Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
  • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C219/12—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C219/20—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
  • C07C219/22—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
  • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/28—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C317/00—Sulfones; Sulfoxides
  • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
  • C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
  • C07C321/12—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to acyclic carbon atoms
  • C07C321/14—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
  • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
  • C07C49/723—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic
  • C07C49/727—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic a keto group being part of a condensed ring system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
  • C07C69/12—Acetic acid esters
  • C07C69/21—Acetic acid esters of hydroxy compounds with more than three hydroxy groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
  • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
  • C07C69/33—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with hydroxy compounds having more than three hydroxy groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
  • C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/608—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a ring other than a six-membered aromatic ring in the acid moiety
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
  • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
  • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
  • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
  • C07C69/75—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring of acids with a six-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
  • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
  • C07D205/12—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/55—Acids; Esters
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
  • C07D303/02—Compounds containing oxirane rings
  • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
  • C07D303/14—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by free hydroxyl radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
  • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/02—Ortho- or ortho- and peri-condensed systems
  • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
  • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
  • C07C2603/08—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing three- or four-membered rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/02—Ortho- or ortho- and peri-condensed systems
  • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/56—Ring systems containing bridged rings
  • C07C2603/58—Ring systems containing bridged rings containing three rings
  • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
  • C07C2603/74—Adamantanes
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
  • C07K5/06043—Leu-amino acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
  • C07K5/06052—Val-amino acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
  • C07K5/0802—Tripeptides with the first amino acid being neutral
  • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic

