WO2018031680A1 - Novel compounds, uses and methods for their preparation - Google Patents

Novel compounds, uses and methods for their preparation 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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PCT/US2017/046138
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French (fr)
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Bohan Jin
Qing Dong
Gene Hung
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Fronthera U.S. Pharmaceuticals Llc
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Publication of WO2018031680A1 publication Critical patent/WO2018031680A1/en

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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.

Abstract

The present disclosure relates to novel compounds HIF-2α inhibitors and pharmaceutical compositions thereof which may be useful in the treatment and/or prevention of various conditions. The present disclosure also provides methods of preparing such HIF-2α inhibitors and compositions, and methods of using the same.

Description

NOVEL COMPOUNDS, USES AND METHODS FOR THEIR PREPARATION
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Application Serial No. 62/373,304, filed August 10, 2016, which is hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 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.
[0003] Hypoxia inducible factors (HIFs), including HIF-Ια and HIF -2a, 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). In the majority of ccRCC tumors, the tumor suppressor von Hippel-Lindau protein (pVHL) that targets HIF -2a for degradation is inactivated, leading to the accumulation of HIF -2a and the transcription of genes that drive kidney cancer tumorigenesis.
[0004] 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.
SUMMARY OF THE INVENTION
[0005] Disclosed herein is a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000003_0001
wherein:
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
L is a bond or -CR7R8-;
X is -0-, -S-, or - RX;
Z is -0-, -S-, or - RZ;
Yi is N or CR1;
Y2 is N or CR2;
R1 and R2 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, - RcRd, -S(=0)2R , - RaS(=0)2R , -S(=0)2 RcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0) RcRd, -OC(=0) RcRd, - RaC(=0) RcRd, - RaC(=0)R , - RaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R3 is halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, -NRcRd, -S(=0)2R , -NRaS(=0)2R , - S(=0)2NRcRd, -C(=0)R , -OC(=0)R , -C02Ra, -OC02Ra, -C(=0)NRcRd, - OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaC(=0)R , -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R4 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, -NRcRd, -S(=0)2R , -NRaS(=0)2R , -S(=0)2NRcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0)NRcRd, -OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaC(=0)R , - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R5 is halogen;
each R6 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, - RcRd, -S(=0)2R , - RaS(=0)2R , -S(=0)2 RcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0) RcRd, -OC(=0) RcRd, - RaC(=0) RcRd, - RaC(=0)R , - RaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R7 and R8 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, - NRcRd, -S(=0)2R , -NRaS(=0)2R , -S(=0)2NRcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0)NRcRd, -OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaC(=0)R , - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Rx and Rz are independently hydrogen, -SRa, -S(=0)R , -S(=0)2R , -S(=0)2NRcRd, - C(=0)R , -C02Ra, -C(=0)NRcRd, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each Ra is independently hydrogen, optionally substituted Ci-C6 alkyl, optionally
substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each Rc and Rd are independently hydrogen, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or Rc and Rd together with the nitrogen atom to which they are attached form an
optionally substituted heterocycloalkyl or optionally substituted heteroaryl; n is 1-3;
m is 1-4; and
p is 1-6.
[0006] In some embodiments of a compound of Formula (A) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, L is -CR7R8-; and R7 and R8 are independently hydrogen, halogen, or Ci-C6 alkyl. In some embodiments of a compound of Formula (A) or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, L is a bond.
[0007] In some embodiments of a compound of Formula (A) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 1 or 2.
[0008] In some embodiments of a compound of Formula (A) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y1 is CR1; and Y2 is CR2. In some embodiments of a compound of Formula (A) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y1 is N; and Y2 is CR2. In some embodiments of a compound of Formula (A) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y1 is CR1; and Y2 is N.
[0009] In some embodiments of a compound of Formula (A) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p is 1-3.
[0010] In some embodiments of a compound of Formula (A) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound of Formula (A) is of Formula (Al):
Figure imgf000005_0001
(Formula Al)
wherein:
pi is 1-3.
[0011] In some embodiments of a compound of Formula (Al) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, pi is 1 or 2.
[0012] In some embodiments of a compound of Formula (A) or (Al) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is - RX-; and Rx is hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (A) or (Al) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is -S-. In some embodiments of a compound of Formula (A) or (Al) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is -0-.
[0013] In some embodiments of a compound of Formula (A) or (Al) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is -0-. [0014] In some embodiments of a compound of Formula (A) or (Al) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound of Formula (A) or Formula (Al) is of Formula (A2):
Figure imgf000006_0001
(Formula A2);
wherein:
R5 is halogen; and
p2 is 1 or 2.
[0015] In some embodiments of a compound of Formula (A2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R5 is fluoro.
[0016] In some embodiments of a compound of Formula (A2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, p2 is 1.
[0017] In some embodiments of a compound of Formula (A), (Al), or (A2) or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, 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
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperizanyl, tetrahydropyranyl, or tetrahydrofuranyl. In some embodiments of a compound of Formula (A), (Al), or (A2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring A is heteroaryl selected from pyridinyl, pyrimidyl, pyrazinyl, or pyridazinyl.
[0018] In some embodiments of a compound of Formula (A), (Al), or (A2) or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R4 is independently hydrogen, halogen, -CN, -ORa, - RcRd, -C02Ra, -C(=0) RcRd, or optionally substituted Ci-C6 alkyl; and m is 1 or 2. In some embodiments of a compound of Formula (A), (Al), or (A2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R4 is independently hydrogen, halogen, or -CN; and m is 1 or 2.
[0019] In some embodiments of a compound of Formula (A), (Al), or (A2) or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R1 and R2 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. [0020] In some embodiments of a compound of Formula (A), (Al), or (A2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R3 is halogen, -CN, - S(=0)2R , optionally substituted Ci-C6 alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (A), (Al), or (A2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R3 is -S(=0)2R , Ci- C6 alkyl, Ci-C6 haloalkyl, or heteroaryl optionally substituted with halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 hydroxyalkyl. In some embodiments of a compound of Formula (A), (Al), or (A2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R3 is a 5- membered heteroaryl.
[0021] In some embodiments of a compound of Formula (A), (Al), or (A2) or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R6 is independently hydrogen, halogen, or -ORa.
[0022] In some embodiments of a compound of Formula (A), (Al), or (A2) or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Ra is independently hydrogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (A), (Al), or (A2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R is independently Ci-C6 alkyl or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (A), (Al), or (A2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rc and Rd are independently hydrogen, Ci-C6 alkyl, or Ci-C6 haloalkyl.
[0023] Also disclosed herein is a compound of Formula (B), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000007_0001
(Formula B)
wherein:
Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Li is a bond or -CR17R18-;
Xi is -0-, -S-, or - RX1;
Wi is N or CR11; W2 is N or CR12;
R11 and R12 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, - RcRd, -S(=0)2R , - RaS(=0)2R , -S(=0)2 RcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0) RcRd, -OC(=0) RcRd, - RaC(=0) RcRd, - RaC(=0)R , - RaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R14 and R19 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , - N02, -NRcRd, -S(=0)2R , -NRaS(=0)2R , -S(=0)2NRcRd, -C(=0)R , -OC(=0)R , - C02Ra, -OC02Ra, -C(=0)NRcRd, -OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaC(=0)R , -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R15 is halogen;
each R16 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, -NRcRd, -S(=0)2R , -NRaS(=0)2R , -S(=0)2NRcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0)NRcRd, -OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaC(=0)R , - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R17 and R18 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, - NRcRd, -S(=0)2R , -NRaS(=0)2R , -S(=0)2NRcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0)NRcRd, -OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaC(=0)R , - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
RX1 is hydrogen, -SRa, -S(=0)R , -S(=0)2R , -S(=0)2NRcRd, -C(=0)R , -C02Ra, - C(=0)NRcRd, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each Ra is independently hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each Rc and Rd is independently hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or Rc and Rd together with the nitrogen atom to which they are attached form an
optionally substituted heterocycloalkyl or optionally substituted heteroaryl; s is 1-3;
u is 1-4;
w is 1-4; and
v is 1-6.
[0024] In some embodiments of a compound of Formula (B) or a pharmaceutically acceptable
17 18 17 18
salt, solvate, or stereoisomer thereof, Li is -CR R -; and R and R are independently hydrogen, halogen, or Ci-C6 alkyl. In some embodiments of a compound of Formula (B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Li is a bond.
[0025] In some embodiments of a compound of Formula (B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, s is 1 or 2.
[0026] In some embodiments of a compound of Formula (B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Wi is CR11; and W2 is CR12. In some embodiments of a compound of Formula (B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Wi is N; and W2 is CR12. In some embodiments of a compound of Formula (B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Wi is CR11; and W2 is N.
[0027] In some embodiments of a compound of Formula (B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, v is 1-3
[0028] In some embodiments of a compound of Formula (B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound of Formula (B) is of Formula (Bl):
Figure imgf000010_0001
(Formula Bl)
wherein:
vl is 1-4.
[0029] In some embodiments of a compound of Formula (Bl) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, vl is 1 or 2.
[0030] In some embodiments of a compound of Formula (B) or (Bl) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X1 is - Rx1-; and Rxl is hydrogen or Ci-C6 alkyl.
[0031] In some embodiments of a compound of Formula (B) or (Bl) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X1 is -S-. In some embodiments of a compound of Formula (B) or (Bl) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Xi is -0-.
[0032] In some embodiments of a compound of Formula (B) or (Bl) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound of Formula (B) or Formula (Bl) is of Formula (B2):
Figure imgf000010_0002
(Formula B2);
wherein:
R15 is halogen; and
v2 is 1 or 2.
[0033] In some embodiments of a compound of Formula (B2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R15 is fluoro.
[0034] In some embodiments of a compound of Formula (B2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, v2 is 1. [0035] In some embodiments of a compound of Formula (B), (Bl), or (B2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B is cycloalkyl selected from cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of a compound of Formula (B), (Bl), or (B2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B is phenyl. In some embodiments of a compound of Formula (B), (Bl), or (B2) or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B is heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperizanyl, tetrahydropyranyl, or tetrahydrofuranyl. In some embodiments of a compound of Formula (B), (Bl), or (B2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring B is heteroaryl selected from pyridinyl, pyrimidyl, pyrazinyl, or pyridazinyl.
[0036] In some embodiments of a compound of Formula (B), (Bl), or (B2) or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R14 is independently hydrogen, halogen, -CN, -ORa, - RcRd, -C02Ra, -C(=0) RcRd, or optionally substituted Ci-C6 alkyl; and u is 1 or 2.
[0037] In some embodiments of a compound of Formula (B), (Bl), or (B2) or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R14 is independently hydrogen, halogen, or -CN; and u is 1 or 2.
[0038] In some embodiments of a compound of Formula (B), (Bl), or (B2) or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring C is a 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (B), (Bl), or (B2) or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring C is a 5-membered heteroaryl selected from pyrrolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, or pyrazolyl. In some embodiments of a compound of Formula (B), (Bl), or (B2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring C is a cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments of a compound of Formula (B), (Bl), or (B2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Ring C is a heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperizanyl, tetrahydropyranyl, or tetrahydrofuranyl.
[0039] In some embodiments of a compound of Formula (B), (Bl), or (B2) or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R19 is independently hydrogen, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 hydroxyalkyl; and w is 1 or 2.
[0040] In some embodiments of a compound of Formula (B), (Bl), or (B2) or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R11 and R12 are independently hydrogen or halogen. [0041] In some embodiments of a compound of Formula (B), (Bl), or (B2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R16 is independently hydrogen, halogen, or -ORa.
[0042] In some embodiments of a compound of Formula (B), (Bl), or (B2) or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Ra is independently hydrogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (B), (Bl), or (B2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R is independently Ci-C6 alkyl or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (B), (Bl), or (B2) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each Rc and Rd are independently hydrogen, Ci-C6 alkyl, or Ci-C6 haloalkyl.
[0043] Also disclosed herein is a pharmaceutical composition comprising an effective amount of a compound disclosed herein and a pharmaceutically acceptable excipient.
[0044] 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. In some embodiment, the cancer is glioblastoma.
[0045] 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.
[0046] Also disclosed herein is a method of treating Von Hippel-Lindau (VUL) disease, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutical composition disclosed herein. In some embodiments, the subject also suffers from a hemangioblastoma, a pheochromocytoma, a pancreatic neuroendocrine tumor, a renal cell carcinoma, or any combinations thereof. In some embodiments, the subject suffers from renal cell carcinoma. In some embodiments, the renal cell carcinoma is clear cell renal cell carcinoma.
[0047] 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.
[0048] 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.
INCORPORATION BY REFERENCE
[0049] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein. DETAILED DESCRIPTION OF THE INVENTION
[0050] A need exists for new drug therapies having greater receptor selectivity for the treatment of subjects suffering from or susceptible to the diseases, disorders or conditions described herein. In addition, a need exists for new drugs having one or more improved properties either alone or when combined with other agents (such as safety profile, efficacy, or physical properties) relative to those therapies currently available.
Certain Exemplary Terminology
[0051] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. In the event that there is a plurality of definitions for terms herein, those in this section prevail. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.
[0052] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and/or" unless otherwise stated.
Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting.
[0053] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, but not limited to, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose.
[0054] Definition of standard chemistry terms may be found in reference works, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 sup.TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art are employed. Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. 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.
[0055] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods and compositions described herein.
[0056] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of or "consist essentially of the described features.
[0057] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.
[0058] "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, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as "Ci-C6 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. In some embodiments, the alkyl is a Ci-Cio alkyl, a C1-C9 alkyl, a Ci-C8 alkyl, a C1-C7 alkyl, a Ci-C6 alkyl, a C1-C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a Ci-C2 alkyl, or a Ci alkyl. Unless stated otherwise specifically in the specification, 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. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, - CF3, -OH, -OMe, - H2, or -N02. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe.
[0059] "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. Examples include, but are not limited to ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as "C2- C6 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. In some embodiments, the alkenyl is a C2-Cio alkenyl, a C2-Cg alkenyl, a C2-C8 alkenyl, a C2-C7 alkenyl, a C2-C6 alkenyl, a C2-C5 alkenyl, a C2-C4 alkenyl, a C2-C3 alkenyl, or a C2 alkenyl. Unless stated otherwise specifically in the specification, 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. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe.
[0060] "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. Whenever it appears herein, a numerical range such as "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. In some embodiments, the alkynyl is a C2- Cio alkynyl, a C2-Cg alkynyl, a C2-C8 alkynyl, a C2-C7 alkynyl, a C2-C6 alkynyl, a C2-C5 alkynyl, a C2-C4 alkynyl, a C2-C3 alkynyl, or a C2 alkynyl. Unless stated otherwise specifically in the specification, an alkynyl 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. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, - H2, or -N02. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe.
[0061] "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, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe.
[0062] "Alkoxy" refers to a radical of the formula -ORa where Ra 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, -CF3, -OH, - OMe, -NH2, or -N02. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe.
[0063] "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. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, 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. In some
embodiments, 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, -CF3, -OH, -OMe, - H2, or -N02. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.
[0064] "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 (C3-C10 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, 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,
bicyclo[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. Unless stated otherwise specifically in the specification, 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. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, - OMe, -NH2, or -N02. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.
[0065] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
[0066] "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,
1,2-dibromoethyl, and the like.
[0067] "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. Unless stated otherwise specifically in the specification, 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. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6- membered heterocycloalkyl. Examples of such 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, thiomorpholinyl, thiamorpholinyl,
1-oxo-thiomorpholinyl, 1, 1-dioxo-thiomorpholinyl, 1,3 -dihydroisobenzofuran-l-yl, 3-oxo-l,3- dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term 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. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, - H2, or -N02. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.
[0068] "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. In one aspect, a heteroalkyl is a Ci-C6 heteroalkyl. Unless stated otherwise specifically in the specification, 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. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.
[0069] "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. In some embodiments, the heteroaiyl is a 5- to 10-membered heteroaiyl. In some embodiments, 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, 1-phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, 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. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe.
[0070] A "cyano" group refers to a -CN group.
[0071] "Acyl" refers to a RC(=0)- group.
[0072] "Acyloxy" refers to a RC(=0)0- group.
[0073] "Sulfanyl" refers to a -S- moiety.
[0074] "Sulfinyl" or "sulfoxide" refers to a -S(=0)- moiety.
[0075] "Sulfonyl" refers to a -S(=0)2- moiety. [0076] 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-C6alkyl, C3-C8cycloalkyl, aryl, heteroaryl, C2-C6heteroalicyclic, hydroxy, Ci-C6alkoxy, aryloxy, Ci-C6alkylthio, arylthio, Ci-C6alkylsulfoxide, arylsulfoxide, Ci-C6alkylsulfone, arylsulfone, cyano, halo, C2-C8acyl, C2-C8acyloxy, nitro, Ci-C6haloalkyl, Ci-Cefluoroalkyl, and amino, including Ci-C6alkylamino, and the protected derivatives thereof.
[0077] By way of example only, an optional substituents may be LSRS, wherein each Ls is independently selected from a bond, -0-, -C(=0)-, -S-, -S(=0)-, -S(=0)2-, - H-, - HC(=0)-, - C(=0) H-, S(=0)2 H-, - HS(=0)2-, -OC(=0)NH-, - HC(=0)0-, -(Ci-C6alkyl)-, or -(C2- C6alkenyl)-; and each Rs is independently selected from H, (Ci-C4alkyl), (C3-C8cycloalkyl), heteroaryl, aryl, and Ci-C6heteroalkyl. Optionally substituted non-aromatic groups may be substituted with one or more oxo (=0). The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art.
[0078] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.
[0079] As used herein, 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.
[0080] The term "modulate," as used herein, 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.
[0081] As used herein, the term "modulator" refers to a compound that alters an activity of a molecule. For example, 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. In certain embodiments, a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molecule. In certain embodiments, an inhibitor completely prevents one or more activities of a molecule. In certain embodiments, a modulator is an activator, which increases the magnitude of at least one activity of a molecule. In certain embodiments the presence of a modulator results in an activity that does not occur in the absence of the modulator. [0082] As used herein, the term "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.
[0083] The term "cancer," as used herein refers to an abnormal growth of cells, which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread). The 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.
[0084] The term "carrier," as used herein, refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.
[0085] The terms "co-administration" or the like, as used herein, 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.
[0086] The term "diluent" 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.
[0087] The terms "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. For example, 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.
[0088] The terms "enhance" or "enhancing," as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, 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.
[0089] The terms "kit" and "article of manufacture" are used as synonyms.
[0090] By "pharmaceutically acceptable," as used herein, 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.
[0091] The term "subject" or "patient" encompasses mammals and non-mammals. Examples of 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. Examples of non- mammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.
[0092] The terms "treat," "treating" or "treatment," as used herein, 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.
Compounds
[0093] Disclosed herein is a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer there
Figure imgf000022_0001
(Formula A)
wherein,
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; L is a bond or -CR7R8-;
X is -0-, -S-, or - RX;
Z is -0-, -S-, or - RZ;
Yi is N or CR1;
Y2 is N or CR2;
R1 and R2 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, - RcRd, -S(=0)2R , - RaS(=0)2R , -S(=0)2 RcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0) RcRd, -OC(=0) RcRd, - RaC(=0) RcRd, - RaC(=0)R , - RaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R3 is halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, -NRcRd, -S(=0)2R , -NRaS(=0)2R , - S(=0)2NRcRd, -C(=0)R , -OC(=0)R , -C02Ra, -OC02Ra, -C(=0)NRcRd, - OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaC(=0)R , -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R4 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, -NRcRd, -S(=0)2R , -NRaS(=0)2R , -S(=0)2NRcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0)NRcRd, -OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaC(=0)R , - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R5 is halogen;
each R6 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, -NRcRd, -S(=0)2R , -NRaS(=0)2R , -S(=0)2NRcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0)NRcRd, -OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaC(=0)R , - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R7 and R8 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, - NRcRd, -S(=0)2R , -NRaS(=0)2R , -S(=0)2NRcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0)NRcRd, -OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaC(=0)R , - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Rx and Rz are independently hydrogen, -SRa, -S(=0)R , -S(=0)2R , -S(=0)2NRcRd, - C(=0)R , -C02Ra, -C(=0)NRcRd, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each Ra is independently hydrogen, optionally substituted Ci-C6 alkyl, optionally
substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each Rc and Rd are independently hydrogen, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or Rc and Rd together with the nitrogen atom to which they are attached form an
optionally substituted heterocycloalkyl or optionally substituted heteroaryl; n is 1-3;
m is 1-4; and
p is 1-6.
[0094] In some embodiments of a compound of Formula (A), L is -CR7R8-; and R7 and R8 are independently hydrogen, halogen, -CN, -ORa, optionally substituted Ci-C6 alkyl, or optionally substituted Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (A), L is - CR7R8-; and R7 and R8 are independently hydrogen, halogen, or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (A), L is -CR7R8-; and R7 and R8 are independently hydrogen, halogen, or Ci-C6 alkyl. In some embodiments of a compound of Formula (A), L is -CR7R8-; and R7 and R8 are hydrogen. In some embodiments of a compound of Formula (A), L is a bond.
[0095] In some embodiments of a compound of Formula (A), 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.
[0096] In some embodiments of a compound of Formula (A), Yi is CR1; and Y2 is CR2. In some embodiments of a compound of Formula (A), Yi is N; and Y2 is CR2. In some embodiments of a compound of Formula (A), Y1 is CR1; and Y2 is N.
[0097] In some embodiments of a compound of Formula (A), 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.
[0098] In some embodiments, the compound of Formula (A) has the structure of Formula (Al):
Figure imgf000025_0001
a Al)
wherein,
pi is 1-3.
[0099] In some embodiments of a compound of Formula (Al), pi is 1 or 2. In some
embodiments of a compound of Formula (Al), 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.
[00100] In some embodiments of a compound of Formula (A) or (Al), X is - RX-; and Rx is hydrogen, -C(=0)R , -C02Ra, -C(=0) RcRd, or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (A) or (Al), X is - RX-; and Rx is hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (A) or (Al), X is - RX-; and Rx is hydrogen. In some embodiments of a compound of Formula (A) or (Al), X is -S-. In some embodiments of a compound of Formula (A) or (Al), X is -0-.
[00101] In some embodiments of a compound of Formula (A) or (Al), Z is - RZ-; and Rz is hydrogen, -C(=0)R , -C02Ra, -C(=0) RcRd, or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (A) or (Al), Z is - RZ-; and Rz is Ci-C6 alkyl or hydrogen. In some embodiments of a compound of Formula (A) or (Al), Z is -S-. In some embodiments of a compound of Formula (A) or (Al), Z is -0-.
[00102] In some embodiments, the compound of Formula (A) or Formula (Al) has the structure of Formula (A2):
Figure imgf000026_0001
(Formula A2)
wherein,
R5 is halogen; and
p2 is 1 or 2.
[00103] In some embodiments of a compound of Formula (A2), R5 is fluoro, chloro, bromo, or iodo. In some embodiments of a compound of Formula (A2), R5 is fluoro.
[00104] In some embodiments of a compound of Formula (A2), p2 is 1. In some embodiments of a compound of Formula (A2), p2 is 2.
[00105] In some embodiments of a compound of Formula (A), (Al), or (A2), 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. In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is cyclopentyl. In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is cyclohexyl.
[00106] In some embodiments of a compound of Formula (A), (Al), or (A2), 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.
[00107] In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperizanyl, morpholinyl, dioxanyl, oxetanyl, tetrahydropyranyl, or tetrahydrofuranyl. In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperizanyl, tetrahydropyranyl, or
tetrahydrofuranyl. In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is tetrahydropyranyl. [00108] In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is a heteroaryl. In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is a monocyclic heteroaryl.
[00109] In some embodiments of a compound of Formula (A), (Al), or (A2), 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.
[00110] In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is a 5- membered heteroaryl. In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is imidazolyl, pyrazolyl, triazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl.
