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WO2023141522A2 - Composés multicycliques - Google Patents

Composés multicycliques Download PDF

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Publication number
WO2023141522A2
WO2023141522A2 PCT/US2023/060928 US2023060928W WO2023141522A2 WO 2023141522 A2 WO2023141522 A2 WO 2023141522A2 US 2023060928 W US2023060928 W US 2023060928W WO 2023141522 A2 WO2023141522 A2 WO 2023141522A2
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Prior art keywords
compound
unsubstituted
cancer
group
alkyl
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WO2023141522A3 (fr
Inventor
Sunil Paliwal
Ahmed Abdi Samatar
Lawrence Saunders CRIPE
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Slap Pharmaceuticals LLC
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Slap Pharmaceuticals LLC
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Publication of WO2023141522A3 publication Critical patent/WO2023141522A3/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present application relates to the fields of chemistry, biochemistry and medicine.
  • compounds of Formula (I), or pharmaceutically acceptable salt thereof pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same.
  • methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof are also disclosed herein.
  • Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof. [0005] Some embodiments disclosed herein relate to a pharmaceutical composition that can contain an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Some embodiments described herein relate to a method of treating a cancer described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof)
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein.
  • Some embodiments described herein relate to a method for inhibiting growth of a malignant growth or a tumor that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a malignant growth or a tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Some embodiments described herein relate to a method for inhibiting the activity of DNA-dependent protein kinase in a cell that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of DNA- dependent protein kinase.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the activity of DNA-dependent protein kinase.
  • Some embodiments described herein relate to a method for treating a cancer described herein that can include inhibiting the activity of DNA-dependent protein kinase using an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein by inhibiting the activity of DNA-dependent protein kinase.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein by inhibiting the activity of DNA-dependent protein kinase.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein by inhibiting the activity of DNA-dependent protein kinase.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein by inhibiting the activity of DNA-dependent protein kinase.
  • DNA-dependent protein kinase is a serine/threonine protein kinase that plays an important role in the proliferation and survival of cells.
  • DNA-PK is necessary for multiple cellular functions, including the regulation of transcription and in the maintenance of telomeres. It is a member of the phosphatidylinositol 3 -kinase-related kinase family and it mediates the cellular response to DNA damage.
  • DNA-PK consists of a catalytic subunit and a Ku heterodimer that is made up of the Ku70 and Ku80 subunits.
  • DNA-PK plays an important role in the maintenance of genomic integrity because of its involvement in cellular response to DNA damage and in the repair of DNA double-strand break (DNA-DSBs).
  • DNA-PK is involved in repairing double-strand breaks (DSBs) through non-homologous end-joining (NHEJ).
  • NHEJ pathway consist of several steps that include detection of DSBs by the Ku70/80 with subsequent recruitment and stabilization of the NHEJ complex at the damage location. The activation of DNA-PK then leads to ligation of broken DNA ends. Because of the role played by DNA-PK in cellular response to DNA damage and its deregulation in tumor cells, it has become an attractive therapeutic target in cancer. There is an effort to develop selective small molecules that will inhibit the activity of DNA-PK in several cancers as a single agent or in combination with other targeted therapeutics and/or ionizing radiation therapy.
  • the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) (such as 1, 2 or 3) individually and independently selected from deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, C-amido(alkyl), isocyanato, thiocyanato, nitro, azi
  • C a to C b in which “a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the aryl, ring of the heteroaryl or ring of the heterocyclyl can contain from “a” to “b”, inclusive, carbon atoms.
  • a “C 1 to C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, 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-. If no “a” and “b” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, aryl, heteroaryl or heterocyclyl group, the broadest range described in these definitions is to be assumed.
  • alkyl refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group.
  • 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 10 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.
  • the alkyl group of the compounds may be designated as “C 1 -C 4 alkyl” or similar designations.
  • “C 1 -C 4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from 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 and hexyl.
  • the alkyl group may be substituted or unsubstituted.
  • alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.
  • the length of an alkenyl can vary.
  • the alkenyl can be a C 2-4 alkenyl, C 2-6 alkenyl or C 2-8 alkenyl.
  • alkenyl groups include allenyl, vinylmethyl and ethenyl.
  • An alkenyl group may be unsubstituted or substituted.
  • alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.
