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WO2018031680A1 - Nouveaux composés, leurs utilisations et procédés de préparation - Google Patents

Nouveaux composés, leurs utilisations et procédés de préparation Download PDF

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Publication number
WO2018031680A1
WO2018031680A1 PCT/US2017/046138 US2017046138W WO2018031680A1 WO 2018031680 A1 WO2018031680 A1 WO 2018031680A1 US 2017046138 W US2017046138 W US 2017046138W WO 2018031680 A1 WO2018031680 A1 WO 2018031680A1
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Prior art keywords
optionally substituted
compound
solvate
pharmaceutically acceptable
stereoisomer
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Inventor
Bohan Jin
Qing Dong
Gene Hung
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Fronthera US Pharmaceuticals LLC
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Fronthera US Pharmaceuticals LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • 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
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/83—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • 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
    • 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
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring

Definitions

  • An adequate supply of oxygen to tissues is essential in maintaining mammalian cell function and physiology.
  • a deficiency in oxygen supply to tissues is a characteristic of a number of pathophysiologic conditions in which there is insufficient blood flow to provide adequate oxygenation, for example, ischemic disorders, cancer, and atherosclerosis.
  • the hypoxic (low oxygen) environment of tissues activates a signaling cascade that drives the induction or repression of the transcription of a multitude of genes implicated in events such as angiogenesis (neo-vascularization), glucose metabolism, and cell survival/death.
  • a key to this hypoxic transcriptional response lies in the transcription factors, the hypoxia-inducible factors (HIF).
  • HIFs are disregulated in a vast array of cancers through hypoxia-dependent and independent mechanisms and expression is associated with poor patient prognosis.
  • Hypoxia inducible factors including HIF- ⁇ and HIF -2a
  • HIF proteins are transcription factors that mediate cellular responses to diminished oxygen supply. These proteins become stabilized under hypoxia (low oxygen) and subsequently activate the expression of genes to facilitate cell survival and proliferation.
  • HIF proteins are activated in many types of cancers and have been implicated in cancer initiation, progression, and metastasis.
  • the role of HIF -2a is particularly important in clear cell renal cell carcinoma (ccRCC).
  • ccRCC clear cell renal cell carcinoma
  • pVHL tumor suppressor von Hippel-Lindau protein
  • HIF-2a protein has been detected in various human tumors of the bladder, breast, colon, liver, ovaries, pancreas, prostate, and kidney as well as tumor-associated macrophages.
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • L is a bond or -CR 7 R 8 -;
  • X is -0-, -S-, or - R X ;
  • Z is -0-, -S-, or - R Z ;
  • Y 2 is N or CR 2 ;
  • heterocycloalkyl optionally substituted aryl, or optionally substituted heteroaryl
  • R 5 is halogen
  • heterocycloalkyl optionally substituted aryl, or optionally substituted heteroaryl
  • heterocycloalkyl optionally substituted aryl, or optionally substituted heteroaryl
  • each R is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted Ci-C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted Ci-C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
  • each R c and R d are independently hydrogen, optionally substituted Ci-C 6 alkyl,
  • n is 1-3;
  • n 1-4;
  • p 1-6.
  • L is -CR 7 R 8 -; and R 7 and R 8 are independently hydrogen, halogen, or Ci-C 6 alkyl.
  • L is -CR 7 R 8 -; and R 7 and R 8 are independently hydrogen, halogen, or Ci-C 6 alkyl.
  • L is a bond.
  • n 1 or 2.
  • Y 1 is CR 1 ; and Y 2 is CR 2 .
  • Y 1 is N; and Y 2 is CR 2 .
  • Y 1 is CR 1 ; and Y 2 is N.
  • p is 1-3.
  • the compound of Formula (A) is of Formula (Al):
  • pi is 1-3.
  • pi is 1 or 2.
  • X is - R X -; and R x is hydrogen or Ci-C 6 alkyl.
  • X is -S-.
  • X is -0-.
  • Z is -0-.
  • the compound of Formula (A) or Formula (Al) is of Formula (A2):
  • R 5 is halogen
  • p2 is 1 or 2.
  • R 5 is fluoro
  • p2 is 1.
  • Ring A is cycloalkyl selected from cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of a compound of Formula (A), (Al), or (A2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is phenyl. In some embodiments of a compound of Formula (A), (Al), or (A2) or a
  • Ring A is heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperizanyl, tetrahydropyranyl, or tetrahydrofuranyl.
  • Ring A is heteroaryl selected from pyridinyl, pyrimidyl, pyrazinyl, or pyridazinyl.
  • each R 4 is independently hydrogen, halogen, or -CN; and m is 1 or 2.
  • R 1 and R 2 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • R 3 is a 5- membered heteroaryl.
  • each R 6 is independently hydrogen, halogen, or -OR a .
  • each R a is independently hydrogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • each R is independently Ci-C 6 alkyl or Ci-C 6 haloalkyl.
  • each R c and R d are independently hydrogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • Li is a bond or -CR 17 R 18 -;
  • Xi is -0-, -S-, or - R X1 ;
  • Wi is N or CR 11 ;
  • W 2 is N or CR 12 ;
  • heterocycloalkyl optionally substituted aryl, or optionally substituted heteroaryl
  • R 15 is halogen
  • heterocycloalkyl optionally substituted aryl, or optionally substituted heteroaryl
  • heterocycloalkyl optionally substituted aryl, or optionally substituted heteroaryl
  • each R a is independently hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted Ci-C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted Ci-C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
  • each R c and R d is independently hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted Ci-C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or R c and R d together with the nitrogen atom to which they are attached form an
  • s is 1-3;
  • u is 1-4;
  • w is 1-4;
  • v 1-6.
  • Li is -CR R -; and R and R are independently hydrogen, halogen, or Ci-C 6 alkyl.
  • Li is a bond.
  • s is 1 or 2.
  • Wi is CR 11 ; and W 2 is CR 12 .
  • Wi is N; and W 2 is CR 12 .
  • Wi is CR 11 ; and W 2 is N.
  • v is 1-3
  • the compound of Formula (B) is of Formula (Bl): (Formula Bl)
  • vl is 1-4.
  • vl is 1 or 2.
  • X 1 is - R x1 -; and R xl is hydrogen or Ci-C 6 alkyl.
  • X 1 is -S-.
  • Xi is -0-.
  • R 15 is halogen
  • v2 is 1 or 2.
  • R 15 is fluoro.
  • v2 is 1.
  • Ring B is cycloalkyl selected from cyclobutyl, cyclopentyl, or cyclohexyl.
  • Ring B is phenyl.
  • Ring B is heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperizanyl, tetrahydropyranyl, or tetrahydrofuranyl.
  • Ring B is heteroaryl selected from pyridinyl, pyrimidyl, pyrazinyl, or pyridazinyl.
  • each R 14 is independently hydrogen, halogen, or -CN; and u is 1 or 2.
  • Ring C is a 5- or 6-membered heteroaryl.
  • Ring C is a 5-membered heteroaryl selected from pyrrolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, or pyrazolyl.
  • Ring C is a cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • Ring C is a heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperizanyl, tetrahydropyranyl, or tetrahydrofuranyl.
  • each R 19 is independently hydrogen, halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 hydroxyalkyl; and w is 1 or 2.
  • R 11 and R 12 are independently hydrogen or halogen.
  • each R 16 is independently hydrogen, halogen, or -OR a .
  • each R a is independently hydrogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • each R is independently Ci-C 6 alkyl or Ci-C 6 haloalkyl.
  • each R c and R d are independently hydrogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • composition comprising an effective amount of a compound disclosed herein and a pharmaceutically acceptable excipient.
  • Also disclosed herein is a method of treating cancer comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutical composition disclosed herein.
  • the cancer is glioblastoma.
  • Also disclosed herein is a method for modulating the activity of HIF-2a comprising administering an effective amount of a compound or a pharmaceutical composition disclosed herein.
  • VUL Von Hippel-Lindau
  • the subject also suffers from a hemangioblastoma, a pheochromocytoma, a pancreatic neuroendocrine tumor, a renal cell carcinoma, or any combinations thereof.
  • the subject suffers from renal cell carcinoma.
  • the renal cell carcinoma is clear cell renal cell carcinoma.
  • Also disclosed herein is a method of treating renal cell carcinoma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutical composition disclosed herein.
  • Also disclosed herein is a method of treating pulmonary arterial hypertension (PAH), comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutical composition disclosed herein.
  • PAH pulmonary arterial hypertension
  • Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein.
  • the foregoing techniques and procedures can be generally performed of conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification.
  • Alkyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or from one to six carbon atoms, wherein a sp3 -hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond.
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2 -m ethyl- 1 -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3- methyl-1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l -propyl, 2-methyl-l-pentyl, 3 -methyl- 1-pentyl, 4-methyl- 1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l - butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl
  • a numerical range such as "Ci-C 6 alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated.
  • the alkyl is a Ci-Cio alkyl, a C1-C9 alkyl, a Ci-C 8 alkyl, a C1-C7 alkyl, a Ci-C 6 alkyl, a C1-C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a Ci-C 2 alkyl, or a Ci alkyl.
  • an alkyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, - CF 3 , -OH, -OMe, - H 2 , or -N0 2 .
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • Alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein an sp2-hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond.
  • the group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers.
  • a numerical range such as "C 2 - C 6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl" where no numerical range is designated.
  • the alkenyl is a C 2 -Cio alkenyl, a C 2 -Cg alkenyl, a C 2 -C 8 alkenyl, a C 2 -C 7 alkenyl, a C 2 -C 6 alkenyl, a C 2 -C 5 alkenyl, a C 2 -C 4 alkenyl, a C 2 -C 3 alkenyl, or a C 2 alkenyl.
  • an alkenyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • Alkynyl refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like.
  • C2-C6 alkynyl means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl” where no numerical range is designated.
  • the alkynyl is a C 2 - Cio alkynyl, a C 2 -Cg alkynyl, a C 2 -C 8 alkynyl, a C 2 -C 7 alkynyl, a C 2 -C 6 alkynyl, a C 2 -C 5 alkynyl, a C 2 -C 4 alkynyl, a C 2 -C 3 alkynyl, or a C 2 alkynyl.
  • an alkynyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl,
  • an alkynyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, - H 2 , or -N0 2 .
  • an alkynyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 . In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, - OMe, -NH 2 , or -N0 2 . In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6- to 10-membered aryl.
  • the aryl is a 6-membered aryl.
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, ple
  • the aryl is phenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, - H 2 , or -N0 2 . In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • Cycloalkyl refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C 3 -C 10 cycloalkyl), from three to eight carbon atoms (C 3 -C 8 cycloalkyl), from three to six carbon atoms (C 3 -C 6 cycloalkyl), from three to five carbon atoms (C 3 -C 5 cycloalkyl), or three to four carbon atoms (C 3 -C 4 cycloalkyl).
  • the cycloalkyl is a 3- to 6-membered cycloalkyl.
  • the cycloalkyl is a 5- to 6-membered cycloalkyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl,
  • cyclo[3.3.0]octane bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, - OMe, -NH 2 , or -N0 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichlorom ethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,
  • Heterocycloalkyl refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl.
  • the heterocycloalkyl is a 5- to 6- membered heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholin
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyl s have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the
  • heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, - H 2 , or -N0 2 .
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a Ci-C 6 heteroalkyl.
  • a Heteroalkyl is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • Heteroaiyl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur, and at least one aromatic ring.
  • the heteroaiyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaiyl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaiyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized.
  • the heteroaiyl is a 5- to 10-membered heteroaiyl.
  • the heteroaiyl is a 5- to 6-membered heteroaryl.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,
  • benzopyranonyl benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl,
  • a heteroaryl is optionally substituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, - CF 3 , -OH, or -OMe.
  • a "cyano" group refers to a -CN group.
  • the term “optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from Ci-C 6 alkyl, C 3 -C 8 cycloalkyl, aryl, heteroaryl, C 2 -C 6 heteroalicyclic, hydroxy, Ci-C 6 alkoxy, aryloxy, Ci-C 6 alkylthio, arylthio, Ci-C 6 alkylsulfoxide, arylsulfoxide, Ci-C 6 alkylsulfone, arylsulfone, cyano, halo, C 2 -C 8 acyl, C 2 -C 8 acyloxy, nitro, Ci-C 6 haloalkyl, Ci-Cefluoroalkyl, and amino, including Ci-C 6 alkylamino, and
  • amelioration of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.
  • module means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • a modulator refers to a compound that alters an activity of a molecule.
  • a modulator can cause an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of the activity in the absence of the modulator.
  • a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molecule.
  • an inhibitor completely prevents one or more activities of a molecule.
  • a modulator is an activator, which increases the magnitude of at least one activity of a molecule.
  • the presence of a modulator results in an activity that does not occur in the absence of the modulator.