[00111] In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is a bicyclic heteroaryl. In some embodiments of a compound of Formula (A), (Al), or (A2), Ring A is indolyl, indolinyl, indazolyl, indolizinyl, benzimidazolyl, azaindolyl, benzofuranyl, benzothiophenyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl,
phthalazinyl,quinoxalinyl, 1,8-naphthyridinyl, or pteridinyl.
[00112] In some embodiments of a compound of Formula (A), (Al), or (A2), 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. 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.
[00113] In some embodiments of a compound of Formula (A), (Al), or (A2), each R4 is independently hydrogen, halogen, -CN, -ORa, - RcRd, -C02Ra, -C(=0) RcRd, or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (A), (Al), or (A2), each R4 is independently hydrogen, halogen, or -CN.
[00114] In some embodiments of a compound of Formula (A), (Al), or (A2), R1 and R2 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (A), (Al), or (A2), R1 and R2 are hydrogen.
[00115] In some embodiments of a compound of Formula (A), (Al), or (A2), R3 is halogen, - CN, -S(=0)2R , optionally substituted Ci-C6 alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (A), (Al), or (A2), R3 is -S(=0) 2R . In some embodiments of a compound of Formula (A), (Al), or (A2), R is optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (A), (Al), or (A2), R3 is optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (A), (Al), or (A2), R3 is optionally substituted heteroaryl. In some embodiments of a compound of Formula (A), (Al), or (A2), R3 is -S(=0)2R or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (A), (Al), or (A2), R3 is -S(=0)2R or Ci-C6 haloalkyl.
[00116] In some embodiments of a compound of Formula (A), (Al), or (A2), R3 is -S(=0)2R , Ci-C6 alkyl, Ci-C6 haloalkyl, or heteroaryl optionally substituted with halogen, Ci-C6 alkyl, Ci- C6 haloalkyl, or Ci-C6 hydroxyalkyl.
[00117] In some embodiments of a compound of Formula (A), (Al), or (A2), R3 is a monocyclic heteroaryl. In some embodiments of a compound of Formula (A), (Al), or (A2), R3 is a 6-membered heteroaryl or a 5-membered heteroaryl. In some embodiments of a compound of Formula (A), (Al), or (A2), R3 is a 6-membered heteroaryl. In some embodiments of a compound of Formula (A), (Al), or (A2), R3 is selected from pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, or triazinyl.
[00118] In some embodiments of a compound of Formula (A), (Al), or (A2), R3 is a 5- membered heteroaryl. In some embodiments of a compound of Formula (A), (Al), or (A2), R3 is imidazolyl, pyrazolyl, triazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl.
[00119] In some embodiments of a compound of Formula (A), (Al), or (A2), R3 is a bicyclic heteroaryl. In some embodiments of a compound of Formula (A), (Al), or (A2), R3 is indolyl, indolinyl, indazolyl, indolizinyl, benzimidazolyl, azaindolyl, benzofuranyl, benzothiophenyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinoxalinyl, 1,8- naphthyridinyl, or pteridinyl.
[00120] In some embodiments of a compound of Formula (A), (Al), or (A2), each R6 is independently hydrogen, halogen, -CN, -ORa, - RcRd, -C02Ra, -C(=0) RcRd, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (A), (Al), or (A2), each R6 is independently hydrogen, halogen, -CN, -ORa, -NRcRd,or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (A), (Al), or (A2), each R6 is independently hydrogen, halogen, -ORa,or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (A), (Al), or (A2), each R6 is independently hydrogen, halogen, or -ORa. In some embodiments of a compound of Formula (A), (Al), or (A2), R6 is - ORa. [00121] In some embodiments of a compound of Formula (A), (Al), or (A2), R5 is fluoro, chloro, bromo, or iodo. In some embodiments of a compound of Formula (A), (Al), or (A2), R5 is fluoro.
[00122] In some embodiments of a compound of Formula (A), (Al), or (A2), each Ra is independently hydrogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (A), (Al), or (A2), each Ra is hydrogen.
[00123] In some embodiments of a compound of Formula (A), (Al), or (A2), each R is independently Ci-C6 alkyl or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (A), (Al), or (A2), each R is independently C1-C3 alkyl or C1-C3 haloalkyl. In some
embodiments of a compound of Formula (A), (Al), or (A2), each R is independently -CH3, - CH2F, -CHF2, or -CF3.
[00124] In some embodiments of a compound of Formula (A), (Al), or (A2), each Rc and Rd are independently hydrogen, Ci-C6 alkyl, or Ci-C6 haloalkyl.
[00125] Also disclosed herein is a compound of Formula (B), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000029_0001
B)
wherein,
Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Li is a bond or -CR17R18-;
Xi is -0-, -S-, or - RX1;
Figure imgf000029_0002
W2 is N or CR12;
R11 and R12 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, - RcRd, -S(=0)2R , - RaS(=0)2R , -S(=0)2 RcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0) RcRd, -OC(=0) RcRd, - RaC(=0) RcRd, - RaC(=0)R , - RaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R14 and R19 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , - N02, - RcRd, -S(=0)2R , - RaS(=0)2R , -S(=0)2 RcRd, -C(=0)R , -OC(=0)R , - C02Ra, -OC02Ra, -C(=0) RcRd, -OC(=0) RcRd, - RaC(=0) RcRd, - RaC(=0)R , - RaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R15 is halogen;
each R16 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, -NRcRd, -S(=0)2R , -NRaS(=0)2R , -S(=0)2NRcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0)NRcRd, -OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaC(=0)R , - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R17 and R18 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, - NRcRd, -S(=0)2R , -NRaS(=0)2R , -S(=0)2NRcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0)NRcRd, -OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaC(=0)R , - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
RX1 is hydrogen, -SRa, -S(=0)R , -S(=0)2R , -S(=0)2NRcRd, -C(=0)R , -C02Ra, - C(=0)NRcRd, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each Ra is independently hydrogen, optionally substituted Ci-C6 alkyl, optionally
substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each Rc and Rd is independently hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or Rc and Rd together with the nitrogen atom to which they are attached form an
optionally substituted heterocycloalkyl or optionally substituted heteroaryl; s is 1-3;
u is 1-4;
w is 1-4; and
v is 1-6.
17 18 17 18
[00126] In some embodiments of a compound of Formula (B), Li is -CR R -; and R and R are independently hydrogen, halogen, -CN, -ORa, optionally substituted Ci-C6 alkyl, or optionally substituted Ci-C6 heteroalkyl. In some embodiments of a compound of Formula (B),
17 18 17 18
Li is -CR R ; and R and R are independently hydrogen, halogen, or Ci-C6 alkyl. In some
17 18 17 18
embodiments of a compound of Formula (B), Li is -CR R -; and R and R are hydrogen. In some embodiments of a compound of Formula (B), Li is a bond.
[00127] In some embodiments of a compound of Formula (B), s is 1 or 2. 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.
[00128] In some embodiments of a compound of Formula (B), Wi is CR11; and W2 is CR12. In some embodiments of a compound of Formula (B), Wi is N; and W2 is CR12. In some embodiments of a compound of Formula (B), Wi is CR11; and W2 is N.
[00129] In some embodiments of a compound of Formula (B), 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.
[00130] In some embodiments, the compound of Formula (B) has the structure of Formula (Bl):
Figure imgf000032_0001
(Formula Bl)
wherein,
vl is 1-4.
[00131] In some embodiments of a compound of Formula (Bl), 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.
[00132] In some embodiments of a compound of Formula (B) or (Bl), X1 is - RX1-; and RX1 is hydrogen, -C(=0)R , -C02Ra, -C(=0) RcRd, or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (B) or (B l), Xi is - RX1-; and RX1 is hydrogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (B) or (Bl), Xi is - RX1-; and RX1 is hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (B) or (Bl), X1 is - RX1-; and RX1 is hydrogen. In some embodiments of a compound of Formula (B) or (Bl), Xi is -S-. In some embodiments of a compound of Formula (B) or (Bl), Xi is -0-.
[00133] In some embodiments, the compound of Formula (B) or Formula (Bl) has the structure of Formula (B2):
Figure imgf000032_0002
(Formula B2)
wherein,
R15 is halogen; and
v2 is 1 or 2.
[00134] In some embodiments of a compound of Formula (B2), R15 is fluoro, chloro, bromo, or iodo. In some embodiments of a compound of Formula (B2), R15 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.
[00136] In some embodiments of a compound of Formula (B), (Bl), or (B2), 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. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is cyclopentyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is cyclohexyl.
[00137] In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is phenyl or naphtyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is phenyl.
[00138] In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperizanyl, morpholinyl, dioxanyl, oxetanyl, tetrahydropyranyl, or tetrahydrofuranyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperizanyl, tetrahydropyranyl, or
tetrahydrofuranyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is tetrahydropyranyl.
[00139] In some embodiments of a compound of Formula (B), (Bl), or (B2), 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.
[00140] In some embodiments of a compound of Formula (B), (Bl), or (B2), 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
embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is selected from pyridinyl, pyrimidyl, pyrazinyl, or pyridazinyl.
[00141] In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is a 5- membered heteroaryl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is imidazolyl, pyrazolyl, triazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl.
[00142] In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is a bicyclic heteroaryl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring B is indolyl, indolinyl, indazolyl, indolizinyl, benzimidazolyl, azaindolyl, benzofuranyl, benzothiophenyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl,
phthalazinyl,quinoxalinyl, 1,8-naphthyridinyl, or pteridinyl.
[00143] In some embodiments of a compound of Formula (B), (Bl), or (B2), 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. 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.
[00144] In some embodiments of a compound of Formula (B), (Bl), or (B2), each R14 is independently hydrogen, halogen, -CN, -ORa, - RcRd, -C02Ra, -C(=0) RcRd, or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), each R14 is independently hydrogen, halogen, or -CN.
[00145] In some embodiments of a compound of Formula (B), (Bl), or (B2), 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.
[00146] In some embodiments of a compound of Formula (B), (Bl), or (B2), 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.
[00147] In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring C is a 5- membered heteroaryl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring C is imidazolyl, pyrazolyl, triazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring C is a 5-membered heteroaryl selected from pyrrolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, or pyrazolyl. In some
embodiments of a compound of Formula (B), (Bl), or (B2), 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.
[00148] In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring C is a bicyclic heteroaryl. In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring C is indolyl, indolinyl, indazolyl, indolizinyl, benzimidazolyl, azaindolyl, benzofuranyl, benzothiophenyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, 1,8-naphthyridinyl, or pteridinyl. [00149] In some embodiments of a compound of Formula (B), (Bl), or (B2), 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.
[00150] In some embodiments of a compound of Formula (B), (Bl), or (B2), Ring C is a heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperizanyl, tetrahydropyranyl, or tetrahydrofuranyl.
[00151] In some embodiments of a compound of Formula (B), (Bl), or (B2), 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.
[00152] In some embodiments of a compound of Formula (B), (Bl), or (B2), each R19 is independently hydrogen, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 hydroxyalkyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), each R19 is independently hydrogen, fluoro, chloro, bromo, iodo, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, - CH2CF3, -CH2OH, -CH(CH3)OH, or -CH2CH2OH. In some embodiments of a compound of Formula (B), (Bl), or (B2), each R19 is independently hydrogen, fluoro, -CH3, -CH2CH3, - CH(CH3)2, -CHF2, or -CH2OH.
[00153] In some embodiments of a compound of Formula (B), (Bl), or (B2), R11 and R12 are independently hydrogen, halogen, or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), R11 and R12 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), R11 and R12 are independently hydrogen or halogen. In some embodiments of a compound of Formula (B), (Bl), or (B2), R11 and R12 are hydrogen.
[00154] In some embodiments of a compound of Formula (B), (Bl), or (B2), each R16 is independently hydrogen, halogen, -CN, -ORa, - RcRd, -C02Ra, -C(=0) RcRd, optionally substituted Ci-C6 alkyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments of a compound of Formula (B), (Bl), or (B2), each R16 is independently hydrogen, halogen, -CN, -ORa, -NRcRd,or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), each R16 is independently hydrogen, halogen, -ORa,or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (B), (Bl), or (B2), each R16 is independently hydrogen, halogen, or -ORa. In some embodiments of a compound of Formula (B), (B l), or (B2), each R16 is -ORa.
[00155] In some embodiments of a compound of Formula (B), (B l), or (B2), R15 is fluoro, chloro, bromo, or iodo. In some embodiments of a compound of Formula (B), (B l), or (B2), R15 is fluoro.
[00156] In some embodiments of a compound of Formula (B), (B l), or (B2), each Ra is independently hydrogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (B), (B l), or (B2), each Ra is hydrogen.
[00157] In some embodiments of a compound of Formula (B), (B l), or (B2), each R is independently Ci-C6 alkyl or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (B), (B l), or (B2), each R is independently C1-C3 alkyl or C1-C3 haloalkyl. In some
embodiments of a compound of Formula (B), (B l), or (B2), each R is independently -CH3, - CH2F, -CHF2, or -CF3.
[00158] In some embodiments of a compound of Formula (B), (B l), or (B2), each Rc and Rd are independently hydrogen, Ci-C6 alkyl, or Ci-C6 haloalkyl.
[00159] In various embodiments, provided herein are compounds of Formula I, Formula II, Formula III, Formula IV, or Formula III, or pharmaceutically acceptable salt, solvate, analog, prodrug, isomer or tautomer thereof:
Figure imgf000036_0001
IV
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 - R4;
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 -CR4; Gl and G2 can not both be -CH when X is -O; n is 1 or 2;
Formula V: independently, X is -O or - H-; Gl is -CH, or -N; G2 is -CH, -N, or -CR4; G3 is -C, -O, -C(=0)-, -S(=0), or -N; independently, R10 and Rn are -H, halo, cyano, -0-Ra, -N(Ra)2, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, -(C=0)-Ra, -(C=0)-N(Ra)2, -S(=0)2-Ra, - S(=0)2-N(Ra)2, -S(=0)-Ra, -S(=0)-N(Ra)2; Ra is -H, alkyl, cycloalkyl, heteroalkyl,
cycloheteroalkyl, or heteroaryl; G3, R10 and Rn can be taken together to form a 3 to 6 membered spiro cycloalkyl or heteroalkyl ring; R10 and Rn are not attached to G3 when G3 is - O, -S(=0), or -C(=0)-; and
Formula VI: independently, X is -O or - H-; Y is -CH or -N; independently, G4, G5 and G6 are - G3R10R11, wherein G3 is -C, -O, -C(=0)-, -S(=0), -S(=0)2, or -N; independently, R10 and Rn are -H, halo, cyano, -0-Ra, -N(Ra)2, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, -(C=0)-Ra, -(C=0)-N(Ra)2, -S(=0)2-Ra, -S(=0)2-N(Ra)2, -S(=0)-Ra, -S(=0)-N(Ra)2; Ra is -H, alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, or heteroaryl; G3, R10 and Rn can be taken together to form a 3 to 6 membered spiro alkyl or heteroalkyl ring; R10 and Rn are not attached to G3 when G3 is -O, -S(=0)2, -S(=0), or -C(=0)-); G4, G5 and G6 and the atoms attached can be taken together to form a 5-membered cycloalkyl, heterocycloalkyl, or heterocycle ring; and
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;
R2 is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halogen, sulfonyl, alkyl or heteroalkyl;
R3 is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, alkylamino, carboxaldehyde, carboxylic acid, oxime, ester, amido, or acyl, or R2/R3 and the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one sp3 hybridized carbon, wherein the 5- or 6-membered carbocycle is optionally substituted with at least one R3;
R4 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 R3 group;
R5 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 R3 group;
R6 is hydrogen, hydroxyl or amino; each of R7 is independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl and cycloalkyl, or the two R4 groups and the carbon to which they are attached form C3-C8 cycloalkyl or C5-C8 heterocycloalkyl;
R8 is O or R12, wherein Ri2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cyano, heterocycloalkyl, heteroaryl, and heteroalkyl; and
R9 is hydrogen, deuterium, or alkyl.
[00160] In one embodiment, 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,
tetrahydrofuranyl, and tetrahydropyranyl. In another embodiment, Ri is phenyl phenyl substituted with a halogen and a cyano. In another embodiment, the phenyl group is substituted with a halogen and a cyano at the 3 and 5 positions. In a further embodiment the halogen is a fluoro group.
[00161] In some embodiments, Ri is selected from the group consisting of:
Figure imgf000038_0001
[00162] In one embodiment, R2 is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halogen, sulfonyl, alkyl or heteroalkyl. [00163] In further embodiments, R2 is nitro, cyano, halo, alkyl, heteroalkyl, alkynyl or alkenyl. In some embodiments, R2 iscyano, halo, or alkyl. In some embodiments, R2 is halo or alkyl. In another embodiment, R2 is haloalkyl. In a further embodiment, R2 is halogen. In yet another embodiment, R2 is fluorine, chlorine, bromine or iodine. In some embodiments, R2 is C1-C4 fluoroalkyl. In yet another embodiment, R2 is selected from -CH2F, CHF2, and -CF2CH3.
[00164] In some embodiments, R2/R3 and atoms they are attached to form a 5- or 6-membered carbocycle with at least one sp3 carbon. Representative compounds with the carbocycle include, but are not limited to, the following:
Figure imgf000039_0001
wherein the carbocycle formed by linking R2 and R3 may be optionally substituted with fluoro, chloro, hydroxyl, alkyl, or heteroalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, and cyano.
[00165] In one embodiment,R3 is hydrogen, halogen, hydroxyl, amino, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, alkylamino, carboxaldehyde, carboxylic acid, oxime, ester, amido, or acyl. In another embodiment, R3 is hydrogen, halo, cyano, oxime, alkyl, heteroalkyl, alkenyl, alkynyl, alkyamino, or acyl. In another embodiment, R3 is -(CH2)nOH, wherein n is 1, 2, or 3. In a nother embodiment, R2 is halo, cyano, or alkyl; R3 is -CH20H; R4 is fluoroalkyl, sulfonamide, sulfinyl, sulfonyl, or sulfoximinyl.
[00166] In another embodiment, R3 is hydroxyl or amino.
[00167] In one embodiment, R4 is selected from -CF3, -S(=0)CH3, -S(=0)2CH3, -S(=0)2CHF2, -S(=0)2CH2F, -S(=0)2CF3, -S(=0)2 H2, -S(=0)2 HCH3, -S(=0)(= H)CH3, - S(=0)(= H)CH2F, -S(=0)(=NH)CHF2, -S(=0)(= H)CF3.
[00168] In some embodiments R4 is selected from, but not limited to the following:
Figure imgf000039_0002
[00169] In some embodiments, R4/R5 and atoms they are attached to form a 5- or 6-membered heterrocycles or carbocycle with at least one sp3 carbon. Representative compounds include, but are not limited to, the following:
Figure imgf000040_0001
wherein the heterocycle or carbocycle formed by linking R4 and R5 may be optionally substituted with fluoro, chloro, hydroxyl, alkyl, or heteroalkyl. In a further embodiment, the substituent(s) is selected fro the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, and cyano.
[00170] Inone embodiment, R7 is a halogen. In another embodiment, R7 is a fluoro group. In a further embodiment R5 is a substituted alkyl group. In a further embodiment R5 is CHF2. In yet another embodiment, R5 is a halogen. In yet another embodiment R5 is a chloro group. In a further embodiment, R6 is a hydroxyl group. In yet another embodiment, R9 is hydrogen.
[00171] In some specific embodiments, the compounds have the following structures, or harmaceutically acceptable salt, solvate, analog, prodrug, isomer or tautomer thereof:
Figure imgf000040_0002
VII VIII IX X XI XII
Figure imgf000040_0003
XIII XIV XV XVI XVII XVIII wherein Ri, X, Y, Z, R4, R5, R7, Ri2, Gi, G2, G4, G5, G6, and n are described herein.
[00172] In some specific embodiments, the compounds have the following structures, or pharmaceutically acceptable salt, solvate, analog, prodrug, isomer or tautomer thereof:
Figure imgf000042_0001
-41 - wherein Ri, X, Y, R5, R6, R8, R10, Rn, Gi, G2, G3, G5, G6, and n are described herein.
[00173] In some embodiments, the compound described herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
CN s~- fluorob enzonitril e
Figure imgf000048_0001
-
Figure imgf000049_0001
Figure imgf000050_0001
[00174] In some embodiments, the compound described herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:
Figure imgf000050_0002
Figure imgf000051_0001
Further Forms of Compounds Disclosed Herein
Isomers/Stereoisomers
[00175] In some embodiments, 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, entgegen (E), and zusammen (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. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, 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. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent.
Labeled compounds
[00176] In some embodiments, the compounds described herein exist in their isotopically- labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, 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. Examples of 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 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35 S, 18F, and 36C1, 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. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method.
[00177] In some embodiments, 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.
Pharmaceutically acceptable salts
[00178] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some
embodiments, the methods disclosed herein include methods of treating diseases by
administering such pharmaceutically acceptable salts as pharmaceutical compositions.
[00179] In some embodiments, 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. In some embodiments, 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. [00180] 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, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate,
monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate,
propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.
[00181] Further, 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-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l- carboxylic acid), 3 -phenyl propionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.
[00182] In some embodiments, 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. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(Ci-4 alkyl)4, and the like.
[00183] 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
quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
Solvates
[00184] In some embodiments, 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.
[00185] 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
[00186] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described 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.
Metabolites
[00187] A "metabolite" of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term "metabolized," as used herein, 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. For example, 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
Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). 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
[00188] In some embodiments, compounds described herein are prepared as prodrugs. A "prodrug" 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. 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. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is
enzymatically metabolized by one or more steps or processes to the biologically,
pharmaceutically or therapeutically active form of the compound.
[00189] To produce a prodrug, 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. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those of skill in this art, once a pharmaceutically active compound is known, can design prodrugs of the compound. See, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. (1985), each of which is incorporated by reference herein in its entirety.
[00190] 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.
[00191] 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. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64: 181 or 210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated by reference herein in their entirety.
Polymorphs
[00192] Compounds described herein may be in various forms, including but not limited to, amorphous forms, milled forms and nano-particulate forms. In addition, 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.
[00193] 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
(MDCS), Thermogravimetric analysis (TGA), and Thermogravi-metric and Infrared analysis (TG/IR). 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.
Pharmaceutical Compositions/Formulations
[00194] Pharmaceutical 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
Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference in their entirety.
[00195] Provided herein are pharmaceutical compositions that include a compound described herein and a pharmaceutically acceptable diluent(s), excipient(s), and/or carrier(s). In addition, 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.
[00196] A pharmaceutical composition, as used herein, 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. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease or condition to be treated. Preferably, 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.
[00197] For intravenous injections, 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. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For other parenteral injections, appropriate formulations may include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally known in the art.
[00198] For oral administration, 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.
[00199] Pharmaceutical preparations 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. If desired, 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.
[00200] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions 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.
[00201] Pharmaceutical preparations 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. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
[00202] For buccal or sublingual administration, the 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. The
pharmaceutical composition 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. Optionally, 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. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
[00203] 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.
[00204] 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. An absorption enhancer or carrier can include absorbable pharmaceutically acceptable solvents to assist passage through the skin. For example, 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.
[00205] For administration by inhalation, 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,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol 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.
[00206] 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. In suppository forms of the compositions, 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.
[00207] Pharmaceutical 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.
[00208] The pharmaceutical 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. In addition, the 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.
[00209] In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In some embodiments, 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. In addition, the pharmaceutical compositions may include other medicinal or
pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or
emulsifying agents, solution promoters, salts for regulating the osmotic pressure, and/or buffers. In addition, the pharmaceutical compositions can also contain other therapeutically valuable substances.
[00210] Methods for the preparation of 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.
[00211] 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. In some embodiments, a liquid composition may include a gel formulation. In other embodiments, the liquid composition is aqueous.