Definitions

• PLC DITERPENOID COMPOUNDS THAT ACT ON PROTEIN KINASE C
• PLC CROSS-REFERENCE TO RELATED APPLICATIONS
• the present disclosure provides novel protein kinase C (PKC) modulating compounds.
• PKC protein kinase C
• the compounds are diterpenoid PKC modulating compounds displaying enhanced pharmacological properties, including among others, potent PKC enzyme binding activity and anti-proliferative activity against different cancer cells.
• the PKC modulating compounds also have substituents that can enhance solubility and pharmacokinetic profiles.
• the compounds have the structure of formula (I):
• A is -OH, –C(O)OR 1 , or -NR 13 R 13’ ;
• R 1 is H or a M+ counterion;
• R 2 is a C 1 -C 4 alkyl;
• R 3 is O double bonded to the ring carbon when (- - -) is a bond, or -OR a ;
• R a is H or - C(O)R a1 , wherein R a1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 -C 6 alkylaryl, or C 0 -C 6 alkylheteroaryl;
• R 4 and R 5 are each independently H or -OR b , wherein R b is H, C1-C6alkyl, C2-C6alkenyl, C0- C6alkylaryl, or C0-C6alkylheteroaryl;
• R 5 are each independently H or -OR b ,
• A is –OH. In some embodiments, A is –C(O)OR 1 , wherein R 1 is H or a M + counterion. In some embodiments, A is -NR 13 R 13’ , wherein R 13 and R 13’ are each independently H or C 1 -C 4 alkyl. [0007] In some embodiments, the present disclosure provides a compound of formula (II):
• R 2 is a C1-C4alkyl
• R 3 is O double bonded to the ring carbon when (- - -) is a bond, or -OR a
• R a is H or - C(O)R a1
• R a1 is C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl
• R 4 and R 5 are each independently H or -OR b , wherein R b is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 - C6alkylaryl, or C0-C6alkylheteroaryl;
• R 5 ’ and R 6 ’ are H, or R 5 ’ and R 6 ’ form a bond or are bonded to a common O atom to form an epoxide
• the present disclosure provides a compound of formula (IV): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R 2 is a C1-C4alkyl; R 3 is O double bonded to the ring carbon when (- - -) is a bond, or -OR a ; wherein R a is H or - C(O)R a1 , wherein R a1 is C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl; R 4 and R 5 are each independently H or -OR b , wherein R b is H, C1-C6alkyl, C2-C6alkenyl, C0- C 6 alkylaryl, or C 0 -C 6 alkylheteroaryl; R 5 ’ and R 6 ’ are H, or R 5 ’ and R 6 ’ form a bond or are
• the compounds can be used in a method to activate protein kinase C, comprising contacting a mammalian cell with an effective amount of a compound disclosed herein.
• the mammalian cell is a cancer cell.
• the compounds are used for treating cancer by administering a therapeutically effective amount to a subject in need thereof a compound disclosed herein.
• the cancer for treatment is adrenocortical cancer, anal cancer, biliary cancer, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, head and neck cancer, intestinal cancer, liver cancer, lung cancer, oral cancer, ovarian cancer, pancreatic cancer, renal cancer, prostate cancer, salivary gland cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, sarcoma, or soft tissue carcinomas.
• the cancer for treatment is a hematological cancer, such as leukemia or lymphoma.
• the hematological cancer is lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), lymphoma (e.g., Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, Burkitt’s lymphoma), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), Hairy Cell chronic myelogenous leukemia (CML), and multiple myeloma.
• ALL lymphoblastic leukemia
• AML acute myeloid leukemia
• lymphoma e.g., Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, Burkitt’s lymphoma
• CLL chronic lymphocytic leukemia
• CML chronic myelogenous leukemia
• CML Hairy Cell chronic myelogenous leukemia
• multiple myeloma multiple myeloma.
• FIG.1 shows PKC activation in A549 non-small cell lung cancer cells by diterpenoid compounds as assessed by measuring levels of phosphorylated PKC (p-PKC) and phosphorylated ERK1/2 proteins (p-ERK1/2).
• FIG.2 shows PKC activation in A549 non-small cell lung cancer cells by diterpenoid compounds as assessed by measuring levels of phosphorylated PKC (p-PKC) and phosphorylated ERK1/2 proteins (p-ERK1/2).
• FIG.3 shows PKC activation in A549 non-small cell lung cancer cells by diterpenoid compounds assessed by measuring levels of phosphorylated PKC (p-PKC) and phosphorylated ERK1/2 proteins (p-ERK1/2), with prostratin (K101) provided for comparison.
• FIG.4A shows PKC activation in A549 non-small cell lung cancer cells by diterpenoid compounds based on levels of phosphorylated PKC (p-PKC) and phosphorylated ERK1/2 proteins (p- ERK1/2).
• FIG.4B shows PKC activation in A549 non-small cell lung cancer cells by diterpenoid compounds assessed by measuring levels of phosphorylated PKD/PKC ⁇ (p-PKC) and phosphorylated PKC ⁇ .
• FIG.5 shows effect of selected diterpenoid compounds on levels of phosphorylated CaMKii (p-CaMKii), a marker of K-Ras stemness pathway inhibition, in Panc1 pancreatic cancer cell line.
• FIGS.6A-6D show sphere formation by Panc1 pancreatic cancer cell line treated with different diterpenoid compounds.
• FIG.7 shows effect of intratumoral administration (7 daily injections) of diterpenoid compounds into Panc2.13 tumors in mice with Panc2.13 pancreatic cancer cell line xenografts. 5.
• DETAILED DESCRIPTION As used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to “a protein” includes more than one protein, and reference to “a compound” refers to more than one compound. [0023] Also, the use of “or” means “and/or” unless stated otherwise.
• Alkyl refers to straight or branched chain hydrocarbon groups of 1 to 20 carbon atoms, particularly 1 to 12 carbon atoms (C1-C12 or C1-12), and more particularly (C1-C8 or C1-8) carbon atoms.
• alkyl includes, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.
• Alkenyl refers to straight or branched chain hydrocarbon group of 2 to 20 carbon atoms, particularly 2 to 12 carbon atoms (C 2 -C 12 or C 2-12 ), and most particularly 2 to 8 (C 2 -C 8 or C 2-8 )carbon atoms, having at least one double bond.
• alkenyl includes, but are not limited to, vinyl ethenyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl- 1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.
• Alkynyl refers to a straight or branched chain hydrocarbon group of 2 to 12 carbon atoms (C2-C12 or C2-12), particularly 2 to 8 carbon atoms (C2-C8 or C2-8), containing at least one triple bond.
• alkynyl includes ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5- hexynyl.
• Alkylene alkenylene
• alkynylene refers to a straight or branched chain divalent hydrocarbon radical of the corresponding alkyl, alkenyl, and alkynyl, respectively.
• alkylene alkenylene and alkynylene
• alkylene alkenylene
• alkynylene may be optionally substituted, for example with alkyl, alkyloxy, hydroxyl, carbonyl, carboxyl, halo, nitro, and the like.
• Aliphatic refers to an organic compound characterized by substituted or unsubstituted, straight or branched, and/or cyclic chain arrangements of constituent carbon atoms. Aliphatic compounds do not contain aromatic rings as part of the molecular structure of the compounds.
• Aliphatic compound can have 1-20 (C 1 -C 20 or C 1-20 ) carbon atoms, 1-12 (C 1 -C 12 or C 1-12 ) carbon atoms, or particularly 1-8 (C1-C8 or C1-8) carbon atoms.
• “Lower” in reference to substituents refers to a group having between one and six carbon atoms.
• Cycloalkyl refers to any stable monocyclic or polycyclic system which consists of carbon atoms, any ring of which being saturated.
• Cycloalkenyl refers to any stable monocyclic or polycyclic system which consists of carbon atoms, with at least one ring thereof being partially unsaturated.
• cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicycloalkyls and tricycloalkyls (e.g., adamantyl).
• “Heterocycloalkyl” or “heterocyclyl” refers to a substituted or unsubstituted 3 to 14 membered, mono- or bicyclic, non-aromatic hydrocarbon, wherein 1 to 3 carbon atoms a (e replaced by a heteroatom.
• Heteroatoms and/or heteroatomic groups which can replace the carbon atoms include, but are not limited to, -O-, -S-, -S-O-, -NR’-, -PH-, -S(O)-, -S(O) 2 -, -S(O) NR’-, -S(O) 2 NR’-, and the like, including combinations thereof, where each R’ is independently hydrogen or lower alkyl.
• Examples include oxiranyl, oxetanyl, azetidynyl, oxazolyl, thiazolidinyl, thiazolyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, azapanyl, and the like.
• Carbocycle refers to a non-aromatic saturated or unsaturated ring in which each atom of the ring is carbon.
• the ring may be monocyclic, bicyclic, tricyclic, or even of higher order.
• a carbocycle ring contains from 3 to 14 atoms, including 3 to 8 or 5 to 7 atoms, such as for example, 6 atoms.
• Aryl refers to a six- to fourteen-membered, mono- or bi-carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. Examples of “aryl” groups include phenyl, naphthyl, indenyl, biphenyl, phenanthrenyl, naphthacenyl, and the like.
• Heteroaryl refers to an aromatic heterocyclic ring, including both monocyclic and bicyclic ring systems, where at least one carbon atom of one or both of the rings is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur, or at least two carbon atoms of one or both of the rings are replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur.
• the heteroaryl can be a 5 to 6 membered monocyclic, or 7 to 11 membered bicyclic ring systems.
• heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolyl, and the like.
• Bridged bicyclic refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
• a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
• a bridged bicyclic group has 5 to 12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• bridged bicyclic groups include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include: [0039] “Fused ring” refers a ring system with two or more rings having at least one bond and two atoms in common.
• a “fused aryl” and a “fused heteroaryl” refer to ring systems having at least one aryl and heteroaryl, respectively, that share at least one bond and two atoms in common with another ring.
• “Carbonyl” refers to -C(O)-.
• the carbonyl group may be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, aldehydes, amides, esters, and ketones.
• an -C(O)R’, wherein R’ is an alkyl is referred to as an alkylcarbonyl.
• R’ is selected from an optionally substituted: alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.
• Halogen or “halo” refers to fluorine, chlorine, bromine and iodine.
• Haloalkyl refers to an alkyl substituted with 1 or more halogen atoms. Preferably, the alkyl is substituted with 1 to 3 halogen atoms.
• “Hydroxy” refers to –OH.
• Oxy refers to group -O-, which may have various substituents to form different oxy groups, including ethers and esters.
• the oxy group is an –OR’, wherein R’ is selected from an optionally substituted: alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.
• acyl refers to -C(O)R’, where R is hydrogen, or an optionally substituted alkyl, heteroalkyl, cylcoalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl as defined herein.
• exemplary acyl groups include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.
• Alkyloxy or “alkoxy” refers to —OR’, wherein R’ is an optionally substituted alkyl.
• Aryloxy refers to –OR’, wherein R’ is an optionally substituted aryl.
• Carboxy refers to –COO- or COOM, wherein H or a M + counterion.
• Carbamoyl refers to -C(O)NR’R’, wherein each R’ is independently selected from H or an optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocylcoalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.
• Cyano refers to –CN.
• R is selected from an optionally substituted: alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocyclolalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.
• SiR SiR’R’R’, where R’ is as defined in the specification.
• each R’ is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, heterocyloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.
• any heterocyloalkyl or heteroaryl group present in a silyl group has from 1 to 3 heteroatoms selected independently from O, N, and S.
• Thiol refers to –SH.
• “Sulfanyl” refers to –SR’, wherein R’ is selected from an optionally substituted: alkyl, cycloalkyl, cycloalkylalkyl, heterocyloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.
• R is selected from an optionally substituted: alkyl, cycloalkyl, cycloalkylalkyl, heterocyloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.
• -SR wherein R is an alkyl is an alkylsulfanyl.
• “Sulfonyl” refers to -S(O) 2 -, which may have various substituents to form different sulfonyl groups including sulfonic acids, sulfonamides, sulfonate esters, and sulfones.
• -S(O) 2 R’ wherein R’ is an alkyl refers to an alkylsulfonyl.
• R’ is selected from an optionally substituted: alkyl, cycloalkyl, cycloalkylalkyl, heterocyloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.
• Amino refers to the group –NR’R’ or –NR’R’R’, wherein each R’ is independently selected from H and an optionally substituted: alkyl, cycloalkyl, heterocycloalkyl, alkyloxy, aryl, heteroaryl, heteroarylalkyl, acyl, alkyloxycarbonyl, sulfanyl, sulfinyl, sulfonyl, and the like.
• amino groups include, but are not limited to, dimethylamino, diethylamino, trimethylammonium, triethylammonium, methylysulfonylamino, furanyl-oxy-sulfamino, and the like.
• “Spiroalkyl” as used herein refers to a monospiro compound having two alicyclic rings attached together through a single common carbon atom.
• the spiro compounds have 5 to 12 total ring atoms (e.g., C5-C12 or C5-12).
• one or more of the carbon atoms can be replaced with a heteroatom, such as oxygen, nitrogen or sulfur.
• Exemplary spiroalkyl compounds include, among others, spiro[3,3]heptyl, spiro[3.4]octyl, and spiro[3,5]decyl.
• Adamantyl refers to a compound of structural formula: where optional substitutions can be present on one or more of R a , R b , R c , and R d .
• Adamantyl includes substituted adamantyl, e.g., 1- or 2-adamantyl, substituted by one or more substituents, including alkyl, halo, OH, NH2, and alkoxy.
• Exemplary derivatives include methyladamatane, haloadamantane, hydroxyadamantane, and aminoadamantane (e.g., amantadine).
• N-protecting group refers to those groups intended to protect a nitrogen atom against undesirable reactions during synthetic procedures.
• exemplary N-protecting groups include, but is not limited to, acyl groups such acetyl and t-butylacetyl, pivaloyl, alkoxycarbonyl groups such as methyloxycarbonyl and t-butyloxycarbonyl (Boc) , aryloxycarbonyl groups such as benzyloxycarbonyl (Cbz) and fluorenylmethoxycarbonyl (Fmoc and aroyl groups such as benzoyl.
• acyl groups such as acetyl and t-butylacetyl, pivaloyl
• alkoxycarbonyl groups such as methyloxycarbonyl and t-butyloxycarbonyl (Boc)
• aryloxycarbonyl groups such as benzyloxycarbonyl (Cbz) and fluorenylmethoxycarbonyl
• “Optional” or “optionally” refers to a described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not.
• “optionally substituted alkyl” refers to an alkyl group that may or may not be substituted and that the description encompasses both substituted alkyl group and unsubstituted alkyl group.
• “Substituted” as used herein means one or more hydrogen atoms of the group is replaced with a substituent atom or group commonly used in pharmaceutical chemistry. Each substituent can be the same or different.
• substituents include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl, OR ’ (e.g., hydroxyl, alkyloxy (e.g., methoxy, ethoxy, and propoxy), aryloxy, heteroaryloxy, arylalkyloxy, ether, ester, carbamate, etc.), hydroxyalkyl, alkyloxycarbonyl, alkyloxyalkyloxy, perhaloalkyl, alkyloxyalkyl, SR ’ (e.g., thiol, alkylthio, arylthio, heteroarylthio, arylalkylthio, etc.), S + R ’ 2, S(O)R ’ , SO2R ’ , NR ’ R ” (e.g., primary amine (i.e., NH2)
• “Stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
• “stereoisomer thereof” with respect to a compound includes any stereoisomer of the compound and mixtures of stereoisomers, and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
• a compound may have more than one chiral center such that the compound may exist as either an individual diastereomer or as a mixture of diastereomers.
• “Tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. Thus, “tautomers thereof” with respect to a compound includes any tautomers of the compound.
• “Prodrug” refers to a derivative of an active compound (e.g., drug) that requires a transformation under the conditions of use, such as within the body or appropriate in vitro conditions, to release the active drug. Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted into the active drug.
• Prodrugs can be obtained by masking a functional group in the drug believed to be in part required for activity with a progroup to form a promoiety which undergoes a transformation, such as cleavage, under the specified conditions of use to release the functional group, and hence the active drug.
• the cleavage of the promoiety may proceed spontaneously, such as by way of a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature.
• the agent may be endogenous to the conditions of use, such as an enzyme present in the cells to which the prodrug is administered or the acidic conditions of the stomach, or it may be supplied exogenously.
• hydroxyl functional group may be masked as a sulfonate, ester or carbonate promoiety, which may be hydrolyzed in vivo to provide the hydroxyl group.
• An amino functional group may be masked as an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenyl promoiety, which may be hydrolyzed, e.g., in vivo or under appropriate in vitro conditions, to provide the amino group.
• a carboxyl group may be masked as an ester (including silyl esters and thioesters), amide or hydrazide promoiety, which may be hydrolyzed in vivo to provide the carboxyl group.
• ester including silyl esters and thioesters
• amide or hydrazide promoiety which may be hydrolyzed in vivo to provide the carboxyl group.
• prodrugs include, among others, “biohydrolyzable carbonate”, “biohydrolyzable ureide”, “biohydrolyzable carbamate”, “biohydrolyzable ester”, “biohydrolyzable amide”, and “biohydrolyzable phosphate” groups.
• Solvate refers to a complex of variable stoichiometry formed by a solute, such as a PKC activator compound, and a solvent.
• Solvents are selected to minimally interfere with the biological activity of the solute.
• Solvents may be, by way of example and not limitation, water, ethanol, or acetic acid.
• “Hydrate” refers to a combination of water with a solute, such as a PKC activator compound, wherein the water retains its molecular state as water and is either absorbed, adsorbed or contained within a crystal lattice of the solute (e.g., PKC activating compound).
• “Pharmaceutically acceptable salts” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
• base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
• pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
• acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
• Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, phosphoric, partially neutralized phosphoric acids, sulfuric, partially neutralized sulfuric, hydroiodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
• salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.
• Certain specific compounds of the present disclosure may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., Mack Publishing Company, Easton, Pa., (1985) and Journal of Pharmaceutical Science, 66:2 (1977), each of which is incorporated herein by reference in its entirety.
• “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” refers to an excipient, carrier or adjuvant that can be administered to a subject, together with at least one therapeutic agent, and which does not destroy the pharmacological activity thereof and is generally safe, nontoxic and neither biologically nor otherwise undesirable when administered in doses sufficient to deliver a therapeutic amount of the agent.
• “K-RAS” refers to Kirsten rat sarcoma viral oncogene homolog, a small GTPase and a member of the RAS family of proteins involved in signal transduction. Exemplary human K-RAS nucleic acid and protein sequences are provided in GenBank Nos. M54968.1 and AAB414942.1, respectively.
• K-RAS as used herein encompasses variants, including orthologs and interspecies homologs, of the human K-RAS protein.
• “Mutant K-RAS polypeptide”, “mutant K- RAS protein” and “mutant K- RAS” are used interchangeably and refer to a K- RAS polypeptide comprising at least one K- RAS mutation as compared to the corresponding wild-type K- RAS sequence.
• Certain exemplary mutant K- RAS polypeptides include, but are not limited to, allelic variants, splice variants, derivative variants, substitution variants, deletion variants, insertion variants, and fusion polypeptides.