  • target activity refers to a biological activity capable of being modulated by a selective modulator.
  • Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, inflammation or inflammation-related processes, and amelioration of one or more symptoms associated with a disease or condition.
  • cancer refers to an abnormal growth of cells, which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread).
  • types of cancer include, but is not limited to, solid tumors (such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organ (thyroid), prostate, skin (melanoma) or hematological tumors (such as the leukemias). See, Ding X Z et al., Anticancer Drugs. 2005 June; 16(5):467-73. Review; Chen X et al., Clin Cancer Res. 2004 Oct. 1; 10(19):6703-9, each of which are incorporated by reference herein in their entirety.
  • carrier refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.
  • co-administration are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • dilute refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffered solutions (which also can provide pH control or maintenance) are utilized as diluents in the art, including, but not limited to a phosphate buffered saline solution.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
  • the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • pharmaceutically acceptable refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • subject or “patient” encompasses mammals and non-mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non- human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non- mammals include, but are not limited to, birds, fish and the like.
  • the mammal is a human.
  • treat include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; L is a bond or -CR 7 R 8 -;
  • X is -0-, -S-, or - R X ;
  • Z is -0-, -S-, or - R Z ;
  • Y 2 is N or CR 2 ;
  • heterocycloalkyl optionally substituted aryl, or optionally substituted heteroaryl
  • heterocycloalkyl optionally substituted aryl, or optionally substituted heteroaryl
  • R 5 is halogen
  • heterocycloalkyl optionally substituted aryl, or optionally substituted heteroaryl
  • each R is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted Ci-C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted Ci-C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
  • each R c and R d are independently hydrogen, optionally substituted Ci-C 6 alkyl,
  • n is 1-3;
  • n 1-4;
  • p 1-6.
  • L is -CR 7 R 8 -; and R 7 and R 8 are independently hydrogen, halogen, -CN, -OR a , optionally substituted Ci-C 6 alkyl, or optionally substituted Ci-C 6 heteroalkyl.
  • L is - CR 7 R 8 -; and R 7 and R 8 are independently hydrogen, halogen, or optionally substituted Ci-C 6 alkyl.
  • L is -CR 7 R 8 -; and R 7 and R 8 are independently hydrogen, halogen, or Ci-C 6 alkyl.
  • L is -CR 7 R 8 -; and R 7 and R 8 are hydrogen.
  • L is a bond.
  • n is 1 or 2. In some embodiments of a compound of Formula (A), n is 1. In some embodiments of a compound of Formula (A), n is 2. In some embodiments of a compound of Formula (A), n is 3.
  • Yi is CR 1 ; and Y 2 is CR 2 .
  • Yi is N; and Y 2 is CR 2 .
  • Y 1 is CR 1 ; and Y 2 is N.
  • p is 1-3. In some embodiments of a compound of Formula (A), p is 1 or 2. In some embodiments of a compound of Formula (A), p is 1. In some embodiments of a compound of Formula (A), p is 2. In some embodiments of a compound of Formula (A), p is 3. In some embodiments of a compound of Formula (A), p is 4. In some embodiments of a compound of Formula (A), p is 5. In some embodiments of a compound of Formula (A), p is 6.
  • the compound of Formula (A) has the structure of Formula (Al):
  • pi is 1-3.
  • pi is 1 or 2.
  • pi is 1. In some embodiments of a compound of Formula (Al), pi is 2. In some embodiments of a compound of Formula (Al), pi is 3.
  • X is - R X -; and R x is hydrogen or Ci-C 6 alkyl.
  • X is - R X -; and R x is hydrogen.
  • X is -S-.
  • X is -0-.
  • Z is - R Z -; and R z is Ci-C 6 alkyl or hydrogen.
  • Z is -S-.
  • Z is -0-.
  • the compound of Formula (A) or Formula (Al) has the structure of Formula (A2):
  • R 5 is halogen
  • p2 is 1 or 2.
  • R 5 is fluoro, chloro, bromo, or iodo. In some embodiments of a compound of Formula (A2), R 5 is fluoro.
  • p2 is 1. In some embodiments of a compound of Formula (A2), p2 is 2.
  • Ring A is cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is cycloalkyl selected from cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is cyclopropyl. In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is cyclobutyl.
  • Ring A is cyclopentyl. In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is cyclohexyl.
  • Ring A is aryl. In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is phenyl or naphthyl. In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is phenyl.
  • Ring A is heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperizanyl, morpholinyl, dioxanyl, oxetanyl, tetrahydropyranyl, or tetrahydrofuranyl.
  • Ring A is heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperizanyl, tetrahydropyranyl, or
  • Ring A is tetrahydrofuranyl.
  • Ring A is tetrahydropyranyl.
  • Ring A is a heteroaryl.
  • Ring A is a monocyclic heteroaryl.
  • Ring A is a 6- membered heteroaryl or a 5-membered heteroaryl. In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is a 6-membered heteroaryl. In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is selected from pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, or triazinyl. In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is selected from pyridinyl, pyrimidyl, pyrazinyl, or pyridazinyl.
  • Ring A is a 5- membered heteroaryl.
  • Ring A is imidazolyl, pyrazolyl, triazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl.
  • Ring A is a bicyclic heteroaryl.
  • Ring A is indolyl, indolinyl, indazolyl, indolizinyl, benzimidazolyl, azaindolyl, benzofuranyl, benzothiophenyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl,
  • m is 1 or 2. In some embodiments of a compound of Formula (A), (Al), or (A2), m is 1-3. In some embodiments of a compound of Formula (A), (Al), or (A2), m is 1-3. In some embodiments of a compound of Formula (A), (Al), or (A2), m is 1-3. In some
  • m is 1. In some embodiments of a compound of Formula (A), (Al), or (A2), m is 2. In some embodiments of a compound of Formula (A), (Al), or (A2), m is 3. In some embodiments of a compound of Formula (A), (Al), or (A2), m is 4.
  • each R 4 is independently hydrogen, halogen, or -CN.
  • R 1 and R 2 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (A), (Al), or (A2), R 1 and R 2 are hydrogen.
  • R 3 is a monocyclic heteroaryl. In some embodiments of a compound of Formula (A), (Al), or (A2), R 3 is a 6-membered heteroaryl or a 5-membered heteroaryl. In some embodiments of a compound of Formula (A), (Al), or (A2), R 3 is a 6-membered heteroaryl. In some embodiments of a compound of Formula (A), (Al), or (A2), R 3 is selected from pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, or triazinyl.
  • R 3 is a 5- membered heteroaryl.
  • R 3 is imidazolyl, pyrazolyl, triazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl.
  • R 3 is a bicyclic heteroaryl.
  • R 3 is indolyl, indolinyl, indazolyl, indolizinyl, benzimidazolyl, azaindolyl, benzofuranyl, benzothiophenyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinoxalinyl, 1,8- naphthyridinyl, or pteridinyl.
  • each R 6 is independently hydrogen, halogen, -CN, -OR a , -NR c R d ,or optionally substituted Ci-C 6 alkyl.
  • each R 6 is independently hydrogen, halogen, -OR a ,or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (A), (Al), or (A2), each R 6 is independently hydrogen, halogen, or -OR a . In some embodiments of a compound of Formula (A), (Al), or (A2), R 6 is - OR a . [00121] In some embodiments of a compound of Formula (A), (Al), or (A2), R 5 is fluoro, chloro, bromo, or iodo. In some embodiments of a compound of Formula (A), (Al), or (A2), R 5 is fluoro.
  • each R a is independently hydrogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (A), (Al), or (A2), each R a is hydrogen.
  • each R is independently Ci-C 6 alkyl or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (A), (Al), or (A2), each R is independently C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. In some embodiments of a compound of Formula (A), (Al), or (A2), each R is independently Ci-C 6 alkyl or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (A), (Al), or (A2), each R is independently C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. In some
  • each R is independently -CH 3 , - CH 2 F, -CHF 2 , or -CF 3 .
  • each R c and R d are independently hydrogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • Li is a bond or -CR 17 R 18 -;
  • Xi is -0-, -S-, or - R X1 ;
  • W 2 is N or CR 12 ;
  • R 15 is halogen
  • heterocycloalkyl optionally substituted aryl, or optionally substituted heteroaryl
  • heterocycloalkyl optionally substituted aryl, or optionally substituted heteroaryl
  • each R a is independently hydrogen, optionally substituted Ci-C 6 alkyl, optionally
  • each R is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted Ci-C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted Ci-C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
  • each R c and R d is independently hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted Ci-C 6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or R c and R d together with the nitrogen atom to which they are attached form an
  • s is 1-3;
  • u is 1-4;
  • w is 1-4;
  • v 1-6.
  • Li is -CR R -; and R and R are independently hydrogen, halogen, -CN, -OR a , optionally substituted Ci-C 6 alkyl, or optionally substituted Ci-C 6 heteroalkyl.
  • R and R are independently hydrogen, halogen, -CN, -OR a , optionally substituted Ci-C 6 alkyl, or optionally substituted Ci-C 6 heteroalkyl.
  • Li is -CR R ; and R and R are independently hydrogen, halogen, or Ci-C 6 alkyl. In some
  • Li is -CR R -; and R and R are hydrogen. In some embodiments of a compound of Formula (B), Li is a bond.
  • s is 1 or 2.
  • s is 1. In some embodiments of a compound of Formula (B), s is 1. In some embodiments of a compound of
  • Formula (B), s is 2. In some embodiments of a compound of Formula (B), s is 3.
  • Wi is CR 11 ; and W 2 is CR 12 .
  • Wi is N; and W 2 is CR 12 .
  • Wi is CR 11 ; and W 2 is N.
  • v is 1-4. In some embodiments of a compound of Formula (B), v is 1-3. In some embodiments of a compound of Formula (B), v is 1 or 2. In some embodiments of a compound of Formula (B), v is 1. In some embodiments of a compound of Formula (B), v is 2. In some embodiments of a compound of Formula (B), v is 3. In some embodiments of a compound of Formula (B), v is 4. In some embodiments of a compound of Formula (B), v is 5. In some embodiments of a compound of Formula (B), v is 6.
  • the compound of Formula (B) has the structure of Formula (Bl): (Formula Bl)
  • vl is 1-4.
  • vl is 1 or 2. In some embodiments of a compound of Formula (Bl), vl is 1. In some embodiments of a compound of Formula (Bl), vl is 2. In some embodiments of a compound of Formula (Bl), vl is 3. In some embodiments of a compound of Formula (Bl), vl is 4.
  • Xi is - R X1 -; and R X1 is hydrogen or optionally substituted Ci-C 6 alkyl.
  • Xi is - R X1 -; and R X1 is hydrogen or Ci-C 6 alkyl.
  • X 1 is - R X1 -; and R X1 is hydrogen.
  • Xi is -S-.
  • Xi is -0-.
  • the compound of Formula (B) or Formula (Bl) has the structure of Formula (B2):
  • R 15 is halogen
  • v2 is 1 or 2.
  • R 15 is fluoro, chloro, bromo, or iodo. In some embodiments of a compound of Formula (B2), R 15 is fluoro [00135] In some embodiments of a compound of Formula (B2), v2 is 1. In some embodiments of a compound of Formula (B2), v2 is 2.
  • Ring B is cycloalkyl selected from cyclyopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is cycloalkyl selected from cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is cyclopropyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is cyclobutyl.
  • Ring B is cyclopentyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is cyclohexyl.
  • Ring B is phenyl or naphtyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is phenyl.
  • Ring B is heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperizanyl, morpholinyl, dioxanyl, oxetanyl, tetrahydropyranyl, or tetrahydrofuranyl.
  • Ring B is heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperizanyl, tetrahydropyranyl, or
  • Ring B is tetrahydropyranyl.
  • Ring B is a heteroaryl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is a monocyclic heteroaryl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is a 6-membered heteroaryl or a 5-membered heteroaryl.
  • Ring B is a 6- membered heteroaryl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is selected from pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, or triazinyl. In some
  • Ring B is selected from pyridinyl, pyrimidyl, pyrazinyl, or pyridazinyl.
  • Ring B is a 5- membered heteroaryl.
  • Ring B is imidazolyl, pyrazolyl, triazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl.
  • Ring B is a bicyclic heteroaryl.
  • Ring B is indolyl, indolinyl, indazolyl, indolizinyl, benzimidazolyl, azaindolyl, benzofuranyl, benzothiophenyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl,
  • u is 1 or 2. In some embodiments of a compound of Formula (B), (Bl), or (B2), u is 1-3. In some embodiments of a compound of Formula (B), (Bl), or (B2), u is 1-3. In some embodiments of a compound of Formula (B), (Bl), or (B2), u is 1-3. In some embodiments of a compound of Formula (B), (Bl), or (B2), u is 1-3. In some
  • u is 1. In some embodiments of a compound of Formula (B), (Bl), or (B2), u is 2. In some embodiments of a compound of Formula (B), (Bl), or (B2), u is 3. In some embodiments of a compound of Formula (B), (Bl), or (B2), u is 4.
