis by administering an effective amount of an inventive compound to a subject.
  • the invention provides a method of inhibiting the proliferation of endothelial cells by contacting endothelial cells with an effective amount of an inventive compound.
  • the present invention provides pharmaceutical compositions comprising the inventive compounds.
  • the pharmaceutical composition comprises an amount of the inventive compound effective to inhibit angiogenesis in a subject and optionally a therapeutically acceptable excipient.
  • a compound of the invention is typically combined with a pharmaceutically acceptable excipient to form a pharmaceutical composition for administration to a subject.
  • the present invention provides methods of using an inventive compound or pharmaceutical composition thereof to treat diseases associated with angiogenesis. Methods of treating a disease associated with angiogenesis, including many types of cancer, benign neoplasms, diabetic retinopathy, rheumatoid arthritis, macular degeneration, obesity, and atherosclerosis, are provided wherein a therapeutically effective amount of an inventive compound is administered to a subject.
  • the present invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more pharmaceutical composition of the invention.
  • the kit or pack includes multiple dosage units (e.g., multiple tablets with each containing a specified amount of an inventive compound).
  • the pack or kit includes an additional therapeutic agent for use in a combination therapy.
  • the pack or kit includes instructions for use and/or prescribing.
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomer ratios are all contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • protecting group it is meant that a particular functional moiety, e.g., O, S, or N, is temporarily blocked so that a reaction can be carried out selectively at another reactive site in a multifunctional compound.
  • a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group should be selectively removable in good yield by readily available, preferably non-toxic reagents that do not attack the other functional groups; the protecting group forms an easily separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group has a minimum of additional functionality to avoid further sites of reaction.
  • oxygen, sulfur, nitrogen, and carbon protecting groups may be utilized.
  • Hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydr
  • the protecting groups include methylene acetal, ethylidene acetal, 1-t-butylethylidene ketal, 1-phenylethylidene ketal, (4-methoxyphenyl)ethylidene acetal, 2,2,2-trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p-methoxybenzylidene acetal, 2,4-dimethoxybenzylidene ketal, 3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ortho ester, 1-methoxyethylidene ortho ester,
  • Amino-protecting groups include methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-d
  • protecting groups are detailed herein. However, it will be appreciated that the present invention is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and utilized in the method of the present invention. Additionally, a variety of protecting groups are described in Protective Groups in Organic Synthesis , Third Ed. Greene, T. W. and Wuts, P. G., Eds., John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
  • the compounds, as described herein, may be substituted with any number of substituents or functional moieties.
  • substituted whether preceeded by the term “optionally” or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
  • this invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment, for example, of infectious diseases or proliferative disorders.
  • stable as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
  • aliphatic includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups.
  • aliphatic is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.
  • alkyl includes straight, branched and cyclic alkyl groups.
  • alkyl alkenyl
  • alkynyl alkynyl
  • the terms “alkyl”, “alkenyl”, “alkynyl”, and the like encompass both substituted and unsubstituted groups.
  • lower alkyl is used to indicate those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) having 1-6 carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-4 carbon atoms.
  • Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, —CH 2 -cyclopropyl, vinyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, —CH 2 -cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, —CH 2 -cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, —CH 2 -cyclohexyl moieties and the like, which again, may bear one or more substituents.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
  • Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.
  • alkoxy refers to an alkyl group, as previously defined, attached to the parent molecule through an oxygen atom or through a sulfur atom.
  • the alkyl, alkenyl, and alkynyl groups contain 1-20 alipahtic carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups contain 1-10 aliphatic carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups contain 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups contain 1-4 aliphatic carbon atoms.
  • alkoxy include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy, and n-hexoxy.
  • alkylthio include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
  • alkylamino refers to a group having the structure —NHR′, wherein R′ is aliphatic, as defined herein.
  • the aliphatic group contains 1-20 aliphatic carbon atoms.
  • the aliphatic group contains 1-10 aliphatic carbon atoms.
  • the aliphatic group employed in the invention contain 1-8 aliphatic carbon atoms.
  • the aliphatic group contains 1-6 aliphatic carbon atoms.
  • the aliphatic group contains 1-4 aliphatic carbon atoms.
  • alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, iso-propylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and the like.
  • dialkylamino refers to a group having the structure —NRR′, wherein R and R′ are each an aliphatic group, as defined herein. R and R′ may be the same or different in an dialkyamino moiety.
  • the aliphatic groups contains 1-20 aliphatic carbon atoms. In certain other embodiments, the aliphatic groups contains 1-10 aliphatic carbon atoms. In yet other embodiments, the aliphatic groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the aliphatic groups contains 1-6 aliphatic carbon atoms. In yet other embodiments, the aliphatic groups contains 1-4 aliphatic carbon atoms.
  • dialkylamino groups include, but are not limited to, dimethylamino, methyl ethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(iso-propyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino, di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclohexyl)amino, and the like.
  • R and R′ are linked to form a cyclic structure.
  • cyclic structure may be aromatic or non-aromatic.
  • cyclic diaminoalkyl groups include, but are not limited to, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,3,4-trianolyl, and tetrazolyl.
  • substituents of the above-described aliphatic (and other) moieties of compounds of the invention include, but are not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; —F; —Cl; —Br; —I; —OH; —NO 2 ; —CN; —CF 3 ; —CH 2 CF 3 ; —CHCl 2 ; —CH 2 OH; —CH 2 CH 2 OH; —CH 2 NH 2 ; —CH 2 SO 2 CH 3 ; —C(O)R x ; —CO 2 (R x ); —CON(R x ) 2 ; —OC(O)R x ; —OCO 2 R x ;
  • aryl and “heteroaryl”, as used herein, refer to stable mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted.
  • Substituents include, but are not limited to, any of the previously mentioned substitutents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like.
  • heteroaryl refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
  • aryl and heteroaryl groups can be unsubstituted or substituted, wherein substitution includes replacement of one, two, three, or more of the hydrogen atoms thereon independently with any one or more of the following moieties including, but not limited to: aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; —F; —Cl; —Br; —I; —OH; —NO 2 ; —CN; —CF 3 ; —CH 2 CF 3 ; —CHCl 2 ; —CH 2 OH; —CH 2 CH 2 OH; —CH 2 NH 2 ; —CH 2 SO 2 CH 3 ; —C(O)R x ; —CO 2 (R x ); —
  • cycloalkyl refers specifically to groups having three to seven, preferably three to ten carbon atoms. Suitable cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case of other aliphatic, heteroaliphatic, or heterocyclic moieties, may optionally be substituted with substituents including, but not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; —F; —Cl; —Br; —I; —OH; —NO 2 ; —CN; —CF 3 ; —CH 2 CF 3
  • heteroaliphatic refers to aliphatic moieties that contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g., in place of carbon atoms. Heteroaliphatic moieties may be branched, unbranched, cyclic or acyclic and include saturated and unsaturated heterocycles such as morpholino, pyrrolidinyl, etc.
  • heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more moieties including, but not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; —F; —Cl; —Br; —I; —OH; —NO 2 ; —CN; —CF 3 ; —CH 2 CF 3 ; —CHCl 2 ; —CH 2 OH; —CH 2 CH 2 OH; —CH 2 NH 2 ; —CH 2 SO 2 CH 3 ; —C(O)R x ; —CO 2 (R x ); —CON(R x ) 2 ; —OC(O)R x ; —CO 2 (R
  • halo and “halogen” as used herein refer to an atom selected from fluorine, chlorine, bromine, and iodine.
  • haloalkyl denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.
  • heterocycloalkyl refers to a non-aromatic 5-, 6-, or 7-membered ring or a polycyclic group, including, but not limited to a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to a benzene ring.
  • heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • a “substituted heterocycloalkyl or heterocycle” group refers to a heterocycloalkyl or heterocycle group, as defined above, substituted by the independent replacement of one, two or three of the hydrogen atoms thereon with but are not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; —F; —Cl; —Br; —I; —OH; —NO 2 ; —CN; —CF 3 ; —CH 2 CF 3 ; —CHCl 2 ; —CH 2 OH; —CH 2 CH 2 OH; —CH 2 NH 2 ; —CH 2 SO 2 CH 3 ; —C(O)R x ;
  • label As used herein, the term “labeled” is intended to mean that a compound has at least one element, isotope, or chemical compound attached to enable the detection of the compound. In general, labels typically fall into five classes: a) isotopic labels, which may be radioactive or heavy isotopes, including, but not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 31 P, 32 P, 35 S, 67 Ga, 99m Tc (Tc-99m), 111 In, 123 I, 125 I, 169 Yb, and 186 Re; b) immune labels, which may be antibodies or antigens, which may be bound to enzymes (such as horseradish peroxidase) that produce detectable agents; c) colored, luminescent, phosphorescent, or fluorescent dyes; d) photoaffinity labels; and e) ligands with known binding partners (such as biotin-streptavidin, FK506-FKBP, etc.).
  • the labels may be incorporated into the compound at any position that does not interfere with the biological activity or characteristic of the compound that is being detected.
  • hydrogen atoms in the compound are replaced with deuterium atoms ( 2 H) to slow the degradation of compound in vivo. Due to isotope effects, enzymatic degradation of the deuterated compounds may be slowed thereby increasing the half-life of the compound in vivo.
  • the compound is labeled with a radioactive isotope, preferably an isotope which emits detectable particles, such as 13 particles.
  • photoaffinity labeling is utilized for the direct elucidation of intermolecular interactions in biological systems.
  • a variety of known photophores can be employed, most relying on photoconversion of diazo compounds, azides, or diazirines to nitrenes or carbenes (see, Bayley, H., Photogenerated Reagents in Biochemistry and Molecular Biology (1983), Elsevier, Amsterdam, the entire contents of which are incorporated herein by reference).
  • the photoaffinity labels employed are o-, m- and p-azidobenzoyls, substituted with one or more halogen moieties, including, but not limited to 4-azido-2,3,5,6-tetrafluorobenzoic acid.
  • biotin labeling is utilized.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977; incorporated herein by reference.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base functionality with a suitable organic or inorganic acid.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate, and aryl sulfonate.
  • ester refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic, and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates.
  • the esters are cleaved by enzymes such as esterases.
  • prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • tautomers are particular isomers of a compound in which a hydrogen and double bond have changed position with respect to the other atoms of the molecule. For a pair of tautomers to exist there must be a mechanism for interconversion. Examples of tautomers include keto-enol forms, imine-enamine forms, amide-imino alcohol forms, amidine-aminidine forms, nitroso-oxime forms, thio ketone-enethiol forms, N-nitroso-hydroxyazo forms, nitro-aci-nitro forms, and pyridone-hydroxypyridine forms.
  • biological probe comprises modifications of the compounds of the invention to include substituents, such as biotin or biotin derivatives, which have high affinities for known biological targets, such as avidin (also streptavidin and neutravidin).
  • the attachment of a biotin or a biotin derivative to compounds of the invention is referred to herein as “biotinylation.”
  • the attachment of biological probes to compounds of the invention, including the biotinylation of compounds of the invention can be used to study the biological basis of diseases including protein localization, protein interactions, transcription, translation, and replication, or the mechanism of action of a compound (e.g., cortistatin or an analog thereof).
  • biological probe is synonymous with the term label.
  • Animal refers to humans as well as non-human animals, including, for example, mammals, birds, reptiles, amphibians, and fish.
  • the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a primate, or a pig).
  • a non-human animal may be a transgenic animal.
  • association When two entities are “associated with” one another as described herein, they are linked by a direct or indirect covalent or non-covalent interaction. Preferably, the association is covalent. Desirable non-covalent interactions include hydrogen bonding, van der Waals interactions, hydrophobic interactions, magnetic interactions, electrostatic interactions, etc.
  • the “effective amount” of an active agent refers to an amount sufficient to elicit the desired biological response.
  • the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the patient
  • the effective amount of a compound with anti-angiogenic activity is the amount that results in a sufficient concentration to inhibit the growth of blood vessels or the proliferation of endothelial cells.
  • FIG. 1 depicts various exemplary cortistatins.
  • the present invention is based upon the synthetic approaches described herein for preparing cortistatins A, J, K, L, cortistatin analogs, and other inventive compounds.
  • the cortistatins have unique structural features and potent anti-angiogenesis activity.
  • the relative paucity of data concerning both their structure-activity relationships and biological target(s) has made these compounds particularly interesting and important in designing novel anti-angiogenic agents.
  • the present invention provides the synthesis of cortistatins A, J, K, L, and cortistatin analogs, for the purpose of developing cortistatin analogs with improved anti-angiogenic biological activity and/or improving its pharmacological properties.
  • Such compounds may find use in the treatment of diseases associated with aberrant angiogenesis.
  • the present invention provides novel compounds.