• N-RAS refers to Neuroblastoma RAS Viral (V-RAS) oncogene homolog, a small GTPase and a member of the RAS family of proteins involved in signal transduction.
• V-RAS Neuroblastoma RAS Viral
• Exemplary human N- RAS nucleic acid and protein sequences are provided in NCBI Accession No. NP_002515 and GenBank Accession No. X02751, respectively.
• N-RAS as used herein encompasses variants, including orthologs and interspecies homologs of the human N-RAS protein.
• mutant N- RAS polypeptide “mutant N- RAS protein” and “mutant N-RAS” are used interchangeably and refer to an N-RAS polypeptide comprising at least one N- RAS mutation as compared to the corresponding wild-type N- RAS sequence.
• Certain exemplary mutant N- RAS polypeptides include, but are not limited to, allelic variants, splice variants, derivative variants, substitution variants, deletion variants, insertion variants, and fusion polypeptides.
• H- RAS refers to Harvey Rat Sarcoma viral oncogene homolog, a small GTPase and a member of the RAS family of proteins involved in signal transduction.
• H-RAS nucleic acid and protein sequences are provided in NCBI Accession No. P01112 and GenBank Accession No. NM_176795, respectively.
• H- RAS as used herein encompasses variants, including orthologs and interspecies homologs of the human H- RAS protein.
• “Mutant H-RAS polypeptide”, “mutant H-RAS protein” and “mutant H-RAS” are used interchangeably and refer to an H-RAS polypeptide comprising at least one H- RAS mutation as compared to the corresponding wild-type H- RAS sequence.
• Certain exemplary mutant H- RAS polypeptides include, but are not limited to, allelic variants, splice variants, derivative variants, substitution variants, deletion variants, insertion variants, and fusion polypeptides.
• “Activating K- RAS” refers to a form of K- RAS that has increased activity compared to wild-type K- RAS. The activation of K- RAS activity can result from a mutation or in some embodiments, overexpression of the K- RAS protein.
• Activating N- RAS refers to a form of N- RAS that has increased activity compared to wild-type N- RAS.
• N- RAS activity can result from a mutation, or in some embodiments, overexpression of the N- RAS protein.
• Activating H- RAS refers to a form of H- RAS that has increased activity compared to wild- type H- RAS.
• the activation of H- RAS activity can result from a mutation, or in some embodiments, overexpression of the H- RAS protein.
• “Mutation” or “mutant” refers to an amino acid or polynucleotide sequence which has been altered by substitution, insertion, and/or deletion. In some embodiments, a mutant or variant sequence can have increased, decreased, or substantially similar activities or properties in comparison to the parental sequence.
• “Identified” or “determined” refers to analyzing for, detection of, or carrying out a process for the presence or absence of one or more specified characteristics.
• “Wild-type” or “naturally occurring” refers to the form found in nature. For example, a naturally occurring or wild-type polypeptide or polynucleotide sequence is a sequence present in an organism that can be isolated from a source in nature and which has not been intentionally modified by human manipulation.
• “Control” or “control sample” or “control group” refers to a sample or group that is compared to another sample or group, where generally the control sample or group are the same as a comparison group except for one or more factors being compared.
• Selecting refers to the process of determining that a subject will receive an agent to treat the occurrence of a condition. Selecting can be based on an individual susceptibility to a particular disease or condition due to, for example, presence of an identifying cellular, physiological or environment factor or factors. In some embodiments, selecting can be based on determining or identifying whether that subject will be responsive to an agent, for example as assessed by identifying the presence of a biomarker and/or drug target marker that makes the subject sensitive, insensitive, responsive, or unresponsive to an agent or treatment.
• Bio sample refers to any sample including a biomolecule, such as a protein, a peptide, a nucleic acid, a lipid, a carbohydrate or a combination thereof, that is obtained from an organism, particularly a mammal.
• a biomolecule such as a protein, a peptide, a nucleic acid, a lipid, a carbohydrate or a combination thereof.
• mammals include humans; veterinary animals like cats, dogs, horses, cattle, and swine; and laboratory animals like mice, rats and primates.
• a human subject in the clinical setting is referred to as a patient.
• Biological samples include tissue samples (such as tissue sections and needle biopsies of tissue), cell samples (for example, cytological smears such as Pap or blood smears or samples of cells obtained by microdissection), or cell fractions, fragments or organelles (such as obtained by lysing cells and separating their components by centrifugation or otherwise).
• tissue samples such as tissue sections and needle biopsies of tissue
• cell samples for example, cytological smears such as Pap or blood smears or samples of cells obtained by microdissection
• cell fractions, fragments or organelles such as obtained by lysing cells and separating their components by centrifugation or otherwise.
• biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (for example, obtained by a surgical biopsy or a needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
• the biological sample is a “cell free sample”, such as cell free or extracellular polynucleotides, and cell free or extracellular proteins.
• cell free DNA or cfDNA refers to extracellular DNA obtained from blood, particularly the serum.
• Subject refers to a mammal, for example a dog, a cat, a horse, or a rabbit.
• the subject is a non-human primate, for example a monkey, chimpanzee, or gorilla.
• the subject is a human, sometimes referred to herein as a patient.
• Treating” or “treatment” of a disease, disorder, or syndrome includes (i) preventing the disease, disorder, or syndrome from occurring in a subject, i.e., causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome.
• “Therapeutically effective amount” refers to that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease, disorder, or condition.
• “Therapeutically effective amount” refers to that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease, disorder, or condition.
• the present disclosure provides protein kinase C (PKC) modulating compounds.
• the compounds are diterpenoid PKC modulating compounds displaying potent PKC modulating activity, as well as enhanced solubility and pharmacokinetic profiles.
• the diterpenoid PKC modulating compounds show potent activity against tumor cells, and can be applied to treatment of cancer.
• the present disclosure provides a compound of formula (I): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein A is -OH, –C(O)OR 1 , or -NR 13 R 13’ ; R 1 is H or a M+ counterion; R 2 is a C 1 -C 4 alkyl; R 3 is O double bonded to the ring carbon when (- - -) is a bond, or -OR a ; wherein R a is H or - C(O)R a1 , wherein R a1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 -C 6 alkylaryl, or C 0 -C 6 alkylheteroaryl; R 4 and R 5 are each independently H or -OR b , wherein R b is H
• the carbon atom marked with “*” is chiral and thus can be present in S or R stereochemical configuration.
• the stereochemical configuration is S isomer.
• the stereochemical configuration is R isomer.
• A is –OH.
• A is –C(O)OR 1 , wherein R 1 is H or a M + counterion.
• A is -NR 13 R 13’ , wherein R 13 and R 13’ are each independently H or C1-C4alkyl.
• M + is a metal cation, an ammonium group, or a suitable organic cation.
• M + is a cation of an alkaline or alkaline earth metal, for example, K + , Na + , Li + , or Ca +2 .
• M + is an ammonium ion NH4 + , or an organic cation derived from an amine.
• the compound has the structure of formula (Ia): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein A is -OH; R 2 is a C 1 -C 4 alkyl; R 3 is O double bonded to the ring carbon when (- - -) is a bond, or -OR a ; wherein R a is H or - C(O)R a1 , wherein R a1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 -C 6 alkylaryl, or C 0 -C 6 alkylheteroaryl; R 4 and R 5 are each independently H or -OR b , wherein R b is H, C1-C6alkyl, C2-C6alkenyl, C0- C 6 alkylaryl, or C 0 -C 6 alkylheteroaryl; R 5 ’ and R 6 ’ are H,
• the compound has the structure of formula (Ib): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein counterion; R 2 is a C1-C4alkyl; R 3 is O double bonded to the ring carbon when (- - -) is a bond, or -OR a ; wherein R a is H or - C(O)R a1 , wherein R a1 is C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl; R 4 and R 5 are each independently H or -OR b , wherein R b is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl,
• the carbon atom marked with “*” is chiral and thus can be present in S or R stereochemical configuration.
• the stereochemical configuration is S isomer.
• the stereochemical configuration is R isomer.
• the present disclosure provides a compound of formula (II): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R 2 is a C 1 -C 4 alkyl; R 3 is O double bonded to the ring carbon when (- - -) is a bond, or -OR a ; wherein R a is H or - C(O)R a1 , wherein R a1 is C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl; R 4 and R 5 are each independently H or -OR b , wherein R b is H, C1-C6alkyl, C2-C6alkenyl, C0- C6alkylaryl, or C0-C6alkylheteroaryl; R 5 ’ and R 6 ’ are H, or R 5 ’ and R 6 ’ form a bond or
• the carbon atom marked with “*” is chiral and thus compound may be present in S or R stereochemical configuration.
• the stereochemical configuration is S isomer.
• the stereochemical configuration is R isomer.
• the compound of formula (II) has the structure of formula (II’):
• R 2 , R 3, R 4 , R 5 , R 5 ’, R 6 , R 6 ’, R 7 , R 7 ’, R 9 , R 11 , R 12 , R 13 , R 13’ , R 14 , R 17 , R 18 , L and R 21 are as defined for formula (II).
• the compound of formula (II) has the structure of formula (II”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3, R 4 , R 5 , R 5 ’, R 6 , R 6 ’, R 7 , R 7 ’, R 9 , R 11 , R 12 , R 13 , R 13’ , R 14 , R 17 , R 18 , L and R 21 are as defined for formula (II).
• the compound has the structure of formula (IIa):
• R 2 is a C 1 -C 4 alkyl
• R 3 is O double bonded to the ring carbon when (- - -) is a bond, or -OR a
• R a is H or - C(O)R a1
• R a1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 -C 6 alkylaryl, or C 0 -C 6 alkylheteroaryl
• R 4 and R 5 are each independently H or -OR b , wherein R b is H, C1-C6alkyl, C2-C6alkenyl, C0- C6alkylaryl, or C0-C6alkylheteroaryl
• R 6 is OH, halo, or -OC(O)R c , wherein R c is -C1-C6alkyl, -C
• the compound of formula (IIa) has the structure for formula (IIa’): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3, R 4 , R 5 , R 6 , R 7 , R 9 , R 11 , R 12 , R 13 , R 13’ , R 14 , R 17 , R 18 , L and R 21 are as defined for formula (II).
• the compound of formula (IIa) has the structure for formula (IIa”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3, R 4 , R 5 , R 6 , R 7 , R 9 , R 11 , R 12 , R 13 , R 13’ , R 14 , R 17 , R 18 , L and R 21 are as defined for formula (II).
• the compound has the structure of formula (IIb): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R 2 is a C1-C4alkyl; R 3 is O double bonded to the ring carbon when (- - -) is a bond, or -OR a ; wherein R a is H or - C(O)R a1 , wherein R a1 is C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl; R 4 and R 5 are each independently H or -OR b , wherein R b is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 - C 6 alkylaryl, or C 0 -C 6 alkylheteroaryl; R 6 is OH, halo, or -OC(O)R c
• the compound has the structure of formula (IIb’): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3, R 4 , R 5 , R 6 , R 9 , R 11 , R 12 , R 13 , R 13’ , R 14 , R 17 , R 18 , L and R 21 are as defined for formula (II).
• the compound has the structure of formula (IIb”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3, R 4 , R 5 , R 6 , R 9 , R 11 , R 12 , R 13 , R 13’ , R 14 , R 17 , R 18 , L and R 21 are as defined for formula (II).
• R 3 is -OR a ; wherein R a is H or -C(O)R a1 , wherein R a1 is C 1 -C 6 alkyl, C 2 - C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl.
• the aryl of C0-C6alkylaryl is phenyl.
• the aryl of C0-C6alkylaryl is optionally substituted with 1 to 3 of OH, CN, halo, C 1 -C 4 alkyl, and haloC 1 -C 4 alkyl.
• R a1 is selected from: [0107] In some embodiments, R a1 is selected from: [0108] In some embodiments of the compound of formula (I), (Ia), (Ib), (II), (II’), (II”), (IIa), (IIa’), (IIa”), (IIb), (IIb’), and (IIb”), R 3 is O double bonded to the carbon atom.
• R 2 , R 11 , R 17 , and R 18 are –CH3. In some embodiments, each of R 2 , R 11 , R 17 , and R 18 is –CH 3 .
• R 4 and R 5 are each independently H or -OH.
• R 2 , R 11 , R 17 , and R 18 are –CH3; R 3 is O double bonded to the carbon atom; and R 4 and R 5 are each independently H or -OH.
• the compound has the structure of formula (IIc):
• the compound has the structure of formula (IIc’): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , R 12 , R 13 , R 13’ , L and R 21 are as defined for formula (IIc). [0114] In some embodiments, the compound has the structure of formula (IIc”):
• the compound has the structure of formula (IId): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R 6 is OH, halo, or -OC(O)R c , wherein R c is -C1-C6alkyl, -C1-C6alkyl-(NR c1 )2 or -C1- C6alkylC(O)OR k , R c1 is H, C1-C6alkyl, or two R c1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or wherein, each occurrence of R A is independently selected from a side chain of a natural
• the compound has the structure of formula (IId”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , R 12 , R 13 , R 13’ , L and R 21 are as defined for formula (IId).
• the compound has the structure of formula (IId”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , R 12 , R 13 , R 13’ , L and R 21 are as defined for formula (IId).
• R 12 is –OC(O)R f , wherein R f is C 1 - C12alkyl, C2-C12alkenyl, -C0-C12aliphatic-C3-C7cycloalkyl, -C0-C12aliphatic-heterocycloalkyl, -C0- C12aliphatic-aryl, or -C0-C12aliphatic-heteroaryl.
• R f is selected from [0119] In some some embodiments, R f is selected from: [0120] In some embodiments, the compound has the structure of formula (III): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R 2 is a C 1 -C 4 alkyl; R 3 is O double bonded to the ring carbon when (- - -) is a bond, or -OR a ; wherein R a is H or - C(O)R a1 , wherein R a1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 -C 6 alkylaryl, or C 0 -C 6 alkylheteroaryl; R 4 and R 5 are each independently H or -OR b , wherein R b is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 - C6alkylaryl, or
• R 2 , R 3, R 4 , R 5 , R 5 ’, R 6 ’, R 6 , R 6 ’, R 7 ’, R 7 , R 9 , R 11 , R 13 , R 13’ , R 14 , R 17 , R 18 , L and R 21 are as defined for formula (III).
• the compound has the structure of formula (III”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3, R 4 , R 5 , R 5 ’, R 6 ’, R 6 , R 6 ’, R 7 ’, R 7 , R 9 , R 11 , R 13 , R 13’ , R 14 , R 17 , R 18 , L and R 21 are as defined for formula (III). [0123] In some embodiments, the compound has the structure of formula (IIIa):
• R 2 is a C1-C4alkyl
• R 3 is O double bonded to the ring carbon when (- - -) is a bond, or -OR a
• R a is H or - C(O)R a1
• R a1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 -C 6 alkylaryl, or C 0 -C 6 alkylheteroaryl
• R 4 and R 5 are each independently H or -OR b , wherein R b is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 - C 6 alkylaryl, or C 0 -C 6 alkylheteroaryl
• R 6 is OH, halo, or -OC(O)R c , wherein R c is -C1-C
• the compound has the structure of formula (IIIa’): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3, R 4 , R 5 , R 6 , R 7 , R 9 , R 11 , R 12 , R 13 , R 13’ , R 14 , R 17 , R 18 , L and R 21 are as defined for formula (III).
• the compound has the structure of formula (IIIa”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3, R 4 , R 5 , R 6 , R 7 , R 9 , R 11 , R 12 , R 13 , R 13’ , R 14 , R 17 , R 18 , L and R 21 are as defined for formula (III).
• the compound has the structure of formula (IIIb): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R 2 is a C1-C4alkyl; R 3 is O double bonded to the ring carbon when (- - -) is a bond, or -OR a ; wherein R a is H or - C(O)R a1 , wherein R a1 is C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl; R 4 and R 5 are each independently H or -OR b , wherein R b is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 - C 6 alkylaryl, or C 0 -C 6 alkylheteroaryl; R 6 is OH, halo, or -OC(O)R c ,
• the compound has the structure of formula (IIIb”): (IIIb”) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3, R 4 , R 5 , R 6 , R 9 , R 11 , R 13 , R 13’ , R 14 , R 17 , R 18 , L and R 21 are as defined for formula (III).
• the compound has the structure of formula (IIIb”): (IIIb”) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3, R 4 , R 5 , R 6 , R 9 , R 11 , R 13 , R 13’ , R 14 , R 17 , R 18 , L and R 21 are as defined for formula (III).
• R 3 is -OR a ; wherein R a is H or -C(O)R a1 , wherein R a1 is C1-C6alkyl, C2- C 6 alkenyl, C 0 -C 6 alkylaryl, or C 0 -C 6 alkylheteroaryl.
• the aryl of C 0 -C 6 alkylaryl is phenyl.
• the aryl of C0-C6alkylaryl is optionally substituted with 1 to 3 of OH, CN, halo, C1-C4alkyl, and haloC1-C4alkyl.
• R a1 is selected from: [0130] In some embodiments, R a1 is selected from: [0131] In some embodiments of the compound of formula (III), (III’), (III”), (IIIa), (IIIa’), (IIIa”), (IIIb), (IIIb’) and (IIIb”), R 3 is O double bonded to the carbon atom.
• R 2 , R 11 , R 17 , and R 18 are –CH3. In some embodiments, each of R 2 , R 11 , R 17 , and R 18 is –CH3.
• R 4 and R 5 are each independently H or -OH.
• R 2 , R 11 , R 17 , and R 18 are –CH 3 ; R 3 is O double bonded to the carbon atom; and R 4 and R 5 are each independently H or -OH.
• the compound has the structure of formula (IIIc): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R 6 is OH, halo, or -OC(O)R c , wherein R c is -C 1 -C 6 alkyl, -C 1 -C 6 alkyl-(NR c1 ) 2 or -C 1 - C 6 alkylC(O)OR k , R c1 is H, C 1 -C 6 alkyl, or two R c1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or wherein, each occurrence of R A is independently selected from a side chain of a natural or non- natural amino acid, wherein each occurrence of R A is same or different; each occurrence of R B is independently H, or R B together with the adjacent R A and the N atom to which it is attached form
• the compound has the structure of formula (IIIc”): (IIIc”) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , R 13 , R 13’ , L and R 21 are as defined for formula (IIIc). [0138] In some embodiments, the compound has the structure of formula (IIId):
• the compound has the structure of formula (IIId’): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , R 13 , R 13’ , L and R 21 are as defined for formula (IIId).
• the compound has the structure of formula (IIId”): (IIId”) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , R 13 , R 13’ , L and R 21 are as defined for formula (IIId).
• n is 0.
• each of R 13 and R 13 ’ is H.
• the compound has the structure of formula (IIIe): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R 6 is OH, halo, or -OC(O)R c , wherein R c is -C1-C6alkyl, -C1-C6alkyl-(NR c1 )2 or -C1- C6alkylC(O)OR k , R c1 is H, C1-C6alkyl, or two R c1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is wherein, each occurrence of R A is independently selected from a side chain of a natural or non- natural amino acid, wherein each occurrence of R A is same or
• the compound has the structure of formula (IIIe’): (IIIe’) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , L and R 21 are as defined for formula (IIIe).
• the compound has the structure of formula (IIIe”): (IIIe”) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , L and R 21 are as defined for formula (IIIe).
• the compound has the structure of formula (IIIf): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R 6 is OH, halo, or -OC(O)R c , wherein R c is -C1-C6alkyl, -C1-C6alkyl-(NR c1 )2 or -C1- C6alkylC(O)OR k , R c1 is H, C1-C6alkyl, or two R c1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or wherein, each occurrence of R A is independently selected from a side chain of a natural or non- natural amino acid, wherein each occurrence of R A is same or different; each occurrence of R B is independently H, or R B together with the adjacent R A and the N atom to which it is attached form a heterocycl
• the compound has the structure of formula (IIIf’): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R 6 , L and R 21 are as defined for formula (IIIf).
