WO2014123900A1 - Anti-cancer and anti-hiv compounds - Google Patents

Anti-cancer and anti-hiv compounds Download PDF

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Publication number
WO2014123900A1
WO2014123900A1 PCT/US2014/014668 US2014014668W WO2014123900A1 WO 2014123900 A1 WO2014123900 A1 WO 2014123900A1 US 2014014668 W US2014014668 W US 2014014668W WO 2014123900 A1 WO2014123900 A1 WO 2014123900A1
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optionally substituted
group
alkyl
hydrogen
halogen
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PCT/US2014/014668
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French (fr)
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Ippei USUI
Jacob Neal BEVERAGE
Venkata Rami Reddy MACHERLA
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Sirenas Marine Discovery
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Publication of WO2014123900A1 publication Critical patent/WO2014123900A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems

Definitions

  • This application relates to the fields of chemistry and medicine, more particularly to anti-cancer and anti-HIV compounds, pharmaceutical compositions, and methods of treatment.
  • the human immunodeficiency virus type 1 (HIV) Tat protein a potent activator of HIV gene expression, is essential for integrated viral genome expression and represents a potential antiviral target.
  • Tat binds the 5 '-terminal region of HIV mRNA's stem- bulge-loop structure, the transactivation-responsive (TAR) element, to activate transcription.
  • TAR transactivation-responsive
  • Inhibition of Tat-mediated transactivation of the integrated provirus by targeting the TAR- binding domain of Tat is under investigation. Identification of active agents that reduce Tat- mediated transcriptional initiation/elongation from the viral promoter to inhibit HIV-1 and HIV- 2 replication in acutely and chronically infected cells is an attractive target for drug discovery research. It is thought compounds that abrogate spontaneous viral particle release from CD4+T cells from virally suppressed subjects on highly active antiretro viral therapy (HAART) may have advantageous properties for treating individuals with diseases that arise from viral sources.
  • HAART highly active antiretro viral therapy
  • n 1 or 3;
  • p is 1 or 3;
  • q is l or 3;
  • each R 1 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted hydroxyl, an optionally substituted amino, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C3-C 7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
  • R 4 is selected from the group consisting of halogen, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
  • R 5 is selected from the group consisting of -L 1 -R 5A , an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
  • R 5A is selected from the group consisting of an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
  • R 6 is selected from the group consisting of hydrogen, halogen, hydro xyl, -SH, an optionally substituted Ci-C 6 alkyl, and an optionally substituted Ci-C 6 alkoxy;
  • R 7 is selected from the group consisting of hydrogen, halogen, hydro xyl, -SH, an optionally substituted Ci-C 6 alkyl, and an optionally substituted Ci-C 6 alkoxy, or optionally R and R together are oxygen or sulfur;
  • R 8 is selected from the group consisting of hydrogen, halogen, and an optionally substituted Ci-C 6 alkyl;
  • each R 9 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
  • R 10 is selected from the group consisting of hydrogen, hydroxyl, an optionally substituted Ci-C 6 alkoxy, and optionally substituted Ci-C 6 alkyl;
  • R 11 is selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl, or optionally R 10 and R 11 together are oxo;
  • R 3 and R 12 are hydrogen then R 5 is no
  • R may be selected from the group consisting of hydrogen, hydroxyl and optionally substituted Ci-C 6 alkyl.
  • R 10 may be selected from the group consisting of hydrogen, hydroxyl and methyl.
  • R 10 may be selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl.
  • n 1, p is 1, q
  • R 5 is not
  • each R 1 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted hydroxyl, an optionally substituted amino, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
  • R 2 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
  • R 4 is selected from the group consisting of halogen, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
  • R 5 is selected from the group consisting of -L 1 -R 5A , an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
  • R 5A is selected from the group consisting of an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
  • R 6 is selected from the group consisting of hydrogen, halogen, hydroxy, -SH, an optionally substituted Ci-C 6 alkyl;
  • R 8 is selected from the group consisting of hydrogen, halogen, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
  • each R 9 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
  • R 10 is selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl
  • R 11 is selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl, or optionally R 10 and R 11 together are oxo;
  • each dashed line independently represents an optional double bond.
  • Still other embodiments described herein include a compound of Formula III:
  • p is 1 or 3;
  • q is 1 or 3;
  • each R 1 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted hydroxyl, an optionally substituted amino, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
  • each R 3 is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl, or optionally two adjacent R 3 together with the atoms to which they are attached is an optionally substituted C 3 -C 7 cycloalkyl or optionally substituted 3-7 membered heterocycle ring;
  • R 4 is selected from the group consisting of halogen, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
  • R 5 is selected from the group consisting of -L 1 -R 5A , an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
  • R 5A is selected from the group consisting of an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
  • R 6 is selected from the group consisting of hydrogen, halogen, hydro xyl, -SH, an optionally substituted Ci-C 6 alkyl, and an optionally substituted Ci-C 6 alkoxy;
  • R 7 is selected from the group consisting of hydrogen, halogen, hydro xyl, -SH, an optionally substituted Ci-C 6 alkyl, and an optionally substituted Ci-C 6 alkoxy, or optionally R and R together are oxygen or sulfur;
  • R 8 is selected from the group consisting of hydrogen, halogen, and an optionally substituted Ci-C 6 alkyl;
  • each R 9 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
  • R 10 is selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl
  • R 11 is selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl, or optionally R 10 and R 11 together are oxo;
  • each dashed line independently represents an optional double bond.
  • n 1 or 3;
  • q is 1 or 3;
  • each R 1 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted hydroxyl, an optionally substituted amino, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
  • R 4 is selected from the group consisting of halogen, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
  • R 5 is selected from the group consisting of -L 1 -R 5A , an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
  • R 5A is selected from the group consisting of an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
  • R 6 is selected from the group consisting of hydrogen, halogen, hydro xyl, -SH, an optionally substituted Ci-C 6 alkyl, and an optionally substituted Ci-C 6 alkoxy;
  • R 7 is selected from the group consisting of hydrogen, halogen, hydro xyl, -SH, an optionally substituted Ci-C 6 alkyl, and an optionally substituted Ci-C 6 alkoxy, or optionally R and R together are oxygen or sulfur;
  • R 8 is selected from the group consisting of hydrogen, halogen, and an optionally substituted Ci-C 6 alkyl;
  • each R 9 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 alkoxy, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
  • R 10 is selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl
  • R 11 is selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl, or optionally R 10 and R 11 together are oxo;
  • each dashed line independently represents an optional double bond.
  • Some embodiments described herein include a pharmaceutical composition, comprising a compound described herein and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • Some embodiments described herein include a method of inhibiting angiogenesis, comprising administering a compound described herein to a subject in need thereof.
  • Some embodiments described herein include a method of treating a disease selected from the group consisting of bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, non-Hodgkin lymphoma, pancreatic cancer, prostate cancer, thyroid cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, psoriasis, systematic lupus erythematosus, erythematosus, proliferative retinopathy, and atherosclerosis, comprising administering a compound described herein to a subject in need thereof.
  • a disease selected from the group consisting of bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, non-Hodgkin lymphoma, pancreatic cancer, prostate cancer, thyroid cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, psorias
  • Some embodiments provide a method of inhibiting CDK8, comprising contacting CDK8 with a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.
  • the contacting CDK8 comprises administering a compound to a subject that has cancer.
  • Some embodiments provide a method of inhibiting CDK8, comprising contacting CDK8 with dedihydrocortistatin A, or a pharmaceutically acceptable salt thereof.
  • the contacting CDK8 comprises administering dedihydrocortistatin A to a subject that has cancer.
  • the contacting CDK8 comprises administering a compound to a subject that has a viral infection.
  • the viral infection is HBV, HCV, CMV, and HIV.
  • Some embodiments provide a method of treating a cancer that is not treatable by inhibiting angiogenesis, comprising administering a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • Some embodiments provide a method of treating a cancer that is not treatable by inhibiting angiogenesis, comprising administering dedihydrocortistatin A, or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the cancer is leukemia.
  • the cancer is multiple myeloma.
  • Some embodiments provide a method of treating melanoma, comprising administering dedihydrocortistatin A, or a pharmaceutically acceptable salt thereof to a subject in need thereof. Some embodiments provide a method of treating multiple myeloma, comprising administering dedihydrocortistatin A, or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • Some embodiments provide a method of treating melanoma, comprising administering a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof to a subject in need thereof. Some embodiments provide a method of treating multiple myeloma, comprising administering a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • Some embodiments described herein include a method of inhibiting HIV replication, comprising administering a compound described herein to a subject infected with HIV.
  • some embodiments described herein include a method of preventing an HIV infection, comprising administering a compound described herein to a subject at risk for said infection.
  • Solidvate refers to the compound formed by the interaction of a solvent and a compound described herein or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of a compound and, which are not biologically or otherwise undesirable for use in a pharmaceutical.
  • the compounds disclosed herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297, Johnston et al, published September 11, 1987 (incorporated by reference herein in its entirety).
  • C a to C b or "C a _b” in which "a” and “b” are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from “a” to "b", inclusive, carbon atoms.
  • a “Ci to C 4 alkyl” or “Ci_ 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-.
  • halogen or "halo,” as used herein, means any one of the radio- stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.
  • alkyl refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds).
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 9 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 4 carbon atoms.
  • the alkyl group may be designated as "Ci_ 4 alkyl” or similar designations.
  • “Ci_ 4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, and t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.
  • alkoxy refers to the formula -OR wherein R is an alkyl as is defined above, such as "Ci_ 9 alkoxy", including but not limited to methoxy, ethoxy, n- propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, and the like.
  • alkylthio refers to the formula -SR wherein R is an alkyl as is defined above, such as "Ci_g alkylthio” and the like, including but not limited to methylmercapto, ethylmercapto, n-propylmercapto, 1-methylethylmercapto
  • alkenyl refers to a straight or branched hydrocarbon chain containing one or more double bonds.
  • the alkenyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl” where no numerical range is designated.
  • the alkenyl group may also be a medium size alkenyl having 2 to 9 carbon atoms.
  • the alkenyl group could also be a lower alkenyl having 2 to 4 carbon atoms.
  • the alkenyl group may be designated as "C 2 _ 4 alkenyl" or similar designations.
  • C 2 _ 4 alkenyl indicates that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-l-yl, propen-2-yl, propen-3-yl, buten-l-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-l-yl, 2-methyl-propen-l-yl, 1 -ethyl-ethen-l-yl, 2-methyl-propen-3-yl, buta-l ,3-dienyl, buta-1 ,2,- dienyl, and buta-l ,2-dien-4-yl.
  • Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl, and the like.
  • alkynyl refers to a straight or branched hydrocarbon chain containing one or more triple bonds.
  • the alkynyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl” where no numerical range is designated.
  • the alkynyl group may also be a medium size alkynyl having 2 to 9 carbon atoms.
  • the alkynyl group could also be a lower alkynyl having 2 to 4 carbon atoms.
  • the alkynyl group may be designated as "C 2 _ 4 alkynyl” or similar designations.
  • “C 2 _ 4 alkynyl” indicates that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-l-yl, propyn-2-yl, butyn-l-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl.
  • Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.
  • heteroalkyl refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone.
  • the heteroalkyl group may have 1 to 20 carbon atom, although the present definition also covers the occurrence of the term "heteroalkyl” where no numerical range is designated.
  • the heteroalkyl group may also be a medium size heteroalkyl having 1 to 9 carbon atoms.
  • the heteroalkyl group could also be a lower heteroalkyl having 1 to 4 carbon atoms.
  • the heteroalkyl group may be designated as "Ci_ 4 heteroalkyl" or similar designations.
  • the heteroalkyl group may contain one or more heteroatoms.
  • “Ci_ 4 heteroalkyl” indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.
  • aromatic refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine).
  • carbocyclic aromatic e.g., phenyl
  • heterocyclic aromatic groups e.g., pyridine
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.
  • aryl refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, every ring in the system is aromatic.
  • the aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term "aryl” where no numerical range is designated. In some embodiments, the aryl group has 6 to 10 carbon atoms.
  • the aryl group may be designated as "C 6 -io aryl,” “C 6 or C 10 aryl,” or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.
  • aryloxy and arylthio refers to RO- and RS-, in which R is an aryl as is defined above, such as “C 6 -io aryloxy” or “C 6 -io arylthio” and the like, including but not limited to phenyloxy.
  • an "aralkyl” or “arylalkyl” is an aryl group connected, as a substituent, via an alkylene group, such as "C 7-14 aralkyl” and the like, including but not limited to benzyl, 2- phenylethyl, 3-phenylpropyl, and naphthylalkyl.
  • the alkylene group is a lower alkylene group (i.e., a C 1-4 alkylene group).
  • heteroaryl refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone.
  • heteroaryl is a ring system, every ring in the system is aromatic.
  • the heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heteroaryl" where no numerical range is designated.
  • the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members.
  • the heteroaryl group may be designated as "5-7 membered heteroaryl,” "5-10 membered heteroaryl,” or similar designations.
  • heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.
  • a “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2-thienylmethyl, 3- thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazoUylalkyl, and imidazolylalkyl.
  • the alkylene group is a lower alkylene group (i.e., a Ci_ 4 alkylene group).
  • carbocyclyl means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When the carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion. Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic. Thus, carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls.
  • the carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term "carbocyclyl” where no numerical range is designated.
  • the carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms.
  • the carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms.
  • the carbocyclyl group may be designated as "C 3 _ 6 carbocyclyl" or similar designations.
  • carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.
  • a "(carbocyclyl)alkyl” is a carbocyclyl group connected, as a substituent, via an alkylene group, such as "C 4 _io (carbocyclyl)alkyl” and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like.
  • the alkylene group is a lower alkylene group.
  • cycloalkyl means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • cycloalkenyl means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic.
  • An example is cyclohexenyl.
  • heterocyclyl means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system.
  • the heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heterocyclyl” where no numerical range is designated.
  • the heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members.
  • the heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members.
  • the heterocyclyl group may be designated as "3-6 membered heterocyclyl" or similar designations.
  • the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S.
  • heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1 ,4-dioxinyl, 1 ,4-dioxanyl, 1,3-oxathianyl, 1,4- oxathiinyl, 1 ,4-oxathianyl, 2H-l,2-oxazinyl, triox
  • a "(heterocyclyl)alkyl” is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.
  • R is hydrogen, Ci_ 6 alkyl, C 2 -6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.
  • R is selected from hydrogen, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 7 carbocyclyl, C 6 _io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • a "cyano” group refers to a "-CN” group.
  • a "cyanato” group refers to an "-OCN” group.
  • An "isocyanato” group refers to a "-NCO” group.
  • a "thiocyanato" group refers to a "-SCN” group.
  • An "isothiocyanato" group refers to an " -NCS” group.
  • a “sulfonyl” group refers to an "-SO 2 R” group in which R is selected from hydrogen, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3 _ 7 carbocyclyl, C 6-1 o aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • S-sulfonamido refers to a "-S0 2 NRAR B " group in which RA and R B are each independently selected from hydrogen, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3 _ 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • N-sulfonamido refers to a "-N(RA)S02R B " group in which RA and R b are each independently selected from hydrogen, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3 _ 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • An “amino” group refers to a "-NR A R B " group in which R A and R B are each independently selected from hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C3- 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • R A and R B are each independently selected from hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C3- 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
  • a non-limiting example includes free amino (i.e., -NH 2 ).
  • aminoalkyl refers to an amino group connected via an alkylene group.
  • alkoxyalkyl refers to an alkoxy group connected via an alkylene group, such as a "C 2 _g alkoxyalkyl” and the like.
  • a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group. Unless otherwise indicated, when a group is deemed to be "substituted,” it is meant that the group is substituted with one or more subsitutents independently selected from Ci-C 6 alkyl, Ci-C 6 alkenyl, Ci-C 6 alkynyl, Ci-C 6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), C 3 -C 7 -carbocyclyl-Ci- C 6 -alkyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6
  • radical naming conventions can include either a mono-radical or a di-radical, depending on the context.
  • a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical.
  • a substituent identified as alkyl that requires two points of attachment includes di-radicals such as -CH 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, and the like.
  • Other radical naming conventions clearly indicate that the radical is a di-radical such as "alkylene” or "alkenylene.”
  • R groups are said to form a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring) "together with the atom to which they are attached," it is meant that the collective unit of the atom and the two R groups are the recited ring.
  • the ring is not otherwise limited by the definition of each R group when taken individually. For example, when following substructure is present:
  • R 1 and R 2 are defined as selected from the group consisting of hydrogen and alkyl, or R and R 2 together with the nitrogen to which they are attached form a heteroaryl, it is meant that R 1 and R 2 can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:
  • ring E is a heteroaryl ring contain ng the depicted nitrogen.
  • R 1 and R 2 are defined as selected from the group consisting of hydrogen and alkyl, or R and R 2 together with the atoms to which they are attached form an aryl or carbocylyl, it is meant that R 1 and R 2 can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:
  • E is an aryl ring or a carbocylyl containing the depicted double bond.
  • depicted as -AE- or E includes the substituent being oriented such that the A is attached at the leftmost attachment point of the molecule as well as the case in which A is attached at the rightmost attachment point of the molecule.
  • Subject as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
  • mammal is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice guinea pigs, or the like.
  • primates including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice guinea pigs, or the like.
  • an "effective amount” or a “therapeutically effective amount” as used herein refers to an amount of a therapeutic agent that is effective to relieve, to some extent, or to reduce the likelihood of onset of, one or more of the symptoms of a disease or condition, and includes curing a disease or condition. “Curing” means that the symptoms of a disease or condition are eliminated; however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).
  • Treatment refers to administering a compound or pharmaceutical composition to a subject for prophylactic and/or therapeutic purposes.
  • prophylactic treatment refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition.
  • therapeutic treatment refers to administering treatment to a subject already suffering from a disease or condition.
  • Isotopes may be present in the compounds described. Each chemical element present in a compound either specifically or generically described hereinmay include any isotope of said element.
  • a hydrogen atom may be explicitly disclosed or understood to be present in the compound and each such hydrogen atom is any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium).
  • reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
  • Some embodiments include compounds of Formula I as described above. In some embodiments the compounds of Formula I have the structure of Formula la:
  • each R is hydrogen
  • each R 1 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted hydroxyl, and an optionally substituted amino;
  • each R 2 is independently selected from the group consisting of hydrogen, halogen, and hydroxy, or optionally two adjacent R 2 together with the atoms to which they are attached is an optionally substituted C3-C7 cycloalkyl;
  • each R 3 is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, and an optionally substituted Ci-C 6 alkyl;
  • R 10 is selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • R 11 is selected from the group consisting of hydrogen and Ci-C 6 alkyl.
  • each R 1 is independently selected from the group consisting of hydrogen, hydroxyl, and -N(Methyl) 2 ;
  • each R 2 is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, and hydroxy, or optionally two adjacent R 2 together with the atoms to which they are attached is an optionally substituted cyclopropyl;
  • each R 3 is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, cyano, thiocyanato, methyl, and trifluoromethyl;
  • R 5 is selected from the group consisting of -L 1 -R 5A and an optionally substituted heteroaryl;
  • R 5A is an optionally substituted heteroaryl
  • R 10 is selected from the group consisting of hydrogen and methyl
  • R 11 is selected from the group consisting of hydrogen and methyl.
  • the compound of Formula la may have the structure of Formula Iaa:
  • R 5 is selected from the group consisting of -L 1 -R 5A , an optionally substituted aryl and an optionally substituted heteroaryl;
  • R 5A is selected from the group consisting of an optionally substituted aryl and an optionally substituted heteroaryl.
  • the compound of Formula la may have the structure of Formula lab:
  • R 5 is selected from the group consisting of -L 1 -R 5A , an optionally substituted aryl and an optionally substituted heteroaryl;
  • R 5A is selected from the group consisting of an optionally substituted aryl and an optionally substituted heteroaryl.
  • the compound of Formula la may have the structure of Formula lac:
  • R 5 is selected from the group consisting of -I ⁇ -R 5 ⁇ an optionally substituted aryl and optionally substituted heteroaryl;
  • R 5A is selected from the group consisting of an optionally substituted aryl and an optionally substituted heteroaryl.
  • at least one R 1 is hydroxyl.
  • at least two R 1 are hydroxyl.
  • at least one R 1 is -N(CH 3 ) 2 .
  • R 5 is an optionally substituted aryl.
  • R 5 is an optionally substituted phenyl.
  • R 5 is phenyl. In some embodiments of any of Formulae I-IV and any of the foregoing embodiments defining R 1 , R 5 is an optionally substituted heteroaryl.
  • R 5 is pyridinyl, quinolinyl, quinazolinyl, phthalazinyl, 3-methyl-iH- indazolyl, iH-indazolyl, l-(difluoromethyl)-isoquinolinyl, 3-amino-7-quinazolinyl, isoquinol-1- one-7-yl, N-propyl-isoquinolin-7-yl-l -amine, or N-propyl-quinazolin-7-yl-4-amine.
  • R 5 is -C ⁇ C-R 5A , where R 5A is as defined herein, and in some embodiments, is optionally substituted heteroaryl (or specifically pyridinyl).
  • each R 1 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted hydroxyl, and an optionally substituted amino;
  • R 2 is hydrogen or Ci-C 3 alkyl
  • each R 3 is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, and an optionally substituted Ci-C 6 alkyl;
  • R 10 is selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • R 11 is selected from the group consisting of hydrogen and Ci-C 6 alkyl.
  • each R 12 is hydrogen.
  • each R 1 is independently selected from the group consisting of hydrogen, hydroxyl, and -N(Methyl) 2 ;
  • RR 55 is selected from the group consisting of -L X -R 5A and an optionally substituted heteroaryl;
  • R is an optionally substituted heteroaryl.
  • Still other embodiments include a compound of Formula IV as described above.
  • R 5A may be substuituted with a tetrahydro-lH-thieno[3,4-d]imidazol-2(3H)-one containing moiety, In some alternative embodiments of Formulae I-IV, R 5A may be substuituted with
  • the compounds disclosed herein may be synthesized by methods described below, or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc., known to those skilled in the art.
  • Ways of modifying the methodology include, among others, temperature, solvent, reagents etc., known to those skilled in the art.
  • it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973); and P.G.M. Green, T.W.
  • Scheme I provides compounds of general Formula I having the structure of I- II- A.
  • the compound of Formula I-A may be obtained using procedures know in the art and simple modificatons thereof, for example as described in U.S. Pub. No. 2011/0060140 and Shi et al., "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011, 133(20): 8014-8027 each disclosure of which is incorporated herein by reference in its entirety.
  • the compound of Formula I-A may be reacted under conditions known in the art, for example under Stille or Suzuki conditions, to afford the compounds of Formula II-A.
  • the variables R 5 and R in Scheme I are defined appropriate to the reaction conditions and procedures.
  • R 5 may be aryl or heteroaryl.
  • n, p, and q are 0, or 2 and at least one n, p, or q is 2.
  • Scheme II provides compounds of general Formula I having the structure of II-B.
  • the compound of Formula II-A may be reacted under conditions known in the art, for example as described in Leggans et al, Org. Lett., 2011, 14, 1428-1431; Barker et al., J. Am. Chem. Soc, 2012, 134, 13588-13591; Gaspar et al, Angew. Chem. Int. Ed., 2007, 46, 4519- 4522; Gaspar et al, Synthesis, 2007, 3839-3845; Gaspar et al, Angew. Chem. Int. Ed., 2008, 47, 5758-5760; and Isayama et al, Chem. Lett.
  • each R 2 , R 3 , and R 12 in the compound of Formula II-B are defined appropriate to the reaction conditions and procedures.
  • each R 2 , R 3 , and R 12 may be independently selected from, but is not limited to, the group consisting of hydrogen, hydroxyl, chloro, fluoro, cyano, and nitro.
  • Scheme III provides compounds of general Formula I having the structure of Formula III-A.
  • the compound of Formula II-A may be reacted under cyclopropanation conditions known in the art, for example as described in Grieco et al., J. Org. Chem., 1977, 42(25): 4113-4118 the disclosure of which is incorporated herein by reference in its entirety.
  • the compound of Formula II-A may be reacted under Simmons-Smith reaction conditions to afford a compound of Formula III-A.
  • the variables R 5 and R in Scheme III are defined appropriate to the reaction conditions and procedures.
  • R 5 may be aryl or heteroaryl.
  • Scheme IV provides compounds of general Formula I having the structure of IV-D.
  • the compound of Formula IV-A may be prepared according to the procedures described in U.S. Pub. No. 2011/0060140.
  • the compound of Formula IV-A may be reacted under conditions known in the art, for example under Sharpless Epoxidation conditions as described in Johnson et al., "Catalytic Asymmetric Epoxidation of Allylic Alcohols,” Catalytic Asymmetric Synthesis, 2nd ed., Ojima, I. Ed., Wiley-CVH: New York, 2000; 231-280; Katsuki, T., "Epoxidation of Allylic Alcohols," Comprehensive Asymmetric Catalysis,” 1st ed., Jacobsen, E.
  • variable R 2 in the compound of Formula IV-D are defined appropriate to the reaction conditions and procedures.
  • R 2 may be chloro, fluoro, or bromo, but is not limited thereto.
  • the variable R 5 may be defined appropriate to the reaction conditions and procedures.
  • R 5 may be aryl or heteroaryl.
  • the process of Scheme V provides compounds of general Formula I having the structure of Formula V-A.
  • the compound of Formula V-A may be prepared according to the procedures described in U.S. Pub. No. 2011/0060140.
  • the compound of Formula V-A may be reacted under conditions known in the art, for example under nucleophilic trifuoromethylation conditions as described in Singh et al., "Nucleophilic Trifuoromethylation Reactions of Organic Compounds with (Trifuoromethyl)trimethylsilane," Tetrahedron, 2000, 56: 7613 the disclosure of which is incorporated herein by reference in its entirety, to afford a compound of Formula V- B.
  • the compound of Formula V-B may be reacted under conditions described in U.S.
  • variable R 3 in the compound of Formula V-C is defined appropriate to the reaction conditions and procedures.
  • R 3 may be methyl or trifluoromethyl, but is limited thereto.
  • the variable R 5 may be defined appropriate to the reaction conditions and procedures.
  • R 5 may be aryl or heteroaryl.
  • the process of Scheme VI provides compounds of general Formula I having the structure of Formula VI-E and VI-F.
  • the compound of Formula V-A may be reacted under conditions known in the art, for example under electrophilic reaction using LDA and a reagent including an electrophile to afford a compound of Formula VI-A and VI-B.
  • the reagent including an electrophile may be methyl iodide (E-I where the methyl group corresponds to E) providing R 10 and R 11 defined as methyl in the formula of Scheme VI.
  • E-I methyl iodide
  • the compound of Formula VI-A and VI-B may be reacted under conditions known in the art, for example described in U.S. Pub. No.
  • the compound of Formula VI-C or VI-D may be reacted under conditions known in the art, for example under conditions described in U.S. Pub. No. 2011/0060140 and Shi et al, "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011, 133(20): 8014- 8027 to afford a compound of Formula VI-E or VI-F.
  • the variables R 5 , R 10 , and R 11 may be defined appropriate to the reaction conditions and procedures.
  • R 5 may be aryl or heteroaryl
  • R 10 , and R 11 may be methyl, chloro, fluoro, or bromo.
  • Scheme VII provides compounds of general Formula I having the structure of Formula VII-B.
  • the compound of Formula VII-A may be obtained according to procedures known in the art, for example described in U.S. Pub. No. 2011/0060140 and Shi et al., "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011,
  • R 5 may be defined appropriate to the reaction conditions and procedures.
  • R 5 may be aryl or heteroaryl.
  • Scheme VIII provides compounds of general Formula I having the structure of Formula VIII-C and VIII-D.
  • the compound of Formula VIII-A and VIII-B may be reacted under conditions known in the art, for example described in U.S. Pub. No. 2011/0060140 and Shi et al, "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011, 133(20): 8014-8027, to afford a compound of Formula VIII-A or VIII-B.
  • the compound of Formula VIII-A or VIII-B may be reacted under conditions known in the art, for example under conditions described in U.S. Pub. No.
  • R 5 , R 10 , and R 11 may be defined appropriate to the reaction conditions and procedures.
  • R 5 may be aryl or heteroaryl
  • R 10 , and R 11 may be methyl, chloro, fluoro, or bromo.
  • compound IX-B in DMSO may be reacted with 7-trimethylstannylisoquinoline in the presence of CuCl, LiCl, and Pd(PPh 3 ) 4 under appropriate conditions to afford dehydrocortistatin A.
  • Dehydrocortistatin A may be reacted under conditions described in U.S. Pub. No. 2011/0060140 and Shi et al., "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011, 133(20): 8014-8027 to afford cortistatin A and compound 101.
  • dehydrocortistatin A in THF may be reacted with triisopropylbenzenesulfonyl hydrazide in the presence of triethyl amine under appropriate conditions to afford cortistatin A and compound 101.
  • Scheme X
  • compound XV-A in DMSO may be reacted with 7-trimethylstannylisoquinoline in the presence of CuCl, LiCl, and Pd(PPh 3 ) 4 under appropriate conditions to afford compound 102.
  • Administration and Pharmaceutical Compositions may be reacted with 7-trimethylstannylisoquinoline in the presence of CuCl, LiCl, and Pd(PPh 3 ) 4 under appropriate conditions to afford compound 102.
  • a daily dose may be from about 0.25 mg/kg to about 120 mg/kg or more of body weight, from about 0.5 mg/kg or less to about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body weight, or from about 1.5 mg/kg to about 10 mg/kg of body weight.
  • the dosage range would be from about 17 mg per day to about 8000 mg per day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg to about 3000 mg per day.
  • the amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
  • Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments.
  • compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereoisomers, tautomers, polymorphs, and solvates thereof), or pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
  • various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.
  • substances which can serve as pharmaceutically- acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyr
  • a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.
  • compositions described herein are preferably provided in unit dosage form.
  • a "unit dosage form" is a composition containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice.
  • the preparation of a single or unit dosage form does not imply that the dosage form is administered once per day or once per course of therapy.
  • Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specifically excluded.
  • the skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.
  • compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration.
  • routes for administration for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration.
  • oral and nasal compositions include compositions that are administered by inhalation, and made using available methodologies.
  • a variety of pharmaceutically-acceptable carriers well-known in the art may be used.
  • Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances.
  • Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric- coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
  • the pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for peroral administration is well-known in the art.
  • Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc.
  • Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture.
  • Coloring agents such as the FD&C dyes, can be added for appearance.
  • Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets.
  • Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.
  • Peroral compositions also include liquid solutions, emulsions, suspensions, and the like.
  • the pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art.
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.
  • Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
  • compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action.
  • dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
  • compositions described herein may optionally include other drug actives.
  • compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms.
  • Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystallme cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
  • a liquid composition which is formulated for topical ophthalmic use, is formulated such that it can be administered topically to the eye.
  • the comfort may be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort.
  • the liquid may be formulated such that the liquid is tolerable to the patient for topical ophthalmic use.
  • an ophthalmically acceptable liquid may either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.
  • solutions or medicaments are often prepared using a physiological saline solution as a major vehicle.
  • Ophthalmic solutions may preferably be maintained at a comfortable pH with an appropriate buffer system.
  • the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
  • Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuric nitrate.
  • a useful surfactant is, for example, Tween 80.
  • various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
  • Tonicity adjusters may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster.
  • buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
  • an ophthalmically acceptable antioxidant includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
  • excipient components which may be included in the ophthalmic preparations, are chelating agents.
  • a useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.
  • Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.
  • the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HC1, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7.
  • Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA.
  • Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al., Compendium of
  • Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.
  • compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration.
  • a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration.
  • the compositions are provided in solution ready to administer parenterally.
  • the compositions are provided in a solution that is further diluted prior to administration.
  • the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.
  • Some embodiments include methods of inhibiting angiogenesis by administering a compound described herein to a subject in need of anti-angiogenesis therapy.
  • the disease treated may be any disease or disorder associated with abnormal or undesirable angiogenesis.
  • angiogenesis is inhibited in a cancerous tumor.
  • Anti- angiogenesis therapy is expected to be effective to treat all types of cancerous tumors regardless of etimology, including but not limited to a carcinoma, a sarcoma, a lymphoma, and a blastoma.
  • Non-limiting cancers that can be treated using the compounds described herein include bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, non-Hodgkin lymphoma, glioblastoma, pancreatic cancer, prostate cancer, and thyroid cancer.
  • any other non-cancer disease or disorder associated with angiogenesis may be treated, including but not limited to diabetic blindness, age-related macular degeneration, rheumatoid arthritis, psoriasis, systematic lupus erythematosus, proliferative retinopathy, and atherosclerosis.
  • the compounds disclosed herein may be used as a transcription inhibitor, such as through inhibition of CDK8.
  • the inhibition of CDK8 inhibits cell division.
  • some embodiments include the treatment of proliferative disorders such as cancer through a mechanism distinct or in addition to anti- angiogenesis.
  • some embodiments include the treatment of cancer including, but not limited to a carcinoma, a sarcoma, a lymphoma, a leukemia, and a blastoma.
  • Non-limiting cancers that can be treated using the compounds described herein include bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, non-Hodgkin lymphoma, leukemia, glioblastoma, pancreatic cancer, prostate cancer, and thyroid cancer.
  • compounds that specifically inhibit CDK8 inhibit HIV-1 replication.
  • compounds disclosed herein may be used to treat viral diseases through the inhibition of CDK8.
  • other embodiments include methods of treating an HIV infection or inhibiting HIV replication by administering a compound described herein that inhibits CDK8.
  • Some embodiments include treating a subject already infected with HIV to ameliorate or cure the infection by administering a compound described herein that inhibits CDK8.
  • Other embodiments include administering a compound to subject at risk for infection with HIV to reduce the likelihood that the subject will contract an HIV infection by administering a compound described herein that inhibits CDK8.
  • Some embodiments provide a method of inhibiting CDK8, comprising contacting CDK8 with a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.
  • the contacting CDK8 comprises administering a compound to a subject that has cancer.
  • Some embodiments provide a method of inhibiting CDK8, comprising contacting CDK8 with dedihydrocortistatin A, or a pharmaceutically acceptable salt thereof.
  • the contacting CDK8 comprises administering dedihydrocortistatin A to a subject that has cancer.
  • Some embodiments provide a method of treating a cancer that is not treatable by inhibiting angiogenesis, comprising administering a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof to a subject in need thereof. Some embodiments provide a method of treating a cancer that is not treatable by inhibiting angiogenesis, comprising administering dedihydrocortistatin A, or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the cancer is leukemia. In some embodiments, the cancer is multiple myeloma.
  • Some embodiments provide a method of treating melanoma, comprising administering dedihydrocortistatin A, or a pharmaceutically acceptable salt thereof to a subject in need thereof. Some embodiments provide a method of treating multiple myeloma, comprising administering dedihydrocortistatin A, or a pharmaceutically acceptable salt thereof to a subject in need thereof. [0234] Some embodiments provide a method of treating melanoma, comprising administering a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof to a subject in need thereof. Some embodiments provide a method of treating multiple myeloma, comprising administering a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • Other embodiments include methods of treating an HIV infection or inhibiting HIV replication by administering a compound described herein to a subject in need thereof. Some embodiments include treating a subject already infected with HIV to ameliorate or cure the infection. Other embodiments include administering a compound to subject at risk for infection with HIV to reduce the likelihood that the subject will contract an HIV infection.
  • the subject is a human.
  • Further embodiments include administering a combination of compounds to a subject in need thereof.
  • a combination can include a compound, composition, pharmaceutical composition described herein with an additional medicament.
  • Some embodiments include co-administering a compound, composition, and/or pharmaceutical composition described herein, with an additional medicament.
  • coadministration it is meant that the two or more agents may be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered.
  • the agents are administered simultaneously.
  • administration in combination is accomplished by combining the agents in a single dosage form.
  • the agents are administered sequentially.
  • the agents are administered through the same route, such as orally.
  • the agents are administered through different routes, such as one being administered orally and another being administered i.v.
  • patient includes human and animal subjects.