  • each R 14 is independently hydrogen, halogen, or -CN.
  • Ring C is a monocycyclic heteroaryl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring C is a 6-membered heteroaryl or a 5-membered heteroaryl.
  • Ring C is a 6- membered heteroaryl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring C is selected from pyridinyl, pyrimidyl, pyrazinyl, or pyridazinyl, or triazinyl.
  • Ring C is a 5- membered heteroaryl.
  • Ring C is imidazolyl, pyrazolyl, triazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl.
  • Ring C is a 5-membered heteroaryl selected from pyrrolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, or pyrazolyl.
  • Ring C is pyrrolyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring C is thienyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring C is furyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring C is isothiazolyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring C is pyrazolyl.
  • Ring C is a bicyclic heteroaryl.
  • Ring C is indolyl, indolinyl, indazolyl, indolizinyl, benzimidazolyl, azaindolyl, benzofuranyl, benzothiophenyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, 1,8-naphthyridinyl, or pteridinyl.
  • Ring C is a cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring C is cyclopropyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring C is cyclobutyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring C is cyclopentyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring C is cyclohexyl.
  • Ring C is a heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperizanyl, tetrahydropyranyl, or tetrahydrofuranyl.
  • w is 1 or 2. In some embodiments of a compound of Formula (B), (Bl), or (B2), w is 1. In some embodiments of a compound of Formula (B), (Bl), or (B2), w is 2. In some embodiments of a compound of Formula (B), (Bl), or (B2), w is 3. In some embodiments of a compound of Formula (B), (Bl), or (B2), w is 4.
  • each R 19 is independently hydrogen, halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or Ci-C 6 hydroxyalkyl.
  • each R 19 is independently hydrogen, fluoro, chloro, bromo, iodo, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 F, -CHF 2 , -CF 3 , - CH 2 CF 3 , -CH 2 OH, -CH(CH 3 )OH, or -CH 2 CH 2 OH.
  • each R 19 is independently hydrogen, fluoro, -CH 3 , -CH 2 CH 3 , - CH(CH 3 ) 2 , -CHF 2 , or -CH 2 OH.
  • R 11 and R 12 are independently hydrogen, halogen, or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), R 11 and R 12 are independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), R 11 and R 12 are independently hydrogen or halogen. In some embodiments of a compound of Formula (B), (Bl), or (B2), R 11 and R 12 are hydrogen.
  • each R 16 is independently hydrogen, halogen, -CN, -OR a , -NR c R d ,or optionally substituted Ci-C 6 alkyl.
  • each R 16 is independently hydrogen, halogen, -OR a ,or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), each R 16 is independently hydrogen, halogen, or -OR a . In some embodiments of a compound of Formula (B), (B l), or (B2), each R 16 is -OR a .
  • R 15 is fluoro, chloro, bromo, or iodo. In some embodiments of a compound of Formula (B), (B l), or (B2), R 15 is fluoro.
  • each R a is independently hydrogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (B), (B l), or (B2), each R a is hydrogen.
  • each R is independently Ci-C 6 alkyl or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (B), (B l), or (B2), each R is independently C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. In some embodiments of a compound of Formula (B), (B l), or (B2), each R is independently C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. In some
  • each R is independently -CH 3 , - CH 2 F, -CHF 2 , or -CF 3 .
  • each R c and R d are independently hydrogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • Formula I independently, X is -O or - H-; Y is -CH or -N; Y can not be -CH when X is -O;
  • Formula II independently, X is -O or -NH-; Y and Z are -CH or -N; Y and Z can not both be - CH when X is -O;
  • Formula III independently, X is -O or - H-; Gl is -CH, - H, or - R 4 ;
  • Formula IV independently, X is -O or - H-; Gl and G2 are -CH, or -N; Gl and G2 can not both be -CH when X is -O; Formula IV: independently, X is -O or - H-; Gl is -CH, or -N; G2 is -CH, -N, or -CR 4 ; Gl and G2 can not both be -CH when X is -O; n is 1 or 2;
  • Ri is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with at least one halogen, nitro, cyano, alkyl, and hydroxyl;
  • R 2 is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halogen, sulfonyl, alkyl or heteroalkyl;
  • R 3 is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, alkylamino, carboxaldehyde, carboxylic acid, oxime, ester, amido, or acyl, or R 2 /R 3 and the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one sp 3 hybridized carbon, wherein the 5- or 6-membered carbocycle is optionally substituted with at least one R 3 ;
  • R 4 is nitro, halogen, cyano, alkyl, cycloalkyl, heterocycloalkyl, keto, aryl, heteroaryl, sulfinyl, sulfonamide, sulfonyl, or sulfoximinyl; wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with at least one R 3 group;
  • R 5 is hydrogen, nitro, cyano, halo, alkyl, heteroalkyl, alkynyl, or alkenyl; or R4/R5 and the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein th cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are optionally substituted with at least one R 3 group;
  • R 6 is hydrogen, hydroxyl or amino; each of R 7 is independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl and cycloalkyl, or the two R 4 groups and the carbon to which they are attached form C 3 -C 8 cycloalkyl or C 5 -C 8 heterocycloalkyl;
  • R 8 is O or R 12 , wherein Ri 2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cyano, heterocycloalkyl, heteroaryl, and heteroalkyl; and
  • R9 is hydrogen, deuterium, or alkyl.
  • Ri is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, Ri is cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, Ri is heterocycloalkyl, aryl or heteroaryl. In other embodiments, Ri is aryl or heteroaryl. In a further embodiment, Ri is phenyl. In another embodiment, Ri is pyridyl. In yet another embodiment the phenyl or pyridyl is substituted with at least one halogen, nitro, cyano, alkyl, and hydroxyl. In another embodiment, Ri is selected from cyclobutyl, cyclohexyl,
  • Ri is phenyl phenyl substituted with a halogen and a cyano.
  • the phenyl group is substituted with a halogen and a cyano at the 3 and 5 positions.
  • the halogen is a fluoro group.
  • Ri is selected from the group consisting of:
  • R 2 is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halogen, sulfonyl, alkyl or heteroalkyl.
  • R 2 is nitro, cyano, halo, alkyl, heteroalkyl, alkynyl or alkenyl.
  • R 2 iscyano, halo, or alkyl.
  • R 2 is halo or alkyl.
  • R 2 is haloalkyl.
  • R 2 is halogen.
  • R 2 is fluorine, chlorine, bromine or iodine.
  • R 2 is C 1 -C 4 fluoroalkyl.
  • R 2 is selected from -CH 2 F, CHF 2 , and -CF 2 CH 3 .
  • Representative compounds with the carbocycle include, but are not limited to, the following:
  • the carbocycle formed by linking R 2 and R 3 may be optionally substituted with fluoro, chloro, hydroxyl, alkyl, or heteroalkyl.
  • the substituent(s) is selected from the group consisting of halo, C 1 -C 4 alkyl, C1-C4 alkoxy, and cyano.
  • R 3 is hydrogen, halogen, hydroxyl, amino, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, alkylamino, carboxaldehyde, carboxylic acid, oxime, ester, amido, or acyl.
  • R 3 is hydrogen, halo, cyano, oxime, alkyl, heteroalkyl, alkenyl, alkynyl, alkyamino, or acyl.
  • R 3 is -(CH 2 ) n OH, wherein n is 1, 2, or 3.
  • R 2 is halo, cyano, or alkyl
  • R 3 is -CH20H
  • R 4 is fluoroalkyl, sulfonamide, sulfinyl, sulfonyl, or sulfoximinyl.
  • R 3 is hydroxyl or amino.
  • R 4 is selected from, but not limited to the following:
  • Representative compounds include, but are not limited to, the following:
  • heterocycle or carbocycle formed by linking R 4 and R5 may be optionally substituted with fluoro, chloro, hydroxyl, alkyl, or heteroalkyl.
  • the substituent(s) is selected fro the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and cyano.
  • R 7 is a halogen. In another embodiment, R 7 is a fluoro group. In a further embodiment R 5 is a substituted alkyl group. In a further embodiment R 5 is CHF2. In yet another embodiment, R 5 is a halogen. In yet another embodiment R 5 is a chloro group. In a further embodiment, R 6 is a hydroxyl group. In yet another embodiment, R 9 is hydrogen.
  • the compounds have the following structures, or harmaceutically acceptable salt, solvate, analog, prodrug, isomer or tautomer thereof:
  • the compounds have the following structures, or pharmaceutically acceptable salt, solvate, analog, prodrug, isomer or tautomer thereof:
  • the compound described herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:
  • the compound described herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent.
  • the compounds described herein exist in their isotopically- labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds disclosed herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • Compounds described herein, and the metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvate, hydrates or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2 H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by
  • the compounds described herein possess acidic or basic groups and therefor react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6- dioate,
  • monohydrogenphosphate 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate,
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (Ci-4 alkyl) 4 , and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the
  • the compounds described herein exist as solvates.
  • the invention provides for methods of treating diseases by administering such solvates.
  • the invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • a "metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • metabolism refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyl transferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. Further information on metabolism may be obtained from The
  • Metabolites of the compounds disclosed herein can be identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds. Both methods are well known in the art.
  • prodrugs refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • prodrug an example, without limitation, of a prodrug would be a compound described herein, which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • a prodrug upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is
  • a pharmaceutically active compound is modified such that the active compound will be regenerated upon in vivo administration.
  • the prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a derivative as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed.
  • Compounds described herein may be in various forms, including but not limited to, amorphous forms, milled forms and nano-particulate forms.
  • compounds described herein include crystalline forms, also known as polymorphs.
  • Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
  • the screening and characterization of the pharmaceutically acceptable salts, polymorphs and/or solvates may be accomplished using a variety of techniques including, but not limited to, thermal analysis, x-ray diffraction, spectroscopy, vapor sorption, and microscopy.
  • Thermal analysis methods address thermo chemical degradation or thermo physical processes including, but not limited to, polymorphic transitions, and such methods are used to analyze the relationships between polymorphic forms, determine weight loss, to find the glass transition temperature, or for excipient compatibility studies.
  • Such methods include, but are not limited to, Differential scanning calorimetry (DSC), Modulated Differential Scanning Calorimetry
  • X-ray diffraction methods include, but are not limited to, single crystal and powder diffractometers and synchrotron sources.
  • the various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UV-VIS, and NMR (liquid and solid state).
  • the various microscopy techniques include, but are not limited to, polarized light microscopy, Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis (EDX), Environmental Scanning Electron Microscopy with EDX (in gas or water vapor atmosphere), IR microscopy, and Raman microscopy.
  • compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well- known techniques, carriers, and excipients may be used as suitable and as understood in the art. A summary of pharmaceutical compositions described herein may be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa. : Mack
  • compositions that include a compound described herein and a pharmaceutically acceptable diluent(s), excipient(s), and/or carrier(s).
  • the compounds described herein can be administered as pharmaceutical compositions in which compounds described herein are mixed with other active ingredients, as in combination therapy.
  • a pharmaceutical composition refers to a mixture of a compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease or condition to be treated.
  • the mammal is a human.
  • a therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • the compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.
  • compounds described herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • appropriate formulations may include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally known in the art.
  • compounds described herein can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers or excipients well known in the art.
  • Such carriers enable the compounds described herein to be formulated as tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • compositions for oral use can be obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients include, but are not limited to, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium
  • carboxymethylcellulose or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • PVP polyvinylpyrrolidone
  • disintegrating agents may be added, such as the cross-linked
  • croscarmellose sodium polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner.
  • Parental injections may involve bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • compositions of the compounds described herein may be in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compound(s) in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the compounds described herein can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments.
  • Such pharmaceutical compounds can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • Formulations suitable for transdermal administration of compounds described herein may employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Still further, transdermal delivery of the compounds described herein can be accomplished by means of iontophoretic patches and the like. Additionally, transdermal patches can provide controlled delivery of the compounds described herein. The rate of absorption can be slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound 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 means to secure the device to the skin.
  • the compounds described herein may be in a form as an aerosol, a mist, or a powder.
  • Pharmaceutical compositions of compounds described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane,
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds described herein may also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like.
  • a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.
  • compositions may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well- known techniques, carriers, and excipients may be used as suitable and as understood in the art.
  • Pharmaceutical compositions that include a compound described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • compositions will include at least one pharmaceutically acceptable carrier, diluent and/or excipient and a compound described herein as an active ingredient in free- acid or free-base form, or in a pharmaceutically acceptable salt form.
  • methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity.
  • compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
  • cyclic compounds described herein may exist in equilibrium with open chain forms. Both forms, cyclic and open form, are included. Additionally, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • the pharmaceutical compositions may include other medicinal or
  • compositions can also contain other therapeutically valuable substances.