  • the length of an alkynyl can vary.
  • the alkynyl can be a C 2-4 alkynyl, C 2-6 alkynyl or C 2-8 alkynyl.
  • Examples of alkynyls include ethynyl and propynyl.
  • An alkynyl group may be unsubstituted or substituted.
  • cycloalkyl refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system.
  • Cycloalkyl groups can contain 3 to 10 atoms in the ring(s). 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s).
  • a cycloalkyl group may be unsubstituted or substituted.
  • Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • cycloalkenyl refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused- or spiro-fashion.
  • a cycloalkenyl can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s).
  • a cycloalkenyl group may be unsubstituted or substituted.
  • aryl refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings.
  • the number of carbon atoms in an aryl group can vary.
  • the aryl group can be a C 6 -C 14 aryl group, a C 6 -C 10 aryl group, or a C 6 aryl group.
  • Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene.
  • An aryl group may be substituted or unsubstituted.
  • heteroaryl refers to a monocyclic, bicyclic and tricyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1 to 5 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
  • the number of atoms in the ring(s) of a heteroaryl group can vary.
  • the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s).
  • heteroaryl includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond.
  • heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3- thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrim
  • heterocyclyl refers to a monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system.
  • a heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings.
  • the number of atoms in the ring(s) of a heterocyclyl group can vary.
  • the heterocyclyl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s).
  • the heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen.
  • a heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heterocyclyl may be quatemized. Heterocyclyl groups may be unsubstituted or substituted.
  • heterocyclyl groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4- dioxane, 1,2-dioxolane, 1,3 -dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3- oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro- 1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1, 3, 5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazoline, o
  • cycloalkyl(alkyl) refer to a cycloalkyl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and aryl group of a cycloalkyl(alkyl) may be substituted or unsubstituted.
  • Examples include but are not limited to cyclopropyl-CH 2 -, cyclobutyl-CH 2 -, cyclopentyl-CH 2 -, cyclohexyl-CH 2 -, cyclopropyl-CH 2 CH 2 -, cyclobutyl- CH 2 CH 2 -, cyclopentyl-CH 2 CH 2 -, cyclohexyl-CH 2 CH 2 -, cyclopropyl-CH 2 CH 2 CH 2 -, cyclobutyl-CH 2 CH 2 CH 2 -, cyclopentyl-CH 2 CH 2 CH 2 -, cyclohexyl-CH 2 CH 2 CH 2 -, cyclopropyl- CH 2 CH 2 CH 2 CH 2 -, cyclobutyl-CH 2 CH 2 CH 2 -, cyclopentyl-CH 2 CH 2 CH 2 CH 2 - and cyclohexyl-CH 2 CH 2 CH 2 CH 2 -.
  • aryl(alkyl) refer to an aryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and aryl group of an aryl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl).
  • heteroaryl(alkyl) refer to a heteroaryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heteroaryl group of heteroaryl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to 2- thienyl(alkyl), 3-thienyl(alkyl), furyl(alkyl), thienyl(alkyl), pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl), and their benzo-fused analogs.
  • heterocyclyl(alkyl) refer to a heterocyclic group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heterocyclyl of a heterocyclyl(alkyl) may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H- thiopyran-4-yl(methyl) and l,3-thiazinan-4-yl(methyl).
  • “Lower alkylene groups” are straight-chained -CH 2 - tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -) and butylene (-CH 2 CH 2 CH 2 CH 2 -).
  • a lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group with a substituent(s) listed under the definition of “substituted.” Further, when a lower alkylene group is substituted, the lower alkylene can be substituted by replacing both hydrogens on the same carbon with a cycloalkyl group (e.g., )•
  • alkoxy refers to the formula -OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein.
  • a non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec -butoxy, tert-butoxy, phenoxy and benzyloxy.
  • an alkoxy can be -OR, wherein R is an unsubstituted C 1-4 alkyl. An alkoxy may be substituted or unsubstituted.
  • acyl refers to a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted.
  • hydroxyalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group.
  • exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxyethyl, 3 -hydroxypropyl, 2-hydroxypropyl and 2,2-dihydroxyethyl.
  • a hydroxyalkyl may be substituted or unsubstituted.
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl and tri-haloalkyl).