[00212] Aqueous suspensions can also contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulosic polymers, e.g.,
hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl- containing polymers. Useful 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.
[00213] Compositions may also include solubilizing agents to aid in the solubility of a compound described herein. The term "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
ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.
[00214] 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. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
[00215] Compositions may also include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such 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.
[00216] Other 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.
[00217] Still other 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.
[00218] Still other 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.
[00219] Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition.
[00220] Alternatively, other delivery systems for 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. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various 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. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
[00221] All of the formulations described herein may benefit from antioxidants, metal chelating agents, thiol containing compounds and other general stabilizing agents. Examples of such 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. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof. Methods of Dosing and Treatment Regimens
[00222] The compounds described herein can be used in the preparation of medicaments for the treatment or prevention of a specific disease or condition. In addition, 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,
pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.
[00223] The compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, 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
therapeutically effective amounts by routine experimentation (including, but not limited to, a dose escalation clinical trial).
[00224] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose. "In this use, the precise amounts also depend on the patient's state of health, weight, and the like. It is considered well within the skill of the art for one to determine such prophylactically effective amounts by routine experimentation (e.g., a dose escalation clinical trial). When used in a patient, 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.
[00225] In the case wherein the patient's condition does not improve, upon the doctor's discretion 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.
[00226] In the case wherein the patient's status does improve, upon the doctor's discretion 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%.
[00227] Once improvement of the patient's conditions has occurred, 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.
[00228] 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. In general, however, 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.
[00229] The pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, 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.
Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, 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.
[00230] 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.
[00231] 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 LD50 (the dose lethal to 50% of the population) and the ED50 (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 LD50 and ED50. 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
concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. [00232] In effecting treatment of a patient in need of such treatment, 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,
intravenously, transdermally, intranasally, rectally, vaginally, occularly, topically, sublingually, and buccally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, intraadiposally, intrathecally and via local delivery for example by catheter or stent.
[00233] One skilled in the art can readily select the proper form and route of administration depending upon the particular characteristics of the compound selected, the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances. The pharmaceutical 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.
[00234] In another embodiment, 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. In another embodiment, the invention provides a method of inhibiting a HIF-2: comprising, contacting the enzyme with a compound of the invention. In a further embodiment, 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.
[00235] "Conditions 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. Where general terms are used herein to describe conditions associated with HIF-2 it is understood that the more specifically described conditions mentioned in the various diagnostic manuals and other materials are included within the scope of this invention. In some embodiments, the condition associated with HIF-2 is cancer. In some embodiments, the condition associated with HIF-2 is Von Hippel- Lindau disease. In some embodiments, the condition associated with HIF-2 is pulmonary arterial hypertension (PAH).
[00236] In some embodiments, the condition associated with HIF-2 is cancer. It is understood that the treatment of cancer includes treatment of all neoplasia, regardless of their
histopathological appearance. Particularly, 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 myeloma, lymphomas, basal cell carcinoma, squamous cell carcinoma of both ulcerating and papillary type, osteo sarcoma, Ewing's sarcoma, veticulum cell sarcoma, myeloma, giant cell tumor, islet cell tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuronms, intestinal ganglioneuromas, hyperplastic corneal nerve tumor, marfanoid habitus tumor, Wilm's tumor, seminoma, ovarian tumor, leiomyomater tumor, cervical dysplasia and in situ carcinoma, neuroblastoma, retinoblastoma, myelodysplastic syndrome, mycosis fungicide, rhabdomyosarcoma,
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.
[00237] In some embodiments, the cancer is glioblastoma multiforme. Glioblastoma multiforme (glioblastoma or GBM) is the most common and most aggressive malignant primary brain tumor in humans. They are highly lethal and characterized by extensive necrosis as well as a high rate of angiogenesis. 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 (GBMs) typically contain zones of tissue that are hypoxic, which are highly resistant to radiotherapy, and therefore post-treatment recurrence rates are high.
[00238] 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 Peutz-Jeghers Syndrome (PJS), Cowden disease, Bannayan-Riley-Ruvalcaba Syndrome (BRRS), Proteus syndrome, Lhermitte-Duclos disease and Tuberous Sclerosis (TSC).
[00239] 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.
Diseases that produce fibrotic tissue include emphysema. Repetitive motion disorders that may be treated using the present invention include carpal tunnel syndrome.
[00240] The compounds of the present invention may also be used to treat Von Hippel-Lindau Disease (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%). 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
pheochromocytoma, a pancreatic neuroendocrine tumor, a renal cell carcinoma, or any combinations thereof. In some embodiments, the subject suffers from renal cell carcinoma. In some embodiments, the renal cell carcinoma is clear cell renal cell carcinoma.
[00241] The compounds of the present invention may also be used to treat renal cell carcinoma. Renal cell carcinoma (RCC) 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).
[00242] The initial symptoms of RCC often include: blood in the urine (occurring in 40% of affected persons at the time they first seek medical attention), flank pain (40%), a mass in the abdomen or flank (25%), weight loss (33%>), fever (20%>), high blood pressure (20%>), night sweats and generally feeling unwell. When RCC metastasises, it most commonly spreads to the lymph nodes, lungs, liver, adrenal glands, brain or bones. Immunotherapy and targeted therapy have improved the outlook for metastatic RCC. RCC is also associated with a number of paraneoplastic syndromes (PNS) which are conditions caused by either the hormones produced by the tumour or by the body's attack on the tumour and are present in about 20% of those with RCC. These syndromes most commonly affect tissues which have not been invaded by the cancer. The most common PNSs seen in people with RCC are: high blood calcium levels, polycythaemia (the opposite of anemia, due to an overproduction of erythropoietin),
thrombocytosis (too many platelets in the blood, leading to an increased tendency for blood clotting and bleeds) and secondary amyloidosis.
[00243] In some embodiments, compounds of the present invention may also be used to treat a cardiovascular disease. Exemplary 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, Budd-Chiari syndrome, Paget-Schroetter disease, coronary heart disease, coronary artery disease, need for coronary revascularization, peripheral artery disease, a pulmonary circulatory disease, pulmonary embolism, a cerebrovascular disease, cellular proliferation and endothelial dysfunction, graft occlusion or failure, need for or an adverse clinical outcome after peripheral bypass graft surgery, need for or an adverse clinical outcome after coronary artery bypass (CABG) surgery, failure or adverse outcome after angioplasty, internal mammary artery graft failure, vein graft failure, autologous vein grafts, vein graft occlusion, ischaemic diseases, intravascular coagulation, cerebrovascular disease, or any other cardiovascular disease related to obesity or an overweight condition. In some embodiments, the cardiovascular disease is pulmonary arterial hypertension (PAH).
[00244] 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.
[00245] 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.
[00246] 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 abstractive diseases, chronic uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosis, retinopathy of prematurity, Eales disease, diabetic retinopathy, macular degeneration, Bechets diseases, infections causing a retinitis or chroiditis, presumed ocular histoplasmosis, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, trauma and post- laser complications, diseases associated with rubesis (neovascularization of the angle), diseases caused by the abnormal proliferation of fibrovascular or fibrous tissue including all forms of proliferative vitreoretinopathy, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea, phylectenulosis, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, Mooren's ulcer, Terrien's marginal degeneration, marginal keratolysis, polyarteritis, Wegener sarcoidosis, scleritis, periphigoid radial keratotomy, neovascular glaucoma and retrolental fibroplasia, syphilis, Mycobacteria infections, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections, protozoan infections, and Kaposi sarcoma, Alzheimer's disease, Parkinson's disease amyotrophic lateral sclerosis (ALS), epilepsy, seizures, Huntington's disease, polyglutamine diseases, traumatic brain injury, ischemic and hemorrhaging stroke, cerebral ischemias or neurodegenerative disease, including apoptosis-driven neurodegenerative disease, caused by traumatic injury, acute hypoxia, ischemia or glutamate neurotoxicity.
[00247] For example, it is understood that 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
multisystem granulomatous disorder.
[00248] For example, it is understood that 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.
[00249] The compounds of the present invention are also useful for treating obesity, diabetes, insulin resistance, metabolic syndrome, and hyperlipidemia.
Combination Therapy
[00250] Disclosed herein are combination therapy using a compounds disclosed herein and an additional therapeutic agent.
[00251] 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. It is noted that 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.
[00252] 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.
[00253] In some embodiments, 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, angiostatin™ protein, endostatin™ 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-dehydroproline, thiaproline, beta-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone, methotrexate, mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin, beta.-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodium thiomalate, d-penicillamine (CDPT), beta-1- anticollagenase-serum, alpha-2-antiplasmin, bisantrene,lobenzarit disodium, n-(2- carboxyphenyl-4-chloroanthronilic acid disodium or "CCA", thalidomide, angostatic steroid, cargboxynaminolmidazole, metalloproteinase inhibitors such as BB94. Other anti-angiogenesis agents that may be used 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.
[00254] In some embodiments, 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. In some embodiments, the VEGFR-TK inhibitor is selected from pazopanib, bevacizumab, sunitinib, sorafenib, axitinib, ponatinib, cabozantinib, regorafenib , cabozantinib, vandetanib, ramucirumab, lenvatinib, and ziv-aflibercept .
[00255] NAE inhibitors, VPS34 inhibitors, Aurora kinase, including Aurora A inhibitors, and EGFR inhibitors (both antibodies and kinase inhibitors) are useful in combination with the compounds of the present invention.
[00256] In some embodiments, 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
(carboplastin and cisplatin). 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.
[00257] In some embodiments, the additional therapeutic agent is an antibiotic. Examples of 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.
[00258] In some embodiments, 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.
[00259] In some embodiments, 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.
[00260] In some embodiments, 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). These plant-derived agents generally act as antimitotic agents that bind to tubulin and inhibit mitosis. 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.
[00261] In some embodiments, 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. In some embodiments, the immunotherapy agent is selected from
alemtuzumab, atezolizumab, ipilimumab, ofatumumab, nivolumab, pembrolizumab, rituximab, and durvalumab.
[00262] As used herein, 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. In determining the effective amount, the dose, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific condition, disorder, or disease involved; the degree of or involvement or the severity of the condition, disorder, or disease, the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. An effective amount of the present use invention, including a compound of the 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.
[00263] In a particular embodiment 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.
[00264] 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
manufacturer, doses, conditions to be treated, and the use of the compound or pharmaceutical composition.
[00265] In another embodiment 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.
Preparation of Compounds
[00266] The synthesis of compounds described herein may be accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof.
[00267] Compounds described herein may be synthesized using standard synthetic techniques known to those of skill in the art or using methods known in the art in combination with methods described herein. In addition, solvents, temperatures and other reaction conditions presented herein may vary according to those of skill in the art.
[00268] 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. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3.sup.rd Ed., (Wiley 1999), each of which is incorporated by reference herein in its entirety.
[00269] General methods for the preparation of compound as disclosed herein may be derived from known reactions in the field, and the reactions may be modified by the use of appropriate reagents and conditions, as would be recognized by the skilled person, for the introduction of the various moieties found in the formulae as provided herein. As a guide the following synthetic methods may be utilized. Having now generally described the invention, the same will be more readily understood through reference to the following examples which are provided by way of illustration, and are not intended to be limiting of the present invention, unless specified.
Example 1: General Procedure for synthesis of compound Example 1
Figure imgf000075_0001
Example 1a Example 1b Example 1d Example 1e
nBuLi
THF/-10°C/2 h
Step 4
Figure imgf000075_0002
Example 1f Example 1g Example 1i
Figure imgf000075_0003
Step 1: Example lb
[00270] To a solution of Example la (32 g, 246.2 mmol) and /PrNH2 (15 g, 246.2 mmol) in dry THF (550 mL) was added NBS (92 g, 516.9 mmol) portion wise at -40°C. After addition, 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). The combined organic layers were concentrated and the residue was purified by silica gel chromatography (Petroleum Ether/EtOAc = 97/3) to afford crude product Example lb (50 g, crude yield 98%) as a yellow oil, which was directly used for the next step. MS [M-l]" = 207.0/209.0.
Step 2: Example Id
[00271] A mixture of Example lb (50 g, 240.2 mmol), Example lc (59 g, 288.5 mmol) and K2C03 (100 g, 721.1 mmol) in DMF (400 mL) was stirred at ambient temperature for 20 hours. 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 Na2S04, 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.
Step 3: Example le
[00272] To a solution of Example Id (40 g, 121.2 mmol) in EtOH (100 mL) / H20 (50 mL) was added LiOHH20 (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 Na2S04, 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.
Step 4: Example If
[00273] 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). The combined organic phase was washed with brine, dried over Na2S04, 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 If (1.5 g, yield 28%) as a yellow oil.1H NMR (400 MHz, Chloroform-i ) δ 7.54 (td, J= 9.1, 4.2 Hz, 1H), 6.88 (ddd, J= 9.3, 7.3, 2.7 Hz, 1H).
Step 5: Example lg
[00274] A mixture of Example If (300 mg, 1.46 mmol) and MeS02Na (152 mg, 1.49 mmol) in DMSO (3 mL) was stirred at room temperature for 2 hours. Water (10 mL) was added, the mixture was extracted by EtOAc (20 mL*3). The combined organic phase was washed with brine, dried over Na2S04, 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 lg (150 mg, yield 39%) as a yellow solid. MS [M+l]+= 267.0.
Step 6: Example li
[00275] To a solution of Example lg (90 mg, 0.33 mmol) in DMF (1.5 mL) was added
Example lh (129 mg, 1.02 mmol) and K2C03 (141 mg, 1.02 mmol). The mixture was stirred at ambient temperature for 1.5 hours. Water (20 mL) was added, the mixture was extracted by EtOAc (30 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure to give the crude product Example li (310 mg) as a yellow oil which was used for next step without any further purification. MS [M+l]+= 311.0.
Step 7: Example lk
[00276] To a 10-mL Schlenk tube was added Example li (310 mg, 1.0 mmol), Example lj (162 mg, 1.5 mmol), K2C03 (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 Na2S04, 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.
1H MR (400 MHz, Chloroform-i ) δ 7.73 (d, J= 8.7 Hz, 1H), 6.91 (d, J= 8.7 Hz, 1H), 4.80 (s, 1H), 4.52 (s, 2H), 4.30-4.23 (m, 2H), 3.16 (s, 5H), 2.94-2.82 (m, 2H).
Step 8: Example 11
[00277] To a solution of Example lk (60 mg, 0.15 mmol) in DCM (1 mL) was added perchloric acid (0.5 mL). The mixture was allowed to stir at ambient temperature for 24 hours. The reaction was quenched by adding satd. NaHC03 aqueous solution slowly until pH= 7 to 8. The mixture was extracted by EtOAc (10 mL*2). The combined organic phase was washed with brine, dried over Na2S04, 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 (31 mg, yield 59%) as a white solid. MS [M+l]+= 354.9.
Step 9: Example 1
[00278] To a solution of Example 11 (31 mg, 0.09 mmol) in THF (1 mL) was added
NaBH(OAc)3 (28 mg, 0.13 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, extracted with EtOAc (15 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure to give the crude product which was further purified by prep-HPLC to give the pure product Example 1 (5.6 mg, yield 18%) as a white solid. MS [M+23]+= 379.0.1H NMR (400 MHz, OMSO-d6) δ 7.56 (d, J= 8.7 Hz, 1H), 7.29 (d, J= 5.1 Hz, 1H), 7.27 (d, J= 6.4 Hz, 1H), 5.49 (dd, J= 10.1, 7.5 Hz, 1H), 4.95 (s, 1H), 3.24 (s, 3H), 2.79 (t, J = 14.1 Hz, 2H).
Example 2: General Procedure for synthesis of compound Example 2
Figure imgf000078_0001
Example 1i Example 2b Example 2c Example 2
Step 1: Example 2b
[00279] A mixture of Example li (1.7 g, 5.5 mmol), Example 2a (900 mg, 6.6 mmol) and K2C03 (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 Na2S04, 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.
Step 2: Example 2c
[00280] Example 2b (740 mg, 1.73 mmol) and HC104 (2 mL) in DCM (6 mL) was stirred at
25°C for two days. The mixture was basified by sat. NaHC03 to pH= 7 to 8 and extracted by
EtOAc (30 mL*3). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure to give the crude product Example 2c (710 mg) as a light yellow oil, which was used for the next step directly without any other
purification.
Step 3: Example 2
[00281] To a solution of Example 2c (560 mg, 1.46 mmol) in DCM (25 mL) was added
RuCl(p-cymene)[(R,R)-Ts-DPEN] (CAS: 192139-92-7, 20 mg, 0.029 mmol), TEA (295 mg, 2.92 mmol), HC02H (202 mg, 4.39 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 2 (306 mg, yield 55%) as a white solid. MS [M-l]" = 384.0.1H NMR (400 MHz, Chloroform-^ δ 7.69 (d, J= 8.6 Hz, 1H), 7.26-7.20 (m, 2H), 7.11 (dt, J= 2.3, 1.1 Hz, 1H), 7.03 (dt, J= 9.2, 2.3 Hz, 1H), 5.77 (dd, J= 10.8, 2.9 Hz, 1H), 3.24 (s, 3H). Example 3: General Procedure for synthesis of Example 3
Figure imgf000079_0001
Example 1i Step 1 Example 3b Step 2 Example 3c Step 3 Example 3
Step 1: Example 3b
[00282] A solution of Example li (310 mg, 1.0 mmol) and Example 3a (136 mg, l .Ommol) in DMF (5 mL) was treated with Cs2C03 (391 mg, 1.2 mmol) and 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 Na2S04, 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.
1H MR (400 MHz, Chloroform-i ) δ 7.73 (d, J= 8.7 Hz, 1H), 7.38 (d, J= 8.7 Hz, 1H), 7.25 (s, 1H), 7.18-7.06 (m, 2H), 6.28 (s, 1H), 4.59-4.52 (m, 2H), 4.28 (d, J= 7.0 Hz, 2H), 3.17 (s, 3H). Step 2: Example 3c
[00283] A solution of Example 3b (100 mg, 0.23 mmol) in DCM (1 mL) at 25°C was treated with perchloric acid (70% in water, lmL) and stirred for 18 hours. The reaction mixture was carefully quenched by the addition of sat. NaHC03 (100 mL), and then extracted with DCM (50 mL*3). The combined organic phase was washed with brine, dried over Na2S04, 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.
Step 3: Example 3
[00284] Sodium borohydride (11 mg, 0.29 mmol) was added to an ice cooled solution of
Example 3c (55 mg, 0.14 mmol) in THF (5 mL). The reaction mixture was stirred for 10 min, after which it was quenched with sat. H4C1. The resulting mixture was extracted with EtOAc (50 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure to give the crude product which was further purified by prep-HPLC to give Example 3 (5 mg, yield 9%) as a white solid. MS [M+l]+= SSS. l H MR (400 MHz, Chloroform-ύ δ 7.60 (d, J= 8.6 Hz, 1H), 7.37 (d, J= 8.6 Hz, 1H), 7.13 (dd, J = 15.9, 8.8 Hz, 2H), 6.28 (s, 1H), 5.74 (d, J= 11.4 Hz, 1H), 3.79 (d, J= 4.3 Hz, 1H), 3.19 (s, 3H). Example 4: General Procedure for synthesis of Example 4
Figure imgf000080_0001
Example 1i Step l Example 4b Step 2 Example 4c Step 3 Example 4
Step 1: Example 4b
[00285] A solution of Example li (140 mg, 0.45 mmol) and Example 4a (140 mg, 0.54 mmol) in DMF (2 mL) was treated with K2C03 (120 mg, 0.9mmol) and stirred at 80°C for 18 hours. 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 Na2S04, 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. 1H MR (400 MHz, Chloroform-i ) δ 7.76 (d, J= 8.7 Hz, 1H), 7.20 (d, J= 8.7 Hz, 1H), 6.68 (tt, J = 8.8, 2.3 Hz, 1H), 6.63-6.55 (m, 1H), 6.49-6.40 (m, 1H), 4.54 (td, J= 6.2, 5.3, 3.1 Hz,2H), 4.32- 4.25 (m, 2H), 3.20 (s, 3H).
Step 2: Example 4c
[00286] A solution of Example 4b (50.0 mg, 0.12 mmol) in DCM (2 mL) at 25°C was treated with perchloric acid (1 mL) and stirred for 18 hours. The reaction mixture was carefully quenched by the addition of sat. NaHC03 (100 mL), and then extracted with EtOAc (10 mL*3). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure to give the crude product Example 4c (50 mg, crude yield 100%) as a light yellow oil. MS [M-18-l]" = 357.
Step 3: Example 4
[00287] Sodium borohydride (7.6 mg, 0.2 mmol) was added to an ice cooled solution of
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. H4C1. The resulting mixture was extracted with EtOAc (20 mL*2). The combined organic phase was washed with brine, dried over Na2S04, 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. MS [M-l]" = 377.0.1H MR (400 MHz, Chloroform-i ) δ 7.64 (d, J= 8.7 Hz, 1H), 7.19 (d, J= 8.7 Hz, 1H), 6.69 (dd, J= 9.8, 7.5 Hz, 1H), 6.61 (dd, J= 7.6, 2.2 Hz, 2H), 5.76 (d, J= 10.9 Hz, 1H), 3.73 (d, J= 8.2 Hz, 1H), 3.22 (s, 3H). Example 5: G neral Procedure for synthesis of compound Example 5
Figure imgf000081_0001
Example 1g
Step 1: Example 5b
[00288] To a suspension of Example lg (280 mg, 1.05 mmol) and Na2C03 (167 mg, 1.58 mmol) in DMF (5 mL) was added 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 Na2S04, 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. MS [M+l]+= 376.9.1H MR (400 MHz, Chloroform-i ) δ 7.93 (d, J= 8.5 Hz, 1H), 7.47 (d, J= 8.5 Hz, 1H), 6.77 (tt, J= 8.8, 2.3 Hz, 1H), 6.72-6.63 (m, 2H), 3.36 (s, 3H).
Step 2: Example 5
[00289] To a solution of 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). The combined organic phase was washed with brine, dried over Na2S04, 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 5 (205 mg, yield 60%) as a white solid. MS [M-20-l]" = 356.9.1H MR (400 MHz, Chloroform-i ) δ 7.64 (d, J= 8.7 Hz, 1H), 7.19 (d, J= 8.7 Hz, 1H), 6.69 (tt, J= 8.8, 2.3 Hz, 1H), 6.65-6.55 (m, 2H), 5.76 (dd, J= 10.9, 2.9 Hz, 1H), 3.75 (s, 1H), 3.22 (s, 3H). Example 6: General Procedure for synthesis of compound Example 6
Figure imgf000082_0001
Example 6a Step 1 Example 6b Step 2 Example 6c Step 3 Example 6d
Example 1 i
Figure imgf000082_0002
Step 4 Example 6e Step 5 Example 6f Step 6 Example 6
Step 1: Example 6b
[00290] 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 Na2S04, filtrated and concentrated under reduced pressure to give the crude product Example 6b (3.9g, yield 77%) as a white solid.
Step 2: Example 6c
[00291] 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 Na2S04, 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. MS [M+l]+= 184.1.1H MR (400 MHz, Chloroform-i ) δ 7.70 (t, J= 1.5 Hz, 1H), 7.67 (ddd, J= 7.4, 2.5, 1.5 Hz, 1H), 7.49 (ddd, J= 7.6, 2.5, 1.3 Hz, 1H), 2.79 (s, 3H).
Step 3: Example 6d
[00292] Example 6c (366 mg, 2.0 mmol) was dissolved in trifluoroacetic anhydride (4 mL), which was heated at reflux for 30 min. Volatiles were removed by evaporation. To the residue was added MeOH/TEA=l : 1 (5 mL) with stirring, and the mixture was concentrated to dryness. The residue was dissolved in EtOAc (50 mL), and washed with sat. H4C1 (100 mL). The organic phase was dried over Na2S04, filtrated and concentrated under reduced pressure to give the crude product Example 6d (300 mg, yield 98%) as a white solid, which was used directly for the next step without further purification. MS [M-l]" = 152.1. 1H MR (400 MHz, DMSO- d6) δ 7.77 (dt, J= 5.8, 2.2 Hz, 1H), 7.68 (p, J= 2.9 Hz, 1H), 7.61-7.57 (m, 1H).