  • contacting refers to bringing two or more materials into close enough proximity that they may interact.
  • contacting can be accomplished in a vessel such as a test tube, a petri dish, or the like.
  • contacting may be performed in the presence of additional materials.
  • contacting may be performed in the presence of cells.
  • one or more of the materials that are being contacted may be inside a cell. Cells may be alive or may dead. Cells may or may not be intact. Examples
  • the layers were partitioned and the aqueous layer was extracted with DCM (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na 2 S04, filtered, and concentrated in vacuo.
  • the crude mixture was purified by PTLC furnishing the carbamate intermediate (4.2 mg, 32%) as a yellow foam.
  • the resulting mixture was treated with aq. NaHC0 3 , then extracted with mixture of DCM:MeOH (10: 1).
  • the combined extract was dried over Na 2 S0 4 and concentrated in vacuo to afford a deprotected amine intermediate.
  • HUVECs were seeded at 3000 cells/well in 96-well microculture plate (Costar flat bottom # 3997) in a total volume of 100 (jL/well. After 24 hours of incubation in a humidified incubator at 37°C with 5% C0 2 and 95% air, 100 iL of 2X, serially 1 :4 diluted test compounds in growth medium with a final maximal concentration of 10 ⁇ (0.1% DMSO) were added to each well. After 72 hours of culture in a C0 2 incubator, the plated cells and Cell Titer-Glo® (Promega # G7571) reagents were brought to room temperature to equilibrate for 30 minutes.
  • Cell Titer-Glo® Promega # G7571
  • One hundred (100) ⁇ , of the growth medium was removed and 50 ⁇ , of Cell Titer- Glo® reagent was added to each well. The plate was shaken for 10 minutes and then left to equilibrate for 2 minutes before reading luminescence on the Tecan GENios microplate reader.
  • Example 3-2 Percent inhibition of cell growth was calculated relative to untreated control wells. All tests were performed in eight replicates at each concentration level (total 10 concentrations 38 pM to 10 ⁇ ). ⁇ 1 ⁇ 6 IC 50 value for the test agents was estimated using Prism 6.00 by curve-fitting the data. The results for selected compounds disclosed herein are indicated in the table of Example 10 below.
  • Example 3-2
  • HUVEC cells are collected and counted.
  • Cell suspensions are added to each well at a suitable density, with complete medium including endothelial cell growth supplements.
  • the margin wells are filled with PBS.
  • Test compounds at various concentrations (10 concentrations, 10 fold dilutions starting from 10 ⁇ ) are added in duplicate and the cells were incubated for 72 h. After incubation, CellTiter-Glo® Reagent are added to each test well and mixed for 2 minutes on an orbital shaker. The plates are shortly centrifuged at 90g and incubated at room temperature for additional 10 minutes to stabilize the luminescent signal. Luminescence signals are detected on PHERAstar Plus. And data is collected in Microsoft excel forms and analyzed Graphpad Prism software.
  • HeLa-CD4-LTR-LacZ cells are plated at lxl 0 4 cells per well of a 96-well plate. Twenty- four hours later HIV-1 pNL4-3 is added in the presence of testing compound or DMSO control in a total volume of 200 ⁇ .
  • lysis buffer 60 mM Na 2 HPO 4 ,40 mM NaH 2 P0 4 , 10 mM KC1, 10 mM MgS0 4 , 2.5 mM EDTA, 50 mM ⁇ -mercaptoethanol, 0.125% Nonidet P-40
  • CPRG chlorophenol red- ⁇ - ⁇ - galactopyranoside
  • the cell extracts are incubated in a reaction buffer (0.9 M phosphate buffer [pH 7.4], 9 mM MgCl 2 , 11 mM ⁇ - mercaptoethanol, 7 mM CPRG) until a red color develops (from approximately 10 min to 4 h) and is measurable using an LP400 (Becton Dickinson) plate reader at 572 nm. Experiments are performed in triplicate.
  • a reaction buffer 0.9 M phosphate buffer [pH 7.4], 9 mM MgCl 2 , 11 mM ⁇ - mercaptoethanol, 7 mM CPRG
  • a radiometric protein kinase assay ( 33 PanQinase ® Activity Assay) was used for measuring the kinase activity of the CDK8/CycC protein kinases. All kinase assays were performed in 96-well FlashPlatesTM from PerkinElmer (Boston, MA, USA) in a 50 reaction volume. The reaction cocktail was pipetted in four steps in the following order:
  • test compound in 10 % DMSO
  • the assay for all protein kinases contained 70 mM HEPES-NaOH pH 7.5, 3 mM MgCl 2 , 3 mM MnCl 2 , 3 ⁇ Na-orthovanadate, 1.2 mM DTT, 50 ⁇ PEG 20 ooo, ATP cone. (3 ⁇ , [ ⁇ - 33 ⁇ ]- ⁇ (approx. 1 x 10 06 cpm per well), protein kinase (CDK8/CycC, ProQinase Lot 002, Kinase Cone. 50 3 ⁇ 4/50 ⁇ , Kinase Cone.
  • OPM-2 cells were seeded at 3000 cells/well in 96-well microculture plate (Costar flat bottom # 3997) in a total volume of 100 ⁇ . After 24 hours of incubation in a humidified incubator at 37 °C with 5% C02 and 95% air, 100 ⁇ , of 2X, serially 1 :4 diluted SMD-1001 analogs in growth medium with a final maximal concentration of 10 ⁇ (0.1% DMSO) were added to each well. After 72 hours of culture in a C02 incubator, the plated cells and Cell Titer-Glo® (Promega # G7571) reagents were brought to room temperature to equilibrate for 30 minutes.
  • Cell Titer-Glo® Promega # G7571
  • Top is the maximal % of control absorbance
  • Bottom is the minimal % of control absorbance at the highest agent concentration
  • Y is the % of control absorbance
  • X is the agent concentration
  • IC50 is the concentration of agent that inhibits cell growth by 50% compared to the control cells
  • n is the slope of the curve.
  • HIV particles were initially prepared by transient transfection of 293T cells with the pro viral HIV-1 pNL4-3 DNA (1) or ROD/A.
  • Virus stocks for infections were produced by amplification of the virus by acutely infecting CEM-SS cells with HIV-1 pNL4-3 and concentration by ultracentrifugation of the cell supernatant.
  • Virus titers were determined with HIV-1 p24 ELISA from AdvancesBioscience Laboratories. Results were reported as LacZ expression as a percent of DMSO control and the dose response curve fitted to determine IC 50 . The results for selected compounds disclosed herein are indicated in the table of Example 10 below.
  • mice Age-related Macular Degeneration testing uses adult C57BL/6 mice. On day 1 the mice receive laser treatments to the retina of a single eye. In addition mice receive a single intravitreal injection of of the test compound in vehicle (PBS) to the laser treated eye. The volume of the injection is 2 ⁇ . On day 14 post laser treatment the mice are euthanized by cardiac perfusion with FITC-conjugated dextran/4% paraformaldehyde/PBS. Eyes are harvested for analysis. Six mice per group are used (Vehicle, 1 nM dCA, 10 nM dCA, 100 nM dCA, 1 ⁇ dCA, 10 ⁇ dCA) for a total of 36 adult C57BL/6 mice. Controls include laser eyes injected with PBS.
  • the human tumor cell lines of the cancer screening panel are grown in RPMI 1640 medium containing 5% fetal bovine serum and 2 mM L-glutamine.
  • cells are inoculated into 96 well microtiter plates in 100 at plating densities ranging from 5,000 to 40,000 cells/well depending on the doubling time of individual cell lines. After cell inoculation, the microtiter plates are incubated at 37° C, 5 % C0 2 , 95 % air and 100 % relative humidity for 24 h prior to addition of experimental drugs.
  • the plates are incubated for an additional 48 h at 37°C, 5 % C0 2 , 95 % air, and 100 % relative humidity.
  • the assay is terminated by the addition of cold TCA.
  • Cells are fixed in situ by the gentle addition of 50 ⁇ ⁇ of cold 50 % (w/v) TCA (final concentration, 10 % TCA) and incubated for 60 minutes at 4°C. The supernatant is discarded, and the plates are washed five times with tap water and air dried.
  • SRB Sulforhodamine B
  • SRB Sulforhodamine B
  • 1 % acetic acid 1 % acetic acid
  • Bound stain is subsequently solubilized with 10 mM trizma base, and the absorbance is read on an automated plate reader at a wavelength of 515 nm.
  • the methodology is the same except that the assay is terminated by fixing settled cells at the bottom of the wells by gently adding 50 ⁇ of 80 % TCA (final concentration, 16 % TCA).
  • Dedihydrocortistatin A was screened using the above-described procedure. Dedihydrocortistatin A showed negative growth percent for Ml 4 - melanoma and UACC-62 melanoma cell lines indicating a cytotoxic effect. Additionally, Dedihydrocortistatin A showed cytostatic effects for leukemia/multiple myeloma cell lines.

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Abstract

Disclosed herein are compounds useful as anti-cancer and anti-HIV agents. Also disclosed are pharmaceutical compositions and methods of treatment. The compounds disclosed herein can be used to treat a variety of conditions, diseases and ailments such as bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, non-Hodgkin lymphoma, glioblastoma, pancreatic cancer, prostate cancer, and thyroid cancer, and HIV related disorders.

Description

ANTI-CANCER AND ANTI-HIV COMPOUNDS
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application No. 61/761,169, filed February 5, 2013 incorporated herein by reference in its entirety.
BACKGROUND
Field
[0002] This application relates to the fields of chemistry and medicine, more particularly to anti-cancer and anti-HIV compounds, pharmaceutical compositions, and methods of treatment.
Description of the Related Technology
[0003] Since the isolation of the first angiogenesis inhibitors, pathological angiogenesis has become recognized as an "organizing principle" for understanding a variety of otherwise disparate disorders. The most familiar application of anti-angiogenesis therapy effects the regression of solid tumors, where inhibitors are responsible for both direct anti-tumor activity and increased chemotherapeutic uptake through vascular in the clinic. Thus, the has been significant effort to identify new inhibitors of angiogenesis.
[0004] The human immunodeficiency virus type 1 (HIV) Tat protein, a potent activator of HIV gene expression, is essential for integrated viral genome expression and represents a potential antiviral target. Tat binds the 5 '-terminal region of HIV mRNA's stem- bulge-loop structure, the transactivation-responsive (TAR) element, to activate transcription. Inhibition of Tat-mediated transactivation of the integrated provirus by targeting the TAR- binding domain of Tat is under investigation. Identification of active agents that reduce Tat- mediated transcriptional initiation/elongation from the viral promoter to inhibit HIV-1 and HIV- 2 replication in acutely and chronically infected cells is an attractive target for drug discovery research. It is thought compounds that abrogate spontaneous viral particle release from CD4+T cells from virally suppressed subjects on highly active antiretro viral therapy (HAART) may have advantageous properties for treating individuals with diseases that arise from viral sources.
[0005] Development of small-molecule compounds that inhibit angiogenesis or inhibit Tat-mediated transactivation remains an attractive area of research for medicinal chemists. SUMMARY
Some embodiments described herein include a compound of Formula I
Figure imgf000003_0001
[0007] or a pharmaceutically acceptable salt thereof,
[0008] wherein:
[0009] n is 1 or 3;
[0010] p is 1 or 3;
[0011] q is l or 3;
[0012] each R1 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted hydroxyl, an optionally substituted amino, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
[0013] each R2 is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci- C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl, or optionally two geminal R2 together with the atom to which they are attached is an optionally substituted C3-C7 cycloalkyl, or optionally substituted 3-7 membered heterocycle ring, or optionally two adjacent R2 together with the atoms to which they are attached is an optionally substituted C3-C7 cycloalkyl or optionally substituted 3-7 membered heterocycle ring, or optionally two geminal R2 together are oxo;
[0014] each R3 is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci- C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl, or optionally two geminal R3 together with the atom to which they are attached is an optionally substituted C3-C7 cycloalkyl or optionally substituted 3-7 membered heterocycle ring, or optionally two adjacent R3 together with the atoms to which they are attached is an optionally substituted C3-C7 cycloalkyl or optionally substituted 3-7 membered heterocycle ring;
[0015] R4 is selected from the group consisting of halogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
[0016] R5 is selected from the group consisting of -L1-R5A, an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
[0017] L1 is selected from the group consisting of -NHC(=0)-, an optionally substituted Ci-C6 alkyl, an optionally substituted C2-C6 alkenyl and an optionally substituted C2- C6 alkynyl;
[0018] R5A is selected from the group consisting of an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
[0019] R6 is selected from the group consisting of hydrogen, halogen, hydro xyl, -SH, an optionally substituted Ci-C6 alkyl, and an optionally substituted Ci-C6 alkoxy;
[0020] R7 is selected from the group consisting of hydrogen, halogen, hydro xyl, -SH, an optionally substituted Ci-C6 alkyl, and an optionally substituted Ci-C6 alkoxy, or optionally R and R together are oxygen or sulfur;
[0021] R8 is selected from the group consisting of hydrogen, halogen, and an optionally substituted Ci-C6 alkyl;
[0022] each R9 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
[0023] R10 is selected from the group consisting of hydrogen, hydroxyl, an optionally substituted Ci-C6 alkoxy, and optionally substituted Ci-C6 alkyl;
[0024] R11 is selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl, or optionally R10 and R11 together are oxo;
[0025] each R12 is independently selected from the group consisting of hydrogen, halogen, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; and [0026] each dashed line independently represents an optional double bond,
[0027] with the proviso that at least one of R2, R3 or R12 is not hydrogen,
[0028] or with the proviso that when n is 1 , p is 1 , q is 1 , one R1 is -N(CH3)2 and R2
R3 and R12 are hydrogen then R5 is no
[0029] or with the proviso
Figure imgf000005_0001
that R is substituted . In some embodiments, R may be selected from the group consisting of hydrogen, hydroxyl and optionally substituted Ci-C6 alkyl. In some embodiments, R10 may be selected from the group consisting of hydrogen, hydroxyl and methyl. In some embodiments, R10 may be selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl. In some embodiments, L1 may be selected from the group consisting of -NHC(=0)-, an optionally substituted Ci-C6 alkyl, and an optionally substituted C2-C6 alkenyl. In some embodiments, when n is 1, p is 1, q
is 1, and R2, R3 and R12 are hydrogen then R5 is not
Figure imgf000005_0002
[0030] Other embodimens described herein include a compound of Formula II:
Figure imgf000005_0003
[0031] or a pharmaceutically acceptable salt thereof,
[0032] wherein:
[0033] q is 1 or 3; [0034] each R1 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted hydroxyl, an optionally substituted amino, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
[0035] R2 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
[0036] each R3 is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci- C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl, or optionally the two R3 together with the atom to which they are attached is an optionally substituted C3-C7 cycloalkyl or optionally substituted 3-7 membered heterocycle ring;
[0037] R4 is selected from the group consisting of halogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
[0038] R5 is selected from the group consisting of -L1-R5A, an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
[0039] L1 is selected from the group consisting of -NHC(=0)-, an optionally substituted Ci-C6 alkyl, and an optionally substituted C2-C6 alkenyl;
[0040] R5A is selected from the group consisting of an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
[0041] R6 is selected from the group consisting of hydrogen, halogen, hydroxy, -SH, an optionally substituted Ci-C6 alkyl;
[0042] R8 is selected from the group consisting of hydrogen, halogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
[0043] each R9 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
[0044] R10 is selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl; [0045] R11 is selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl, or optionally R10 and R11 together are oxo;
[0046] each R12 is independently selected from the group consisting of hydrogen, halogen, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; and
[0047] each dashed line independently represents an optional double bond.
0048] Still other embodiments described herein include a compound of Formula III:
Figure imgf000007_0001
[0049] and pharmaceutically acceptable salts thereof;
[0050] wherein:
[0051] p is 1 or 3;
[0052] q is 1 or 3;
[0053] each R1 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted hydroxyl, an optionally substituted amino, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
[0054] R2A is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
[0055] R2B is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl, or optionally R2A and R2B together with the atoms to which they are attached is an optionally substituted C3-C7 cycloalkyl or optionally substituted 3-7 membered heterocycle ring;
[0056] each R3 is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl, or optionally two adjacent R3 together with the atoms to which they are attached is an optionally substituted C3-C7 cycloalkyl or optionally substituted 3-7 membered heterocycle ring;
[0057] R4 is selected from the group consisting of halogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
[0058] R5 is selected from the group consisting of -L1-R5A, an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
[0059] L1 is selected from the group consisting of -NHC(=0)-, an optionally substituted Ci-C6 alkyl, and an optionally substituted C2-C6 alkenyl;
[0060] R5A is selected from the group consisting of an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
[0061] R6 is selected from the group consisting of hydrogen, halogen, hydro xyl, -SH, an optionally substituted Ci-C6 alkyl, and an optionally substituted Ci-C6 alkoxy;
[0062] R7 is selected from the group consisting of hydrogen, halogen, hydro xyl, -SH, an optionally substituted Ci-C6 alkyl, and an optionally substituted Ci-C6 alkoxy, or optionally R and R together are oxygen or sulfur;
[0063] R8 is selected from the group consisting of hydrogen, halogen, and an optionally substituted Ci-C6 alkyl;
[0064] each R9 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
[0065] R10 is selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl;
[0066] R11 is selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl, or optionally R10 and R11 together are oxo; [0067] each R12 is independently selected from the group consisting of hydrogen, halogen, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; and
[0068] each dashed line independently represents an optional double bond.