  • a halogen e.g., mono-haloalkyl, di-haloalkyl and tri-haloalkyl.
  • groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl and 2-fluoroisobutyl.
  • a haloalkyl may be substituted or unsubstituted.
  • haloalkoxy refers to a O-alkyl group and O-monocyclic cycloalkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy).
  • Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy, chloro-substituted cyclopropyl, fluoro-substituted cyclopropyl, chlorosubstituted cyclobutyl and fluoro-substituted cyclobutyl.
  • a haloalkoxy can be -OR, wherein R is a C 1-4 alkyl substituted by 1, 2 or 3 halogens. A haloalkoxy may be substituted or unsubstituted.
  • a “sulfenyl” group refers to an “-SR” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • a sulfenyl may be substituted or unsubstituted.
  • a sulfinyl may be substituted or unsubstituted.
  • a “sulfonyl” group refers to an “SO 2 R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.
  • An O-carboxy may be substituted or unsubstituted.
  • An ester and C-carboxy may be substituted or unsubstituted.
  • a thiocarbonyl may be substituted or unsubstituted.
  • a “trihalomethanesulfonyl” group refers to an “X 3 CSO 2 -” group wherein each X is a halogen.
  • a “trihalomethanesulfonamido” group refers to an “X 3 CS(O) 2 N(RA)-” group wherein each X is a halogen, and RA is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • amino refers to a -NH 2 group.
  • hydroxy refers to a -OH group.
  • a “cyano” group refers to a “-CN” group.
  • azido refers to a -N3 group.
  • An “isocyanato” group refers to a “-NCO” group.
  • a “thiocyanato” group refers to a “-CNS” group.
  • An “isothiocyanato” group refers to an “-NCS” group.
  • a “mercapto” group refers to an “-SH” group.
  • S-sulfonamido refers to a “-SO 2 N(R A R B )” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An S-sulfonamido may be substituted or unsubstituted.
  • N-sulfonamido refers to a “RSO 2 N(R A )-” group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An N-sulfonamido may be substituted or unsubstituted.
  • An O-carbamyl may be substituted or unsubstituted.
  • R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An N-carbamyl may be substituted or unsubstituted.
  • An O-thiocarbamyl may be substituted or unsubstituted.
  • R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An N-thiocarbamyl may be substituted or unsubstituted.
  • a C-amido may be substituted or unsubstituted.
  • R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An N-amido may be substituted or unsubstituted.
  • a “mono-substituted amine” refers to a “-NHR A ” in which RA can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • a mono-substituted amine may be substituted or unsubstituted.
  • a mono-substituted amine can be -NHRA, wherein RA can be an unsubstituted C 1-6 alkyl or an unsubstituted or a substituted benzyl.
  • a “di-substituted amine” refers to a “-NR A R B ” in which RA and RB can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • a mono-substituted amine may be substituted or unsubstituted.
  • a mono-substituted amine can be -NR A R B , wherein RA and RB can be independently an unsubstituted C 1-6 alkyl or an unsubstituted or a substituted benzyl.
  • a ketoamide may be substituted or unsubstituted.
  • halogen atom or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.
  • substituents there may be one or more substituents present.
  • haloalkyl may include one or more of the same or different halogens.
  • C 1 -C 3 alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two or three atoms.
  • salt refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • the salt is an acid addition salt of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid.
  • compositions can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic or naphthalenesulfonic acid.
  • organic acid such as aliphatic or aromatic carboxylic or sulfonic acids
  • Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C 1 -C 7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C 1 -C 7 alkylamine, cyclohexy
  • the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”.
  • the term “comprising” means that the compound or composition includes at least the recited features or components but may also include additional features or components.
  • each center may independently be of (R)-configuration or (S)-configuration or a mixture thereof.
  • the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture.
  • each double bond may independently be E or Z a mixture thereof.
  • each chemical element as represented in a compound structure may include any isotope of said element.
  • a hydrogen atom may be explicitly disclosed or understood to be present in the compound.
  • the hydrogen atom can be 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.
