WO2016077581A1 - Triazoles d'isostéviol et leurs utilisations - Google Patents

Triazoles d'isostéviol et leurs utilisations Download PDF

Info

Publication number
WO2016077581A1
WO2016077581A1 PCT/US2015/060372 US2015060372W WO2016077581A1 WO 2016077581 A1 WO2016077581 A1 WO 2016077581A1 US 2015060372 W US2015060372 W US 2015060372W WO 2016077581 A1 WO2016077581 A1 WO 2016077581A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
compound
certain embodiments
formula
hydrogen
Prior art date
Application number
PCT/US2015/060372
Other languages
English (en)
Inventor
Xin Qi
Ravil KHAYBULLIN
Paul Okunieff
Mei Zhang
Original Assignee
University Of Florida Research Foundation, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University Of Florida Research Foundation, Inc. filed Critical University Of Florida Research Foundation, Inc.
Publication of WO2016077581A1 publication Critical patent/WO2016077581A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • diterpenoids constitute an important class of secondary metabolites that are involved in numerous processes in bio-systems and exhibit considerable pharmacological activities.
  • diterpenoid isosteviol 1-1 (Figure 1) has become one of the most popular platforms for the design of novel pharmacological agents not only because of its remarkably broad spectrum of biological activities such as
  • isosteviol derivatives With its unique rigid skeletal structure with six stereo centers, isosteviol derivatives have been shown to have numerous biological activities, particularly in the anticancer area [14-19]. Therefore, isosteviol and its derivatives have been employed in the synthesis of diverse small-molecule libraries, and stereochemical approaches have been explored to connect heterocyclic ring systems to the isosteviol core. For example, a series of pyrazoline [19], pyrazole [19] and isoxazolidine [20] derivatives ( Figure 2) have been recently synthesized.
  • Diterpenoids represent an important class of secondary metabolites that are involved in numerous processes in bio-systems and exhibit various pharmacological activities.
  • Some of the published synthetic isosteviol derivatives exhibited several new biological activities. For example, dimer 2-1 as well as macrocyclic derivatives 3-1 exhibited tuberculostatic activity [23,24], and ammonium derivatives 4-1 demonstrated an inhibitory effect against acetylcholinesterase [25] ( Figure 1). Although some effective chemotherapeutic agents have been developed, they still possess high toxicity and are of relatively high cost. To overcome these challenges, isosteviol represents an attractive scaffold for cancer drug development. Indeed, recently published novel cytotoxic isosteviol derivatives starting from commercially available Stevia glycosides have shown promising results.
  • the present disclosure relates to the development of isosteviol derivatives for the treatment of proliferative disorders such as cancer.
  • the cancer is leukemia, lung cancer, pancreatic cancer, breast cancer, prostate cancer, colon cancer, or cervical cancer,
  • the present invention provides compounds of Formulae (I)-(VI), and
  • the present invention further provides methods of using the inventive compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof, to prevent and/or treat proliferative diseases, such as cancers (e.g., leukemia, lung cancer, pancreatic cancer, breast cancer, prostate cancer, colon cancer, or cervical cancer), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases in a subject.
  • cancers e.g., leukemia, lung cancer, pancreatic cancer, breast cancer, prostate cancer, colon cancer, or cervical cancer
  • benign neoplasms e.g., diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases in a subject.
  • the present invention provides compounds of Formula (I):
  • the present invention provides compounds of Formula (II):
  • R N1 , L 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 14 , and R 15 are as defined herein.
  • the present invention provides compounds of Formula (III):
  • R N1 , L 1 , R 2 , R 3 , R 4 , R 5 , and R 14 are as defined herein.
  • the present invention provides compounds of Formula (IV):
  • R N2 , R 2 , R 3 , R 4 , R 9 , and R 14 are as defined herein.
  • the present invention provides compounds of Formula (VI):
  • Exemplary compounds of Formulae (I)-(VI) include, but are not limited to:
  • the present invention also provides a method of preparing a compound of any one of Formulae (I)-(IV) comprising reacting an azido compound of the formula: R ⁇ -Na, with a compound of Formula (VII):
  • R 32 , R , R , R , R , R , L , and L are as define herein.
  • the present invention also provides a method of preparing a compound of any one of Formulae (I)-(V) comprising dehydroxylating a compound of Formula (Vlll-a):
  • R 2 , R 3 , R 4 , R 5 , R 9 , R 14 , and R A are as define herein.
  • the compound of Formula (IX-a) can be functionlized with any suitable organic transformation.
  • oxidation e.g. epoxidation
  • dihydroxylation e.g. halohydration
  • halogenation e.g. acetylation
  • dipolar cycloaddition e.g. cycloaddition
  • [2+2] cycloaddition e.g. cycloaddition
  • Diels-Alder reaction e.g. cycloaddition
  • carbene insertion e.g., addition, Diels-Alder reaction, or carbene insertion may be suitable transformations.
  • the method of preparing a compound of any one of Formulae (I)-(VI) further comprises oxidizing the compound of Formula (IX-a):
  • the oxidation provides a compound comprising an epoxide moiety or a salt thereof.
  • the the oxidation provides a compound of Formula (VI):
  • the oxidation provides a compound comprising an thiiranyl moiety or a salt thereof. In certain embodiments, the the oxidation provides a compound of the formula:
  • the present invention also provides pharmaceutical compositions comprising a compound of any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions described herein include a therapeutically effective amount of a compound of any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
  • the pharmaceutical composition may be useful for treating and/or preventing a proliferative disease such as cancer, benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.
  • the present invention provides methods for treating and/or preventing proliferative diseases.
  • proliferative diseases include cancer (e.g., leukemia, melanoma, multiple myeloma), benign neoplasm, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.
  • kits comprising a compound of any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.
  • the kits of the invention may include a single dose or multiple doses of a compound of any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.
  • kits may be useful for the treatment of proliferative diseases, inflammatory diseases, autoimmune diseases, autoinflammatory diseases, and metabolic diseases.
  • the kits described herein further include instructions for administering the compound of any one of Formulae (I)-(VI), or the pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or the pharmaceutical composition thereof.
  • the kits may also include packaging information describing the use or prescribing information for the subject or a health care professional. Such information may be required by a regulatory agency such as the U.S. Food and Drug Administration (FDA).
  • FDA U.S. Food and Drug Administration
  • the kit may also optionally include a device for administration of the compound or composition, for example, a syringe for parenteral administration.
  • a device for administration of the compound or composition for example, a syringe for parenteral administration.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • aliphatic refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.
  • heteroaliphatic refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C] 10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C] 9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C] 8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“Ci_ 7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C ⁇ alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“Ci_5 alkyl”).
  • an alkyl group has 1 to 4 carbon atoms ("C ⁇ alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“Ci_3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“Ci_ 2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“d alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”).
  • alkyl groups include methyl (d), ethyl (C 2 ), n- propyl (C3), isopropyl (C3), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n- pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 ).
  • alkyl groups include n-heptyl (C 7 ), n- octyl (C 8 ) and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents. In certain embodiments, the alkyl group is an unsubstituted Ci -1 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is a substituted C] lo alkyl.
  • heteroalkyl refers to an alkyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi lo alkyl").
  • a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroC] 9 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroC] 8 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC] 7 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC] 6 alkyl").
  • a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroCi 5 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms within the parent chain ("heteroC ⁇ alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain
  • heteroC 3 alkyl is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC] 2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC] alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 2 6 alkyl").
  • each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents.
  • the heteroalkyl group is an unsubstituted heteroC] 10 alkyl.
  • the heteroalkyl group is a substituted heteroC ⁇ o alkyl.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds).
  • an alkenyl group has 2 to 9 carbon atoms ("C 2 9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms ("C 2 8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms (“C 2 7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C 2 6 alkenyl”).
  • an alkenyl group has 2 to 5 carbon atoms ("C 2 5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2 - alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2 3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms ("C 2 alkenyl”).
  • the one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • C 2 ⁇ alkenyl groups examples include ethenyl (C 2 ), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2 -6 alkenyl groups include the aforementioned C 2 - alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a
  • substituted alkenyl with one or more substituents.
  • the alkenyl group is an unsubstituted C 2 10 alkenyl.
  • the alkenyl group is a substituted C 2 _ lo alkenyl.
  • heteroalkenyl refers to an alkenyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 lo alkenyl").
  • a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 9 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 _ 8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 7 alkenyl").
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 6 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2
  • heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms within the parent chain ("heteroC ⁇ alkenyl”).
  • a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 2 3 alkenyl”).
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2 6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is
  • the heteroalkenyl group is an unsubstituted heteroC 2 lo alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC ⁇ o alkenyl.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 2 lo alkynyl").
  • an alkynyl group has 2 to 9 carbon atoms ("C 2 9 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C 2 8 alkynyl”).
  • an alkynyl group has 2 to 7 carbon atoms (“C 2 7 alkynyl”).
  • an alkynyl group has 2 to 6 carbon atoms ("C 2 _6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2 _5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2 _ alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2 3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms ("C 2 alkynyl”).
  • the one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1- butynyl).
  • Examples of C 2 _ alkynyl groups include, without limitation, ethynyl (C 2 ), 1- propynyl (C3), 2-propynyl (C3), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • Examples of C 2 _6 alkenyl groups include the aforementioned C 2 _ alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like.
  • alkynyl examples include heptynyl (C 7 ), octynyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C 2 _ lo alkynyl. In certain embodiments, the alkynyl group is a substituted C 2 _ lo alkynyl.
  • heteroalkynyl refers to an alkynyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 lo alkynyl").
  • a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 9 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 8 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 7 alkynyl").
  • a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 6 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC 2 5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“heteroC ⁇ alkynyl").
  • a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain ("heteroC 2 3 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC 2 -6 alkynyl"). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC 2 ! o alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC ⁇ !o alkynyl.
  • carbocyclyl or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C 3 10 carbocyclyl") and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3 _ 8 carbocyclyl”).
  • a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3 _ 7 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3 6 carbocyclyl”).
  • a carbocyclyl group has 4 to 6 ring carbon atoms ("C ⁇ carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ("Cs ⁇ carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C5 lo carbocyclyl”).
  • Exemplary C 3 6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3 _ 8 carbocyclyl groups include, without limitation, the aforementioned C 3 6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3 lo carbocyclyl groups include, without limitation, the aforementioned C 3 8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C lo ), cyclodecenyl (C lo ), octahydro-lH-indenyl (C9), decahydronaphthalenyl (C lo ), spiro[4.5]decanyl (C lo ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3 _ lo carbocyclyl.
  • the carbocyclyl group is a substituted C 3 _ lo carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C 3 lo cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3 _ 8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3 _6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C ⁇ cycloalkyl").