  • compositions that include the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid.
  • Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • Liquid compositions include solutions in which a compound is dissolved, emulsions that include a compound described herein, or a solution containing liposomes, micelles, or nanoparticles that include a compound as disclosed herein.
  • Semi-solid compositions include, but are not limited to, gels, suspensions and creams. The compositions may be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions may also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.
  • a composition that includes a compound described herein can illustratively take the form of a liquid where the agents are present in solution, in suspension, or both. Typically when the composition is administered as a solution or suspension, a first portion of the compound is present in solution and a second portion of the compound is present in particulate form, in suspension in a liquid matrix.
  • a liquid composition may include a gel formulation. In other embodiments, the liquid composition is aqueous.
  • Aqueous suspensions can also contain one or more polymers as suspending agents.
  • Useful polymers include water-soluble polymers such as cellulosic polymers, e.g.,
  • compositions can also include a mucoadhesive polymer, selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate, and dextran.
  • a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate, and dextran.
  • compositions may also include solubilizing agents to aid in the solubility of a compound described herein.
  • solubilizing agent generally includes agents that result in formation of a mi cellar solution or a true solution of the agent.
  • Certain acceptable nonionic surfactants for example polysorbate 80, can be useful as solubilizing agents, as can
  • glycols e.g., polyethylene glycol 400
  • glycol ethers e.g., glycol ethers
  • compositions may also include one or more pH adjusting agents or buffering agents, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid and hydrochloric acid; bases such as sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris- hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid and hydrochloric acid
  • bases such as sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris- hydroxymethylaminomethane
  • buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable
  • compositions may also include one or more salts in an amount required to bring osmolality of the composition into an acceptable range.
  • salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
  • compositions may also include one or more preservatives to inhibit microbial activity.
  • Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.
  • compositions may include one or more surfactants to enhance physical stability or for other purposes.
  • Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and
  • polyoxyethylene alkylethers and alkylphenyl ethers e.g., octoxynol 10, octoxynol 40.
  • compositions may include one or more antioxidants to enhance chemical stability where required.
  • Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.
  • Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.
  • multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as N-methylpyrrolidone also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds over the course of 4-24 hours.
  • additional strategies for protein stabilization may be employed.
  • All of the formulations described herein may benefit from antioxidants, metal chelating agents, thiol containing compounds and other general stabilizing agents.
  • stabilizing agents include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1%) to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v.
  • the compounds described herein can be used in the preparation of medicaments for the treatment or prevention of a specific disease or condition.
  • a method for treating any of the diseases or conditions described herein in a subject in need of such treatment involves administration of pharmaceutical compositions containing at least one compound described herein or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide,
  • compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. It is considered well within the skill of the art for one to determine such
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition.
  • a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition is defined to be a "prophylactically effective amount or dose.
  • prophylactically effective amounts or dose are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition.
  • prophylactically effective amounts or dose is defined to be a "prophylactically effective amount or dose.
  • dose escalation clinical trial.
  • effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • the administration of the compounds described herein may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.
  • the administration of the compounds described herein may be given continuously; alternatively, the dose of the compounds described herein being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday").
  • the length of the drug holiday can vary between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days.
  • the dose reduction during a drug holiday may be from 10%- 100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved state of the disease, disorder or condition is maintained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., age, weight, gender, etc.) of the subject or host in need of treatment, but can nevertheless be routinely determined in a manner known in the art according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, in some embodiments 1-1500 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compound.
  • the unit dosage may be in the form of a package containing discrete quantities of the formulation.
  • Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.
  • multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition.
  • formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.
  • the daily dosages appropriate for the compounds described herein are from about 0.01 to 2.5 mg/kg per body weight.
  • An indicated daily dosage in the larger mammal, including, but not limited to, humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered in divided doses, including, but not limited to, up to four times a day or in extended release form.
  • Suitable unit dosage forms for oral administration include from about 1 mg to about 50 mg active ingredient.
  • the foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon. Such dosages may be altered depending on a number of variables, not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of 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 the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD 50 and ED 50 .
  • Compounds exhibiting high therapeutic indices are preferred.
  • the data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating
  • a compound of the invention can be administered in any form and route which makes the compound bioavailable.
  • the compounds of the invention can be administered by a variety of routes, including oral and parenteral routes, more particularly by inhalation, subcutaneously, intramuscularly,
  • compositions of the invention may be administered to the patient, for example, in the form of tablets, capsules, cachets, papers, lozenges, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, solutions, and suspensions.
  • the invention provides methods of treating conditions associated with HIF-2, comprising: administering to a patient in need thereof an effective amount of a compound of the invention.
  • the invention provides a method of inhibiting a HIF-2: comprising, contacting the enzyme with a compound of the invention.
  • the invention provides a method of inhibiting a HIF-2: comprising, administering a first compound to a subject that is converted in vivo to a compound of the invention.
  • Condition associated with HIF-2 include disorders and diseases in which the inhibition of HIF-2 provides a therapeutic benefit, such as cancer, allergy/asthma, diseases and conditions of the immune system, inflammation, disease and conditions of the central nervous system (CNS), cardiovascular disease, viral infections, dermatological disease, and diseases and conditions related to uncontrolled angiogenesis, and the like.
  • CNS central nervous system
  • cardiovascular disease a chronic obstructive pulmonary embosis .
  • PAH pulmonary arterial hypertension
  • the condition associated with HIF-2 is cancer. It is understood that the treatment of cancer includes treatment of all neoplasia, regardless of their
  • the cancers that can be treated include, but are not limited to, cancer of blood, including myelofibrosis, leukemia (including acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia), cancer of the skin, including melanoma, basal cell carcinoma, and squamous cell carcinoma, bone, liver, lung (including small-cell lung tumor, non small-cell lung cancer and bronchioalveolar cancer), brain, breast, prostate, larynx, gall bladder, pancreas, rectum, bile duct, parathyroid, thyroid, adrenal, neural tissue, bladder, spleen, head and neck, included the jaw, mouth, and nose, colon, stomach, testes, esophagus, uterus, cervix and vulva, colorectal, bronchi, bile duct, bladder, kidney, ovary, pancreas, multiple myelofibrosis, le
  • astrocytoma non-Hodgkin's lymphoma, Kaposi's sarcoma, osteogenic and other sarcoma
  • malignant hypercalcemia polycythemia vera
  • adenocarcinoma glioblastoma multiforme
  • glioma lymphomas
  • epidermoid carcinomas and other carcinomas and sarcomas.
  • the cancer is glioblastoma multiforme.
  • Glioblastoma multiforme glioblastoma or GBM
  • GBM glioblastoma
  • Treatment typically involves resection, chemotherapy, or radiation.
  • Median survival with standard of care (temozolomide) is 15 months, while survival with no treatment is 4.5 months.
  • Glioblastomas typically contain zones of tissue that are hypoxic, which are highly resistant to radiotherapy, and therefore post-treatment recurrence rates are high.
  • Benign tumors may also be treated by the compounds of the present invention and include, but are not limited to, hemangiomas, hepatocellular adenoma, cavernous haemangioma, focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia, trachomas, pyogenic granulomas, and the like, and hamartoma conditions such as Koz-Jeghers Syndrome (PJS), Cowden disease, Bannayan-Riley-Ruvalcaba Syndrome (BRRS), Proteus syndrome, Lhermitte-Duclos disease and Tuberous Sclerosis (TSC).
  • JPS Job-Jeghers Syndrome
  • BRRS Bannayan-Riley-Ruval
  • the compounds of the present invention may also be used to treat abnormal cell proliferation due to insults to body tissue during surgery. These insults may arise as a result of a variety of surgical procedures such as joint surgery, bowel surgery, and cheloid scarring.
  • fibrotic tissue Diseases that produce fibrotic tissue include emphysema.
  • Repetitive motion disorders that may be treated using the present invention include carpal tunnel syndrome.
  • VHL Von Hippel-Lindau Disease
  • VHL is a disease which results from a mutation in the von Hippel-Lindau tumor suppressor gene on chromosome 3p25.3. Signs and symptoms associated with VHL disease include headaches, problems with balance and walking, dizziness, weakness of the limbs, vision problems, and high blood pressure.
  • Conditions associated with VHL disease include angiomatosis, hemangioblastomas, pheochromocytoma, renal cell carcinoma, pancreatic cysts (pancreatic serous cystadenoma), endolymphatic sac tumor, and bilateral papillary cystadenomas of the epididymis (men) or broad ligament of the uterus (women).
  • Angiomatosis occurs in 37.2% of patients presenting with VHL disease and usually occurs in the retina. As a result, loss of vision is very common. However, other organs can be affected: strokes, heart attacks, and cardiovascular disease are common additional symptoms. Approximately 40% of VHL disease presents with CNS hemangioblastomas and they are present in around 60-80%).
  • VHL disease Spinal hemangioblastomas are found in 13-59%) of VHL disease and are specific because 80%> are found in VHL disease. Although all of these tumours are common in VHL disease, around half of cases present with only one tumour type. In some embodiments, the subject suffering from VHL disease also suffers from a hemangioblastoma, a
  • the subject suffers from renal cell carcinoma.
  • the renal cell carcinoma is clear cell renal cell carcinoma.
  • the compounds of the present invention may also be used to treat renal cell carcinoma.
  • Renal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine.
  • RCC is the most common type of kidney cancer in adults, responsible for approximately 90-95%) of cases.
  • Initial treatment is most commonly either partial or complete removal of the affected kidney(s).
  • RCC paraneoplastic syndromes
  • thrombocytosis too many platelets in the blood, leading to an increased tendency for blood clotting and bleeds
  • secondary amyloidosis too many platelets in the blood, leading to an increased tendency for blood clotting and bleeds
  • cardiovascular diseases include, but are not limited to, atherosclerosis, stenosis, restenosis, hypertension, pulmonary arterial hypertension (PAH), heart failure, left ventricular hypertrophy (LVH), myocardial infarction, acute coronary syndrome, stroke, transient ischemic attack, impaired circulation, heart disease, cholesterol and plaque formation, ischemia, ischemia reperfusion injury, peripheral vascular disease, myocardial infection, cardiac disease (e.g, risk stratification of chest pain and interventional procedures), cardiopulmonary resuscitation, kidney failure, thrombosis (e.g., venous thrombosis, deep vein thrombosis, portal vein thrombosis, renal vein thrombosis, jugular vein thrombosis, cerebral venous sinus thrombosis, arterial thrombosis, etc.), thrombus formation, thrombotic event or complication, Bud
  • the compounds of the invention may also be useful in the prevention of restenosis that is the control of undesired proliferation of normal cells in the vasculature in response to the introduction of stents in the treatment of vasculature disease.
  • Proliferative responses associated with organ transplantation that may be treated using HIF-2 inhibitors of the invention include proliferative responses contributing to potential organ rejections or associated complications. Specifically, these proliferative responses may occur during transplantation of the heart, lung, liver, kidney, and other body organs or organ systems.
  • the compounds of the invention may also be useful the treatment of abnormal angiogenesis including the abnormal angiogenesis accompanying rheumatoid arthritis, ischemic- reperfusion related brain edema and injury, cortical ischemia, ovarian hyperplasia and hypervascularity, (polycystic ovary syndrome), endometriosis, psoriasis, diabetic retinopaphy, and other ocular angiogenic diseases such as retinopathy of prematurity (retrolental fibroplastic), macular degeneration, corneal graft rejection, neuroscular glaucoma, Oster Webber syndrome, retinal/choroidal neovascularization and corneal neovascularization, Best's disease, myopia, optic pits, Stargart's diseases, Pagets disease, vein occlusion, artery occlusion, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum carotid
  • treatments of inflammation include, but are not limited to, acute pancreatitis, chronic pancreatitis, asthma, allergies, chronic obstructive pulmonary disease, adult respiratory distress syndrome and chronic inflammatory diseases associated with uncontrolled angiogenesis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, psoriasis, sarcoidois, and rheumatoid arthritis, sarcoidosis, and
  • treatment of autoimmune includes, but is not limited to, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease, multiple sclerosis, or Sjoegren's syndrome.
  • the compounds of the present invention are also useful for treating obesity, diabetes, insulin resistance, metabolic syndrome, and hyperlipidemia.
  • a wide variety of therapeutic agents may have a therapeutic additive or synergistic effect with the compounds according to the present invention.
  • Combination therapies that comprise one or more compounds of the present invention with one or more other therapeutic agents can be used, for example, to: (1) enhance the therapeutic effect(s) of the one or more compounds of the present invention and/or the one or more other therapeutic agents; (2) reduce the side effects exhibited by the one or more compounds of the present invention and/or the one or more other therapeutic agents; and/or (3) reduce the effective dose of the one or more compounds of the present invention and/or the one or more other therapeutic agents.