0069] Other embodiments described herein include a compound of Formula IV:
Figure imgf000009_0001
[0070] and pharmaceutically acceptable salts thereof;
[0071] wherein:
[0072] n is 1 or 3;
[0073] q is 1 or 3;
[0074] each R1 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted hydroxyl, an optionally substituted amino, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
[0075] each R2 is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci- C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl, or optionally two adjacent R2 together with the atoms to which they are attached is an optionally substituted C3-C7 cycloalkyl or optionally substituted 3-7 membered heterocycle ring;
[0076] R3A is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
[0077] R3B is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl, or optionally R3A and R3B together with the atoms to which they are attached is an optionally substituted C3-C7 cycloalkyl or optionally substituted 3-7 membered heterocycl ring;
[0078] R4 is selected from the group consisting of halogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
[0079] R5 is selected from the group consisting of -L1-R5A, an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
[0080] L1 is selected from the group consisting of -NHC(=0)-, an optionally substituted Ci-C6 alkyl, and an optionally substituted C2-C6 alkenyl;
[0081] R5A is selected from the group consisting of an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
[0082] R6 is selected from the group consisting of hydrogen, halogen, hydro xyl, -SH, an optionally substituted Ci-C6 alkyl, and an optionally substituted Ci-C6 alkoxy;
[0083] R7 is selected from the group consisting of hydrogen, halogen, hydro xyl, -SH, an optionally substituted Ci-C6 alkyl, and an optionally substituted Ci-C6 alkoxy, or optionally R and R together are oxygen or sulfur;
[0084] R8 is selected from the group consisting of hydrogen, halogen, and an optionally substituted Ci-C6 alkyl;
[0085] each R9 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
[0086] R10 is selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl;
[0087] R11 is selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl, or optionally R10 and R11 together are oxo;
[0088] each R12 is independently selected from the group consisting of hydrogen, halogen, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; and
[0089] each dashed line independently represents an optional double bond.
[0090] Some embodiments described herein include a pharmaceutical composition, comprising a compound described herein and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
[0091] Some embodiments described herein include a method of inhibiting angiogenesis, comprising administering a compound described herein to a subject in need thereof.
[0092] Some embodiments described herein include a method of treating a disease selected from the group consisting of bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, non-Hodgkin lymphoma, pancreatic cancer, prostate cancer, thyroid cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, psoriasis, systematic lupus erythematosus, erythematosus, proliferative retinopathy, and atherosclerosis, comprising administering a compound described herein to a subject in need thereof.
[0093] Some embodiments provide a method of inhibiting CDK8, comprising contacting CDK8 with a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting CDK8 comprises administering a compound to a subject that has cancer. Some embodiments provide a method of inhibiting CDK8, comprising contacting CDK8 with dedihydrocortistatin A, or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting CDK8 comprises administering dedihydrocortistatin A to a subject that has cancer. In some embodiments, the contacting CDK8 comprises administering a compound to a subject that has a viral infection. In some embodiments, the viral infection is HBV, HCV, CMV, and HIV. Some embodiments provide a method of treating a cancer that is not treatable by inhibiting angiogenesis, comprising administering a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof to a subject in need thereof. Some embodiments provide a method of treating a cancer that is not treatable by inhibiting angiogenesis, comprising administering dedihydrocortistatin A, or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is multiple myeloma.
[0094] Some embodiments provide a method of treating melanoma, comprising administering dedihydrocortistatin A, or a pharmaceutically acceptable salt thereof to a subject in need thereof. Some embodiments provide a method of treating multiple myeloma, comprising administering dedihydrocortistatin A, or a pharmaceutically acceptable salt thereof to a subject in need thereof.
[0095] Some embodiments provide a method of treating melanoma, comprising administering a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof to a subject in need thereof. Some embodiments provide a method of treating multiple myeloma, comprising administering a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof to a subject in need thereof.
[0096] Some embodiments described herein include a method of inhibiting HIV replication, comprising administering a compound described herein to a subject infected with HIV.
[0097] Finally, some embodiments described herein include a method of preventing an HIV infection, comprising administering a compound described herein to a subject at risk for said infection.
DETAILED DESCRIPTION
[0098] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the embodiments claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "includes," and "included," is not limiting.
[0099] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, but not limited to, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose.
Definitions
[0100] "Solvate" refers to the compound formed by the interaction of a solvent and a compound described herein or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.
[0101] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of a compound and, which are not biologically or otherwise undesirable for use in a pharmaceutical. In many cases, the compounds disclosed herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297, Johnston et al, published September 11, 1987 (incorporated by reference herein in its entirety).
[0102] As used herein, "Ca to Cb" or "Ca_b" in which "a" and "b" are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from "a" to "b", inclusive, carbon atoms. Thus, for example, a "Ci to C4 alkyl" or "Ci_4 alkyl" group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-.
[0103] The term "halogen" or "halo," as used herein, means any one of the radio- stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.
[0104] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; e.g., "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 9 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be designated as "Ci_4 alkyl" or similar designations. By way of example only, "Ci_4 alkyl" indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.
[0105] As used herein, "alkoxy" refers to the formula -OR wherein R is an alkyl as is defined above, such as "Ci_9 alkoxy", including but not limited to methoxy, ethoxy, n- propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, and the like.
[0106] As used herein, "alkylthio" refers to the formula -SR wherein R is an alkyl as is defined above, such as "Ci_g alkylthio" and the like, including but not limited to methylmercapto, ethylmercapto, n-propylmercapto, 1-methylethylmercapto
(isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec-butylmercapto, tert- butylmercapto, and the like.
[0107] As used herein, "alkenyl" refers to a straight or branched hydrocarbon chain containing one or more double bonds. The alkenyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl" where no numerical range is designated. The alkenyl group may also be a medium size alkenyl having 2 to 9 carbon atoms. The alkenyl group could also be a lower alkenyl having 2 to 4 carbon atoms. The alkenyl group may be designated as "C2_4 alkenyl" or similar designations. By way of example only, "C2_4 alkenyl" indicates that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-l-yl, propen-2-yl, propen-3-yl, buten-l-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-l-yl, 2-methyl-propen-l-yl, 1 -ethyl-ethen-l-yl, 2-methyl-propen-3-yl, buta-l ,3-dienyl, buta-1 ,2,- dienyl, and buta-l ,2-dien-4-yl. Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl, and the like.
[0108] As used herein, "alkynyl" refers to a straight or branched hydrocarbon chain containing one or more triple bonds. The alkynyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl" where no numerical range is designated. The alkynyl group may also be a medium size alkynyl having 2 to 9 carbon atoms. The alkynyl group could also be a lower alkynyl having 2 to 4 carbon atoms.
The alkynyl group may be designated as "C2_4 alkynyl" or similar designations. By way of example only, "C2_4 alkynyl" indicates that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-l-yl, propyn-2-yl, butyn-l-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl. Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.
[0109] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone. The heteroalkyl group may have 1 to 20 carbon atom, although the present definition also covers the occurrence of the term "heteroalkyl" where no numerical range is designated. The heteroalkyl group may also be a medium size heteroalkyl having 1 to 9 carbon atoms. The heteroalkyl group could also be a lower heteroalkyl having 1 to 4 carbon atoms. The heteroalkyl group may be designated as "Ci_4 heteroalkyl" or similar designations. The heteroalkyl group may contain one or more heteroatoms. By way of example only, "Ci_4 heteroalkyl" indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.
[0110] The term "aromatic" refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.
[0111] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, every ring in the system is aromatic. The aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term "aryl" where no numerical range is designated. In some embodiments, the aryl group has 6 to 10 carbon atoms. The aryl group may be designated as "C6-io aryl," "C6 or C10 aryl," or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.
[0112] As used herein, "aryloxy" and "arylthio" refers to RO- and RS-, in which R is an aryl as is defined above, such as "C6-io aryloxy" or "C6-io arylthio" and the like, including but not limited to phenyloxy.
[0113] An "aralkyl" or "arylalkyl" is an aryl group connected, as a substituent, via an alkylene group, such as "C7-14 aralkyl" and the like, including but not limited to benzyl, 2- phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C1-4 alkylene group). [0114] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone. When the heteroaryl is a ring system, every ring in the system is aromatic. The heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heteroaryl" where no numerical range is designated. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group may be designated as "5-7 membered heteroaryl," "5-10 membered heteroaryl," or similar designations. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.
[0115] A "heteroaralkyl" or "heteroarylalkyl" is heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2-thienylmethyl, 3- thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazoUylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a Ci_4 alkylene group).
[0116] As used herein, "carbocyclyl" means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When the carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion. Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic. Thus, carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls. The carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term "carbocyclyl" where no numerical range is designated. The carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms. The carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms. The carbocyclyl group may be designated as "C3_6 carbocyclyl" or similar designations. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.
[0117] A "(carbocyclyl)alkyl" is a carbocyclyl group connected, as a substituent, via an alkylene group, such as "C4_io (carbocyclyl)alkyl" and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. In some cases, the alkylene group is a lower alkylene group.
[0118] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[0119] As used herein, "cycloalkenyl" means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. An example is cyclohexenyl.
[0120] As used herein, "heterocyclyl" means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system. The heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heterocyclyl" where no numerical range is designated. The heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members. The heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members. The heterocyclyl group may be designated as "3-6 membered heterocyclyl" or similar designations. In preferred six membered monocyclic heterocyclyls, the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1 ,4-dioxinyl, 1 ,4-dioxanyl, 1,3-oxathianyl, 1,4- oxathiinyl, 1 ,4-oxathianyl, 2H-l,2-oxazinyl, trioxanyl, hexahydro-l,3,5-triazinyl, 1,3-dioxolyl,
1.3 - dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-
1.4- thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline. [0121] A "(heterocyclyl)alkyl" is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.
[0122] As used herein, "acyl" refers to -C(=0)R, wherein R is hydrogen, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.
[0123] An "O-carboxy" group refers to a "-OC(=0)R" group in which R is selected from hydrogen, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0124] A "C-carboxy" group refers to a "-C(=0)OR" group in which R is selected from hydrogen, Ci_6 alkyl, C2-6 alkenyl, C2_6 alkynyl, C3_7 carbocyclyl, C6_io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. A non- limiting example includes carboxyl (i.e., -C(=0)OH).
[0125] A "cyano" group refers to a "-CN" group.
[0126] A "cyanato" group refers to an "-OCN" group.
[0127] An "isocyanato" group refers to a "-NCO" group.
[0128] A "thiocyanato" group refers to a "-SCN" group.
[0129] An "isothiocyanato" group refers to an " -NCS" group.
[0130] A "sulfinyl" group refers to an "-S(=0)R" group in which R is selected from hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0131] A "sulfonyl" group refers to an "-SO2R" group in which R is selected from hydrogen, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_7 carbocyclyl, C6-1o aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0132] An "S-sulfonamido" group refers to a "-S02NRARB" group in which RA and RB are each independently selected from hydrogen, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_7 carbocyclyl, C6-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0133] An "N-sulfonamido" group refers to a "-N(RA)S02RB" group in which RA and Rb are each independently selected from hydrogen, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_7 carbocyclyl, C6-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. [0134] An "O-carbamyl" group refers to a "-OC(=0)NRARB" group in which RA and RB are each independently selected from hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 carbocyclyl, C6-1o aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0135] An "N-carbamyl" group refers to an "-N(RA)C(=0)ORB" group in which RA and RB are each independently selected from hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3- 7 carbocyclyl, C6-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0136] An "O-thiocarbamyl" group refers to a "-OC(=S)NRARB" group in which RA and RB are each independently selected from hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3- 7 carbocyclyl, C6-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0137] An "N-thiocarbamyl" group refers to an "-N(RA)C(=S)ORB" group in which RA and RB are each independently selected from hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 carbocyclyl, C6-1o aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0138] A "urea" group refers to a "-N(RA)C(=0)NRARB" group in which RA and RB are each independently selected from hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 carbocyclyl, C6-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0139] A "C-amido" group refers to a "-C(=0)NRARB" group in which RA and RB are each independently selected from hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 carbocyclyl, C6-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0140] An "N-amido" group refers to a "-N(RA)C(=0)RB" group in which RA and RB are each independently selected from hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 carbocyclyl, C6-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0141] An "amino" group refers to a "-NRARB" group in which RA and RB are each independently selected from hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 carbocyclyl, C6-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. A non-limiting example includes free amino (i.e., -NH2).
[0142] An "aminoalkyl" group refers to an amino group connected via an alkylene group. [0143] An "alkoxyalkyl" group refers to an alkoxy group connected via an alkylene group, such as a "C2_g alkoxyalkyl" and the like.
[0144] As used herein, a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group. Unless otherwise indicated, when a group is deemed to be "substituted," it is meant that the group is substituted with one or more subsitutents independently selected from Ci-C6 alkyl, Ci-C6 alkenyl, Ci-C6 alkynyl, Ci-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy), C3-C7-carbocyclyl-Ci- C6-alkyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy), 5-10 membered heterocyclyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy), 5-10 membered heterocyclyl-Ci-C6-alkyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy), aryl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy), aryl(Ci-C6)alkyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy), 5-10 membered heteroaryl(Ci-Ce)alkyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy), halo, cyano, hydroxy, Ci-C6 alkoxy, Ci-C6 alkoxy(Ci- C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(Ci-C6)alkyl (e.g., -CF3), halo(Ci- C6)alkoxy (e.g., -OCF3), Ci-C6 alkylthio, arylthio, amino, amino(Ci-C6)alkyl, nitro, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N- sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfmyl, sulfonyl, and oxo (=0). Wherever a group is described as "optionally substituted" that group can be substituted with the above substituents.
[0145] It is to be understood that certain radical naming conventions can include either a mono-radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical. For example, a substituent identified as alkyl that requires two points of attachment includes di-radicals such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, and the like. Other radical naming conventions clearly indicate that the radical is a di-radical such as "alkylene" or "alkenylene."
[0146] When two R groups are said to form a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring) "together with the atom to which they are attached," it is meant that the collective unit of the atom and the two R groups are the recited ring. The ring is not otherwise limited by the definition of each R group when taken individually. For example, when following substructure is present:
Figure imgf000021_0001
and R1 and R2 are defined as selected from the group consisting of hydrogen and alkyl, or R and R2 together with the nitrogen to which they are attached form a heteroaryl, it is meant that R1 and R2 can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:
Figure imgf000021_0002
where ring E is a heteroaryl ring contain ng the depicted nitrogen.
[0147] Similarly, when two "adjacent" R groups are said to form a ring "together with the atom to which they are attached," it is meant that the collective unit of the atoms, intervening bonds, and the two R groups are the recited ring. For example, when the following substructure is present:
Figure imgf000021_0003
and R1 and R2 are defined as selected from the group consisting of hydrogen and alkyl, or R and R2 together with the atoms to which they are attached form an aryl or carbocylyl, it is meant that R1 and R2 can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:
Figure imgf000021_0004
where E is an aryl ring or a carbocylyl containing the depicted double bond.
[0148] Wherever a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated. Thus, for example, a substituent A
depicted as -AE- or E includes the substituent being oriented such that the A is attached at the leftmost attachment point of the molecule as well as the case in which A is attached at the rightmost attachment point of the molecule.
[0149] "Subject" as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
[0150] The term "mammal" is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice guinea pigs, or the like.
[0151] An "effective amount" or a "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent that is effective to relieve, to some extent, or to reduce the likelihood of onset of, one or more of the symptoms of a disease or condition, and includes curing a disease or condition. "Curing" means that the symptoms of a disease or condition are eliminated; however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).
[0152] "Treat," "treatment," or "treating," as used herein refers to administering a compound or pharmaceutical composition to a subject for prophylactic and/or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering treatment to a subject already suffering from a disease or condition.
Compounds
[0153] The skilled artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly represented by other chemical structures, even when kinetically; the artisan recognizes that such structures may only represent a very small portion of a sample of such compound(s). Such compounds are considered within the scope of the structures depicted, though such resonance forms or tautomers are not represented herein.
[0154] Isotopes may be present in the compounds described. Each chemical element present in a compound either specifically or generically described hereinmay include any isotope of said element. For example, in a compound specifically or generically described herein a hydrogen atom may be explicitly disclosed or understood to be present in the compound and each such hydrogen atom is any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
[0155] Some embodiments include compounds of Formula I as described above. In some embodiments the compounds of Formula I have the structure of Formula la:
Figure imgf000023_0001
[0156] or a pharmaceutically acceptable salt thereof, wherein each R is hydrogen.
[0157] In some embodiments of formulae I or la, each R1 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted hydroxyl, and an optionally substituted amino;
[0158] each R2 is independently selected from the group consisting of hydrogen, halogen, and hydroxy, or optionally two adjacent R2 together with the atoms to which they are attached is an optionally substituted C3-C7 cycloalkyl;
[0159] each R3 is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, and an optionally substituted Ci-C6 alkyl; and
[0160] R10 is selected from the group consisting of hydrogen and Ci-C6 alkyl; and
[0161] R11 is selected from the group consisting of hydrogen and Ci-C6 alkyl.
[0162] In some embodiments of formulae I or la, each R1 is independently selected from the group consisting of hydrogen, hydroxyl, and -N(Methyl)2;
[0163] each R2 is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, and hydroxy, or optionally two adjacent R2 together with the atoms to which they are attached is an optionally substituted cyclopropyl;
[0164] each R3 is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, cyano, thiocyanato, methyl, and trifluoromethyl; [0165] R5 is selected from the group consisting of -L1-R5A and an optionally substituted heteroaryl;
[0166] L1 is selected from the group consisting of -NHC(=0)-, C1-C3 alkyl, and an optionally substituted C2-C4 alkenyl;
[0167] R5A is an optionally substituted heteroaryl;
[0168] R10 is selected from the group consisting of hydrogen and methyl; and
[0169] R11 is selected from the group consisting of hydrogen and methyl.
[0170] In some embodiments, the compound of Formula la may have the structure of Formula Iaa:
Figure imgf000024_0001
(Iaa)
or a pharmaceutically acceptable salt thereof,
wherein:
R5 is selected from the group consisting of -L1-R5A, an optionally substituted aryl and an optionally substituted heteroaryl;
L1 is selected from the group consisting of -NHC(=0)- and ethynyl;
R5A is selected from the group consisting of an optionally substituted aryl and an optionally substituted heteroaryl.
[0171] In some embodiments, the compound of Formula la may have the structure of Formula lab:
Figure imgf000025_0001
(lab)
or a pharmaceutically acceptable salt thereof,
wherein:
R5 is selected from the group consisting of -L1-R5A, an optionally substituted aryl and an optionally substituted heteroaryl;
L1 is selected from the group consisting of -NHC(=0)- and ethynyl;
R5A is selected from the group consisting of an optionally substituted aryl and an optionally substituted heteroaryl.