  • a cycloalkyl group has 5 to 6 ring carbon atoms ("Cs ⁇ cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C ⁇ ! o cycloalkyl”). Examples of C5 6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ). Examples of C 3 6 cycloalkyl groups include the aforementioned C5 6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • C 3 8 cycloalkyl groups include the aforementioned C 3 _6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an
  • the cycloalkyl group is an unsubstituted C 3 lo cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C 3 lo cycloalkyl.
  • heterocyclyl or “heterocyclic” refers to a radical of a 3- to 14- membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon- carbon double or triple bonds.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl").
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,
  • Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl.
  • Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl,
  • decahydronaphthyridinyl decahydro-1 ,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, l,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro ⁇ H-furo[3,2-b]pyrrolyl, 6,7-dihydro- 5H-furo [3 ,2-b]pyranyl, 5,7-dihydro ⁇ lH-thieno [2,3-c]pyranyl, 2,3-dihydro-l H- pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("Ce-u aryl").
  • an aryl group has 6 ring carbon atoms ("C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms ("C 10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms ("C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents.
  • the aryl group is an unsubstituted 14 aryl.
  • the aryl group is a substituted C6-i 4 aryl.
  • heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-14 membered heteroaryl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl").
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl").
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl").
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents.
  • the heteroaryl group is an unsubstituted 5-14 membered heteroaryl.
  • the heteroaryl group is a substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5- membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • 6- membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,
  • Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.
  • alkylene is the divalent moiety of alkyl
  • alkenylene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynyl
  • carbocyclylene is the divalent moiety of carbocyclyl
  • heterocyclylene is the divalent moiety of heterocyclyl
  • arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are, in certain embodiments, optionally substituted.
  • Optionally substituted refers to a group which may be substituted or unsubstituted (e.g., "substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, "substituted” or “unsubstituted” heteroalkynyl, "substituted” or “unsubstituted” carbocyclyl, "substituted” or “unsubstituted” heterocyclyl, "substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group).
  • substituted or unsubstituted e
  • substituted means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
  • the present invention contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • halo refers to fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), or iodine (iodo, -I).
  • the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an "amino protecting group").
  • heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R M groups, and wherein R aa , R bb , R cc and R dd are as defined herein.
  • Nitrogen 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, incorporated herein by reference.
  • Nitrogen protecting groups such as carbamate groups include, but are not limited to, 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-(l 0, 10-dioxo-l 0, 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), l-(l-adamantyl)-l- methyl
  • Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, oluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl ⁇ l- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6- dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl- —
  • Ts oluenesulfonamide
  • Mtr 2,3,6,-trimethyl ⁇ l- methoxybenzenesulfonamide
  • Mtb 2,4,6-trimethoxybenzenesulfonamide
  • Pme 2,3,5,6-tetramethyl- —
  • methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy- -methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), ⁇ - trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide,
  • nitrogen protecting groups include, but are not limited to, phenothiazinyl-(lO)- acyl derivative, N '- oluenesulfonylaminoacyl derivative, N -phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl- 3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted 1 ,3-dibenzyl- l,3,5-triazacyclohexan
  • benzenesulfenamide o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro ⁇ l— methoxybenzenesulfenamide,
  • triphenylmethylsulfenamide triphenylmethylsulfenamide
  • 3-nitropyridinesulfenamide Npys
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an "hydroxyl protecting group").
  • Oxygen 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, incorporated herein by reference.
  • oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,
  • 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-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, l-[(2-chloro ⁇ l-methyl)phenyl] ⁇ l—
  • DPMS diphenylmethylsilyl
  • TMPS t-butylmethoxyphenylsilyl
  • dimethylphosphinothioyl dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).
  • amino acid refers to a molecule containing both an amino group and a carboxyl group.
  • Amino acids include alpha-amino acids and beta-amino acids, the structures of which are depicted below.
  • an amino acid is an alpha amino acid.
  • Suitable amino acids include, without limitation, natural alpha-amino acids such as D- and L-isomers of the 20 common naturally occurring alpha-amino acids found in peptides ⁇ e.g., A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V, as provided below), unnatural alpha-amino acids natural beta-amino acids (e.g., beta-alanine), and unnnatural beta-amino acids.
  • natural alpha-amino acids such as D- and L-isomers of the 20 common naturally occurring alpha-amino acids found in peptides ⁇ e.g., A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V, as provided below
  • unnatural alpha-amino acids natural beta-amino acids (e.g., beta-a
  • Exemplary natural alpha-amino acids include L-Alanine (A), L-Arginine (R), L-Asparagine (N), L-Aspartic acid (D), L-Cysteine (C), L-Glutamic acid (E), L- Glutamine (Q), Glycine (G), L-Histidine (H), L-Isoleucine (I), L-Leucine (L), L-Lysine (K), L-Methionine (M), L-Phenylalanine (F), L-Proline (P), L-Serine (S), L-Threonine (T), L-Tryptophan (W), L-Tyrosine (Y), and L- Valine (V).
  • A L-Alanine
  • R L-Arginine
  • N L-Asparagine
  • D L-Aspartic acid
  • C L-Cysteine
  • E L-Glutamic acid
  • Q L- Glutamine
  • G
  • Exemplary unnatural alpha-amino acids include D-Arginine, D-Asparagine, D-Aspartic acid, D-Cysteine, D-Glutamic acid, D-Glutamine, D-Histidine, D-Isoleucine, D-Leucine, D-Lysine, D-Methionine, D- Phenylalanine, D-Proline, D-Serine, D-Threonine, D-Tryptophan, D-Tyrosine, D-Valine, Di-vinyl, a-methyl-Alanine (Aib), a-methyl-Arginine, a-methyl-Asparagine, a-methyl- Aspartic acid, a-methyl-Cysteine, a-methyl-Glutamic acid, a-methyl-Glutamine, a-methyl- Histidine, a-methyl-Isoleucine, a-methyl-Leucine, a-methyl-Lysine,
  • the term "acid” refers to a chemical substance that dissociates in aqueous solution to give H + .
  • the acids include, but are not limited to, l-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4- acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glu
  • salt refers to ionic compounds that result from the neutralization reaction of an acid and a base.
  • a salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge).
  • Salts of the compounds of this invention include those derived from inorganic and organic acids and bases.
  • 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 known in the art such as ion exchange.
  • Other 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, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate,/>-toluenesulfonate, undecanoate, valerate salts, and the like.
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁇ C alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • the term "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 ah, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • 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 known 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 known 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, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate,/>-toluenesulfonate, undecanoate, valerate salts, and the like.
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁇ C ⁇ t alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate, and aryl sulfonate.
  • solvate refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
  • Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds of Formulae (I)-(VI) may be prepared, e.g., in crystalline form, and may be solvated.
  • Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates.
  • the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
  • “Solvate” encompasses both solution-phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound which is associated with water.
  • the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R x H 2 0, wherein R is the compound, and x is a number greater than 0.
  • a given compound may form more than one type of hydrates, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R-0.5 H 2 0)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R-2 H 2 0) and hexahydrates (R-6 H 2 0)).
  • monohydrates x is 1
  • lower hydrates x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R-0.5 H 2 0)
  • polyhydrates x is a number greater than 1, e.g., dihydrates (R-2 H 2 0) and hexahydrates (R-6 H 2 0)
  • tautomer includes two or more interconvertable forms resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a double bond, or vice versa).
  • the exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may be catalyzed by acid or base.
  • Exemplary tautomerizations include keto-to-enol; amide-to-imide; lactam-to- lactim; enamine-to-imine; and enamine-to-(a different) enamine tautomerizations.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • polymorphs refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and/or solubility. Recrystallization solvent, rate of
  • crystallization, storage temperature, and other factors may cause one crystal form to dominate.
  • Various polymorphs of a compound can be prepared by crystallization under different conditions.
  • prodrugs refer to compounds, including derivatives of the compounds of Formula (I), which have cleavable groups and become by solvolysis or under physiological conditions the compounds of Formula (I)-(VI) which are pharmaceutically active in vivo.
  • Such examples include, but are not limited to, choline ester derivatives and the like, N- alkylmorpholine esters and the like.
  • Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
  • Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds of this invention are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as
  • Ci -Cs alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, C 7 -C 12 substituted aryl, and C 7 -C 12 arylalkyl esters of the compounds of Formulae (I)-(VI) may be preferred in certain instances.
  • a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e. , a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) and/or other non-human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g.
  • humans i.e. , a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)
  • mammals e.g., primates (e.g., cy
  • the animal is a mammal.
  • the animal may be a male or female and at any stage of development.
  • a non-human animal may be a transgenic animal.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing an inventive compound, or a pharmaceutical composition thereof.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a "pathological condition” (e.g., a disease, disorder, or condition, or one or more signs or symptoms thereof) described herein.
  • pathological condition e.g., a disease, disorder, or condition, or one or more signs or symptoms thereof
  • treatment may be administered after one or more signs or symptoms have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disease or condition.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • an "effective amount" of a compound of Formulae (I)-(VI) refers to an amount sufficient to elicit a desired biological response, i.e., treating the condition.
  • the effective amount of a compound of Formulae (I)-(VI) may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • An effective amount encompasses therapeutic and prophylactic treatment.
  • an effective amount of an inventive compound may reduce the tumor burden or stop the growth or spread of a tumor.
  • an effective amount of an inventive compound may improve sight, reduce the risk of vision loss, or prevent central vision loss from worsening.
  • a "therapeutically effective amount" of a compound of Formulae (I)-(VI) is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • a “prophylactically effective amount” of a compound of Formulae (I)-(VI) is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • a "proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (W alker, Cambridge Dictionary of Biology;
  • a proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location ⁇ e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as matrix
  • proliferative diseases include cancers ⁇ i.e., "malignant neoplasms"), benign neoplasms, diseases associated with angiogenesis or diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.
  • neoplasm and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue.
  • a neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis.
  • a “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin.
  • a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites.
  • Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias.
  • certain "benign" tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor's neoplastic cells, and these tumors are referred to as "pre-malignant neoplasms.”
  • An example of a pre-malignant neoplasm is a teratoma.
  • a malignant neoplasm is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites.
  • metalastasis refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a "secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located.
  • a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.