  • combination therapy is intended to cover when agents are administered before or after each other (sequential therapy) as well as when the agents are administered at the same time.
  • Examples of additional therapeutic agents that may be used in combination with the present compounds include, but are not limited to, anti-cell proliferation agents, anticancer agents, alkylating agents, antibiotic agents, antimetabolic agents, hormonal agents, plant-derived agents, biologic agents, and immunotherapy agents.
  • the additional therapeutic agent is an anti-cell profiferation agent.
  • Anti-cell proliferation agents useful in combination with the compounds of the present invention include, but are not limited to, retinoid acid and derivatives thereof, 2- methoxyestradiol, angiostatinTM protein, endostatinTM protein, suramin, squalamine, tissue inhibitor of metalloproteinase-I, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor- 1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel, platelet factor 4, protamine sulphate (clupeine), sulphated chitin derivatives (prepared from queen crab shells), sulphated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism, including for example, proline analogs ((l-azetidine-2-carboxylic acid (LACA), cishydroxyproline, d,l-3,4
  • anti-angiogenesis agents include antibodies, preferably monoclonal antibodies against these angiogenic growth factors: bFGF, aFGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF and Ang- l/Ang-2.
  • the additional therapeutic agent is a kinase inhibitor.
  • Inhibitors of VEGFR-TK, mTOR, PI3K, MEK, MAPK, or ERK are useful in combination with the compounds of the present invention. Specifically, (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2- fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione useful in combination with the compounds of the present invention.
  • Inhibitors of Hedgehog kinase are useful in combination with the compounds of the present invention.
  • Proteasome inhibitors in particular bortezomib is useful in combination with the compounds of the present invention.
  • the VEGFR-TK inhibitor is selected from pazopanib, bevacizumab, sunitinib, sorafenib, axitinib, ponatinib, cabozantinib, regorafenib , cabozantinib, vandetanib, ramucirumab, lenvatinib, and ziv-aflibercept .
  • NAE inhibitors are useful in combination with the compounds of the present invention.
  • VPS34 inhibitors include Aurora A inhibitors, and EGFR inhibitors (both antibodies and kinase inhibitors) are useful in combination with the compounds of the present invention.
  • Aurora kinase including Aurora A inhibitors
  • EGFR inhibitors both antibodies and kinase inhibitors
  • the additional therapeutic agent is an alkylating agent.
  • Alkylating agents useful in combination with the compounds disclosed herein include, but are not limited to, bischloroethylamines (nitrogen mustards, e.g. chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil mustard), aziridines (e.g. thiotepa), alkyl alkone sulfonates (e.g. busulfan), nitrosoureas (e.g. carmustine, lomustine, streptozocin), nonclassic alkylating agents (altretamine, dacarbazine, and procarbazine), platinum compounds
  • nitrogen mustards e.g. chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil mustard
  • aziridines e.g. thiotepa
  • Combination therapy including a HIF-2 inhibitor and an alkylating agent is expected to have therapeutic synergistic effects in the treatment of cancer and reduce sides affects associated with these chemotherapeutic agents.
  • the additional therapeutic agent is an antibiotic.
  • antibiotic agents useful in combination with the compounds disclosed herein include, but are not limited to, anthracyclines (e.g. doxorubicin, daunorubicin, epirubicin, idarubicin and
  • anthracenedione mitomycin C, bleomycin, dactinomycin, plicatomycin. These antibiotic agents interfere with cell growth by targeting different cellular components.
  • the additional therapeutic agent is an antimetabolic agent
  • Antimetabolic agents useful in combination with the compounds disclosed herein include, but are not limited to, fluorouracil (5-FU), floxuridine (5-FUdR), methotrexate, leucovorin, hydroxyurea, thioguanine (6-TG), mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine phosphate, cladribine (2-CDA), asparaginase, and gemcitabine.
  • Combination therapy including a compound disclosed herein and an antimetabolic agent is expected to have therapeutic synergistic effects on cancer and reduce sides affects associated with these chemotherapeutic agents.
  • the additional therapeutic agent is a hormonal agent.
  • Hormonal agents useful in combination with the compounds disclosed herein include synthetic estrogens (e.g. diethylstibestrol), antiestrogens (e.g. tamoxifen, toremifene, fluoxymesterol and
  • raloxifene antiandrogens (bicalutamide, nilutamide, and flutamide), aromatase inhibitors (e.g., aminoglutethimide, anastrozole and tetrazole), ketoconazole, goserelin acetate, leuprolide, megestrol acetate and mifepristone.
  • Combination therapy including a compound disclosed herein and a hormonal agent is expected to have therapeutic synergistic effects on cancer and reduce sides affects associated with these chemotherapeutic agents.
  • the additional therapeutic agent is a plant derived agent.
  • Plant- derived agents useful in combination with the compounds disclosed herein include, but are not limited to, vinca alkaloids (e.g., vincristine, vinblastine, vindesine, vinzolidine and vinorelbine), podophyllotoxins (e.g., etoposide (VP- 16) and teniposide (VM-26)), taxanes (e.g., paclitaxel and docetaxel).
  • vinca alkaloids e.g., vincristine, vinblastine, vindesine, vinzolidine and vinorelbine
  • podophyllotoxins e.g., etoposide (VP- 16) and teniposide (VM-26)
  • taxanes e.g., paclitaxel and docetaxel.
  • Podophyllotoxins such as etoposide are believed to interfere with DNA synthesis by interacting with topoisomerase II, leading to DNA strand scission.
  • Combination therapy including a compound disclosed herein and a plant-derived agent is expected to have therapeutic synergistic effects on cancer and reduce sides affects associated with these chemotherapeutic agents.
  • the additional therapeutic agent is an immunotherapy agent.
  • the immunotherapy agents useful in combination with the compounds disclosed herein include, but are not limited to, PD-1 inhibitors, a PD-Ll inhibitors, CTLA-4 inhibitors, CD52 inhibitors, or CD20 inhibitors.
  • the immunotherapy agent is selected from
  • alemtuzumab alemtuzumab, atezolizumab, ipilimumab, ofatumumab, nivolumab, pembrolizumab, rituximab, and durvalumab.
  • the term "effective amount” refers to the amount of compound of the invention which treats, upon single or multiple dose administration, a patient suffering from the mentioned condition.
  • An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances.
  • an effective amount of the present use invention is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 40 mg/kg/day. Specific amounts can be determined by the skilled person.
  • the present invention provides a method for treating cancer, comprising: administering to a patient in need thereof an effective amount of a compound of invention.
  • the invention also provides an article of manufacture: comprising at least one compound of the invention and a label.
  • the label may include information about the
  • the invention provides a kit: comprising, at least one compound of the invention, a label, and apparatus for administration.
  • the apparatus may include mixing vials, liquids for forming solutions or suspensions, tubing, syringes, and the like.
  • the starting material used for the synthesis of the compounds described herein may be synthesized or can be obtained from commercial sources, such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.), or Sigma Chemical Co. (St. Louis, Mo.).
  • the compounds described herein, and other related compounds having different substituents can be synthesized using techniques and materials described herein as well as those that are known to those of skill in the art, such as described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4.sup.th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4.sup.th Ed., Vols.
  • Example 1 General Procedure for synthesis of compound Example 1
  • Example 1a Example 1b Example 1d Example 1e
  • Example 1f Example 1g Example 1i
  • Example la 32 g, 246.2 mmol
  • /PrNH 2 15 g, 246.2 mmol
  • dry THF 550 mL
  • NBS 92 g, 516.9 mmol
  • the mixture was stirred from -40°C to ambient temperature for 22 hours.
  • the reaction was diluted with IN HC1 solution, extracted by MTBE (200 mL*3).
  • MS [M-l] " 207.0/209.0.
  • Example lb 50 g, 240.2 mmol
  • Example lc 59 g, 288.5 mmol
  • K 2 C0 3 100 g, 721.1 mmol
  • DMF 400 mL
  • the reaction was diluted with water (200 mL), stirred for 10 min, extracted with MTBE (200 mL*3).
  • the combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example Id (40 g, yield 51%) as a brown oil.
  • Example Id (40 g, 121.2 mmol) in EtOH (100 mL) / H 2 0 (50 mL) was added LiOHH 2 0 (15.3 g, 363.7 mmol). The mixture was stirred at ambient temperature for 2 hours. The organic layer was removedm vacuo, the aqueous phase was acidified by IN HC1 solution to pH 3-4 and extracted with DCM (50 mL*3). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example le (8 g, yield 22%) as a yellow oil.
  • Example le To a solution of Example le (8 g, 26.5 mmol) in dry THF (180 mL) at -10°C under nitrogen atmosphere was added «-BuLi (2.5 M, 26 mL) drop wise. The mixture was stirred from -10°C to ambient temperature for 2 hours. The reaction was quenched by IN HC1 aqueous solution, extracted with DCM (50 mL*2).
  • Example lg (90 mg, 0.33 mmol) in DMF (1.5 mL) was added
  • Example li (310 mg, 1.0 mmol), Example lj (162 mg, 1.5 mmol), K 2 C0 3 (414 mg, 3.0 mmol) and DMF (4 mL).
  • the tube was sealed and heated at 80°C for 10 hours.
  • the reaction was cooled to room temperature.
  • Water (10 mL) was added, the mixture was extracted by EtOAc (10 mL*3).
  • the combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example lk (60 mg, yield 15%) as a white solid.
  • Example lk 60 mg, 0.15 mmol
  • DCM dimethylethyl sulfoxide
  • perchloric acid 0.5 mL
  • the mixture was allowed to stir at ambient temperature for 24 hours.
  • the mixture was extracted by EtOAc (10 mL*2).
  • the combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product
  • Example 11 To a solution of Example 11 (31 mg, 0.09 mmol) in THF (1 mL) was added
  • Example 2 General Procedure for synthesis of compound Example 2
  • Example 1i Example 2b Example 2c Example 2
  • Example li (1.7 g, 5.5 mmol), Example 2a (900 mg, 6.6 mmol) and K 2 C0 3 (1.9 g, 13.7 mmol) in DMF (30 mL) was stirred at 80°C for 16 hours.
  • the reaction was diluted with water (30 mL), extracted with EtOAc (30 mL*2).
  • the combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 2b (740 mg, yield 32%) as a yellow solid.
  • Example 2b (740 mg, 1.73 mmol) and HC10 4 (2 mL) in DCM (6 mL) was stirred at
  • Example 2c To a solution of Example 2c (560 mg, 1.46 mmol) in DCM (25 mL) was added
  • Example li 310 mg, 1.0 mmol
  • Example 3a 136 mg, l .Ommol
  • DMF DMF
  • Cs 2 C0 3 391 mg, 1.2 mmol
  • the reaction mixture was poured into water (40 mL) and extracted with EtOAc (40 mL*3).
  • the combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 3b (100 mg, yield 89%) as a yellow solid.
  • MS [M+l] + 427.0.
  • Example 3b 100 mg, 0.23 mmol
  • DCM dimethylethyl sulfoxide
  • perchloric acid 70% in water, lmL
  • the reaction mixture was carefully quenched by the addition of sat. NaHC0 3 (100 mL), and then extracted with DCM (50 mL*3).
  • the combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product Example 3c (65 mg, yield 73%) as a light yellow oil.
  • MS [M+l] + 383.1.
  • Example 4 General Procedure for synthesis of Example 4
  • Example 1i Step l Example 4b Step 2
  • Example 4c Step 3 Example 4
  • Example li 140 mg, 0.45 mmol
  • Example 4a 140 mg, 0.54 mmol
  • DMF 2 mL
  • K 2 C0 3 120 mg, 0.9mmol
  • the reaction mixture was poured into water (20 mL) and extracted with EtOAc (10 mL*3).
  • the combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 4b (105 mg, yield 56%) as a yellow solid.
  • Example 4c (50 mg, 0.12 mmol) in THF (5 mL). The reaction mixture was stirred for 10 min, after which it was quenched with sat. H 4 C1. The resulting mixture was extracted with EtOAc (20 mL*2). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by prep-HPLC to give the pure product Example 4 (2.2 mg, yield 4%) as a white solid.
  • Example 4a 144 mg, 1.1 mmol. The mixture was stirred at 65°C for 1 hour. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL*3). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 4c (340 mg, yield 86%) as a white solid.
  • Example 4c (340 mg, 0.9 mmol) in DCM (5 mL) was added formic acid (125 mg, 2.7 mmol) and TEA (227 mg, 2.3 mmol).
  • the reaction mixture was degassed with nitrogen and RuCl(p-cymene)[(R,R)-Ts-DPEN] (CAS: 192139-92-7, 17 mg, 0.03mmol) was added in one portion.
  • the reaction mixture was stirred at room temperature overnight under nitrogen.