[0172] In some embodiments, the compound of Formula la may have the structure of Formula lac:
Figure imgf000025_0002
(lac)
or a pharmaceutically acceptable salt thereof,
wherein:
R5 is selected from the group consisting of -I^-R5^ an optionally substituted aryl and optionally substituted heteroaryl;
L1 is selected from the group consisting of -NHC(=0)- and ethynyl;
R5A is selected from the group consisting of an optionally substituted aryl and an optionally substituted heteroaryl. [0173] In some embodiments of any of Formulae I-IV, at least one R1 is hydroxyl. In some embodiments of any of Formulae I-IV, at least two R1 are hydroxyl. In some embodiments of any of Formulae I-IV, at least one R1 is -N(CH3)2. In some embodiments of any of Formulae I-IV and any of the foregoing embodiments defining R1, R5 is an optionally substituted aryl. In some embodiments of any of Formulae I-IV and any of the foregoing embodiments defining R1, R5 is an optionally substituted phenyl. In some embodiments of any of Formulae I-IV and any of the foregoing embodiments defining R1, R5 is phenyl. In some embodiments of any of Formulae I-IV and any of the foregoing embodiments defining R1, R5 is an optionally substituted heteroaryl. In some embodiments of any of Formulae I-IV and any of the foregoing embodiments defining R1, R5 is pyridinyl, quinolinyl, quinazolinyl, phthalazinyl, 3-methyl-iH- indazolyl, iH-indazolyl, l-(difluoromethyl)-isoquinolinyl, 3-amino-7-quinazolinyl, isoquinol-1- one-7-yl, N-propyl-isoquinolin-7-yl-l -amine, or N-propyl-quinazolin-7-yl-4-amine. In some embodiments of any of Formulae I-IV and any of the foregoing embodiments defining R1, R5 is an optionally substituted isoquinolinyl. In some embodiments of any of Formulae I-IV and any of the foregoing embodiments defining R1, R5 is -LX-R5A. In some such embodiments of any of Formulae I-IV and any of the foregoing embodiments defining R1, R5A an optionally substituted heteroaryl. In some such embodiments of any of Formulae I-IV and any of the foregoing embodiments defining R1, R5A an optionally pyridinyl. In some embodiments of any of Formulae I-IV and any of the foregoing embodiments defining R1, R5 is -C(=0)NH-R5A, where
R5A
is as defined herein, and in some embodiments, is optionally substituted heteroaryl (or specifically pyridinyl). In some embodiments of any of Formulae I-IV and any of the foregoing embodiments defining R1, R5 is -C≡C-R5A, where R5A is as defined herein, and in some embodiments, is optionally substituted heteroaryl (or specifically pyridinyl).
[0174] Other embodiments include compounds of Formula II as described above. In some embodiments of Formula II, each R1 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted hydroxyl, and an optionally substituted amino;
[0175] R2 is hydrogen or Ci-C3 alkyl;
[0176] each R3 is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, and an optionally substituted Ci-C6 alkyl;
[0177] R10 is selected from the group consisting of hydrogen and Ci-C6 alkyl; and
[0178] R11 is selected from the group consisting of hydrogen and Ci-C6 alkyl.
[0179] Some embodiments of Formula II have the structure of Formula Ila:
Figure imgf000027_0001
or a pharmaceutically acceptable salt thereof, wherein each R12 is hydrogen. In some embodiments of Formula II, each R1 is independently selected from the group consisting of hydrogen, hydroxyl, and -N(Methyl)2;
[[00118822]] RR55 is selected from the group consisting of -LX-R5A and an optionally substituted heteroaryl;
[0183] selected from the group consisting of -NHC(=0)-, C 1-C3 alkyl, and C2
C4 alkenyl; and
[0184] R is an optionally substituted heteroaryl.
[0185] Other embodiments include a compound of Formula III as described above.
[0186] Still other embodiments include a compound of Formula IV as described above.
[0187] Specific examples of the compounds described herein are depicted in Table 1 below wherein R5 is selected from the group consisting of the structures depicted in Table 2 in the specification. Other specific examples include the structures depicted in Table 4.
[0188] In some alternative embodiments of Formulae I-IV, R5A may be substuituted with a tetrahydro-lH-thieno[3,4-d]imidazol-2(3H)-one containing moiety, In some alternative embodiments of Formulae I-IV, R 5A may be substuituted with
Figure imgf000027_0002
Methods of Preparation
[0189] The compounds disclosed herein may be synthesized by methods described below, or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc., known to those skilled in the art. In general, during any of the processes for preparation of the compounds disclosed herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973); and P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), which are both hereby incorporated herein by reference in their entirety. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Synthetic chemistry transformations useful in synthesizing applicable compounds are known in the art and include e.g. those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, which are both hereby incorporated herein by reference in their entirety. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.
Scheme
Figure imgf000028_0001
[0190] Scheme I provides compounds of general Formula I having the structure of I- II- A. The compound of Formula I-A may be obtained using procedures know in the art and simple modificatons thereof, for example as described in U.S. Pub. No. 2011/0060140 and Shi et al., "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011, 133(20): 8014-8027 each disclosure of which is incorporated herein by reference in its entirety. The compound of Formula I-A may be reacted under conditions known in the art, for example under Stille or Suzuki conditions, to afford the compounds of Formula II-A. The variables R5 and R in Scheme I are defined appropriate to the reaction conditions and procedures. For example, R5 may be aryl or heteroaryl.
Scheme II
Figure imgf000029_0001
wherein n, p, and q are 0, or 2 and at least one n, p, or q is 2.
[0191] Scheme II provides compounds of general Formula I having the structure of II-B. The compound of Formula II-A may be reacted under conditions known in the art, for example as described in Leggans et al, Org. Lett., 2011, 14, 1428-1431; Barker et al., J. Am. Chem. Soc, 2012, 134, 13588-13591; Gaspar et al, Angew. Chem. Int. Ed., 2007, 46, 4519- 4522; Gaspar et al, Synthesis, 2007, 3839-3845; Gaspar et al, Angew. Chem. Int. Ed., 2008, 47, 5758-5760; and Isayama et al, Chem. Lett. 1989, 1071-1074 each disclosure of which is incorporated herein by reference in its entirety, to afford the compounds of Formula II-B. The variables R2, R3, and R12 in the compound of Formula II-B are defined appropriate to the reaction conditions and procedures. For example, each R2, R3, and R12 may be independently selected from, but is not limited to, the group consisting of hydrogen, hydroxyl, chloro, fluoro, cyano, and nitro.
Scheme III
Figure imgf000029_0002
[0192] The process of Scheme III provides compounds of general Formula I having the structure of Formula III-A. The compound of Formula II-A may be reacted under cyclopropanation conditions known in the art, for example as described in Grieco et al., J. Org. Chem., 1977, 42(25): 4113-4118 the disclosure of which is incorporated herein by reference in its entirety. For example, the compound of Formula II-A may be reacted under Simmons-Smith reaction conditions to afford a compound of Formula III-A. The variables R5 and R in Scheme III, are defined appropriate to the reaction conditions and procedures. For example, R5 may be aryl or heteroaryl.
Scheme IV
Figure imgf000030_0001
[0193] Scheme IV provides compounds of general Formula I having the structure of IV-D. The compound of Formula IV-A may be prepared according to the procedures described in U.S. Pub. No. 2011/0060140. The compound of Formula IV-A may be reacted under conditions known in the art, for example under Sharpless Epoxidation conditions as described in Johnson et al., "Catalytic Asymmetric Epoxidation of Allylic Alcohols," Catalytic Asymmetric Synthesis, 2nd ed., Ojima, I. Ed., Wiley-CVH: New York, 2000; 231-280; Katsuki, T., "Epoxidation of Allylic Alcohols," Comprehensive Asymmetric Catalysis," 1st ed., Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Eds., Springer: New York, 1999; Vol. 2, 621-648; Johnson et al, "Addition Reactions with Formation of Carbon-Oxygen Bonds: Asymmetric Methods of Epoxidation," Comprehensive Organic Synthesis, 1st ed., Trost, B. M., Fleming, I. Eds., Pergamon Press: New York, 1991; Vol. 7, 389-436; and Jacobsen, E., "Transition Metal- catalyzed Oxidations: Asymmetric Epoxidation," Comprehensive Organometallic Chemistry II, 1st ed.; Abel, E. W.; Stone, F. G. A.; Wilkinson, G. Eds., Pergamon Press: New York,1995; Vol. 12, 1097-1135 each disclosure of which is incorporated herein by reference in its entirety, to form an epoxide of Formula IV-B. The compound of Formula IV-B may be reacted under conditions known in the art, for example under acidic conditions as described in Sheppard, W.A.; Sharts, CM., Organic Fluorine Chemistry, W.A. Benjamin, NY, 1969, pp. 52-184, 409- 430 the disclosure of which is incorporated herein by reference in its entirety, to afford a halohydrin of Formula IV-C. The halohydrin of Formula IV-C may be reacted under procedures know in the art, for example as described in U.S. Pub. No. 2011/0060140 and Shi et al, "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011, 133(20): 8014-8027 the disclosure of which is incorporated herein by reference in its entirety, to afford a compound of Formula IV-D. The variable R2 in the compound of Formula IV-D are defined appropriate to the reaction conditions and procedures. For example, R2 may be chloro, fluoro, or bromo, but is not limited thereto. The variable R5 may be defined appropriate to the reaction conditions and procedures. For example, R5 may be aryl or heteroaryl.
Scheme V
Figure imgf000032_0001
[0194] The process of Scheme V provides compounds of general Formula I having the structure of Formula V-A. The compound of Formula V-A may be prepared according to the procedures described in U.S. Pub. No. 2011/0060140. The compound of Formula V-A may be reacted under conditions known in the art, for example under nucleophilic trifuoromethylation conditions as described in Singh et al., "Nucleophilic Trifuoromethylation Reactions of Organic Compounds with (Trifuoromethyl)trimethylsilane," Tetrahedron, 2000, 56: 7613 the disclosure of which is incorporated herein by reference in its entirety, to afford a compound of Formula V- B. The compound of Formula V-B may be reacted under conditions described in U.S. Pub. No. 2011/0060140 and Shi et al., "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011, 133(20): 8014-8027 the disclosure of which is incorporated herein by reference in its entirety, to afford a compound of Formula V-C. The compound of Formula V-C may be reacted under conditions described in U.S. Pub. No. 2011/0060140 and Shi et al., "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011, 133(20): 8014-8027 to afford a compound of Formula V-D. The variable R3 in the compound of Formula V-C is defined appropriate to the reaction conditions and procedures. For example, R3 may be methyl or trifluoromethyl, but is limited thereto. The variable R5 may be defined appropriate to the reaction conditions and procedures. For example, R5 may be aryl or heteroaryl.
Scheme VI
Figure imgf000033_0001
[0195] The process of Scheme VI provides compounds of general Formula I having the structure of Formula VI-E and VI-F. The compound of Formula V-A may be reacted under conditions known in the art, for example under electrophilic reaction using LDA and a reagent including an electrophile to afford a compound of Formula VI-A and VI-B. For example, the reagent including an electrophile may be methyl iodide (E-I where the methyl group corresponds to E) providing R10 and R11 defined as methyl in the formula of Scheme VI. The compound of Formula VI-A and VI-B may be reacted under conditions known in the art, for example described in U.S. Pub. No. 2011/0060140 and Shi et al, "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011, 133(20): 8014-8027 the disclosure of which is incorporated herein by reference in its entirety, to afford a compound of Formula VI-A or VI-B. The compound of Formula VI-A or VI-B may be reacted under conditions known in the art, for example under conditions described in U.S. Pub. No. 2011/0060140 and Shi et al, "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011, 133(20): 8014-8027 to afford a compound of Formula VI-C or VI-D. The compound of Formula VI-C or VI-D may be reacted under conditions known in the art, for example under conditions described in U.S. Pub. No. 2011/0060140 and Shi et al, "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011, 133(20): 8014- 8027 to afford a compound of Formula VI-E or VI-F. The variables R5, R10, and R11 may be defined appropriate to the reaction conditions and procedures. For example, R5 may be aryl or heteroaryl, and R10, and R11 may be methyl, chloro, fluoro, or bromo.
Scheme VII
Figure imgf000034_0001
[0196] The process of Scheme VII provides compounds of general Formula I having the structure of Formula VII-B. The compound of Formula VII-A may be obtained according to procedures known in the art, for example described in U.S. Pub. No. 2011/0060140 and Shi et al., "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011,
133(20): 8014-8027, to afford a compound of Formula VII-A. The compound of Formula VII-A may be reacted under procedures known in the art, for example described in U.S. Pub. No.
2011/0060140 and Shi et al., "Scalable Synthesis of Cortistatin A and Related Structures," J.
Am. Chem. Soc, 2011, 133(20): 8014-8027 the disclosure of which is incorporated herein by reference in its entirety, to afford a compound of Formula VII-B. The variable R5 may be defined appropriate to the reaction conditions and procedures. For example, R5 may be aryl or heteroaryl.
Scheme VIII
Figure imgf000035_0001
[0197] The process of Scheme VIII provides compounds of general Formula I having the structure of Formula VIII-C and VIII-D. The compound of Formula VIII-A and VIII-B may be reacted under conditions known in the art, for example described in U.S. Pub. No. 2011/0060140 and Shi et al, "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011, 133(20): 8014-8027, to afford a compound of Formula VIII-A or VIII-B. The compound of Formula VIII-A or VIII-B may be reacted under conditions known in the art, for example under conditions described in U.S. Pub. No. 2011/0060140 and Shi et al., "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011, 133(20): 8014-8027 to afford a compound of Formula VIII-C or VIII-D. The variables R5, R10, and R11 may be defined appropriate to the reaction conditions and procedures. For example, R5 may be aryl or heteroaryl, and R10, and R11 may be methyl, chloro, fluoro, or bromo. Scheme IX
Figure imgf000036_0001
[0198] The process described in Scheme IX provides cortistatin A and compound 101. Compound IX-A may be reacted under conditions known in the art, for example under conditions described in U.S. Pub. No. 2011/0060140 and Shi et al, "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011, 133(20): 8014-8027 to afford compound IX-B. In some embodiments, compound IX-A in absolute ethyl alcohol may be reacted with hydrazine monohydrate in the presence of triethyl amine and ethyl alcohol. After removal of the solvent the obtained residue may be combined with THF and triethyl amine and then treated with I2 (iodine) in THF under appropriate conditions to afford compound IX-B. Compound IX-B may be reacted under conditions described in U.S. Pub. No. 2011/0060140 and Shi et al., "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011, 133(20): 8014-8027 to afford compound of Formula V-D. In some embodiments, compound IX-B in DMSO may be reacted with 7-trimethylstannylisoquinoline in the presence of CuCl, LiCl, and Pd(PPh3)4 under appropriate conditions to afford dehydrocortistatin A. Dehydrocortistatin A may be reacted under conditions described in U.S. Pub. No. 2011/0060140 and Shi et al., "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011, 133(20): 8014-8027 to afford cortistatin A and compound 101. In some embodiments, dehydrocortistatin A in THF may be reacted with triisopropylbenzenesulfonyl hydrazide in the presence of triethyl amine under appropriate conditions to afford cortistatin A and compound 101. Scheme X
Figure imgf000037_0001
[0199] The process described in Scheme X provides compound 103. Compound IX- B may be reacted under conditions known in the art to afford compound 103. In some embodiments, compound IX-B, Pd(PPh )4 and 3-aminopyridine in degassed DMF/NEt3 may be treatd with CO gas to afford compound compound 103.
Scheme XI
Figure imgf000037_0002
104
[0200] The process described in Scheme XI provides compound 104. Compound IX- B may be reacted under conditions known in the art to afford compound 104. In some embodiments, compound IX-B, 3-ethynylpyridine, Pd(PPh3)2Cl2, Cul and Et3N in degassed DMF/NEt3 may be reacted under appropriate conditions to afford compound 104.
Figure imgf000038_0001
[0201] The process described in Scheme XII provides compounds 105 and 106. Dedihydrocortistatin A may be reacted under conditions known in the art to afford compounds 105 and 106. In some embodiments, dedihydrocortistatin A, and I2 (iodine) in methyl alcohol and water may be treated with NaOH and I2 (iodine) under appropriate conditions to afford compounds 105 and 106.
Scheme XIII
Figure imgf000038_0002
[0202] The process described in Scheme XIII provides compound 107. Compound 105 may be reacted under conditions known in the art to afford compound 107. In some embodiments, compound 105 in water and 2N HCl may be treated with Ac20, NaHC03 and DCM under appropriate conditions to afford compound 107. Scheme XIV
Figure imgf000039_0001
[0203] The process described in Scheme XIV provides compound 102. Compound IX-A may be reacted under conditions known in the art, for example under conditions described in U.S. Pub. No. 2011/0060140 and Shi et al, "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011, 133(20): 8014-8027 to afford dihydro vinyl iodide XV-A. In some embodiments, compound IX-A in absolute ethyl alcohol may be reacted with hydrazine monohydrate in the presence of triethyl amine and ethyl alcohol. After removal of the solvent the obtained residue may be combined with THF and triethyl amine and then treated with I2 (iodine) in THF under appropriate conditions to afford compound XV-A. Compound XV-A may be reacted under conditions described in U.S. Pub. No. 2011/0060140 and Shi et al, "Scalable Synthesis of Cortistatin A and Related Structures," J. Am. Chem. Soc, 2011, 133(20): 8014- 8027 to afford compound 102. In some embodiments, compound XV-A in DMSO may be reacted with 7-trimethylstannylisoquinoline in the presence of CuCl, LiCl, and Pd(PPh3)4 under appropriate conditions to afford compound 102. Administration and Pharmaceutical Compositions
[0204] The compounds are administered at a therapeutically effective dosage. While human dosage levels have yet to be optimized for the compounds described herein, generally, a daily dose may be from about 0.25 mg/kg to about 120 mg/kg or more of body weight, from about 0.5 mg/kg or less to about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body weight, or from about 1.5 mg/kg to about 10 mg/kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be from about 17 mg per day to about 8000 mg per day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg to about 3000 mg per day. The amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
[0205] Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments.