• the compound has the structure of formula (IIIf”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , L and R 21 are as defined for formula (IIIf).
• R 21 is C3-C7cycloalkyl, wherein the C3-C7cycloalkyl is optionally substituted with 1 to 3 of J 1 , wherein J 1 is selected from OH, CN, halo, C 1 -C 4 alkyl, and haloC 1 -C 4 alkyl.
• the C 3 -C 7 cycloalkyl is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
• R 21 is a heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 to 3
• the heterocyclyl is selected from oxiranyl, oxetanyl, azetidynyl, oxazolyl, thiazolidinyl, thiazolyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and azapanyl, wherein the heterocyclyl is optionally substituted with 1 to 3 of OH, CN, halo, C 1 -C 4 alkyl, and haloC 1 -C 4 alkyl.
• R 21 is aryl, wherein the aryl is optionally substituted with 1 to 3 of J 1 , wherein J 1 is selected from OH, CN, halo, C 1 -C 4 alkyl, and haloC 1 -C 4 alkyl.
• R 21 is a phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with 1 to 3 of OH, CN, halo, C1-C4alkyl, and haloC1- C4alkyl.
• R 21 is heteroaryl, wherein the heteroaryl is optionally substituted with 1 to 3 of J 1 , wherein J 1 is selected from OH, CN, halo, C1- C4alkyl, and haloC1-C4alkyl.
• the heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, and quinolyl, wherein the heteroaryl is optionally substituted with 1 to 3 of OH, CN, halo, C1-C4alkyl, and haloC1-C4alkyl.
• R 21 is adamantyl, wherein the adamantyl is optionally substituted with J 1 , wherein J 1 is selected from OH, halo, C1-C4alkyl, and haloC1-C4alkyl.
• R 21 is spiroC 5 -C 12 cycloalkyl, wherein the spiroC 5 -C 12 cycloalkyl has 0-2 carbon atoms replaced with 0-2 heteroatoms selected from N, O and S, and is optionally substituted with 1 to 3 of J 1 , wherein J 1 is selected from OH,
• R 21 is 5 to 12 membered bridged bicyclyl, wherein the bridged bicyclyl has 0-2 carbon atoms replaced with 0-2 heteroatoms selected from N, O and S, and is optionally substituted with 1 to 3 of J 1 , wherein J 1 is selected from OH, CN, halo, C 1 -C 4 al
• R 21 is selected from the following: wherein J 1 is OH, CN, halo, C1-C4alkyl, and haloC1-C4alkyl, and n is 0-3.
• n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, haloC1-C4alkyl is –CH 2 F, –CHF 2 , or –CF 3 . [0157] In some embodiments, for any of the compounds herein, L is C3-C12alkylene. In some embodiments, for any of the compounds herein, L is C3-C6alkylene. In some embodiments, for any of the compounds herein, L is C1-C6alkylene. [0158] In some embodiments, for any of the compounds herein, L is C 3 -C 12 alkenylene.
• L is C3-C6alkenylene. In some embodiments, for any of the compounds herein, L is C1-C6alkenylene. [0159] In some embodiments, L is C 1 -C 12 alkylene, or C 2 -C 12 alkenylene, wherein the C 1 -C 12 alkylene or C 2 -C 12 alkenylene is optionally substituted with C 1 -C 4 alkyl; and R 21 is H.
• -L-R 21 is a C 2 -C 6 alkenyl selected from: [0161] In some embodiments for any of the foregoing compounds, e.g., formula (I), (Ia), (Ib), (II), (II’), (II”), (IIa), (IIa’), (IIa”), (IIb), (IIb’), (IIb”), (III), (III’), (III”), (IIIa), (IIIa’), (IIIa”), (IIIb), (IIIb’), (IIIb”), (IIIc), (IIIc’), (IIIc”), (IIId), (IIId’), (IIId”), (IIIe), (IIIe’), (IIIe”), (IIIf), (IIIf’), and (IIIf”), -L-R 21 is a C 2 -C 6 alkenyl selected from: [0161] In some embodiments for any of the foregoing compounds, e.g., formula (I), (Ia),
• R 6 is each occurrence of R A is independently methyl (alanine), propan-2-y1 (valine), 2- methylpropan-1-y1 (leucine), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 1- hydroxyethyl (thre
• R 6 is each occurrence of R A is independently propan-2-y1 (valine), 2-methylpropan-1-y1 (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4-aminobutan-1-y1 (lysine); each R B
• each occurrence of R A is independently selected from a side chain of a natural or non-natural amino acid, wherein each occurrence of R A is same or different; each occurrence of R B is independently H, or R B together with R A and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of R B is same or different; and p is 0, 1, or 2;
• each occurrence of R A is independently hydrogen (glycine), methyl (alanine), propan-2-yl (valine), propan-1-y1 (norvaline), 2-methylpropan-1-y1 (leucine), 1-methylpropan-1-y1 (isoleucine), butan-1-y1 (norleucine), phenyl (2-phenyl
• each occurrence of R A is independently methyl (alanine), propan-2-y1 (valine), 2-methylpropan-1-y1 (leucine), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 1- hydroxyethyl (threonine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), 4- aminobutan-1-y1 (lysine), carboxymethyl (aspartic acid), 3-guanidinopropan-1-y1 (arginine), benzyl (phenylalanine), or 4-aminobutan-1-y1 (lysine);
• R B is H; and p 0, 1, or 2.
• each occurrence of R A is independently propan-2-y1 (valine), 2- methylpropan-1-y1 (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4- aminobutan-1-y1 (lysine); each R B is H; and p is 0, 1, or 2. [0174] In some embodiments, p is 0. [0175] In some embodiments, p is 1.
• p is 1; first of R A is propan-2-y1 (valine) and second of R A is propan-2-y1 (valine); and each of R B is H (i.e., dipeptide Val-Val); or first of R A is 2-methylpropan-1-y1 (leucine), and second of R A is 2-methylpropan-1-y1 (leucine); and each of R B is H (i.e., dipeptide Leu-Leu); or first of R A is methyl (alanine) and second of R A is methyl (alanine); and each of R B is H (i.e., dipeptide Ala-Ala); or first of R A is 4-aminobutan-1-y1 (lysine); second of R A is 4-aminobutan-1-y1 (lysine); and each of R B is H (i.e., dipeptide Lys-Lys); or first of R A is hydrogen; second of R A is 4-aminobut
• each of the ⁇ -carbon of the amino acid other than glycine is in the L or D configuration. In some embodiments, each of the ⁇ -carbon of the amino acid other than glycine is in the L configuration.
• the present disclosure provides a compound of formula (IV): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R 2 is a C1-C4alkyl; R 3 is O double bonded to the ring carbon when (- - -) is a bond, or -OR a ; wherein R a is H or - C(O)R a1 , wherein R a1 is C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl; R 4 and R 5 are each independently H or -OR b , wherein R b is H, C1-C6alkyl, C
• the compound has the structure of formula (IVa): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R 2 is a C 1 -C 4 alkyl; R 3 is O double bonded to the ring carbon when (- - -) is a bond, or -OR a ; wherein R a is H or - C(O)R a1 , wherein R a1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 -C 6 alkylaryl, or C 0 -C 6 alkylheteroaryl; R 4 and R 5 are each independently H or -OR b , wherein R b is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 - C6alkylaryl, or C0-C6alkylheteroaryl; R 6 is OH, halo, or -OC(
• the compound has the structure of formula (IVb) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R 2 is a C 1 -C 4 alkyl; R 3 is O double bonded to the ring carbon when (- - -) is a bond, or -OR a ; wherein R a is H or - C(O)R a1 , wherein R a1 is C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl; R 4 and R 5 are each independently H or -OR b , wherein R b is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 - C 6 alkylaryl, or C 0 -C 6 alkylheteroaryl; R 6 is OH, halo, or -OC(O)R c ,
• the C 2 -C 6 alkenyl of R a1 is independently selected from: [0184] In some embodiments, R a1 is independently selected from: [0185] In some embodiments, R 3 is -OR a ; wherein R a is H or -C(O)R a1 , wherein R a1 is C 1 -C 6 alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl. In some embodiments, the aryl of C0- C6alkylaryl is phenyl.
• the aryl of C0-C6alkylaryl is optionally substituted with 1 to 3 of OH, CN, halo, C1-C4alkyl, and haloC1-C4alkyl.
• R 3 is O double bonded to the carbon atom.
• the C 2 -C 12 alkenyl of R f is independently selected from: [0188] In some embodiments, R f is independently selected from: [0189] In some embodiments of the compound of formula (IV), (IVa), and (IVb), one or more of R 2 , R 11 , R 17 , and R 18 are –CH 3 . In some embodiments, each of R 2 , R 11 , R 17 , and R 18 is –CH 3 . [0190] In some embodiments of the compound of formula (IV), (IVa), and (IVb), R 4 and R 5 are each independently H or -OH.
• R 2 , R 11 , R 17 , and R 18 are –CH3; R 3 is O double bonded to the carbon atom; and R 4 and R 5 are each independently H or -OH.
• the compound has the structure of formula (V):
• R 2 is a C1-C4alkyl
• R 3 is O double bonded to the ring carbon when (- - -) is a bond, or -OR a
• R a is H or - C(O)R a1
• R a1 is C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl
• R 4 and R 5 are each independently H or -OR b , wherein R b is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 - C 6 alkylaryl, or C 0 -C 6 alkylheteroaryl;
• R 5 ’ and R 6 ’ are H, or R 5 ’ and R 6 ’ form a bond or are bonded to a common O atom to form an ep
• the compound has the structure of formula (Va): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R 2 is a C1-C4alkyl; R 3 is O double bonded to the ring carbon when (- - -) is a bond, or -OR a ; wherein R a is H or - C(O)R a1 , wherein R a1 is C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl; R 4 and R 5 are each independently H or -OR b , wherein R b is H, C1-C6alkyl, C2-C6alkenyl, C0- C6alkylaryl, or C0-C6alkylheteroaryl; R 6 is OH, halo, or -OC(O)R c , wherein R c is -C
• the compound has the structure of formula (Vb): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R 2 is a C1-C4alkyl; R 3 is O double bonded to the ring carbon when (- - -) is a bond, or -OR a ; wherein R a is H or - C(O)R a1 , wherein R a1 is C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl; R 4 and R 5 are each independently H or -OR b , wherein R b is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 - C 6 alkylaryl, or C 0 -C 6 alkylheteroaryl; R 6 is OH, halo, or -OC(O)R c ,
• R 3 is -OR a ; wherein R a is H or -C(O)R a1 , wherein R a1 is C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0- C6alkylheteroaryl.
• the aryl of C0-C6alkylaryl is phenyl.
• the aryl of C 0 -C 6 alkylaryl is optionally substituted with 1 to 3 of OH, CN, halo, C 1 - C4alkyl, and haloC1-C4alkyl.
• R a1 is selected from: [0198] In some embodiments, R a1 is selected from: [0199] In some embodiments of the compound of formula (V), (Va), and (Vb), R 3 is O double bonded to the carbon atom. [0200] In some embodiments of the compound of formula (V), (Va), and (Vb), one or more of R 2 , R 11 , R 17 , and R 18 are –CH3. In some embodiments, each of R 2 , R 11 , R 17 , and R 18 is –CH3. [0201] In some embodiments of the compound of formula (V), (Va), and (Vb), R 4 and R 5 are each independently H or -OH.
• R 2 , R 11 , R 17 , and R 18 are –CH3; R 3 is O double bonded to the carbon atom; and R 4 and R 5 are each independently H or -OH.
• the compound has the structure of formula (Vc): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R 6 is OH, halo, or -OC(O)R c , wherein R c is -C 1 -C 6 alkyl, -C 1 -C 6 alkyl-(NR c1 ) 2 or -C 1 - C 6 alkylC(O)OR k , R c1 is H, C 1 -C 6 alkyl, or two R c1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is wherein, each occurrence of R A is independently selected from a side chain of a natural or non- natural amino acid, wherein each occurrence of R A is same or different; each occurrence of R B is independently H, or R B together with R A and the N atom to which it is attached
• excluded from the compounds of formula (Vc) are compounds in which: - R A is propan-2-yl (valine); R B is H; and p is 0. [0205] In some embodiments, specifically excluded from the compounds of formula (IV), (IVa), (V), (Va) and (Vc) are compounds of the following structure: [0206] In some embodiments, the compound has the structure of formula (Vd):
• R 6 is OH, halo, or -OC(O)R c , wherein R c is -C1-C6alkyl, -C1-C6alkyl-(NR c1 )2 or -C1- C 6 alkylC(O)OR k , R c1 is H, C 1 -C 6 alkyl, or two R c1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is wherein, each occurrence of R A is independently selected from a side chain of a natural or non- natural amino acid, wherein each occurrence of R A is same or different; each occurrence of R B is independently H, or R B together with R A and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence
• R 21 is C3-C7cycloalkyl, wherein the C3-C7cycloalkyl is optionally substituted with 1 to 3 of J 1 .
• the C 3 -C 7 cycloalkyl is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
• R 21 is a heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 to 3 of J 1 .
• the heterocycloalkyl is selected from oxiranyl, oxetanyl, azetidynyl, oxazolyl, thiazolidinyl, thiazolyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3- dihydrofuranyl, dihydropyranyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and azapanyl.
• R 21 is aryl, wherein the aryl is optionally substituted with 1 to 3 of J 1 .
• R 21 is a phenyl, wherein the phenyl is optionally substituted with 1 to 3 of OH, CN, halo, C1-C4alkyl, and haloC1-C4alkyl.
• R 21 is heteroaryl, wherein the heteroaryl is optionally substituted with 1 to 3 of J 1 .
• the heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, and quinolyl, wherein the heteroaryl is optionally substituted with 1 to 3 of OH, CN, halo, C 1 -C 4 alkyl, and haloC 1 -C 4 alkyl.
• R 21 is adamantyl, wherein the adamantyl is optionally substituted with OH, halo, or C 1 -C 4 alkyl.
• R 21 is spiroC5-C12 cycloalkyl, wherein the spiroC5-C12 cycloalkyl has 0-2 carbon atoms replaced with 0-2 heteroatoms selected from N, O and S, and is optionally substituted with 1 to 3 of OH, CN, halo, C 1 -C 4 alkyl, and haloC 1 -C 4 alkyl, or when an N atom is present an N-protecting group.
• R 21 is 5 to 12 membered bridged bicyclyl, wherein the bridged bicyclyl has 0-2 carbon atoms replaced with 0-2 heteroatoms selected from N, O and S, and is optionally substituted with 1 to 3 of OH, CN, halo, C 1 -C 4 alkyl, and haloC 1 -C 4 alkyl, or when an N atom is present an N-protecting group.
• R 21 is selected from the following: wherein J 1 is OH, CN, halo, C 1 -C 4 alkyl, and haloC 1 -C 4 alkyl, and n is 0-3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, haloC 1 -C 4 alkyl is –CH 2 F, –CHF 2 , or –CF 3 . [0215] In some embodiments, for any of the compounds herein, L is C3-C12alkylene.
• L is C 3 -C 6 alkylene. In some embodiments, for any of the compounds herein, L is C 1 -C 6 alkylene. [0216] In some embodiments, for any of the compounds herein, L is C3-C12alkenylene. In some embodiments, for any of the compounds herein, L is C3-C6alkenylene. In some embodiments, for any of the compounds herein, L is C 1 -C 6 alkenylene.
• -L-R 21 is a C2-C6alkenyl selected from: .
• R 6 is each occurrence of R A is independently hydrogen (glycine), methyl (alanine), propan-2-yl (valine), propan-1-y1 (norvaline), 2-methylpropan-1-y1 (leucine), 1-methylpropan-1-y1 (isoleucine), butan-1-y1 (norleucine), phenyl (2-phenylglycine), benzyl (phenylalanine), p-hydroxybenzyl (tyrosine), indol-3-ylmethyl (tryptophan), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 2- hydroxyethyl (homoserine), 1–hydroxyethyl (threonine), mercaptomethyl (cysteine),
• each R A is independently methyl (alanine), propan-2-y1 (valine), 2-methylpropan-1-y1 (leucine), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 1-hydroxyethyl (threonine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), 4-aminobutan-1-y1 (lysine), carboxymethyl (aspartic acid), 3-guanidinopropan-1-y1 (arginine), benzyl (phenylalanine), or 4- aminobutan-1-y1 (lysine); R B is H; and p 0, 1, or 2.
• each occurrence of R A is independently propan-2-y1 (valine), 2-methylpropan-1-y1 (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4-aminobutan-1-y1 (lysine); each R B is H; and p is 0, 1, or 2.
• formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc) and (Vd) p is 0.
• any of the foregoing compounds e.g., formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc) and (Vd), p is 1.
• first of R A is propan-2-y1 (valine) and second of R A is propan-2-y1 (valine); and each of R B is H (i.e., dipeptide Val-Val); or first of R A is 2-methylpropan-1-y1 (leucine), and second of R A is 2-methylpropan-1-y1 (leucine); and each of R B is H (i.e, dipeptide Leu-Leu); or first of R A is methyl (alanine) and second of R A is methyl (alanine); and each of R B is H (i.e, dipeptide Ala-
• each of the compounds of Table 2 the -OH on the C20 carbon atom is substituted with each occurrence of R A is independently selected from a side chain of a natural or non-natural amino acid, wherein each occurrence of R A is same or different; each occurrence of R B is independently H, or R B together with R A and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of R B is same or different; and p is 0, 1, or 2.
• each occurrence of R A is independently hydrogen (glycine), methyl (alanine), propan-2-yl (valine), propan-1-y1 (norvaline), 2-methylpropan-1-y1 (leucine), 1-methylpropan-1-y1 (isoleucine), butan-1-y1 (norleucine), phenyl (2-phenylglycine), benzyl (phenylalanine), p-hydroxybenzyl (tyrosine), indol-3-ylmethyl (tryptophan), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 2- hydroxyethyl (homoserine), 1–hydroxyethyl (threonine), mercaptomethyl (cysteine), methylthiomethyl (S-methylcysteine), 2-mercaptoethyl (homocysteine), 2-methylthioethyl (me
• each occurrence of R A is independently methyl (alanine), propan-2-y1 (valine), 2-methylpropan-1-y1 (leucine), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 1- hydroxyethyl (threonine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), 4- aminobutan-1-y1 (lysine), carboxymethyl (aspartic acid), 3-guanidinopropan-1-y1 (arginine), benzyl (phenylalanine), or 4-aminobutan-1-y1 (lysine);
• R B is H; and p 0, 1, or 2.
• each occurrence of R A is independently propan-2-y1 (valine), 2- methylpropan-1-y1 (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4- aminobutan-1-y1 (lysine); each R B is H; and p is 0, 1, or 2. [0231] In some embodiments, p is 0. [0232] In some embodiments, p is 1.
• p is 1; first of R A is propan-2-y1 (valine) and second of R A is propan-2-y1 (valine); and each of R B is H (dipeptide Val-Val); or first of R A is 2-methylpropan-1-y1 (leucine), and second of R A is 2-methylpropan-1-y1 (leucine); and each of R B is H (dipeptide Leu-Leu); or first of R A is methyl (alanine) and second of R A is methyl (alanine); and each of R B is H (dipeptide Ala-Ala); or first of R A is 4-aminobutan-1-y1 (lysine); second of R A is 4-aminobutan-1-y1 (lysine); and each of R B is H (dipeptide Lys-Lys); or first of R A is hydrogen; second of R A is 4-aminobutan-1-y1, and each of R B is H (dipeptide Val-Val); or first of
• each of the ⁇ -carbon of the amino acid other than glycine is in the L or D configuration.
• compounds disclosed herein can be synthesized according to the general schemes shown outlined below in Scheme 1 and Scheme 2, where suitable reagents can be purchased form commercial sources or synthesized via known methods or methods adapted from the example procedures provided herein: Scheme 1 [0236] In Scheme 1, protection of S1 (K101A shown as example) with trityl chloride (or triphenylmethyl chloride) provides S2 (K101-C20Tr-A shown as example).
• S2 Hydrolysis of S2 (K101- C20Tr-A shown as example) provides S3 (K101-C20Tr-B, shown as example), which can then be coupled with compound S4 under esterification conditions using 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC, or EDCI) as the carboxyl activating agent and 4- dimethylaminopyridine (DMAP) as the catalyst to provide S5.
• EDC 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide
• DMAP 4- dimethylaminopyridine
• S6 Deprotection of S5 followed by further separation and purification provides S6.
• S7 is prepared by epoxidation of S5 with a peroxycarboxylic acid such as meta- chloroperoxybenzoic acid (m-CPBA). Further separation and purification of S7 provides S8.
• m-CPBA meta- chloroperoxybenzoic acid
• synthesis of the prodrugs are prepared by reacting protected amino acids (e.g., N-protected amino acids) with relevant compounds, e.g., compounds having an –OH group at the R 6 position.
• protected amino acids e.g., N-protected amino acids
• relevant compounds e.g., compounds having an –OH group at the R 6 position.
• Guidance is provided in Examples 63 and 64 illustrating synthesis of amino acid prodrugs as well as knowledge of general procedures available in the art for producing such prodrugs (see, e.g., Vale et al., 2018, Molecules.23(9):2318; Beauchamp et al., 1992, Antiviral Chemistry & Chemotherapy 3(3):157-164; incorporated herein by reference).
• PKC modulating compounds are in free form or where appropriate as pharmaceutically acceptable salt.
• Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference.
• Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
• pharmaceutically acceptable salt of the compounds herein can be prepared during final isolation and purification of the compounds.