Step 4: Example 6e
[00293] A solution of Example 6d (310 mg, 1.0 mmol) and Example li (154 mg, 1.1 mmol) in DMF (5 mL) was treated with Cs2C03 (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 Na2S04, 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. MS [M+l]+= 444.0.1H MR (400 MHz, Chloroform-i ) δ 7.73 (d, J= 8.3 Hz, 1H), 7.48- 7.42 (m, 2H), 7.33 (dt, J= 8.2, 1.7 Hz, 2H), 4.56-4.49 (m, 2H), 4.30 -4.24 (m, 2H), 3.21 (s, 3H). Step 5: Example 6f
[00294] A solution of Example 6e (300 mg, 0.68 mmol) in DCM (2 mL) at 25°C was treated with perchloric acid (2 mL) and stir for 18 hours. The reaction mixture was carefully quenched by the addition of sat. NaHC03 (100 mL), and then extracted with EtOAc (50 mL*3). The combined organic phase was washed with brine, dried over Na2S04, 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.
Step 6: Example 6
[00295] Sodium borohydride (38 mg, 1.0 mmol) was added to a cooled (0°C) solution of
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. H4C1. The resulting mixture was extracted with EtOAc (50 mL*2). The combined organic phase was washed with brine, dried over Na2S04, 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. MS [M+l]+= 402.1.1H MR (400 MHz, Chloroform-i ) δ 7.61 (d, J= 8.2 Hz, 1H), 7.49- 7.40 (m, 2H), 7.34 (d, J= 7.9 Hz, 2H), 5.75 (dt, J= 11.0, 3.8 Hz, 1H), 3.72 (d, J= 4.6 Hz, 1H), 3.23 (s, 3H). Example 7: General Procedure for synthesis of compound Example 7
Example 7c
Example 7a
Figure imgf000084_0001
Example 7d
Figure imgf000084_0002
Step 3 Example 7e Step 4 Example 7
Step 1: Example 7b
[00296] To the solution of Example lg (300 mg, 1.13 mmol), Example 7a (0.28 mL, 2.81 mmol) in CHCI3 (5 mL) was added BF3 Et20 (0.35 mL, 2.81 mmol). The mixture was degassed with N2 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. NaHC03 (100 mL), and then extracted with DCM (100 mL*3). The combined organic phase was washed with brine, dried over Na2S04, 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 7b (150 mg, yield 37%) as a brown solid.
Step 2: Example 7d
[00297] A mixture of Example 7b (115 mg 0.32 mmol), Example 7c (0.59 mL, 0.48 mmol) and Cs2C03 (157 mg 0.48 mmol) in DMF (5 mL) was degassed with N2 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 Na2S04, 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 7d (40 mg, yield 27%) as a yellow oil. Step 3: Example 7e
[00298] A mixture of Example 7d (35 mg, 0.08 mmol) and PIFA (147 mg 0.36 mmol), in MeCN/H20 (1.5 mL/0.2 mL) was stirred at room temperature for 18 hours. The mixture was diluted with sat. NaHC03 (30 mL), and then extracted with EtOAc (30 mL*3). The combined organic phase was washed with brine, dried over Na2S04, 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 7e (25 mg, yield 90%) as a yellowish oil. Step 4: Example 7
[00299] The solution of Example 7e (25 mg, 0.07 mmol), RuCl(p-cymene)[(R,R)-Ts-DPEN] (CAS: 192139-92-7, 1 mg, 0.001 mmol), TEA (14 mg, 0.14 mmol) and HC02H (9 mg, 0.20 mmol) in DCM (2 mL) was degassed with N2 and stirred at room temperature for 18 hours. The mixture was quenched with sat. NaHC03 (30 mL), and then extracted with DCM (30 mL*3). The combined organic layer washed with brine (30 mL), dried over Na2S04 and concentrated. The residue was purified by prep-HPLC to give the desire product Example 7 (12.8 mg, yield 38%) as a white solid. MS [M-18+l]+= 453.1H MR (400 MHz, Chloroform-i ) δ 7.61 (d, J = 8.7 Hz, 1H), 7.07 (d, J= 8.7 Hz, 1H), 5.69 (dt, J= 11.3, 3.6 Hz, 1H), 4.20 (d, J= 6.4 Hz, 2H), 3.71 (d, J= 4.3 Hz, 1H), 3.17 (s, 3H), 2.86 -2.74 (m, 2H), 2.71 (d, J= 8.5 Hz, 1H), 2.49 (qd, J = 13.3, 6.1 Hz, 2H).
Example 8: General Procedure for synthesis of compound Example 8
Example 1c
Figure imgf000085_0001
Example 8a Example 8b Example 8c
Figure imgf000085_0002
Example 8e Example 8f Example 8g
Figure imgf000085_0003
Step 1: Example 8b
[00300] To a solution of Example 8a (50 g, 278 mmol) and zPrNH2 (25 g, 417 mmol) in dry THF (600 mL) was added BS (74 g, 417 mmol) portion wise at -40°C. After addition, 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). The combined organic phase was washed with brine, dried over Na2S04, 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 8b (66 g, yield 92%) which was used for next step directly as a yellow oil. Step 2: Example 8c
[00301] A mixture of Example 8b (30 g, 11.6 mol), Example lc (28 g, 13.9 mol) and K2C03 (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 Na2S04, 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.
Step 3: Example 8d
[00302] To a solution of Example 8c (22 g, 57.7 mol) in EtOH (40 mL) / H20 (20 mL) was added LiOHH20 (7.3 g, 173.2 mol). The mixture was stirred at ambient temperature for 3 hours. The aqueous phase was acidified by IN HC1 solution to pH = 3 to 4, and extracted with DCM (50 mL*3). The combined organic phase was washed with brine, dried over Na2S04, 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 8d (3.4 g, yield 17%) as a yellow oil.
Step 4: Example 8e
[00303] 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 Na2S04, 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. 1H NMR (400 MHz, Chloroform-i ) δ 7.54 (td, J= 9.1, 4.2 Hz, 1H), 6.88 (ddd, J= 9.3, 7.3, 2.7 Hz, 1H).
Step 5: Example 8f
[00304] To a solution of Example 8e (1.0 g, 3.9 mmol) in DMF (15 mL) was added Example lh (1.5 g, 11.7 mmol) and K2C03 (1.6 g, 11.7 mmol). The mixture was stirred at ambient temperature for 3 hours. The reaction mixture was used for the next step directly without any further purification.
Step 6: Example 8g
[00305] To a 10-mL Schlenk tube were added Example 8f (240 mg, 0.8 mmol), Example lj (130 mg, 1.2 mmol), K2C03 (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 Na2S04, 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. 1H MR (400 MHz, Chloroform-i ) δ 7.36 (d, J= 8.6 Hz, 1H), 6.86 (d, J= 8.6 Hz, 1H), 4.77 (d, J= 9.3 Hz, 1H), 4.39-4.33 (m, 2H), 4.28-4.23 (m, 2H), 3.13 (ddt, J= 18.9, 12.3, 6.5 Hz, 2H), 2.94-2.81 (m, 2H).
Step 7: Example 8h
[00306] To a solution of Example 8g (92 mg, 0.24 mmol) in DCM (3 mL) was added perchloric acid (1 mL). The mixture was allowed to stir at 25°C for 16 hours. The reaction was quenched by adding sat. NaHC03 aqueous solution slowly until pH = 7-8. The mixture was extracted by EtOAc (20 mL*2). The combined organic phase was washed with brine, dried over Na2S04, 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 8h (71 mg, yield 87%) as a colorless oil.
1H MR (400 MHz, Chloroform-i ) δ 7.49 (d, J= 8.4 Hz, 1H), 7.12 (d, J= 8.4 Hz, 1H), 4.84 (s, 1H), 3.26-3.13 (m, 2H), 2.92 (tdd, J= 15.2, 12.6, 5.4 Hz, 2H).
Step 8: Example 8
[00307] To a solution of Example 8h (71 mg, 0.21 mmol) in THF (1.5 mL) was added
NaBH(OAc)3 (66 mg, 0.31 mmol) slowly at 0°C. After addition, the mixture was stirred at ambient temperature for 16 hours. The reaction was quenched by adding water slowly, extracted with EtOAc (15 mL*2). The organic layer was washed by brine, dried over Na2S04, filtered and concentrated. The crude product was purified by prep-HPLC to afford Example 8 (32 mg, yield 45%) as a colorless oil. 1H MR (400 MHz, Chloroform-i ) δ 7.33 (d, J= 8.6 Hz, 1H), 6.87 (d, J = 8.6 Hz, 1H), 5.44 (t, J= 8.3 Hz, 1H), 4.84-4.75 (m, 1H), 3.19-3.07 (m, 2H), 2.94-2.79 (m, 2H), 2.65 (d, J= 7.2 Hz, 1H). Example 9: General Procedure for synthesis of compound Example 9
Figure imgf000088_0001
Eixample 8f Example 9a Example 9b Example 9
Step 1: Example 9a
[00308] To a 10-mL Schlenk tube were added Example 8f (280 mg, 0.93 mmol), Example 2a (155 mg, 1.12 mmol), K2C03 (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 Na2S04, 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. 1H NMR (400 MHz, Chloroform-i ) δ 7.46 (d, J= 8.6 Hz, 1H), 7.24 (d, J= 8.6 Hz, 1H), 7.17 (ddd, J= 7.6, 2.4, 1.3 Hz, 1H), 7.08 (dt, J = 2.2, 1.1 Hz, 1H), 6.97 (dt, J= 9.3, 2.3 Hz, 1H), 4.43-4.36 (m, 2H), 4.29-4.24 (m, 2H).
Step 2: Example 9b
[00309] To a solution of Example 9a (99 mg, 0.24 mmol) in DCM (3 mL) was added perchloric acid (1.5 mL). The mixture was allowed to stir at 25°C for 7 days. The reaction was quenched by adding sat. NaHC03 aqueous solution slowly until pH = 7-8. The mixture was extracted by DCM (20 mL*2). The combined organic phase was washed with brine, dried over Na2S04, 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 9b (58 mg, yield 66%) as a colorless oil.1H NMR (400 MHz, Chloroform-i ) δ 7.59 (d, J= 8.5 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.26 -7.24 (m, 1H), 7.16 (dt, J= 2.3, 1.1 Hz, 1H), 7.08 (dt, J= 8.9, 2.3 Hz, 1H). Step 3: Example 9
[00310] To a solution of Example 9b (58 mg, 0.16 mmol) in THF (2 mL) was added
NaBH(OAc)3 (100 mg, 0.47 mmol) slowly at 0°C. After addition, the mixture was stirred at ambient temperature for 16 hour. The reaction was quenched by adding water slowly, extracted with EtOAc (15 mL*2). The combined organic phase was washed with brine, dried over
Na2S04, 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 9 (47 mg, yield 81%) as a colorless oil. 1H MR (400 MHz, Chloroform-i ) δ 7.44 (d, J= 8.6 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 7.18 (dt, J= 7.6, 1.7 Hz, 1H), 7.08-7.06 (m, 1H), 6.99 (dt, J= 9.3, 2.3 Hz, 1H), 5.51 (t, J= 8.3 Hz, 1H), 2.76 (dd, J= 7.0, 1.3 Hz, 1H).
Exam le 10: General Procedure for synthesis of compound Example 10
Figure imgf000089_0001
Example 8e Example 10a Example 10
Step 1: Example 10a
[00311] A mixture of Example 8e (500 mg, 2.0 mmol), Example 4a (280 mg, 2.1 mmol) and Na2C03 (420 mg, 3.9 mmol) in DMF (10 mL) was stirred at 75°C for 16 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 Na2S04, 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.
Step 5: Example 10
[00312] To a solution of Example 10a (440 mg, 1.2 mmol) in DCM (6 mL) was added 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). 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 10 (189 mg, yield 43%) as a colorless oil. MS [M-l or 20]" = 346.9. 1H MR (400 MHz,
Chloroform-ύ δ 7.39 (d, J= 8.6 Hz, 1H), 7.18 (d, J= 8.6 Hz, 1H), 6.64 (tt, J= 8.8, 2.3 Hz, 1H), 6.60-6.52 (m, 2H), 5.50 (d, J= 9.7 Hz, 1H), 2.74 (s, 1H).
Ex mple 11: General Procedure for synthesis of compound Example 11
Figure imgf000089_0002
Example 8e Example 11a Example 11 Step 1: Example 11a
[00313] To a suspension of Example 8e (512 mg, 2.0 mmol) and Na2C03 (318 mg, 3 mmol) in DMF (8 mL) was added Example 2a (329 mg, 2.4 mmol). The mixture was stirred at 75°C for 18 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (20 mL*3). The combined organic phase was washed with brine, dried over Na2S04, 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 11a (260 mg, yield 35%) as a yellow solid. MS [M+l]+ = 374.0. 1H MR (400 MHz, Chloroform-i ) δ 7.59 (d, J= 8.4 Hz, 1H), 7.51 (d, J= 8.5 Hz, 1H), 7.30 -7.27 (m, 1H), 7.16 (dt, J= 2.2, 1.1 Hz, 1H), 7.08 (dt, J = 8.9, 2.3 Hz, 1H).
Step2: Example 11
[00314] 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). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product as a yellow solid Example 11 (l lOmg, yield 42%) as a colorless viscous oil. MS[M-1]" = 358.0. 1H MR (400 MHz,
Chloroform-^ δ 7.44 (d, J= 8.6 Hz, 1H), 7.21 (s, 1H), 7.17 (ddd, J= 7.6, 2.3, 1.3 Hz, 1H), 7.07 (dt, J= 2.2, 1.1 Hz, 1H), 6.99 (dt, J = 9.3, 2.3 Hz, 1H), 5.50 (t, J= 8.3 Hz, 1H), 2.98 (d, J= 7.1 Hz, 1H).
Example 12: General Procedure for synthesis of compound Example 12
Figure imgf000090_0001
Example 12a
Step 1: Example 12
[00315] To a solution of Example 12a (55 mg, 0.21 mmol), Example 12b (18 mg, 0.21 mmol) and PPh3 (65 mg, 0.25 mmol) in THF (1.5 mL) was added DIAD (50 mg, 0.25 mmol) slowly at 0°C under N2 atmosphere. After addition, the mixture was stirred from 0°C to ambient temperature for 16 hours. 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. 1H NMR (400 MHz, Chloroform-^ δ 7.58 (d, J= 8.8 Hz, 1H), 7.03 (d, J= 8.7 Hz, 1H), 5.67 (dt, J= 11.6, 3.7 Hz, 1H), 4.93 (dt, J= 5.7, 2.9 Hz, 1H), 3.66 (d, J= 4.2 Hz, 1H), 3.16 (s, 3H), 1.96 (dd, J= 13.5, 6.8 Hz, 4H), 1.90-1.82 (m, 2H), 1.67 (d, J= 7.5 Hz, 2H).
Example 13: General Procedure for synthesis of compound Example 13
Figure imgf000091_0001
Example 12a
Step 1: Example 13
[00316] To a solution of Example 12a (55 mg, 0.21 mmol), Example 13a (21 mg, 0.21 mmol) and PPh3 (65 mg, 0.25 mmol) in THF (1.5 mL) was added DIAD (50 mg, 0.25 mmol) slowly at 0°C under N2 atmosphere. After addition, the mixture was stirred from 0°C to 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 13 (24 mg, yield 33%) as a white solid. MS [M+l-18]+= 333.0. 1H NMR (400 MHz, Chloroform-ύ δ 7.59 (d, J= 8.7 Hz, 1H), 7.08 (d, J= 8.7 Hz, 1H), 5.69 (dd, J= 11.3, 2.9 Hz, 1H), 4.72 (dq, J= 7.9, 3.9 Hz, 1H), 4.06-3.95 (m, 2H), 3.71 (s, 1H), 3.60 (ddd, J= 11.6, 8.2, 3.2 Hz, 2H), 3.17 (s, 3H), 2.10-2.03 (m, 2H), 1.91-1.82 (m, 2H).
Example 14: General Procedure for synthesis of compound Example 14
Figure imgf000091_0002
Step 1
Example 12a
Step 1: Example 14
[00317] To a solution of Example 12a (55 mg, 0.21 mmol), Example 14a (21 mg, 0.21 mmol) and PPh3 (65 mg, 0.25 mmol) in THF (1.5 mL) was added DIAD (50 mg, 0.25 mmol) slowly at 0°C under N2 atmosphere. After addition, the mixture was stirred from 0°C to 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 14 (21 mg, yield 29%) as a white solid. MS [M+l-18]+= 331.0.
1H MR (400 MHz, Chloroform-i ) δ 7.56 (d, J= 8.7 Hz, 1H), 7.05 (d, J= 8.7 Hz, 1H), 5.67 (ddd, J= 11.4, 4.4, 3.0 Hz, 1H), 4.46 (tt, J= 8.7, 3.8 Hz, 1H), 3.73 (d, J= 4.3 Hz, 1H), 3.16 (s, 3H), 2.04-1.97 (m, 2H), 1.83 (s, 2H), 1.62 (d, J= 10.3 Hz, 3H), 1.44-1.33 (m, 3H).
Example 15: General Procedure for synthesis of compound Example 15
Figure imgf000092_0001
Example 15a Step 1 Example 15b Step 2 Example 15c Step 3 Example 15d
Figure imgf000092_0002
Step 7 Example 15i Step 8 Example 15j Step 9 Example 15
Step 1: Example 15b
[00318] A mixture of Example 15a (10.6 g, 0.05 mol), Example 4a (6.5 g, 0.05 mol), and Cs2C03 (16.3 g, 0.05 mol) in DMA (100 mL) was heated at 80°C with stirring for 1.5 hours under N2 atmosphere. Then, the reaction solution was poured into water (500 mL). After extraction with EtOAc (200 mL*2),The combined organic phase was washed with brine, dried over Na2S04, 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 15b (14.6 g, yield 93%) as a white solid. MS [M+l]+ = 313.
Step 2: Example 15c
[00319] A mixture of Example 15b (14.5 g, 47 mmol) and w-CPBA (20.0 g, 117 mmol) in CHC13 (150 mL) was heated at 30°C with stirring for 3 hours under N2 atmosphere. Sat. Na2S03 (50 mL) was added to quench the reaction, followed by addition of NaHC03 (300 mL). After extraction with CH2CI2 (100 mL*2), the combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure to give the crude product
Example 15c (14.1 g) as a yellow liquid. MS [M+l]+ = 329/331.
Step 3: Example 15d
[00320] The crude of Example 15c (14.0 g, 43 mmol) was added into a round-bottom flask, to which MeOH (200 mL) and con. HC1 (0.5 mL) were added. The mixture was stirred for 1.5 hours at room temperature, and then sat. NaHC03 was added to adjust pH to 5. The reaction solution was filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product Example 15d (6.6 g, yield 52%) as a yellow oil. MS [M-l]" =299.
Step 4: Example 15f
[00321] A mixture of Example 15d (6.6 g, 22 mmol), Example 15e (4.2 g, 33 mmol), Pd(dppf)Cl2 (1.6 g, 2 mmol), and Na2C03 (7.0 g, 67 mmol) in dioxane/H20 (80/20 mL) was stirred at 100°C with stirring for 3 hours under N2 atmosphere. Then, the reaction solution was filtrated to remove the solid. After extraction with EtOAc (50 mL*2), the combined organic phase was washed with brine, dried over Na2S04, 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 15f (5.6 g, yield 84%) as a yellow liquid. MS [M-l]" = 303. Step 5: Example 15g
[00322] To a mixture of Example 15f (5.2 g, 17 mmol), /Pr H2 (0.6 g, 15 mmol) in THF (100 mL) at -10°C was added NBS (2.7 g, 15 mol). The mixture was warmed up to room temperature and stirred for 3.5 hours. Then, the reaction solution was poured into water (500 mL). After extraction with EtOAc (200 mL*2),the combined organic phase was washed with brine, dried over Na2S04, 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 15g (5.7 g, yield 87%) as a white solid. MS [M+l]+ = 383/385.
Step 6: Example 15h
A mixture of Example 15g (5.2 g, 13 mmol), Example lc (3.3 g, 16 mmol), and K2C03 (5.6 g, 40 mmol) in DMF (60 mL) was stirred at 30°C with stirring for 2 hours under N2 atmosphere. Then, the reaction solution was poured into water (200 mL). After extraction with EtOAc (100 mL*2), combined organic layer was dried over Na2S04, and concentrated under reduced pressure to give the crude product Example 15h (5.8 g, crude yield 85%) as a yellow oil.
[00323] 1H MR (400 MHz, Chloroform-i ) δ 7.42 (dd, J= 5.1, 1.2 Hz, 1H), 7.40 (d, J= 8.7 Hz, 1H), 7.28 (dd, J= 3.6, 1.2 Hz, 1H), 7.12 (dd, J= 5.2, 3.6 Hz, 1H), 7.05 (d, J= 8.6 Hz, 1H), 6.59 (tt, J= 8.7, 2.1 Hz, 1H), 6.55 (dd, J= 8.0, 2.2 Hz, 2H), 4.36 (q, J= 7.2 Hz, 2H), 1.33 (t, J =
7.2 Hz, 3H).
Step 7: Example 15i
[00324] A mixture of crude Example 15h (5.8 g, 12 mmol) and LiOHH20 (1.5 g, 35 mmol) in EtOH/H20 (40/20 mL) was stirred at room temperature for 2 hours. Then, the reaction solution was poured into water (50 mL). After extraction with EtOAc (50 mL*2), the combined organic phase was washed with brine, dried over Na2S04, 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 15i (1.1 g, yield 20%) as a white solid.
1H NMR (400 MHz, OMSO-d6) δ 7.65 (dd, J= 5.1, 1.2 Hz, 1H), 7.36 (d, J= 8.6 Hz, 1H), 7.30 (dd, J= 3.6, 1.2 Hz, 1H), 7.21-7.07 (m, 2H), 7.05-6.95 (m, 1H), 6.81 (dd, J= 8.5, 2.3 Hz, 2H). Step 8: Example 15j
[00325] 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). After extraction with EtOAc (20 mL*2), the combined organic phase was washed with brine, dried over Na2S04, 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 15j (595 mg, yield 77%) as a yellow solid.1H NMR (400 MHz, DMSO-i¾) δ 7.93 (dd, J= 3.7, 1.2 Hz, 1H), 7.81 (dd, J= 5.1, 1.2 Hz, 1H), 7.76 (d, J= 8.6 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.24 (dd, J= 5.1, 3.7 Hz, 1H), 7.03 (tt, J= 9.3, 2.3 Hz, 1H), 6.99-6.92 (m, 2H). Step 9: Example 15
[00326] A mixture of Example 15j (200 mg, 0.53 mmol), HCOOH (73 mg, 1.58 mmol), TEA (106 mg, 1.05 mmol), and RuCl(p-cymene)[(R,R)-Ts-DPEN] (CAS: 192139-92-7, 10 mg, 0.016 mmol) was added into a round-bottom flask, to which CH2C12 (2.5 mL) was added. The reaction was stirred at room temperature for 1 hour. Then, water (2 mL) was added to the reaction solution. After extraction with CH2C12 (2 mL*2), organic layer was dried over Na2S04, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the desired product Example 15 (113 mg, yield 56%) as a yellow solid. MS [M+l]+ = 383.1H NMR (400 MHz, DMSO-i¾) δ 7.72-7.64 (m, 2H), 7.43 (d, J= 8.6 Hz, 1H), 7.32 (d, J= 8.6 Hz, 1H), 7.19 (dd, J= 5.1, 3.7 Hz, 1H), 7.02 (tt, J= 9.2, 2.2 Hz, 1H), 6.90 (d, J= 8.4 Hz, 1H), 6.83-6.72 (m, 2H), 5.41 (t, J= 8.8 Hz, 1H). Example 16: General Procedure for synthesis of compound Example 16
Figure imgf000095_0001
Example 1f Step 1 Example 16a Step 2 Example 16b Step 3 Example 16d
2a
Figure imgf000095_0002
Step 4 Example 16e Step 5 Example 16f Step 6
Figure imgf000095_0003
Step 1: Example 16a
[00327] To a solution of Example If (300 mg, 1.5 mmol) in PhCl (2.5 mL) was added TBAB (10 mg, 0.03 mmol) and the mixture was stirred at ambient temperature for a while. KSAc (183 mg, 1.6 mmol) dispersed in water (2 mL) was added drop wise to the solution for 5 min. After being stirred for 1 hour at room temperature, the reaction mixture was diluted with EtOAc (30 mL) and water (20 mL). The organic layers were separated, dried and concentrated. The residue was purified by silica gel chromatography (Petroleum Ether/EtOAc=99/l) to afford the pure product Example 16a (190 mg, yield 50 %) as a yellow oil. 1H NMR (400 MHz, Chloroform- ) δ 7.52 (t, J= 8.9 Hz, 1H), 7.28 (dd, J= 8.5, 3.7 Hz, 1H), 2.51 (s, 3H).