[0206] The compounds useful as described above can be formulated into pharmaceutical compositions for use in treatment of these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), incorporated herein by reference in its entirety. Accordingly, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereoisomers, tautomers, polymorphs, and solvates thereof), or pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
[0207] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.
[0208] Some examples of substances, which can serve as pharmaceutically- acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.
[0209] The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.
[0210] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specifically excluded. The skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.
[0211] The compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration. The skilled artisan will appreciate that oral and nasal compositions include compositions that are administered by inhalation, and made using available methodologies. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all incorporated by reference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).
[0212] Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric- coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
[0213] The pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for peroral administration is well-known in the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.
[0214] Peroral compositions also include liquid solutions, emulsions, suspensions, and the like. The pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
[0215] Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
[0216] Compositions described herein may optionally include other drug actives.
[0217] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystallme cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
[0218] A liquid composition, which is formulated for topical ophthalmic use, is formulated such that it can be administered topically to the eye. The comfort may be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort. In the case that comfort cannot be maximized, the liquid may be formulated such that the liquid is tolerable to the patient for topical ophthalmic use. Additionally, an ophthalmically acceptable liquid may either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.
[0219] For ophthalmic application, solutions or medicaments are often prepared using a physiological saline solution as a major vehicle. Ophthalmic solutions may preferably be maintained at a comfortable pH with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
[0220] Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuric nitrate. A useful surfactant is, for example, Tween 80. Likewise, various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
[0221] Tonicity adjusters may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster.
[0222] Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. For many compositions, the pH will be between 4 and 9. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
[0223] In a similar vein, an ophthalmically acceptable antioxidant includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
[0224] Other excipient components, which may be included in the ophthalmic preparations, are chelating agents. A useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.
[0225] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.
[0226] For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HC1, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7.
Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al., Compendium of
Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future
Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.
[0227] The compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration. In other embodiments, the compositions are provided in solution ready to administer parenterally. In still other embodiments, the compositions are provided in a solution that is further diluted prior to administration. In embodiments that include administering a combination of a compound described herein and another agent, the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.
[0228] The actual dose of the active compounds described herein depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
Methods of Treatment
[0229] Some embodiments include methods of inhibiting angiogenesis by administering a compound described herein to a subject in need of anti-angiogenesis therapy. The disease treated may be any disease or disorder associated with abnormal or undesirable angiogenesis. In some embodiment, angiogenesis is inhibited in a cancerous tumor. Anti- angiogenesis therapy is expected to be effective to treat all types of cancerous tumors regardless of etimology, including but not limited to a carcinoma, a sarcoma, a lymphoma, and a blastoma. Non-limiting cancers that can be treated using the compounds described herein include bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, non-Hodgkin lymphoma, glioblastoma, pancreatic cancer, prostate cancer, and thyroid cancer. In addition, any other non-cancer disease or disorder associated with angiogenesis may be treated, including but not limited to diabetic blindness, age-related macular degeneration, rheumatoid arthritis, psoriasis, systematic lupus erythematosus, proliferative retinopathy, and atherosclerosis.
[0230] In other embodiments, the compounds disclosed herein may be used as a transcription inhibitor, such as through inhibition of CDK8. In other embodiments, the inhibition of CDK8 inhibits cell division. Thus, some embodiments include the treatment of proliferative disorders such as cancer through a mechanism distinct or in addition to anti- angiogenesis. Thus, some embodiments include the treatment of cancer including, but not limited to a carcinoma, a sarcoma, a lymphoma, a leukemia, and a blastoma. Non-limiting cancers that can be treated using the compounds described herein include bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, non-Hodgkin lymphoma, leukemia, glioblastoma, pancreatic cancer, prostate cancer, and thyroid cancer.
[0231] It has previously been shown that compounds that specifically inhibit CDK8 inhibit HIV-1 replication. In some embodiments, compounds disclosed herein may be used to treat viral diseases through the inhibition of CDK8. Thus, other embodiments include methods of treating an HIV infection or inhibiting HIV replication by administering a compound described herein that inhibits CDK8. Some embodiments include treating a subject already infected with HIV to ameliorate or cure the infection by administering a compound described herein that inhibits CDK8. Other embodiments include administering a compound to subject at risk for infection with HIV to reduce the likelihood that the subject will contract an HIV infection by administering a compound described herein that inhibits CDK8.
[0232] Some embodiments provide a method of inhibiting CDK8, comprising contacting CDK8 with a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting CDK8 comprises administering a compound to a subject that has cancer. Some embodiments provide a method of inhibiting CDK8, comprising contacting CDK8 with dedihydrocortistatin A, or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting CDK8 comprises administering dedihydrocortistatin A to a subject that has cancer. Some embodiments provide a method of treating a cancer that is not treatable by inhibiting angiogenesis, comprising administering a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof to a subject in need thereof. Some embodiments provide a method of treating a cancer that is not treatable by inhibiting angiogenesis, comprising administering dedihydrocortistatin A, or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is multiple myeloma.
[0233] Some embodiments provide a method of treating melanoma, comprising administering dedihydrocortistatin A, or a pharmaceutically acceptable salt thereof to a subject in need thereof. Some embodiments provide a method of treating multiple myeloma, comprising administering dedihydrocortistatin A, or a pharmaceutically acceptable salt thereof to a subject in need thereof. [0234] Some embodiments provide a method of treating melanoma, comprising administering a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof to a subject in need thereof. Some embodiments provide a method of treating multiple myeloma, comprising administering a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof to a subject in need thereof.
[0235] Other embodiments include methods of treating an HIV infection or inhibiting HIV replication by administering a compound described herein to a subject in need thereof. Some embodiments include treating a subject already infected with HIV to ameliorate or cure the infection. Other embodiments include administering a compound to subject at risk for infection with HIV to reduce the likelihood that the subject will contract an HIV infection.
[0236] In some embodiments, the subject is a human.
[0237] Further embodiments include administering a combination of compounds to a subject in need thereof. A combination can include a compound, composition, pharmaceutical composition described herein with an additional medicament.
[0238] Some embodiments include co-administering a compound, composition, and/or pharmaceutical composition described herein, with an additional medicament. By "coadministration," it is meant that the two or more agents may be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered. In one embodiment, the agents are administered simultaneously. In one such embodiment, administration in combination is accomplished by combining the agents in a single dosage form. In another embodiment, the agents are administered sequentially. In one embodiment the agents are administered through the same route, such as orally. In another embodiment, the agents are administered through different routes, such as one being administered orally and another being administered i.v.
[0239] The term "patient" includes human and animal subjects.
[0240] The term "contacting" refers to bringing two or more materials into close enough proximity that they may interact. In certain embodiments, contacting can be accomplished in a vessel such as a test tube, a petri dish, or the like. In certain embodiments, contacting may be performed in the presence of additional materials. In certain embodiments, contacting may be performed in the presence of cells. In certain of such embodiments, one or more of the materials that are being contacted may be inside a cell. Cells may be alive or may dead. Cells may or may not be intact. Examples
[0241] The following examples are set forth merely to assist in understanding the embodiments and should not be construed as limiting the embodiments described and claimed herein in any way. Variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those skilled in the art, and changes in formulation or minor changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein.
EXAMPLE 1
Figure imgf000048_0001
(Compound 101)
[0242] To a solution of dehydrocortistatin A (5 mg, 0.010 mmol) in THF (1.0 mL) was added 2,4,6- triisopropylbenzenesulfonyl hydrazide (13 mg, 0.040 mmol, 4 equiv) and NEt3 (30 μί, 0.20 mmol, 20 equiv). The reaction was heated to 60 °C and stirred for 9h. The solution was cooled to rt and distributed between EtOAc (5 mL) and NaHC03(aq) sat solution (5 mL). The aqueous solution was extracted with EtOAc (3 x 5 mL). The combined organic layer was dried over Na2S04 and concentrated under reduced pressure. The crude mixture was purified by PTLC to afford 2.0 mg of compound 101 (42% yield) as colorless film.
EXAMPLE 1-1
Figure imgf000049_0001
[0243] Compound IX-B was dissolved in DMSO (300 L, 0.06 M). To this solution was added 7-trimethylstannylisoquinoline (20 mg, 68 μιηοΐ, 4 equiv.), CuCl (15 mg, 170 μιηοΐ, 10 equiv.), LiCl (7 mg, 170 μιηοΐ, 10 equiv.) and Pd(PPli3)4 (10 mg, 85 μιηοΐ, 0.5 equiv.). The mixture was degassed by bubbling argon through the solution for 10 min and then immersed in a preheated oil bath at 60°C for 1 h. The resulting mixture was allowed to cool to rt, diluted with EtOAc (5 mL) and washed with 5% aq. NH4OH. The layers were partitioned and the aqueous layer was extracted four times (4 x 5 mL) with EtOAc. The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo. The isolated residue was purified by PTLC (NH3 deactivation; 10% MeOH : CH2CI2) to obtain dedihydrocortistatm A (4 mg, 53% from compound IX-A) as a yellow foam. The 1H-NMR (CD3OD, 400 MHz) and MS (ESI) at m/z All [M+H]+ of dedihydrocortistatm A were obtained for characterization. -2
Figure imgf000049_0002
[0244] To a solution of dedihydrocortistatin A (5 mg, 0.010 mmol) in THF (1.0 mL) was added 2,4,6- triisopropylbenzenesulfonyl hydrazide (13 mg, 0.040 mmol, 4 equiv.) and NEt3 (30 μΐ,, 0.20 mmol, 20 equiv.). The resulting mixture was heated to 60°C and stirred for 9h. The mixture was cooled to rt and distributed between EtOAc (5 mL) and NaHC03 (aq) sat solution (5 mL). The aqueous layer was extracted with EtOAc (3 >< 5 mL). The combined organic layers were dried over Na2S04 and concentrated under reduced pressure. The crude mixture was purified by PTLC to afford cortistatin A (2.4 mg, 51%) and compound 101 (2.0 mg, 42% yield) as colorless film. The 1H-NMR (CDC13, 400 MHz) and MS (ESI) at m/z 473 [M+H]+ was obtained for cortistatin A and the 1H-NMR (CD3OD, 400 MHz,) and MS (ESI) m/z 475 [M+H]+ was obtained for compound 101 for characterization. -3
Figure imgf000050_0001
[0245] Compound IX-B (5 mg, 10.5 μιηοΐ), Pd(PPh3)4 (2.5 mg, 2.1 μιηοΐ) and 3- aminopyridine (49 mg, 525 μιηοΐ) were dissolved in degassed DMF/NEt3 (1 mL, 10:1). The mixture was placed under CO by bubbling with CO gas for 15 min, and then heated at 80 °C. The mixture was diluted with DCM (5 mL) and washed with 5% aq. NH4OH. The aqueous layer was extracted four times (4 x 5 mL) with DCM. Then the combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified by PTLC to furnish compound 103 (4.5 mg, 93%>) as a yellow foam. The 1H-NMR (CD3OD, 400 MHz) and MS (ESI) m/z 464 [M+H] + of compound 103 were obtained for characterization. -4
Figure imgf000051_0001
[0246] Compound IX-B (10 mg, 21 μιηοΐ), quinolin-7-yl boronic acid (7.2 mg, 42 μιηοΐ), Pd2(dba)3 (3.8 mg, 4.2 μιηοΐ), Ruphos (6.9 mg, 16.8 μιηοΐ) and potassium phosphate (13.3 mg, 63 μιηοΐ) were dissolved in degassed n-BuOH (1 mL), then heated at 60 °C for 48 h. The mixture was allowed to cool to rt, diluted with EtOAc (5 mL) and washed with 5% aq. NaHC03. The layers were partitioned and the aqueous layer was extracted four times (4 x 5 mL) with EtOAc. The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified by HPLC to furnish compound 108 (2.9 mg, 21%) as a yellow foam. The 1H-NMR (CD3OD, 400 MHz) and MS (ESI) m/z 471 [M+H] + of compound 108 were obtained for characterization. -5
Figure imgf000051_0002
[0247] Compound IX-B (10 mg, 21 μιηοΐ), 6-trimethylstannylnaphthalene (7.3 mg,
25 μιηοΐ), Pd(PPh3)4 (12 mg, 10.5 μιηοΐ), CuCl (21 mg, 210 μιηοΐ) and LiCl (8.8 mg, 210 μιηοΐ) were dissolved in degassed DMSO (1 mL), then heated at 60 °C for 1 h. The mixture was allowed to cool to rt, diluted with DCM (5 mL) and washed with 5% aq. NH4OH. The layers were partitioned and the aqueous layer was extracted with DCM (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified by HPLC to obtain compound 109 (1 mg, 7.2%) as a yellow foam. The 1H-NMR (CD3OD, 400 MHz) and MS (ESI) m/z 470 [M+H] + of compound 109 were obtained for characterization.
EXAMPLE 1-6
Figure imgf000052_0001
[0248] Compound IX-B (10 mg, 21 μιηοΐ), quinolin-7-yl boronic acid (7.2 mg, 42 μιηοΐ), Pd2(dba)3 (3.8 mg, 4.2 μιηοΐ), Ruphos (6.9 mg, 16.8 μιηοΐ) and potassium phosphate (13.3 mg, 63 μιηοΐ) were dissolved in degassed n-BuOH (1 mL) and water (0.2 mL), then heated at 60 °C for 36 h. The mixture was allowed to cool to rt, diluted with EtOAc (5 mL) and washed with 5% aq. NaHC03. The layers were partitioned and the aqueous layer was extracted with EtOAc (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified by HPLC to obtain compound 110 (3.1 mg, 23%) as a yellow foam. The 1H-NMR (CD3OD, 400 MHz) and MS (ESI) m/z 471 [M+H] + of compound 110 were obtained for characterization.
EXAMPLE 1-7
Figure imgf000053_0001
[0249] Compound IX-B (10 mg, 21 μιηοΐ), 6-trimethylstannylquinazoline (7.5 mg, 25 μιηοΐ), Pd(PPh3)4 (12 mg, 10.5 μιηοΐ), CuCl (21 mg, 210 μιηοΐ) and LiCl (8.8 mg, 210 μπιοΐ) was dissolved in degassed DMSO (0.35 ml), then heated at 60 °C for 1 h. The mixture was allowed to cool to rt, diluted with DCM (5 mL) and washed with 5% aq. NH4OH. The layers were partitioned and the aqueous layer was extracted with DCM (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified by HPLC to obtain compound 111 (3.2 mg, 23%) as a yellow foam. The 1H-NMR (CD3OD, 400 MHz) and MS (ESI) m/z 472 [M+H] + of compound 111 were obtained for characterization.
EXAMPLE 1-
Figure imgf000053_0002
[0250] Compound IX-B (10 mg, 21 μιηοΐ), 7-trimethylstannylisoquinoline (7.3 mg, 25 μιηοΐ), Pd(PPh3)4 (12 mg, 10.5 μιηοΐ), CuCl (21 mg, 210 μιηοΐ) and LiCl (8.8 mg, 210 μπιοΐ) were dissolved in degassed DMSO (0.35 mL), then heated at 60 °C for 1 h. The mixture was allowed to cool to rt, diluted with DCM (5 mL) and washed with 5% aq. NH4OH. The layers were partitioned and the aqueous layer was extracted with DCM (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified by HPLC to obtain compound 112 (1.7 mg, 12%) as a yellow foam. The 1H-NMR (CD3OD, 400 MHz) and MS (ESI) m/z 471 [M+H] + of compound 112 were obtained for characterization.
EXAMPLE 1-9
Figure imgf000054_0001
[0251] Compound IX-B (9.4 mg, 20 μιηοΐ), 6-trimethylstannylphthalazine (11.7 mg, 40 μιηοΐ), Pd(PPh3)4 (11.6 mg, 10 μιηοΐ), CuCl (19.8 mg, 200 μιηοΐ) and LiCl (10.2 mg, 240 μιηοΐ) were dissolved in degassed DMSO (0.8 ml), then heated at 60 °C for 1 h. The mixture was allowed to cool to rt, diluted with DCM (5 mL) and washed with 5% aq. NH4OH. The layers were partitioned and the aqueous layer was extracted with DCM (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified by PTLC to furnish compound 113 (1.5 mg, 16%) as a yellow foam. The 1H-NMR (CD3OD, 400 MHz) and MS (ESI) m/z 472 [M+H] + of compound 113 were obtained for characterization.
-10
Figure imgf000055_0001
[0252] Compound IX-B (9.4 mg, 20 μιηοΐ), 3-methyl-6-trimethylstannyl-lH- indazole (11.7 mg, 40 μιηοΐ), Pd(PPh3)4 (11.6 mg, 10 μιηοΐ), CuCl (19.8 mg, 200 μιηοΐ) and LiCl (10.2 mg, 240 μπιοΐ) were dissolved in degassed DMSO (0.8 ml), then heated at 60 °C for 1 h. The mixture was allowed to cool to rt, diluted with DCM (5 mL) and washed with 5% aq. ΝΗ4ΟΗ. The layers were partitioned and the aqueous layer was extracted with DCM (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified by PTLC to obtain compound 114 (1.2 mg, 12%) as a yellow foam. The 1H-NMR (CDC13, 400 MHz) and MS (ESI) m/z 474 [M+H] + of compound 114 were obtained for characterization. -11
Figure imgf000055_0002
[0253] Compound IX-B (9.4 mg, 20 μιηοΐ), 5-trimethylstannylisoquinoline (9.7 mg, 40 μιηοΐ), Pd(PPh3)4 (11.6 mg, 10 μιηοΐ), CuCl (19.8 mg, 200 μιηοΐ) and LiCl (10.2 mg, 240 μιηοΐ) were dissolved in degassed DMSO (0.8 ml), then heated at 60 °C for 1 h. The mixture was allowed to cool to rt, diluted with DCM (5 mL) and washed with 5% aq. NH4OH. The layers were partitioned and the aqueous layer was extracted with DCM (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified by PTLC to furnish compound 115 (1.7 mg, 18%) as a yellow foam. The 1H-NMR (CDC13, 400 MHz) and MS (ESI) m/z 471 [M+H] + of compound 115 were obtained for characterization. -12
Figure imgf000056_0001
[0254] Compound IX-B (9.4 mg, 20 μιηοΐ), 3-trimethylstannylpyridine (9.7 mg, 40 μιηοΐ), Pd(PPh3)4 (11.6 mg, 10 μιηοΐ), CuCl (19.8 mg, 200 μιηοΐ) and LiCl (10.2 mg, 240 μιηοΐ) were dissolved in degassed DMSO (0.8 mL), then heated at 60 °C for 1 h. The mixture was allowed to cool to rt, diluted with DCM (5 mL) and washed with 5% aq. NH4OH. The layers were partitioned and the aqueous layer was extracted with DCM (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified by PTLC to obtain compound 116 (1.0 mg, 12%) as a yellow foam. The 1H-NMR (CD3OD, 400 MHz) and MS (ESI) m/z 421 [M+H] + of compound 116 were obtained for characterization.