  • cancer refers to a malignant neoplasm (Stedman 's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990).
  • Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma,
  • angiosarcoma e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma
  • appendix cancer e.g.
  • adenocarinoma adenocarinoma
  • Ewing's sarcoma eye cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach
  • adenocarcinoma gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B- cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hod
  • liver cancer e.g., hepatocellular cancer (HCC), malignant hepatoma
  • lung cancer e.g., bronchogenic carcinoma,small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
  • leiomyosarcoma LMS
  • mastocytosis e.g., systemic mastocytosis
  • muscle cancer myelodysplasia syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a.
  • myelofibrosis MF
  • chronic idiopathic myelofibrosis CML
  • chronic neutrophilic leukemia CML
  • hypereosinophilic syndrome HES
  • neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis
  • NF neurofibromatosis
  • neuroendocrine cancer e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma;
  • GEP-NET gastroenteropancreatic neuroendocrine tumor
  • carcinoid tumor e.g., carcinoid tumor
  • osteosarcoma e.g., bone cancer
  • ovarian cancer e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma
  • papillary adenocarcinoma adenocarcinoma
  • pancreatic cancer e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors
  • penile cancer e.g., Paget's disease of the penis and scrotum
  • pinealoma primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms
  • prostate cancer e.g., prostate adenocarcinoma
  • rectal cancer rhabdomyosarcoma
  • salivary gland cancer skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcom
  • angiogenesis refers to the formation and growth of new blood vessels.
  • Normal angiogenesis occurs in the body of a healthy subject during wound healing and for restoring blood flow to tissues after injury.
  • the body controls angiogenesis through a number of means, e.g., angiogenesis-stimulating growth factors and angiogenesis inhibitors.
  • Many disease states such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and psoriasis, are characterized by abnormal (i.e., increased or excessive) angiogenesis.
  • Abnormal angiogenesis refers to angiogenesis greater than that in a normal body, especially angiogenesis in an adult not related to normal angiogenesis (e.g., menstruation or wound healing).
  • Abnormal angiogenesis can result in new blood vessels that feed diseased tissues and/or destroy normal tissues, and in the case of cancer, the new vessels can allow tumor cells to escape into the circulation and lodge in other organs (tumor metastases).
  • the disease associated with angiogenesis is tumor angiogenesis.
  • the diseases associated with angiogenesis include, but are not limited to breast cancer, colorectal cancer, esophageal cancer, gastrointestinal stromal tumor (GIST), kidney (renal cell) cancer, liver (adult primary) cancer, lymphoma, melanoma, lung cancer, ovarian epithelial cancer, pancreatic cancer, prostate cancer, stomach (gastric) cancer.
  • an "inflammatory disease” refers to a disease caused by, resulting from, or resulting in inflammation.
  • the term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and/or T-lymphocytes leading to abnormal tissue damage and/or cell death.
  • An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes.
  • Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyosifis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto's thyroditis, Graves' disease, Goodpasture's disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn's disease, ulcerative co
  • chorioamnionitis conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, ulceris, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis
  • an "autoimmune disease” refers to a disease arising from an inappropriate immune response in the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture's disease which may affect the basement membrane in both the lung and kidney).
  • the treatment of autoimmune diseases is typically with immunosuppressants, e.g., medications which decrease the immune response.
  • Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodspature's syndrome, necrotizing vasculitis,
  • lymphadenitis peri-arteritis nodosa
  • systemic lupus erythematosis rheumatoid
  • arthritis psoriatic arthritis
  • systemic lupus erythematosis psoriasis
  • ulcerative colitis systemic sclerosis, dermatomyositis/polymyositis, anti-phospholipid antibody syndrome, scleroderma, perphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), urveitis, Sjogren's syndrome, Crohn's disease, Reiter's syndrome, ankylosing spondylitis, Lyme arthritis, Guillain-Barre syndrome, Hashimoto's thyroiditis, and cardiomyopathy.
  • vasculitis e.g., Wegener's granulomatosis, microscopic polyangiitis
  • autoinflammatory disease refers to a category of diseases that are similar but different from autoimmune diseases. Autoinflammatory and autoimmune diseases share common characteristics in that both groups of disorders result from the immune system attacking a subject's own tissues and result in increased inflammation. In autoinflammatory diseases, a subject's innate immune system causes inflammation for unknown reasons. The innate immune system reacts even though it has never encountered autoantibodies or antigens in the subject. Autoinflammatory disorders are characterized by intense episodes of inflammation that result in such symptoms as fever, rash, or joint swelling. These diseases also carry the risk of amyloidosis, a potentially fatal buildup of a blood protein in vital organs.
  • Autoinflammatory diseases include, but are not limited to, familial Mediterranean fever (FMF), neonatal onset multisystem inflammatory disease (NOMID), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), deficiency of the interleukin-1 receptor antagonist (DIRA), and Behcet's disease.
  • FMF familial Mediterranean fever
  • NOMID neonatal onset multisystem inflammatory disease
  • TNF tumor necrosis factor
  • TRAPS tumor necrosis factor receptor-associated periodic syndrome
  • DIRA deficiency of the interleukin-1 receptor antagonist
  • Behcet's disease Behcet's disease.
  • tissue sample refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise).
  • tissue samples such as tissue sections and needle biopsies of a tissue
  • cell samples e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection) or samples of cells obtained by microdissection
  • samples of whole organisms such as samples of yeasts or bacteria
  • cell fractions, fragments or organelles such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise.
  • biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
  • Biological samples also include those biological samples that are transgenic, such as transgenic oocyte, sperm cell, blastocyst, embryo, fetus, donor cell, or cell nucleus.
  • inhibitors refer to the ability of a compound to reduce, slow, halt, or prevent the activity of a particular biological process involving Ras in a cell relative to vehicle.
  • Figure 1 shows exemplary isosteviol derivative 1-1 and selected biological active derivatives.
  • Figure 2 shows isosteviol and selected known heterocyclic derivatives as diverse templates suitable for small molecule library discovery.
  • Figure 3 shows isosteviol derivatives that have exhibited anti-cancer activity.
  • Figure 4a shows IC50 fitting curves of isosteviol derivative la on colon cancer cells (HCT116) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.
  • Figure 4b shows IC50 fitting curves of isosteviol derivative la on leukemia cells (MOLT-4) using CellTiter-Glo ® Luminescent Cell Viability Assay.
  • Figure 5 a shows validation of expression of MMP11 using real-time polymerase chain reaction (RT-qPCR).
  • the present invention provides compounds of Formulae (I)-(VI), which are derivatives of isosteviol. These compounds may be useful in the prevention and/or treatment of a proliferative disease. Also provided are methods of using compounds of Formulae (I)- (VI) to treat and/or prevent proliferative diseases.
  • proliferative diseases include, but are not limited to, cancers, benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.
  • the disease is cancer.
  • L 1 is a bond, optionally substituted aliphatic, or optionally substituted heteroaliphatic;
  • R 1 is hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • R is hydrogen or optionally substituted .(, alkyl
  • R is hydrogen or optionally substituted .(, alkyl
  • R 4 is hydrogen or optionally substituted .(, alkyl
  • each of R 5 and R 6 is independently hydrogen, halogen, -OR A , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and
  • each instance of R A is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
  • each of R 14 and R 15 is independently hydrogen, halogen, -OR A , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • R 6 and R 15 are taken together to form a bond; or optionally R 5 and R 14 are taken together with the intervening atoms to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • At least one ofR ⁇ R ⁇ and R 6 comprises optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
  • L 1 is a bond, optionally substituted aliphatic, or optionally substituted heteroaliphatic. In certain embodiments, L 1 is a bond. In certain embodiments, L 1 is optionally substituted aliphatic. In certain embodiments, L 1 is optionally substituted C alkylene. In certain embodiments, L 1 is unsubstituted Ci ⁇ alkylene. In certain embodiments, L 1 is methylene. In certain embodiments, L 1 is ethylene.
  • R 1 is hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 is optionally substituted aliphatic, optionally substituted
  • R 1 is optionally substituted alkyl. In certain embodiments, R 1 is unsubstituted C alkyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is optionally substituted heteroaryl. In certain embodiments, R 1 is optionally substituted triazole. In certain embodiments, R 1 is substituted triazole.
  • R is hydrogen or optionally substituted C alkyl.
  • R is hydrogen. In certain embodiments, R is unsubstituted C e alkyl. In certain embodiments, R 2 is methyl.
  • R 3 is hydrogen or optionally substituted Cue alkyl. In certain embodiments, R is hydrogen. In certain embodiments, R is unsubstituted Cue alkyl. In certain embodiments, R 3 is methyl.
  • R 4 is hydrogen or optionally substituted Cue alkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is unsubstituted Cue alkyl. In certain embodiments, R 4 is methyl.
  • R 5 is hydrogen, halogen, -OR A , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; wherein R A is as defined herein.
  • R 5 is -OR A , wherein R A is hydrogen, optionally substituted aliphatic, or an oxygen protecting group.
  • R 5 is -OH.
  • R 5 is -OR A , wherein R A is optionally substituted C alkyl.
  • R 5 is -OR A , wherein R A is unsubstituted C ⁇ alkyl.
  • R 5 is -OCH3 or -OC2H5. In certain embodiments, R 5 is -OR A , wherein R A is an oxygen protecting group. In certain embodiments, R 5 is -OR A , wherein R A is substituted alkyl. In certain embodiments, R 5 is -CN.
  • R 6 is hydrogen, halogen, -OR A , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; wherein R A is as defined herein.
  • R 6 is -OR A , wherein R A is hydrogen, optionally substituted aliphatic, or an oxygen protecting group.
  • R 6 is -OH.
  • R 6 is -OR A , wherein R A is optionally substituted C e alkyl.
  • R 6 is -OR A , wherein R A is unsubstituted C ⁇ alkyl.
  • R 6 is -OCH3 or -OC2H5. In certain embodiments, R 6 is -OR A , wherein R A is an oxygen protecting group. In certain embodiments, R 6 is -OR A , wherein R A is substituted C e alkyl. In certain embodiments, R 6 is -CN.
  • R 5 and R 6 taken together form 0.
  • R 14 is hydrogen, halogen, -OR A , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; wherein R A is as defined herein.
  • R 14 is -OR A , wherein R A is hydrogen, optionally substituted aliphatic, or an oxygen protecting group.
  • R 14 is -OH.
  • R 14 is -OR A , wherein R A is optionally substituted C e alkyl.
  • R 14 is -OR A , wherein R A is unsubstituted C alkyl.
  • R 14 is -OCH3 or -OC2H5. In certain embodiments, R 14 is -OR A , wherein R A is an oxygen protecting group. In certain embodiments, R 14 is -OR A , wherein R A is substituted C e alkyl. In certain embodiments, R 14 is -CN.
  • R 15 is hydrogen, halogen, -OR A , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; wherein R A is as defined herein.
  • R 15 is -OR A , wherein R A is hydrogen, optionally substituted aliphatic, or an oxygen protecting group.
  • R 15 is -OH.
  • R 15 is -OR A , wherein R A is optionally substituted C alkyl.
  • R 15 is -OR A , wherein R A is unsubstituted C 6 alkyl.
  • Rl 5 is -OCH3 or -OC2H5.
  • R 15 is -OR A , wherein R A is an oxygen protecting group.
  • R 15 is -OR A , wherein R A is substituted C alkyl.
  • R 15 is -CN.
  • R 14 and R 15 taken together form 0.
  • R 6 and R 15 are taken together to form a bond.
  • R 5 and R 14 are taken together with the intervening atoms to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, R 5 and R 14 are taken together with the intervening atoms to form three-membered heterocyclyl. In certain embodiments, R 5 and R 14 are taken together with the intervening atoms to form optionally substituted three-membered heterocyclyl with an heteroatom selected from the group consisting of O, S, and N. In certain embodiments, R 5 and R 14 are taken together to form optionally substituted epoxide.
  • R 5 and R 14 are taken together to form unsubstituted epoxide. In certain embodiments, R 5 and R 14 are taken together to form substituted epoxide. In certain embodiments, R 5 and R 14 are taken together to form optionally substituted thiirane. In certain embodiments, R 5 and R 14 are taken together to form unsubstituted thiirane. In certain embodiments, R 5 and R 14 are taken together to form substituted thiirane. In certain embodiments, R 5 and R 14 are taken together to form optionally substituted aziridine. In certain embodiments, R 5 and R 14 are taken together to form unsubstituted aziridine. In certain embodiments, R 5 and R 14 are taken together to form substituted aziridine.
  • R A is hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl; or an oxygen protecting group.
  • R A is hydrogen.
  • R A is optionally substituted aliphatic.
  • R A is optionally substituted C e alkyl.
  • R A is unsubstituted C alkyl (e.g., methyl).
  • At least one ofR ⁇ R ⁇ and R 6 comprises optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
  • one ofR ⁇ R ⁇ and R 6 compnses optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