Step 2: Example 16b
[00328] To a solution of Example 16a (190 mg, 0.73 mmol) in MeOH (5 mL) and H20 (2.5 mL) was added K2C03 (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 aqueous phase was collected and acidified by IN HCl to pH=5~6, and then extracted by DCM (20 mL*2) again. The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2S04 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.
Step 3: Example 16d
[00329] To a solution of Example 16b (350 mg, 1.6 mmol) in ACN (8 mL) was added a solution of K2CO3 (4.4 g) in water (8 mL) under N2 atmosphere. The reaction was cooled to - 78°C, and Example 16c (850 mg, 3.2 mmol) was added all in once. The resulting mixture was warmed to ambient temperature and vigorously stirred for another 2 hours. The reaction was partitioned between EtOAc and water, extracted and separated. The organic layers were combined, dried over Na2S04, filtered and concentrated to give a residue which was purified by silica gel chromatography (Petroleum Ether/EtOAc=97/3) to afford the pure product Example 16d (270 mg, yield 63%) as a yellow oil.
1H NMR (400 MHz, Chloroform-i ) δ 7.55 (t, J= 8.9 Hz, 1H), 7.42 (dd, J= 8.6, 3.6 Hz, 1H), 7.08 (t, J= 56.0 Hz, 1H).
Step 4: Example 16e
[00330] Sodium periodate (1.2 g 5.56 mmol) was added all at once to Example 16d (600 mg, 2.22 mmol) and RuCl3 (23 mg, 0.11 mmol) in ACN (10 mL)/CCl4 (10 mL)/H20 (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). The combined organic phase was washed with brine, dried over Na2S04, 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 16e (435 mg, yield 65%) as a yellow solid. MS [M+l]+= 302.9.
Step 5: Example 16f
[00331] A mixture of Example 16e (90 mg, 0.30 mmol), Example lh (75 mg, 0.60 mmol) and K2C03 (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). The combined organic phase was washed with brine, dried over Na2S04, 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 16f (30 mg, yield 29%) as a white solid.1H NMR (400 MHz, Chloroform-i ) δ 7.83 (dd, J= 8.8, 4.0 Hz, 1H), 7.47 (t, J = 8.8 Hz, 1H), 6.43 (t, J= 54.0 Hz, 1H), 4.54-4.50 (m, 2H), 4.31-4.27 (m, 2H). Step 6: Example 16g
[00332] A mixture of Example 16f (30 mg, 0.09 mmol), Example 2a (15 mg, 0.10 mmol) and K2C03 (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 Na2S04, 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. 1H MR (400 MHz, Chloroform- ) δ 7.82 (d, J= 8.8 Hz, 1H), 7.21 (d, J= 8.7 Hz, 1H), 7.03 (s, 1H), 6.93 (d, J= 2.3 Hz, 1H), 6.90- 6.81 (m, 1H), 6.43 (t, J= 54.0 Hz, 1H), 4.50 (d, J= 6.8 Hz, 2H), 4.27 (q, J= 4.8, 3.9 Hz, 2H). Step 7: Example 16h
[00333] Example 16g (30 mg, 0.06 mmol) and HC104 (1.5 mL) in DCM (3 mL) was stirred at 25°C for 3 days. The mixture was basified by sat. NaHC03 to pH=7~8, and then extracted by EtOAc. The organic layer was separated and concentrated to obtain crude product which was further purified by prep-TLC to afford Example 16h (14 mg, yield 52%) as a colorless oil. Step 8: Example 16
[00334] To a solution of Example 16h (14 mg, 0.03 mmol) in THF (1 mL) was added NaBH4 (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 Na2S04, filtered and concentrated. The crude product was purified by prep-HPLC to afford Example 16 (2.5 mg, yield 18%) as a white solid.1H MR (400 MHz, Chloroform-i ) δ 7.72 (d, J= 8.7 Hz, 1H), 7.29-7.27 (m, 1H), 7.24 (s, 1H), 7.18 (dt, J= 2.2, 1.1 Hz, 1H), 7.09 (dt, J= 8.9, 2.3 Hz, 1H), 6.41 (t, J= 53.5 Hz, 1H), 5.66 (d, J= 10.8 Hz, 1H), 3.71 (d, J= 4.7 Hz, 1H).
Example 17: General Procedure for s nthesis of compound Example 17
Figure imgf000097_0001
Example 16h Step 1 Example 17
Step 1: Example 17
[00335] 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. MS [M-l]" = 419.9.1H MR (400 MHz, Chloroform-i ) δ 7.72 (d, J= 8.7 Hz, 1H), 7.29-7.27 (m, 1H), 7.24 (s, 1H), 7.18 (dt, J= 2.2, 1.1 Hz, 1H), 7.09 (dt, J= 8.9, 2.3 Hz, 1H), 6.41 (t, J= 53.5 Hz, 1H), 5.66 (d, J= 10.8 Hz, 1H), 3.71 (d, J= 4.7 Hz, 1H).
Exam le 18: General Procedure for synthesis of compound Example 18
Figure imgf000098_0001
Example 16e Example 8a Example 18
Step 1: Example 18a
[00336] 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 Na2S04, 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.
Step 2: Example 18
[00337] To a solution of Example 18a (146 mg, 0.35 mmol) in DCM (3 mL) was added 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). 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 18 (40 mg, yield 27%) as a brown oil. MS [M-l]" = 412.9.1H MR (400 MHz, Chloroform-i δ 7.67 (d, J= 8.7 Hz, 1H), 7.19 (d, J= 8.7 Hz, 1H), 6.74 (tt, J= 8.8, 2.3 Hz, 1H), 6.70-6.62 (m, 2H), 6.39 (t, J= 53.5 Hz, 1H), 5.65 (ddd, J= 11.0, 4.0, 1.9 Hz, 1H), 3.73 (d, J = 4.1 Hz, 1H). Example 19: General Procedure for s nthesis of compound Example
Figure imgf000099_0001
Example 16f Step 1 Example 19a Step 2 Example 19b
Figure imgf000099_0002
Step 3 Example 19
Step 1: Example 19a
[00338] A mixture of Example 16f (290 mg, 0.8 mmol), Example lj (136 mg, 1.25 mmol) and K2C03 (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 Na2S04, 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.
Step 2: Example 19b
[00339] Example 19a (100 mg, 0.23 mmol) and HC104 (1 mL) in DCM (3 mL) was stirred at 25°C for 24 hours. The mixture was basified by sat. NaHC03 to pH=7~8 and extracted by EtOAc (15 mL*2), separated and concentrated to afford crude Example 19b (85 mg, crude yield 94%) as a white solid which was used for the next step directly.
Step 3: Example 19
[00340] To a solution of Example 19b (85 mg, 0.17 mmol) in DCM (3 mL) was added RuCl( - cymene)[(R,R)-Ts-DPEN] (CAS: 192139-92-7, 3 mg, 0.004 mmol), TEA (44 mg, 0.44 mmol), HCOOH (30 mg, 0.65 mmol). After addition, the mixture was stirred at ambient temperature for 16 hours. 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 19 (5 mg, yield 6%) as a white solid. MS [M-l or 20]" = 371.0. 1H MR (400 MHz, Chloroform-i ) δ 7.67 (d, J= 8.7 Hz, 1H), 6.97 (d, J= 8.7 Hz, 1H), 6.35 (t, J= 53.7 Hz, 1H), 5.60 (d, J= 11.1 Hz, 1H), 4.87 (s, 1H), 3.72 (s, 1H), 3.25-3.12 (m, 2H), 2.98-2.84 (m, 2H).
Example 20: General Procedure for synthesis of compound Example 20
Figure imgf000100_0001
Example 20a Step 1 Example 20b Step 2 Example 20c Step 3 Example 20d
Figure imgf000100_0002
Step 4 Example 20e Step 5 Example 20f Step 6 Example 20g
Figure imgf000100_0003
Step 7 Example 20h Step 8 Example 20
Step 1: Example 20b
[00341] The mixture of Example 20a (21 g, 136 mmol) and pyridine hydrochloride (316 g, 2.7 mol) was degassed with N2 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 Na2S04, 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
[00342] 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 Na2S04, 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.
Step 3: Example 20d
[00343] To the solution of Example 20c (12 g, 74.1 mmol) and propan-2-amine (4.4 g, 74.1 mol) in DCM (400 mL) was added BS (10.5 g, 59.3 mmol) at -40°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The mixture was quenched with ice-water (1 L) and adjusted to pH = 4, which was then extracted with EtOAc (300 mL*3). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure to give the crude product Example 20d (14.5 g, yield 81%) as a light yellow oil, which was used in next step directly.
Step 4 and Step 5: Example 20f
[00344] The mixture of Example 20d (14.5 g, 60.1 mmol), Example lc (12.2 g, 60.1 mmol) and K2C03 (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 Na2S04 and concentrated. The residue was dissolved in THF/EtOH (180 mL/180 mL) and added Li OH (180 mL, 1 N, 181 mmol). The mixture was stirred at room temperature for 2 hours, diluted with water (500 mL), and then extracted with tert-butyl methyl ether (200 mL*3). Then it was adjusted to pH= 2 and extracted with EtOAc (300 mL*5). The combined organic layer was washed with brine (300 mL), dried over Na2S04 and concentrated to give the crude desire product Example 20f (10.4 g, crude yield 48%)) as a light yellow oil, which was used in next step directly.
Step 6: Example 20g
[00345] To a solution of crude Example 20f (10.4 g, 31.1 mmol) in THF (150 mL) was added «-BuLi (241 mg, 0.68 mmol) bellow -60°C. The reaction mixture was stirred at -60°C for 5min. The mixture was quenched with sat. H4C1, and then extracted with EtOAc (20 mL*3). The combined organic phase was washed with brine, dried over Na2S04, 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 20g (2.2 g, yield 30%>) as a yellow oil.
Step 7: Example 20h
[00346] The mixture of Example 20g (358 mg 1.5 mmol), Example 2a (205 mg 1.5 mmol) and Na2C03 (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 Na2S04, 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.
Step 8: Example 20
[00347] 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. NaHC03 (100 mL), and then extracted with EtOAc (50 mL*3). The combined organic layer washed with brine (50 mL), dried over Na2S04 and concentrated. The residue was purified by prep-HPLC to give the desire product Example 20 (136 mg, yield 38%) as a brown oil. MS [M-18+l]+ = 340.0.1H MR (400 MHz, Chloroform-i ) δ 7.34 (d, J= 8.6 Hz, 1H), 7.20 (d, J= 8.5 Hz, 1H), 7.14 (d, J= 7.5 Hz, 1H), 7.04 (s, 1H), 6.97 (dd, J= 9.4, 2.5 Hz, 1H), 6.90 (t, J= 56.0 Hz, 1H), 5.53 (dd, J= 10.2, 3.3 Hz, 1H), 3.24 (s, 1H).
Example 21: General Procedure for synthesis of compound Example 21
Figure imgf000102_0001
Example 20h Step 1 Example 21
Step 1: Example 21
[00348] To a solution of Example 20h (25 mg 0.07 mmol) in THF (2 mL) was added NaBH4 (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 Na2S04 and concentrated. The residue was purified by prep-HPLC to give the desire product Example 21 (15 mg, yield 60%) as a brown solid. MS [M-20+l]+ = 337.9.1H MR (400 MHz, Chloroform-i ) δ 7.34 (dd, J= 8.5, 1.7 Hz, 1H), 7.20 (d, J= 8.5 Hz, 1H), 7.14 (dt, J= 7.6, 1.7 Hz, 1H), 7.04 (d, J= 2.4 Hz, 1H), 6.97 (dt, J = 9.4, 2.4 Hz, 1H), 6.90 (t, J= 56.0 Hz, 1H), 5.54 (dd, J= 10.0, 3.2 Hz, 1H), 3.05 (s, 1H). Example 22: General Procedure for synthesis of compound Example 22
Example 2a
Figure imgf000103_0001
Example 16b Step 1 Example 22a Step 2 Example 22b Step 3
Figure imgf000103_0002
Example 22c Step 4 Example 22
Step 1: Example 22a
[00349] Methyl viologen dichloride hydrate (307 mg, 1.16 mmol) and Example 16b (4.6 g, 22.32 mmol) were dissolved in DMF (250 mL) in a pressure vessel. The solution was cooled in dry ice/acetone bath under nitrogen and trifluoromethyl iodide (6.6 g, 33.7 mmol) was introduced. Then triethylamine (3.39 g, 33.48 mmol) was added and the vial was sealed. The reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and water, filtered through a pad of Celite. The organic layer was separated, washed with brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give Example 22a (700 mg, yield 11%) as a white solid.1H NMR (400 MHz, Chloroform-i ) δ 7.47 (t, J= 9.0 Hz, 1H), 7.35 (dd, J= 8.8, 3.4 Hz, 1H).
Step 2: Example 22b
[00350] Ruthenium(III) chloride (10 mg, 0.05 mmol) was added to a mixture of Example 22a (500 mg, 1.74 mmol) and sodium periodate (928 mg, 8.40 mmol) in CCl4/acetonitrile/water (20/20/20 mL). The mixture was stirred at ambient temperature for 3 hours. DCM (100 mL) was added. The organic layer was separated, washed with brine, dried (Na2S04), filtered, and concentrated under reduced pressure to dryness to afford crude product Example 22b (507 mg, crude yield 80%) as a white solid, which was used in the next step without purification.1H NMR (400 MHz, DMSO-i¾) δ 8.35-8.21 (m, 2H) Step 3: Example 22e
[00351] A solution of Example 22b (400 mg, 1.2 mmol) and Example 2a (197 mg, 1.4 mmol) in DMF (8 mL) was treated with DIEA (1.0 g, 8.0 mmol) and stirred at 70 °C for 0.5 hour. The reaction mixture was poured into water (40 mL) and extracted with EtOAc (40 mL*3). The combined organics were rinsed with brine, dried with Na2S04, filtered, and concentrated to dryness to afford crude product Example 22c (350 mg, crude yield 64%) as a yellow solid, which was used in the next step without purification.1H NMR (400 MHz, Chloroform -i ) 5 8.55 (d, J= 8.5 Hz, 1H), 7.58 (d, J= 8.6 Hz, 1H), 7.32 (d, J= 7.6 Hz, 1H), 7.20 (s, 1H), 7.14-7.09 (m, 1H).
Step4: Example 22
[00352] Formic acid (110 mg, 2.4 mmol) was added to dichloromethane (5 mL) at 0°C, followed by triethylamine (203 mL, 2.0 mmol). Example 22c (350 mg, 0.8 mmol) was then added, followed by addition of RuCl(p-cymene)[(R,R)-Ts-DPEN] (CAS: 192139-92-7, 16 mg, 0.024 mmol) at 0°C. The reaction mixture was stirred at 15°C for 18 hours. Sat. NaHC03 (50 mL) was added. The organic layer was separated, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give Example 22 (22 mg, yield 6%) as a white solid. MS (not ionized wel^ H NMR (400 MHz, Chloroform- d) 5 7.73 (d, J= 8.7 Hz, 1H), 7.25-7.18 (m, 2H), 7.10 (s, 1H), 7.03 (dt, J= 9.0, 2.3 Hz, 1H), 5.85-5.75 (m, 1H), 3.84 (s, 1H).
Example 23: General Procedure for synthesis of compound Example 23
Figure imgf000104_0001
Example 22b Step 1 Example 23a Step 2 Example 23b Step 3
Figure imgf000104_0002
Example 23c Step 4 Example 23 Step 1: Example 23a
[00353] To a suspension of Example 22b (240 mg, 0.75 mmol) and potassium carbonate (150 mg, 1.12 mmol) in DMF (5 mL) was added Example lh (113 mg, 0.9 mmol) at ambient temperature. 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 (Na2S04), 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.
Step 2: Example 23b
[00354] A solution of Example 23a (110 mg, 0.30 mmol), Example lj (36 mg, 0.33 mmol) and K2C03 (63 mg, 0.45 mmol) in DMF (5mL) was stirred at 80°C for 18 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (25 mL*3). The combined organics were rinsed with brine, dried with Na2S04, filtered, and concentrated to dryness he residue obtained was purified by prep-TLC (Petroleum Ether/EtOAc= 100/20) to give the pure product Example 23b (110 mg, yield 80%) as a white solid.1H MR (400 MHz, Chloroform-i ) δ 7.53 (d, J= 8.8 Hz, 1H), 6.83 (d, J= 8.8 Hz, 1H), 4.75 (dt, J= 7.9, 2.5 Hz, 1H), 4.58-4.47 (m, 2H), 4.29-4.16 (m, 2H), 3.12 (dddd, J= 15.3, 12.5, 7.2, 5.8 Hz, 2H), 2.85 (tdd, J= 15.3, 12.6, 5.4 Hz, 2H).
Step3: Example 23c
[00355] A solution of 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. NaHC03 (100 mL), and then extracted with CH2C12 (50 mL*3). The combined organics were rinsed with brine, dried with MgS04, 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.
Step4: Example 23
[00356] To a solution of formic acid (35 mg, 0.73 mmol) in DCM (5 mL) at 0°C was added triethylamine (62 mg, 0.61 mmol). Example 23c (100 mg, 0.24 mmol) was then added, followed by RuCl(p-cymene)[(R,R)-Ts-DPEN] (CAS: 192139-92-7, 5 mg, 0.007 mmol) at 0°C. The reaction mixture was stirred at 15°C for 18 hours. Sat. NaHC03 (50 mL) was added. The organic layer was separated, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC (Petroleum Ether/EtOAc= 100/30) to give the desired product Example 23 (10 mg, yield 10%) as a white solid. MS (not ionized well). 1H MR (400 MHz, Chloroform-i ) δ 7.61 (d, J= 8.7 Hz, 1H), 6.89 (d, J= 8.7 Hz, 1H), 5.61 (dd, J= 11.0, 1.7 Hz, 1H), 4.88-4.70 (m, 1H), 3.90 (s, 1H), 3.28-3.05 (m, 2H), 3.04-2.76 (m, 2H). Example 24: General Procedure for synthesis of compound Example 24
Example 4a
Figure imgf000106_0001
Example 22b Step 1 Example 24a Step 2 Example 24
Step 1: Example 24a
[00357] A solution of Example 22b (400 mg, 0.28 mmol) and Example 4a (40 mg, 0.30 mmol) in DMF (0.5 mL) was treated with DIEA (0.1 mL) and stirred at 20°C for 1.5 hours. The reaction mixture was poured into water (40 mL) and extracted with EtOAc (30 mL*3). The combined organics were rinsed with brine, dried with Na2S04, filtered, and concentrated to dryness to afford crude product Example 24a (110 mg, crude yield 20%) as a yellow solid, which was used in the next step without purification.1H NMR (400 MHz, Chloroform-<f) δ 7.81 (t, J= 8.7 Hz, 1H), 7.76-7.69 (m, 1H), 7.2 (d, J= 8.8 Hz, 1H), 7.10 (s, 1H), 7.05-7.00 (m, 1H). Step2: Example 24
[00358] To a solution of formic acid (37 mg, 0.81 mmol) in DCM (5 mL) at 0°C was added triethylamine (69 mg, 0.68 mmol). Example 24a (110 mg, 0.27 mmol) was then added, followed by RuCl(p-cymene)[(R,R)-Ts-DPEN] (CAS: 192139-92-7, 5 mg, 0.008 mmol) at 0°C. The reaction mixture was stirred at 15°C for 18 hours. Sat. NaHC03 (50 mL) was added. The organic layer was separated, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue obtained was purified by prep-TLC Petroleum Ether/EtOAc= 100/30) to give the desired product Example 24 (4 mg, yield 3%) as a white solid. MS (not ionized well). 1H NMR (400 MHz, Chloroform-i ) δ 7.65 (d, J= 8.8 Hz, 1H), 7.15 (d, J= 8.8 Hz, 1H), 6.74 - 6.64 (m, 1H), 6.60 (dd, J= 7.5, 2.2 Hz, 2H), 5.75 (d, J= 10.8 Hz, 1H), 3.77 (d, J= 4.3 Hz, 1H). Example 25k, 251, 25m: General Procedure for synthesis of compound Example 25k, Example 251, Example 25m
Figure imgf000107_0001
Example 25a Step 1 Example 25c Step 2 Example 25e Step 3
Figure imgf000107_0002
Example 25f Step 4 Example 25g Step 5 Example 25h
Figure imgf000107_0003
Step 6 Example 25i Step 7 Example 25k
Figure imgf000107_0004
Step 1: Example 25c
[00359] TEA (17.6 mL, 127 mmol) was slowly added to formic acid (13.2 g, 288 mmol) at 0°C, then Example 25b (14.6 g, 102 mmol) was added, followed by a solution of Example 25a (17.0 g, 85 mmol) in DMF (40 mL). Then the mixture was stirred at room temperature for 1 hour and then heated to 100°C for 6 hours. After cooling to room temperature, 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 Na2S04, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography
(DCM/MeOH=95/5), to give the pure product Example 25c (13.6 g, yield 67%) as a white solid. Step 2: Example 25e
[00360] A mixture of 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 N2 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 Na2S04, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (Petroluem Ether/EtOAc =70/30) to give the pure product Example 25e (6.5g, yield 45%) as a white solid. MS [M+l]+= 364.0.
Step 3: Example 25f
[00361] 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 A1C13 (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). The organic layer was separated and washed with sat. NaHC03 (50 mL*2) and brine, dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (Petroleum Ether/EtOAc =82/18) to give the pure product Example 25f (2.3 g, yield 86%) as a yellow solid.
Step 4: Example 25g
[00362] A mixture of Example 25f (2.3 g, 6.7 mmol), 3-methoxy propylamine (24.0 g, 266.7 mmol) and trifuoroacetic acid (380 mg, 3.3 mmol) in toluene (67 mL) was heated to reflux for 16 hours. After cooling to room temperature, water (50 mL) was added to the reaction mixture, which was then extracted with toluene (30 mL*2), washed with brine, dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure to give the crude product Example 25g (2.7 g, crude yield 100%) as a brown oil, which was used in the next step without further purification. MS [M+l]+ = 418.1.
Step 5: Example 25h
[00363] To a solution of 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 Na2S04, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (Petroleum Ether/EtOAc =83/17) to give the crude product Example 25h (1.2 g, crude yield 51%) as a yellow solid, which was used in the next step without further purification. MS [M+l]+= 382.0.1H MR (400 MHz, Chloroform-i ) δ 7.68 (d, J= 8.6 Hz, 1H), 7.21 (ddd, J= 7.6, 2.4, 1.3 Hz, 1H), 7.16 (d, J= 8.6 Hz, 1H), 7.09 (dt, J= 2.3, 1.1 Hz, 1H), 6.99 (dt, J= 9.2, 2.3 Hz, 1H), 3.47-3.41 (m, 2H).