• a pharmaceutically acceptable salt of the compounds herein can be prepared by (1) reacting the compound in free base form with a suitable organic or inorganic acid, and (2) isolating the salt thus formed.
• Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
• organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
• Base addition salts can be prepared by (1) reacting the compound, such as the purified compound, in its acid form with a suitable organic or inorganic base, and (2) isolating the salt thus formed.
• Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1–C4alkyl)4 salts.
• Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• compositions described herein include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
• counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
• the compounds can be used as monotherapy, or as further provided below, in a combination therapy with one or more therapeutic treatments, particularly in combination with one or more chemotherapeutic agents.
• the compounds are used in combination with a second therapeutic agent, where the compounds are used at levels that sensitizes the cancer or cancer cell to the second therapeutic agent, for example at levels of the compound that do not cause significant cell death.
• the compounds can be used in combination with radiation therapy, either to sensitize the cells to radiation therapy or as an adjunct to radiation therapy (e.g., at doses sufficient to activate cell death pathway).
• the cancer for treatment with the compound can be selected from, among others, adrenocortical cancer, anal cancer, biliary cancer, bladder cancer, bone cancer (e.g., osteosarcoma), brain cancer (e.g., gliomas, astrocytoma, neuroblastoma, etc.), breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, head and neck cancer, hematologic cancer (e.g., leukemia and lymphoma), intestinal cancer (small intestine), liver cancer, lung cancer (e.g., bronchial cancer, small cell lung cancer, non-small cell lung cancer, etc.), oral cancer, ovarian cancer, pancreatic cancer, renal cancer, prostate cancer, salivary gland cancer, skin cancer (e.g., basal cell carcinoma, melanoma), stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, sarcoma, and soft tissue carcinoma
• the cancer for treatment with the compound is pancreatic cancer.
• the pancreatic cancer for treatment with the compounds is pancreatic adenocarcinoma or metastatic pancreatic cancer.
• the cancer for treatment with the compounds is stage 1, stage II, stage III, or stage IV pancreatic adenocarcinoma.
• the cancer for treatment with the compounds is lung cancer.
• the lung cancer for treatment with the compounds is small cell lung cancer or non- small cell lung cancer.
• the non-small cell lung cancer for treatment with the compounds is an adenocarcinoma, squamous cell carcinoma, or large cell carcinoma.
• the lung cancer for treatment with the compounds is metastatic lung cancer.
• the cancer for treatment with the compounds is a hematologic cancer.
• the hematologic cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), lymphoma (e.g., Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, Burkitt’s lymphoma), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), Hairy Cell chronic myelogenous leukemia (CML), and multiple myeloma.
• ALL acute lymphoblastic leukemia
• AML acute myeloid leukemia
• lymphoma e.g., Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, Burkitt’s lymphoma
• CLL chronic lymphocytic leukemia
• CML chronic myelogenous leukemia
• the cancer for treatment with the compounds is a leukemia selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), Hairy Cell chronic myelogenous leukemia (CML), and multiple myeloma.
• ALL acute lymphoblastic leukemia
• AML acute myeloid leukemia
• CLL chronic lymphocytic leukemia
• CML chronic myelogenous leukemia
• CML Hairy Cell chronic myelogenous leukemia
• multiple myeloma multiple myeloma.
• the cancer for treatment with the compound is a lymphoma selected from Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, and Burkitt’s lymphoma).
• the cancer for treatment with the compound is a cancer characterized by mesenchymal features or mesenchymal phenotype.
• gain of mesenchymal features is associated with migratory (e.g., intravasation) and invasiveness of cancers.
• Mesenchymal features can include, among others, enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and increased production of extracellular matrix (ECM) components.
• ECM extracellular matrix
• the mesenchymal features can include expression of certain biomarkers, including among others, E-cadherin, N-cadherin, integrins, FSP-1, ⁇ -SMA, vimentin, ⁇ -catenin, collagen I, collagen II, collagen III, collagen IV, fibronectin, laminin 5, SNAIL-1, SNAIL-2, Twist-1, Twist-2, and Lef-1.
• the cancer selected for treatment with the compounds herein include, among others, breast cancer, lung cancer, head and neck cancer, prostate cancer, and colon cancer.
• the mesenchymal features can be inherent to the cancer type or induced by or selected for by treatment of cancers with chemotherapy and/or radiation therapy.
• the cancer for treatment with the compound is identified as having or determined to have an activating or oncogenic RAS activity.
• the RAS is K- RAS, H-RAS or N-RAS.
• the activating or oncogenic RAS is an activating or oncogenic RAS mutation.
• the cancer for treatment is identified as having or determined to have an activating or oncogenic K-RAS mutation.
• the cancer selected for treatment is identified as having or determined to have an activating or oncogenic mutation in human K-RAS at one or more of codon 5, codon 9, codon 12, codon 13, codon 14, codon 18, codon 19, codon 22, codon 23, codon 24, codon 26, codon 33, codon 36, codon 57, codon 59, codon 61, codon 62, codon 63, codon 64, codon 68, codon 74, codon 84, codon 92, codon 35, codon 97, codon 110, codon 115, codon 117, codon 118, codon 119, codon 135, codon 138, codon 140, codon 146, codon 147, codon 153, codon 156, codon 160, codon 164, codon 171, codon 176, codon 185, and codon 188.
• the activating or oncogenic K-RAS mutation can be a mutation in which: codon 5 is K5E; codon 9 is V91; codon 12 is G12A, G12C, G12D, G12F, G12R, G12S, G12V, or G12Y; codon 13 is G13C, G13D, or G13V; codon 14 is V14I or V14L; codon 18 is A18D; codon 19 is L19F; codon 22 is Q22K; codon 23 is L23R; codon 24 is I24N; codon 26 is N26K; codon 33 is D33E; codon 36 is I36L or I36M; codon 57 is D57N; codon 59 is A59E, A59G, or A59T; codon 61 is Q61H, Q61K, Q61L, or Q61R; codon 62 is E62G or E62K; codon 63 is E63K; codon 64 is Y
• the cancer for treatment is identified as having or determined to have an oncogenic or activating K-RAS mutations at codon 12, codon 13 and/or codon 61.
• the oncogenic or activating K-RAS mutation at codon 12 is G12A, G12C, G12D, G12F, G12R, G12S, G12V, or G12Y; at codon 13 is G13C, G13D, or G13V; and at codon 61 is Q61H, Q61K, Q61L, or Q61R.
• the oncogenic or activating K-RAS mutation is a combination of oncogenic or activating K-RAS mutations at codon 12 and codon 13; codon 12 and codon 61; codon 13 and 61; or codon 12, codon 13 and codon 61.
• the cancer for treatment is identified as having or determined to have an activating or oncogenic N-RAS mutation.
• the cancer is identified as having or determined to have an activating or oncogenic mutation in human N-RAS at one or more of codon 12, codon 13 and codon 61.
• the activating or oncogenic N-RAS mutation at codon 12 is G12A, G12C, G12D, G12R, G12S, or G12V.
• the activating or oncogenic N-RAS mutation at codon 13 is G13A, G13C, G13D, G13R, G13S, or G13V.
• the activating or oncogenic N-RAS mutation at codon 61 is Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R.
• the oncogenic or activating N-RAS mutation is a combination of activating or oncogenic N-RAS mutations at codon 12 and codon 13; codon 12 and codon 61; codon 13 and 61; or codon 12, codon 13 and codon 61.
• the cancer for treatment is identified as having or determined to have an activating or oncogenic H-RAS mutation.
• the cancer selected for treatment is identified as having an activating or oncogenic mutation in human H-RAS at one or more of codon 12, codon 13 and codon 61.
• the activating or oncogenic H-RAS mutation at codon 12 is G12A, G12C, G12D, G12R, G12S, or G12V.
• the activating or oncogenic H-RAS mutation at codon 13 is G13A, G13C, G13D, G13R, G13S, or G13V.
• the activating or oncogenic H-RAS mutation at codon 61 is Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R.
• the oncogenic or activating H-RAS mutation is a combination of activating or oncogenic H-RAS mutations at codon 12 and codon 13; codon 12 and codon 61; codon 13 and 61; or codon 12, codon 13 and codon 61.
• the cancer for treatment can be a cancer having prevalence (e.g., at least about 10% or more, or about 15% or more of the cancers), of an activating or oncogenic RAS mutation, such as cancer of the biliary tract, cervix, endometrium, pancreas, lung, colon, head and neck, stomach (gastric), biliary tract, endometrium, hematologic (e.g., leukemia, lymphomas, etc.), large intestine, lung, ovary, pancreas, prostate, salivary gland, skin, small intestine, stomach thyroid, aerodigestive tract, urinary tract, and ovary, small intestine, and urinary tract.
• an activating or oncogenic RAS mutation such as cancer of the biliary tract, cervix, endometrium, pancreas, lung, colon, head and neck, stomach (gastric), biliary tract, endometrium, hematologic (e.g., leukemia, lymphomas,
• Bio sample for the method herein include any samples are amenable to analysis herein, such as tissue or biopsy samples containing cancer cells, or any biological fluids that contain the material of interests (e.g., DNA), such as blood, plasma, saliva, tissue swabs, and intestinal fluids.
• exosomes extruded by cancer cells and obtained from blood or other body fluids can be used to detect nucleic acids and proteins produced by the cancer cells.
• the diterpenoid PKC modulating compounds are used in combination with one or more second therapeutic agents.
• the second therapeutic agent is selected from a platinating agent, alkylating agent, antibiotic agent, antimetabolic agent (e.g., folate antagonists, purine analogs, pyrimidine analogs, etc.), topoisomerase inhibiting agent, antimicrotubule agent (e.g., taxanes, vinca alkaloids), hormonal agent (e.g., aromatase inhibitors), plant-derived agent and synthetic derivatives thereof, anti- angiogenic agent, differentiation inducing agent, cell growth arrest inducing agent, apoptosis inducing agent, cytotoxic agent, agent affecting cell bioenergetics, i.e., affecting cellular ATP levels and molecules/activities regulating these levels, anti-cancer biologic agent (e.g., monoclonal antibodies), kinase inhibitors and inhibitors of growth factors and their receptors.
• anti-cancer biologic agent e.g., monoclonal antibodies
• the second chemotherapeutic agent is selected from afatinib, afuresertib, alectinib, alisertib, alvocidib, amsacrine, amonafide, amuvatinib, axitinib, azacitidine, azathioprine, bafetinib, barasertib, bendamustine, bleomycin, bosutinib, bortezomib, busulfan, cabozantinib, camptothecin, canertinib, capecitabine, cabazitaxel, carboplatin, carmustine, cenisertib, ceritinib, chlorambucil, cisplatin, cladribine, clofarabine, crenolanib, crizotinib, cyclophosphamide, cytarabine, dabrafeni
• the second therapeutic agent is selected from the group consisting of a phosphoinositol-3 kinase (PI3K) inhibitor, AKT inhibitor, mammalian target of rapamycin (mTOR) inhibitor, poly ADP ribose polymerase (PARP) inhibitor, platinum-based anti-cancer compound (PBAC), CBP/ ⁇ -catenin inhibitor, Tankyrase (TNKS) inhibitor, probable protein-cysteine N- palmitoyltransferase (PORCN) inhibitor, scr kinase/bcr-abl kinase inhibitor, Smoothened (SMO) inhibitor, anti-cancer nucleoside analog or anti-metabolite, histone deacetylase (HDAC) inhibitor, Bromodomain and Extra-Terminal motif (BET) inhibitor, all-trans-retinoic acid (ATRA), Bruton’s tyrosine kinase (BTK) inhibitor, EGFR receptor inhibitor, and combinations thereof.
• PI3K phosphoi
• the second therapeutic agent is selected from the group consisting of idelalisib, pictilisib, duvelisib, pilaralisib, alpelisib, copanlisib, voxtalisib, dactolisib, gedatolisib, apitolisib, perifosine, miltefosine, ipatasertib, sirolimus, everolimus, temsirolimus, tacrolimus, ridaforolimus, ridaforolimus, dactolisib, olaparib, veliparib, rucaparib, talazoparib, niraparib, cisplatin, carboplatin, oxaliplatin, dicycloplatin, nedaplatin, lobaplatin, heptaplatin, phenathriplatin, phosphaplatin, LA-12, ICG-
• the pharmaceutical compositions of the therapeutic agents can be formulated by standard techniques using one or more physiologically acceptable carriers or excipients. Suitable pharmaceutical carriers are described herein and in Remington: The Science and Practice of Pharmacy, 21 st Ed. (2005).
• the therapeutic compounds and their physiologically acceptable salts, hydrates and solvates can be formulated for administration by any suitable route, including, among others, topically, nasally, orally, parenterally, rectally or by inhalation.
• the compounds and pharmaceutical compositions thereof are administered by intradermal, subdermal, intravenous, intramuscular, intranasal, intracerebral, intratracheal, intraarterial, intraperitoneal, intravesical, intrapleural, intracoronary or intratumoral injection, such as with a syringe or other devices.
• Transdermal administration is also contemplated, as are inhalation or aerosol administration.
• Tablets, capsules, and solutions can be administered orally, rectally or vaginally.
• a pharmaceutical composition can take the form of, for example, a tablet or a capsule prepared by conventional means with a pharmaceutically acceptable excipient.
• Tablets and capsules comprising the active ingredient can be prepared together with excipients such as: (a) diluents or fillers, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose (e.g., ethyl cellulose, microcrystalline cellulose), glycine, pectin, polyacrylates and/or calcium hydrogen phosphate, calcium sulfate; (b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, metallic stearates, colloidal silicon dioxide, hydrogenated vegetable oil, corn starch, sodium benzoate, sodium acetate and/or polyethyleneglycol; (c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and/or hydroxypropyl methylcellulose; (d)
• compositions are prepared according to conventional mixing, granulating or coating methods.
• Tablets may be either film coated or enteric coated according to methods known in the art.
• Liquid preparations for oral administration can take the form of, for example, solutions, syrups, or suspensions, or they can be presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable carriers and additives, for example, suspending agents, e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats; emulsifying agents, for example, lecithin or acacia; non-aqueous vehicles, for example, almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils; and preservatives, for example, methyl or propyl-p-hydroxybenzoates or sorbic acid.
• the preparations can also contain buffer salts, flavoring, coloring, and/or sweetening agents as appropriate. If desired, preparations for oral administration can be suitably formulated to give controlled release of the active compound.
• the therapeutic agents can be formulated for parenteral administration, for example by bolus injection or continuous infusion.
• Formulations for injection can be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an optionally added preservative.
• Injectable compositions can be aqueous isotonic solutions or suspensions.
• the therapeutic agents can be prepared with a surfactant, such as Cremaphor, or lipophilic solvents, such as triglycerides or liposomes.
• the compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
• the therapeutic agent can be in powder form for reconstitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.
• a suitable vehicle for example, sterile pyrogen-free water
• they may also contain other therapeutically effective substances.
• the therapeutic agent e.g., the diterpenoid PKC modulating compounds
• the therapeutic agent is administered directly into the tumor, allowing for high local concentration of the therapeutic agent and in some embodiments, increased bioavailability of the therapeutic agent at the site of the tumor. Any formulation of the therapeutic agent suitable for intratumoral administration can be used in the embodiments herein.
• Intratumoral administration can be by injection of the therapeutic agent into the tumor (see, e.g., Celikoglu et al., 2008, Cancer Therapy, 6:545-552) or by intravenous administration to blood vessels feeding to the tumor.
• the injection device has a porous delivery channel (e.g., needle) for wider distribution or infusion of the therapeutic agent for treating tumors with large volume.
• the therapeutic agent may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
• a suitable propellant for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
• the dosage unit can be determined by providing a valve to deliver a metered amount.
• Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base, for example, lactose or starch.
• Suitable formulations for transdermal application include an effective amount of a therapeutic agent with a carrier.
• Preferred carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the subject.
• transdermal devices are in the form of a bandage or patch comprising a backing member, a reservoir containing the therapeutic agent optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and a means to secure the device to the skin.
• Matrix transdermal formulations may also be used.
• Suitable formulations for topical application are preferably aqueous solutions, ointments, creams or gels well-known in the art.
• the formulations may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
• the therapeutic agent can also be formulated as a rectal composition, for example, suppositories or retention enemas, for example, containing conventional suppository bases, for example, cocoa butter or other glycerides, or gel forming agents, such as carbomers.
• the therapeutic agent can be formulated as a depot preparation.
• Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
• the therapeutic agent can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil), ion exchange resins, biodegradable polymers, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
• the carrier is a cyclodextrins, such as to enhance solubility and/or bioavailability of the compounds herein.
• the cyclodextrin for use in the pharmaceutical compositions can be selected from ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, derivatives thereof, and combinations thereof.
• the cyclodextrin is selected from ⁇ - cyclodextrin, ⁇ -cyclodextrin, derivatives thereof, and combinations thereof.
• the compounds can be formulated with a cyclodextrin or derivative thereof selected from carboxyalkyl cyclodextrin, hydroxyalkyl cyclodextrin, sulfoalkylether cyclodextrin, and an alkyl cyclodextrin.
• the alkyl group in the cyclodextrin is methyl, ethyl, propyl, butyl, or pentyl.
• the cyclodextrin is ⁇ -cyclodextrin or a derivative thereof.
• the ⁇ -cyclodextrin or derivative thereof is selected from carboxyalkyl- ⁇ -cyclodextrin, hydroxyalkyl- ⁇ -cyclodextrin, sulfoalkylether- ⁇ -cyclodextrin, alkyl- ⁇ -cyclodextrin, and combinations thereof.
• the alkyl group in the ⁇ -cyclodextrin derivative is methyl, ethyl, propyl, butyl, or pentyl.
• the cyclodextrin is ⁇ -cyclodextrin or a derivative thereof.
• the ⁇ -cyclodextrin or derivative thereof is selected from carboxyalkyl- ⁇ - cyclodextrin, hydroxyalkyl- ⁇ -cyclodextrin, sulfoalkylether- ⁇ -cyclodextrin, alkyl- ⁇ -cyclodextrin, and combinations thereof.
• the alkyl group in the ⁇ -cyclodextrin derivative is methyl, ethyl, propyl, butyl, or pentyl.
• the ⁇ -cyclodextrin or a derivative thereof is hydroxyalkyl- ⁇ - cyclodextrin or sulfoalkylether- ⁇ -cyclodextrin.
• the hydroxyalkyl- ⁇ - cyclodextrin is hydroxypropyl- ⁇ -cyclodextrin.
• the sulfoalkylether- ⁇ - cyclodextrin is sulfobutylether- ⁇ -cyclodextrin.
• ⁇ -cyclodextrin or a derivative thereof is alkyl- ⁇ -cyclodextrin, in particular methyl- ⁇ -cyclodextrin. In some embodiments using methyl- ⁇ -cyclodextrin, the ⁇ -cyclodextrin is randomly methylated ⁇ -cyclodextrin. [0282] In some embodiments, the cyclodextrin is ⁇ -cyclodextrin or a derivative thereof.
• the ⁇ -cyclodextrin or derivative thereof is selected from carboxyalkyl- ⁇ -cyclodextrin, hydroxyalkyl- ⁇ -cyclodextrin, sulfoalkylether- ⁇ -cyclodextrin, and alkyl- ⁇ -cyclodextrin.
• the alkyl group in the ⁇ -cyclodextrin derivative is methyl, ethyl, propyl, butyl, or pentyl.