  • the reaction mixture was poured into water (20 mL) and extracted with DCM (20 mL*2).
  • Example 6a A solution of Example 6a (4.2 g, 30 mmol) in THF (50 mL) was treated with NaSMe (20% in water, 11 mL) and stirred at 50°C for 18 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL*3). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product Example 6b (3.9g, yield 77%) as a white solid.
  • Example 6b To a solution of Example 6b (1.67 g, 10 mmol) in MeOH (100 mL) stirred at 0°C was added a solution of sodium periodate (2.14 g, 10 mmol) in water (50 mL). The resulting suspension was stirred at 0°C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL*4). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product
  • Example 6c (1.5 g, yield 82%) as a yellow oil, which solidified on standing.
  • Example 6d (310 mg, 1.0 mmol) and Example li (154 mg, 1.1 mmol) in DMF (5 mL) was treated with Cs 2 C0 3 (391 mg, 1.2 mmol), which was stirred at 45°C for 18 hours.
  • the reaction mixture was poured into water (40 mL) and extracted with EtOAc (40 mL*3).
  • the combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 6e (315 mg, yield 71%) as a yellow solid.
  • Example 6e 300 mg, 0.68 mmol
  • DCM dimethylethyl sulfoxide
  • perchloric acid 2 mL
  • the reaction mixture was carefully quenched by the addition of sat. NaHC0 3 (100 mL), and then extracted with EtOAc (50 mL*3).
  • the combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 6f (200 mg, yield 74%) as a light yellow oil.
  • MS [M+l] + 400.1.
  • Example 6f (200 mg, 0.5 mmol) in THF (5 mL). The reaction mixture was stirred for 10 min, after which it was quenched with sat. H 4 C1. The resulting mixture was extracted with EtOAc (50 mL*2). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 6 (50 mg, yield 25%) as a white solid.
  • Example 7a (0.28 mL, 2.81 mmol) in CHCI 3 (5 mL) was added BF 3 Et 2 0 (0.35 mL, 2.81 mmol). The mixture was degassed with N 2 and stirred at 50°C for 18 hours. LCMS detected most Example lg was consumed. The mixture was cooled to room temperature, quenched with sat. NaHC0 3 (100 mL), and then extracted with DCM (100 mL*3).
  • Example 7b A mixture of Example 7b (115 mg 0.32 mmol), Example 7c (0.59 mL, 0.48 mmol) and Cs 2 C0 3 (157 mg 0.48 mmol) in DMF (5 mL) was degassed with N 2 and stirred at 80°C for 2 hours. LCMS detected most Example 7b was consumed. The mixture was cooled to room temperature, quenched with water (100 mL), extracted with EtOAc (50 mL*3). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel
  • Example 7d 35 mg, 0.08 mmol
  • PIFA 147 mg 0.36 mmol
  • MeCN/H 2 0 1.5 mL/0.2 mL
  • the mixture was diluted with sat. NaHC0 3 (30 mL), and then extracted with EtOAc (30 mL*3).
  • the combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel
  • Example 8 General Procedure for synthesis of compound Example 8
  • Example 8a 50 g, 278 mmol
  • zPrNH 2 25 g, 417 mmol
  • dry THF 600 mL
  • BS 74 g, 417 mmol
  • the mixture was stirred from -40°C to ambient temperature for 16 hours.
  • the reaction was diluted with IN HC1 solution, extracted by MTBE (200 mL*2).
  • Example 8b (30 g, 11.6 mol), Example lc (28 g, 13.9 mol) and K 2 C0 3 (48 g, 34.7 mol) in DMF (150 mL) was stirred at ambient temperature for 16 hours.
  • the reaction was diluted with water (200 mL), stirred for 10 min, and extracted with EtOAc (200 mL*2).
  • the combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 8c (21 g, yield 48%) as a yellow oil.
  • Example 8d To a solution of Example 8d (3.4 g, 9.6 mmol) in dry THF (65 mL) at -10°C under nitrogen atmosphere was added «-BuLi (2.5 M, 10 mL) drop wise. The mixture was stirred from -10°C to ambient temperature for 1 hour. The reaction was quenched by IN HC1 aqueous solution, extracted with EtOAc (50 mL*2). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 8e (1.4 g, yield 56%) as a yellow oil.
  • Example 8e 1.0 g, 3.9 mmol
  • DMF DMF
  • Example lh 1.5 g, 11.7 mmol
  • K 2 C0 3 1.6 g, 11.7 mmol
  • Example 8f (240 mg, 0.8 mmol), Example lj (130 mg, 1.2 mmol), K 2 C0 3 (221 mg, 1.6 mmol) and DMF (4 mL). The tube was sealed and heated at 80°C for 16 hours. The reaction was cooled to room temperature. Water (10 mL) was added, the mixture was extracted by EtOAc (10 mL*3). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 8g (92 mg, yield 30%) as a white solid.
  • Example 8h To a solution of Example 8h (71 mg, 0.21 mmol) in THF (1.5 mL) was added
  • Example 8 (32 mg, yield 45%) as a colorless oil.
  • Example 8f (280 mg, 0.93 mmol), Example 2a (155 mg, 1.12 mmol), K 2 C0 3 (386 mg, 2.8 mmol) and DMF (4 mL). The tube was sealed and heated at 120°C for 16 hours. The reaction was cooled to room temperature. Water (10 mL) was added, the mixture was extracted by EtOAc (20 mL*3). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 9a (98 mg, yield 25%) as a white solid.
  • Example 8e 500 mg, 2.0 mmol
  • Example 4a 280 mg, 2.1 mmol
  • Na 2 C0 3 420 mg, 3.9 mmol
  • DMF 10 mL
  • the reaction was diluted with water (20 mL), extracted with EtOAc (30 mL*2).
  • the combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 10a (440 mg, yield 62%) as a white solid.
  • Example 10a 440 mg, 1.2 mmol
  • DCM dimethylethyl sulfoxide
  • RuCl(p- cymene)[(R,R)-Ts-DPEN] CAS: 192139-92-7, 15 mg, 0.024 mmol
  • TEA 243 mg, 2.4 mmol
  • HCOOH 166 mg, 3.6 mmol
  • the mixture was stirred at ambient temperature for 16 hours.
  • the solvent was removed in vacuo, diluted with EtOAc and washed with water.
  • the organic layers were separated, concentrated and purified by prep-HPLC to afford Example 10 (189 mg, yield 43%) as a colorless oil.
  • MS [M-l or 20] " 346.9.
  • 1H MR 400 MHz,
  • Example 8e Example 11a
  • Example 11 Step 1 Example 11a
  • Example 11a To a solution of Example 11a (260 mg, 0.7 mmol) in DCM (15 mL) was added formic acid (97 mg, 2.1 mmol) and triethylamine (177 mg, 1.8 mmol). The reaction mixture was sparged with nitrogen and RuCl(p-cymene)[(R,R)-Ts-DPEN] (CAS: 192139-92-7, 14 mg, 0.03 mmol) was added in one portion. The reaction mixture was stirred at room temperature overnight under nitrogen. The reaction mixture was poured into water (20 mL) and extracted with DCM (20 mL*2).
  • Example 12 General Procedure for synthesis of compound Example 12
  • Example 12a 55 mg, 0.21 mmol
  • Example 12b 18 mg, 0.21 mmol
  • PPh 3 65 mg, 0.25 mmol
  • THF 1.5 mL
  • DIAD 50 mg, 0.25 mmol
  • the solvent was removedm vacuo, diluted with EtOAc and washed with water. The organic layers were separated, concentrated and purified by prep-HPLC to afford Example 12 (6 mg, yield 9%) as a white solid.
  • MS [M+l-18] + 317.0.
  • Example 13 General Procedure for synthesis of compound Example 13
  • Example 12a 55 mg, 0.21 mmol
  • Example 13a 21 mg, 0.21 mmol
  • PPh 3 65 mg, 0.25 mmol
  • THF 1.5 mL
  • DIAD 50 mg, 0.25 mmol
  • the solvent was removed in vacuo, diluted with EtOAc and washed with water. The organic layers were separated, concentrated and purified by prep-HPLC to afford Example 13 (24 mg, yield 33%) as a white solid.
  • MS [M+l-18] + 333.0.
  • Example 14 General Procedure for synthesis of compound Example 14
  • Example 14a 21 mg, 0.21 mmol
  • PPh 3 65 mg, 0.25 mmol
  • THF 1.5 mL
  • DIAD 50 mg, 0.25 mmol
  • the solvent was removed in vacuo, diluted with EtOAc and washed with water. The organic layers were separated, concentrated and purified by prep-HPLC to afford Example 14 (21 mg, yield 29%) as a white solid.
  • MS [M+l-18] + 331.0.
  • Example 15 General Procedure for synthesis of compound Example 15
  • Example 15b (14.5 g, 47 mmol) and w-CPBA (20.0 g, 117 mmol) in CHC1 3 (150 mL) was heated at 30°C with stirring for 3 hours under N 2 atmosphere. Sat. Na 2 S0 3 (50 mL) was added to quench the reaction, followed by addition of NaHC0 3 (300 mL). After extraction with CH 2 CI 2 (100 mL*2), the combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product
  • Example 15d (6.6 g, 22 mmol), Example 15e (4.2 g, 33 mmol), Pd(dppf)Cl 2 (1.6 g, 2 mmol), and Na 2 C0 3 (7.0 g, 67 mmol) in dioxane/H 2 0 (80/20 mL) was stirred at 100°C with stirring for 3 hours under N 2 atmosphere. Then, the reaction solution was filtrated to remove the solid.
  • Example 15g (5.2 g, 13 mmol), Example lc (3.3 g, 16 mmol), and K 2 C0 3 (5.6 g, 40 mmol) in DMF (60 mL) was stirred at 30°C with stirring for 2 hours under N 2 atmosphere. Then, the reaction solution was poured into water (200 mL). After extraction with EtOAc (100 mL*2), combined organic layer was dried over Na 2 S0 4 , and concentrated under reduced pressure to give the crude product Example 15h (5.8 g, crude yield 85%) as a yellow oil.
  • Example 15i To a solution of Example 15i (1.0 g, 2.0mmol) in THF (10 mL) at -70°C was added n- BuLi (2.0 mL, 5.0 mmol) slowly. After being stirred for 5 min, the reaction solution was poured into water (50 mL).
  • Example 15j 200 mg, 0.53 mmol
  • HCOOH 73 mg, 1.58 mmol
  • TEA 106 mg, 1.05 mmol
  • RuCl(p-cymene)[(R,R)-Ts-DPEN] CAS: 192139-92-7, 10 mg, 0.016 mmol
  • Example 15 (113 mg, yield 56%) as a yellow solid.
  • Example 16 General Procedure for synthesis of compound Example 16
  • Example 16a (190 mg, yield 50 %) as a yellow oil.
  • Example 16a 190 mg, 0.73 mmol
  • MeOH MeOH
  • H 2 0 2.5 mL
  • K 2 C0 3 200 mg, 1.45 mmol
  • the mixture was stirred at ambient temperature for 1 hour.
  • Water (10 mL) was added, and the mixture was extracted by DCM (10 mL*2).
  • the combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na 2 S0 4 and filtered.
  • the solvent was removed in vacuo to afford the crude product Example 16b (120 mg, crude yield 76 %) as a yellow oil, which was used for next step without any further purification.
  • MS [M-l] " 219.0.
  • Example 16b 350 mg, 1.6 mmol
  • ACN 8 mL
  • K 2 CO 3 4.4 g
  • Example 16c 850 mg, 3.2 mmol
  • Example 16d Sodium periodate (1.2 g 5.56 mmol) was added all at once to Example 16d (600 mg, 2.22 mmol) and RuCl 3 (23 mg, 0.11 mmol) in ACN (10 mL)/CCl 4 (10 mL)/H 2 0 (10 mL). The mixture was stirred at ambient temperature for 16 hours. The solid was filtered, rinsed by DCM. The organic layer was separated; the aqueous phase was extracted with DCM (30 mL*2).
  • Example 16e (90 mg, 0.30 mmol), Example lh (75 mg, 0.60 mmol) and K 2 C0 3 (125 mg, 0.90 mmol, 3.0 eq.) in DMF (1.5 mL) was stirred at ambient temperature for 5 hours. The reaction was diluted with water (20 mL), stirred for 10 min, and extracted with EtOAc (20 mL*2).
  • Example 16f (30 mg, 0.09 mmol), Example 2a (15 mg, 0.10 mmol) and K 2 C0 3 (36 mg, 0.26 mmol) in DMF (0.6 mL) was stirred at 25°C for 2 hours.
  • the reaction was diluted with water (10 mL), extracted with EtOAc (20 mL*2).
  • the combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 16g (30 mg, yield 75%) as a white solid.