  • one of R ⁇ R ⁇ and R 6 comprises optionally substituted heteroaryl or optionally substituted heterocyclyl. In certain embodiments, one of R 1 , R 5 , and R 6 comprises optionally substituted heteroaryl. In certain embodiments, one ofR ⁇ R ⁇ and R 6 comprises optionally substituted five-membered heteroaryl. In certain embodiments, one of R 1 , R 5 , and R 6 comprises optionally substituted triazole. In certain embodiments, one of R 1 , R 5 , and R 6 comprises substituted triazole. In certain embodiments, R comprises optionally substituted heteroaryl. In certain embodiments, R 1 comprises optionally substituted five- membered heteroaryl.
  • R 1 comprises optionally substituted triazole. In certain embodiments, R 1 comprises substituted triazole. In certain embodiments, R 5 comprises optionally substituted heteroaryl. In certain embodiments, R 5 comprises optionally substituted five-membered heteroaryl. In certain embodiments, R 5 is optionally substituted five-membered heteroaryl. In certain embodiments, R 5 is optionally substituted triazole. In certain embodiments, R 5 is substituted triazole. In certain embodiments, R 6 comprises optionally substituted heteroaryl. In certain embodiments, R 6 comprises optionally substituted five-membered heteroaryl. In certain embodiments, R 6 is optionally substituted five- membered heteroaryl. In certain embodiments, R 6 is optionally substituted triazole. In certain embodiments, R 6 is substituted triazole.
  • R 5 comprises optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • R 6 is hydrogen, halogen, -OR A , optionally substituted aliphatic, or optionally substituted heteroaliphatic; L 1 is a bond; and
  • R 1 is hydrogen, optionally substituted aliphatic, or optionally substituted heteroaliphatic.
  • R 5 comprises optionally substituted heteroaryl;
  • R 6 is hydrogen, halogen, -OR A , optionally substituted aliphatic or optionally substituted heteroaliphatic; L 1 is a bond; and R 1 is optionally substituted aliphatic.
  • R 5 is optionally substituted five-membered heteroaryl
  • R 6 is hydrogen, halogen, -OR A , optionally substituted aliphatic, or optionally substituted heteroaliphatic
  • L 1 is a bond
  • R 1 is optionally substituted aliphatic.
  • R 5 is optionally substituted triazole
  • R 6 is -OR A
  • L 1 is a bond
  • R 1 is optionally substituted aliphatic (e.g., optionally substituted Ci- ⁇ alkyl).
  • R 6 comprises optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • R 5 is hydrogen, halogen, -OR A , optionally substituted aliphatic, or optionally substituted heteroaliphatic;
  • L 1 is a bond;
  • R 1 is hydrogen, optionally substituted aliphatic, or optionally substituted heteroaliphatic.
  • R 6 comprises optionally substituted heteroaryl;
  • R 5 is hydrogen, halogen, -OR A , optionally substituted aliphatic, or optionally substituted heteroaliphatic;
  • L 1 is a bond; and
  • R 1 is optionally substituted aliphatic.
  • R 6 is optionally substituted five-membered heteroaryl;
  • R 5 is hydrogen, halogen, -OR A , optionally substituted aliphatic, or optionally substituted heteroaliphatic;
  • L 1 is a bond; and
  • R 1 is optionally substituted aliphatic.
  • R 6 is optionally substituted triazole;
  • R 5 is -OR A ;
  • L 1 is a bond;
  • R 1 is optionally substituted aliphatic (e.g., optionally substituted Ci- ⁇ alkyl).
  • the present disclosure provides compounds of
  • L 1 is a bond, optionally substituted aliphatic, or optionally substituted heteroaliphatic;
  • R is hydrogen, optionally substituted aliphatic, optionally substituted
  • heteroaliphatic optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or a nitrogen protecting group.
  • R 1 is hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • R is hydrogen or optionally substituted C alkyl
  • R is hydrogen or optionally substituted C alkyl
  • R 4 is hydrogen or optionally substituted C alkyl
  • each of R 5 and R 6 is independently hydrogen, halogen, -OR A , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and
  • each instance of R A is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
  • each of R 14 and R 15 is independently hydrogen, halogen, -OR A , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • R 6 and R 15 are taken together to form a bond
  • R 5 and R 14 are taken together with the intervening atoms to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R ⁇ R ⁇ and R 6 comprises optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
  • the compounds of Formula (II) are of one of the following formulae:
  • R is hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl; or a nitrogen protecting group.
  • R N1 is hydrogen.
  • R N1 is optionally substituted aliphatic.
  • R N1 is optionally substituted C O alkyl.
  • R N1 is unsubstituted C MO alkyl.
  • R N1 is methyl or ethyl.
  • R N1 is substituted C MO alkyl.
  • R N1 is C MO alkyl substituted by one or more R 7 , wherein each occurrence of R 7 is independently as defined herein.
  • R c is optionally substituted aliphatic.
  • R c is optionally substituted heteroaliphatic.
  • R N1 is optionally substituted amino acid.
  • R N1 is optionally substituted natural amino acid.
  • R N1 is optionally substituted natural amino acid or a fragment thereof. In certain embodiments, R N1 is optionally substituted C MO alkyl-optionally substituted aryl. In certain embodiments, R N1 is optionally substituted C MO alkyl-optionally substituted phenyl. In certain embodiments, R is of the formula: -(CH 2 ) 1 - 1 o-optionally substituted phenyl.
  • R N1 is one of the following formulae:
  • the present disclosure provides compounds of
  • L 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 14 and R 15 are as defined herein;
  • R 7 is hydrogen, halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • L 2 is a bond, optionally substituted aliphatic, or optionally substituted heteroaliphatic.
  • L 2 is a bond, optionally substituted aliphatic, or optionally substituted heteroaliphatic.
  • L 2 is a bond.
  • L 2 is optionally substituted aliphatic.
  • L 2 is optionally substituted C 1-6 alkylene.
  • L 2 is methylene.
  • L 2 is ethylene.
  • L 2 is propylene.
  • L 2 is butylene.
  • L 2 is optionally substituted heteroaliphatic.
  • L 2 is optionally substituted heteroalkyl.
  • R 7 is hydrogen, halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. In certain embodiments, R 7 is hydrogen. In certain embodiments, R is optionally substituted aliphatic. In certain embodiments, R 7 is optionally substituted aryl. In certain embodiments, R 7 is optionally substituted phenyl. In certain embodiments, R 7 is unsubstituted phenyl. In certain
  • R 7 is substituted phenyl. In certain embodiments, R 7 is mono-substituted phenyl. In certain embodiments, R 7 is di-substituted phenyl. In certain embodiments, R 7 is tri- substituted phenyl. In certain embodiments, R 7 is tetra-substituted phenyl. In certain embodiments, R 7 is penta-substituted phenyl.
  • L 2 is optionally substituted C 1-6 alkylene and R 7 is optionally substituted aryl. In certain embodiments, L 2 is optionally substituted C!-6 alkylene and R 7 is optionally phenyl. In certain embodiments, L 2 is unsubstituted alkylene and R 7 is optionally phenyl. In certain embodiments, L 2 is -(CH 2 ) 1-6 - and R 7 is optionally phenyl.
  • the present disclosure provides compounds of
  • L 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 14 and R 15 are as defined herein;
  • p 0, 1, 2, 3, 4, or 5;
  • each instance of R A is independently hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
  • each instance of R B is independently hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • 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.
  • p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5.
  • R p is hydrogen. In certain embodiments, R p is halogen. In certain embodiments, R p is F. In certain embodiments, R p is I. In certain embodiments, R p is Br. In certain embodiments, R p is CI. In certain embodiments, R p is -CN. In certain embodiments, R p is -N0 2 . In certain embodiments, R p is -N 3 . In certain embodiments, R p is optionally substituted aliphatic. In certain embodiments, R p is optionally substituted heteroaliphatic. In certain embodiments, R p is optionally substituted aryl. In certain embodiments, R p is optionally substituted heteroaryl.
  • R p is optionally substituted heterocyclyl.
  • R is hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl; or a nitrogen protecting group.
  • R B is hydrogen.
  • R B is optionally substituted aliphatic.
  • R B is optionally substituted C!-6 alkyl.
  • R B is unsubstituted C!-6 alkyl.
  • R B is methyl.
  • the present disclosure provides compounds of
  • the present disclosure provides compounds of
  • R 16 is hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • R 8 is -OR 8a or -N(R 8b ) 2 ;
  • each instance of R 8a is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
  • each instance of R is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or a nitrogen protecting group;
  • the compound of Formula (II-c) is of one of the following formulae:
  • R is hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
  • R 16 is hydrogen.
  • R 16 is optionally substituted aliphatic.
  • R 16 is optionally substituted C 1-10 alkyl.
  • R 16 is unsubstituted C 1-10 alkyl.
  • R 16 is methyl or ethyl.
  • R 16 is optionally substituted C 1-lo alkyl-optionally substituted aryl.
  • R 16 is optionally substituted C 1-lo alkyl-optionally substituted phenyl. In certain embodiments, R 16 is C 1-lo alkyl substituted with unsubstituted phenyl. In certain embodiments, R 16 is of the formula: - (CH 2 ) 1-10 -optionally substituted phenyl.
  • R 8 is -OR 8a or -N(R 8b ) 2 . In certain embodiments, R 8 is -OR 8a . In certain embodiments, R 8 is -N(R 8b ) 2 .
  • each instance of R 8a is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group.
  • R 8a is hydrogen. In certain embodiments, R 8a is optionally substituted aliphatic. In certain embodiments, R 8a is optionally substituted C 1-6 alkyl. In certain embodiments, R 8a is unsubstituted C 1-6 alkyl. In certain embodiments, R 8a is methyl or ethyl. In certain embodiments, R 8a is an oxygen protecting group.
  • R 8b is hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl; or a nitrogen protecting group.
  • R is hydrogen.
  • R is optionally substituted aliphatic.
  • R is optionally substituted C 1-6 alkyl.
  • R 8b is an oxygen protecting group.
  • L 1 is a bond, optionally substituted aliphatic, or optionally substituted heteroaliphatic;
  • R N1 is hydrogen, optionally substituted aliphatic, optionally substituted
  • heteroaliphatic optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or a nitrogen protecting group.
  • R 2 is hydrogen or optionally substituted C 1-6 alkyl
  • R 3 is hydrogen or optionally substituted C 1-6 alkyl
  • R 4 is hydrogen or optionally substituted C 1-6 alkyl
  • R 5 is hydrogen, halogen, -OR A , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and each instance of R A is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
  • R 14 is hydrogen, halogen, -OR A , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • R 5 and R 14 are taken together with the intervening atoms to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring;
  • R ! , R 5 , and R 6 comprises optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
  • the present disclosure provides compounds of
  • L 1 , L 2 , R 2 , R 3 , R 4 , R 5 , R 7 , and R 14 are as defined herein.
  • the present disclosure provides compounds of
  • L 1 , n, R p , p, R 2 , R 3 , R 4 , R 5 , and R 14 are as defined herein.
  • the present disclosure provides compounds of
  • R p , p, R 2 , R 3 , R 4 , R 5 , and R 14 are as defined herein.
  • R p , p, R 2 , R 3 , R 4 , R 5 , and R 14 are as defined herein.
  • R 2 , R 3 , R 4 , R 5 , R 8 , R 14 and R 16 are as defined herein.
  • the compounds of Formula (III-c) are of one of the following formulae:
  • L 3 is a bond, optionally substituted aliphatic, or optionally substituted heteroaliphatic;
  • R 9 is hydrogen or optionally substituted C 1-6 alkyl;
  • R 10 is hydrogen, halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
  • R is hydrogen or optionally substituted C!-6 alkyl
  • R 3 is hydrogen or optionally substituted C 1-6 alkyl
  • R 4 is hydrogen or optionally substituted C!-6 alkyl
  • R 6 is hydrogen, halogen, -OR A , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and each instance of R A is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
  • each of R 14 and R 15 is independently hydrogen, halogen, -OR A , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • R 6 and R 15 are taken together to form a bond
  • L 3 -R 10 and R 14 are taken together with the intervening atoms to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 6 or L 3 -R 10 comprises optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
  • L 3 is a bond, optionally substituted aliphatic, or optionally substituted heteroaliphatic. In certain embodiments, L 3 is a bond. In certain embodiments, L 3 is optionally substituted aliphatic. In certain embodiments, L 3 is optionally substituted C!-6 alkylene. In certain embodiments, L 3 is unsubstituted alkylene. In certain embodiments,
  • L is methylene. In certain embodiments, L is ethylene.
  • R 10 is hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. In certain embodiments, R 10 is hydrogen. In certain embodiments, R 10 is optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, R 10 is optionally substituted C 1-6 alkyl. In certain embodiments, R 10 is unsubstituted alkyl. In certain embodiments, R 10 is methyl. In certain embodiments, R 10 is optionally substituted heteroaryl. In certain embodiments, R 10 is optionally substituted triazole. In certain embodiments, R 10 is substituted triazole.
  • R 9 is hydrogen or optionally substituted C 1-6 alkyl. In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is optionally substituted C 1-6 alkyl. In certain embodiments, R 9 is substituted C 1-6 alkyl. In certain embodiments, R 9 is unsubstituted C!-6 alkyl (e.g. methyl).
  • the compounds of Formula (IV) are of one of the following formulae:
  • the present disclosure provides compounds of
  • R 2 , R 3 , R 4 , R 6 , R 9 , R 14 and R 16 are as defined herein.
  • R N2 is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or a nitrogen protecting group;
  • R 6 and R 14 are taken together with the intervening atoms to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring.
  • R N2 is hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl; or a nitrogen protecting group.
  • R N2 is hydrogen.
  • R N2 is optionally substituted aliphatic.
  • R N2 is optionally substituted C 1-10 alkyl.