• the ⁇ -cyclodextrin or derivative thereof is hydroxyalkyl ⁇ - cyclodextrin or sulfoalkylether- ⁇ -cyclodextrin.
• the hydroxyalkyl ⁇ - cyclodextrin is hydroxypropyl ⁇ -cyclodextrin.
• the cyclodextrin can be present at about 0.1 w/v to about 30% w/v, about 0.1 w/v to about 20% w/v, about 0.5% w/v to about 10% w/v, or about 1% w/v to about 5% w/v.
• the cyclodextrin is present at about 0.1% w/v, about 0.2% w/v, about 0.5% w/v, about 1% w/v, about 2% w/v, about 3% w/v, about 4% w/v, about 5% w/v, about 6% w/v, about 7% w/v, about 8% w/v, about 9% w/v, about 10% w/v, about 12% w/v, about 14% w/v, about 16% w/v, about 18% w/v, about 20% w/v, about 25% w/v, or about 30% w/v or more.
• the pharmaceutical compositions can, if desired, be presented in a pack or dispenser device that can contain one or more unit dosage forms containing the active ingredient.
• the pack can, for example, comprise metal or plastic foil, for example, a blister pack.
• the pack or dispenser device can be accompanied by instructions for administration.
• Effective Amount and Dosing [0285]
• a pharmaceutical composition of the therapeutic agent is administered to a subject, preferably a human, at a therapeutically effective dose to prevent, treat, or control a condition or disease as described herein.
• the pharmaceutical composition is administered to a subject in an amount sufficient to elicit an effective therapeutic response in the subject.
• An effective therapeutic response is a response that at least partially arrests or slows the symptoms or complications of the condition or disease.
• the dosage of therapeutic agents can take into consideration, among others, the species of warm-blooded animal (mammal), the body weight, age, condition being treated, the severity of the condition being treated, the form of administration, route of administration. The size of the dose also will be determined by the existence, nature, and extent of any adverse effects that accompany the administration of a particular therapeutic compound in a particular subject.
• the diterpenoid PKC activating compound the compound can be administered in a dose in the range from about 0.001 mg per kg of subject weight (0.001 mg/kg) to about 1000 mg/kg.
• the dose is in the range of about 0.001 mg/kg to about 500 mg/kg. In some embodiments, the dose is in the range of about 1 mg/kg to about 500 mg/kg. In some embodiments, the dose is about 2 mg/kg to about 250 mg/kg. In another embodiment, the dose is about 5 mg/kg to about 100 mg/kg. In another embodiment, the dose is about 5 mg/kg to about 100 mg/kg.
• the dose is about 0.001 mg/kg, 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/ kg, 40 mg/ kg, 50 mg/kg, 100 mg/kg, 200 mg/kg or 500 mg/kg.
• the dose can be administered once per day or divided into subdoses and administered in multiple doses, e.g., twice, three times, or four times per day.
• the diterpenoid PKC activator can be administered with one or more of the second therapeutic agent sequentially or concurrently, either by the same route or by different routes of administration.
• the time between administrations is selected to benefit, among others, the therapeutic efficacy and/or safety of the combination treatment.
• the diterpenoid PKC activator can be administered first followed by a second therapeutic agent, or alternatively, the second therapeutic agent administered first followed by the diterpenoid PKC activator.
• the time between administrations is about 1 hr, about 2 hr, about 4hr, about 6 hr, about 12 hr, about 16 hr or about 20 hr.
• the time between administrations is about 1, about 2, about 3, about 4, about 5, about 6, or about 7 more days. In some embodiments, the time between administrations is about 1 week, 2 weeks, 3 weeks, or 4 weeks or more. In some embodiments, the time between administrations is about 1 month or 2 months or more.
• the diterpenoid PKC modulator can be administered separately at the same time as the second therapeutic agent, by the same or different routes, or administered in a single composition by the same route.
• the amount and frequency of administration of the second therapeutic agent can used standard dosages and standard administration frequencies used for the particular therapeutic agent.
• the dosages can be the dosages used for systemic administration, such as dosages used for intravenous, intramuscular, and intraperitoneal administration.
• the dose for localized administration e.g., intratumoral administration
• the administered dose is sufficient for the intended effect, for example killing or necrotization of tumor tissue.
• intratumoral administration is done once, twice, three times, four times, five time or up to six times or more, where each administration is separated in time, for example, until the desired outcome is achieved.
• optimum dosages, toxicity, and therapeutic efficacy of such therapeutic agents may vary depending on the relative potency of individual therapeutic agent and can be determined by pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
• the dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio, LD 50 /ED 50 .
• Therapeutic agents or combinations thereof that exhibit large therapeutic indices are preferred.
• the data obtained from, for example, cell culture assays and animal studies can be used to formulate a dosage range for use in humans.
• the dosage of such small molecule compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
• the dosage can vary within this range depending upon the dosage form employed and the route of administration.
• the therapeutically effective dose can be estimated initially from cell culture assays.
• a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography (HPLC).
• HPLC high performance liquid chromatography
• the reaction mixture was concentrated by drumming N2 to give the crude product.
• Example 2 Synthesis Scheme of K101-C13OH.
• the scheme for synthesis of compound K101-C13OH is illustrated below.
• [0305] Preparation of Compound K101-C13OH.
• K101A 40.00 mg, 102.44 ⁇ mol, 1.00 eq
• MeOH 20.00 mL
• Ba(OH) 2 .8H 2 O 322.69 mg, 1.02 mmol, 10.00 eq
• the reaction mixture was quenched withsaturated NH4Cl (10 mL) and extracted with dichloromethane (DCM) (100 mL x 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product.
• reaction mixture was combined with a second preparation of the compound and purified by prep-HPLC (column: Waters XSELECT C18150 x 30mm x 5um; mobile phase: [A: water (0.1%TFA)-B: B: ACN]; B%: 33%-63%, 10 min) to give K101-C1302 (10.60 mg, 18.56 ⁇ mol, 52.42% yield, 96.032% purity) as a white solid.
• Example 5 Synthesis Scheme of K101-C1303 [00253]Preparation of Compound K101-C1303-A: To a solution of K101-C20Tr-B (30.00 mg, 50.78 ⁇ mol, 1.00 eq) in DCM (2.00 mL) were added (2S)-2-(tert-butoxycarbonylamino)-3-phenyl- propanoic acid (C13-03) (26.95 mg, 101.57 ⁇ mol, 2.00 eq), DMAP (24.82 mg, 203.13 ⁇ mol, 4.00 eq) and EDC (19.47 mg, 101.57 ⁇ mol, 2.00 eq). The mixture was stirred at 20°C for 48 hours to give a yellow solution.
• Example 6 Synthesis Scheme of K101-C1304.
• the scheme for synthesis of compound K101-C1304 is illustrated below.
• Preparation of Compound K101-C1304-A To a solution of K101-C20Tr-B (40.00 mg, 67.71 ⁇ mol, 1.00 eq) in DCM (2.00 mL) were added 2-phenylacetic acid (C13-04) (11.06 mg, 81.25 ⁇ mol, 10.24 uL, 1.20 eq), DMAP (33.09 mg, 270.84 ⁇ mol, 4.00 eq) and EDC (25.96 mg, 135.42 ⁇ mol, 2.00 eq).
• the mixture was purified by prep-HPLC (column: Waters XSELECT C18150 x 30mm x 5um; mobile phase: [A: water (0.1%TFA)-B: B: ACN]; B%: 33%-63%, 10 min) to give K101-C1304 (16.30 mg, 34.94 ⁇ mol, 61.91% yield) as a white solid.
• K101-C1306 [0269] The scheme for synthesis of compound K101-C1306 is illustrated below.
• K101-C1306 [0269] Preparation of Compound K101-C1306-A. To a solution of K101-C20Tr-B (40.00 mg, 67.71 ⁇ mol, 1.00 eq) in DCM (2.00 mL) were added 2-(2-tert-butoxycarbonyl-2-azaspiro[3.3]heptan- 6-yl)acetic acid (25.93 mg, 101.56 ⁇ mol, 1.50 eq), DMAP (33.09 mg, 270.84 ⁇ mol, 4.00 eq), DIEA (26.25 mg, 203.13 ⁇ mol, 35.47 uL, 3.00 eq) and EDC (25.96 mg, 135.42 ⁇ mol, 2.00 eq).
• the mixture was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150 x 30 x 5um; mobile phase: [A: water (0.05% ammonia hydroxide v/v)-B: ACN]; B%: 45%-75%, 10min) to give K101-C1306-A (3.80 mg, 6.49 ⁇ mol, 53.71% yield) as a white solid.
• the mixture was combined with a second preparation of the compound and concentrated byN 2 to give the desired product.
• the product was lyophilized to give K101-C1306 (4.20 mg, 7.00 ⁇ mol, 25.80% yield, TFA) as a yellow gum.
• the product (13.4 mg) was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [water (0.1%TFA)-ACN]; B%: 20%-50%, 10min) to give K101-C1306 (4.20 mg, 7.00 ⁇ mol, 25.80% yield, TFA) as a white solid.
• the mixture was purified by prep-HPLC (column: Waters Xbridge 150 x 25 x 5u; mobile phase: [A: water (0.05% ammonia hydroxide v/v)-B: ACN]; B%: 40%-70%, 10min) to give K101-C1311 (3.30 mg, 5.77 ⁇ mol, 21.36% yield, 100% purity) as a yellow solid.
• the mixture was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150 x 30 x 5u; mobile phase: [A: water (0.05% ammonia hydroxide v/v)-B: ACN]; B%: 45%-75%, 10 min) to give K101-C1306-A (3.80 mg, 6.49 ⁇ mol, 53.71% yield) as a white solid.
• the mixture was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 55%-85%, 10min) to give K101-C1313 (4.40 mg, 6.10 ⁇ mol, 22.90% yield, 91.518% purity, TFA) as a yellow solid.
• Example 12 Synthesis Scheme of K101-C1315.
• the scheme for synthesis of compound K101-C1315 is illustrated below.
• Preparation of Compound K101-C1315-A To a solution of K101-C20Tr-B (20.00 mg, 33.86 ⁇ mol, 1.00 eq) and C13-15 (15.35 mg, 101.58 ⁇ mol, 3.00 eq) in DCM (1.00 mL) was added EDC (19.47 mg, 101.58 ⁇ mol, 3.00 eq) and DMAP (20.68 mg, 169.30 ⁇ mol, 5.00 eq). The reaction solution was stirred at 25 °C for 3 hours to give a brown solution. LC-MS showed the reaction was complete.
• the reaction solution was quenched by adding K 2 CO 3 (34 mg) in water (1 mL) dropwise at 0 °C to adjust the pH to 9.
• the mixture was filtered and the filtrate purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 15%-45%, 10min) to give K101-C1315 (3.60 mg, 97% purity, TFA salt) as a white solid after lyophilization.
• Example 13 Synthesis Scheme of K101-C1316.
• the scheme for synthesis of compound K101-C1316 is illustrated below.
• [0295] Preparation of Compound K101-C1316-A.
• C13-16 51.18 mg, 338.55 ⁇ mol, 5.00 eq
• DMAP 33.09 mg, 270.84 ⁇ mol, 4.00 eq
• hydroxybenzotriazole HOBt
• EDC 25.96 mg, 135.42 ⁇ mol, 2.00 eq.
• the mixture was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 20%-50%, 10min) to give K101-C1316 (11.40 mg, 18.81 ⁇ mol, 50.43% yield, 98.3% purity, TFA salt) as a white solid.
• Example 14 Synthesis Scheme of K101-C1317. [0299] The scheme for synthesis of compound K101-C1317 is illustrated below. [0300] Preparation of Compound K101-C1317-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 ⁇ mol, 1.00 eq) in DCM (1.00 mL) were added (2S)-2-(tert-butoxycarbonylamino) hexanoic acid (C13-17) (23.49 mg, 101.57 ⁇ mol, 2.00 eq), DMAP (24.82 mg, 203.13 ⁇ mol, 4.00 eq) and EDC (19.47 mg, 101.57 ⁇ mol, 2.00 eq).
• the reaction mixture was concentrated, dissolved with MeOH (20 mL), and stirred at 20°C for 14 h to give a yellow liquid.
• the product was concentrated to give a yellow solid, which was then purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%:30%-60%, 8 min).
• the separated layers were lyophilized to give K101-C1317 (7.00 mg, 12.16 ⁇ mol, 21.26% yield, 100% purity, TFA) as a white solid.
• Example 15 Synthesis Scheme of K101-C1318.
• the scheme for synthesis of compound K101-C1318 is illustrated below.
• [0305] Preparation of Compound K101-C1318-A.
• K101-C20Tr-B 30.00 mg, 50.78 ⁇ mol, 1.00 eq
• DCM 2.00 mL
• (2S)-2-(tert-butoxycarbonylamino)-4-phenyl- butanoic acid (C13-18) (28.37 mg, 101.56 ⁇ mol, 2.00 eq)
• DMAP 24.82 mg, 203.12 ⁇ mol, 4.00 eq
• EDC (19.47 mg, 101.56 ⁇ mol, 2.00 eq).
• the product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 23%-53%, 10 min) to give K101-C1318 (10.80 mg, 17.24 ⁇ mol, 48.98% yield, 99.58% purity, TFA) as a white solid.
• Example 16 Synthesis Scheme of K101-C1319. [0309] The scheme for synthesis of compound K101-C1319 is illustrated below. [0310] Preparation of compound K101-C1319-A. To a solution of K101-C20Tr-B (200.00 mg, 338.55 ⁇ mol, 1.00 eq) and C13-19 (119.18 mg, 406.26 ⁇ mol, 1.20 eq) in anhydrous DCM (2.00 mL) were added EDC (194.70 mg, 1.02 mmol, 3.00 eq) and DMAP (124.08 mg, 1.02 mmol, 3.00 eq). The reaction solution was stirred at 20°C for 16 hours to give a light brown solution. LC-MS showed the reaction was complete.
• Example 17 Synthesis Scheme of K101-C1320.
• the scheme for synthesis of compound K101-C1320 is illustrated below.
• [0315] Preparation of Compound K101-C1320-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 ⁇ mol, 1.00 eq) and C13-20 (26.09 mg, 152.34 ⁇ mol, 3.00 eq) in DCM (2.00 mL) were added EDC (58.41 mg, 304.68 ⁇ mol, 6.00 eq) and DMAP (37.22 mg, 304.68 ⁇ mol, 6.00 eq). The reaction solution was stirred at 25 °C for 16 hours to give a brown solution.
• Example 18 Synthesis Scheme of K101-C1321.
• the scheme for synthesis of compound K101-C1321 is illustrated below.
• [0320] Preparation of Compound K101-C1321-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 ⁇ mol, 1.00 eq) and C13-21 (76.68 mg, 304.68 ⁇ mol, 6.00 eq) in DCM (1.00 mL) were added EDC (58.41 mg, 304.68 ⁇ mol, 6.00 eq) and DMAP (37.22 mg, 304.68 ⁇ mol, 6.00 eq). The reaction solution was stirred at 25 °C for 2 hours to give a light brown solution.
• the product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 22%-52%, 10min) to give K101-C1322 (17.40 mg, 27.42 ⁇ mol, 69.73% yield, TFA salt) as a yellow solid.
• reaction solution was stirred at 25°C for 0.5 hour to give a clear solution.
• LC-MS showed the reaction was complete.
• the reaction solution was directly purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 25%-55%, 10min) to give K101-C1323 (9.10 mg, 40.48% yield, 94.9% purity) as a white solid.
• the product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 25%- 55%, 10min) to give K101-C1327 (5.10 mg, 7.95 ⁇ mol, 27.97% yield, 95.99% purity, TFA) as a white solid.
• Example 25 Synthesis Scheme of K101-C1328.
• the scheme for synthesis of compound K101-C1328 is illustrated below.
• [0359] Preparation of Compound K101-C1328-A.
• K101-C20Tr-B 30.00 mg, 50.78 ⁇ mol, 1.00 eq
• DCM 2.00 mL
• 4- dimethyl-pentanoic acid C13-28
• DMAP 24.82 mg, 203.12 ⁇ mol, 4.00 eq
• HOBt 13.72 mg, 101.56 ⁇ mol, 2.00 eq
• EDC (19.47 mg, 101.56 ⁇ mol, 2.00 eq).
• reaction mixture was concentrated byN 2 and the resultant product purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 30%-70%, 10min) to give K101-C1328 (9.50 mg, 15.88 ⁇ mol, 46.38% yield, 98.54% purity, TFA) as a white solid.
• Example 26 Synthesis Scheme of K101-C1329.
• the scheme for synthesis of compound K101-C1329 is illustrated below.
• Preparation of Compound K101-C1329-A To a solution of K101-C20Tr-B (20.00 mg, 33.86 ⁇ mol, 1.00 eq) and C13-29 (14.80 mg, 50.79 ⁇ mol, 1.50 eq) in DCM (2.00 mL) were added EDC (38.95 mg, 203.16 ⁇ mol, 6.00 eq) and DMAP (24.82 mg, 203.16 ⁇ mol, 6.00 eq). The reaction solution was stirred at 25 °C for 16 hours to give a brown solution.
• the product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 30%-60%, 10min) to give K101-C1329 (2.00 mg, 3.62 ⁇ mol, 19.92% yield, 94.4% purity) and K101-C1329-Cl (2.70 mg, 4.47 ⁇ mol, 24.60% yield, 92.4% purity), both as white solids after lyophilization.
• Example 27 Synthesis Scheme of K101-C1330. [03
• the residue was diluted with CH3CN (1mL) and water (1 mL) and the solution adjusted to pH 8 with addition of solid K2CO3 (5 mg).
• the product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 25%-55%, 10min) to give K101-C1330 (4.70 mg, 65.05% yield, 99.0% purity, TFA salt) as a white powder after lyophilization.
• reaction mixture was concentrated byN2, and the product purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 27%-57%, 10min) to give K101- C1331 (10.00 mg, 15.73 ⁇ mol, 42.48% yield, 100% purity, TFA salt) as a white solid.
• reaction mixture was combined with reaction mixture of ES5329-184 (5 mg of K101- C20Tr-B was used in this batch) and concentrated under reduced pressure.
• Example 31 Synthesis Scheme of K101-C1334.
• the scheme for synthesis of compound K101-C1334 is illustrated below.
• Preparation of Compound K101-C1334-A To a solution of K101-C20Tr-B (35.00 mg, 59.25 ⁇ mol, 1.00 eq) and C13-34 (136.45 mg, 592.47 ⁇ mol, 10.00 eq) in DCM (1.00 mL) was added EDCI (34.07 mg, 177.74 ⁇ mol, 3.00 eq) and DMAP (21.71 mg, 177.74 ⁇ mol, 3.00 eq), then the mixture was stirred at 20°C for 14 hours to give colorless solution.
• Example 32 Synthesis Scheme of K101-C1335.
• the scheme for synthesis of compound K101-C1335 is illustrated below.
• K101-C1335 [0398] Preparation of Compound K101-C1335-A: To a solution of K101-C20Tr-B (30.00 mg, 50.78 ⁇ mol, 1.00 eq) in DCM (2.00 mL) were added tridecanedioic acid (62.04 mg, 253.90 ⁇ mol, 5.00 eq), DMAP (37.22 mg, 304.68 ⁇ mol, 6.00 eq) and EDCI (58.41 mg, 304.68 ⁇ mol, 6.00 eq).
• the yellow oil was purified by prep-HPLC (column: Phenomenex Gemini 150*25mm*10um; mobile phase: [water (0.1%TFA)-ACN]; B%: 70%-70%, 10min).
• the separated layers were lyophilized to give K101-C1335 (5.40 mg, 9.15 ⁇ mol, 31.16% yield, 97.4% purity, Free) as a white solid.
• the reaction mixture was concentrated byN2, and the product purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 25%-55%, 10min) to give K101-C1337 (5.20 mg, 10.37 ⁇ mol, 48.62% yield, 100% purity) as a white solid.
• Example 35 Synthesis Scheme of K101-C1338.
• the scheme for synthesis of compound K101-C1338 is illustrated below.
• [0414] Preparation of compound K101-C1338-A.
• K101-C20Tr-B 30.00 mg, 50.78 ⁇ mol, 1.00 eq
• DCM 2.00 mL
• (2S)-2-(tert-butoxycarbonylamino)-4-methylsulfanyl- butanoic acid C13-38
• DMAP 24.82 mg, 203.12 ⁇ mol, 4.00 eq
• HOBt 13.72 mg, 101.56 ⁇ mol, 2.00 eq
• EDC (19.47 mg, 101.56 ⁇ mol, 2.00 eq).
• the reaction mixture was concentrated byN2 and the product purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 20%-50%, 10min) to give K101-C1338 (13.20 mg, 20.95 ⁇ mol, 47.83% yield, 94.2% purity, TFA salt) as a white solid.
• Example 36 Synthesis Scheme of K101-C1339.
• the scheme for synthesis of compound K101-C1339 is illustrated below.
• Preparation of Compound K101-C1339-A To a solution of K101-C20Tr-B (30.00 mg, 50.78 ⁇ mol, 1.00 eq) in DCM (2.00 mL) were added (2R)-2-(tert-butoxycarbonylamino)-3- methylsulfanyl-propanoic acid (C13-39) (23.90 mg, 101.56 ⁇ mol, 2.00 eq), DMAP (24.82 mg, 203.12 ⁇ mol, 4.00 eq), HOBt (13.72 mg, 101.56 ⁇ mol, 2.00 eq) and EDC (19.47 mg, 101.56 ⁇ mol, 2.00 eq).
• reaction mixture was concentrated byN 2 and the product purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 18%-48%, 10min) to give K101-C1339 (4.40 mg, 7.11 ⁇ mol, 16.41% yield, 93.63% purity, TFA salt) as a white solid.
• Example 37 Synthesis Scheme of K101-C1340.
• the scheme for synthesis of compound K101-C1340 is illustrated below.
• the reaction was concentrated under reduced pressure to give a yellow solid, and the product purified by prep-HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 55%-95%, 10 min).
• the separated layers were lyophilized to give K101-C1340 (3.80 mg, 7.11 ⁇ mol, 31.17% yield, 96.78% purity, TFA salt) as a pale yellow solid.
• Example 38 Synthesis Scheme of K101-C1341.
• the scheme for synthesis of compound K101-C1341 is illustrated below.
• [0429] Preparation of Compound K101-C1341-A.
• reaction mixture was concentrated and dissolved with DCM (2 mL) followed by addition of TFA (0.5 mL). This reaction mixture was stirred at 20°C for 1hr to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated to give a yellow oil, which was then dissolved in MeOH (4 mL) and stirred at 20°C for 14hr to give a yellow liquid.
• the product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 20%-50%, 10min).
• the product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 25%-55%, 10 min) to give K101-C1342 (10.70 mg, 18.99 ⁇ mol, 34.40% yield, 98.84% purity, TFA salt) as a white solid.
• Example 40 Synthesis Scheme of K101-C1343.
• the scheme for synthesis of compound K101-C1343 is illustrated below.
• the solution was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.05% HCl)-B: ACN]; B%: 15%-45%, 10min) to give K101-C1343 (7.60 mg, 47.02% yield, 98.2% purity, HCl salt) as a white solid.
• Example 41 Synthesis Scheme of K101-C1344.
• the scheme for synthesis of compound K101-C1344 is illustrated below.
• [0444] Preparation of Compound K101-C1344-A. To a solution of K101-C20Tr-B (35.00 mg, 59.25 ⁇ mol, 1.00 eq) and C13-44 (41.37 mg, 148.12 ⁇ mol, 2.50 eq) in DCM (1.00 mL) were added EDC (68.15 mg, 355.48 ⁇ mol, 6.00 eq) and DMAP (21.71 mg, 177.74 ⁇ mol, 3.00 eq). The mixture was stirred at 20°C for 18hr to give a yellow solution.