  • Example 16h To a solution of Example 16h (14 mg, 0.03 mmol) in THF (1 mL) was added NaBH 4 (2 mg, 0.05 mmol) slowly at 0°C. After addition, the mixture was stirred at ambient temperature for 1 hour. The reaction was quenched by adding water slowly, and extracted with EtOAc (20 mL*2). The organic layer was washed by brine, dried over Na 2 S0 4 , filtered and concentrated.
  • Example 17 General Procedure for s nthesis of compound Example 17
  • Example 16h To a solution of Example 16h (35 mg, 0.08 mmol) in DCM (2 mL) was added RuCl(p- cymene)[(R,R)-Ts-DPEN] (CAS: 192139-92-7, 2 mg, 0.001 mmol), TEA (16 mg, 0.16 mmol), HCOOH (11 mg, 0.24 mmol). After addition, the mixture was stirred at ambient temperature for 16 hours. The solvent was removed in vacuo, diluted with EtOAc and washed with water. The organic layers were separated, concentrated and purified by prep-HPLC to afford Example 17 (30 mg, yield 89%) as a white solid.
  • Example 16e A mixture of Example 16e (107 mg, 0.35 mmol), Example 4a (55 mg, 0.42 mmol) and DIPEA (114 mg, 0.89 mmol) in DMF (2 mL) was stirred at 25°C for 0.5 hour. The reaction was diluted with water (10 mL), extracted with EtOAc (20 mL*2). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 18a (146 mg, crude yield 100%) as a yellow oil.
  • Example 18a 146 mg, 0.35 mmol
  • DCM 3 mL
  • RuCl(p-cymene)[(R,R)-Ts-DPEN] CAS: 192139-92-7, 5 mg, 0.007 mmol
  • TEA 72 mg, 0.71 mmol
  • HCOOH 49 mg, 1.06 mmol
  • the mixture was stirred at ambient temperature for 16 hours.
  • the solvent was removed in vacuo, diluted with EtOAc and washed with water.
  • the organic layers were separated, concentrated and purified by prep-HPLC to afford Example 18 (40 mg, yield 27%) as a brown oil.
  • Example 16f (290 mg, 0.8 mmol), Example lj (136 mg, 1.25 mmol) and K 2 C03 (289 mg, 2.0 mmol) in DMF (4 mL) was stirred at 80°C for 3 hours.
  • the reaction was diluted with water (20 mL), extracted with EtOAc (30 mL*2).
  • the combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 19a (100 mg, yield 29%) as a white solid.
  • MS [M+l] + 434.9.
  • Example 20 General Procedure for synthesis of compound Example 20
  • Example 20a Step 1 Example 20b Step 2
  • Example 20c Step 3 Example 20d
  • Example 20a The mixture of Example 20a (21 g, 136 mmol) and pyridine hydrochloride (316 g, 2.7 mol) was degassed with N 2 and stirred at 180°C for 2.5 hours. The mixture was cooled to room temperature and quenched with water (2 L), and then extracted with EtOAc (1 L*3). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 20b (16.5 g, yield 86 %) as a pale solid. Step 2: Example 20c
  • Example 20b To the solution of Example 20b (18 g, 129 mmol) in DCM (300 mL) was added DAST (41.4 g, 257 mmol). The reaction mixture was warmed to 25°C and stirred for 18 hours. The mixture was quenched with water (800 mL), and then extracted with EtOAc (100 mL*3). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 20c (12 g, yield 58%) as a green oil.
  • Example 20d (14.5 g, yield 81%) as a light yellow oil, which was used in next step directly.
  • Example 20d (14.5 g, 60.1 mmol), Example lc (12.2 g, 60.1 mmol) and K 2 C0 3 (12.4 g, 90.2 mmol) in DMF (200 mL) was stirred at room temperature for 18 hours.
  • the mixture was diluted with water (2 L), and extracted with EtOAc (500 mL*5).
  • the combined organic layer washed with brine (500 mL), dried over Na 2 S0 4 and concentrated.
  • the residue was dissolved in THF/EtOH (180 mL/180 mL) and added Li OH (180 mL, 1 N, 181 mmol).
  • Example 20g (358 mg 1.5 mmol), Example 2a (205 mg 1.5 mmol) and Na 2 C0 3 (240 mg 2.25 mmol) in DMF (200 mL) was degassed and stirred at 100°C for 3 hours. The mixture was cooled to room temperature and quenched with water (100 mL), extracted with EtOAc (50 mL*3). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 20h (200 mg, yield 38%) as a yellow solid.
  • Example 20h The solution of Example 20h (355 mg 1.0 mmol), RuCl(p-cymene)[(R,R)-Ts-DPEN] (CAS: 192139-92-7, 13 mg, 0.02 mmol), TEA (202 mg 2.0 mmol) and HCOOH (138 mg 3.0 mmol) in DCM (10 ml) was degassed and stirred at room temperature for 18 hours. The mixture was quenched with sat. NaHC0 3 (100 mL), and then extracted with EtOAc (50 mL*3). The combined organic layer washed with brine (50 mL), dried over Na 2 S0 4 and concentrated.
  • Example 21 General Procedure for synthesis of compound Example 21
  • Example 20h 25 mg 0.07 mmol
  • THF 2 mL
  • NaBH 4 5.4 mg, 0.14 mmol
  • the reaction mixture was stirred at room temperature for 1 hour.
  • the mixture was quenched with water (50 mL), and extracted with EtOAc (20 mL*3).
  • the combined organic layer washed with brine (20 mL), dried over Na 2 S0 4 and concentrated.
  • the residue was purified by prep-HPLC to give the desire product Example 21 (15 mg, yield 60%) as a brown solid.
  • Example 22b 400 mg, 1.2 mmol
  • Example 2a 197 mg, 1.4 mmol
  • DIEA 1.0 g, 8.0 mmol
  • the reaction mixture was poured into water (40 mL) and extracted with EtOAc (40 mL*3).
  • Example 22 (22 mg, yield 6%) as a white solid.
  • Example 23 General Procedure for synthesis of compound Example 23
  • Example 23c Step 4 Example 23 Step 1: Example 23a
  • Example 22b 240 mg, 0.75 mmol
  • potassium carbonate 150 mg, 1.12 mmol
  • DMF 5 mL
  • Example lh 113 mg, 0.9 mmol
  • the mixture was stirred at ambient temperature for 2 hours.
  • Water (50 mL) and EtOAc 100 mL were added.
  • the organic layer was separated, washed with brine, dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure to give crude product Example 23a (237 mg, crude yield 100%) as a yellow solid, which was used in the next step without purification.
  • Example 23a 110 mg, 0.30 mmol
  • Example lj 36 mg, 0.33 mmol
  • K 2 C0 3 63 mg, 0.45 mmol
  • Example 23b (110 mg, 0.24 mmol) in DCM (1 mL) at 25 °C was treated with perchloric acid (70% in water, lmL) and stirred for 48 hours. The reaction mixture was carefully quenched by sat. NaHC0 3 (100 mL), and then extracted with CH 2 C1 2 (50 mL*3). The combined organics were rinsed with brine, dried with MgS0 4 , filtered, and concentrated to afford the crude product Example 23c (100 mg, crude yield 100%) as a light yellow oil, which was used in the next step without purification.
  • Example 24 General Procedure for synthesis of compound Example 24
  • Example 22b 400 mg, 0.28 mmol
  • Example 4a 40 mg, 0.30 mmol
  • DMF 0.5 mL
  • DIEA 0.1 mL
  • the reaction mixture was poured into water (40 mL) and extracted with EtOAc (30 mL*3).
  • Example 25k, 251, 25m General Procedure for synthesis of compound Example 25k, Example 251, Example 25m
  • TEA 17.6 mL, 127 mmol
  • Example 25b (14.6 g, 102 mmol) was added
  • a solution of Example 25a (17.0 g, 85 mmol) in DMF (40 mL).
  • the mixture was stirred at room temperature for 1 hour and then heated to 100°C for 6 hours.
  • the mixture was poured into ice water and stirred for 10 min, and then extracted with EtOAc (200 mL*3).
  • the combined organic phase was washed with brine, dried over Na 2 S0 4 , and filtered.
  • the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography
  • Example 25c (9.8 g, 40.2 mmol), Example 25d (13.9 g, 100.4 mmol) and cesium carbonate (39.3 g, 120.5 mmol) in sulfolane/s-butanol (115 mL/13 mL) was heated to 105°C under N 2 protection and stirred for 3 hours. After cooling to room temperature, the mixture was poured into ice water and stirred for 10 min, and then extracted with EtOAc (150 mL*3). The combined organic phase was washed with brine, dried over Na 2 S0 4 , and filtered.
  • Example 25e To a mixture of Example 25e (2.7 g, 7.4 mmol) and oxalyl chloride (1.1 g, 8.9 mmol) in DCM (15 mL) was added a drop of DMF, which was stirred at room temperature for 1 hour. After completion, the mixture was concentrated under reduced pressure and dissolved in DCM (5 mL), which was added slowly into a suspension of A1C1 3 (2.0 g, 14.9 mmol) in DCM (15 mL) at 0°C. The resulting mixture was slowly warmed to room temperature and stirred for 18 hours. After cooling to 0°C, 1 N HCl solution was added to the reaction mixture, followed by water (50 mL) and DCM (100 mL).
  • Example 25g (2.7 g, 6.7 mmol) in acetonitrile (100 mL) was added Select-F (5.9 g, 16.7 mmol) and sodium sulfate (1.8 g, 13.0 mmol). The mixture was heated to reflux for 5 hours. After cooling to room temperature, water (50 mL) was added to the mixture, which was then extracted with EtOAc (100 mL), washed with brine, dried over Na 2 S0 4 , and filtered.
  • Select-F 5.9 g, 16.7 mmol
  • sodium sulfate 1.8 g, 13.0 mmol
  • Example 25i 76 mg, 0.20 mmol
  • toluene 4 mL
  • Example 25j (50 mg, 0.24 mmol), K 3 P0 4 (128 mg, 0.60 mmol), Pd(OAc) 2 (9.6 mg, 0.02 mmol) and Sphos (16 mg, 0.04 mmol).
  • the degassed mixture was stirred at 90°C under N 2 for 3 hours.
  • the solvent was evaporated and the residue was purified by Prep-HPLC to give the desired product Example 25k (10 mg, yield 13%) as a white solid.
  • MS [M+H] + 386.1.
  • Example 251 and Example 25m were obtained by doing Chiral Separation of Example 25k applying the following condition.
  • Example 26 General Procedure for synthesis of compound Example 26
  • Example 26b (36 mg, 0.09 mmol) in THF (1 mL) under N 2 at room temperature was added NaBH 4 (7 mg, 0.19 mmol). The resulting mixture was stirred at room temperature for 0.5 hour. The mixture was quenched with H 2 0 and then concentrated. The residue was purified by prep-HPLC to afford Example 26 (11 mg, yield 30%) as a white solid.
  • Example 25h 200 mg, 0.52 mmol
  • Example 27a 89 mg, 0.62 mmol
  • Pd(OAc) 2 26 mg, 0.05 mmol
  • Sphos 44 mg, 0.10 mmol
  • K 3 P0 4 334 mg, 1.56 mmol
  • PhMe 1.5 mL
  • the mixture was quenched with H 2 0, extracted with EtOAc twice.
  • the combined organic layers were saturated with brine, dried over Na 2 S0 4 , filtered, and concentrated.
  • MS [M+l] + 400.0.
  • Example 27b To a yellow solution of Example 27b (30 mg, 0.08 mmol) in THF (0.5 mL) under N 2 at room temperature was added NaBH 4 (5 mg, 0.16 mmol). The resulting mixture was stirred at room temperature for 3 hours. The mixture was quenched with sat. NH 4 C1 and then extracted with DCM twice. The combined organic layers were saturated with brine, dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by prep-HPLC to afford Example 27 (4 mg, yield 13%) as a white solid.
  • Example 28 General Procedure for synthesis of compound Example 28
  • Example 25h 117 mg, 0.31 mmol
  • toluene 5 mL
  • K 3 P0 4 197 mg, 0.93 mmol
  • Pd(OAc) 2 15 mg, 0.031 mmol
  • Sphos 25 mg, 0.062 mmol
  • the degassed mixture was stirred at 90°C under N 2 for 5 hours.
  • MS [M+H] + 370.3.
  • Example 28b (80 mg, 0.22 mmol) in THF (5 mL) was added NaBH 4 (13 mg, 0.35 mmol). The mixture was stirred at room temperature for 1 hour. Then the reaction mixture was quenched by adding water and extracted with EtOAc (15 mL*2). The combined organic layers was dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give the product Example 28 (12 mg, yield 15%) as a white solid.
  • Example 29 General Procedure for synthesis of compound Example 29
  • Example 25h 200 mg, 0.52 mmol
  • Example 29a 80 mg, 0.63 mmol
  • Pd(OAc) 2 24 mg, 0.05 mmol
  • Sphos 43 mg, 0.104 mmol
  • K 3 P0 4 331 mg, 1.56 mmol
  • the mixture was cooled to room temperature and diluted with water (100 mL), extracted with EtOAc (50 mL*3).