  • R N2 is unsubstituted C 1-lo alkyl.
  • R N2 is methyl or ethyl.
  • R N2 is substituted C 1-lo alkyl.
  • R N2 is C 1-lo alkyl substituted by one or more R 11 , wherein each occurrence of R 11 is independently as defined herein.
  • R° is optionally substituted aliphatic.
  • R° is optionally substituted heteroaliphatic.
  • R N2 is optionally substituted amino acid.
  • R N2 is optionally substituted natural amino acid.
  • R N2 is optionally substituted natural amino acid or a fragment thereof. In certain embodiments, R N2 is optionally substituted C 1-lo alkyl- optionally substituted aryl. In certain embodiments, R N2 is optionally substituted C 1-lo alkyl- optionally substituted phenyl. In certain embodiments, R N2 is of the formula: -(CH 2 ) 1-10 - optionally substituted phenyl.
  • R 6 and R 14 are taken together with the intervening atoms to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In certain embodiments, R 6 and R 14 are taken together with the intervening atoms to form three-membered heterocyclyl. In certain embodiments, R 6 and R 14 are taken together to form an epoxide.
  • the present disclosure provides compounds of
  • R 2 , R 3 , R 4 , R 6 , R 9 , R 14 and R 15 are as defined herein;
  • L 4 is a bond, optionally substituted aliphatic, or optionally substituted heteroaliphatic
  • R 11 is independently hydrogen, halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
  • L 4 is a bond, optionally substituted aliphatic, or optionally substituted heteroaliphatic. In certain embodiments, L 4 is a bond. In certain embodiments, L 4 is optionally substituted aliphatic. In certain embodiments, L 4 is optionally substituted C alkylene. In certain embodiments, L 4 is methylene. In certain embodiments, L 4 is ethylene. In certain embodiments, L 4 is propylene. In certain embodiments, L 4 is butylene. In certain embodiments, L 4 is optionally substituted heteroaliphatic. In certain embodiments, L 4 is optionally substituted heteroalkyl.
  • R 11 is hydrogen, halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. In certain embodiments, R 11 is hydrogen. In certain embodiments, R 11 is optionally substituted aliphatic. In certain embodiments, R 11 is optionally substituted aryl. In certain embodiments, R 11 is optionally substituted phenyl. In certain embodiments, R 11 is unsubstituted phenyl. In certain embodiments, R 11 is substituted phenyl. In certain embodiments, R 11 is mono-substituted phenyl.
  • R 11 is di-substituted phenyl. In certain embodiments, R 11 is tri-substituted phenyl. In certain embodiments, R 11 is tetra-substituted phenyl. In certain embodiments, R 11 is penta-substituted phenyl. [00154] In certain embodiments, L 4 is optionally substituted C alkylene and R 11 is optionally substituted aryl. In certain embodiments, L 4 is optionally substituted C alkylene and R 11 is optionally phenyl. In certain embodiments, L 4 is unsubstituted C e alkylene and R 11 is optionally phenyl. In certain embodiments, L 4 is -(CH 2 )i-6- and R 11 is optionally phenyl.
  • the compounds of Formula (IV-b) are of one of the following formulae:
  • the present disclosure provides compounds of
  • R 2 , R 3 , R 4 , R 6 , R 9 , R 14 and R 15 are as defined herein;
  • s is 0, or an integer of 1 to 6, inclusive;
  • q 0, 1, 2, 3, 4, or 5;
  • each instance of R A is independently hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • each instance of R B is independently hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4. In certain embodiments, s is 5. In certain embodiments, s is 6.
  • q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 4. In certain embodiments, q is 5.
  • R q is hydrogen. In certain embodiments, R q is halogen. In certain embodiments, R q is F. In certain embodiments, R q is I. In certain embodiments, R q is Br. In certain embodiments, R q is CI. In certain embodiments, R q is -CN. In certain embodiments, R q is -N0 2 . In certain embodiments, R q is -N 3 . In certain embodiments, R q is optionally substituted aliphatic. In certain embodiments, R q is optionally substituted heteroaliphatic. In certain embodiments, R q is optionally substituted aryl. In certain embodiments, R q is optionally substituted heteroaryl. In certain embodiments, R q is optionally substituted heterocyclyl.
  • the compounds of Formula (IV-c) are of one of the following formulae:
  • the present disclosure provides compounds of
  • R q , q, R 2 , R 3 , R 4 , R 6 , R 9 , R 14 and R 15 are as defined herein.
  • the compounds of Formula (IV-cl) are of one of the following formulae:
  • the compounds of Formula (IV-c2) are of one of the following formulae:
  • the present disclosure provides compounds of
  • R 2 , R 3 , R 4 , R 6 , R 9 , R 14 and R 15 are as defined herein;
  • R 12 is -OR 12a or -N(R 12b ) 2 ;
  • R a is hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
  • each instance of R 12b is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or a nitrogen protecting group;
  • R 12b are taken together with the intervening nitrogen to form optionally substituted heterocyclyl
  • R is hydrogen, halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
  • R is hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted
  • R is hydrogen
  • R is optionally substituted aliphatic. In certain embodiments, R is optionally substituted C alkyl. In certain embodiments, R 17 is C e alkyl substituted with phenyl.
  • R 12 is -OR 12a or -N(R 12b ) 2 . In certain embodiments, R 12 is -OR 12a . In certain embodiments, R 12 is -N(R 12b ) 2 .
  • each instance of R 12a is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group.
  • R 12a is hydrogen. In certain embodiments, R 12a is optionally substituted aliphatic. In certain embodiments, R 12a is optionally substituted C e alkyl. In certain embodiments, R 12a is unsubstituted Cue alkyl. In certain embodiments, R 12a is methyl.
  • R 12b is hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl; or a nitrogen protecting group.
  • R 12b is hydrogen.
  • R 12b is optionally substituted aliphatic.
  • R 12b is optionally substituted Cue alkyl.
  • R 12b is unsubstituted Cu 6 alkyl.
  • R 12b is methyl or ethyl.
  • R 12b is substituted Cue alkyl.
  • the compounds of Formula (IV-d) are of one of the following formulae:
  • R 2 , R 3 , R 4 , R 9 , R 15 , and R N2 are as defined herein.
  • the compounds of Formula (IV-e) are of one of the following formulae:
  • the compounds of Formula (IV-a) are of Formula
  • R 2 , R 3 , R 4 , R 9 , R 15 , and R N2 are as defined herein.
  • the compounds of Formula (IV-f) are of one of the following formulae:
  • R 2 , R 3 , R 4 , R 9 , R 15 , and R N2 are as defined herein;
  • R N3 is hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or a nitrogen protecting group; [00178] As generally defined herein, R is hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl; or a nitrogen protecting group. In certain embodiments, R N3 is hydrogen. In certain embodiments, R N3 is optionally substituted aliphatic. In certain embodiments, R N3 is optionally substituted heteroaliphatic.
  • R N3 is optionally substituted aryl In certain embodiments, R N3 is optionally substituted heteroaryl. In certain embodiments, R N3 is optionally substituted heterocyclyl. In certain embodiments, R N3 is a nitrogen protecting group.
  • the compounds of Formula (IV-g) are of one of the following formulae:
  • the compounds of Formula (IV-a) are of Formula
  • the compounds of Formula (IV-h) are of one of the following formulae:
  • R 2 , R 3 , R 4 , R 9 , R 14 , R A and R N2 are as defined herein.
  • the compounds of Formula (IV-i) are of one of the following formulae:
  • the compounds of Formula (IV-a) are of Formula
  • R 2 , R 3 , R 4 , R 9 , R 14 , R A and R N2 are as defined herein.
  • the compounds of Formula (IV-j) are of one of the following formulae:
  • the compounds of Formula (IV-a) are of the Formula
  • R 2 , R 3 , R 4 , R 9 , R 15 , R A and R N2 are as defined herein;
  • each instance of R ca is independently hydrogen, halogen, -OR A , -N(R B ) 2 , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • each instance of R A is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
  • each instance of R B is independently hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
  • the compounds of Formula (IV-k) are of one of the following formulae:
  • R 2 , R 3 , R 4 , R 9 , R 15 , R A and R N2 are as defined herein;
  • each instance of R ca is independently hydrogen, halogen, -OR A , -N(R B ) 2 , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • each instance of R A is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
  • each instance of R B is independently hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
  • the compounds of Formula (IV-L) are of one of the following formulae:
  • the compounds of Formula (IV-L) are of one of the following formulae:
  • the compounds of Formula (IV-L) are of one of the following formulae:
  • the present disclosure provides compounds of
  • R 9 is hydrogen or optionally substituted C alkyl
  • R 2 is hydrogen or optionally substituted C alkyl
  • R is hydrogen or optionally substituted C ⁇ alkyl
  • R 4 is hydrogen or optionally substituted .(, alkyl
  • R 14 is hydrogen, halogen, -OR A , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • each instance of R A is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and R is hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or a nitrogen protecting group.
  • the present disclosure provides compounds of
  • L 4 , R 2 , R 3 , R 4 , R 9 , R 11 , and R 14 are as defined herein.
  • the present disclosure provides compounds of
  • R q , q, R 2 , R 3 , R 4 , R 9 , and R 14 are as defined herein.
  • the present disclosure provides compounds of
  • R q , q, R 2 , R 3 , R 4 , R 9 , and R 14 are as defined herein.
  • the present disclosure provides compounds of
  • R 2 , R 3 , R 4 , R 9 , R 12 , R 14 and R 17 are as defined herein.
  • the compounds of Formula (V-c) are of one of the follo
  • the present disclosure provides compounds of
  • L 1 is a bond, optionally substituted aliphatic, or optionally substituted heteroaliphatic;
  • R 1 is hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • R is hydrogen or optionally substituted C ⁇ alkyl
  • R is hydrogen or optionally substituted C ⁇ alkyl
  • R 4 is hydrogen or optionally substituted C alkyl
  • R 6 is hydrogen, halogen, -OR A , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and R 15 is hydrogen, halogen, -OR A , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
  • the compounds of Formula (VI) are of one of the following formulae:
  • R 2 , R 3 , R 4 , R 9 , R 15 , and R N2 are as defined herein.
  • the compounds of Formula (Vl-b) are of one of the foll
  • the present disclosure provides compounds of
  • R 2 , R 3 , R 4 , R 9 , R 15 , L 4 and R 11 are as defined herein.
  • the compounds of Formula (Vl-bl) are of one of the foll
  • the present disclosure provides compounds of
  • the compounds of Formula (VI-b2) are of one of the following formulae:
  • the present disclosure provides compounds of
  • R q , q, R 2 , R 3 , R 4 , R 9 , and R 15 are as defined herein.
  • the compounds of Formula (VI-b3) are of one of the following formulae:
  • the present disclosure provides compounds of
  • R q , q, R 2 , R 3 , R 4 , R 9 , and R 15 are as defined herein.
  • the compounds of Formula (VI-b4) are of one of the following formulae:
  • the present disclosure provides compounds of
  • L 1 , R N1 , R 2 , R 3 , R 4 , R 6 , and R 15 are as defined herein.
  • the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction [33,34] is a highly efficient and rapid technique for the synthesis of large varieties of complex compounds and has been successfully employed in the elaboration of the isosteviol core into diverse triazole conjugates types 1 and 2 (Scheme 1) [17].
  • This strategy involving the modification of both ketone and carboxylic groups, further enriches the diversity of synthesized triazole small -molecule conjugates. With this strategy, a panel of isosteviol triazole conjugates have been identified which possess promising anticancer activities [17].
  • the compounds of Formula (I)-(VI) can be prepared from the precursor compounds of Formula (VII) by reacting with a compound of formula R ⁇ -Na through a click chemistry reaction, wherein R 32 is optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
  • R 32 is hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl. In certain embodiments, R 32 is hydrogen. In certain embodiments, R 32 is optionally substituted aliphatic. In certain embodiments, R 32 is substituted CMO alkyl. In certain embodiments, R 32 is unsubstituted CMO alkyl. In certain embodiments, R 32 is methyl or ethyl. In certain embodiments, R 32 is CMO alkyl substituted by one or more R 7 , wherein each occurrence of R 7 is independently as defined herein.
  • R 32 is optionally substituted CMO alkyl-optionally substituted phenyl. In certain embodiments, R 32 is of the formula: -(CP ⁇ MO-optionally substituted phenyl. [00217] In certain embodiments, provided herein is a precursor compound of Formula (VII):
  • R is hydrogen or optionally substituted C alkyl
  • R is hydrogen or optionally substituted d-6 alkyl
  • R 4 is hydrogen or optionally substituted C alkyl
  • R 5 is hydrogen, halogen, -OR A , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • L is a bond, optionally substituted aliphatic, or optionally substituted heteroaliphatic
  • L 5 is a bond, optionally substituted aliphatic, or optionally substituted heteroaliphatic;
  • R 10 is hydrogen, halogen, -OR A , optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • R 13 is hydrogen, halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • each of R 14 and R 15 is independently hydrogen, halogen, -OR A , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • each instance of R A is hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl; or an oxygen protecting group;
  • R 5 and R 15 are taken together to form a bond; or optionally R 5 and R 14 are taken together with the intervening atoms to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring;
  • R 10 or R 13 comprises an optionally substituted alkynyl.
  • the compound of Formula (VII) is of Formula (VII- a):
  • R 2 , R 3 , R 4 , R 5 , L 5 , and R 13 are as defined herein;
  • the compound of Formula (VII) is of Formula (VII-
  • y2 is 1 , 2, 3, 4, or 5;
  • R is hydrogen or optionally substituted C ⁇ alkyl.
  • L is a bond, optionally substituted aliphatic, or optionally substituted heteroaliphatic. In certain embodiments, L is a bond. In certain embodiments, L is optionally substituted aliphatic. In certain embodiments, L is optionally substituted Ci-e alkylene. In certain embodiments, L is unsubstituted Ci-e alkylene. In certain