  • inventive compounds are cortistatin analogs or intermediates useful in the synthesis of cortistatins A, J, K, L, or analogs thereof.
  • the various inventive compounds are described herein.
  • inventive analogs may be prepared by the synthetic methods described herein. Such compounds may have anti-angiogenic activity, making them useful in the treatment of diseases associated with angiogenesis.
  • the present invention provides compounds of the formula:
  • each of the dashed lines independently represents the presence or absence of a bond
  • n is an integer between 0 and 6, inclusive
  • n is an integer between 0 and 8, inclusive;
  • each occurrence of R 1 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C( ⁇ O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; ⁇ O; ⁇ N(R A ); ⁇ S; —N(R A ) 2 ; —NHC( ⁇ O)R A ; —
  • R 2 is hydrogen or C 1 -C 6 aliphatic
  • R 3 is hydrogen or C 1 -C 6 aliphatic
  • each occurrence of R 4 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR D ; —C( ⁇ O)R D ; —CO 2 R D ; —CN; —SCN; —SR D ; —SOR A ; —SO 2 R D ; —NO 2 ; —N 3 ; ⁇ O; ⁇ N(R D ); ⁇ S; —N(R D ) 2 ; —NHC( ⁇ O)R D ; —
  • the inventive compound is not a naturally occurring cortistatin analogs. In certain embodiments, the inventive compound is not a previously isolated and characterized, naturally occurring cortistatin analog. In certain embodiments, the inventive compound is not any of the compounds, cortistatin A-L, or didehydrocortistatin A. In certain embodiments, the invention provides compounds of the general formula:
  • the invention provides compound of the formula:
  • the invention provides compound of the formula:
  • the invention provides compounds of the general formula:
  • the invention provides compounds of the general formula:
  • the invention provides compounds of the general formula:
  • the present invention provides compounds of the formula:
  • each of the dashed lines independently represents the presence or absence of a bond
  • n is an integer between 0 and 6, inclusive
  • n is an integer between 0 and 8, inclusive;
  • each occurrence of R 1 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C( ⁇ O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; ⁇ O; ⁇ N(R A ); ⁇ S; —N(R A ) 2 ; —NHC( ⁇ O)R A ; —
  • R 2 is hydrogen or C 1 -C 6 aliphatic
  • R 3 is hydrogen or C 1 -C 6 aliphatic
  • each occurrence of R 4 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR D ; —C( ⁇ O)R D ; —CO 2 R D ; —CN; —SCN; —SR D ; —SOR A ; —SO 2 R D ; —NO 2 ; —N 3 ; ⁇ O; ⁇ N(R D ); ⁇ S; —N(R D ) 2 ; —NHC( ⁇ O)R D ; —
  • the inventive compound is not a naturally occurring cortistatin analogs. In certain embodiments, the inventive compound is not a previously isolated and characterized, naturally occurring cortistatin analog. In certain embodiments, the inventive compound is not any of the compounds, cortistatin A-L.
  • the inventive compound is of the formula:
  • the inventive compound is of the formula:
  • the inventive compound is of the formula:
  • m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6.
  • n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain embodiments, n is 7. In certain embodiments, n is 8.
  • At least one R 1 is hydrogen. In certain embodiments, at least one R 1 is halogen. In certain embodiments, at least one R 1 is fluorine. In certain embodiments, at least one R 1 is substituted or unsubstituted aliphatic. In some embodiments, at least one R 1 is substituted or unsubstituted alkyl. In certain embodiments, at least one R 1 is C 1 -C 6 alkyl. In certain embodiments, at least one R 1 is methyl. In certain embodiments, at least one R 1 is ethyl. In certain embodiments, at least one R 1 is propyl. In certain embodiments, at least one R 1 is substituted or unsubstituted aryl.
  • At least one R 1 is substituted or unsubstituted phenyl. In certain embodiments, at least one R 1 is substituted phenyl. In certain embodiments, at least one R 1 is unsubstituted phenyl. In certain embodiments, at least one R 1 is substituted or unsubstituted naphthyl. In certain embodiments, at least one R 1 is substituted naphthyl. In certain embodiments, at least one R 1 is unsubstituted naphthyl. In certain embodiments, at least one R 1 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoquinolinyl.
  • At least one R 1 is substituted isoquinolinyl. In certain embodiments, at least one R 1 is unsubstituted isoquinolinyl. In certain embodiments, at least one R 1 is unsubstituted 5-isoquinolinyl. In certain embodiments, at least one R 1 is unsubstituted 6-isoquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoindolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted benzothienyl.
  • At least one R 1 is substituted or unsubstituted benzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted dibenzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted benzimidazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted benzthiazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoquinolyl.
  • At least one R 1 is substituted or unsubstituted cinnolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phthalazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinazolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinoxalinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted 4H-quinolizinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted carbazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted acridinyl.
  • At least one R 1 is substituted or unsubstituted phenazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenothiazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenoxazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted tetrahydroquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted tetrahydroisoquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted pyrido[2,3-b]-1,4-oxazin-3(4H)-one.
  • R 2 is hydrogen. In certain embodiments, R 2 is or C 1 -C 6 aliphatic. In some embodiments, R 2 is substituted or unsubstituted alkyl. In certain embodiments, R 2 is C 1 -C 6 alkyl. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is ethyl. In certain embodiments, R 2 is propyl. In certain embodiments, R 2 is butyl. In certain embodiments, R 2 is pentyl. In certain embodiments, R 2 is hexyl.
  • R 3 is hydrogen. In certain embodiments, R 3 is C 1 -C 6 aliphatic. In some embodiments, R 3 is substituted or unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 3 is unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is ethyl. In certain embodiments, R 3 is propyl. In certain embodiments, R 3 is butyl. In certain embodiments, R 3 is pentyl. In certain embodiments, R 3 is hexyl.
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen or methyl.
  • R 2 is methyl
  • R 3 is hydrogen.
  • R 2 is hydrogen
  • R 3 is methyl.
  • both R 2 and R 3 are hydrogen.
  • both R 2 and R 3 are methyl.
  • At least one R 4 is hydrogen. In certain embodiments, at least one R 4 is halogen. In certain embodiments, at least one R 4 is fluorine. In certain embodiments, at least one R 4 is substituted or unsubstituted aliphatic. In some embodiments, at least one R 4 is substituted or unsubstituted alkyl. In certain embodiments, at least one R 4 is C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is methyl. In certain embodiments, at least one R 4 is ethyl. In certain embodiments, at least one R 4 is propyl. In certain embodiments, at least one R 4 is substituted alkyl.
  • At least one R 4 is substituted C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is substituted C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is C 1 -C 6 alkyl substituted with an aryl group. In certain embodiments, at least one R 4 comprises biotin or a biotin derivative. In certain embodiments, at least one R 4 is a
  • At least one R 4 is a
  • At least one R 4 is a benzyl group. In certain embodiments, at least one R 4 is —OR D wherein R D is hydrogen. In certain embodiments, at least one R 4 is —OR D wherein R D is C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is —OR D wherein R D is methyl. In certain embodiments, at least one R 4 is —OR D wherein R D is ethyl. In certain embodiments, at least one R 4 is —OR D wherein R D is propyl.
  • At least one R 4 is —N(R D ) 2 , wherein each R D is hydrogen or C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is —N(R D ) 2 , wherein each R D is C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is —N(R D ) 2 , wherein each R D is methyl. In certain embodiments, at least one R 4 is —N(R D ) 2 , wherein each R D is ethyl. In certain embodiments, at least one R 4 is —N(R D ) 2 , wherein each R D is propyl.
  • At least one R 4 is —N(R D ) 2 , wherein each R D is butyl. In certain embodiments, at least one R 4 is —N(R D ) 2 , wherein each R D is pentyl. In certain embodiments, at least one R 4 is —N(R D ) 2 , wherein each R D is hexyl.
  • any two combinations of the above (R 4 ) n substituents may concurrently be present on the same ring, or any three combinations of the above (R 4 ) n substituents may concurrently be present on the same ring.
  • the compound is of formula:
  • R 1 , R 2 , R 3 , R 4 , and n are as defined herein.
  • the compound is of formula:
  • R 1 , R 2 , R 3 , R 4 , and n are as defined herein.
  • the compound is of formula:
  • R 1 , R 4 , and n are as defined herein.
  • the compound is of formula:
  • R 1 , R 4 , and n are as defined herein.
  • the compound is of formula:
  • R 1 , R 4 , and n are as defined herein.
  • the compound is of formula:
  • R 1 , R 4 , and n are as defined herein.
  • the compound is of formula:
  • R 1 , R 4 , and n are as defined herein.
  • the compound is of formula:
  • R 1 , R 4 , and n are as defined herein.
  • the compound is of formula:
  • R 1 and R 4 are as defined herein.
  • the compound is of formula:
  • R 1 and R 4 are as defined herein.
  • the compound is of formula:
  • R 1 , R 2 , R 3 , R 4 , and n are as defined herein.
  • the compound is of formula:
  • R 1 , R 2 , R 3 , R 4 , and n are as defined herein.
  • the compound is of formula:
  • R 1 , R 2 , R 3 , R 4 , and n are as defined herein.
  • the compound is of formula:
  • R 1 , R 2 , R 3 , R 4 , and n are as defined herein.
  • the compound is of formula:
  • R 1 , R 4 , and n are as defined herein.
  • the compound is of formula:
  • R 1 , R 4 , and n are as defined herein.
  • the compound is of formula:
  • R 1 and R 4 are as defined herein.
  • the compound is of formula:
  • R 1 and R D are as defined herein.
  • the compound is of formula:
  • R 1 and R 2 are as defined herein; and X is ⁇ O, ⁇ NR, ⁇ NOH, or ⁇ NSO 2 R. In certain embodiments, X is ⁇ O.
  • the compound is of formula:
  • R 1 and R 2 are as defined herein; and X is —R, —Ar, —NR 2 , or —OR. In certain embodiments, X is —OR. In certain embodiments, X is —OH.
  • the compound is of formula:
  • R 1 is as defined herein.
  • the compound is of formula:
  • R 1 and R 2 are as defined herein; and X is ⁇ O, ⁇ NR, ⁇ NOH, or ⁇ NSO 2 R. In certain embodiments, X is ⁇ O.
  • the compound is of formula:
  • R 1 and R 2 are as defined herein; and X is ⁇ O, ⁇ NR, ⁇ NOH, or ⁇ NSO 2 R. In certain embodiments, X is ⁇ O.
  • the compound is of formula:
  • R 1 and R 2 are as defined herein; and X is —R, —Ar, —NR 2 , or —OR. In certain embodiments, X is —OH.
  • the compound is of formula:
  • R 1 and R 2 are as defined herein; and X is —R, —Ar, —NR 2 , or —OR. In certain embodiments, X is —OH.
  • the present invention also provides truncated cortistatin analogues.
  • Such analogues may include bicyclic, tricyclic, or four cyclic moieties of the cortistatin skeleton.
  • the analogs may contain any subset of contiguous rings of the cortistatin skeleton (e.g., A-B, B-C, C-D, A-B-C, or B-C-D)
  • the compound of the invention includes the C-D ring system (i.e., a 6-5 fused ring system) of the cortistatin skeleton.
  • the compound is of formula:
  • the dashed line independently represents the presence or absence of a bond
  • X when X is present with a single bond, then X is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR y ; —C( ⁇ O)R y ; —CO 2 R y ; —CN; —SCN; —SR y ; —SOR y ; —SO 2 R y ; —NSO 2 R y ; —NO 2 ; —N 3 ; —NH(R y ); —N(R y ) 2 ; —
  • R y is independently selected from the group consisting of hydrogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl.
  • each occurrence of R 1 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C( ⁇ O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; ⁇ O; ⁇ N(R A ); ⁇ S; —N(R A ) 2 ; —NHC( ⁇ O)R A ; —
  • each occurrence of R 5 is independently selected from the group consisting of cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; —C( ⁇ O)R E ; —C( ⁇ O)OR E ; —C( ⁇ O)N(R E ) 2 ; —SO 2 R E ; —SO 2 NR E ; wherein each occurrence of R E is independently a hydrogen, a protecting group, a substituted or unsubstituted, branched or unbranched moiety selected from an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio
  • the dashed line is absent to form a single bond with X.
  • X when X is present with a single bond, then X is —OR y , wherein R y is hydrogen or C 1-6 alkyl.
  • R y when X is present with a single bond, then X is —OH.
  • X when X is present with a single bond, then X is substituted or unsubstituted aliphatic. Exemplary aliphatic groups include hydrogen or C 1-6 alkyl.
  • X when X is present with a single bond, then X is —N(R y ) 2 .
  • R y groups include hydrogen to form X as —NH 2 , or methyl to form X as —NHCH 3 or —N(CH 3 ) 2 .