  • R 1 can be selected from wherein R 1 can be unsubstituted or substituted with 1 or 2 substituents selected from a halogen, an unsubstituted C 1-4 alkyl, a deuterium-substituted C 1-4 alkyl and an unsubstituted C 1-4 alkoxy; and R 1A can be hydrogen or an unsubstituted C 1-4 alkyl; R 2 can be selected from an unsubstituted or a substituted monocyclic cycloalkyl and an unsubstituted or a substituted monocyclic heterocyclyl; R 3 can be selected from hydrogen, an unsubstituted C 1-4 alkyl, an unsubstituted C 1-4 alkoxy and an unsubstituted monocyclic C 3-6 cycloalkyl; and R 4 can be selected from hydrogen, an unsubstituted C 1-4 alkyl, an unsubstituted C 1-4 alkoxy and an unsubstituted monocycl
  • R 1 can be In other embodiments,
  • R 1 can be . In still other embodiments, R 1 can be In yet still other embodiments, R 1 can be Each bicyclic structure for R 1 can be unsubstituted or substituted. Various groups can be present on a substituted version of R 1 , such as those provided for “optionally substituted.” For example, R 1 can be substituted one or more times (1, 2 or 3 times) with a group independently selected from a halogen (such as F, Cl or Br), an unsubstituted C 1-4 alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl and tert-butyl) and a deuterium-substituted C 1-4 alkyl (for example, -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CD 3 and -CD 2 CD 3 )
  • a halogen such as F, Cl or Br
  • R 1 bicyclic structures can be selected from:
  • R 2 can be a monocyclic cycloalkyl, such as a monocyclic C4-6 cycloalkyl.
  • R 2 can be a monocyclic heterocyclyl.
  • the monocyclic heterocyclyl for R 2 can include 1 or 2 ring heteroatoms.
  • the monocyclic heterocyclyl for R 2 can include 1 or 2 ring heteroatoms selected from O (oxygen), S (sulfur) or N (nitrogen).
  • Examples of monocyclic cycloalkyls for R 2 include cyclobutyl, cyclopentyl and cyclohexyl, including the following: wherein each shown ring can be unsubstituted or substituted.
  • Various sizes of monocyclic heterocyclyls can be present for R 2 .
  • R 2 can be a 4-6 membered monocyclic heterocyclyl.
  • Exemplary monocyclic heterocyclyls for R 2 include tetrahydrofuran, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1 -dioxide, morpholine, thiomorpholine, thiomorpholine 1,1 -dioxide, piperidine, piperazine and 3,6-dihydro-2H-pyran.
  • R 2 can be selected from unsubstituted or substituted.
  • R 2 can be unsubstituted. In other embodiments, R 2 can be substituted. A variety of substituents can be present for R 2 . Similarly, the number of substituents present on R 2 can vary. In some embodiments, R 2 can be substituted 1, 2 or 3 times with a substituent described herein, including those provided for “optionally substituted.” For example, R 2 can be substituted with one or more substituents selected from halogen, cyano, hydroxy, an unsubstituted C 1-4 alkyl, an unsubstituted C 1-4 alkoxy, an unsubstituted monocyclic C 3-6 cycloalkyl and an unsubstituted C 1-4 haloalkyl.
  • R 2 can be substituted with one or more substituents selected from fluoro, chloro, cyano, hydroxy, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec -butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CF 3 , -CHF 2 , -C(CH 3 )F 2 , -CHCI2, -CH 2 F, -CH(CH 3 )F, -CH 2 CF 3 , -CH 2 CI, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F and -CH 2 CH 2 CH 2 Cl.
  • substituents
  • R 2 When R 2 is substituted, one or both hydrogens on a ring carbon and/or the hydrogen on a ring nitrogen can be replaced with a substituent described herein.
  • the ring NH group of a piperazine can be substituted with an unsubstituted C 1-4 alkyl group, such as methyl.
  • R 3 can be hydrogen.
  • R 3 can be an unsubstituted C 1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
  • R 3 can be an unsubstituted C 1-4 alkoxy (for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy).
  • R 3 can be an unsubstituted monocyclic C 3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 4 can be hydrogen. In other embodiments, R 4 can be an unsubstituted C 1-4 alkyl, such as those described herein. In still other embodiments, R 4 can be a deuterium-substituted C 1-4 alkyl. For example, R 4 can be -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CD 3 and -CD 2 CD 3 . In yet still other embodiments, R 4 can be an unsubstituted monocyclic C 3 -6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 4 can be an unsubstituted bicyclic C 5-6 cycloalkyl.