  • L is methylene. In certain embodiments, L is ethylene.
  • L 5 is a bond, optionally substituted aliphatic, or optionally substituted heteroaliphatic. In certain embodiments, L 5 is a bond. In certain embodiments, L 5 is optionally substituted aliphatic. In certain embodiments, L 5 is optionally substituted C ⁇ alkylene. In certain embodiments, L 5 is unsubstituted Ci ⁇ alkylene. In certain embodiments, L 5 is methylene. In certain embodiments, L 5 is ethylene.
  • R 10 is hydrogen, halogen, -OR A , optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
  • R 10 is hydrogen.
  • R 10 is optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 10 is optionally substituted .(, alkyl.
  • R 10 is unsubstituted .(, alkyl.
  • R 10 is methyl.
  • R 1 is -OR A , wherein R A is as defined herein. In certain
  • R 10 is -OH.
  • R A is optionally substituted .(, alkyl.
  • R is hydrogen, halogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
  • R is hydrogen.
  • R is optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, or optionally substituted heteroaryl.
  • R is optionally substituted C ⁇ alkyl.
  • R is
  • R is methyl
  • L is a bond and R comprises an optionally substituted alkyne. In certain embodiments, L is a bond and R is an optionally substituted alkyne. In certain embodiments, L is optionally substituted Ci-e alkylene and R is an optionally substituted alkyne. In certain embodiments, L is - ⁇ CR2)i-e- and R is an optionally substituted alkyne.
  • L is a bond and R comprises an optionally substituted alkyne.
  • L is a bond and R is .(, alkylene substituted by an optionally substituted alkyne.
  • L 5 is optionally substituted C ⁇ .(,
  • R is an optionally substituted alkyne.
  • L is -(CH2)i-6- and R is an optionally substituted alkyne.
  • yl is 0. In certain embodiments, yl is 1. In certain embodiments, yl is 2. In certain embodiments, yl is 3. In certain embodiments, yl is 4.
  • y2 is 1. In certain embodiments, y2 is 2. In certain embodiments, y2 is 3. In certain embodiments, y2 is 4. In certain embodiments, y2 is 5.
  • R Y1 is hydrogen. In certain embodiments, R Y1 is
  • R is unsubstituted C ⁇ .(, alkyl ⁇ e.g., methyl or ethyl).
  • R is hydrogen. In certain embodiments, R is optionally substituted .(, alkyl. In certain embodiments, R Y2 is unsubstituted .(, alkyl ⁇ e.g., methyl or ethyl).
  • yl is 0 and R is hydrogen. In certain embodiments,
  • Yl Yl yl is 0 and R is optionally substituted .(, alkyl. In certain embodiments, yl is 0 and R is unsubstituted C . alkyl ⁇ e.g. methyl or ethyl).
  • y2 is 1 and R is hydrogen. In certain embodiments, y2 is 1 and R Y2 is optionally substituted .(, alkyl. In certain embodiments, y2 is 1 and R Y2 is unsubstituted .(, alkyl ⁇ e.g. methyl).
  • a catalyst is present in the click chemistry reaction. In certain embodiments, the catalyst is a copper catalyst. In certain embodiments, the catalyst is Cu(II) salt. In certain embodiments, the catalyst is cupric sulfate. In certain embodiments, the catalyst is Cu(I) salt. In certain embodiments, the catalyst is Cul and an amine. In certain embodiments, the catalyst is CuBr and and amine. In certain embodiments, the catalyst is Cu(I) salt with DIPEA/HOAc. In certain embodiment, the catalyst is Cul with DIPEA/HOAc.
  • compounds of Formula (I)-(VII) can be prepared by dehydroxylating precursor compounds of Formula (VHI-a).
  • VHI-a precursor compound of Formula (Vlll-a):
  • R is hydrogen or optionally substituted Ci-e alkyl
  • R 4 is hydrogen or optionally substituted C ⁇ alkyl
  • R 5 is hydrogen, halogen, -OR A , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and
  • R is hydrogen or optionally substituted C ⁇ alkyl; and each instance of R A is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
  • R 14 is hydrogen, halogen, -OR A , -CN, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • R 5 and R 14 are taken together with the intervening atoms to form optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • the product of the dehydroxylation reaction is of
  • R 2 , R 3 , R 4 , R 14 , R A , R N2 are as defined herein.
  • the precursor compound of Formula (Vlll-a) is of
  • R 2 , R 3 , R 4 , R 14 , R A , R N2 are defined herein.
  • each instance of R A is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group.
  • R A is hydrogen. In certain embodiments, R A is optionally substituted aliphatic. In certain embodiments, R A is optionally substituted heterocyclyl. In certain embodiments, R A is optionally substituted aryl. In certain embodiments, R A is optionally substituted heteroaryl. In certain embodiments, R A is an oxygen protecting group.
  • an acid is present in the dehydroxylation reaction.
  • the acid is a carboxylic acid.
  • the acid is trifluoroacetic acid and formic acid.
  • the acid is formic acid.
  • R -CH 2 C(0)-Leu (2f) TFA/(THF or CH 3 CN)/60°C/48 h 10% ⁇
  • the preparation of compounds of Formula (I)-(VI) further comprises contacting a compound of the formula:
  • organometallic reagent refers to any compound with a carbon- metal bond.
  • the organometallic reagent is organolithium.
  • the organometallic reagent is organocuprate.
  • the organometallic reagent is organozinc.
  • the organometallic reagent is organomagnesium.
  • the organometallic reagent is an
  • the organometallic reagent is an organomagnesium iodide. In certain embodiments, the organometallic reagent is an organomagnesium chloride. In certain embodiments, the organometallic reagent is an organomagnesium bromide. In certain embodiments, the organometallic reagent is ethynylmagnesium bromide.
  • Dehydroisosteviol conjugates (3) are attractive templates for further derivatization to achieve skeletal diversity and stereochemical complexity. It has been shown that chemical transformations of the isosteviol core can be frequently performed in a stereoselective manner in the absence of any enantioselective catalysts or chiral auxiliaries [20,35]. The high stereoselectivity of those reactions can be attributed to the unique space structure of the rigid isosteviol skeleton with several chiral centers. For example, oxidation (e.g.
  • Formulae (I)-(VI) further comprises a reaction of a precursor compound of Formula (IX-a):
  • the reaction is an oxidation reaction.
  • the oxidation provides a compound comprising an epoxide moiety or a salt thereof.
  • the oxidation provides a compound of Formula (IX):
  • the oxidation provides a compound comprising an thiiranyl moiety or a salt thereof. In certain embodiments, the oxidation provides a compound of the formula:
  • reaction provides a compound comprising an aziridine moiety or a salt thereof. In certain embodiments, the reaction provides a compound of the formula:
  • reaction provides a compound comprising a ketone moiety or a salt thereof. In certain embodiments, the reaction provides a compound of the formula:
  • the reaction provides a compound comprising a cyano moiety or a salt thereof. In certain embodiments, the reaction provides a compound comprising a hydroxyl moiety or a salt thereof. In certain embodiments, the reaction provides a compound comprising a hydroxyl moiety and a cyano moiety or a salt thereof. In certain embodiments, the reaction provides a compound of the formula:
  • reaction provides a compound of the formula:
  • reaction is a [2 + 2] cycloaddition. In certain embodiments, the reaction provides a compound of the formula:
  • reaction is a [4 + 2] cycloaddition. In certain embodiments, the reaction provides a compound of the formula:
  • the compound of Formula (IX) is of Formula (IX- al):
  • R N2 is hydrogen, optionally substituted aliphatic, optionally substituted
  • the compounds of Formula (IX-al) are of one of the following formulae:
  • the compound of Formula (IX-al) is of Formula (IX-
  • a peroxyacid is present in the oxidation reaction.
  • a peroxyacid is a compound with an -OOH group.
  • the peroxyacid is peroxyacetic acid.
  • the peroxyacid is potassium peroxymonosulfate.
  • the peroxyacid is peroxy benzoic acid.
  • the peroxyacid is meta-chloroperoxy benzoic acid (m-CPBA).
  • the present invention provides pharmaceutical compositions comprising a compound of any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, as described herein, and optionally a pharmaceutically acceptable excipient.
  • the pharmaceutical composition of the invention comprises a compound of any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
  • the compound of any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof is provided in an effective amount in the pharmaceutical composition.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • compositions described herein can be prepared by any method known in the art of pharmacology.
  • preparatory methods include the steps of bringing the compound of any one of Formulae (I)-(VI) into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a "unit dose" is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (V eegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
  • V eegum magnesium aluminum silicate
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers
  • colloidal clays e.g. bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)
  • long chain amino acid derivatives e.g.
  • stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g.
  • polyoxyethylene sorbitan monolaurate Tween 20
  • polyoxyethylene sorbitan Tween 60
  • polyoxyethylene sorbitan monooleate Tween 80
  • sorbitan monopalmitate Span 40
  • sorbitan monostearate Span 60
  • sorbitan tristearate Span 65
  • polyoxyethylene monostearate Myrj 45
  • polyoxyethylene hydrogenated castor oil polyethoxylated castor oil
  • polyoxymethylene stearate polyethoxylated castor oil
  • polyoxymethylene stearate polyethoxylated castor oil
  • Solutol sucrose fatty acid esters
  • polyethylene glycol fatty acid esters e.g. CremophorTM
  • polyoxyethylene ethers e.g.
  • polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.
  • Exemplary binding agents include starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
  • starch e.g. cornstarch and starch paste
  • gelatin e.g. cornstarch and starch paste
  • sugars e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.
  • natural and synthetic gums e.g. acacia
  • methylcellulose methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • the preservative is an antioxidant.
  • the preservative is a chelating agent.
  • antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g. , sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.
  • BHA butylated hydroxyanisol
  • BHT butylated hydroxytoluened
  • SLS sodium lauryl sulfate
  • SLES sodium lauryl ether sulfate
  • sodium bisulfite sodium metabisulfite
  • potassium sulfite potassium metabisulfite
  • Glydant Plus Phenoni
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic s
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury,
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
  • Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, so
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates of the invention are mixed with solubilizing agents such as CremophorTM, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and
  • Solid compositions of a similar type can be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type can be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active ingredient can be in a micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • Dosage forms for topical and/or transdermal administration of a compound of this invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and/or any needed preservatives and/or buffers as can be required.
  • the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • compositions described herein include short needle devices.
  • Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin.
  • Jet injection devices which deliver liquid compositions to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable.
  • Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.
  • conventional syringes can be used in the classical mantoux method of intradermal administration.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi liquid preparations such as liniments, lotions, oil-in-water and/or water-in- oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions.
  • Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity.
  • a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers or from about 1 to about 6 nanometers.
  • Such compositions are conveniently in the form of dry powders for
  • a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling
  • solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
  • Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure.
  • the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition.
  • the propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • compositions of the invention formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension.
  • Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
  • Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition of the invention.
  • Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
  • Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation for buccal
  • formulations may, for example, be in the form of tablets, and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein.
  • formulations for buccal administration may comprise a powder and/or an aerosolized and or atomized solution and or suspension comprising the active ingredient.
  • Such powdered, aerosolized, and/or aerosolized formulations, when dispersed may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention can be prepared, packaged, and or sold in a formulation for ophthalmic administration.
  • Such formulations may, for example, be in the form of eye drops including, for example, a 0.1/1.0% (w/w) solution and or suspension of the active ingredient in an aqueous or oily liquid carrier.
  • Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
  • Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and or in a liposomal preparation. Ear drops and or eye drops are contemplated as being within the scope of this invention.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.
  • compositions of the present invention are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the compounds and compositions provided herein can be administered by any route, including enteral (e.g. , oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g. , oral
  • parenteral intravenous
  • intramuscular intra-arterial
  • intramedullary intrathecal
  • subcutaneous intraventricular
  • transdermal transdermal
  • interdermal interdermal
  • rectal intravaginal
  • topical as by powders, ointments, creams, and/or drops