  • X when X is present with a single bond, then X is a substituted or unsubstituted aryl.
  • the dashed line is present to form a double bond with X.
  • X when X is present with a double bond, then X is ⁇ O.
  • X when X is present with a double bond, then X is ⁇ S.
  • X when X is present with a double bond, then X is ⁇ NR y , wherein R y is hydrogen or C 1-6 alkyl.
  • R y when X is present with a double bond, then X is ⁇ N(OR y ), wherein R y is hydrogen or C 1-6 alkyl.
  • X when X is present with a double bond, then X is ⁇ NSO 2 R y , wherein R y is hydrogen or C 1-6 alkyl.
  • At least one R 1 is hydrogen. In certain embodiments, at least one R 1 is halogen. In certain embodiments, at least one R 1 is fluorine. In certain embodiments, at least one R 1 is substituted or unsubstituted aliphatic. In some embodiments, at least one R 1 is substituted or unsubstituted alkyl. In certain embodiments, at least one R 1 is C 1 -C 6 alkyl. In certain embodiments, at least one R 1 is methyl. In certain embodiments, at least one R 1 is ethyl. In certain embodiments, at least one R 1 is propyl. In certain embodiments, at least one R 1 is substituted or unsubstituted aryl.
  • At least one R 1 is substituted or unsubstituted phenyl. In certain embodiments, at least one R 1 is substituted phenyl. In certain embodiments, at least one R 1 is unsubstituted phenyl. In certain embodiments, at least one R 1 is substituted or unsubstituted naphthyl. In certain embodiments, at least one R 1 is substituted naphthyl. In certain embodiments, at least one R 1 is unsubstituted naphthyl. In certain embodiments, at least one R 1 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoquinolinyl.
  • At least one R 1 is substituted isoquinolinyl. In certain embodiments, at least one R 1 is unsubstituted isoquinolinyl. In certain embodiments, at least one R 1 is unsubstituted 5-isoquinolinyl. In certain embodiments, at least one R 1 is unsubstituted 6-isoquinolinyl.
  • At least one R 1 is substituted or unsubstituted indolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoindolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted benzothienyl. In certain embodiments, at least one R 1 is substituted or unsubstituted benzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted dibenzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted benzimidazolyl.
  • At least one R 1 is substituted or unsubstituted benzthiazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoquinolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted cinnolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phthalazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinazolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinoxalinyl.
  • At least one R 1 is substituted or unsubstituted 4H-quinolizinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted carbazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted acridinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenothiazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenoxazinyl.
  • At least one R 1 is substituted or unsubstituted tetrahydroquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted tetrahydroisoquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted pyrido[2,3-b]-1,4-oxazin-3(4H)-one.
  • R 5 is substituted or unsubstituted, branched or unbranched aliphatic. In certain embodiments, R 5 is C 1-6 alkyl. In certain embodiments, R 5 is —N(R E ) 2 , wherein R E is hydrogen or C 1-6 alkyl. In certain embodiments, R 5 is —(C 1-3 alkyl)-N(R E ) 2 , wherein R E is hydrogen or C 1-6 alkyl. In certain embodiments, R 5 is —C( ⁇ O)R E , wherein R E is hydrogen or C 1-6 alkyl. In certain embodiments, R 5 is —C( ⁇ O)OR E , wherein R E is hydrogen or C 1-6 alkyl.
  • R 5 is —C( ⁇ O)N(R E ) 2 , wherein R E is hydrogen or C 1-6 alkyl. In certain embodiments, R 5 is —SO 2 R E , wherein R E is hydrogen or C 1-6 alkyl. In certain embodiments, R 5 is —SO 2 NR E , wherein R E is hydrogen or C 1-6 alkyl.
  • the compound has the stereochemistry as shown in the formula below:
  • the compound has the stereochemistry as shown in the formula below:
  • the compound has the stereochemistry as shown in the formula below:
  • Such compounds may be useful not only as cortistatin analogs but also as intermediate in the synthesis of cortistatin analogs.
  • the compounds may have anti-angiogenic activity. In certain embodiments, the compounds may not have anti-angiogenic activity.
  • the compound when X is connected to the carbon skeleton through a double bond, the compound is of formula:
  • the compound when X is connected to the carbon skeleton through a single bond, the compound is of formula:
  • the compound when X is hydrogen, the compound is of formula:
  • R 1 and R E are as defined herein.
  • R 1 is a quinolinyl and X is hydrogen
  • the compound is of formula:
  • R E is as defined herein.
  • the compound when X is hydrogen, the compound is of formula:
  • R 1 and R E are as defined herein.
  • the compound when X is hydrogen, the compound is of formula:
  • R 1 and R E are as defined herein.
  • R E is as defined herein.
  • R E is as defined herein.
  • the compound when X is connected to the carbon skeleton through a double bond, the compound is of formula:
  • the compound when X is connected to the carbon skeleton through a single bond, the compound is of formula:
  • the present invention also provides compounds that include the 6-6-5 fused ring system when X is connected to the carbon skeleton through either a single bond or a double bond, as shown in the formula:
  • each of the dashed lines independently represents the presence or absence of a bond
  • X when X is present with a single bond, then X is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR y ; —C( ⁇ O)R y ; —CO 2 R y ; —CN; —SCN; —SR y ; —SOR y ; —SO 2 R y ; —NSO 2 R y ; —NO 2 ; —N 3 ; —NH(R y ); —N(R y ) 2 ; —
  • R y is independently selected from the group consisting of hydrogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl.
  • each occurrence of R 1 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C( ⁇ O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; ⁇ O; ⁇ N(R A ); ⁇ S; —N(R A ) 2 ; —NHC( ⁇ O)R A ; —
  • each occurrence of R 5 is independently selected from the group consisting of cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; —C( ⁇ O)R E ; —C( ⁇ O)OR E ; —C( ⁇ O)N(R E ) 2 ; —SO 2 R E ; —SO 2 NR E ; wherein each occurrence of R E is independently a hydrogen, a protecting group, a substituted or unsubstituted, branched or unbranched moiety selected from an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio
  • the dashed line is absent to form a single bond with X.
  • X when X is present with a single bond, then X is —OR y , wherein R y is hydrogen or C 1-6 alkyl.
  • R y when X is present with a single bond, then X is —OH.
  • X when X is present with a single bond, then X is substituted or unsubstituted aliphatic. Exemplary aliphatic groups include hydrogen or C 1-6 alkyl.
  • X when X is present with a single bond, then X is —N(R y ) 2 .
  • R y groups include hydrogen to form X as —NH 2 , or methyl to form X as —NHCH 3 or —NH(CH 3 ) 2 .
  • X when X is present with a single bond, then X is substituted or unsubstituted aryl.
  • the dashed line represents a bond to form a double bond with X.
  • X when X is present with a double bond, then X is ⁇ O.
  • X when X is present with a double bond, then X is ⁇ S.
  • X when X is present with a double bond, then X is ⁇ NR y , wherein R y is hydrogen or C 1-6 alkyl.
  • R y when X is present with a double bond, then X is ⁇ N(OR y ), wherein R y is hydrogen or C 1-6 alkyl.
  • X when X is present with a double bond, then X is ⁇ NSO 2 R y , wherein R y is hydrogen or C 1-6 alkyl.
  • At least one R 1 is hydrogen. In certain embodiments, at least one R 1 is halogen. In certain embodiments, at least one R 1 is fluorine. In certain embodiments, at least one R 1 is substituted or unsubstituted aliphatic. In some embodiments, at least one R 1 is substituted or unsubstituted alkyl. In certain embodiments, at least one R 1 is C 1 -C 6 alkyl. In certain embodiments, at least one R 1 is methyl. In certain embodiments, at least one R 1 is ethyl. In certain embodiments, at least one R 1 is propyl. In certain embodiments, at least one R 1 is substituted or unsubstituted aryl.
  • At least one R 1 is substituted or unsubstituted phenyl. In certain embodiments, at least one R 1 is substituted phenyl. In certain embodiments, at least one R 1 is unsubstituted phenyl. In certain embodiments, at least one R 1 is substituted or unsubstituted naphthyl. In certain embodiments, at least one R 1 is substituted naphthyl. In certain embodiments, at least one R 1 is unsubstituted naphthyl. In certain embodiments, at least one R 1 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoquinolinyl.
  • At least one R 1 is substituted isoquinolinyl. In certain embodiments, at least one R 1 is unsubstituted isoquinolinyl. In certain embodiments, at least one R 1 is unsubstituted 5-isoquinolinyl. In certain embodiments, at least one R 1 is unsubstituted 6-isoquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoindolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted benzothienyl.
  • At least one R 1 is substituted or unsubstituted benzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted dibenzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted benzimidazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted benzthiazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoquinolyl.
  • At least one R 1 is substituted or unsubstituted cinnolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phthalazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinazolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinoxalinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted 4H-quinolizinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted carbazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted acridinyl.
  • At least one R 1 is substituted or unsubstituted phenazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenothiazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenoxazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted tetrahydroquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted tetrahydroisoquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted pyrido[2,3-b]-1,4-oxazin-3(4H)-one.
  • R 5 is substituted or unsubstituted, branched or unbranched aliphatic. In certain embodiments, R 5 is C 1-6 alkyl. In certain embodiments, R 5 is —N(R E ) 2 , wherein R E is hydrogen or C 1-6 alkyl. In certain embodiments, R 5 is —(C 1-3 alkyl)-N(R E ) 2 , wherein R E is hydrogen or C 1-6 alkyl. In certain embodiments, R 5 is —C( ⁇ O)R E , wherein R E is hydrogen or C 1-6 alkyl. In certain embodiments, R 5 is —C( ⁇ O)OR E , wherein R E is hydrogen or C 1-6 alkyl.
  • R 5 is —C( ⁇ O)N(R E ) 2 , wherein R E is hydrogen or C 1-6 alkyl. In certain embodiments, R 5 is —SO 2 R E , wherein R E is hydrogen or C 1-6 alkyl. In certain embodiments, R 5 is —SO 2 NR E , wherein R E is hydrogen or C 1-6 alkyl.
  • R 1 is an optionally substituted heterocyclic moiety
  • R 4 is a substituted aliphatic moiety
  • the compound is of formula:
  • R 1 , and R 5 are as defined herein.
  • R 1 is an optionally substituted heterocyclic moiety and R 4 is a substituted aliphatic moiety
  • the compound is of formula:
  • R 1 and R E are as defined herein.
  • the present invention also provides compounds that include the 6-6-6-5 fused ring system, as shown in the formula:
  • the dashed line independently represents the presence or absence of a bond
  • X when X is present with a single bond, then X is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR y ; —C( ⁇ O)R y ; —CO 2 R y ; —CN; —SCN; —SR y ; —SOR y ; —SO 2 R y ; —NSO 2 R y ; —NO 2 ; —N 3 ; —NH(R y ); —N(R y ) 2 ; —
  • R y is independently selected from the group consisting of hydrogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl;
  • each occurrence of R 1 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C( ⁇ O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; ⁇ O; ⁇ N(R A ); ⁇ S; —N(R A ) 2 ; —NHC( ⁇ O)R A ; —
  • each occurrence of R 5 is independently selected from the group consisting of cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; —C( ⁇ O)R E ; —C( ⁇ O)OR E ; —C( ⁇ O)N(R E ) 2 ; —SO 2 R E ; —SO 2 NR E ; wherein each occurrence of R E is independently a hydrogen, a protecting group, a substituted or unsubstituted, branched or unbranched moiety selected from an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio
  • the dashed line is absent to form a single bond with X.
  • X when X is present with a single bond, then X is —OR y ; wherein R y is hydrogen or C 1-6 alkyl.
  • R y when X is present with a single bond, then X is —OH.
  • X when X is present with a single bond, then X is substituted or unsubstituted aliphatic. Exemplary aliphatic groups include hydrogen or C 1-6 alkyl.
  • X when X is present with a single bond, then X is —N(R y ) 2 .
  • R y groups include hydrogen to form X as —NH 2 , or methyl to form X as —NHCH 3 or —NH(CH 3 ) 2 .
  • X when X is present with a single bond, then X is a substituted or unsubstituted aryl.
  • the dashed line is present to form a double bond with X.
  • X when X is present with a double bond, then X is ⁇ O.
  • X when X is present with a double bond, then X is ⁇ S.
  • X when X is present with a double bond, then X is ⁇ NR y , wherein R y is hydrogen or C 1-6 alkyl.
  • R y when X is present with a double bond, then X is ⁇ N(OR y ), wherein R y is hydrogen or C 1-6 alkyl.
  • X when X is present with a double bond, then X is ⁇ NSO 2 R y , wherein R y is hydrogen or C 1-6 alkyl.