  • exemplary bicyclic C 5-6 cycloalkyls include bicyclo [1.1.1] pentyl and bicyclo [2.1.1] hexyl.
  • R 4 can be an unsubstituted C 1-4 haloalkyl, such as those described herein and including -CF 3 , -CHF 2 , -C(CH 3 )F 2 , -CHCI2, -CH 2 F, -CH(CH 3 )F, -CH 2 CF 3 , -CH 2 CI, -CH 2 CH 2 F, -CH 2 CH 2 CI, -CH 2 CH 2 CH 2 F and -CH 2 CH 2 CH 2 CI.
  • Examples of compounds of Formula (I), include the following: [0080] Further examples of a compound of Formula (I), include the following:
  • Additional examples of a compound of Formula (I) can be selected from: , or a pharmaceutically acceptable salt of any of the foregoing.
  • Some embodiments disclosed herein relate to a compound having the structure or a pharmaceutically acceptable salt thereof.
  • Other embodiments disclosed herein relate to a compound having the structure or a pharmaceutically acceptable salt thereof, wherein PG 1 can be a protecting group. Suitable protecting groups are known to those skilled in the art.
  • PG 1 can be a triflate.
  • Still other embodiments disclosed herein relate to a compound having the structure or a pharmaceutically acceptable salt thereof.
  • Some embodiments disclosed herein relate to a method of preparing a compound having the structure , or a pharmaceutically acceptable salt thereof, that can include coupling a boronic ester to a compound having the structure
  • the boronic ester can have the structure wherein each R B1 and R B2 can be a C 1-6 alkyl (such as an unsubstituted C 1-6 alkyl), or R B1 and R B2 can be taken together along with the -O-B-O- to form a
  • the boronic ester can be Other embodiments disclosed herein relate to a method of preparing a compound having the structure or a pharmaceutically acceptable salt thereof, that can include hydrogenating a compound having the structure or a pharmaceutically acceptable salt thereof.
  • the hydrogenation of can include using a suitable hydrogenation compound, such as palladium on carbon.
  • compositions described herein relate to a pharmaceutical composition, which can include an effective amount of a compound described herein (e.g., a compound, or a pharmaceutically acceptable salt thereof, as described herein) and a pharmaceutically acceptable carrier, excipient or combination thereof.
  • a pharmaceutical composition described herein is suitable for human and/or veterinary applications.
  • a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • DMSO dimethyl sulfoxide
  • a “diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable.
  • a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation.
  • a common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
  • an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition.
  • a “diluent” is a type of excipient.
  • Proper formulation is dependent upon the route of administration chosen.
  • Techniques for formulation and administration of the compounds described herein are known to those skilled in the art. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, rectal, topical, aerosol, injection, inhalation and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections.
  • Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
  • the liposomes may be targeted to and taken up selectively by the organ.
  • compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.
  • compounds used in a pharmaceutical composition may be provided as salts with pharmaceutically compatible counterions.
  • Some embodiments described herein relate to a method for treating a cancer described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof)
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein.
  • Some embodiments described herein relate to a method for inhibiting growth of a malignant growth or a tumor that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a malignant growth or a tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Some embodiments described herein relate to a method for inhibiting the activity of DNA-dependent protein kinase that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein.
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of DNA- dependent protein kinase.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the activity of DNA-dependent protein kinase.
  • Some embodiments described herein relate to a method for inhibiting the activity of DNA-dependent protein kinase that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein.
  • a method for inhibiting the activity of DNA-dependent protein kinase that can include contacting a cancer cell from a cancer described herein with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), and thereby inhibiting the activity of DNA-dependent protein kinase.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • Some embodiments described herein relate to a method for treating a cancer described herein that can include inhibiting the activity of DNA-dependent protein kinase using an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein by inhibiting the activity of DNA-dependent protein kinase.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein by inhibiting the activity of DNA-dependent protein kinase.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein by inhibiting the activity of DNA-dependent protein kinase.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein by inhibiting the activity of DNA-dependent protein kinase.
  • Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a cancer cell with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the compound inhibits the activity of DNA-dependent protein kinase.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • Some embodiments disclosed herein relate to a method for inhibiting the activity of DNA-dependent protein kinase that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein or a cancer cell from a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • inventions disclosed herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of DNA-dependent protein kinase.