Step 6: Example 25i
[00364] To a solution of Example 25h (204 mg, 0.54 mmol) in THF (5 mL) was added NaBH4 (30 mg, 0.79 mmol). The mixture was stirred at room temperature for 45 min. After completion of the reaction, the reaction was quenched by adding water (5 mL) slowly. The mixture was extracted with EtOAc (30 mL*3). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the pure product Example 25i (120 mg, yield 60%) as a white solid. MS [M+Na]+= 407.1.
Step 7: Example 25k
[00365] To a solution of Example 25i (76 mg, 0.20 mmol) in toluene (4 mL) was added
Example 25j (50 mg, 0.24 mmol), K3P04 (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 N2 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.
1H MR (400 MHz, OMSO-d6) δ 7.67 (dt, J= 8.5, 1.8 Hz, 1H), 7.48 (d, J= 1.9 Hz, 1H), 7.45- 7.32 (m, 2H), 7.16 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 1.9 Hz, 1H), 6.18 (s, 1H), 4.74 (d, J= 11.7 Hz, 1H), 3.72 (s, 3H), 3.35-3.13 (m, 2H).
Step 8: Example 251and Example 25m
Example 251 and Example 25m were obtained by doing Chiral Separation of Example 25k applying the following condition.
Column CHIRALPAKIC
Column size 0.46 cm I D. χ 15 cm L
Injection 0.5 ul
Mobile phase DCM/EA=80/20(V/V)
Flow rate 1.0 ml/min
Wave length UV 254 nm
Temperature 35 °C
Example 251 (ee value: 99.76%) was obtained as a white solid. MS [M+H]+ = 386.1.
1H MR (400 MHz, OMSO-d6) δ 7.67 (dt, J= 8.5, 1.8 Hz, 1H), 7.48 (d, J= 1.9 Hz, 1H), 7.45- 7.32 (m, 2H), 7.16 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 1.9 Hz, 1H), 6.18 (s, 1H), 4.74 (d, J= 11.7 Hz, 1H), 3.72 (s, 3H), 3.35-3.13 (m, 2H). Example 25m (ee value: 99.34%) was obtained as a white solid. MS [M+H]+ = 386.1.
1H MR (400 MHz, OMSO-d6) δ 7.67 (dt, J= 8.5, 1.8 Hz, 1H), 7.48 (d, J= 1.9 Hz, 1H), 7.45- 7.32 (m, 2H), 7.16 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 1.9 Hz, 1H), 6.18 (s, 1H), 4.74 (d, J= 11.7 Hz, 1H), 3.72 (s, 3H), 3.35-3.13 (m, 2H).
Example 26: General Procedure for synthesis of compound Example 26
Figure imgf000110_0001
Example 25h Step 1 Example 26b Step 2 Example 26
Step 1: Example 26b
[00366] A mixture of Example 25h (76 mg, 0.20 mmol), Example 26a (32 mg, 0.24 mmol), Pd(OAc)2 (10 mg, 0.02 mmol), Sphos (16 mg, 0.04 mmol) and K3P04 (128 mg, 0.60 mmol) in PhMe (2 mL) in a Schlenk tube was stirred at 90°C under N2 for 3 hours. The mixture was filtered, concentrated, and then purified by prep-TLC (Petroleum ether/EtOAc = 5/1), to afford the product Example 26b (30 mg, yield 39%) as a yellow solid. MS [M+l]+ = 386.0.
1H MR (400 MHz, Chloroform-i ) δ 7.71 (dd, J= 4.0, 1.0 Hz, 1H), 7.64 (d, J= 8.4 Hz, 1H), 7.47 (dd, J= 5.2, 0.8 Hz, 1H),7.29 (d, J= 8.8 Hz, 1H),7.20-7.16 (m,2H), 7.11 (s, 1H), 7.01 (td, J = 9.2, 2.2 Hz, 1H), 3.46 (t, J= 12.8 Hz, 2H).
Step 2: Example 26
[00367] To a yellow solution of Example 26b (36 mg, 0.09 mmol) in THF (1 mL) under N2 at room temperature was added NaBH4 (7 mg, 0.19 mmol). The resulting mixture was stirred at room temperature for 0.5 hour. The mixture was quenched with H20 and then concentrated. The residue was purified by prep-HPLC to afford Example 26 (11 mg, yield 30%) as a white solid. MS [M+l-18]+ = 370.0.1H MR (400 MHz, OMSO-d6) δ 7.65-7.64 (m, 2H), 7.61 (dd, J= 3.6, 0.8 Hz, 1H), 7.57 (d, J= 8.4 Hz, 1H),7.37 (s, 1H),7.33 (td, J= 10.0, 2.2 Hz, 1H), 7.16 (d, 7= 8.8 Hz, 1H), 6.44 (brs, 1H), 4.85 (d, 7= 12.0 Hz, 1H), 3.44-3.19 (m, 2H). Example 27: General Procedure for synthesis of compound Example 27
Figure imgf000111_0001
Example 25h Step 1 Example 27b Step 2 Example 27
Step 1: Example 27b
[00368] A mixture of 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) and K3P04 (334 mg, 1.56 mmol) in PhMe (1.5 mL) in a Schlenk tube was stirred at 80°C under N2 for 4 hours. The mixture was quenched with H20, extracted with EtOAc twice. The combined organic layers were saturated with brine, dried over Na2S04, filtered, and concentrated. The residue was purified by prep-TLC (Petroleum ether/EtOAc = 5/1) to afford the product Example 27b (30 mg, yield 14%) as a yellow solid. MS [M+l]+ = 400.0.
Step 2: Example 27
[00369] To a yellow solution of Example 27b (30 mg, 0.08 mmol) in THF (0.5 mL) under N2 at room temperature was added NaBH4 (5 mg, 0.16 mmol). The resulting mixture was stirred at room temperature for 3 hours. The mixture was quenched with sat. NH4C1 and then extracted with DCM twice. The combined organic layers were saturated with brine, dried over Na2S04, filtered and concentrated. The residue was purified by prep-HPLC to afford Example 27 (4 mg, yield 13%) as a white solid. MS [M+l]+ = 402.1.1H MR (400 MHz, Chloroform-i ) δ 7.34-7.31 (m, 2H), 7.14-7.12 (m, 1H), 7.08 (s, 1H), 7.02 (d, J= 8.4 Hz, 1H), 7.00-6.96(m, 2H),5.07 (dd, J = 11.4, 3.4 Hz, 2H), 3.48-3.24 (m, 2H), 2.32 (d, J= 3.2 Hz, 1H), 2.19 (s, 3H).
Example 28: General Procedure for synthesis of compound Example 28
Figure imgf000111_0002
Example 25h Step 1 Example 28b Step 2 Example 28
Step 1: Example 28b
[00370] To a solution of Example 25h (117 mg, 0.31 mmol) in toluene (5 mL) was added 2 (41 mg, 0.37 mmol), K3P04 (197 mg, 0.93 mmol), Pd(OAc)2 (15 mg, 0.031 mmol) and Sphos (25 mg, 0.062 mmol). The degassed mixture was stirred at 90°C under N2 for 5 hours. The solvent was evaporated and the residue was purified by prep-TLC (Petroleum Ether/EtOAc =10/1) to give the desired product Example 28b (85 mg, yield 75%) as a yellow solid. MS [M+H]+= 370.3.
Step 2: Example 28
[00371] To a solution of Example 28b (80 mg, 0.22 mmol) in THF (5 mL) was added NaBH4 (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 Na2S04, 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. MS [M+H]+= 372.0.1H MR (400 MHz, Chloroform-i ) δ 7.70 (d, J= 8.6 Hz, 1H), 7.57 (d, J= 1.8 Hz, 1H), 7.11 (dt, J= 7.6, 1.8 Hz, 1H), 7.08-6.98 (m, 2H), 6.95-6.86 (m, 2H), 6.55 (dd, J= 3.5, 1.8 Hz, 1H), 5.29 (dd, J= 12.7, 3.5 Hz, 1H), 3.50-3.17 (m, 2H), 2.85-2.67 (m, 1H).
Example 29: General Procedure for synthesis of compound Example 29
Figure imgf000112_0001
Example 25h Step 1 Example 29b Step 2
Step 1: Example 29b
[00372] The mixture of 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) and K3P04 (331 mg, 1.56 mmol) in toluene (10 mL) was degassed with N2 and stirred at 90°C for 4 hours. The mixture was cooled to room temperature and diluted with water (100 mL), extracted with EtOAc (50 mL*3). The combined organic phase was washed with brine, dried over Na2S04, 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 29b (160 mg, yield 80%) as a yellow solid.
Step 2: Example 29
[00373] To the solution of Example 29b (160 mg, 0.42 mmol) in THF (5 mL) was added NaBH4 (32 mg, 0.83 mmol). The reaction mixture was stirred at room temperature for 3 hours. A drop of MeOH and another batch of NaBH4 (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. H4C1 (50 mL), and then extracted with EtOAc (20 mL*3). The combined organic layer washed
- I l l - with brine (20 mL), dried over Na2S04 and concentrated. The residue was purified by prep- HPLC to give the desire product Example 29 (67 mg, yield 48 %) as a white solid. MS [M+H]+ = 388.0.
1H NMR (400 MHz, Chloroform-i ) δ 7.74 (t, J= 2.2 Hz, 1H), 7.49 (d, J= 8.5 Hz, 1H), 7.43 (d, J= 2.2 Hz, 2H), 7.10 (dt, J= 7.7, 1.9 Hz, 1H), 7.08-7.01 (m, 2H), 6.95 (dt, J= 9.6, 2.4 Hz, 1H), 4.99 (d, J= 11.1 Hz, 1H), 3.54-3.22 (m, 2H), 2.74 (s, 1H).
Example 30: General Procedure for synthesis of compound Example 30
Figure imgf000113_0001
Example 25i Step 1 Example 30
Step 1: Example 30
[00374] The mixture of 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 N2 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 Na2S04, 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. MS [M+H]+ = 385.0. 1H NMR (400 MHz, DMSO-i¾) δ 7.65 (ddd, J= 8.3, 2.4, 1.3 Hz, 1H), 7.42-7.30 (m, 3H), 7.12 (d, J= 8.5 Hz, 1H), 6.90-6.83 (m, 1H), 6.40 (dd, J= 3.6, 1.8 Hz, 1H), 6.14 (d, J = 7.3 Hz, 1H), 6.08 (dd, J = 3.6, 2.7 Hz, 1H), 4.62 (dd, J= 11.4, 7.3 Hz, 1H), 3.54 (s, 3H), 3.29-3.14 (m, 2H).
Example 31: General Procedure for synthesis of compound Example 31
Figure imgf000113_0002
Example 251 Step l Example 31a Step 2 & 3 Example 31b Step 4 Example 31c
Figure imgf000113_0003
Step 5 Example 31d Step 6 Example 31f Step 7 Example 31 Step 1: Example 31a
[00375] 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 N2, then MOMC1 (1.13 mL, 14.82 mmol) was added via a syringe slowly at 0 °C under N2. 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. The organic layer was washed with water and brine, dried over Na2S04, filtered and concentrated to give a waxy solid (Example 31a, 2.71 g, crude yield 100%) which was used for next step without further purification. MS [M+Na]+= 452.0 . Step 2&3: Example 31b
[00376] A degassed mixture of Example 31a (2.4 g, 5.59 mmol), Example 31f (4.04 g, 1 1.18 mmol) and Pd(PPh3)2Cl2 (78 mg, 0.1 1 18 mmol) in dioxane (50 mL) was stirred and heated to 1 10°C for overnight under N2. 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. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure to give crude residue which was further purified by silica gel chromatography to give the pure product Example 31b (2.0 g, 91.2%) as a grey brown solid. MS [M+Na]+= 414.1.
Step 4: Example 31c
[00377] A solution of Example 31b (1.242 g, 3.17 mmol) in DMF-DMA (12 mL) was stirred and refluxed overnight. Then the mixture was diluted with EtOAc, washed with water and brine, dried over Na2S04, filtered and concentrated to give a dark residue which was further purified by silica gel chromatography to give the pure product Example 31c (1.13 g, yield 80%) as a brown oil. MS [M+l]+= 447.1.
Step 5: Example 31d
[00378] To a stirred solution of Example 31c (832 mg, 1.864 mmol) in toluene (20 mL) was added Lawesson's Reagent (461 mg, 1.141 mmol). The reddish reaction mixture was stirred at room temperature for 1.5 hours. Then the reaction mixture was directly purified by silica gel chromatography to give the pure product Example 31d (567 mg, yield 66%) as a reddish foam. MS [M+l]+= 463.1.
Step 6: Example 31e
[00379] To an ice-cooled stirred solution of Example 31d (565 mg, 1.22 mmol) in a mixture of absolute EtOH (9.5 mL) and pyridine (231 mg, 2.92 mmol) was added a solution of Example 31e (168 mg, 1.48 mmol) in absolute MeOH (2.7 mL) over a period of 2 min. The reaction mixture was stirred at room temperature for 0.5hour, then diluted with EtOAc, washed with water and sat. NaHC03. The organic layer was concentrated under reduced pressure to give residue which was purified on prep-TLC to give pure product Example 31f (149 mg, 28.2%) as a light yellow solid. MS [M+l]+= 433.1.
Step 7: Example 31
[00380] To an ice-cooled stirred solution of Example 31f (149 mg, 0.344 mmol) in DCM (31.5 mL) was added TFA (10.5 mL) dropwise via a syringe over a period of 10 min. 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. MS [M+l]+= 389.1.1H MR (400 MHz, Chloroform-i ) δ 8.52 (d, J= 1.8 Hz, 1H), 7.67-7.45 (m, 2H), 7.19-6.88 (m, 4H), 5.04 (d, J= 11.6 Hz, 1H), 3.59-3.27 (m, 3H).
Example 32: General Procedure for synthesis of compound Example 32
Figure imgf000115_0001
Step 1: Example 32b
[00381] A mixture of Example 32a (14 g, 49 mmol), Example 26a (9.2 mg, 73 mmol), Na2C03 (15.6 g, 147 mmol) and Pd(PPh3)2Cl2 (3.4 g, 4.9 mmol) in dioxane (140 mL)/H20 (70 mL) was stirred at 90°C under N2 for 3 hours. The reaction mixture was cooled to room temperature, and extracted with EtOAc (50 mL*3). The combined organic phase was washed with brine, dried over Na2S04, 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 32b (5.6 g, yield 47%) as a pale white solid.
Step 2: Example 32c
[00382] 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 N2 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 Na2S04, 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.
Step 3: Example 32d
[00383] A mixture of Example 32c (4.6 g crude, 12.3 mmol), Select-F (13.2 g, 36.9 mmol) and Na2S04 (8.5 g, 60 mmol) in CH3CN (40 mL) was stirred at 80°C under N2 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 Na2S04, 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.
Step 4: Example 32g
[00384] A mixture of Example 32f (2.9 g crude, 10.3 mmol) and Py HC1 (36 g, 313 mmol) was stirred at 180°C under N2 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 Na2S0 , 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.
Step 5: Example 32h
[00385] To a solution of Example 32g (800 mg, 3.0 mmol) in THF (10 mL) was added NaBH4 (227 mg, 6.0 mmol) at 0°C. The mixture was slowly warmed to room temperature and stirred for 2 hours. The mixture was quenched with sat. NH C1 (aq.), and then extracted with EtOAc (50 mL*3). The combined organic phase was washed with brine, dried over Na2S0 , 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.
Step 6: Example 32
[00386] A mixture of Example lj (40 mg, 0.37 mmol) in DCM (2 mL) at -78°C was added TEA (37 mg, 0.37 mmol) and Tf20 (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. The organic layer was concentrated, and the residue was purified by prep-HPLC to afford the desired product Example 32 (12 mg, yield 9%) as a white solid. MS [M+H]+ = 359.1.1H MR (400 MHz, DMSO-i¾) δ 7.56 (d, J= 4.8 Hz, 1 H), 7.49 (d, J= 2.8 Hz, 1H), 7.44 (d, J= 8.4 Hz, 1H), 7.13 (dd, J= 4.8, 3.6 Hz, 1H), 6.97 (d, J= 8.8 Hz, 1H), 6.33 (d, J= 7.2 Hz, 1H), 4.87-4.81 (m, 1H), 4.78 (dd, J= 12.4, 7.2 Hz, 1H), 3.44-3.25 (m, 2H), 3.23-3.19 (m, 2H), 2.73-2.68 (m, 2H).
Example 33: General Procedure for synthesis of compound Example 33
Example 33c F
Figure imgf000117_0001
Figure imgf000117_0002
Step 2 Example 33b
Step 3 Example 33
Step 1: Example 33a
[00387] A mixture of Example 31a (171 mg, 0.4 mmol) in DMSO (0.8 mL) was added
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][BF4] (0.8 mL). The mixture was stirred at 115°C overnight under N2. The reaction mixture was extracted with EtOAc (10 mL) and water. The organic layer was dried (Na2S04) and concentrated. The residue was purified by silica gel chromatography to give the product Example 33a (45 mg, yield 25%) as a yellow solid.
Step 2: Example 33b
[00388] To a solution of Example 33a (40 mg, 0.1 mmol) in DCM (1 mL) was added CH2I2 (268 mg, 1.0 mmol) and ZnEt2 (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.
H4C1. The organic layer was dried (Na2S04) and concentrated. The residue was purified by silica gel chromatography to give the product Example 33b (25 mg, yield 60%) as a yellow solid. MS [M+l]+= 358.0.
Step 3: Example 33
[00389] To a solution of Example 33b (25 mg, 0.06 mmol) in DCM (0.5 mL) was added TFA (2 drops). The mixture was stirred at room temperature for 6 hours. The reaction mixture was extracted with DCM (10 mL) and sat. NaHC03. The organic layer was dried (Na2S04) and concentrated. The residue was purified by prep-TLC to give Example 33 (1 mg, yield 4%) as a colorless oil. MS [M+l]+= 358.0.1H NMR (400 MHz, Chloroform-i ) δ 7.39 (d, J= 8.4 Hz, 1H), 7.09 (d, J= 7.7 Hz, 1H), 7.01-6.89 (m, 3H), 5.25 (d, J= 12.6 Hz, 1H), 4.11 (dd, J= 10.5, 1.7 Hz, 1H), 3.46-3.12 (m, 3H), 2.29-2.20 (m, 1H), 2.05-1.98 (m, 1H), 1.12-0.89 (m, 4H).
Example 34: General Procedure for synthesis of compound Example 34
Figure imgf000118_0001
Example 31b Step 1 Example 34a Step 2 Example 34
Step 1: Example 34a
[00390] To a solution of Example 31b (100 mg, 0.26 mmol) in CHC13 (1.5 mL) was added DAST (103 mg, 0.64 mmol) and EtOH (0.1 mL). The tube was sealed and the mixture was heated at 80°C for 16 hours. To the mixture was added MeOH, concentrated and purified by prep-HPLC to give Example 34a (77 mg, yield 73%) as a colorless oil.1H NMR (400 MHz, Chloroform-^ δ 7.46 (d, J= 8.6 Hz, 1H), 7.17-7.12 (m, 1H), 7.06-7.02 (m, 1H), 7.00 (d, J= 8.5 Hz, 1H), 6.94 (dt, J= 9.4, 2.3 Hz, 1H), 5.26 (d, J= 11.1 Hz, 1H), 4.92 (d, J= 1.6 Hz, 2H), 3.50 (s, 3H), 3.38-3.17 (m, 2H), 2.02 (t, J= 18.4 Hz, 3H).
Step 2: Example 34
[00391] 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. MS [M+l or 20]+= 350.0.1H NMR (400 MHz, Chloroform-i ) δ 7.47 (d, J= 8.6 Hz, 1H), 7.14 (ddd, J= 7.6, 2.4, 1.3 Hz, 1H), 7.06-7.03 (m, 1H), 7.00 (d, J= 8.5 Hz, 1H), 6.95 (dt, J= 9.4, 2.3 Hz, 1H), 5.32 (d, J= 12.0 Hz, 1H), 3.44-3.24 (m, 2H), 2.58 (s, 1H), 2.05 (t, J= 18.6 Hz, 3H). Example 35: General Procedure for synthesis of compound Example 35
Figure imgf000119_0001
Example 31a Step 1 Example 35a Step 2 Example 35b
Figure imgf000119_0002
Step 3 Example 35c Step 4 Example 35
Step 1: Example 35a
[00392] A mixture of Example 31a (2 g, 4.6 mmol), Example 35d (604 mg, 7.0 mmol), TEA (2 mL, 13.8 mmol), PPh3 (262 mg, 1.4 mmol) and Pd2(dba)3 (410 mg, 0.5 mmol) in CH3CN (30 mL) was stirred at 80°C under N2 for 16 hours. The reaction mixture was cooled to room temperature, remove solvents under reduced pressure, the residue was then purified by silica gel chromatography to give the pure product Example 35a (160 mg, yield 8%) as a yellow solid. Step 2: Example 35b
[00393] To a mixture of Example 35a (160 mg, 0.37 mmol) and TEBAC (12 mg, 0.05 mmol) in THF (2 mL) / H20 (4 mL) was added Os04 (12 drops, 2% solution in water 0.004 mmol) at 5~10°C. Then added NaI04 (200 mg, 0.93 mmol) in batch at 5~10°C and keep for another 1 hour, then slowly warmed to 20°C for 2 hours. The mixture was quenched with sat. Na2S203 (aq.) at 5~10°C, and then extracted with EtOAc (10 mL*2). The organic layer washed with brine, dried over Na2S04. Filtered and the filtrate was concentrated, which was then purified by prep-TLC to afford the Example 35a (100 mg, yield 62%) as a yellow oil.
Step 3: Example 35c
[00394] To a solution of Example 35b (30 mg, 0.08 mmol) in DCM (1.5 mL) was added DAST (64 mg, 0.4 mmol) at 0°C under N2 and then slowly warmed to room temperature for 16 hours. The mixture was quenched with sat. H4C1 (10 mL), Extracted with DCM (10 mL*2), washed with NaHC03 (aq.) and brine, and the organic layer was dried over Na2S04, filtered and concentrated to give the crude product Example 35c (20 mg, yield 60%) as a yellow oil, which was applied for the next step directly without purification.
Step 4: Example 35
[00395] To a solution of Example 35c (20 mg, 0.05 mmol) in DCM (3 mL) was added TFA (1 mL) dropwise at room temperature and stirred for 5 hours. Remove the solvents under reduced pressure, and the residue was then purified by prep-TLC to afford the desired product Example 35 (3 mg, yield 11%) as a white solid. MS [M+l]+ = 336. 1H MR (400 MHz, OMSO-d6) δ 7.69 (d, J= 7.7 Hz, 1H), 7.58 (d, J= 8.5 Hz, 1H), 7.42 (s, 1H), 7.41-7.36 (m, 1H), 7.15-7.09 (m, 1H), 6.47 (d, J= 7.8 Hz, 1H), 5.28 (dt, J= 13.3, 6.7 Hz, 1H).
Example 36: General Procedure for synthesis of compound Example 36
Figure imgf000120_0001
Example 25h Step 1 Example 36b Step 2 Example 36
Step 1: Example 36b
[00396] To a solution of Example 25h (50 mg, 0.13 mmol) in toluene (3 mL) was added
Example 36a (24 mg, 0.16 mmol), K3P04 (83 mg, 0.39 mmol), Pd(OAc)2 (6 mg, 0.013 mmol) and Sphos (11 mg, 0.026 mmol). The degassed mixture was stirred at 90°C under N2 for 4 hours. The solvent was evaporated and the residue was purified by prep-TLC (Petroleum ether/EtOAc =3/1) to give the desired product Example 36b (51 mg, yield 95%) as a yellow solid. MS
[M+l]+= 412.1.