  • At least one R 1 is hydrogen. In certain embodiments, at least one R 1 is halogen. In certain embodiments, at least one R 1 is fluorine. In certain embodiments, at least one R 1 is substituted or unsubstituted aliphatic. In some embodiments, at least one R 1 is substituted or unsubstituted alkyl. In certain embodiments, at least one R 1 is C 1 -C 6 alkyl. In certain embodiments, at least one R 1 is methyl. In certain embodiments, at least one R 1 is ethyl. In certain embodiments, at least one R 1 is propyl. In certain embodiments, at least one R 1 is substituted or unsubstituted aryl.
  • At least one R 1 is substituted or unsubstituted phenyl. In certain embodiments, at least one R 1 is substituted phenyl. In certain embodiments, at least one R 1 is unsubstituted phenyl. In certain embodiments, at least one R 1 is substituted or unsubstituted naphthyl. In certain embodiments, at least one R 1 is substituted naphthyl. In certain embodiments, at least one R 1 is unsubstituted naphthyl. In certain embodiments, at least one R 1 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoquinolinyl.
  • At least one R 1 is substituted isoquinolinyl. In certain embodiments, at least one R 1 is unsubstituted isoquinolinyl. In certain embodiments, at least one R 1 is unsubstituted 5-isoquinolinyl. In certain embodiments, at least one R 1 is unsubstituted 6-isoquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoindolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted benzothienyl.
  • At least one R 1 is substituted or unsubstituted benzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted dibenzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted benzimidazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted benzthiazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoquinolyl.
  • At least one R 1 is substituted or unsubstituted cinnolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phthalazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinazolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinoxalinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted 4H-quinolizinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted carbazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted acridinyl.
  • At least one R 1 is substituted or unsubstituted phenazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenothiazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenoxazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted tetrahydroquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted tetrahydroisoquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted pyrido[2,3-b]-1,4-oxazin-3(4H)-one.
  • R 5 is substituted or unsubstituted, branched or unbranched aliphatic. In certain embodiments, R 5 is C 1-6 alkyl. In certain embodiments, R 5 is —N(R E ) 2 , wherein R E is hydrogen or C 1-6 alkyl. In certain embodiments, R 5 is alkyl)-N(R E ) 2 , wherein R E is hydrogen or C 1-6 alkyl. In certain embodiments, R 5 is —C( ⁇ O)R E , wherein R E is hydrogen or C 1-6 alkyl. In certain embodiments, R 5 is —C( ⁇ O)OR E , wherein R E is hydrogen or C 1-6 alkyl.
  • R 5 is —C( ⁇ O)N(R E ) 2 , wherein R E is hydrogen or C 1-6 alkyl. In certain embodiments, R 5 is —SO 2 R E , wherein R E is hydrogen or C 1-6 alkyl. In certain embodiments, R 5 is —SO 2 NR E , wherein R E is hydrogen or C 1-6 alkyl.
  • the compound is of formula:
  • the compound is of formula:
  • the compound when X is not present, the compound is of formula:
  • R 1 and R 5 are as defined herein.
  • the compound when X is not present, the compound is of formula:
  • R 1 and R E are as defined herein.
  • the present invention provides methods of preparing cortistatins A, J, K, L, and cortistatin analogs.
  • the present invention provides methods of synthesizing an inventive compound.
  • the present invention provides methods of synthesizing a cortistatin natural product (e.g., cortistatin A, cortistatin B, cortistatin C, cortistatin J, cortistatin K, cortistatin L, etc.).
  • a cortistatin natural product e.g., cortistatin A, cortistatin B, cortistatin C, cortistatin J, cortistatin K, cortistatin L, etc.
  • the synthetic methods described herein may be modified without departing from the scope of the present invention. For example, different starting materials and/or different reagents may be used in the inventive synthetic methods.
  • the inventive compounds are prepared via a route that goes through the epoxide depicted below (see exemplary Route I or Route II as described below), followed by conversion to Intermediate 2.
  • Intermediate 2 is then converted to cortistatin A or a cortistatin analog.
  • the present invention provides a process for preparing intermediate 2 according to the steps depicted in the scheme above.
  • R 1 , R 2 , R 3 , R 4 , and R D are as defined herein.
  • a compound of formula 12 is cyclized under suitable conditions in the presence of an olefin metathesis catalyst to form a compound of formula 13.
  • the olefin metathesis catalyst is a Grubbs catalyst.
  • the olefin metathesis catalyst is a Grubbs III catalyst.
  • the catalyst is a ruthenium-based catalyst. In certain embodiments, approximately 5 mol % of the catalyst is used. In certain embodiments, approximately 10 mol % of the catalyst is used.
  • the ring closing metathesis reaction is performed in a suitable solvent.
  • the suitable solvent is a hydrocarbon solvent.
  • toluene is used as the solvent.
  • a compound of formula 13 is reduced using a suitable reducing agent to form a compound of formula 14.
  • a suitable reducing agent for example, reduction of the double bond is achieved by catalytic reduction with Pd(OH) 2 under a hydrogen atmosphere.
  • Pd(OH) 2 under a hydrogen atmosphere.
  • Other suitable reductive conditions may also be used.
  • the reduction step may be performed using other methods known to one of ordinary skill in the art.
  • the compound of formula 14 is deoxygenated under suitable conditions to form an alkene as shown in the scheme above.
  • the suitable conditions include the presence of HC(OEt) 3 .
  • the deoxygenation step is done in the presence of a suitable solvent.
  • the solvent is a halogenated hydrocarbon solvent.
  • the halogenated hydrocarbon solvent is 1,2-dichlorobenzene.
  • the deoxygenation step is performed in the presence of an organic acid.
  • the organic acid is acetic acid.
  • the alkene is epoxidized under suitable conditions to form an epoxide.
  • the epoxidizing agent is a peroxycarboxylic acid.
  • the epoxidizing agent is meta-chloroperoxybenzoic acid (mCPBA).
  • the epoxidizing agent is DMDO.
  • Other epoxidizing reagents may also be used.
  • a compound of formula X wherein R 4 is a suitably protected hydroxyl group, is deprotected to form a compound 20.
  • the protecting group of R 4 can be exchanged with a different protecting group prior to deprotection and the epoxide ring opening to form compound 20.
  • the protecting group is a silyl protecting group.
  • the suitable protecting group is triisopropylsilyl (to form a TIPSO group).
  • the deprotecting agent is a suitable quaternary ammonium salt.
  • the deprotecting agent is TBAF.
  • a compound of formula 20 is cyclized under suitable conditions in the presence of a suitable Vargolis hypervalent iodine reagent, to form Intermediate 2.
  • the hypervalent iodine reagent is PhI(OCOCF 3 ) 2 .
  • the cyclizing step is typically done in the presence of a suitable solvent and a suitable buffer.
  • exemplary solvents include dichloromethane.
  • An exemplary buffer includes 2,6-lutidine.
  • the R D groups of formulae 12 and 13 optionally include a suitable oxygen protecting groups.
  • Suitable hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis , T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • Exemplary R D groups of formulae 12 and 13 include benzyl, TIPS, TBS, PMB, TES, and the like.
  • the present invention provides a process for preparing compound 2 according to the steps depicted in the scheme above.
  • a compound of formula i is coupled to a compound of formula II in the presence of an appropriate coupling reagent to form a compound of formula iii.
  • the coupling reagent is a palladium-containing coupling reagent.
  • the coupling reagent is Pd 2 dba 3 .
  • the coupling step is typically performed in the presence of a suitable organophosphorous compound.
  • An exemplary organophosphorus compound is S-Phos.
  • the coupling reaction is typically performed in a suitable solvent.
  • the suitable solvent is a mixture of polar, aprotic solvents.
  • the polar, aprotic solvents include NMP and THF.
  • the compound of formula iii is cyclized under suitable conditions in the presence of an olefin metathesis catalyst to form a compound of formula iv.
  • the olefin metathesis catalyst is a Grubbs III catalyst. In certain embodiments, approximately 5 mol % of the catalyst is used. In certain embodiments, approximately 10 mol % of the catalyst is used. In certain embodiments, approximately 15 mol % of the catalyst is used.
  • the cyclization reaction is done in a suitable solvent.
  • the solvent is a hydrocarbon solvent. Exemplary solvents include toluene.
  • the compound of formula iv is epoxidized under suitable conditions in the presence of a suitable oxidizing agent to form an epoxide-containing compound of formula v.
  • the oxidizing agent is a peroxycarboxylic acid.
  • the oxidizing agent is meta-chloroperoxybenzoic acid (mCPBA).
  • the oxidizing agent is DMDO.
  • the compound of formula v is reduced using a suitable reducing agent to form a compound of formula Y, followed by the removal of the R 4 protecting group of formula Y using a suitable deprotecting agent to afford the compound of formula 20.
  • the reduction of the double bond of compound v is achieved using Pd/BaSO 4 and hydrogen in a suitable solvent.
  • An exemplary solvent is ethyl acetate.
  • the reduction of the double bond is achieved using nBSH in the presence of N(Et 3 ) in a suitable solvent.
  • An exemplary solvent is DCM.
  • the protecting group is a silyl protecting group.
  • the protecting group is a triisopropylsilyl protecting group.
  • the deprotecting agent is a suitable quaternary ammonium salt.
  • the deprotecting agent is TBAF.
  • a compound of formula 20 is cyclized under suitable conditions in the presence of a suitable Vargolis hypervalent iodine reagent, to form Intermediate 2.
  • the hypervalent iodine reagent is PhI(OCOCF 3 ) 2 .
  • the cyclizing step is typically done in the presence of a suitable solvent and a suitable buffer.
  • exemplary solvents include dichloromethane.
  • An exemplary buffer includes 2,6-lutidine.
  • the R D group of formulae 12 and 13 is a suitable hydroxyl protecting group.
  • Suitable hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis , T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • Exemplary R D groups of formulae 12 and 13 include benzyl, TIPS, TBS, PMB, TES, Tf, and the like.
  • the present invention provides a process for preparing cortistatins, including cortistatin A, or analogs thereof, from intermediate 2 according to the steps depicted in the scheme above.
  • Cyclohexyldienone 2 is initially subjected to a Michael addition of hydride, and the intermediate is quenched by an electrophilic halogen source as depicted above.
  • Reduction of the ketone and protection of the resulting alcohol yields diene 36.
  • reduction is accomplished with tributoxylithium aluminum hydride.
  • Allylic oxidation yields epoxide 37.
  • oxidation is accomplished with dimethyldioxirane. Rearrangement yields alcohol 38.
  • Stereoselective S N 2 displacement of X is accomplished with azide.
  • Deprotection, reduction of azide 39 to the primary amine, and reductive amination to dimethylamine 40 is followed by protection of the hydroxyl groups to yield protected precursor 16, which can be converted to (+)-cortistatin A according to the methods described herein.
  • protection of the hydroxyl groups is accomplished with acetyl esters.
  • the present invention provides alternative processes for preparing cortistatins, including cortistatin A, or analogs thereof, from intermediate 2 according to the steps depicted in the scheme above.
  • R 1 , R 2 , R 3 , and PG are as defined herein.
  • cyclohexyldienone 2 is subjected to a transition metal-catalyzed Michael addition of hydride.
  • the transition metal catalyst is rhodium. Quenching a proposed enol intermediate with an electrophilic halogen source stereoselectively yields the ⁇ -halide product shown.
  • the electrophilic halogen source is N-bromosuccinimide (NBS).
  • S N 2 displacement of the ⁇ -halide substituent with azide and reduction of the ketone yield the azidohydroxydiene derivative shown.
  • S N 2 displacement is accomplished with tetramethylguanidinium azide (TMGA).
  • reduction is accomplished by hydroboration.
  • An electrophilic reagent in alcohol solvent stereoselectively adds alkoxide and an electrophile (X) across the diene functionality.
  • the electrophilic reagent is NBS.
  • the solvent is an alcohol (e.g., methanol, ethanol, or propanol).
  • S N 2 displacement of substituent X yields the diol shown which is subsequently converted to the corresponding diene under acidic conditions.
  • S N 2 displacement is accomplished with Crown ether and potassium superoxide in polar aprotic solvent.
  • the diol functionality is protected before an oxidation sequence yields the corresponding cyclopentanone structure shown above.
  • oxidation is accomplished with Dess-Martin periodinane.
  • Stereoselective 1,2-addition of 7-lithioisoquinoline to the cyclopentanone results in the tertiary alcohol shown, which is reduced with inversion of configuration.
  • reduction is accomplished with tributyltin hydride and AIBN. Deprotection of the diol functionality furnishes cortistatin A.