EXAMPLE 1-13
Figure imgf000057_0001
[0255] Compound IX-B (9.4 mg, 20 μιηοΐ), 5-trimethylstannyl-lH-indazole (11.6 mg, 41 μιηοΐ). Pd(PPh3)4 (11 mg, 10 μιηοΐ), CuCl (20 mg, 200 μιηοΐ) and LiCl (10.2 mg, 240 μιηοΐ) were dissolved in degassed DMSO (0.80 mL), then heated at 60 °C for 1 h. The mixture was allowed to cool to rt, diluted with DCM (5 mL) and washed with 5% aq. ΝΗ4ΟΗ. The layers were partitioned and the aqueous layer was extracted with DCM (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified by PTLC to furnish compound 117 (1.3 mg, 14%) as a yellow foam. The 1H-NMR (CDC13, 400 MHz) and MS (ESI) m/z 460 [M+H] + of compound 117 were obtained for characterization.
EXAMPLE 1-14
Figure imgf000057_0002
[0256] Compound IX-B (9.4 mg, 20 μιηοΐ), 3-methyl-5-trimethylstannyl-lH- indazole (11.7 mg, 40 μιηοΐ), Pd(PPh3)4 (11 mg, 10 μιηοΐ), CuCl (20 mg, 200 μιηοΐ) and LiCl
(10.2 mg, 240 μιηοΐ) were dissolved in degassed DMSO (0.80 mL), then heated at 60 °C for 1 h. The mixture was allowed to cool to rt, diluted with DCM (5 mL) and washed with 5% aq. NH4OH. The layers were partitioned and the aqueous layer was extracted with DCM (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified by PTLC to furnish compound 118 (1.4 mg, 15%) as a yellow foam. The 1H-NMR (CDC13, 400 MHz) and MS (ESI) m/z 474 [M+H] + of compound 118 were obtained for characterization. -15
Figure imgf000058_0001
[0257] Compound IX-B (14.1 mg, 30 μιηοΐ), l-(difiuoromethyl)-7- trimethylstannylisoquinoline (15 mg, 45 μιηοΐ), Pd(PPh3)4 (17 mg, 15 μιηοΐ), CuCl (30 mg, 300 μιηοΐ) and LiCl (15 mg, 360 μιηοΐ) were dissolved in degassed DMSO (1.2 mL), then heated at 60 °C for 1 h. The mixture was allowed to cool to rt, diluted with DCM (5 mL) and washed with 5% aq. NH4OH. The layers were partitioned and the aqueous layer was extracted with DCM (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified by PTLC to obtain compound 119 (1.9 mg, 12%) as a yellow foam. The 1H-NMR (CDC13, 400 MHz) and MS (ESI) m/z 421 [M+H] + of compound 119 were obtained for characterization.
EXAMPLE 1-16
Figure imgf000059_0001
[0258] Compound IX-B (14.1 mg, 30 μιηοΐ), 3-amino-7-trimethylstannylquinazoline (14 mg, 45 μιηοΐ), Pd(PPh3)4 (17 mg, 15 μιηοΐ), CuCl (30 mg, 300 μιηοΐ) and LiCl (15 mg, 360 μιηοΐ) were dissolved in degassed DMSO (1.2 mL), then heated at 60 °C for 1 h. The mixture was allowed to cool to rt, diluted with DCM (5 mL) and washed with 5% aq. NH4OH. The layers were partitioned and the aqueous layer was extracted with DCM (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified by PTLC to furnish compound 120 (3.3 mg, 22%) as a yellow foam. The 1H-NMR (CDC13, 400 MHz) and MS (ESI) m/z 487 [M+H] + of compound 120 were obtained for characterization. -17
[0259] Compound IX-B (11 mg, 23 μιηοΐ), 7-trimethylstannylisoquinol-l-one (11 mg, 35 μιηοΐ), Pd(PPh3)4 (12 mg, 11 μιηοΐ), CuCl (20 mg, 200 μιηοΐ) and LiCl (10 mg, 280 μηιοΐ) were dissolved in degassed DMSO (0.8 mL), then heated at 60 °C for 1 h. The mixture was allowed to cool to rt, diluted with DCM (5 mL) and washed with 5% aq. NH4OH. The layers were partitioned and the aqueous layer was extracted with DCM (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified by HPLC to obtain compound 121 (3.0 mg, 30%) as a yellow foam. The 1H-NMR (CDC13, 400 MHz) and MS (ESI) m/z 487 [M+H] + of compound 121 were obtained for characterization.
EXAMPLE 1-18
Figure imgf000060_0001
[0260] Compound IX-B (9.4 mg, 20 μιηοΐ), N-propyl-6- (trimethylstannyl)quinazolin-4-amine (14 mg, 40 μιηοΐ), Pd(PPh3)4 (12 mg, 11 μιηοΐ), CuCl (20 mg, 200 μιηοΐ) and LiCl (10 mg, 280 μιηοΐ) was dissolved in degassed DMSO (0.8 mL), then heated at 60 °C for 1 h. The mixture was allowed to cool to rt, diluted with DCM (5 mL) and washed with 5% aq. NH4OH. The layers were partitioned and the aqueous layer was extracted with DCM (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified by PTLC to obtain compound 122 (4.2 mg, 40%) as a yellow foam. The 1H-NMR (CDC13, 400 MHz) and MS (ESI) m/z 529 [M+H] + of compound 122 were obtained for characterization. EXAMPLE 1-19
Figure imgf000061_0001
[0261] Compound IX-B (9.4 mg, 20 μιηοΐ), tert-butyl (4-((6- (trimethylstannyl)quinazolin-4-yl)amino)butyl)carbamate (20 mg, 42 μmol), Pd(PPli3)4 (12 mg, 11 μmol), CuCl (20 mg, 200 μιηοΐ) and LiCl (10 mg, 280 μιηοΐ) was dissolved in degassed DMSO (0.8 ml), then heated at 60 °C for 1 h. The mixture was allowed to cool to rt, diluted with DCM (5 mL) and washed with 5% aq. NH4OH. The layers were partitioned and the aqueous layer was extracted with DCM (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified by PTLC furnishing the carbamate intermediate (4.2 mg, 32%) as a yellow foam. The carbamate intermediate (4.2 mg) was treated with 0.5 mL (DCM:TFA=4: 1) for 2 h. The resulting mixture was treated with aq. NaHC03, then extracted with mixture of DCM:MeOH (10: 1). The combined extract was dried over Na2S04 and concentrated in vacuo to afford a deprotected amine intermediate. The amine intermediate was dissolved in DMF (0.5 mL) and treated with 2,5-dioxopyrrolidin-l-yl 5-((3aS,4S,6aR)-2-oxohexahydro-lH-thieno[3,4- d]imidazol-4-yl)pentanoate (biotin NHS ester) and Et3N (4 μΐ). After stirring 12 h, the mixture was concentrated and purified by PTLC to obtain compound 122 (4.2 mg, 40%) as a yellow foam. The 1H-NMR (CD3OD, 400 MHz) and MS (ESI) m/z 784 [M+H] + of compound 123 were obtained for characterization. -20
Figure imgf000062_0001
[0262] To a solution of dedihydrocortistatin A (4.7 mg, 10 μηιοΐ) in MeOH (0.1 mL) and H20 (0.02 mL) was added NaOAc (8.2 mg, 100 μιηοΐ) and iodine (3.8 mg, 15 μιηοΐ), the resulting mixture was then stirred for 1 h at 45 °C. Subsequently, the mixture was treated with 2N NaOH solution (0.1 mL) and iodine (2.5 mg, 10 μιηοΐ) at 45 °C and stirred for 1 h. The mixture was diluted with DCM and washed with NaS203 soltuion and NaHC03. The layers were partitioned and the aqueous layer was extracted with DCM (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified by PTLC to furnish compound 105 (3.6 mg, 77%) and compound 106 (1.1 mg, 23 %). The 1H-NMR (CDC13, 400 MHz) and MS (ESI) m/z 457 [M+H]+ of compound 105 and the 1H-NMR (CD3OD, 400 MHz) and MS (ESI) m/z 443 [M+H]+ of compound 106 were obtained for characterization. -21
Figure imgf000063_0001
[0263] To a solution of compound 105 (1.1 mg, 2.4 μιηοΐ) in water (0.1 mL) and 2N HC1 (0.1 mL) was added Ac20 (68 μιηΐ, 7.2 μιηοΐ), NaHC03 (2.0 mg, 24 μιηοΐ) at 25 °C and DCM (0.2 ml), the resulting mixture was then stirred for 1 h. The layers were partitioned and the aqueous layer was extracted with DCM (4 x 5 mL). The combined organic portions were dried over Na2S04, filtered, and concentrated in vacuo. The crude mixture was purified by PTLC to obtain compound 107 (1.0 mg, 83%) as a yellow foam. The 1H-NMR (CDC13, 400 MHz) and MS (ESI) m/z 499 [M+Hf of compound 107 was obtained for characterization. -22
Figure imgf000063_0002
[0264] Dedihydrocortistatin A (160 mg) was left at -80 °C under air for 4 weeks. About 10%) of dedihydrocortistatin A was slowly oxidized and formed compound 124. The crude mixture was purified by HPLC to yield about 15 mg of compound 124 as pure compound. The 1H-NMR (CD3OD, 400 MHz) and MS (ESI) m/z 487 [M+H]+ of compound 124 was obtained for characterization. -23
Figure imgf000064_0001
104
[0265] Compound IX-B (14 mg, 30 μιηοΐ), 3-ethynylpyridine (15 mg, 150 μιηοΐ), Pd(PPh3)2Cl2 (4.2 mg, 60 μιηοΐ) Cul (1.1 mg, 60 μιηοΐ), and Et3N (30 μί) were dissolved in degassed THF (0.30 ml), then heated at 60 °C for 2 h. The mixture was allowed to cool to rt, diluted with DCM (5 mL) and washed with 5% aq. NH4OH. The layers were partitioned and the aqueous layer was extracted with DCM (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (5 mL), dried over Na2S04, filtered, and concentrated in vacuo, he crude mixture was purified by PTLC to obtain compound 104 (11.2 mg, 84%) as a yellow foam. The 1H-NMR (CDC13, 400 MHz) and MS (ESI) m/z 445 [M+H] + of compound 104 were obtained for characterization.
Figure imgf000064_0002
and Et3N (0.08 mL, 0.56 mmol, 10 equiv). The reaction vessel was immersed in a preheated oil bath at 50 °C for 6 h, after which the mixture was allowed to cool to rt and the solvent removed in vacuo. The residue so obtained was dissolved in THF (0.93 mL, 0.06 M), and Et3N (0.02 mL, 0.168 mmol, 3 equiv) was added. A stock solution of L (28 mg, 0.112 mmol, 2 equiv) in THF (0.28 mL) was prepared and added drop wise to the prepared mixture; addition was halted when the iodine was not decolorized after 30 sec. The mixture was then diluted with EtOAc (5 mL) and washed with sat. aq. Na2S2C"3 (5 mL). The layers were partitioned and the aqueous layer was extracted with EtOAc (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (1 mL), dried over MgSCn, filtered, and concentrated in vacuo to furnish vinyl iodide (IX- B) which was carried forward directly without purification. The residue from the previous reaction (yield assumed to be quantitative) was dissolved in DMSO (0.93 mL, 0.06 M). To this solution was added 7-trimethylstannylisoquinoline (16 mg, 0.056 mmol, 1 equiv), CuCl (55 mg, 0.56 mmol, 10 equiv), LiCl (23 mg, 0.56 mmol, 10 equiv) and Pd(PPh3)4 (32 mg, 0.03 mmol, 0.5 equiv). The reaction was degassed by bubbling argon through the solution for 10 min. The reaction vessel was then immersed in a preheated oil bath at 60°C for 1 h. The mixture was then diluted with EtOAc (3 mL) and washed with 5% aq. NLLOH. The layers were partitioned and the aqueous layer was extracted with EtOAc (4 x 5 mL). The combined organic portions were washed with sat. aq. NaCl (25 mL), dried over MgSO-*, filtered, and concentrated in vacuo. The residue so obtained was purified by silica (NFL deactivated; 10% MeOH : CH2CI2) to furnish compound 102 (1 mg). The 1H-NMR (CD3OD, 400 MHz) and MS (ESI) m/z 473 [M+H] + of compound 102 were obtained for characterization.
EXAMPLE 2
[0267] The compounds in Table 1 may be prepared according to the general Schemes discussed above where R5 is any group defined in Table 2 and R15 is any group defined in Table 3. Similarly, the compounds depicted in Table 4 can be prepared according the general Schemes discussed above and methods known in the art. Table 1
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Table 3
ΝΗ2 ίγγΝΗ2
ΟΗ
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Table 4
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Example 3-1
Growth Inhibition Assay (I)
[0268] HUVECs were seeded at 3000 cells/well in 96-well microculture plate (Costar flat bottom # 3997) in a total volume of 100 (jL/well. After 24 hours of incubation in a humidified incubator at 37°C with 5% C02 and 95% air, 100 iL of 2X, serially 1 :4 diluted test compounds in growth medium with a final maximal concentration of 10 μΜ (0.1% DMSO) were added to each well. After 72 hours of culture in a C02 incubator, the plated cells and Cell Titer-Glo® (Promega # G7571) reagents were brought to room temperature to equilibrate for 30 minutes. One hundred (100) μΐ, of the growth medium was removed and 50 μΐ, of Cell Titer- Glo® reagent was added to each well. The plate was shaken for 10 minutes and then left to equilibrate for 2 minutes before reading luminescence on the Tecan GENios microplate reader.
[0269] Percent inhibition of cell growth was calculated relative to untreated control wells. All tests were performed in eight replicates at each concentration level (total 10 concentrations 38 pM to 10 μΜ).Τ1ΐ6 IC50 value for the test agents was estimated using Prism 6.00 by curve-fitting the data. The results for selected compounds disclosed herein are indicated in the table of Example 10 below. Example 3-2
Growth Inhibition Assay (II)
[0270] HUVEC cells are collected and counted. Cell suspensions are added to each well at a suitable density, with complete medium including endothelial cell growth supplements. The margin wells are filled with PBS. Test compounds at various concentrations (10 concentrations, 10 fold dilutions starting from 10μΜ) are added in duplicate and the cells were incubated for 72 h. After incubation, CellTiter-Glo® Reagent are added to each test well and mixed for 2 minutes on an orbital shaker. The plates are shortly centrifuged at 90g and incubated at room temperature for additional 10 minutes to stabilize the luminescent signal. Luminescence signals are detected on PHERAstar Plus. And data is collected in Microsoft excel forms and analyzed Graphpad Prism software.
[0271] Data analysis
[0272] Data were recorded by Pherastar and stored on the GenScript computer network for off-line analysis. Data acquisition and analysis were performed using MicroSoft Excel2007 and GraphPad Prism software. The potential effect of the testing compounds on cell proliferation was calculated by the formula below:
% Cell growth inhibition=100%-RLUsampie/RLU O.I%DMSO-
Example 4
CPRG-based Assay
[0273] HeLa-CD4-LTR-LacZ cells are plated at lxl 04 cells per well of a 96-well plate. Twenty- four hours later HIV-1 pNL4-3 is added in the presence of testing compound or DMSO control in a total volume of 200 μί. Forty hours post infection cells are disrupted in lysis buffer (60 mM Na2HPO4,40 mM NaH2P04, 10 mM KC1, 10 mM MgS04, 2.5 mM EDTA, 50 mM β-mercaptoethanol, 0.125% Nonidet P-40) and a quantitative chlorophenol red-β-Ο- galactopyranoside (CPRG)-based (Boehringer Mannheim) assay is performed. The cell extracts are incubated in a reaction buffer (0.9 M phosphate buffer [pH 7.4], 9 mM MgCl2, 11 mM β- mercaptoethanol, 7 mM CPRG) until a red color develops (from approximately 10 min to 4 h) and is measurable using an LP400 (Becton Dickinson) plate reader at 572 nm. Experiments are performed in triplicate.
Example 5
CD 8 Assay
[0274] A radiometric protein kinase assay (33PanQinase® Activity Assay) was used for measuring the kinase activity of the CDK8/CycC protein kinases. All kinase assays were performed in 96-well FlashPlates™ from PerkinElmer (Boston, MA, USA) in a 50 reaction volume. The reaction cocktail was pipetted in four steps in the following order:
1. 20 μΐ, of assay buffer (standard buffer)
2. 5 μΐ. of ATP solution (in H20)
3. 5 μΐ. of test compound (in 10 % DMSO)
4. 20 μΐ^ enzyme/subtrate mix
[0275] The assay for all protein kinases contained 70 mM HEPES-NaOH pH 7.5, 3 mM MgCl2, 3 mM MnCl2, 3 μΜ Na-orthovanadate, 1.2 mM DTT, 50 μ^πιΐ PEG20ooo, ATP cone. (3 μΜ, [γ-33Ρ]-ΑΤΡ (approx. 1 x 1006 cpm per well), protein kinase (CDK8/CycC, ProQinase Lot 002, Kinase Cone. 50 ¾/50μΕ, Kinase Cone. 8.3 nM), Substrate Name (RBER- IRStide, Substrate Lot 006, Substrate 1 μg/50μL). The reaction cocktails were incubated at 30° C for 60 minutes. The reaction was stopped with 50 μΐ, of 2 % (v/v) H3P04, plates were aspirated and washed two times with 200 μΐ, 0.9 % (w/v) NaCl. Incorporation of 33P; was determined with a microplate scintillation counter (Microbeta, Wallac). All assays were performed with a BeckmanCoulter/SAGIAN™ Core System. The results for selected compounds disclosed herein are indicated in the table of Example 10 below.