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).
  • the exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like.
  • the desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.
  • the compounds of any one of Formulae (I)-(V1) may be at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • a compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents.
  • the compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and or modify their distribution within the body.
  • additional pharmaceutical agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and or modify their distribution within the body.
  • the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.
  • the compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies.
  • Pharmaceutical agents include therapeutically active agents.
  • Pharmaceutical agents also include prophylactically active agents.
  • Each additional pharmaceutical agent may be administered at a dose and or on a time schedule determined for that pharmaceutical agent.
  • the additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses.
  • the particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional pharmaceutical agents and/or the desired therapeutic and/or prophylactic effect to be achieved.
  • it is expected that the additional pharmaceutical agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
  • Exemplary additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressant agents, and a pain-relieving agent.
  • Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the U.S.
  • CFR Code of Federal Regulations
  • proteins proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.
  • CFR Code of Federal Regulations
  • kits e.g., pharmaceutical packs.
  • the inventive kits may be useful for preventing and/or treating a proliferative disease (e.g., cancer (e.g., leukemia, melanoma, multiple myeloma), benign neoplasm, angiogenesis,
  • a proliferative disease e.g., cancer (e.g., leukemia, melanoma, multiple myeloma), benign neoplasm, angiogenesis,
  • kits provided may comprise an inventive pharmaceutical composition or compound and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
  • a container e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of an inventive pharmaceutical composition or compound.
  • the inventive pharmaceutical composition or compound provided in the container and the second container are combined to form one unit dosage form.
  • kits including a first container comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, and prodrug thereof, or a pharmaceutical composition thereof.
  • the kit of the invention includes a first container comprising a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the kits are useful in preventing and/or treating a proliferative disease in a subject.
  • kits further include instructions for administering the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, and prodrug thereof, or a
  • composition thereof to a subject to prevent and/or treat a proliferative disease.
  • the present invention also provides methods of using the compounds of of of
  • a proliferative disease such as cancer ⁇ e.g. leukemia, lung cancer, pancreatic cancer, breast cancer, prostate cancer, colon cancer, or cervical cancer
  • benign neoplasm diseases related to angiogenesis, inflammatory disease, autoinflammatory disease, or autoimmune disease in a subject.
  • a provided compound is useful in treating a cancer.
  • a provided compound is useful to delay the onset of, slow the progression of, or ameliorate the symptoms of cancer.
  • a provided compound is administered in combination with other compounds, drugs, or therapeutics to treat cancer.
  • compounds described herein are useful for treating a cancer including, but not limited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma ⁇ e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer ⁇ e.g., cholangiocarcinoma), bladder cancer, breast cancer ⁇ e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer ⁇ e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma;
  • bronchus cancer carcinoid tumor, cervical cancer ⁇ e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer ⁇ e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma ⁇ e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer ⁇ e.g., uterine cancer, uterine sarcoma), esophageal cancer ⁇ e.g., adenocarcinoma of the esophagus, Barrett's adenocarinoma), Ewing sarcoma, eye cancer ⁇ e.g., intraocular melanoma, retinoblasto
  • HCC hepatocellular cancer
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • MDS myelodysplasia syndrome
  • MDS myelodysplasia syndrome
  • MMD mye
  • myelofibrosis MF
  • chronic idiopathic myelofibrosis CML
  • chronic neutrophilic leukemia CML
  • hypereosinophilic syndrome HES
  • neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis
  • NF neurofibromatosis
  • neuroendocrine cancer e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumors), penile cancer (e.g., Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanom
  • a provided compound is useful in treating a hematologic cancer.
  • the hematologic cancer is a leukemia.
  • the hematologic cancer is a lymphoma.
  • the leukemia is AML.
  • the leukemia is CML.
  • the leukemia is CLL.
  • the hematologic cancer is multiple myeloma.
  • a provided compound is useful in treating a solid tumor.
  • the solid tumor is lung cancer, pancreatic cancer, breast cancer, prostate cancer, colon cancer, or cervical cancer.
  • a provided compound is useful in treating lung cancer.
  • a provided compound is useful in treating pancreatic cancer. In some embodiments, a provided compound is useful in treating breast cancer. In some embodiments, a provided compound is useful in treating prostate cancer. In some embodiments, a provided compound is useful in treating colon cancer. In some embodiments, a provided compound is useful in treating cervical cancer.
  • a provided compound is useful in treating advanced staged cancer. In some embodiments, a provided compound is useful in treating metastatic cancer. In some embodiments, a provided compound is useful in treating metastatic hematologic cancer (e.g. , leukemia, lymphoma, or myeloma). In some embodiments, a provided compound is useful in treating a metastatic solid tumor (e.g., lung cancer, pancreatic cancer, breast cancer, prostate cancer, colon cancer, or cervical cancer).
  • a metastatic solid tumor e.g., lung cancer, pancreatic cancer, breast cancer, prostate cancer, colon cancer, or cervical cancer.
  • the proliferative disease is a benign neoplasm. All types of benign neoplasms disclosed herein or known in the art are contemplated as being within the scope of the invention.
  • the proliferative disease is associated with angiogenesis. All types of angiogenesis disclosed herein or known in the art are contemplated as being within the scope of the invention.
  • the proliferative disease is an inflammatory disease. All types of inflammatory diseases disclosed herein or known in the art are contemplated as being within the scope of the invention.
  • the inflammatory disease is rheumatoid arthritis.
  • the proliferative disease is an autoinflammatory disease.
  • the proliferative disease is an autoimmune disease. All types of autoimmune diseases disclosed herein or known in the art are contemplated as being within the scope of the invention.
  • the cell described herein may be an abnormal cell.
  • the cell may be in vitro or in vivo.
  • the cell is a proliferating or dividing cell.
  • the cell is a blood cell.
  • the cell is a lymphocyte.
  • the cell is a cancer cell.
  • the cell is a leukemia cell.
  • the cell is a melanoma cell.
  • the cell is a multiple myeloma cell.
  • the cell is a neoplastic cell.
  • the cell is an endothelial cell.
  • the cell is an immune cell.
  • the present invention also provides methods of inhibiting cell growth in a biological sample or subject.
  • the present invention provides methods of inducing apoptosis of a cell in a biological sample or a subject.
  • the methods described herein include administering to a subject or contacting a biological sample with an effective amount of a compound of any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.
  • the methods described herein include administering to a subject or contacting a biological sample with an effective amount of a compound of any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the compound is administered in combination with one or more additional pharmaceutical agents described herein.
  • the additional pharmaceutical agent is an anti-cancer agent.
  • Anti-cancer agents encompass biotherapeutic anti-cancer agents as well as chemotherapeutic agents.
  • biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon a, interferon ⁇ ), vaccines, hematopoietic growth factors, monoclonal serotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) and antibodies (e.g.
  • HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)).
  • chemotherapeutic agents include, but are not limited to, anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g. goscrclin and leuprolide), anti-androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g. carmustine (BCNU) and lomustine
  • anti-estrogens e.g. tamoxifen, raloxifene, and megestrol
  • LHRH agonists
  • alkylsulphonates e.g. busulfan and treosulfan
  • triazenes e.g. dacarbazine, temozolomide
  • platinum containing compounds e.g. cisplatin, carboplatin, oxaliplatin
  • vinca alkaloids e.g. vincristine, vinblastine, vindesine, and vinorelbine
  • taxoids e.g.
  • paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel
  • ABRAXANE docosahexaenoic acid bound-paclitaxel
  • DHA-paclitaxel docosahexaenoic acid bound-paclitaxel
  • Taxoprexin polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT- 2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2'-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g.
  • etoposide etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C
  • anti-metabolites DHFR inhibitors (e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g. hydroxyurea and deferoxamine), uracil analogs (e.g.
  • 5-fluorouracil 5-FU
  • floxuridine floxuridine
  • doxifluridine doxifluridine
  • ratitrexed tegafur-uracil
  • capecitabine cytosine analogs
  • cytosine analogs e.g. cytarabine (ara C)
  • ara C cytarabine
  • fludarabine purine analogs (e.g. mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g. l-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g. staurosporine), actinomycin (e.g. actinomycin D, dactinomycin), bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g.
  • purine analogs e.g. mercaptopurine and Thioguanine
  • Vitamin D3 analogs e.g. EB 1089, CB 1093, and KH 1060
  • isoprenylation inhibitors e.g. lovastatin
  • dopaminergic neurotoxins e.g
  • daunorubicin daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR
  • inhibitors e.g. verapamil
  • Ca ATPase inhibitors e.g. thapsigargin
  • imatinib thalidomide, lenalidomide
  • tyrosine kinase inhibitors e.g., axitinib (AGO 13736), bosutinib (SKI-606), cediranib (RECENTINTM, AZD2171), dasatinib (SPRYCEL ® , BMS-354825), erlotinib (TARCEVA ® ), gefitinib (IRESSA ® ), imatinib (Gleevec ® , CGP57148B, STI-571), lapatinib (TYKERB ® , TYVERB ® ), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib
  • TASIGNA ® semaxanib (semaxinib, SU5416), sunitinib (SUTENT ® , SU11248), toceranib (PALLADIA ® ), vandetanib (ZACTIMA ® , ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN ® ), bevacizumab (AVASTIN ® ), rituximab (RITUXAN ® ), cetuximab (ERBITUX ® ), panitumumab (VECTIBIX ® ), ranibizumab (Lucentis ® ), nilotinib (TASIGNA ® ), sorafenib (NEXAVAR ® ), everolimus (AFINITOR ® ), alemtuzumab
  • CAMPATH ® gemtuzumab ozogamicin
  • MYLOTARG ® gemtuzumab ozogamicin
  • TORISEL ® temsirolimus
  • ENMD-2076 PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOKTM), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF ® ), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)),
  • the subject being treated is a mammal.
  • the subject is a human.
  • the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
  • the subject is a companion animal such as a dog or cat.
  • the subject is a livestock animal such as a cow, pig, horse, sheep, or goat.
  • the subject is a zoo animal.
  • the subject is a research animal such as a rodent, dog, or non-human primate.
  • the subject is a non-human transgenic animal such as a transgenic mouse or transgenic pig. Examples
  • DMSO dimethyl sulfoxide
  • MTT 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H- tetrazolium bromide
  • MTT 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H- tetrazolium bromide
  • CellTiter-Glo ® Luminescent Cell Viability Assay was purchased from Promega (Madison, USA).
  • Dulbecco's Modified Eagle Medium (DMEM) and fetal bovine serum (FBS) were purchased from Gibco (Grand Island, USA). All cell lines were purchased from ATCC (Manassas, USA).
  • the anti-proliferative activities of the isosteviol triazole compounds were assessed by the tetrazolium-based MTT assay.
  • Human breast carcinoma MDA 231 cell line was cultured in DMEM medium supplied with 10% FBS. Cells were seeded in 96 well plates at the density of 5000 cells per well, respectively. Cancer cells were treated with respective compounds for 48 h and then incubated with 100 ⁇ L of 0.5 mg/niL 3-(4,5-Dimethyl-2- thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) solution for 4 h. The supernatant was discarded and DMSO was added to each well. Absorbance at 570 nm was measured using a SpectraMax M2 reader (Molecular Devices, Sunnyvale, USA). The number of viable cells in the control group was assigned a relative value of 100%.
  • MDA-231 a (Breast) HL-60" (Leukemia)
  • Cell viability was analyzed by the MTT assay. All measurements were performed in triplicate. Data was represented as mean ⁇ standard deviation (SD).
  • 6Cell viability was analyzed by the CellTiter-Glo ® Luminescent Cell Viability Assay. All measurements were performed in triplicate. Data was represented as mean ⁇ standard deviation (SD).
  • the leukemia cell line HL-60 was cultured in DMEM medium, 10% FBS was supplied to the culture system.
  • HL-60 was plated in 96-well plates at 10,000 cells/well. Cells were treated with isostevol triazole compounds at various concentrations. On Day 2, cells were lysed with CellTiter-Glo ® Luminescent Cell Viability Assay reagent (Promega) following manufacture's instruction and luminescence was read using the PerkinElmer Victor V plate reader (PerkinElmer, Waltham, USA). Percent cell growth was calculated relative to control cells.
  • cDNA was generated using Superscript ® VILOTM MasterMix (Invitrogen).