  • the present invention provides another process for preparing cortistatin analogs and isomers, including cortistatin J, from intermediate 2 according to the steps depicted in the scheme above.
  • intermediate 2 is converted to a hydroxyazide intermediate.
  • Reductive amination of the hydroxyazide intermediate, followed by dehydration under acidic conditions yield the dimethylaminotriene shown above.
  • dehydration is accomplished with a strong acid, such as concentrated HCl, in an organic solvent, such as chloroform.
  • Oxidation to the corresponding cyclopentanone is accomplished with reagents such as the Dess-Martin periodinane.
  • the present invention also provides yet another approach for preparing cortistatin A and analogs thereof as depicted below.
  • the present invention provides a process for preparing cortistatin A and various cortistatin analogs according to the steps depicted in the cheme above.
  • R 1 , R 2 , R 4 , m, and n are as defined herein.
  • a compound of formula vii is converted under suitable conditions in the presence of a fluoride source to form a compound of formula viii.
  • a fluoride source may be used.
  • the fluoride source is TBAF.
  • the fluoride source is TASF.
  • the compound of formula viii is cross-coupled under suitable coupling conditions to form a compound of formula ix.
  • the suitable conditions include a catalyzed cross-coupling reaction using a suitable ester.
  • an exemplary catalyst comprises palladium.
  • the suitable ester includes suitable ethenyl esters.
  • the suitable ethenyl ester is vinyl boronic ester.
  • the compound of formula ix is modified to form a compound of formula x, which is then cyclized, followed by a transannular etherification reaction to form a compound of formula xi.
  • the cyclization is performed in the presence of a suitable Lewis acid, a suitable amine, and a suitable solvent.
  • the suitable Lewis acid is zinc bromide.
  • the suitable amine is dimethylamine.
  • the suitable solvent is a polar, aprotic solvents.
  • the polar, aprotic solvent includes acetonitrile.
  • the compound of formula xi is converted to a compound of formula xii under suitable conditions.
  • the suitable conditions include deprotection, followed by oxidation, deacetylation, hydrazone formation, conversion to an appropriate iodide compound, and Stille cross-coupling with an appropriate isoquinolinyl compound.
  • the oxidation is performed in the presences of a suitable oxidizing agent.
  • the oxidizing agent is TPAP/NMO.
  • the invention provides a process for preparing a compound of the formula:
  • each occurrence of R 1 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C( ⁇ O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; ⁇ O; ⁇ N(R A ); ⁇ S; —N(R A ) 2 ; —NHC( ⁇ O)R A ; —
  • R 2 is hydrogen or C 1 -C 6 aliphatic
  • R 3 is hydrogen or C 1 -C 6 aliphatic
  • each occurrence of R 4 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR D ; —C( ⁇ O)R D ; —CO 2 R D ; —CN; —SCN; —SR D ; —SOR D ; —SO 2 R D ; —NO 2 ; —N 3 ; —N(R D ) 2 ; —NHC( ⁇ O)R D ; —NR A C( ⁇ O)N(R D ) 2 ;
  • the invention provides a process for preparing a compound of formula:
  • the present invention is directed to a process for preparing a compound of formula:
  • each occurrence of R 1 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C( ⁇ O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; ⁇ O; ⁇ N(R A ); ⁇ S; —N(R A ) 2 ; —NHC( ⁇ O)R A ; —
  • R 2 is hydrogen or C 1 -C 6 aliphatic
  • R 3 is hydrogen or C 1 -C 6 aliphatic
  • each occurrence of R 4 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR D ; —C( ⁇ O)R D ; —CO 2 R D ; —CN; —SCN; —SR D ; —SOR D ; —SO 2 R D ; —NO 2 ; —N 3 ; —N(R D ) 2 ; —NHC( ⁇ O)R D ; —NR A C( ⁇ O)N(R D ) 2 ;
  • the invention provides a process for preparing a compound of formula:
  • each occurrence of R 1 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C( ⁇ O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; ⁇ O; ⁇ N(R A ); ⁇ S; —N(R A ) 2 ; —NHC( ⁇ O)R A ; —
  • R 2 is hydrogen or C 1 -C 6 aliphatic
  • R 3 is hydrogen or C 1 -C 6 aliphatic
  • X is a halogen; and salts thereof.
  • the invention provides a process for preparing a compound of formula:
  • each occurrence of R 1 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C( ⁇ O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; ⁇ O; ⁇ N(R A ); ⁇ S; —N(R A ) 2 ; —NHC( ⁇ O)R A ; —
  • R 2 is hydrogen or C 1 -C 6 aliphatic
  • R 3 is hydrogen or C 1 -C 6 aliphatic
  • X is a halogen; and salts thereof.
  • the invention provides a process for preparing a compound of formula:
  • each occurrence of R 1 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C( ⁇ O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; ⁇ O; ⁇ N(R A ); ⁇ S; —N(R A ) 2 ; —NHC( ⁇ O)R A ; —
  • R 2 is hydrogen or C 1 -C 6 aliphatic
  • R 3 is hydrogen or C 1 -C 6 aliphatic
  • X is a halogen; and salts thereof.
  • the invention provides a process for preparing a compound of the formula:
  • the invention provides a process for preparing a compound of formula:
  • the present invention also provides intermediates useful in the synthesis of cortistatin A or analogs thereof.
  • the intermediates are useful in the synthetic approaches described herein.
  • the intermediates may also have biological activity (e.g. anti-angiogenic activity).
  • the present invention provides compounds of the formula:
  • each of the dashed lines independently represents the presence or absence of a bond
  • n is an integer between 0 and 6, inclusive
  • n is an integer between 0 and 4, inclusive;
  • each occurrence of R 1 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C( ⁇ O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; ⁇ O; ⁇ N(R A ); ⁇ S; —N(R A ) 2 ; —NHC( ⁇ O)R A ; —
  • R 2 is hydrogen or C 1 -C 6 aliphatic
  • R 3 is hydrogen or C 1 -C 6 aliphatic
  • each occurrence of R 4 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR D ; —C( ⁇ O)R D ; —CO 2 R D ; —CN; —SCN; —SR D ; —SOR D ; —SO 2 R D ; —NO 2 ; —N 3 ; —N(R D ) 2 ; —NHC( ⁇ O)R D ; —NR A C( ⁇ O)N(R D ) 2 ;
  • m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6.
  • n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4.
  • At least one R 1 is hydrogen. In certain embodiments, at least one R 1 is substituted or unsubstituted aliphatic. In some embodiments, at least one R 1 is substituted or unsubstituted alkyl. In certain embodiments, at least one R 1 is C 1 -C 6 alkyl. In certain embodiments, at least one R 1 is methyl. In certain embodiments, at least one R 1 is ethyl. In certain embodiments, at least one R 1 is propyl. In certain embodiments, at least one R 1 is substituted or unsubstituted aryl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenyl.
  • At least one R 1 is substituted phenyl. In certain embodiments, at least one R 1 is unsubstituted phenyl. In certain embodiments, at least one R 1 is substituted or unsubstituted naphthyl. In certain embodiments, at least one R 1 is substituted naphthyl. In certain embodiments, at least one R 1 is unsubstituted naphthyl. In certain embodiments, at least one R 1 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoquinolinyl. In certain embodiments, at least one R 1 is substituted isoquinolinyl.
  • At least one R 1 is unsubstituted isoquinolinyl. In certain embodiments, at least one R 1 is unsubstituted 5-isoquinolinyl. In certain embodiments, at least one R 1 is unsubstituted 6-isoquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl isoindolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl benzothienyl.
  • At least one R 1 is substituted or unsubstituted indolyl benzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl dibenzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl indazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl benzimidazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted benzthiazolyl.
  • At least one R 1 is substituted or unsubstituted quinolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoquinolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted cinnolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phthalazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinazolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinoxalinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted 4H-quinolizinyl.
  • At least one R 1 is substituted or unsubstituted carbazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted acridinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenothiazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenoxazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted tetrahydroquinolinyl.
  • At least one R 1 is substituted or unsubstituted tetrahydroisoquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted pyrido[2,3-b]-1,4-oxazin-3(4H)-one.
  • At least one R 1 is —OR A .
  • at least one R A is a protecting group.
  • the protecting group is an oxygen protecting group.
  • the oxygen protecting group is a silyl group.
  • Exemplary oxygen protecting groups include TBS, TMS, TES, TIPS, Ac, Bz and substituted or unsubstituted C 1 -C 6 alkyl, and others as described herein.
  • the oxygen protecting group is methyl.
  • the oxygen protecting group is ethyl.
  • the oxygen protecting group is propyl.
  • the oxygen protecting group is butyl.
  • the oxygen protecting group is pentyl.
  • the oxygen protecting group is hexyl.
  • R A is an alkylaryl group.
  • the alkylaryl group is a benzyl group.
  • the oxygen protecting group is TBS (tert-butyldimethylsilyl).
  • R 2 is hydrogen. In certain embodiments, R 2 is or C 1 -C 6 aliphatic. In some embodiments, R 2 is substituted or unsubstituted alkyl. In certain embodiments, R 2 is C 1 -C 6 alkyl. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is ethyl. In certain embodiments, R 2 is propyl. In certain embodiments, R 2 is butyl. In certain embodiments, R 2 is pentyl. In certain embodiments, R 2 is hexyl.
  • R 3 is hydrogen. In certain embodiments, R 3 is C 1 -C 6 aliphatic. In some embodiments, R 3 is substituted or unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 3 is unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is ethyl. In certain embodiments, R 3 is propyl. In certain embodiments, R 3 is butyl. In certain embodiments, R 3 is pentyl. In certain embodiments, R 3 is hexyl.
  • At least one R 4 is hydrogen. In certain embodiments, at least one R 4 is substituted or unsubstituted aliphatic. In some embodiments, at least one R 4 is substituted or unsubstituted alkyl. In certain embodiments, at least one R 4 is C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is methyl. In certain embodiments, at least one R 4 is ethyl. In certain embodiments, at least one R 4 is propyl. In certain embodiments, at least one R 4 is substituted alkyl. In certain embodiments, at least one R 4 is substituted C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is substituted C 1 -C 6 alkyl.
  • At least one R 4 is C 1 -C 6 alkyl substituted with an aryl group. In certain embodiments, at least one R 4 comprises biotin or a biotin derivative. In certain embodiments, at least one R 4 is a
  • At least one R 4 is a
  • At least one R 4 is a benzyl group. In certain embodiments, at least one R 4 is —OR D wherein each R D is hydrogen. In certain embodiments, at least one R 4 is —OR D wherein R D is C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is —OR D wherein R D is methyl. In certain embodiments, at least one R 4 is —OR D wherein R D is ethyl. In certain embodiments, at least one R 4 is —OR D wherein R D is propyl.
  • At least one R 4 is —N(R D ) 2 wherein each R D is hydrogen or C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is methyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is ethyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is propyl.
  • At least one R 4 is —N(R D ) 2 wherein each R D is butyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is pentyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is hexyl.
  • any two combinations of the above (R 4 ) n substituents may concurrently be present on the same ring, or any three combinations of the above (R 4 ) n substituents may concurrently be present on the same ring.
  • At least one R 4 is —OR D .
  • at least one R D is a protecting group.
  • the protecting group is an oxygen protecting group.
  • the oxygen protecting group is a silyl group.
  • Exemplary oxygen protecting groups include TBS, TMS, TES, TIPS, Ac, Bz and substituted or unsubstituted C 1 -C 6 alkyl, and others as described herein.
  • the oxygen protecting group is methyl.
  • the oxygen protecting group is ethyl.
  • the oxygen protecting group is propyl.
  • the oxygen protecting group is butyl.
  • the oxygen protecting group is pentyl.
  • the oxygen protecting group is hexyl.
  • R D is an alkylaryl group.
  • the alkylaryl group is a benzyl group.
  • the oxygen protecting group is triisopropylsilyl (TIPS).
  • the compound is of formula:
  • the compound is of formula:
  • the compound is of formula:
  • the compound is of formula:
  • the compound is of formula:
  • the compound is of formula:
  • the compound is of formula:
  • the compound is of formula:
  • the present invention provides compounds of the formula:
  • the dashed line represents the presence or absence of a bond
  • n is an integer between 0 and 6, inclusive
  • each occurrence of R 1 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C( ⁇ O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; ⁇ O; ⁇ N(R A ); ⁇ S; —N(R A ) 2 ; —NHC( ⁇ O)R A ; —
  • R 2 is hydrogen or C 1 -C 6 aliphatic
  • R 3 is hydrogen or C 1 -C 6 aliphatic; and salts thereof.
  • m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6.