  • Still other embodiments disclosed herein relate to a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the activity of DNA-dependent protein kinase.
  • suitable cancers include, but are not limited to: a lung cancer, a pancreatic cancer, a colon cancer (e.g., colorectal cancer), a myeloid leukemia (e.g., AML, CML, and CMML), a thyroid cancer, a myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancers (e.g., squamous cell cancer of the head and neck), an ovarian cancer, a brain cancer (e.g., gliomas, such as glioma blastoma multiforme), a cancer of mesenchymal origin (e.g., fibrosarcomas and rhabdomyosarcomas), a sarcoma, a teratocarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma,
  • treat do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.
  • a “subject” refers to an animal that is the object of treatment, observation or experiment.
  • Animal includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals.
  • “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, camels, non-human primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
  • the subject can be human, for example a human subject that is 18 years old or older.
  • an effective amount is used to indicate an amount of an active compound, or pharmaceutical agent, which elicits the biological or medicinal response indicated.
  • an effective amount of compound can be the amount needed to alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein.
  • the effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
  • the aqueous phase was extracted with EA (3 x 2000 mL).
  • the mixture was purified by prep-HPLC (HC1 as additive) and twice purification by prep-HPLC (NH4HCO3 as additive) to give A1 (2.5 mg, 6.39 umol, 9.77e-l% yield).
  • Additional compounds of Formula (I) can be prepared using similar materials and methods described herein, such as those described herein.
  • a kinase buffer (40 mM Tris, pH 7.5, 0.0055% Brij-35, 20 mM MgCl 2 , 0.05 mM DTT) was prepared, and the compounds were diluted to 100X of the final desired highest inhibitor concentration in reaction by 100% DMSO.
  • the compounds were in tubes to one well on a 96-well storage plate and serially by transferring 15 ⁇ L to 30 ⁇ L of 100% DMSO into the well. 50 nL of compound was transferred from source plate to 384-well plate.
  • Solution (2X) of substrate and ATP in kinase reaction buffer was prepared, and 2.5 ⁇ L of substrate solution was added to each well of the assay plate to initiate the reaction.
  • DNA- PK in 1x kinase buffer at 2-fold the final concentration of each reagent was prepared, and 2.5 ⁇ L of kinase solution was added to each well.
  • 2.5 ⁇ L of substrate solution was added to each well of the assay plate to start reaction and incubated at room temperature for 3 h.
  • 5 ⁇ L of ADP-Glo reagent was added to each well of the assay plate to terminate the reaction.
  • the solution was mixed briefly, centrifuged and equilibrated for 120 min. 10 uL Kinase Detection Reagent was added to each well, and shaken and left to equilibrate for 30 min before reading on a plate reader for luminescence.
  • Percent inhibition (max-sample RLU)/(max-min) x 100 was calculated and fitted the data in XLFit excel add-in version 5.4.0.8 to obtain IC 50 values.

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Abstract

L'invention concerne des composés de formule (I), ou des sels pharmaceutiquement acceptables de ceux-ci, des compositions pharmaceutiques qui comprennent un composé selon l'invention (y compris des sels pharmaceutiquement acceptables d'un composé selon l'invention) et des procédés de synthèse de ceux-ci. L'invention concerne également des procédés de traitement de maladies et/ou d'états avec un composé de formule (I), ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2023/060928 2022-01-21 2023-01-19 Composés multicycliques Ceased WO2023141522A2 (fr)

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WO2025179188A1 (fr) * 2024-02-22 2025-08-28 Juno Therapeutics, Inc. Inhibiteurs à base de pyrazole de protéine kinase dépendante de l'adn et compositions et applications dans l'édition génique

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US20060142312A1 (en) * 2004-12-23 2006-06-29 Pfizer Inc C6-aryl and heteroaryl substituted pyrido[2,3-D] pyrimidin-7-ones
WO2014015523A1 (fr) * 2012-07-27 2014-01-30 Hutchison Medipharma Limited Nouveaux composés hétéroaryliques et hétérocycliques et compositions et procédés s'y rapportant
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UA124804C2 (uk) * 2016-08-15 2021-11-24 Пфайзер Інк. Піридопіримідинонові інгібітори cdk2/4/6
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