Step 2: Example 36
[00397] To a solution of Example 36b (51 mg, 0.12 mmol) in THF (5 mL) was added NaBH4 (8.4 mg, 0.22 mmol). The mixture was stirred at room temperature for 1 hour. Then the reaction mixture was quenched by adding brine and extracted with EtOAc (15 mL*2). The combined organic layers was dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give the product Example 36 (15 mg, yield 26%) as a white powder. MS [M+l]+= 414.1.1H MR (400 MHz, Chloroform-i ) δ 7.60 (d, J= 1.9 Hz, 1H), 7.27 (s, 1H), 7.18-6.94 (m, 3H), 6.37 (d, J= 1.9 Hz, 1H), 4.91 (dd, J= 11.5, 3.6 Hz, 1H), 4.36 (p, J= 6.6 Hz, 1H), 3.53-3.25 (m, 2H), 2.72 (d, J= 3.9 Hz, 1H), 1.45 (dd, J= 16.9, 6.6 Hz, 6H). Example 37: General Procedure for synthesis of compound Example 37
Figure imgf000121_0001
Example 25i Step 1 Example 37
Step 1: Example 37
[00398] To a solution of Example 25i (30 mg, 0.08 mmol) in toluene (3 mL) was added 3 (26 mg, 0.12 mmol), K3P04 (50 mg, 0.24 mmol), Pd(OAc)2 (3.7 mg, 0.008 mmol) and Sphos (6.4 mg, 0.0157 mmol). The degassed mixture was stirred at 90°C under N2 for 4 hours. The solvent was evaporated and the residue was purified by prep-TLC (Petroleum ether/EtOAc = 7/2) to give the desired product Example 37 (12 mg, yield 39%) as a white solid. MS [M+l]+= 400.1. 1H MR (400 MHz, Chloroform-i ) δ 7.58 (s, 1H), 7.30 (d, J= 8.4 Hz, 1H), 7.20-6.79 (m, 4H), 6.43 (s, 1H), 4.90 (d, J= 11.3 Hz, 1H), 4.08 (q, J= 7.2 Hz, 2H), 3.53-3.26 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H).
Exam le 38: General Procedure for synthesis of compound Example 38
Figure imgf000121_0002
Example 25k Step 1 Example 38
Step 1: Example 38
[00399] To a stirred solution of Example 25k (49 mg, 0.13 mmol) in CH3CN (4 mL) was added Select-F (68 mg, 0.19 mmol). The degassed mixture was stirred at 45°C for 24 hour. The mixture was filtered and concentrated in vacuo. The residue was purified by prep-TLC
(Petroleum ether/ EtOAc =1/1) to give the desired product Example 38 (5 mg, yield 10%,) as a white solid. MS [M+Na]+ = 404.1.1H MR (400 MHz, Chloroform-i ) δ 7.42 (d, J= 4.5 Hz, 1H), 7.30 (d, J= 8.3 Hz, 1H), 7.22-6.91 (m, 4H), 5.08 (dd, J= 11.4, 3.0 Hz, 1H), 3.73 (s, 3H), 3.57-3.26 (m, 3H). Example 39: General Procedure for synthesis of compound Example 39
Example 39a
Figure imgf000122_0001
Example 25h Step 1 Example 39b Step 2 Example 39
Step 1: Example 39b
[00400] To a solution of Example 25h (164 mg, 0.43 mmol) in toluene (12 mL) was added Example 39a (73 mg, 0.65 mmol), K3P04 (273 mg, 1.29 mmol), Pd(OAc)2 (22 mg, 0.043 mmol) and Sphos (35 mg, 0.086 mmol). The degassed mixture was stirred at 90°C under N2 for 5 hours. The solvent was evaporated and the residue was purified by prep-TLC (Petroleum ether/EtOAc = 7/2) to give the desired product Example 39b (39.5 mg, yield 25%) as a yellow solid. MS [M+l]+= 370.1.
Step 2: Example 39
[00401] To a solution of Example 39b (39.5 mg, 0.11 mmol) in THF (5 mL) was added NaBH (8.1 mg, 0.22 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 Na2S04, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give the product Example 39 (30 mg, yield 76%) as a white powder. MS [M+l]+= 372.1.1H MR (400 MHz, Chloroform-i ) δ 7.94 (d, J= 2.6 Hz, 1H), 7.80 (d, J= 1.9 Hz, 1H), 7.38 (d, J= 8.7 Hz, 1H), 7.16-7.01 (m, 3H), 6.94 (dt, J= 9.5, 2.3 Hz, 1H), 6.56 (t, J= 2.2 Hz, 1H), 5.71 (s, 1H), 5.09 (d, J= 15.7 Hz, 1H), 3.56-3.27 (m, 2H). Example 40: General Procedure for synthesis of compound Example 40
Example 40a
Figure imgf000122_0002
Example 39 Step 1 Example 40
Step 1: Example 40
[00402] To a solution of Example 39 (200 mg, 0.54 mmol) in EtOAc (3 mL) was added
Example 40a (144 mg, 0.81 mmol). The mixture was stirred at 25°C for 18 hours. The mixture was quenched with water (30 mL) and extracted EtOAc (20 mL*3). The organic layer was washed with brine (20 mL), dried over Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography (Petroleum Ether/EtOAc = 9/1) to give the desired product Example 40 (30 mg, yield 13%) as a white solid. MS [M+l]+ = 422.1H MR (400 MHz, Chloroform-ύ δ 7.76 (d, J= 1.7 Hz, 1H), 7.42 (d, J= 8.4 Hz, 1H), 7.31 (s, 1H), 7.16 (t, J= 2.5 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J= 8.4 Hz, 1H), 7.04-6.98 (m, 1H), 6.63 (d, J= 1.6 Hz, 1H), 4.91 (dd, J= 11.1, 4.3 Hz, 1H), 3.56-3.47 (m, 1H), 3.47-3.25 (m, 2H).
Example 41: General Procedure for synthesis of compound Example 41
Figure imgf000123_0001
Example 25h Step 1 Example 41b Step 2 Example 41
Step 1: Example 41b
[00403] To a solution of Example 25h (200 mg, 0.52 mmol) in Dioxane/MeOH/H20 (4 mL/0.8 mL/0.8 mL) was added Example 41a (508 mg, 2.62 mmol), Na2C03 (166 mg, 1.57 mmol), CsF (159 mg, 1.04 mml) and Pd(PPh3)4 (60 mg, 0.05 mmol). The mixture was stirred at 90°C for 2 hours under N2. The mixture was extracted with EtOAc (20 mL) and water (20 mL). The organic layer was dried (Na2S04) and concentrated. The residue was purified by prep-TLC (Petroleum ether/EtOAc = 3/2) to give the crude product Example 41b (240 mg, crude yield 100%) as a yellow solid, which was used in the next step directly without purification. MS [M+l]+= 370.1. Step 2: Example 41
[00404] To a solution of Example 41b (240 mg, 0.65 mmol) in THF (4 mL) was added NaBH4 (74 mg, 1.95 mmol). The mixture was stirred at room temperature for 1 hour under N2. The mixture was extracted with EtOAc (10 mL) and water (10 mL). The organic layer was dried (Na2S04) and concentrated. The residue was purified by prep-HPLC to give the desired product Example 41 (30 mg, yield 12%) as a white solid. MS [M+l]+= 372.1.1H MR (500 MHz, DMSO-i¾) δ 13.10 (s, 1H), 8.20 (s, 1H), 8.01 (s, 1H), 7.64 (dd, J= 8.4, 1.9 Hz, 2H), 7.32 (t, J = 1.7 Hz, 1H), 7.28 (dt, J= 10.2, 2.4 Hz, 1H), 7.17 (d, J= 8.5 Hz, 1H), 6.35 (d, J= 7.8 Hz, 1H), 4.81 (dd, J= 12.5, 7.7 Hz, 1H), 3.46-3.37 (m, 1H), 3.21 (t, J= 17.5 Hz, 1H). Example 42: General Procedure for synthesis of compound Example 42
nBuLi 4.0 eq
Figure imgf000124_0001
Example 42b
Example 42a Step 1 Example 42c Step 2 Example 208d Step 3 Example 42e
Pd/C, H2
THF/MeOH/r.t./3 h
Figure imgf000124_0002
Step 4 Example 42f Step 5 Example 42g Step 6 Example 42i
Figure imgf000124_0003
Step 0 Example 42m Step 11 Example 42o Step 12
Figure imgf000124_0004
Step 13 Step 15
Step 1: Example 42c
[00405] To a solution of Example 42b (22.1 g, 157.1 mmol) in THF (250 mL) was added n- BuLi (84 mL, 209.4 mmol, 2.5 M in THF) at -70°C, followed, after 0.5 h, by the addition of a solution of Example 42a (10 g, 52.3 mmol) in THF (40 mL). The solution was stirred at -70 °C for 20 min, followed by warming to -50°C for 1 h. In a separate flask, C2C16 (37.2 g, 157.1 mmol) was dissolved in THF (250 mL) and cooled to -15°C. The solution containing the lithiated pyridine was added to the C2Cl6 solution. After complete addition, the mixture was warmed to r.t. and stirred for 0.5 h. The reaction was quenched with water (250 mL), followed by removal of THF in vacuo. The aqueous residue was extracted with MTBE (250 mL). The aqueous layer was acidified with HC1 (1 M, 60 mL), extracted with EtOAc (250 mL*2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtrate was concentrated under reduced pressure to give the desired product (Example 42c, 10.4 g, yield 88%) as a yellow solid. LCMS [M+l]+ = 225.9.1H MR (400 MHz, DMSO-i¾) δ 8.78 (d, J = 5.3 Hz, 1H), 8.04 (d, J= 5.3 Hz, 1H).
Step 2: Example 42d
[00406] To a solution of Example 42c (10.4 g, 46.1 mmol) in THF/MeOH (70 mL/70 mL) was added TMSCHN2 (69 mL, 138.3 mmol, 2.0 M in hexanes) at 0°C. The mixture was stirred at r.t. for 4 h. The reaction was quenched with HO Ac (40% in water) and extracted with EtOAc (200 mL * 2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by doing silica gel chromatography (Petroleum Ether/EtOAc = 10/1) to give the desired product (Example 42d, 7.2 g, yield 65%) as a yellow oil. LCMS [M+l]+ = 239.9.
Step 3: Example 42e
[00407] To a solution of BnOH (2.48 g, 22.9 mmol) in DMF (50 mL) was added NaH (1.08 g, 27.1 mmol) at 0°C. After 10 min, Example 42d (5 g, 20.9 mmol) was added. The resulting mixture was stirred at 0°C for 30 min. The mixture was extracted with EtOAc (100 mL * 2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtrate was concentrated under reduced pressure to give the desired product (Example 42e, 7.3 g, crude) as a yellow oil. LCMS [M+l]+ = 312.0.
Step 4: Example 42f
To a solution of Example 42e (7.3 g, 23.5 mmol) in THF/MeOH (80 mL/40 mL) was added 10%) Pd/C (700 mg). The mixture was stirred at r.t. for 3 h under 1 atm hydrogen atmosphere.
[00408] The reaction mixture was filtrated and the filtrate was concentrated under reduced pressure to give the desired product (Example 42f, 5.1 g, crude) as a yellow oil. LCMS [M+l]+ = 221.9.
Step 5: Example 42g
[00409] To a solution of Example 42f (5.1 g, 23.1 mmol) in CHC13 (70 mL) was added BS (4.5 g, 25.3 mmol). The mixture was stirred at r.t. for 2 h. The mixture was extracted with DCM (100 mL * 2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtrate was concentrated under reduced pressure to give the desired product (Example 42g, 6.7 g, crude) as a yellow oil. LCMS [M+l]+ = 299.9. Step 6: Example 42i
[00410] To a solution of Example 42g (1 g, 3.33 mmol) in DMF (8 mL) was added Example 42h (668 mg, 4.0 mmol) and K2C03 (552 mg, 4.0 mmol). The mixture was stirred at 35°C overnight. The mixture was extracted with EtOAc (20 mL * 2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by doing silica gel chromatography (Petroleum ether/EtOAc = 9/1) to give the desired product (Example 42i, 530 mg, yield 41%) as a yellow oil. LCMS [M+l]+ = 385.9.
Step 7: Example 42j
[00411] To a solution of Example 42i (500 mg, 1.29 mmol) in DMF (5 mL) was added NaH (104 mg, 2.59 mmol) at 0°C. The mixture was stirred at 0°C for 1 h. The reaction mixture was quenched with H20 and acidified by HO Ac (40% in water) to pH=3-4. The suspension was filtered and dried to give the desired product (Example 42j, 350 mg, yield 76%) as a red solid. LCMS [M+l]+ = 353.9.
Step 8: Example 42k
[00412] To a solution of Example 42j (9.3 g, 26.3 mmol) in acetone/DMF (80 mL/20 mL) was added Etl (8.2 g, 52.5 mmol) and K2C03 (7.2 g, 52.5 mmol). The mixture was stirred at 60°C for 2 h. The mixture was extracted with EtOAc (150 mL * 2). The combined organic phase was washed with water and brine, dried over Na2S04, filtrated and the filtrate was concentrated under reduced pressure to give the desired product (Example 42k, 9.4 g, crude) as a yellow oil. LCMS [M+l]+ = 381.8.
Step 9: Example 421
[00413] To a solution of Example 42k (9.4 g, 24.6 mmol) in THF/MeOH/H20 (40 mL/40 mL/13 mL) was added LiOH H20 (5.17 g, 123.0 mmol). The mixture was stirred at r.t. for 2 h. The mixture was acidified by 1M HC1 to pH=2 and extracted with EtOAc (150 mL * 2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtrate was concentrated under reduced pressure to give the desired product (Example 421, 8.4 g, crude) as a yellow solid. LCMS [M+l]+ = 353.8.
Step 10: Example 42m
[00414] To a solution of Example 421 (4 g, 11.3 mmol) in pyridine (40 mL) was added Cu20 (3.2 g, 22.6 mmol). The mixture was stirred at 100°C overnight under N2. The mixture was extracted with EtOAc (100 mL * 2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by doing silica gel chromatography (Petroleum ether/EtOAc = 5/1) to give the desired product (Example 42m, 2.3 g, yield 65%) as a white solid. LCMS [M+l]+ = 309.8. Step 11: Example 42o
[00415] To a solution of Example 42m (910 mg, 2.94 mmol) in 1,4-Dioxane (13 mL) was added Example 42n (804 mg, 5.87 mmol), Cul (111 mg, 0.59 mmol), 2-(dimethylamino)acetic acid (151 mg, 1.47 mmol) and Cs2C03 (1.9 g, 5.87 mmol). The mixture was stirred at 110°C overnight under N2. The mixture was extracted with EtOAc (50 mL * 2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by doing silica gel chromatography (Petroleum ether/EtOAc = 10/1) to give the desired product (Example 42o, 150 mg, yield 14%) as a yellow solid. LCMS [M+l]+ = 366.9.
Step 12: Example 42p
[00416] To a solution of Example 42o (510 mg, 1.39 mmol) in MeCN (10 mL) was added Selectfluor (1.23 g, 3.48 mmol). The mixture was stirred at 80°C for 1.5 h under N2. The mixture was extracted with EtOAc (20 mL * 2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by Pre-HPLC to give the desired product (Example 42p, 93 mg, crude) as a yellow oil. LCMS [M+l]+ = 374.9.
Step 13: Example 42q
[00417] To a solution of Example 42p (450 mg, 1.26 mmol) in DCM (12 mL) was addedTEA (766 mg, 7.58 mmol) and TBSOTf (1 g, 3.79 mmol). The mixture was stirred at r.t. for 2 h. The mixture was extracted with DCM (20 mL * 2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by doing silica gel chromatography (Petroleum ether/EtOAc = 10/1) to give the desired product (Example 42q, 230 mg, crude) as a red oil. LCMS [M+l]+ = 470.9.1H MR (400 MHz, Chloroform-ύ δ 8.31 (s, 1H), 7.21 (ddd, J= 7.6, 2.3, 1.3 Hz, 1H), 7.10 (dt, J= 2.3, 1.1 Hz, 1H), 7.03 (dt, J= 9.2, 2.3 Hz, 1H), 1.03 (s, 9H), 0.28 (d, J= 1.9 Hz, 6H).
Step 14: Example 42r
[00418] To a solution of Example 42q (200 mg, 0.42 mmol) in MeCN (7 mL) was added Selectfluor (377 mg, 1.06 mmol). The mixture was stirred at r.t. for 2 h. The mixture was extracted with EtOAc (15 mL * 2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (Petroleum ether/EtOAc = 2/1) to give the desired product (Example 42r, 108 mg, yield 68%) as a yellow oil. LCMS [M+l]+ = 392.9.
Step 15: Example 42
[00419] To a solution of Example 42r (108 mg, 0.29 mmol) in DCM (3 mL) was added HCOOH (40 mg, 0.87 mmol), TEA (58 mg, 0.58 mmol) and 192139-92-7 (4 mg, 0.0058 mmol). The mixture was stirred at r.t. overnight. The mixture was extracted with DCM (10 mL * 2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by Pre-HPLC to give Example 42 (8 mg, yield 7%) as a yellow solid. LCMS [M+l]+ = 376.9.1H MR (400 MHz, DMSO-i¾) δ 8.68 (s, 1H), 7.72 (ddd, J= 8.3, 2.3, 1.2 Hz, 1H), 7.62 (d, J= 2.6 Hz, 1H), 7.58 (dt, J= 9.9, 2.4 Hz, 1H), 7.22 (d, J= 8.5 Hz, 1H), 5.63 (t, J= 9.2 Hz, 1H).
Example 43: General Procedure for synthesis of compound Example 43
Figure imgf000128_0001
Example 43a Step 1 Example 43c Step 2 Example 43d Step 3 Example 43e
Figure imgf000128_0002
Step 4 Example 43f Step 5 Example 43g Step 6 Example 43h Step 7 Example 43i
Figure imgf000128_0003
Step 8 Example 43k Step 9 Example 43
Step 1: Example 43c
[00420] To a solution of Example 43a (11.7 g, 45.2 mmol) in THF (200 mL) was added
Example 43b (90.5 mL, 1 M, 90.5 mmol). Then, the reaction was started at r.t. with stirring for 1 h. Then, the reaction solution was poured into water (500 mL). After extraction with EtOAc (200 mL*2), combined organic layer was dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc = 9/1) to give the desired product (Example 43c, 13.4 g, yield 96%) as a yellow liquid. LCMS [M+l]+ = 245/247. Step 2: Example 43d
To a solution of Example 43c (13.4 g, 51.0 mmol) in THF (200 mL) was added NaH (6.12 g, purity = 60%, 152.9 mmol) at 0°C and stirred for 0.5 h. Next, TIPSC1 (24.5 g, 127.4 mmol) was added to the mixture with stirring at r.t. overnight. Then, the reaction solution was poured into water (500 mL). After extraction with EtOAc (200 mL*2), combined organic layer was dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (pure petroleum ether) to give the desired product (Example 43d, 13.5 g, mixed with some TIPSCl) as a colorless liquid. No MS.
Step 3: Example 43e
[00421] To a solution of Example 43d (3.3 g, 7.9 mmol) in xylene (40 mL) was added K2C03 (1.09 g, 7.9 mmol), t-BuC02K (0.11 g, 0.79 mmol), Pd(PPh3)4 (0.47 g, 0.39 mmol) in sequence. Then, the reaction solution was stirred at 140°C for about 7 h. In order to make the reaction completed, some more Pd(PPh3)4 (1 g, 0.8 mmol) was added to the solution and keep stirring at 130°C overnight. Next, TIPSCl (24.5 g, 127.4 mmol) was added to the mixture with stirring at r.t. overnight. Then, the reaction solution was poured into water (200 mL). After extraction with EtOAc (100 mL*2), combined organic layer was dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (pure petroleum ether) to give the desired product (Example 43e, 4.2 g, mixed with some TIPSCl and xylene) as a colorless liquid. No MS.
Step 4: Example 43f
[00422] To a solution of Example 43e (4.2 g, regarded as 2.66g if yield of Step 3 was 100%, 7.9 mmol) in THF (40 mL) was added TBAF (4.1 1 g, 15.7 mmol) at r.t. with stirring for 2 h. Then, the reaction solution was poured into water (200 mL). After extraction with EtOAc (100 mL*2), combined organic layer was dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc = 9/1) to give the desired product (Example 43f, 385 mg, yield 27%) as a pale-yellow oil. LCMS
[M+l]+ = 183.
Step 5: Example 43g
[00423] To a solution of Example 43f (385 mg, 2.1 mmol) in CHC13 (10 mL) was added Dess- Martin periodinane (DMP, 900 mg, 2.1 mmol) at r.t. with stirring overnight. Then, the reaction solution was poured into water (30 mL). After extraction with DCM (10 mL*2), combined organic layer was dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc = 9/1) to give the desired product (Example 43g, 233 mg, yield 60%) as a pale-yellow oil (it became solid then). LCMS [M+l]+ = 181. Step 6: Example 43h
[00424] To a solution of Example 43g (210 mg, 1.2 mmol) in DMF (10 mL) was added NaSMe aq. (20%, 613 mg, 1.8 mmol) at r.t. with stirring for 4 h. Then, the reaction solution was poured into water (30 mL). After extraction with EtOAc (10 mL*2), combined organic layer was dried over Na2S04, and concentrated under reduced pressure to give the crude of desired product (Example 43h, 410 mg crude) as a pale-yellow oil (it became solid then). LCMS [M+l]+ = 209. Step 7: Example 43i
[00425] To a solution of Example 43h (410 mg crude, 1.2 mmol if yield of Step 6 was 100%) in MeCN/H20 (8 mL/8 mL) was added oxone (3.03 g, 4.9 mmol) at 50°C with stirring for 3 h. Then, the reaction solution was poured into water (30 mL). After extraction with EtOAc (10 mL*2), combined organic layer was dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc = 2/1) to give the desired product (Example 43i, 170 mg, yield 61%) as a white solid. LCMS [M+l]+= 241.
Step 8: Example 43k
[00426] To a solution of Example 43i (150 mg, 0.63 mmol) in DMF (8 mL) was added
Example 43j (214 mg, 1.56 mmol) and Cs2C03 (509 mg, 1.56 mmol) in sequence. After being purged with N2 in the flask, the reaction was started at 80°C with stirring overnight. Then, the reaction solution was poured into water (50 mL) and filtrated. After extraction with EtOAc (10 mL*2), combined organic layer was dried over Na2S04, and concentrated under reduced pressure, and purified by doing silica gel chromatography (Petroleum ether/EtOAc = 2/1) to give the desired product (Example 43k, 224 mg, yield 100%) as a pale-yellow solid. LCMS [M+l]+ = 358.
Step 9: Example 43
[00427] To a solution of Example 43k (100 mg, 0.28 mmol) in DCM (3 mL) was added HCOOH (39 mg, 0.84 mmol), TEA (57 mg, 0.56 mmol), and a catalyst (CAS NO. 192139-92-7, 18 mg, 0.03 mmol) in sequence with stirring at r.t. for 1 h. Then, the reaction solution was purified by Prep-TLC (Petroleum ether/EtOAc = 2/1) to give the crude, and the crude was purified again by Prep-HPLC to give the desired product (Example 43,26 mg, yield 26%) as a white solid. LCMS [M+l]+ = 342. 1H NMR (400 MHz, Chloroform-i ) δ 7.75 (dd, J= 13.9, 8.5 Hz, 2H), 7.19-7.12 (m, 2H), 7.07 (d, J= 6.8 Hz, 2H), 6.99 (ddd, J= 9.2, 7.4, 4.3 Hz, 4H), 6.08 (dd, J= 6.6, 4.3 Hz, 1H), 5.47 (dd, J= 4.0, 2.0 Hz, 1H), 3.76 (dd, J= 21.7, 4.2 Hz, 2H), 3.17 (d, J= 1.8 Hz, 6H), 2.58-2.50 (m, 1H), 2.34 (ddd, J= 7.7, 6.0, 3.5 Hz, 1H), 2.23 (dq, J= 10.4, 5.6 Hz, 2H), 1.27 (td, J= 8.0, 5.0 Hz, 1H), 1.06 (td, J= 7.9, 4.8 Hz, 1H), 0.89 (q, J= 4.2 Hz, 1H), 0.17-0.09 (m, 1H). Example 44:
[00428] Example 44 was synthesized as described in Example 42.