• the product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 20%-50%, 10min).
• the separated layers were lyophilized to give K101-C1344 (5.00 mg, 8.02 ⁇ mol, 19.52% yield, TFA salt) as a white solid.
• Example 42 Synthesis Scheme of K101-C1345.
• the scheme for synthesis of compound K101-C1345 is illustrated below.
• Preparation of Compound K101-C1345-A To a solution of K101-C20Tr-B (30.00 mg, 50.78 ⁇ mol, 1.00 eq) and C13-45 (36.23 mg, 126.96 ⁇ mol, 2.50 eq) in DCM (1.00 mL) were added EDC (48.68 mg, 253.91 ⁇ mol, 5.00 eq) and DMAP (18.61 mg, 152.35 ⁇ mol, 3.00 eq). The reaction mixture was stirred at 20°C for 18hr. The reaction was complete as detected by LC-MS.
• the solution was stirred at 20°C for 18 hr to give a yellow solution.
• the reaction was complete as detected by LC- MS.
• the reaction solution was diluted with H 2 O (10 mL), neutralized with NaHCO 3 aqueous solution and then extracted with DCM (8 mL x 5). The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to give a yellow solid.
• the reaction mixture was concentrated to give a yellow oil, which was dissolved with MeOH (2 mL) and stirred at 20°C for 14h to give a buff liquid.
• the product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 25%-55%, 10min).
• the separated layers were lyophilized to give K101-C1347 (6.50 mg, 9.94 ⁇ mol, 67.44% yield, 100% purity, TFA salt) as a white solid.
• Boc anhydride (Boc2O) (2.23 g, 10.20 mmol, 2.34 mL, 2.00 eq) was added to the preparation of C13-48-E, and the mixture stirred at 20°C for 2hr to give a yellow suspension.
• LC-MS and TLC eluting with: 100%EtOAc showed the reaction was complete.
• the mixture was combined with a second preparation, and the combined mixture was diluted with H 2 O (20 mL) followed by extraction with PE (20 mL x 3). The water layer was adjusted to pH 5 with HCl (1N) and extracted with EtOAc (30 mL x 3). The organic layers were dried over Na 2 SO 4 and concentrated to give the crude product.
• K101-C134801 LC-MS (m/z): 588.2 [M+Na] + K101-C134801: 1 H NMR (400MHz, CD3OD) ⁇ 7.53 (s, 1H), 7.30-7.10 (m, 5H), 5.65-5.55 (m, 1H), 4.00-3.90 (m, 2H), 3.50-3.45(m, 1H), 3.25-3.20 (m, 1H), 3.15-3.05 (m, 1H), 2.65-2.55 (m, 2H), 2.55- 2.40 (m, 2H), 2.20-1.95 (m, 2H), 1.807-1.55 (m, 8H), 1.40-1.25 (m, 6H), 1.20 (s,3H), 1.10 (s,3H), 0.95-0.85 (m, 4H).
• K101-C134802 LC-MS (m/z): 588.3 [M+Na] + [0474] K101-C134802: 1 H NMR (400MHz, CD3OD) ⁇ 7.53 (s, 1H), 7.30-7.10 (m, 5H), 5.65-5.55 (m, 1H), 4.0-3.85 (m, 2H), 3.70-3.60 (m, 1H), 3.20-3.10 (m, 1H), 3.05-3.0 (m, 1H), 2.70-2.55 (m, 2H), 2.55-2.40 (m, 2H), 2.15-2.15 (m, 2H), 1.85-1.45 (m, 8H), 1.45-1.30 (m, 6H), 1.20 (s, 3H), 1.09 (s, 3H), 0.95-0.90 (m, 4H).
• Example 45A Synthesis Scheme of K101-C134801 [0475] The scheme for synthesis of compound K101-C134801 is illustrated below.
• K101-C134801 LC-MS (m/z): 588.2 [M+Na] + [0486] K101-C134801: 1 H NMR (400MHz, CD 3 OD) ⁇ 7.56 (s, 1H), 7.30-7.10 (m, 5H), 5.65-5.55 (m, 1H), 4.00-3.90 (m, 2H), 3.50-3.45(m, 1H), 3.25-3.20 (m, 1H), 3.15-3.05 (m, 1H), 2.65-2.40 (m, 4H), 2.20-1.95 (m, 2H), 1.807-1.55 (m, 8H), 1.40-1.25 (m, 6H), 1.20 (s,3H), 1.10 (s,3H), 0.95-0.85 (m, 4H).
• K101-C134801-C 1 H NMR (400MHz, CDCl3) ⁇ 7.51 (s, 1H), 7.36-7.35 (m, 6H), 7.24-7.22 (m, 7H), 7.18-7.10 (m, 7H), 5.54 (s, 1H), 5.26 (brs, 1H), 3.45-3.42 (m, 2H), 3.36- 3.34(m, 1H), 3.21 (s, 1H), 2.87 (s, 1H), 2.54-2.36 (m, 4H), 1.99-1.97 (m, 3H), 1.71 (s, 3H), 1.27-1.21 (m, 6H), 1.13 (s,3H), 1.01 (s,3H), 0.81-0.71 (m, 4H).
• Example 45B Synthesis Scheme of K101-C134802
• the scheme for synthesis of compound K101-C134802 is illustrated below.
• [0492] Preparation of compound C1348-F. To a solution of C1348-E (20 g, 146.85 mmol, 20.00 mL, 1 eq) in DCM (200 mL) was added 2,4-lutidine (25.18 g, 234.96 mmol, 27.16 mL, 1.6 eq) at - 78°C. Then triflic anhydride (Tf2O) (45.58 g, 161.54 mmol, 26.65 mL, 1.1 eq) was added dropwise at -78°C.
• Tf2O triflic anhydride
• Example 47 Synthesis Scheme of K101-C1350.
• the scheme for synthesis of compound K101-C1350 is illustrated below.
• [0522] Preparation of Compound K101-C1350-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 ⁇ mol, 1.00 eq) in DCM (1.00 mL) were added C13-50 (74.49 mg, 253.91 ⁇ mol, 5.00 eq), EDC (58.41 mg, 304.70 ⁇ mol, 6.00 eq) and DMAP (37.22 mg, 304.70 ⁇ mol, 6.00 eq). The mixture was stirred at 20°C for 14hr to give a yellow solution.
• Example 48 Synthesis Scheme of K101-C1351.
• the scheme for synthesis of compound K101-C1351 is illustrated below.
• [0527] Preparation of Compound K101-C1351-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 ⁇ mol, 1.00 eq) and C13-51 (72.31 mg, 152.34 ⁇ mol, 3.00 eq) in DCM (1.00 mL) were added EDC (38.94 mg, 203.12 ⁇ mol, 4.00 eq) and DMAP (24.82 mg, 203.12 ⁇ mol, 4.00 eq). The mixture was stirred at 20°C for 18h to give a yellow solution.
• the product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 23%-53%, 10 min) to give K101-C1351 (3.80 mg, 7.26 ⁇ mol, 20.95% yield, 100% purity, TFA salt) as a white solid.
• reaction solution was stirred at 0°C for 15 minutes and 15 °C for 2 hours to give a brown solution.
• LCMS showed the reaction was completed and the desired MS was observed.
• the reaction solution was combined with ES5329-254 (10 mg of K101-C20Tr-B was used in this batch) and diluted with DCM (5 mL), washed with 0.1 M HCl solution (5 mL x 2), brine (1 mL), dried over anhydrous Na 2 SO 4 , filtered, concentrated under reduced pressure to give the crude product as a brown gum.
• the product was purified by prep-HPLC (column: Phenomenex Gemini 150*25mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 35%-65%,10min) to give K101-C1353 (5.30 mg, 30.74% yield, 99.2% purity) as a white solid after lyophilization.
• the product is a mixture of two isomers as shown in the synthetic scheme with a ratio of about 1:1 based on NMR and HPLC.
• Example 51 Synthesis Scheme of K101-C1354.
• the scheme for synthesis of compound K101-C1354 is illustrated below.
• Preparation of Compound C13-54-B To a solution of methyl C13-54-A (499.15 mg, 2.77 mmol, 1.00 eq) in DCM (2.00 mL) was added triisopropylsilyl chloride (TIPSCl) (640.87 mg, 3.32 mmol, 712.08 uL, 1.20 eq), imidazole (565.74 mg, 8.31 mmol, 3.00 eq) and DMAP (33.84 mg, 277.00 ⁇ mol, 0.10 eq).
• TIPSCl triisopropylsilyl chloride
• Preparation of Compound K101-C1355-A Preparation of Compound K101-C1355-A: To a solution of K101-C20Tr-B (30.00 mg, 50.78 ⁇ mol, 1.00 eq) in DCM (1.00 mL) were added C13-55 (32.76 mg, 101.57 ⁇ mol, 2.00 eq) and DMAP (6.20 mg, 50.78 ⁇ mol, 1.00 eq), DCC (20.96 mg, 101.57 ⁇ mol, 20.55 uL, 2.00 eq). The mixture was stirred at 10°C for 12hr to give yellow solution.
• Example 53 Synthesis Scheme of K101-C1356.
• the scheme for synthesis of compound K101-C1356 is illustrated below.
• the mixture was stirred at 40°C for 12hr.
• the mixture was concentrated to give the crude product.
• K101-C135601 LC-MS (m/z): 600.2 [M+Na] + [0578] K101-C135601 1 H NMR (400MHz, CD 3 OD) ⁇ 7.62-7.58 (m, 3H), 7.46-7.38 (m, 2H), 5.63 (s, 1H), 3.97 (s, 2H), 3.54-3.53 (m, 1H), 3.19-3.09 (m, 2H), 2.84-2.82 (m, 2H), 2.57-2.42 (m, 2H), 2.20- 2.08 (m, 4H), 1.77 (s, 3H), 1.64-1.61 (m, 1H), 1.21 (s, 3H), 1.10 (s, 3H), 0.95-0.93 (m, 4H).
• Example 54 Synthesis Scheme of K101-C1357.
• the scheme for synthesis of compound K101-C1357 is illustrated below.
• [0582] Preparation of Compound K101-C1357-A.
• EDC 58.41 mg, 304.70 ⁇ mol, 6 eq
• DMAP 37.22 mg, 304.70 ⁇ mol, 6 eq.
• the mixture was stirred at 20°C for 16 hours to give a yellow solution.
• the reaction was complete detected by LC-MS.
• the product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10 um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 20%-50%, 10 min).
• the separated layers were lyophilized to give K101-C1358 (5.00 mg, 9.81 ⁇ mol, 21.43% yield, 92.55% purity, TFA salt) as a light yellow solid.
• Boc2O (4.76 g, 21.82 mmol, 5.01 mL, 2 eq) was added to a preparation of C13-59E (3.31 g, 10.91 mmol, 1 eq) in THF (20 mL), and the mixture stirred at 10°C for 16hr to give a yellow suspension.
• the reaction mixture was concentrated, and the resultant residue diluted with H 2 O (30 mL) and extracted with PE/MTBE (5/1, 40 mL x 3). The water layer was adjusted to pH 4 with HCl (1N) and extracted with EtOAc (50 mL x 3).
• the P1 and P2 products were purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water(0.1%TFA)-B: ACN];B%: 30%-60%, 10min) to give K101- C135901 (10.2 mg, 13.64 ⁇ mol, 25.12% yield, 100% purity, TFA) and K101-C135902 (9.8 mg, 12.53 ⁇ mol, 23.07% yield, 95.59% purity, TFA) also as white solids.
• K101-C135901 LC-MS (m/z): 656.2 [M+Na] + [0602] K101-C135901: 1 H NMR (400MHz, CD 3 OD) ⁇ 7.58-7.56 (m, 3H), 7.40-7.38 (m, 2H), 5.62- 5.61 (m, 1H), 3.99-3.92 (m, 2H) 3.58 (s, 1H), 3.18 (s, 1H), 3.09 (s, 1H), 2.74-2.71 (m, 2H), 2.52-2.42 (m, 2H), 2.19-2.05 (m, 2H), 1.77-1.67 (m, 7H), 1.40-1.39 (m, 6H), 1.19 (s, 3H), 1.10 (s, 3H), 0.93- 0.90 (m, 4H).
• K101-C135902 LC-MS (m/z): 656.2 [M+Na] + [0604] K101-C135902: 1 H NMR (400MHz, CD3OD) ⁇ 7.58-7.56 (m, 3H), 7.41-7.39 (m, 2H), 5.63- 5.62 (m, 1H), 3.99-3.95 (m, 2H) 3.50 (s, 1H), 3.19-3.15 (m, 2H), 3.09 (s, 1H), 2.75-2.71 (m, 2H), 2.57-2.42 (m, 2H), 2.13-2.05 (m, 1H), 1.77-1.68 (m, 7H), 1.41-1.40 (m, 6H), 1.19 (s, 3H), 1.09(s, 3H), 0.96-0.90 (m, 4H).
• Example 57 Synthesis Scheme of K101-C1361.
• the scheme for synthesis of K101-C1361 is illustrated below.
• [0606] Preparation of Compound C13-61A. To a solution of C13A (13.63 g, 29.81 mmol, 1 eq) in THF (50 mL) was added NaHMDS (1 M, 59.62 mL, 2 eq) at 0°C. Following stirring at 0°C for 0.5hr, 3-phenylpropanal (4 g, 29.81 mmol, 3.92 mL, 1 eq) in THF (50 mL) was added dropwise at 0°C.
• the reaction mixture was concentrated, dissolved in DCM (30 ml) and the solution adjusted to pH 8 with saturated NaHCO 3 .
• the organic layer was separated, dried over Na 2 SO 4 and concentrated to give the crude product.
• K101-C136101 LC-MS (m/z): 616.2 [M+Na] + [0616] K101-C136101: 1 H NMR (400MHz, CD 3 OD) ⁇ 7.56 (s, 1H), 7.28-7.13 (m, 5H), 5.6-5.61 (m, 1H), 3.98-3.91 (m, 2H), 3.51-3.50 (m, 1H), 3.19 (s, 1H), 3.09 (s, 1H), 2.64-2.62 (m, 2H), 2.60-2.47 (m, 2H), 2.18-2.06 (m, 2H), 1.76-1.60 (m, 8H), 1.35-1.31 (m, 10H), 1.21 (s, 3H), 1.10 (s, 3H), 0.94- 0.89 (m, 4H).
• K101-C136102 LC-MS (m/z): 616.3 [M+Na] + [0618] K101-C136102: 1 H NMR (400MHz, CD3OD) ⁇ 7.56 (s, 1H), 7.28-7.13 (m, 5H), 5.6-5.61 (m, 1H), 3.99-3.92 (m, 2H), 3.46-3.45 (m, 1H), 3.19 (s, 1H), 3.09 (s, 1H), 2.64-2.62 (m, 2H), 2.60-2.47 (m, 2H), 2.14-2.03 (m, 2H), 1.77-1.61 (m, 8H), 1.36-1.26 (m, 10H), 1.21 (s, 3H), 1.10 (s, 3H), 0.95- 0.92 (m, 4H).
• Example 58 Synthesis Scheme of K101-C1364.
• the scheme for synthesis of K101-C1364 is illustrated below.
• [0620] Preparation of Compound K101-C1364-A. To a solution of K101-C20Tr-B (30 mg, 50.78 ⁇ mol, 1 eq) and C13-64 (36.23 mg, 126.96 ⁇ mol, 2.5 eq) in DCM (1 mL) were added EDC (48.68 mg, 253.92 ⁇ mol, 5 eq) and DMAP (18.61 mg, 152.35 ⁇ mol, 3 eq). The mixture was stirred at 20°C for 5hr to give a pale yellow solution. The reaction was complete as detected by LC-MS.
• Example 59 Synthesis Scheme of K101-C1365.
• the scheme for synthesis of K101-C1365 is illustrated below.
• [0625] Preparation of Compound K101-C1365. To a solution of K101-C1327 (5.00 mg, 9.97 ⁇ mol, 1 eq) in CH3CN (0.5 mL) were added formaldehyde (8.09 mg, 99.67 ⁇ mol, 7.42 uL, 10 eq) and AcOH (598.54 ug, 9.97 ⁇ mol, 0.57 uL, 1 eq).
• the product was further purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.05% HCl)-B: ACN]; B%: 20%-50%, 10min) to give K101-C1365 (1.5 mg, 2.83 ⁇ mol, 20.29% yield) as a white solid.
• K101-C137002 LC-MS (m/z): 638.6 [M+Na] + [0634] K101-C137002 1 H NMR (400MHz, CD3OD) ⁇ 7.56 (s, 1H), 7.46-7.44 (m, 2H), 7.33-7.31 (m, 2H), 6.87-6.58 (m, 1H), 5.63 (s, 1H), 3.99 (s, 2H), 3.54-3.50 (m, 1H), 3.19 (s, 1H), 3.09 (s, 1H), 2.71- 2.67 (m, 2H), 2.52-2.47 (m, 2H), 1.76-1.39 (m, 11H), 1.20 (s, 3H), 1.09 (s, 3H), 0.95-0.90 (m, 4H).
• Example 61 Synthesis Scheme of K101-C1373. [0635] The scheme for synthesis of K101-C1373 is illustrated below.
• Example 62 Synthesis Scheme of K101-C1375.
• the scheme for synthesis of K101-C1375 is illustrated below.
• [0650] Preparation of Compound BB-C1375. To a solution of C1375-A (50 mg, 203.56 ⁇ mol, 1 eq, HCl) in THF (2 mL)/H2O (1 mL) were added NaHCO3 (42.75 mg, 508.90 ⁇ mol, 19.79 uL, 2.5 eq) and Boc 2 O (53.31 mg, 244.27 ⁇ mol, 56.12 uL, 1.2 eq) at 0°C. The mixture was stirred at 20°C for 12hr to give a yellow solution.
• the mixture was concentrated to give the crude product, which was dissolved in MBTE (20 mL) and washed with saturated NaHCO3 (10 mL). The organic layer was separated, and the water layer extracted with MBTE (20 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product.
• Example 65 Compound Binding to C1b Domain of PKC Isoforms
• Compounds described in this disclosure were tested for binding affinity to C1b domain of PKC isoforms.
• Compound binding affinity to C1b domain of PKC isoforms was derived from competitive binding assay using radioactive tracer 3 H-PDBu and recombinant GST-C1b or full-length of human PKC proteins based on modified procedures from Methods in Molecular Biology, vol.233: Protein Kinase C Protocols Edited by: A. C. Newton, Humana Press Inc., Totowa, NJ (2003) and Beans et al., Proc Natl Acad Sci U S A.2013, 110(29):11698-703.
• the plate was incubated at 37 0 C on a shaker at 300rpm for 10 minutes and then put on ice for 20 minutes.
• the reaction mixtures were filtered through the GF/B filter plate (PE-6005177) and the plate was washed with the wash buffer (20mM Tris-HCl pH7.4, stored at 4 0 C) for 6 times before drying at 50 0 C for 1 hour.
• the bottom of the filter plate was sealed and 50 ⁇ L of MicroScint-20 (PerkinElmer) cocktail was added to each well. 3 H- PDBu trapped in each well was counted using PerkinElmer MicroBeta2 Reader. Data were analyzed using GraphPad Prism5 with the model “log(inhibitor) vs.
• Ki IC50/(1+added radio ligand/Kd).
• Kd is the binding affinity of each protein preparation to 3 H-PDBu, determined experimentally. Unrelated protein made in similar expression system did not have specific binding to 3 H-PDBu. Ki values of Diterpenoid compounds for human PKC ⁇ , ⁇ , ⁇ , ⁇ , and PKD1 (PKC ⁇ ) were reported in Table 3.
• NT Not tested
• Example 66 Western Blot to Assess Activation of PKC and Downstream Target Protein by the Diterpenoid Compounds [0682]
• A549 lung cancer cells ( ⁇ 3 million cells) were seeded in 10cm tissue culture dishes (or ⁇ 1 million cells in 6cm dish) and grown overnight. Cells were then treated with different drugs at indicated concentrations for 30 minutes. Cell lysate preparation, protein quantitation, SDS-PAGE, and Western blotting procedures are described (WO/2017/083783). ⁇ -actin or Vinculin was used as loading controls.
• Imagequant LAS4000 (GE) was used to scan membranes if secondary antibodies anti-mouse IgG HRP conjugate or anti-rabbit IgG HRP conjugate (dilutions from 1:2000 – 1:10000) were used.
• manufacture For ProteinSimple Wes system, manufacture’s procedure was followed (ProteinSimple 12-230 kDa Wes Separation Module) for sample preparation, loading, running, and data analysis.
• K101-C1337 an enantiomer of K101- C1327, induced much lower levels of phosphorylation on these proteins, indicating that the stereochemistry of the moiety on the C12 is very important in determining the potency of the compound.
• Other less potent compounds such as K101-C1303, -C1315, -C1316, and -C1336, induced phosphorylation at 3 ⁇ M.
• K-101 prostratin, 1 ⁇ M was included as reference compounds.
• the results are shown in FIGS.2, 3, 4A, and 4B.
• all of these compounds demonstrated activation of PKC ⁇ , PKC ⁇ , and Erk1/2 in a dose-dependent manner in the concentration range tested.
• the relative strength of cellular PKC activation correlated well with that of binding affinity of these compounds to PKC isoforms.
• Example 67 Effect of Compounds on CaMKii Phosphorylation in PANC1 Cell Line
• Panc1 a pancreatic cancer cell line
• PANC1 pancreatic cancer cell line
• Protein quantification, SDS-PAGE, and Western blot procedures were performed as described in Example 65, except that a different lysis buffer (1ml of 10X TNE [20mL 1M Tris pH7.5; 30mL 5M NaCl; 2mL 0.5M EDTA; 48mL d2H2O], 1ml of 10% NP40, 7.7mL of dH2O, 100 ⁇ L of 10x Protease inhibitors, 100 ⁇ L of 10x Phosphatase inhibitors, and 10 ⁇ l DTT) was used.
• 10X TNE 10X TNE
• 10x Protease inhibitors 100 ⁇ L of 10x Phosphatase inhibitors
• 10 ⁇ l DTT 10 ⁇ l DTT
• Phosphorylation of CaMKii at T286 is a marker for activation of CaMKii kinase in the Wnt/Ca 2+ signaling pathway when and CaM are dissociated and thus a downstream marker for inhibition of K-Ras stemness (Wang et al., Cell.2015, 163(5):1237-51). As shown in FIG.5, all compounds induced phosphorylation of CaMKii at T286.
• Example 68 Effect of Compounds on Proliferation of A549 [0687]
• the diterpenoid compounds were tested in A549, a non-small cell lung cancer cell line harboring a K-Ras activating mutation. Briefly, A549 cells at a density of 1,000 cells/well were seeded in 96-well plates and incubated at 37°C for 24 hours. A series of different concentrations of compound stocks (500x) were prepared by 3-fold serial dilution in DMSO. These compounds were further diluted in culture media and then added to cells so that the final DMSO concentration was not exceeding 0.25%.
• TPA 12-O-Tetradecanoylphorbol-13-acetate
• PMA phorbol 12-myristate 13-acetate
• Example 69 Effect of Compounds on Proliferation of Multiple Cancer Cell Lines
• the compounds in this disclosure were tested for their potency in blocking proliferation of a few other cancer cells lines, including K-Ras mutant pancreatic cell lines Panc2.13 and KP-4, leukemia cell line HL-60, and lymphoma cell lines Namalwa and Mino. Similar procedures as in Example 67 were followed.
• PANC1 cells were harvested, re-suspended as single cell suspensions, counted and seeded into Ultra Low Attachment Culture 96-well plate (Corning, Cat#3474) at 100 cells/well in 100 ⁇ l of complete media (with 10% FBS) containing 2% Matrigel (Corning, Cat#354234) and DMSO or compounds. Six replicates per condition were seeded. The seeded cells were placed in the 37 ° C tissue culture incubator.10 ⁇ l of low serum containing media (with 0.1% FBS) was added to each well every week. Spheres formed after 3-4 weeks were counted. Sphere forming efficiency was expressed as percentage of # of spheres/# of cells seeded.
• K101 or K101A is prostratin.
• Compounds exhibiting at least 50% inhibition on the sphere forming efficiency K101-C1347 and K101-C134802 at a concentration of ⁇ 50nM; K101-C1308, K101-C1329, K101-C1345, and K101-C134801 at a concentration of ⁇ 150nM; K101 at a concentration of ⁇ 500nM; and K101-C1346 and K101-C1319 at a concentration of ⁇ 1500nM.
• Example 71 Testing Compounds in Animals – Pharmacokinetic studies [0693] Pharmacokinetic (PK) studies were conducted for compounds described in this disclosure, and the PK study of K101-C1327 administered by intravenous injection in rats is given as an example. Briefly, K101-C1327 was dissolved in a pH 5 buffer solution at the concentrations of 2.0 mg/mL, and diluted to 0.04 and 0.08 mg/mL to achieve the doses of 0.1 and 0.2 mg/kg with a dosing volume of 2.5 mL/kg, respectively. The K101-C1327 dosing solutions were administered via intravenous bolus injection in 3 rats (Sprague Dawley).
• Plasma samples were taken at 1 minute, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 7 hours, and 24 hours.
• the drug concentrations at each time point were determined by LC-MS.
• the results of drug concentrations and pharmacokinetic parameters are presented in the Table 6 and Table 7, respectively, below.
• Table 6 K101-C1327 Concentration in plasma after bolus injection in rats
• Table 7 PK parameters for K101-C1327 in rat plasma after bolus injection
• Example 71 Tumor clearance in xenograft model by intra-tumoral (IT) injected compounds
• IT intra-tumoral
• FIG.7 shows tumor growth curves of various treatment groups. IT injection of K101-K134801 resulted in complete clearance of tumors in mice. K101-C1347 cleared tumors from two out of three mice and K101-C134802 cleared tumors from one out of three mice. [0697] All publications, patents, patent applications and other documents cited in this application are hereby incorporated by reference in their entireties for all purposes to the same extent as if each individual publication, patent, patent application or other document were individually indicated to be incorporated by reference for all purposes. [0698] While various specific embodiments have been illustrated and described, it will be appreciated that various changes can be made without departing from the spirit and scope of the invention(s).