  • Example 29b 160 mg, 0.42 mmol
  • THF THF
  • NaBH 4 32 mg, 0.83 mmol
  • the reaction mixture was stirred at room temperature for 3 hours.
  • a drop of MeOH and another batch of NaBH 4 (32 mg, 0.83 mmol) was added.
  • the reaction mixture was stirred at room temperature for another 1 hour.
  • the mixture was quenched with sat. H 4 C1 (50 mL), and then extracted with EtOAc (20 mL*3).
  • EtOAc 20 mL*3
  • Example 30 General Procedure for synthesis of compound Example 30
  • Example 25i (270 mg, 0.7 mmol), Example 30a (227 mg, 2.8 mmol), Pd(OAc) 2 (29 mg, 0.07 mmol) and KOAc (137 mg, 1.4 mmol) in DMA (10 mL) was degassed with N 2 and stirred at 150°C for 2 hours. The mixture was cooled to room temperature and diluted with water (100 mL), extracted with EA (50 mL*3). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by prep-HPLC to give the pure product Example 30 (11 mg, yield 4 %) as a pale solid.
  • Example 31 General Procedure for synthesis of compound Example 31
  • Example 251 Step l Example 31a Step 2 & 3
  • Example 31b Step 4
  • Example 31c Example 31c
  • Example 31a Example 31a
  • Example 25i To an ice-cooled solution of Example 25i (2.4 g, 6.28 mmol) in THF (25 mL) was added NaH (530 mg, 60% disperse in oil, 13.27 mmol) at 0°C slowly by portions, the mixture was stirred at 0 °C for 30 min under N 2 , then MOMC1 (1.13 mL, 14.82 mmol) was added via a syringe slowly at 0 °C under N 2 . After addition the reaction mixture was stirred at 0 °C to room temperature for 2 h until no SM could be detected by TLC. The reaction was quenched by adding water, and extracted with EtOAc.
  • Example 31a (2.4 g, 5.59 mmol), Example 31f (4.04 g, 1 1.18 mmol) and Pd(PPh 3 ) 2 Cl 2 (78 mg, 0.1 1 18 mmol) in dioxane (50 mL) was stirred and heated to 1 10°C for overnight under N 2. After being treated with 15% citric acid, the reaction mixture was stirred at room temperature overnight. Then the grey reaction mixture was filtered through Celite, the filtered cake was washed with EtOAc, the filtrate was extracted with EtOAc, washed with brine, KF solution (aq. 1.4 N) and brine.
  • Example 31f 149 mg, 0.344 mmol
  • DCM 31.5 mL
  • TFA 10.5 mL
  • the reaction mixture was stirred at 0°C to room temperature for 3 hours.
  • the reaction mixture was diluted with DCM, washed with water and brine, the organic layer was concentrated under reduced pressure to give residue which was purified on prep-HPLC to give pure product Example 31 (83 mg, yield 66%) as a white solid.
  • Example 32 General Procedure for synthesis of compound Example 32
  • Example 32a 14 g, 49 mmol
  • Example 26a 9.2 mg, 73 mmol
  • Na 2 C0 3 (15.6 g, 147 mmol)
  • Pd(PPh 3 ) 2 Cl 2 3.4 g, 4.9 mmol
  • dioxane 140 mL
  • H 2 0 70 mL
  • EtOAc 50 mL*3
  • Example 32b A mixture of Example 32b (3 g, 12.3 mmol), 3-methoxy propyl amine (44 g, 492 mmol) and TFA (0.5 mL, 6.2 mmol) in PhMe (30 mL) was stirred at 115°C under N 2 for 16 hours using a Dean-Stark apparatus. The mixture was cooled to room temperature, and extracted with EtOAc (100 mL*3). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product Example 32c (4.6 g, crude yield 100%) as a black oil, which was then directly used in the next step.
  • Example 32c (4.6 g crude, 12.3 mmol), Select-F (13.2 g, 36.9 mmol) and Na 2 S0 4 (8.5 g, 60 mmol) in CH 3 CN (40 mL) was stirred at 80°C under N 2 for 3 hours. After cooling to room temperature, the mixture was diluted with water, and extracted with EtOAc (50 mL*3). The combined organic phase was washed with brine, dried over Na 2 S0 4 , filtrated and concentrated under reduced pressure to give the crude product Example 32f (2.9 g, crude yield 100%)) as a black oil, which was then directly used in the next step.
  • Example 32f (2.9 g crude, 10.3 mmol) and Py HC1 (36 g, 313 mmol) was stirred at 180°C under N 2 for 2.5 hours. After cooling to room temperature, the mixture was diluted with water, and extracted with EtOAc (50 mL*3). The combined organic phase was washed with brine, dried over Na 2 S0 , filtrated and concentrated under reduced pressure. The residue was further purified by silica gel chromatography to give the pure product Example 32g (800 mg, yield 24%> over 3 steps) as a white solid.
  • Example 32g 800 mg, 3.0 mmol
  • THF 10 mL
  • NaBH 4 227 mg, 6.0 mmol
  • EtOAc 50 mL*3
  • the combined organic phase was washed with brine, dried over Na 2 S0 , filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product Example 32h (600 mg, yield 75%>) as a colorless oil.
  • Example lj 40 mg, 0.37 mmol in DCM (2 mL) at -78°C was added TEA (37 mg, 0.37 mmol) and Tf 2 0 (104 mg, 0.37 mmol). The mixture was stirred at -78°C for 30 min, then warmed to room temperature and stirred for lhour. After that, Example 32h (100 mg, 0.37 mmol) and DBU (112 mg, 0.74 mmol) were added to the mixture, which was stirred at 50°C overnight. The mixture was diluted with DCM, and then washed with water.
  • Example 33 General Procedure for synthesis of compound Example 33
  • Example 33c (58 mg, 0.6 mmol), TEA (120 mg, 1.2 mmol), DPPP (33 mg, 0.08 mmol, 0.2 eq), Pd(OAc) 2 (9 mg, 0.04 mmol) and [bmim][BF 4 ] (0.8 mL). The mixture was stirred at 115°C overnight under N 2 . The reaction mixture was extracted with EtOAc (10 mL) and water. The organic layer was dried (Na 2 S0 4 ) and concentrated. The residue was purified by silica gel chromatography to give the product Example 33a (45 mg, yield 25%) as a yellow solid.
  • Example 33a (40 mg, 0.1 mmol) in DCM (1 mL) was added CH 2 I 2 (268 mg, 1.0 mmol) and ZnEt 2 (0.5 mL, 0.5 mmol) at -10°C. The mixture was stirred at room temperature for 5 hours. The reaction mixture was extracted with EtOAc (10 mL) and sat.
  • Example 33b 25 mg, 0.06 mmol
  • DCM 0.5 mL
  • TFA 2 drops
  • the reaction mixture was stirred at room temperature for 6 hours.
  • the reaction mixture was extracted with DCM (10 mL) and sat. NaHC0 3 .
  • the organic layer was dried (Na 2 S0 4 ) and concentrated.
  • the residue was purified by prep-TLC to give Example 33 (1 mg, yield 4%) as a colorless oil.
  • Example 34 General Procedure for synthesis of compound Example 34
  • Example 31b 100 mg, 0.26 mmol
  • CHC1 3 1.5 mL
  • DAST 103 mg, 0.64 mmol
  • EtOH 0.1 mL
  • Example 34a (85 mg, 0.21 mmol) was dissolved in DCM (3 mL), to the solution was added TFA (1 mL) slowly and the mixture was stirred at ambient temperature for 1 hour. LCMS showed reaction was completed. The reaction mixture was concentrated and purified by prep- HPLC to afford Example 34 (7 mg, yield 24%) as a white solid.

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Abstract

La présente invention concerne de nouveaux composés inhibiteurs de HIF-2α et des compositions pharmaceutiques les contenant, qui peuvent être utiles dans le traitement et/ou la prévention de divers états pathologiques. La présente invention concerne également des méthodes de préparation desdits composés inhibiteurs de HIF-2α et compositions, et méthodes d'utilisation de ceux-ci.
PCT/US2017/046138 2016-08-10 2017-08-09 Nouveaux composés, leurs utilisations et procédés de préparation Ceased WO2018031680A1 (fr)

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WO2020081695A1 (fr) 2018-10-17 2020-04-23 Nikang Therapeutics, Inc. Dérivés d'indane utilisés en tant qu'inhibiteurs du facteur 2 inductible par l'hypoxie (alpha)
WO2020214853A1 (fr) * 2019-04-18 2020-10-22 Nikang Therapeutics, Inc. Dérivés de tétrahydro-1h-cyclopenta [cd] indène en tant qu'inhibiteurs du facteur 2 inductible par l'hypoxie (alpha)
WO2021105069A1 (fr) 2019-11-26 2021-06-03 Merck Patent Gmbh Dérivés de thiophène condensés en tant qu'inhibiteurs du facteur inductible par l'hypoxie (hif)
WO2021212062A1 (fr) * 2020-04-16 2021-10-21 Nikang Therapeutics, Inc. Inhibiteurs du facteur-2(alpha) inductible par l'hypoxie et leur utilisation dans le traitement de maladies
WO2021249463A1 (fr) * 2020-06-11 2021-12-16 贝达药业股份有限公司 Composé bicyclique et son application
WO2021254417A1 (fr) * 2020-06-17 2021-12-23 贝达药业股份有限公司 Composé bicyclique et son utilisation
WO2021262563A1 (fr) * 2020-06-22 2021-12-30 Merck Sharp & Dohme Corp. MÉTHODES DE TRAITEMENT DU CANCER OU DE LA MALADIE DE VON-HIPPEL LINDAU FAISANT APPEL À UNE ASSOCIATION D'UN INHIBITEUR DE HIF-2α ET DU LENVATINIB
WO2021262562A3 (fr) * 2020-06-17 2022-03-03 Merck Sharp & Dohme Corp. Méthodes de traitement du cancer ou de la maladie de von hippel-lindau à l'aide d'une combinaison d'un antagoniste de pd-1, d'un inhibiteur de hif-2 alpha et de lenvatinib ou d'un sel pharmaceutiquement acceptable associé
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WO2022082329A1 (fr) * 2020-10-19 2022-04-28 Nikang Therapeutics, Inc. Procédés de préparation de 3-fluoro-5-(((1s, 2ar)-1, 3, 3, 4, 4-pentafluoro-2a-hydroxy-2, 2a, 3, 4-tétrahydro-1 h-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile
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EP3866927A4 (fr) * 2018-10-17 2022-07-27 Nikang Therapeutics, Inc. Dérivés d'indane utilisés en tant qu'inhibiteurs du facteur 2 inductible par l'hypoxie (alpha)
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WO2020214853A1 (fr) * 2019-04-18 2020-10-22 Nikang Therapeutics, Inc. Dérivés de tétrahydro-1h-cyclopenta [cd] indène en tant qu'inhibiteurs du facteur 2 inductible par l'hypoxie (alpha)
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WO2021105069A1 (fr) 2019-11-26 2021-06-03 Merck Patent Gmbh Dérivés de thiophène condensés en tant qu'inhibiteurs du facteur inductible par l'hypoxie (hif)
US11407712B2 (en) 2020-03-19 2022-08-09 Arcus Biosciences, Inc. Tetralin and tetrahydroquinoline compounds as inhibitors of HIF-2α
US12103907B2 (en) 2020-03-19 2024-10-01 Arcus Biosciences, Inc. Tetralin and tetrahydroquinoline compounds as inhibitors of HIF-2alpha
US11787762B2 (en) 2020-03-19 2023-10-17 Arcus Biosciences, Inc. Tetralin and tetrahydroquinoline compounds as inhibitors of HIF-2alpha
US11420936B2 (en) 2020-04-16 2022-08-23 Nikang Therapeutics, Inc. Hypoxia inducible factor-2(alpha) inhibitors and their use in the treatment of diseases
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WO2021212062A1 (fr) * 2020-04-16 2021-10-21 Nikang Therapeutics, Inc. Inhibiteurs du facteur-2(alpha) inductible par l'hypoxie et leur utilisation dans le traitement de maladies
JP2023529471A (ja) * 2020-06-11 2023-07-10 貝達薬業股▲ふん▼有限公司 二環化合物及びその使用
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WO2021249463A1 (fr) * 2020-06-11 2021-12-16 贝达药业股份有限公司 Composé bicyclique et son application
CN115884966A (zh) * 2020-06-11 2023-03-31 贝达药业股份有限公司 双环化合物及其应用
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WO2021254417A1 (fr) * 2020-06-17 2021-12-23 贝达药业股份有限公司 Composé bicyclique et son utilisation
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