Example 6
Multiple Myeloma Experimental Procedures
[0276] OPM-2 cells were seeded at 3000 cells/well in 96-well microculture plate (Costar flat bottom # 3997) in a total volume of 100 μίΛνεΙΙ. After 24 hours of incubation in a humidified incubator at 37 °C with 5% C02 and 95% air, 100 μΐ, of 2X, serially 1 :4 diluted SMD-1001 analogs in growth medium with a final maximal concentration of 10 μΜ (0.1% DMSO) were added to each well. After 72 hours of culture in a C02 incubator, the plated cells and Cell Titer-Glo® (Promega # G7571) reagents were brought to room temperature to equilibrate for 30 minutes. One hundred (100) μΐ, of the growth medium was removed and 50 μΐ^ of Cell Titer-Glo® reagent was added to each well. The plate was shaken for 10 minutes and then left to equilibrate for 2 minutes before reading luminescence on the Tecan GENios microplate reader. Percent inhibition of cell growth was calculated relative to untreated control wells. All tests were performed in eight replicates at each concentration level (total 10 concentrations 38 pM to 10 μΜ).
[0277] The IC50 value for the test agents was estimated using Prism 6.00 by curve- fitting the data using the following four parameter-logistic equation: Top - Bottom
Y + Bottom
Figure imgf000148_0001
[0278] where Top is the maximal % of control absorbance, Bottom is the minimal % of control absorbance at the highest agent concentration, Y is the % of control absorbance, X is the agent concentration, IC50 is the concentration of agent that inhibits cell growth by 50% compared to the control cells, and n is the slope of the curve. The results for selected compounds disclosed herein are indicated in the table of Example 10 below.
Example 7
P24 Assay Methods
[0279] HIV particles were initially prepared by transient transfection of 293T cells with the pro viral HIV-1 pNL4-3 DNA (1) or ROD/A. Virus stocks for infections were produced by amplification of the virus by acutely infecting CEM-SS cells with HIV-1 pNL4-3 and concentration by ultracentrifugation of the cell supernatant. Virus titers were determined with HIV-1 p24 ELISA from AdvancesBioscience Laboratories. Results were reported as LacZ expression as a percent of DMSO control and the dose response curve fitted to determine IC50. The results for selected compounds disclosed herein are indicated in the table of Example 10 below.
Example 8
Age-related Macular Degeneration Choroidal Neovascularization Dose Response Experimental Procedures
[0280] Age-related Macular Degeneration testing uses adult C57BL/6 mice. On day 1 the mice receive laser treatments to the retina of a single eye. In addition mice receive a single intravitreal injection of of the test compound in vehicle (PBS) to the laser treated eye. The volume of the injection is 2 μΕ. On day 14 post laser treatment the mice are euthanized by cardiac perfusion with FITC-conjugated dextran/4% paraformaldehyde/PBS. Eyes are harvested for analysis. Six mice per group are used (Vehicle, 1 nM dCA, 10 nM dCA, 100 nM dCA, 1 μΜ dCA, 10 μΜ dCA) for a total of 36 adult C57BL/6 mice. Controls include laser eyes injected with PBS. Example 9
NCI-60 DTP Human Tumor Cell Line Screen
[0281] The human tumor cell lines of the cancer screening panel are grown in RPMI 1640 medium containing 5% fetal bovine serum and 2 mM L-glutamine. For a typical screening experiment, cells are inoculated into 96 well microtiter plates in 100 at plating densities ranging from 5,000 to 40,000 cells/well depending on the doubling time of individual cell lines. After cell inoculation, the microtiter plates are incubated at 37° C, 5 % C02, 95 % air and 100 % relative humidity for 24 h prior to addition of experimental drugs.
[0282] After 24 h, two plates of each cell line are fixed in situ with TCA, to represent a measurement of the cell population for each cell line at the time of drug addition (Tz). Experimental drugs are solubilized in dimethyl sulfoxide at 400-fold the desired final maximum test concentration and stored frozen prior to use. At the time of drug addition, an aliquot of frozen concentrate is thawed and diluted to twice the desired final maximum test concentration with complete medium containing 50 μg/ml gentamicin. Additional four, 10-fold or ½ log serial dilutions are made to provide a total of five drug concentrations plus control. Aliquots of 100 of these different drug dilutions are added to the appropriate microtiter wells already containing 100 μΐ, of medium, resulting in the required final drug concentrations.
[0283] Following drug addition, the plates are incubated for an additional 48 h at 37°C, 5 % C02, 95 % air, and 100 % relative humidity. For adherent cells, the assay is terminated by the addition of cold TCA. Cells are fixed in situ by the gentle addition of 50 μΐ^ of cold 50 % (w/v) TCA (final concentration, 10 % TCA) and incubated for 60 minutes at 4°C. The supernatant is discarded, and the plates are washed five times with tap water and air dried. Sulforhodamine B (SRB) solution (100 μΐ) at 0.4 % (w/v) in 1 % acetic acid is added to each well, and plates are incubated for 10 minutes at room temperature. After staining, unbound dye is removed by washing five times with 1 % acetic acid and the plates are air dried. Bound stain is subsequently solubilized with 10 mM trizma base, and the absorbance is read on an automated plate reader at a wavelength of 515 nm. For suspension cells, the methodology is the same except that the assay is terminated by fixing settled cells at the bottom of the wells by gently adding 50 μΐ of 80 % TCA (final concentration, 16 % TCA). Using the seven absorbance measurements [time zero, (Tz), control growth, (C), and test growth in the presence of drug at the five concentration levels (Ti)], the percentage growth is calculated at each of the drug concentrations levels. Percentage growth inhibition is calculated as:
[(Ti-Tz)/(C-Tz)] x 100 for concentrations for which Ti>/=Tz [(Ti-Tz)/Tz] x 100 for concentrations for which Ti<Tz.
[0284] Three dose response parameters are calculated for each experimental agent. Growth inhibition of 50 % (GI50) is calculated from [(Ti-Tz)/(C-Tz)] x 100 = 50, which is the drug concentration resulting in a 50% reduction in the net protein increase (as measured by SRB staining) in control cells during the drug incubation. The drug concentration resulting in total growth inhibition (TGI) is calculated from Ti = Tz. The LC50 (concentration of drug resulting in a 50% reduction in the measured protein at the end of the drug treatment as compared to that at the beginning) indicating a net loss of cells following treatment is calculated from [(Ti-Tz)/Tz] x 100 = -50. Values are calculated for each of these three parameters if the level of activity is reached; however, if the effect is not reached or is exceeded, the value for that parameter is expressed as greater or less than the maximum or minimum concentration tested.
[0285] Dedihydrocortistatin A was screened using the above-described procedure. Dedihydrocortistatin A showed negative growth percent for Ml 4 - melanoma and UACC-62 melanoma cell lines indicating a cytotoxic effect. Additionally, Dedihydrocortistatin A showed cytostatic effects for leukemia/multiple myeloma cell lines.
Example 10
Examples of activity:
[0286] wherein:
A indicates an ICso of<100nM
B indicates an ICso of ΙΟΟηΜ to Ι μΜ
C indicates an ICso of > Ι μΜ
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Multiple
HIV
STRUCTURE HUVEC1 HUVEC2 CDK8 Myeloma
(Lacz) OPM-2
OH
- - - - B
121
1) Example 3-1; 2) Example 3-2
[0287] While one or more embodiments of the present disclosure have been described, it will be understood by those of ordinary skill in the art that various changes in form and details may be made therein without departing from the spirit and scope of the present embodiments as defined by the following claims.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula I:
Figure imgf000155_0001
or a pharmaceutically acceptable salt thereof,
wherein:
n is 1 or 3;
p is 1 or 3;
q is 1 or 3;
each R1 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted hydroxyl, an optionally substituted amino, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
each R2 is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl, or optionally two geminal R2 together with the atom to which they are attached is an optionally substituted C3-C7 cycloalkyl, or optionally substituted 3-7 membered heterocycle ring, or optionally two adjacent R2 together with the atoms to which they are attached is an optionally substituted C3-C7 cycloalkyl or optionally substituted 3-7 membered heterocycle ring;
each R3 is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl, or optionally two geminal R3 together with the atom to which they are attached is an optionally substituted C3-C7 cycloalkyl or optionally substituted 3-7 membered heterocycle ring, or optionally two adjacent R3 together with the atoms to which they are attached is an optionally substituted C3-C7 cycloalkyl or optionally substituted 3-7 membered heterocycle ring;
R4 is selected from the group consisting of halogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R5 is selected from the group consisting of -L1-R5A, an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
L1 is selected from the group consisting of-NHC(=0)-, an optionally substituted Ci-C6 alkyl, and an optionally substituted C2-C6 alkenyl;
R5A is selected from the group consisting of an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, -SH, an optionally substituted Ci-C6 alkyl, and an optionally substituted Ci-C6 alkoxy;
R7 is selected from the group consisting of hydrogen, halogen, hydroxyl, -SH, an optionally substituted Ci-C6 alkyl, and an optionally substituted Ci-C6 alkoxy, or optionally R6 and R7 together are oxygen or sulfur;
R8 is selected from the group consisting of hydrogen, halogen, and an optionally substituted Ci-C6 alkyl;
each R9 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R10 is selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl;
R11 is selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl, or optionally R10 and R11 together are oxo;
each R12 is independently selected from the group consisting of hydrogen, halogen, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; and
each dashed line independently represents an optional double bond,
with the proviso that at least one of R2, R3 or R12 is not hydrogen, or with the proviso that when n is 1, p is 1, q is 1, and R2, R3 and R12 are hydrogen then
R is not
Figure imgf000157_0001
;h the proviso that R is substituted
The compound of claim 1 having the structure of Formula la
Figure imgf000157_0002
or a pharmaceutically acceptable salt thereof, wherein each R12 is hydrogen.
3. The compound of claim 1 or 2,
wherein:
each R1 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted hydroxyl, and an optionally substituted amino;
each R2 is independently selected from the group consisting of hydrogen, halogen, and hydroxy, or optionally two adjacent R2 together with the atoms to which they are attached is an optionally substituted C3-C7 cycloalkyl;
each R3 is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, and an optionally substituted Ci-C6 alkyl; and
R10 is selected from the group consisting of hydrogen and Ci-C6 alkyl; and
R11 is selected from the group consisting of hydrogen and Ci-C6 alkyl.
4. The compound of any one of claims 1 - 3,
wherein:
each R1 is independently selected from the group consisting of hydrogen, hydroxyl, and -N(Methyl)2; each R2 is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, and hydroxy, or optionally two adjacent R2 together with the atoms to which they are attached is an optionally substituted cyclopropyl;
each R3 is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, cyano, thiocyanato, methyl, and trifluoromethyl;
R5 is selected from the group consisting of -L1-R5A and an optionally substituted heteroaryl;
L1 is selected from the group consisting of -NHC(=0)-, C1-C3 alkyl, and an optionally substituted C2-C4 alkenyl;
R5A
is an optionally substituted heteroaryl;
R10 is selected from the group consisting of hydrogen and methyl; and
R11 is selected from the group consisting of hydrogen and methyl.
5. A compound of Formula II :
Figure imgf000158_0001
or a pharmaceutically acceptable salt thereof,
wherein:
q is 1 or 3;
each R1 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted hydroxyl, an optionally substituted amino, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R2 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
each R3 is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl, or optionally the two R3 together with the atom to which they are attached is an optionally substituted C3-C7 cycloalkyl or optionally substituted 3-7 membered heterocycle ring;
R4 is selected from the group consisting of halogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R5 is selected from the group consisting of -L1-R5A, an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
L1 is selected from the group consisting of-NHC(=0)-, an optionally substituted Ci-C6 alkyl, and an optionally substituted C2-C6 alkenyl;
R5A is selected from the group consisting of an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
R6 is selected from the group consisting of hydrogen, halogen, hydroxy, -SH, an optionally substituted Ci-C6 alkyl;
R8 is selected from the group consisting of hydrogen, halogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
each R9 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R10 is selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl;
R11 is selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl, or optionally R10 and R11 together are oxo;
each R12 is independently selected from the group consisting of hydrogen, halogen, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; and
each dashed line independently represents an optional double bond.
6. The compound of claim 5,
wherein: each R1 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted hydroxyl, and an optionally substituted amino;
R2 is hydrogen or C1-C3 alkyl;
each R3 is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, and an optionally substituted Ci-C6 alkyl;
R10 is selected from the group consisting of hydrogen and Ci-C6 alkyl; and
R11 is selected from the group consisting of hydrogen and Ci-C6 alkyl.
7. The compound of claim 5 having the structure of Formula Ila:
Figure imgf000160_0001
or a pharmaceutically acceptable salt thereof, wherein each R is hydrogen.
8. The compound of any one of claims 5 - 7,
wherein:
each R1 is independently selected from the group consisting of hydrogen, hydroxyl, and -N(Methyl)2;
R5 is selected from the group consisting of -L1-R5A and an optionally substituted heteroaryl;
L1 is selected from the group consisting of -NHC(=0)-, C1-C3 alkyl, and C2-C4 alkenyl; and
R5A is an optionally substituted heteroaryl.
9. A compound of Formula III:
Figure imgf000161_0001
and pharmaceutically acceptable salts thereof;
wherein:
p is 1 or 3;
q is 1 or 3;
each R1 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted hydroxyl, an optionally substituted amino, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R2A is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R2B is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl, or optionally R2A and R2B together with the atoms to which they are attached is an optionally substituted C3-C7 cycloalkyl or optionally substituted 3-7 membered heterocycle ring;
each R3 is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci- C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl, or optionally two adjacent R3 together with the atoms to which they are attached is an optionally substituted C3-C7 cycloalkyl or optionally substituted 3-7 membered heterocycle ring; R4 is selected from the group consisting of halogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R5 is selected from the group consisting of -L1-R5A, an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
L1 is selected from the group consisting of-NHC(=0)-, an optionally substituted Ci-C6 alkyl, and an optionally substituted C2-C6 alkenyl;
R5A is selected from the group consisting of an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, -SH, an optionally substituted Ci-C6 alkyl, and an optionally substituted Ci-C6 alkoxy;
R7 is selected from the group consisting of hydrogen, halogen, hydroxyl, -SH, an optionally substituted Ci-C6 alkyl, and an optionally substituted Ci-C6 alkoxy, or optionally R6 and R7 together are oxygen or sulfur;
R8 is selected from the group consisting of hydrogen, halogen, and an optionally substituted Ci-C6 alkyl;
each R9 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R10 is selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl;
R11 is selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl, or optionally R10 and R11 together are oxo;
each R12 is independently selected from the group consisting of hydrogen, halogen, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; and
each dashed line independently represents an optional double bond.
10. A compound of Formula IV:
Figure imgf000163_0001
and pharmaceutically acceptable salts thereof;
wherein:
n is 1 or 3;
q is 1 or 3;
each R1 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted hydroxyl, an optionally substituted amino, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
each R2 is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl, or optionally two adjacent R2 together with the atoms to which they are attached is an optionally substituted C3-C7 cycloalkyl or optionally substituted 3-7 membered heterocycle ring;
R3A is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R3B is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, thiocyanato, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl, or optionally R3A and R3B together with the atoms to which they are attached is an optionally substituted C3-C7 cycloalkyl or optionally substituted 3-7 membered heterocycl ring; R4 is selected from the group consisting of halogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R5 is selected from the group consisting of -L1-R5A, an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
L1 is selected from the group consisting of-NHC(=0)-, an optionally substituted Ci-C6 alkyl, and an optionally substituted C2-C6 alkenyl;
R5A is selected from the group consisting of an optionally substituted aryl, an optionally substituted heterocyclyl, and an optionally substituted heteroaryl;
R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, -SH, an optionally substituted Ci-C6 alkyl, and an optionally substituted Ci-C6 alkoxy;
R7 is selected from the group consisting of hydrogen, halogen, hydroxyl, -SH, an optionally substituted Ci-C6 alkyl, and an optionally substituted Ci-C6 alkoxy, or optionally R6 and R7 together are oxygen or sulfur;
R8 is selected from the group consisting of hydrogen, halogen, and an optionally substituted Ci-C6 alkyl;
each R9 is independently selected from the group consisting of hydrogen, halogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R10 is selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl;
R11 is selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl, or optionally R10 and R11 together are oxo;
each R12 is independently selected from the group consisting of hydrogen, halogen, nitro, -OC(=0)CH3, a urea, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; and
each dashed line independently represents an optional double bond.
1 1. A compound selected from the group consisting of the structures depicted in Table 4, or pharmaceutically acceptable salts thereof.
12. A pharmaceutical composition, comprising a compound according to any one of claims 1-1 1 and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
13. A method of inhibiting angiogenesis, comprising administering a compound according to any one of claims 1-11 to a subject in need thereof.
14. The method of claim 13, wherein angiogenesis is inhibited in a cancerous tumor.
15. The method of claim 14, wherein the cancer is selected from the group consisting of a carcinoma, a sarcoma, a lymphoma, and a blastoma.
16. The method of claim 14, wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, non-Hodgkin lymphoma, glioblastoma, pancreatic cancer, prostate cancer, and thyroid cancer.
17. The method of claim 13, wherein the angiogenesis is inhibited in a condition selected from the group consisting of diabetic blindness, age-related macular degeneration, rheumatoid arthritis, psoriasis, systematic lupus erythematosus, proliferative retinopathy, and atherosclerosis.
18. A method of treating a disease selected from the group consisting of bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, non-Hodgkin lymphoma, leukemia, pancreatic cancer, prostate cancer, thyroid cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, psoriasis, systematic lupus erythematosus, erythematosus, proliferative retinopathy, and atherosclerosis, comprising administering a compound according to any one of claims 1-11 to a subject in need thereof.
19. A method of inhibiting HIV replication, comprising administering a compound according to any one of claims 1-11 to a subject infected with HIV.
20. A method of preventing an HIV infection, comprising administering a compound according to any one of claims 1-11 to a subject at risk for said infection.
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