Abstract

L'invention concerne des dérivés d'isostérol de formule (I), et des sels pharmaceutiquement acceptables et leurs compositions pharmaceutiques. La présente invention concerne en outre des procédés, des utilisations et des kits impliquant les composés ou compositions de l'invention pour traiter ou prévenir des maladies prolifératives comme des cancers, des néoplasmes bénins, des maladies associées à une angiogenèse, des maladies inflammatoires, des maladies auto-inflammatoires et des maladies auto-immunes chez un sujet.
PCT/US2015/060372 2014-11-12 2015-11-12 Triazoles d'isostéviol et leurs utilisations WO2016077581A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201462078853P 2014-11-12 2014-11-12
US62/078,853 2014-11-12
US201562203275P 2015-08-10 2015-08-10
US62/203,275 2015-08-10

Publications (1)

Publication Number Publication Date
WO2016077581A1 true WO2016077581A1 (fr) 2016-05-19

Family

ID=55955052

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2015/060372 WO2016077581A1 (fr) 2014-11-12 2015-11-12 Triazoles d'isostéviol et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2016077581A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106543032A (zh) * 2016-11-10 2017-03-29 北京大学 四环二萜化合物及制备和应用
CN108299339A (zh) * 2018-02-02 2018-07-20 山东大学 甜菊苷衍生物及其制备方法和用途

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090074935A1 (en) * 2007-09-17 2009-03-19 Pepsico, Inc. Steviol glycoside isomers
WO2009071099A1 (fr) * 2007-12-05 2009-06-11 Aarhus Universitet Augmentation du taux de cholestérol hdl plasmatique
US20100179097A1 (en) * 2004-05-19 2010-07-15 Wen Tan Use of kauranes compounds in the manufacture of medicament
WO2012010624A2 (fr) * 2010-07-23 2012-01-26 Dsm Ip Assets B.V. Utilisation topique du stéviol ou de ses dérivés dans les soins capillaires
WO2012083408A1 (fr) * 2010-12-23 2012-06-28 Universidade Federal De Minas Gerais - Ufmg Compositions pharmaceutiques antipaludiques contenant des dérivés de diterpènes kauréniques
WO2012116990A2 (fr) * 2011-03-01 2012-09-07 Dsm Ip Assets B.V. Nouvelle utilisation
WO2013017136A1 (fr) * 2011-08-02 2013-02-07 Pensieve Biosciences Cyprus Limited Traitement d'un trouble cognitif

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100179097A1 (en) * 2004-05-19 2010-07-15 Wen Tan Use of kauranes compounds in the manufacture of medicament
US20090074935A1 (en) * 2007-09-17 2009-03-19 Pepsico, Inc. Steviol glycoside isomers
WO2009071099A1 (fr) * 2007-12-05 2009-06-11 Aarhus Universitet Augmentation du taux de cholestérol hdl plasmatique
WO2012010624A2 (fr) * 2010-07-23 2012-01-26 Dsm Ip Assets B.V. Utilisation topique du stéviol ou de ses dérivés dans les soins capillaires
US20130115182A1 (en) * 2010-07-23 2013-05-09 Dsm Nutritional Products Ltd. Topical use of steviol or derivatives in hair care
WO2012083408A1 (fr) * 2010-12-23 2012-06-28 Universidade Federal De Minas Gerais - Ufmg Compositions pharmaceutiques antipaludiques contenant des dérivés de diterpènes kauréniques
WO2012116990A2 (fr) * 2011-03-01 2012-09-07 Dsm Ip Assets B.V. Nouvelle utilisation
WO2013017136A1 (fr) * 2011-08-02 2013-02-07 Pensieve Biosciences Cyprus Limited Traitement d'un trouble cognitif

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106543032A (zh) * 2016-11-10 2017-03-29 北京大学 四环二萜化合物及制备和应用
CN108299339A (zh) * 2018-02-02 2018-07-20 山东大学 甜菊苷衍生物及其制备方法和用途
CN108299339B (zh) * 2018-02-02 2019-12-06 山东大学 甜菊苷衍生物及其制备方法和用途

Similar Documents

Publication Publication Date Title
US10723753B2 (en) Ras inhibitors and uses thereof
AU2017363313B2 (en) Inhibitors of interleukin-1 receptor-associated kinases and uses thereof
EP3535254A1 (fr) Composés pour la dégradation de malt1
WO2017040304A1 (fr) Inhibiteurs de malt1 et leurs utilisations
WO2018165385A1 (fr) Inhibiteurs de malt1 et leurs utilisations
EP4003319A2 (fr) Inhibiteurs de hdac6 et leurs utilisations
AU2021203883A1 (en) Phenylsulfonamido-benzofuran derivatives and uses thereof in the treatment of proliferative diseases
WO2016077581A1 (fr) Triazoles d'isostéviol et leurs utilisations
WO2016201374A1 (fr) Dérivés d'adénosine sulfanide et leurs utilisations
US11014876B2 (en) Polyamine sulfonamides and uses thereof
WO2023196714A9 (fr) Inhibiteurs de ddr1 et ddr2 pour le traitement de l'arthrite
WO2024077023A2 (fr) Agents de dégradation doubles de bcl-xl/bcl-2 de recrutement de céréblon
US20200062776A1 (en) Hedgehog acyltransferase inhibitors and uses thereof
WO2023150203A1 (fr) Inhibiteurs de hdac6 et leurs utilisations
WO2024097948A1 (fr) Agents de dégradation de mdm2 et leurs utilisations
WO2021050702A1 (fr) Inhibiteurs de kdm et leurs utilisations

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15858190

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15858190

Country of ref document: EP

Kind code of ref document: A1