  • At least one R 1 is hydrogen. In certain embodiments, at least one R 1 is substituted or unsubstituted aliphatic. In some embodiments, at least one R 1 is substituted or unsubstituted alkyl. In certain embodiments, at least one R 1 is C 1 -C 6 alkyl. In certain embodiments, at least one R 1 is methyl. In certain embodiments, at least one R 1 is ethyl. In certain embodiments, at least one R 1 is propyl. In certain embodiments, at least one R 1 is substituted or unsubstituted aryl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenyl.
  • At least one R 1 is substituted phenyl. In certain embodiments, at least one R 1 is unsubstituted phenyl. In certain embodiments, at least one R 1 is substituted or unsubstituted naphthyl. In certain embodiments, at least one R 1 is substituted naphthyl. In certain embodiments, at least one R 1 is unsubstituted naphthyl. In certain embodiments, at least one R 1 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoquinolinyl. In certain embodiments, at least one R 1 is substituted isoquinolinyl.
  • At least one R 1 is unsubstituted isoquinolinyl. In certain embodiments, at least one R 1 is unsubstituted 5-isoquinolinyl. In certain embodiments, at least one R 1 is unsubstituted 6-isoquinolinyl.
  • At least one R 1 is substituted or unsubstituted indolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl isoindolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl benzothienyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl benzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl dibenzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl.
  • At least one R 1 is substituted or unsubstituted indolyl indazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl benzimidazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted benzthiazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoquinolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted cinnolinyl.
  • At least one R 1 is substituted or unsubstituted phthalazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinazolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinoxalinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted 4H-quinolizinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted carbazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted acridinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenazinyl.
  • At least one R 1 is substituted or unsubstituted phenothiazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenoxazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted tetrahydroquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted tetrahydroisoquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted pyrido[2,3-b]-4,4-oxazin-3(4H)-one.
  • At least one R 1 is —OR A .
  • at least one R A is a protecting group.
  • the protecting group is an oxygen protecting group.
  • the oxygen protecting group is a silyl group.
  • Exemplary oxygen protecting groups include TBS, TMS, TES, TIPS, Ac, Bz and substituted or unsubstituted C 1 -C 6 alkyl, and others as described herein.
  • the oxygen protecting group is methyl.
  • the oxygen protecting group is ethyl.
  • the oxygen protecting group is propyl.
  • the oxygen protecting group is butyl.
  • the oxygen protecting group is pentyl.
  • the oxygen protecting group is hexyl.
  • R A is an alkylaryl group.
  • the alkylaryl group is a benzyl group.
  • the oxygen protecting group is TBS (tert-butyldimethylsilyl).
  • R 2 is hydrogen. In certain embodiments, R 2 is or C 1 -C 6 aliphatic. In some embodiments, R 2 is substituted or unsubstituted alkyl. In certain embodiments, R 2 is C 1 -C 6 alkyl. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is ethyl. In certain embodiments, R 2 is propyl. In certain embodiments, R 2 is butyl. In certain embodiments, R 2 is pentyl. In certain embodiments, R 2 is hexyl.
  • R 3 is hydrogen. In certain embodiments, R 3 is C 1 -C 6 aliphatic. In some embodiments, R 3 is substituted or unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 3 is unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is ethyl. In certain embodiments, R 3 is propyl. In certain embodiments, R 3 is butyl. In certain embodiments, R 3 is pentyl. In certain embodiments, R 3 is hexyl.
  • the compound is of formula:
  • the compound is of formula:
  • the compound is of formula:
  • the present invention provides compounds of the formula:
  • n is an integer between 0 and 6, inclusive
  • n is an integer between 0 and 4, inclusive;
  • each occurrence of R 1 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C( ⁇ O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; ⁇ O; ⁇ N(R A ); ⁇ S; —N(R A ) 2 ; —NHC( ⁇ O)R A ; —
  • R 2 is hydrogen or C 1 -C 6 aliphatic
  • R 3 is hydrogen or C 1 -C 6 aliphatic
  • each occurrence of R 4 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR D ; —C( ⁇ O)R D ; —CO 2 R D ; —CN; —SCN; —SR D ; —SOR D ; —SO 2 R D ; —NO 2 ; —N 3 ; —N(R D ) 2 ; —NHC( ⁇ O)R D ; —NR A C( ⁇ O)N(R D ) 2 ;
  • m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6.
  • n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4.
  • At least one R 1 is hydrogen. In certain embodiments, at least one R 1 is substituted or unsubstituted aliphatic. In some embodiments, at least one R 1 is substituted or unsubstituted alkyl. In certain embodiments, at least one R 1 is C 1 -C 6 alkyl. In certain embodiments, at least one R 1 is methyl. In certain embodiments, at least one R 1 is ethyl. In certain embodiments, at least one R 1 is propyl. In certain embodiments, at least one R 1 is substituted or unsubstituted aryl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenyl.
  • At least one R 1 is substituted phenyl. In certain embodiments, at least one R 1 is unsubstituted phenyl. In certain embodiments, at least one R 1 is substituted or unsubstituted naphthyl. In certain embodiments, at least one R 1 is substituted naphthyl. In certain embodiments, at least one R 1 is unsubstituted naphthyl. In certain embodiments, at least one R 1 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoquinolinyl. In certain embodiments, at least one R 1 is substituted isoquinolinyl.
  • At least one R 1 is unsubstituted isoquinolinyl. In certain embodiments, at least one R 1 is unsubstituted 5-isoquinolinyl. In certain embodiments, at least one R 1 is unsubstituted 6-isoquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl isoindolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl benzothienyl.
  • At least one R 1 is substituted or unsubstituted indolyl benzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl dibenzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl indazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl benzimidazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted benzthiazolyl.
  • At least one R 1 is substituted or unsubstituted quinolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoquinolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted cinnolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phthalazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinazolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinoxalinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted 4H-quinolizinyl.
  • At least one R 1 is substituted or unsubstituted carbazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted acridinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenothiazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenoxazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted tetrahydroquinolinyl.
  • At least one R 1 is substituted or unsubstituted tetrahydroisoquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted pyrido[2,3-b]-1,4-oxazin-3(4H)-one.
  • At least one R 1 is —OR A .
  • at least one R A is a protecting group.
  • the protecting group is an oxygen protecting group.
  • the oxygen protecting group is a silyl group.
  • Exemplary oxygen protecting groups include TBS, TMS, TES, TIPS, Ac, Bz and substituted or unsubstituted C 1 -C 6 alkyl, and others as described herein.
  • the oxygen protecting group is methyl.
  • the oxygen protecting group is ethyl.
  • the oxygen protecting group is propyl.
  • the oxygen protecting group is butyl.
  • the oxygen protecting group is pentyl.
  • the oxygen protecting group is hexyl.
  • R A is an alkylaryl group.
  • the alkylaryl group is a benzyl group.
  • the oxygen protecting group is TBS (tert-butyldimethylsilyl).
  • R 2 is hydrogen. In certain embodiments, R 2 is or C 1 -C 6 aliphatic. In some embodiments, R 2 is substituted or unsubstituted alkyl. In certain embodiments, R 2 is C 1 -C 6 alkyl. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is ethyl. In certain embodiments, R 2 is propyl. In certain embodiments, R 2 is butyl. In certain embodiments, R 2 is pentyl. In certain embodiments, R 2 is hexyl.
  • R 3 is hydrogen. In certain embodiments, R 3 is C 1 -C 6 aliphatic. In some embodiments, R 3 is substituted or unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 3 is unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is ethyl. In certain embodiments, R 3 is propyl. In certain embodiments, R 3 is butyl. In certain embodiments, R 3 is pentyl. In certain embodiments, R 3 is hexyl.
  • R 4 is hydrogen. In certain embodiments, at least one R 4 is substituted or unsubstituted aliphatic. In some embodiments, at least one R 4 is substituted or unsubstituted alkyl. In certain embodiments, at least one R 4 is C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is methyl. In certain embodiments, at least one R 4 is ethyl. In certain embodiments, at least one R 4 is propyl. In certain embodiments, at least one R 4 is substituted alkyl. In certain embodiments, at least one R 4 is substituted C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is substituted C 1 -C 6 alkyl. In certain embodiments, at least one R 4 comprises biotin or a biotin derivative. In certain embodiments, at least one R 4 is a
  • At least one R 4 is a
  • At least one R 4 is C 1 -C 6 alkyl substituted with an aryl group. In certain embodiments, at least one R 4 is a benzyl group. In certain embodiments, at least one R 4 is —OR D wherein R D is hydrogen. In certain embodiments, at least one R 4 is —OR D wherein R D is C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is —OR D wherein R D is methyl. In certain embodiments, at least one R 4 is —OR D wherein R D is ethyl. In certain embodiments, at least one R 4 is —OR D wherein R D is propyl.
  • At least one R 4 is —N(R D ) 2 wherein each R D is hydrogen or C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is methyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is ethyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is propyl.
  • At least one R 4 is e —N(R D ) 2 wherein each R D is butyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is pentyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is hexyl.
  • any two combinations of the above (R 4 ) n substituents may concurrently be present on the same ring, or any three combinations of the above (R 4 ) n substituents may concurrently be present on the same ring.
  • At least one R 4 is —OR D .
  • at least one R D is a protecting group.
  • the protecting group is an oxygen protecting group.
  • the oxygen protecting group is a silyl group.
  • Exemplary oxygen protecting groups include TBS, TMS, TES, TIPS, Ac, Bz and substituted or unsubstituted C 1 -C 6 alkyl, and others as described herein.
  • the oxygen protecting group is methyl.
  • the oxygen protecting group is ethyl.
  • the oxygen protecting group is propyl.
  • the oxygen protecting group is butyl.
  • the oxygen protecting group is pentyl.
  • the oxygen protecting group is hexyl.
  • R D is an alkylaryl group.
  • the alkylaryl group is a benzyl group.
  • the oxygen protecting group is triisopropylsilyl (TIPS).
  • the compound is of formula:
  • the compound is of formula:
  • the compound is of formula:
  • the compound is of formula:
  • the compound is of formula:
  • the present invention provides compounds of the formula:
  • n is an integer between 0 and 6, inclusive
  • n is an integer between 0 and 4, inclusive;
  • each occurrence of R 1 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C( ⁇ O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; ⁇ O; ⁇ N(R D ); ⁇ S; —N(R A ) 2 ; —NHC( ⁇ O)R A ; —
  • R 2 is hydrogen or C 1 -C 6 aliphatic
  • R 3 is hydrogen or C 1 -C 6 aliphatic
  • each occurrence of R 4 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR D ; —C( ⁇ O)R D ; —CO 2 R D ; —CN; —SCN; —SR D ; —SOR D ; —SO 2 R D ; —NO 2 ; —N 3 ; —N(R D ) 2 ; —NHC( ⁇ O)R D ; —NR A C( ⁇ O)N(R D ) 2 ;
  • m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6.
  • n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4.
  • R 1 is hydrogen. In certain embodiments, R 1 is substituted or unsubstituted aliphatic. In some embodiments, R 1 is substituted or unsubstituted alkyl. In certain embodiments, R 1 is C 1 -C 6 alkyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl. In certain embodiments, R 1 is propyl. In certain embodiments, R 1 is substituted or unsubstituted aryl. In certain embodiments, R 1 is substituted or unsubstituted phenyl. In certain embodiments, R 1 is substituted phenyl. In certain embodiments, R 1 is unsubstituted phenyl.
  • R 1 is substituted or unsubstituted naphthyl. In certain embodiments, R 1 is substituted naphthyl. In certain embodiments, R 1 is unsubstituted naphthyl. In certain embodiments, R 1 is substituted or unsubstituted heteroaryl. In certain embodiments, R 1 is substituted or unsubstituted isoquinolinyl. In certain embodiments, R 1 is substituted isoquinolinyl. In certain embodiments, R 1 is unsubstituted isoquinolinyl. In certain embodiments, R 1 is unsubstituted 5-isoquinolinyl. In certain embodiments, R 1 is unsubstituted 6-isoquinolinyl.
  • At least one R 1 is substituted or unsubstituted indolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl isoindolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl benzothienyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl benzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl dibenzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl.
  • At least one R 1 is substituted or unsubstituted indolyl indazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl benzimidazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted benzthiazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoquinolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted cinnolinyl.
  • At least one R 1 is substituted or unsubstituted phthalazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinazolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinoxalinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted 4H-quinolizinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted carbazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted acridinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenazinyl.
  • At least one R 1 is substituted or unsubstituted phenothiazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenoxazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted tetrahydroquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted tetrahydroisoquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted pyrido[2,3-b]-1,4-oxazin-3(4H)-one. In certain embodiments, R 1 is not isoquinoline.
  • At least one R 1 is —OR A .
  • at least one R A is a protecting group.
  • the protecting group is an oxygen protecting group.