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• General Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Molecular Biology (AREA)
• Biochemistry (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Genetics & Genomics (AREA)
• Biophysics (AREA)
• Pulmonology (AREA)
• Oncology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Hematology (AREA)
• Engineering & Computer Science (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pyridine Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Priority Applications (9)

Applications Claiming Priority (2)

Publications (1)

Family

ID=75165333

Family Applications (1)

Country Status (9)

Cited By (2)

Families Citing this family (2)

Citations (4)

Family Cites Families (5)

• 2020
  • 2020-09-24 IL IL291697A patent/IL291697B2/en unknown
  • 2020-09-24 AU AU2020352641A patent/AU2020352641A1/en active Pending
  • 2020-09-24 JP JP2022519324A patent/JP7753201B2/ja active Active
  • 2020-09-24 US US17/763,611 patent/US20220411362A1/en active Pending
  • 2020-09-24 WO PCT/US2020/052545 patent/WO2021062030A1/en not_active Ceased
  • 2020-09-24 CN CN202080081644.1A patent/CN114786697A/zh active Pending
  • 2020-09-24 KR KR1020227013445A patent/KR20220116143A/ko active Pending
  • 2020-09-24 EP EP20867438.2A patent/EP4041268A4/en active Pending
  • 2020-09-24 CA CA3155650A patent/CA3155650A1/en active Pending
• 2025
  • 2025-10-01 JP JP2025165441A patent/JP2025186528A/ja active Pending

Patent Citations (4)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events