Exam le 45: General s nthetic scheme for the synthesis of compound Example 45
Figure imgf000131_0001
Step6 Step7 xampe The following compounds were made using the scheme above:
Figure imgf000132_0001
Example A: Biological Assay
[00192] HIF-2 activity was determined using the method described below:
EPO ELISA Assay:
1. Reagents:
[00193] Complete cell culture medium EMEM medium (ATCC, Cat#30-2003) supplemented with 10% Fetal Bovine Serum (Seradigm, Cat#1500) and Pen/Strep antibiotics.
[00194] DMSO (Sigma, Cat# D4540)
[00195] Compounds 20mM in DMSO
2. Equipment
• Countess® Automated Cell Counter (Invitrogen, Cat# CI 00227)
• EnVisionMultilabel Reader(Perkin Elmer, Cat# 2104- 10010)
[00196] Method:
[00197] Work flow
1. Cell seeding
• Removed the medium, trypsinize the cells with 0.25% of trypsin for appropriate time, and count cell number via Countess® Automated Cell Counter.
• Seeded cells in 6-well plate with 750,000 cells/well in 2 ml complete cell culture medium. Incubate at 37°C with 5% C02 for 24 h. 2. Compound treatment
• From 20mM stock in DMSO, make 8-point, 1 :3 serial dilutions start from 30uM in cell culture medium; replaced cell culture medium with 2 mL fresh medium with compound. Always include PT-2385 (3-[[(lR)-2,2-difluoro-l-hydroxy-7-methylsulfonyl-l,3- dihydroinden-4-yl]oxy]-5-fluorobenzonitrile) for positive control in every study.
Incubated at 37deg. C with 5% C02 for 2 h.
• Diluted FG4592 20mM into 4mM using DMSO, and add 5μ1 into each well (2mL medium), so the final FG4592 concentration is ΙΟμΜ. Incubate at 37 °C with 5% C02 for 20 h.
3. Sample collection and ELISA assay
• At the end of experiment, centrifuged the plate at 1000 rpm for 5 minutes to settle down dead cells and debris. Used 50μ1 of the supernatant for EPO ELISA.
• Perform the EPO ELISA assay according to supplier's protocol according to the layout below. All supernatants (except reference compound) were duplicated, and PT-2385 (3- [ [( 1 R)-2,2-difluoro- 1 -hydroxy-7-m ethyl sulfonyl- 1 , 3 -dihydroinden-4-yl] oxy] -5 - fluorobenzonitrile) and standard curve were run in single wells.
4. Data analysis: Processed and fited the data with Prism 5.0 and calculate the EC5o- [00198] The exemplified compounds inhibited human HIF2 in the assay with an EC50 of: A < 100 nM, 100 nM< B < 1 μΜ, and C >1 μΜ as shown in Table 1 (NT: not tested).
TABLE 1
Figure imgf000133_0001
21 ND 41 C
22 B

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof:
Figure imgf000135_0001
(Formula A)
wherein:
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
L is a bond or -CR7R8-;
X is -0-, -S-, or - RX;
Z is -0-, -S-, or - RZ;
Yi is N or CR1;
Y2 is N or CR2;
R1 and R2 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, - RcRd, -S(=0)2R , - RaS(=0)2R , -S(=0)2 RcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0) RcRd, -OC(=0) RcRd, - RaC(=0) RcRd, - RaC(=0)R , - RaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R3 is halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, -NRcRd, -S(=0)2R , -NRaS(=0)2R , - S(=0)2NRcRd, -C(=0)R , -OC(=0)R , -C02Ra, -OC02Ra, -C(=0)NRcRd, - OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaC(=0)R , -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R4 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02,
-S(=0)2R , -NRaS(=0)2R , -S(=0)2NRcRd, -C(=0)R , -OC(=0)R , -C02Ra, OC02Ra, -C(=0)NRcRd, -OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaC(=0)R , RaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R5 is halogen;
each R6 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, - RcRd, -S(=0)2R , - RaS(=0)2R , -S(=0)2 RcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0) RcRd, -OC(=0) RcRd, - RaC(=0) RcRd, - RaC(=0)R , - RaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R7 and R8 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, - NRcRd, -S(=0)2R , -NRaS(=0)2R , -S(=0)2NRcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0)NRcRd, -OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaC(=0)R , - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Rx and Rz are independently hydrogen, -SRa, -S(=0)R , -S(=0)2R , -S(=0)2NRcRd, - C(=0)R , -C02Ra, -C(=0)NRcRd, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each Ra is independently hydrogen, optionally substituted Ci-C6 alkyl, optionally
substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each Rc and Rd are independently hydrogen, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or Rc and Rd together with the nitrogen atom to which they are attached form an
optionally substituted heterocycloalkyl or optionally substituted heteroaryl; n is 1-3;
m is 1-4; and
p is 1-6.
2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
L is -CR7R8-; and
R7 and R8 are independently hydrogen, halogen, or Ci-C6 alkyl.
3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
L is a bond.
4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
n is 1 or 2.
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Yi is CR1; and
Y2 is CR2.
6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Yi is N; and
Y2 is CR2.
7. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Yi is CR1; and
Y2 is N.
8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
p is 1-3.
Figure imgf000138_0001
wherein:
pi is 1-3.
10. The compound of claim 9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
pi is 1 or 2.
11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
X is - RX-; and
Rx is hydrogen or Ci-C6 alkyl.
12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
X is -S-.
13. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
X is -0-.
The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Z is -0-.
15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound of Formula (A) or Formula (Al) is of Formula (A2):
Figure imgf000138_0002
(Formula A2); wherein:
R5 is halogen; and
p2 is 1 or 2.
16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
R5 is fluoro.
17. The compound of claim 15 or 16, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
p2 is 1.
18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Ring A is cycloalkyl selected from cyclobutyl, cyclopentyl, or cyclohexyl.
19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Ring A is phenyl.
20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Ring A is heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, pipendinyl, piperizanyl, tetrahydropyranyl, or tetrahydrofuranyl.
21. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Ring A is heteroaryl selected from pyridinyl, pyrimidyl, pyrazinyl, or pyridazinyl.
22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R4 is independently hydrogen, halogen, -CN, -ORa, - RcRd, -C02Ra, -C(=0) RcRd, or optionally substituted Ci-C6 alkyl; and
m is 1 or 2.
23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R4 is independently hydrogen, halogen, or -CN; and
m is 1 or 2.
24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R1 and R2 are independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl.
25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R3 is halogen, -CN, -S(=0)2R , optionally substituted Ci-C6 alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl.
26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R3 is -S(=0)2R , Ci-C6 alkyl, Ci-C6 haloalkyl, or heteroaryl optionally substituted with halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 hydroxyalkyl.
27. The compound of claim 26, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
R3 is a 5-membered heteroaryl.
28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R6 is independently hydrogen, halogen, or -ORa.
29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each Ra is independently hydrogen, Ci-C6 alkyl, or Ci-C6 haloalkyl.
30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R is independently Ci-C6 alkyl or Ci-C6 haloalkyl.
31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each Rc and Rd are independently hydrogen, Ci-C6 alkyl, or Ci-C6 haloalkyl.
32. A compound of Formula (B), or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof:
Figure imgf000140_0001
(Formula B)
wherein: Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Li is a bond or -CR17R18-;
Xi is -0-, -S-, or - RX1;
Figure imgf000141_0001
W2 is N or CR12;
R11 and R12 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, - RcRd, -S(=0)2R , - RaS(=0)2R , -S(=0)2 RcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0) RcRd, -OC(=0) RcRd, - RaC(=0) RcRd, - RaC(=0)R , - RaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R14 and R19 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , - N02, -NRcRd, -S(=0)2R , -NRaS(=0)2R , -S(=0)2NRcRd, -C(=0)R , -OC(=0)R , - C02Ra, -OC02Ra, -C(=0)NRcRd, -OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaC(=0)R , -NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R15 is halogen;
each R16 is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, -NRcRd, -S(=0)2R , -NRaS(=0)2R , -S(=0)2NRcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0)NRcRd, -OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaC(=0)R , - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R17 and R18 are independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=0)R , -N02, - NRcRd, -S(=0)2R , -NRaS(=0)2R , -S(=0)2NRcRd, -C(=0)R , -OC(=0)R , -C02Ra, - OC02Ra, -C(=0)NRcRd, -OC(=0)NRcRd, -NRaC(=0)NRcRd, -NRaC(=0)R , - NRaC(=0)ORa, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; RX1 is hydrogen, -SRa, -S(=0)R , -S(=0)2R , -S(=0)2 RcRd, -C(=0)R , -C02Ra, - C(=0) RcRd, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each Ra is independently hydrogen, optionally substituted Ci-C6 alkyl, optionally
substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each Rc and Rd is independently hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or Rc and Rd together with the nitrogen atom to which they are attached form an
optionally substituted heterocycloalkyl or optionally substituted heteroaryl; s is 1-3;
u is 1-4;
w is 1-4; and
v is 1-6.
33. The compound of claim 32, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
Li is -CR17R18-; and
R17 and R18 are independently hydrogen, halogen, or Ci-C6 alkyl.
34. The compound of claim 32, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
Li is a bond.
35. The compound of any one of claims 32-34, or a pharmaceutically acceptable salt,
solvate, or stereoisomer thereof, wherein:
s is 1 or 2.
36. The compound of any one of claims 32-35, or a pharmaceutically acceptable salt,
solvate, or stereoisomer thereof, wherein:
Figure imgf000143_0001
W2 is CR12.
37. The compound of any one of claims 32-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Figure imgf000143_0002
W2 is CR12.
38. The compound of any one of claims 32-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Figure imgf000143_0003
W2 is N.
39. The compound of any one of claims 32-38, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
v is 1-3
40. The compound of any one of claims 32-36 or 39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound of Formula (B) is of Formula (Bl):
Figure imgf000143_0004
(Formula Bl)
wherein:
vl is 1-4.
41. The compound of claim 40, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
vl is 1 or 2.
42. The compound of any one of claims 32-41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Xi is - Rx1-; and
Rxl is hydrogen or Ci-C6 alkyl.
43. The compound of any one of claims 32-41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Xi is -S-.
44. The compound of any one of claims 32-41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Xi is -0-.
45. The compound of any one of claims 32-44, or a pharmaceutically acceptable salt,
solvate, or stereoisomer thereof, wherein the compound of Formula (B) or Formula (B l) is of Formula (B2):
Figure imgf000144_0001
(Formula B2);
wherein:
R15 is halogen; and
v2 is 1 or 2.
46. The compound of claim 45, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
R15 is fluoro.
47. The compound of claim 45 or 46, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
v2 is 1.
48. The compound of any one of claims 32-47, or a pharmaceutically acceptable salt,
solvate, or stereoisomer thereof, wherein:
Ring B is cycloalkyl selected from cyclobutyl, cyclopentyl, or cyclohexyl.
49. The compound of any one of claims 32-47, or a pharmaceutically acceptable salt,
solvate, or stereoisomer thereof, wherein:
Ring B is phenyl.
50. The compound of any one of claims 32-47, or a pharmaceutically acceptable salt,
solvate, or stereoisomer thereof, wherein:
Ring B is heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, pipendinyl, piperizanyl, tetrahydropyranyl, or tetrahydrofuranyl.
51. The compound of any one of claims 32-47, or a pharmaceutically acceptable salt,
solvate, or stereoisomer thereof, wherein:
Ring B is heteroaryl selected from pyridinyl, pyrimidyl, pyrazinyl, or pyridazinyl.
52. The compound of any one of claims 32-51, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R14 is independently hydrogen, halogen, -CN, -ORa, - RcRd, -C02Ra, -
C(=0) RcRd, or optionally substituted Ci-C6 alkyl; and
u is 1 or 2.
53. The compound of any one of claims 32-52, or a pharmaceutically acceptable salt,
solvate, or stereoisomer thereof, wherein:
each R14 is independently hydrogen, halogen, or -CN; and
u is 1 or 2.
54. The compound of any one of claims 32-53, or a pharmaceutically acceptable salt,
solvate, or stereoisomer thereof, wherein:
Ring C is a 5- or 6-membered heteroaryl.
55. The compound of any one of claims 32-53, or a pharmaceutically acceptable salt,
solvate, or stereoisomer thereof, wherein:
Ring C is a 5-membered heteroaryl selected from pyrrolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, or pyrazolyl.
56. The compound of any one of claims 32-53, or a pharmaceutically acceptable salt,
solvate, or stereoisomer thereof, wherein:
Ring C is a cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
57. The compound of any one of claims 32-53, or a pharmaceutically acceptable salt,
solvate, or stereoisomer thereof, wherein:
Ring C is a heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperizanyl, tetrahydropyranyl, or tetrahydrofuranyl.
58. The compound of any one of claims 32-57, or a pharmaceutically acceptable salt,
solvate, or stereoisomer thereof, wherein:
each R19 is independently hydrogen, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 hydroxyalkyl; and
w is 1 or 2.
59. The compound of any one of claims 32-58, or a pharmaceutically acceptable salt,
solvate, or stereoisomer thereof, wherein:
R11 and R12 are independently hydrogen or halogen.
60. The compound of any one of claims 32-59, or a pharmaceutically acceptable salt,
solvate, or stereoisomer thereof, wherein:
each R16 is independently hydrogen, halogen, or -ORa.
61. The compound of any one of claims 32-60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each Ra is independently hydrogen, Ci-C6 alkyl, or Ci-C6 haloalkyl.
62. The compound of any one of claims 32-61, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R is independently Ci-C6 alkyl or Ci-C6 haloalkyl.
63. The compound of any one of claims 32-62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each Rc and Rd are independently hydrogen, Ci-C6 alkyl, or Ci-C6 haloalkyl.
64. A compound selected from:
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
acceptable salt, solvate, or stereoisomer thereof.
65. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-64 and a pharmaceutically acceptable excipient.
66. A method of treating cancer comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-64 or a pharmaceutical composition of claim 65.
67. The method of claim 66, wherein the cancer is glioblastoma.
68. A method for modulating the activity of HIF-2a comprising administering an effective amount of a compound of any one of claims 1-64 or a pharmaceutical composition of claim 65.
69. A method of treating Von Hippel-Lindau (VHL) disease, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-64 or a pharmaceutical composition of claim 65.
70. The method of claim 69, wherein the subject also suffers from a hemangioblastoma, a pheochromocytoma, a pancreatic neuroendocrine tumor, a renal cell carcinoma, or any combinations thereof.
71. The method of claim 70, wherein the subject suffers from renal cell carcinoma.
72. The method of claim 71, wherein the renal cell carcinoma is clear cell renal cell
carcinoma.
73. A method of treating renal cell carcinoma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-64 or a pharmaceutical composition of claim 65.
74. A method of treating pulmonary arterial hypertension (PAH), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-64 or a pharmaceutical composition of claim 65.
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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019219731A1 (en) 2018-05-18 2019-11-21 Merck Patent Gmbh Thiophene derivatives
WO2020081695A1 (en) 2018-10-17 2020-04-23 Nikang Therapeutics, Inc. Indane derivatives as hypoxia inducible factor-2(alpha) inhibitors
WO2020214853A1 (en) * 2019-04-18 2020-10-22 Nikang Therapeutics, Inc. Tetrahydro-1h-cyclopenta[cd]indene derivatives as hypoxia inducible factor-2(alpha) inhibitors
WO2021105069A1 (en) 2019-11-26 2021-06-03 Merck Patent Gmbh Condensed thiophene derivatives as hypoxia inducible factor (hif) inhibitors
WO2021212062A1 (en) * 2020-04-16 2021-10-21 Nikang Therapeutics, Inc. Hypoxia inducible factor-2(alpha) inhibitors and their use in the treatment of diseases
WO2021249463A1 (en) * 2020-06-11 2021-12-16 贝达药业股份有限公司 Bicyclic compound and application thereof
WO2021254417A1 (en) * 2020-06-17 2021-12-23 贝达药业股份有限公司 Bicyclic compound and application thereof
WO2021262563A1 (en) * 2020-06-22 2021-12-30 Merck Sharp & Dohme Corp. Methods for treating cancer or von-hippel lindau disease using a combination of a hif-2 alpha inhibitor and lenvatinib
WO2021262562A3 (en) * 2020-06-17 2022-03-03 Merck Sharp & Dohme Corp. Methods for treating cancer or von-hippel lindau disease using a combination of a pd-1 antagonist, a hif-2 alpha inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof
WO2022082329A1 (en) * 2020-10-19 2022-04-28 Nikang Therapeutics, Inc. Processes of preparing 3-fluoro-5- ( ( (1s, 2ar) -1, 3, 3, 4, 4-pentafluoro-2a-hydroxy-2, 2a, 3, 4-tetrahydro-1h-cyclopenta [cd] inden-7-yl) oxy) -benzonitrile
WO2022082337A1 (en) * 2020-10-19 2022-04-28 Nikang Therapeutics, Inc. Process of preparing 3-fluoro-5 ( ( (1r, 2ar) -3, 3, 4, 4-tetrafluoro-1, 2a-dihydroxy-2, 2a, 3, 4-tetrahydro-1h-cyclopenta [cd] inden-7-yl) oxy) benzonitrile
US11407712B2 (en) 2020-03-19 2022-08-09 Arcus Biosciences, Inc. Tetralin and tetrahydroquinoline compounds as inhibitors of HIF-2α
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
WO2022179524A1 (en) * 2021-02-23 2022-09-01 上海济煜医药科技有限公司 TRICYCLIC COMPOUND AS HIF2α INHIBITOR, PREPARATION METHOD THEREFOR AND APPLICATION THEREOF
US11618751B1 (en) 2022-03-25 2023-04-04 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives
WO2023069372A1 (en) * 2021-10-18 2023-04-27 Nikang Therapeutics, Inc. Hypoxia inducible factor-2(alpha) inhibitors for the treatment of bladder cancer
WO2023078369A1 (en) * 2021-11-02 2023-05-11 贝达药业股份有限公司 Bicyclic compound and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015035223A1 (en) * 2013-09-09 2015-03-12 Peloton Therapeutics, Inc. Aryl ethers and uses thereof
US9067934B2 (en) * 2011-03-31 2015-06-30 Pfizer Inc. Bicyclic pyridinones
US9242961B2 (en) * 2006-01-23 2016-01-26 Amgen Inc. Aurora kinase modulators and method of use

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9242961B2 (en) * 2006-01-23 2016-01-26 Amgen Inc. Aurora kinase modulators and method of use
US9067934B2 (en) * 2011-03-31 2015-06-30 Pfizer Inc. Bicyclic pyridinones
WO2015035223A1 (en) * 2013-09-09 2015-03-12 Peloton Therapeutics, Inc. Aryl ethers and uses thereof

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11613526B2 (en) 2018-05-18 2023-03-28 Merck Patent Gmbh Thiophene derivatives
WO2019219731A1 (en) 2018-05-18 2019-11-21 Merck Patent Gmbh Thiophene derivatives
WO2020081695A1 (en) 2018-10-17 2020-04-23 Nikang Therapeutics, Inc. Indane derivatives as hypoxia inducible factor-2(alpha) inhibitors
EP3866927A4 (en) * 2018-10-17 2022-07-27 Nikang Therapeutics, Inc. Indane derivatives as hypoxia inducible factor-2(alpha) inhibitors
CN113874350A (en) * 2019-04-18 2021-12-31 尼坎治疗公司 tetrahydro-1H-cyclopenta [ CD ] indene derivatives as hypoxia inducible factor-2 (alpha) inhibitors
US11267782B2 (en) 2019-04-18 2022-03-08 Nikang Therapeutics, Inc. Tetrahydro-1H-cyclopenta[cd]indene derivatives as hypoxia inducible factor-2α inhibitors
WO2020214853A1 (en) * 2019-04-18 2020-10-22 Nikang Therapeutics, Inc. Tetrahydro-1h-cyclopenta[cd]indene derivatives as hypoxia inducible factor-2(alpha) inhibitors
US11753366B2 (en) 2019-04-18 2023-09-12 Nikang Therapeutics, Inc. Tetrahydro-1H-cyclopenta[cd]indene derivatives as hypoxia inducible factor-2(alpha) inhibitors
WO2021105069A1 (en) 2019-11-26 2021-06-03 Merck Patent Gmbh Condensed thiophene derivatives as hypoxia inducible factor (hif) inhibitors
US11787762B2 (en) 2020-03-19 2023-10-17 Arcus Biosciences, Inc. Tetralin and tetrahydroquinoline compounds as inhibitors of HIF-2alpha
US11407712B2 (en) 2020-03-19 2022-08-09 Arcus Biosciences, Inc. Tetralin and tetrahydroquinoline compounds as inhibitors of HIF-2α
WO2021212062A1 (en) * 2020-04-16 2021-10-21 Nikang Therapeutics, Inc. Hypoxia inducible factor-2(alpha) inhibitors and their use in the treatment of diseases
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
WO2021249463A1 (en) * 2020-06-11 2021-12-16 贝达药业股份有限公司 Bicyclic compound and application thereof
WO2021254417A1 (en) * 2020-06-17 2021-12-23 贝达药业股份有限公司 Bicyclic compound and application thereof
WO2021262562A3 (en) * 2020-06-17 2022-03-03 Merck Sharp & Dohme Corp. Methods for treating cancer or von-hippel lindau disease using a combination of a pd-1 antagonist, a hif-2 alpha inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof
WO2021262563A1 (en) * 2020-06-22 2021-12-30 Merck Sharp & Dohme Corp. Methods for treating cancer or von-hippel lindau disease using a combination of a hif-2 alpha inhibitor and lenvatinib
WO2022082337A1 (en) * 2020-10-19 2022-04-28 Nikang Therapeutics, Inc. Process of preparing 3-fluoro-5 ( ( (1r, 2ar) -3, 3, 4, 4-tetrafluoro-1, 2a-dihydroxy-2, 2a, 3, 4-tetrahydro-1h-cyclopenta [cd] inden-7-yl) oxy) benzonitrile
US11634382B2 (en) 2020-10-19 2023-04-25 Nikang Therapeutics, Inc. Process of preparing 3-fluoro-5(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)-oxy)benzonitrile
WO2022082329A1 (en) * 2020-10-19 2022-04-28 Nikang Therapeutics, Inc. Processes of preparing 3-fluoro-5- ( ( (1s, 2ar) -1, 3, 3, 4, 4-pentafluoro-2a-hydroxy-2, 2a, 3, 4-tetrahydro-1h-cyclopenta [cd] inden-7-yl) oxy) -benzonitrile
WO2022179524A1 (en) * 2021-02-23 2022-09-01 上海济煜医药科技有限公司 TRICYCLIC COMPOUND AS HIF2α INHIBITOR, PREPARATION METHOD THEREFOR AND APPLICATION THEREOF
WO2023069372A1 (en) * 2021-10-18 2023-04-27 Nikang Therapeutics, Inc. Hypoxia inducible factor-2(alpha) inhibitors for the treatment of bladder cancer
WO2023078369A1 (en) * 2021-11-02 2023-05-11 贝达药业股份有限公司 Bicyclic compound and application thereof
US11618751B1 (en) 2022-03-25 2023-04-04 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives

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