  • the oxygen protecting group is a silyl group.
  • Exemplary oxygen protecting groups include TBS, TMS, TES, TIPS, Ac, Bz and substituted or unsubstituted C 1 -C 6 alkyl, and others as described herein.
  • the oxygen protecting group is methyl.
  • the oxygen protecting group is ethyl.
  • the oxygen protecting group is propyl.
  • the oxygen protecting group is butyl.
  • the oxygen protecting group is pentyl.
  • the oxygen protecting group is hexyl.
  • R A is an alkylaryl group.
  • the alkylaryl group is a benzyl group.
  • the oxygen protecting group is TBS (tert-butyldimethylsilyl).
  • R 2 is hydrogen. In certain embodiments, R 2 is or C 1 -C 6 aliphatic. In some embodiments, R 2 is substituted or unsubstituted alkyl. In certain embodiments, R 2 is C 1 -C 6 alkyl. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is ethyl. In certain embodiments, R 2 is propyl. In certain embodiments, R 2 is butyl. In certain embodiments, R 2 is pentyl. In certain embodiments, R 2 is hexyl.
  • R 3 is hydrogen. In certain embodiments, R 3 is C 1 -C 6 aliphatic. In some embodiments, R 3 is substituted or unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 3 is unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is ethyl. In certain embodiments, R 3 is propyl. In certain embodiments, R 3 is butyl. In certain embodiments, R 3 is pentyl. In certain embodiments, R 3 is hexyl.
  • R 4 is hydrogen. In certain embodiments, at least one R 4 is substituted or unsubstituted aliphatic. In some embodiments, at least one R 4 is substituted or unsubstituted alkyl. In certain embodiments, at least one R 4 is C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is methyl. In certain embodiments, at least one R 4 is ethyl. In certain embodiments, at least one R 4 is propyl. In certain embodiments, at least one R 4 is substituted alkyl. In certain embodiments, at least one R 4 is substituted C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is substituted C 1 -C 6 alkyl.
  • At least one R 4 is C 1 -C 6 alkyl substituted with an aryl group. In certain embodiments, at least one R 4 comprises biotin or a biotin derivative. In certain embodiments, at least one R 4 is a
  • At least one R 4 is a
  • At least one R 4 is a benzyl group. In certain embodiments, at least one R 4 is —OR D wherein each R D is hydrogen. In certain embodiments, at least one R 4 is —OR D wherein each R D is C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is —OR D wherein each R D is methyl. In certain embodiments, at least one R 4 is —OR D wherein each R D is ethyl. In certain embodiments, at least one R 4 is —OR D wherein each R D is propyl.
  • At least one R 4 is —N(R D ) 2 wherein each R D is hydrogen or C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is methyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is ethyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is propyl.
  • At least one R 4 is —N(R D ) 2 wherein each R D is butyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is pentyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is hexyl.
  • any two combinations of the above (R 4 ) n substituents may concurrently be present on the same ring, or any three combinations of the above (R 4 ) n substituents may concurrently be present on the same ring.
  • R 4 is —OR D .
  • R D is an acyl moiety.
  • the acyl moiety is a C 1 -C 3 acyl moiety.
  • the acyl moiety is —C( ⁇ O)CH 3 .
  • the acyl moiety is —C( ⁇ O)CH 2 CH 3 .
  • the acyl moiety is —C( ⁇ O)CH 2 CH 2 CH 3 .
  • the compound is of formula:
  • the compound is of formula:
  • the present invention provides compounds of the formula:
  • the dashed line represents the presence or absence of a bond
  • n is an integer between 0 and 6, inclusive
  • n is an integer between 0 and 4, inclusive;
  • each occurrence of R 1 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C( ⁇ O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; ⁇ O; ⁇ N(R A ); ⁇ S; —N(R A ) 2 ; —NHC( ⁇ O)R A ; —
  • R 2 is hydrogen or C 1 -C 6 aliphatic
  • R 3 is hydrogen or C 1 -C 6 aliphatic
  • each occurrence of R 4 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR D ; —C( ⁇ O)R D ; —CO 2 R D ; —CN; —SCN; —SR D ; —SOR D ; —SO 2 R D ; —NO 2 ; —N 3 ; —N(R D ) 2 ; —NHC( ⁇ O)R D ; —NR A C( ⁇ O)N(R D ) 2 ;
  • m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6.
  • n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4.
  • R 1 is hydrogen. In certain embodiments, R 1 is substituted or unsubstituted aliphatic. In some embodiments, R 1 is substituted or unsubstituted alkyl. In certain embodiments, R 1 is C 1 -C 6 alkyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl. In certain embodiments, R 1 is propyl. In certain embodiments, R 1 is substituted or unsubstituted aryl. In certain embodiments, R 1 is substituted or unsubstituted phenyl. In certain embodiments, R 1 is substituted phenyl. In certain embodiments, R 1 is unsubstituted phenyl.
  • R 1 is substituted or unsubstituted naphthyl. In certain embodiments, R 1 is substituted naphthyl. In certain embodiments, R 1 is unsubstituted naphthyl. In certain embodiments, R 1 is substituted or unsubstituted heteroaryl. In certain embodiments, R 1 is substituted or unsubstituted isoquinolinyl. In certain embodiments, R 1 is substituted isoquinolinyl. In certain embodiments, R 1 is unsubstituted isoquinolinyl. In certain embodiments, R 1 is unsubstituted 5-isoquinolinyl. In certain embodiments, R 1 is unsubstituted 6-isoquinolinyl.
  • At least one R 1 is substituted or unsubstituted indolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl isoindolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl benzothienyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl benzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl dibenzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl.
  • At least one R 1 is substituted or unsubstituted indolyl indazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl benzimidazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted benzthiazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoquinolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted cinnolinyl.
  • At least one R 1 is substituted or unsubstituted phthalazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinazolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinoxalinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted 4H-quinolizinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted carbazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted acridinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenazinyl.
  • At least one R 1 is substituted or unsubstituted phenothiazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenoxazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted tetrahydroquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted tetrahydroisoquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted pyrido[2,3-b]-1,4-oxazin-3(4H)-one.
  • At least one R 1 is —OR A .
  • at least one R A is a protecting group.
  • the protecting group is an oxygen protecting group.
  • the oxygen protecting group is a silyl group.
  • Exemplary oxygen protecting groups include TBS, TMS, TES, TIPS, Ac, Bz and substituted or unsubstituted C 1 -C 6 alkyl, and others as described herein.
  • the oxygen protecting group is methyl.
  • the oxygen protecting group is ethyl.
  • the oxygen protecting group is propyl.
  • the oxygen protecting group is butyl.
  • the oxygen protecting group is pentyl.
  • the oxygen protecting group is hexyl.
  • R A is an alkylaryl group.
  • the alkylaryl group is a benzyl group.
  • the oxygen protecting group is TBS (tert-butyldimethylsilyl).
  • R 2 is hydrogen. In certain embodiments, R 2 is or C 1 -C 6 aliphatic. In some embodiments, R 2 is substituted or unsubstituted alkyl. In certain embodiments, R 2 is C 1 -C 6 alkyl. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is ethyl. In certain embodiments, R 2 is propyl. In certain embodiments, R 2 is butyl. In certain embodiments, R 2 is pentyl. In certain embodiments, R 2 is hexyl.
  • R 3 is hydrogen. In certain embodiments, R 3 is C 1 -C 6 aliphatic. In some embodiments, R 3 is substituted or unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 3 is unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is ethyl. In certain embodiments, R 3 is propyl. In certain embodiments, R 3 is butyl. In certain embodiments, R 3 is pentyl. In certain embodiments, R 3 is hexyl.
  • R 4 is hydrogen. In certain embodiments, at least one R 4 is substituted or unsubstituted aliphatic. In some embodiments, at least one R 4 is substituted or unsubstituted alkyl. In certain embodiments, at least one R 4 is C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is methyl. In certain embodiments, at least one R 4 is ethyl. In certain embodiments, at least one R 4 is propyl. In certain embodiments, at least one R 4 is substituted alkyl. In certain embodiments, at least one R 4 is substituted C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is substituted C 1 -C 6 alkyl.
  • At least one R 4 is C 1 -C 6 alkyl substituted with an aryl group. In certain embodiments, at least one R 4 comprises biotin or a biotin derivative. In certain embodiments, at least one R 4 is a
  • At least one R 4 is a
  • At least one R 4 is a benzyl group. In certain embodiments, at least one R 4 is —OR D wherein each R D is hydrogen. In certain embodiments, at least one R 4 is —OR D wherein each R D is C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is —OR D wherein each R D is methyl. In certain embodiments, at least one R 4 is —OR D wherein each R D is ethyl. In certain embodiments, at least one R 4 is —OR D wherein each R D is propyl.
  • At least one R 4 is —N(R D ) 2 wherein each R D is hydrogen or C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is methyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is ethyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is propyl.
  • At least one R 4 is —N(R D ) 2 wherein each R D is butyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is pentyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is hexyl.
  • any two combinations of the above (R a ) n substituents may concurrently be present on the same ring, or any three combinations of the above (R 4 ) n substituents may concurrently be present on the same ring.
  • R D is a protecting group.
  • the protecting group is an oxygen protecting group.
  • the oxygen protecting group is a silyl group.
  • Exemplary oxygen protecting groups include TBS, TMS, TES, TIPS, Ac, Bz and substituted or unsubstituted C 1 -C 6 alkyl, and others as described herein.
  • the oxygen protecting group is methyl.
  • the oxygen protecting group is ethyl.
  • the oxygen protecting group is propyl.
  • the oxygen protecting group is butyl.
  • the oxygen protecting group is pentyl.
  • the oxygen protecting group is hexyl.
  • R D is an alkylaryl group.
  • the alkylaryl group is a benzyl group.
  • the compound is of formula:
  • the compound is of formula:
  • the present invention provides compounds of the formula:
  • n is an integer between 0 and 6, inclusive
  • n is an integer between 0 and 4, inclusive;
  • each occurrence of R 1 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C( ⁇ O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; ⁇ O; ⁇ N(R A ); ⁇ S; —N(R A ) 2 ; —NHC( ⁇ O)R A ; —
  • R 2 is hydrogen or C 1 -C 6 aliphatic
  • R 3 is hydrogen or C 1 -C 6 aliphatic
  • each occurrence of R 4 is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR D ; —C( ⁇ O)R D ; —CO 2 R D ; —CN; —SCN; —SR D ; —SOR D ; —SO 2 R D ; —NO 2 ; —N 3 ; —N(R D ) 2 ; —NHC( ⁇ O)R D ; —NR A C( ⁇ O)N(R D ) 2 ;
  • m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6.
  • n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4.
  • R 1 is hydrogen. In certain embodiments, R 1 is substituted or unsubstituted aliphatic. In some embodiments, R 1 is substituted or unsubstituted alkyl. In certain embodiments, R 1 is C 1 -C 6 alkyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl. In certain embodiments, R 1 is propyl. In certain embodiments, R 1 is substituted or unsubstituted aryl. In certain embodiments, R 1 is substituted or unsubstituted phenyl. In certain embodiments, R 1 is substituted phenyl. In certain embodiments, R 1 is unsubstituted phenyl.
  • R 1 is substituted or unsubstituted naphthyl. In certain embodiments, R 1 is substituted naphthyl. In certain embodiments, R 1 is unsubstituted naphthyl. In certain embodiments, R 1 is substituted or unsubstituted heteroaryl. In certain embodiments, R 1 is substituted or unsubstituted isoquinolinyl. In certain embodiments, R 1 is substituted isoquinolinyl. In certain embodiments, R 1 is unsubstituted isoquinolinyl. In certain embodiments, R 1 is unsubstituted 5-isoquinolinyl. In certain embodiments, R 1 is unsubstituted 6-isoquinolinyl.
  • At least one R 1 is substituted or unsubstituted indolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl isoindolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl benzothienyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl benzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl dibenzofuranyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl.
  • At least one R 1 is substituted or unsubstituted indolyl indazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted indolyl benzimidazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted benzthiazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted isoquinolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted cinnolinyl.
  • At least one R 1 is substituted or unsubstituted phthalazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinazolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted quinoxalinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted 4H-quinolizinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted carbazolyl. In certain embodiments, at least one R 1 is substituted or unsubstituted acridinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenazinyl.
  • At least one R 1 is substituted or unsubstituted phenothiazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted phenoxazinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted tetrahydroquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted tetrahydroisoquinolinyl. In certain embodiments, at least one R 1 is substituted or unsubstituted pyrido[2,3-b]-1,4-oxazin-3(4H)-one.
  • At least one R 1 is —OR A .
  • at least one R A is a protecting group.
  • the protecting group is an oxygen protecting group.
  • the oxygen protecting group is a silyl group.
  • Exemplary oxygen protecting groups include TBS, TMS, TES, TIPS, Ac, Bz and substituted or unsubstituted C 1 -C 6 alkyl, and others as described herein.
  • the oxygen protecting group is methyl.
  • the oxygen protecting group is ethyl.
  • the oxygen protecting group is propyl.
  • the oxygen protecting group is butyl.
  • the oxygen protecting group is pentyl.
  • the oxygen protecting group is hexyl.
  • R A is an alkylaryl group.
  • the alkylaryl group is a benzyl group.
  • the oxygen protecting group is TBS (tert-butyldimethylsilyl).
  • R 2 is hydrogen. In certain embodiments, R 2 is or C 1 -C 6 aliphatic. In some embodiments, R 2 is substituted or unsubstituted alkyl. In certain embodiments, R 2 is C 1 -C 6 alkyl. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is ethyl. In certain embodiments, R 2 is propyl. In certain embodiments, R 2 is butyl. In certain embodiments, R 2 is pentyl. In certain embodiments, R 2 is hexyl.
  • R 3 is hydrogen. In certain embodiments, R 3 is C 1 -C 6 aliphatic. In some embodiments, R 3 is substituted or unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 3 is unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is ethyl. In certain embodiments, R 3 is propyl. In certain embodiments, R 3 is butyl. In certain embodiments, R 3 is pentyl. In certain embodiments, R 3 is hexyl.
  • R 4 is hydrogen. In certain embodiments, at least one R 4 is substituted or unsubstituted aliphatic. In some embodiments, at least one R 4 is substituted or unsubstituted alkyl. In certain embodiments, at least one R 4 is C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is methyl. In certain embodiments, at least one R 4 is ethyl. In certain embodiments, at least one R 4 is propyl. In certain embodiments, at least one R 4 is substituted alkyl. In certain embodiments, at least one R 4 is substituted C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is substituted C 1 -C 6 alkyl.
  • At least one R 4 is C 1 -C 6 alkyl substituted with an aryl group. In certain embodiments, at least one R 4 comprises biotin or a biotin derivative. In certain embodiments, at least one R 4 is a
  • At least one R 4 is a
  • At least one R 4 is a benzyl group. In certain embodiments, at least one R 4 is —OR D wherein each R D is hydrogen. In certain embodiments, at least one R 4 is —OR D wherein each R D is C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is —OR D wherein each R D is methyl. In certain embodiments, at least one R 4 is —OR D wherein each R D is ethyl. In certain embodiments, at least one R 4 is —OR D wherein each R D is propyl.
  • At least one R 4 is —N(R D ) 2 wherein each R D is hydrogen or C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is C 1 -C 6 alkyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is methyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is ethyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is propyl.
  • At least one R 4 is —N(R D ) 2 wherein each R D is butyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is pentyl. In certain embodiments, at least one R 4 is —N(R D ) 2 wherein each R D is hexyl.
  • any two combinations of the above (R 4 ) n substituents may concurrently be present on the same ring, or any three combinations of the above (R 4 ) n substituents may concurrently be present on the same ring.
  • At least one R 4 is —OR D .
  • at least one R D is a protecting group.
  • the protecting group is an oxygen protecting group.
  • the oxygen protecting group is a silyl group.
  • Exemplary oxygen protecting groups include TBS, TMS, TES, TIPS, Ac, Bz, and substituted or unsubstituted C 1 -C 6 alkyl, and others as described herein.
  • the oxygen protecting group is methyl.
  • the oxygen protecting group is ethyl.
  • the oxygen protecting group is propyl.
  • the oxygen protecting group is butyl.
  • the oxygen protecting group is pentyl.
  • the oxygen protecting group is hexyl.
  • R D is an alkylaryl group.
  • the alkylaryl group is a benzyl group.
  • the oxygen protecting group is triisopropylsilyl (TIPS).
  • the compound is of formula:
  • R 1 , R 2 , PG, and m are defined as described herein.
  • the compound is of formula:
  • R 1 , R 2 , PG, and m are defined as described herein.
  • the compound is of formula:
  • R 1 , R 2 , PG, X, and m are defined as described herein.
  • the compound is of formula:
  • R 1 , R 2 , PG, X, and m are defined as described herein.
  • the compound is of formula:
  • R 1 , R 2 , PG, X, and m are defined as described herein.
  • the compound is of formula:
  • R 1 , R 2 , PG, and m are defined as described herein.
  • the compound is of formula:
  • R 1 , R 2 , R 4 , PG, n, and m are defined as described herein.
  • the compound is of formula:
  • R 1 , R 2 , R 4 , PG, n, and m are defined as described herein.
  • a trimethylsilyl enol ether intermediate is thought to be formed upon exposure of 2 to trimethylsilyl triflate and 2,6-lutidine, and this intermediate undergoes selective oxidation at position 1 upon treatment with m-chloroperbenzoic acid. It is expected that the hydroxyl group will be introduced with the necessary ⁇ -diastereoselectivity, as the C 6 -C 7 carbon bridge should sterically shield the 13-face of the molecule.
  • the C3 amino group is introduced by enone reductive silylation and electrophilic amination (see Du Bois et al., Nitrogen Transfer from a Nitridomanganese(V) Complex: Amination of Silyl Enol Ethers. J. Am. Chem. Soc. 1996, 118, (4), 915-916) of the resulting silyl enol ether; we anticipate that this reaction may also be diastereoselective as a consequence of the C6-C7 carbon bridge. Reduction of the C2 ketone will be followed by several basic functional group manipulations leading to compound 23, which contains a C17 carbonyl group.
  • ketalization of 2 followed by deprotection and oxidation of the C17 silyl ether is proposed to provide ketone 24.
  • Subsequent enolization with lithium hexamethyldisilazide and trapping of the enolate as the corresponding enol triflate, followed by Suzuki cross-coupling, is proposed to introduce the isoquinoline in protected form.
  • the C17 olefin will be hydrogenated and the C1 and C3 oxidations carried out as previously described to provide intermediate 25.
  • Stereoselective reduction of the ketone and protection of the product alcohol is proposed to provide 26, which will be oxidized, deprotected, and then reductively aminated to furnish cortistatin A. See Williams et al., Isocyanide Addition to Pyridinium Salts. Efficient Entry into Substituted Nicotinonitrile Derivatives. Org. Lett. 2006, 8, (25), 5789-5792.
  • TMGA tetramethylguanidinium azide
  • Oxidation to the corresponding cyclopentanone is accomplished with the Dess-Martin periodinane.
  • Stereoselective 1,2-addition of 7-lithioisoquinoline to the cyclopentanone results in the tertiary alcohol shown, which is converted to the corresponding trifluoroacetate, and deoxygenated with inversion of configuration with tributyltin hydride and AIBN to furnish cortistatin J.
  • the synthesis of the epoxide begins with synthesizing the Exo-Methylene ketone 5 as shown in the scheme below.
  • Ketone 5 was converted to the phosphoniosilylated intermediate 6 also depicted in the Scheme below, (see Evans, D. A. et al., New silicon-phosphorus reagents in organic synthesis—carbonyl and conjugate addition-reactions of silicon phosphite esters and related systems. Journal of the American Chemical Society 1978, 100, (11), 3467-3477; and Kozikowski et al., Phosphoniosilylation—an efficient and practical method for the beta-functionalization of enones. Journal of Organic Chemistry 1986, 51, (17), 3400-3402) and this salt was exposed to n-butyllithium and then paraformaldehyde to achieve a one-carbon Wittig homologation reaction. Rubottom oxidation of silyl enol ether 7 and p-methoxybenzyl protection of the resulting tertiary alcohol 8 provided 4 in 32% overall yield.
  • the starting exo-methylene ketone 5 is converted to the silyl-protected dienol shown above upon treatment with triethylsilyltriflate and triphenylphosphine followed by the addition of n-butyllithium, then formaldehyde. Fluoride-mediated deprotection of the silyl ether is followed by reprotection to the corresponding trifluoromethanesulfonate 15 which undergoes palladium-catalyzed Negishi coupling with organozinc derivative 14 to yield the tricyclic derivative 13.
  • Intramolecular olefin metathesis of the terminal alkene units, regio- and stereoselective dimethyldioxirane-mediated epoxidation of the tetrasubstituted olefin, and rhodium-catalyzed reduction of the remaining disubstituted olefin yield the tetracyclic epoxide 24.
  • Regioselective deprotection with LiNEt 2 in THF yield tertiary alcohol 25.
  • Fluoride-mediated deprotection of the silyl ether and oxidation of the resulting phenol to cyclohexadienone 2 is mediated with by the Vargolis hypervalent organoiodine reagent and hexafluoro-2-propanol in THF/dimethylether.
  • Route D and Route E for the synthesis of analogs of cortistatin A.
  • This invention also provides pharmaceutical compositions comprising at least one of the compounds as described herein, or a pharmaceutically acceptable salt thereof.
  • the compound of the pharmaceutical composition inhibits angiogenesis.
  • Cortistatins have been found to exhibit extremely potent and selective cytostatic activity against human umbilical vein endothelial cells (HUVECs). Therefore, in an embodiment of the invention, cortistatin A and analogs thereof are useful in treating many types of cancer, benign tumors, diabetic retinopathy, rheumatoid arthritis, macular degeneration, atherosclerosis, obesity, and any other diseases or disorders associated with undesired angiogenesis.
  • the present invention provides novel compounds having anti-angiogenesis activity, and thus the compounds of the present invention provided in the pharmaceutical composition are useful for the treating or preventing any disease or condition associated with aberrant angiogenesis, including a variety of proliferative disorders, such as many types of cancer, benign neoplasms (i.e., tumors), diabetic retinopathy, rheumatoid arthritis, macular degeneration, obesity, and atherosclerosis.
  • Antiangiogenic compounds or compositions of the present invention are administered in therapetucially effective doses to a subject suffering from a proliferative disease.
  • the subject suffers from cancer.
  • the subject has a benign tumor.
  • compositions are provided, wherein these compositions comprise any one of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents, e.g., another anti-proliferative agent. In other embodiments, these compositions further comprise an anti-emetic agent, a pain reliever, a multi-vitamin, etc.
  • a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need thereof is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof, e.g., a prodrug.
  • the pharmaceutical compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences Fifteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1975) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof.
  • any conventional carrier medium is incompatible with the anti-cancer compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; Cremophor; Solutol; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other
  • the invention further provides a method of inhibiting tumor growth.
  • the method involves the administration of a therapeutically effective amount of the compound, a pharmaceutical composition, or a pharmaceutically acceptable form thereof to a subject, including, but not limited to, a human or other mammal (e.g., domesticated animals, cats, dogs, mice, rats). Any method of administration may be used to deliver the compound of pharmaceutical compositions to the animal.
  • the compound or pharmaceutical composition is administered orally. In other embodiments, the compound or pharmaceutical composition is administered parenterally.
  • the present invention provides a method of treating a condition associated with aberrant angiogenesis, comprising the step of administering a therapeutically effective amount of the compound, a pharmaceutical composition, or a pharmaceutically acceptable form thereof to a subject.
  • the compound or pharmaceutical composition containing the compound is of formula:
  • the compound or pharmaceutical composition containing the compound is of formula:
  • the compound is:
  • the compound or pharmaceutical composition containing the compound is of formula:
  • the compound or pharmaceutical composition containing the compound is of formula:
  • the present invention provides a method of treating a proliferative disease, comprising the step of administering a therapeutically effective amount of the compound, a pharmaceutical composition, or a pharmaceutically acceptable form thereof to a subject.
  • the compound or pharmaceutical composition containing the compound is of formula
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WO2017004411A1 (fr) * 2015-07-01 2017-01-05 President And Fellows Of Harvard College Analogues de la cortistatine, et synthèses et leurs utilisations
US20170029435A1 (en) * 2013-12-24 2017-02-02 President And Fellows Of Harvard College Cortistatin analogues and syntheses and uses thereof
US9714255B2 (en) 2008-08-28 2017-07-25 President And Fellows Of Harvard College Cortistatin analogues and syntheses thereof

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US10273264B2 (en) 2015-07-01 2019-04-30 President And Fellows Of Harvard College Cortistatin analogues and syntheses and uses thereof

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US9714255B2 (en) 2017-07-25
EP2334686A4 (fr) 2012-05-02
EP2334686A2 (fr) 2011-06-22
US20150376201A1 (en) 2015-12-31
WO2010024930A3 (fr) 2010-07-01
EP2334686B1 (fr) 2019-02-27
US20170320886A1 (en) 2017-11-09
US9127019B2 (en) 2015-09-08
US10202400B2 (en) 2019-02-12
US20150111921A1 (en) 2015-04-23
WO2010024930A2 (fr) 2010-03-04

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