[go: up one dir, main page]

WO2013033310A1 - Modulateurs de rev-erb - Google Patents

Modulateurs de rev-erb Download PDF

Info

Publication number
WO2013033310A1
WO2013033310A1 PCT/US2012/053006 US2012053006W WO2013033310A1 WO 2013033310 A1 WO2013033310 A1 WO 2013033310A1 US 2012053006 W US2012053006 W US 2012053006W WO 2013033310 A1 WO2013033310 A1 WO 2013033310A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
title compound
esi
same general
prepared following
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2012/053006
Other languages
English (en)
Inventor
Theodore Mark Kamenecka
Thomas Burris
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of WO2013033310A1 publication Critical patent/WO2013033310A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/30—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • 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
    • C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with 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 ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • 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
    • C07D333/26—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 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 ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid
    • 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
    • C07D333/26—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 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 ring carbon atoms
    • C07D333/42—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 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 ring carbon atoms with nitro or nitroso radicals directly attached to ring carbon atoms
    • C07D333/44—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 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 ring carbon atoms with nitro or nitroso radicals directly attached to ring carbon atoms attached in position 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered

Definitions

  • Synchronizing rhythms of behavior and metabolic processes is important for cardiovascular health and preventing metabolic diseases.
  • the nuclear receptors REVERB a and EV-E B play an integral role in regulating the expression of core clock proteins driving rhythms in activity and metabolism.
  • Administration of synthetic REV-ERB ligands alters circadian behavior and the circadian pattern of core clock gene expression in the hypothalami of mice.
  • the circadian pattern of expression of an array of metabolic genes in the liver, skeletal muscle, and adipose tissue was also altered resulting in increased energy expenditure.
  • Treatment of diet -induced obese mice with a REV-ERB agonist decreased obesity by reducing fat mass and markedly improving dysiipidemia and hyperglycemia.
  • SCN suprachiasmatic nucleus
  • the regulation of clocks residing outside of the SCN in peripheral tissues is less clear.
  • Optimal coordination of rhythms in metabolic processes with nutrient availability involves signals emanating from the SCN and hypothalamus, as well as autonomous inputs from nutrient-sensors responding to metabolic flux and body temperature 2 .
  • the mammalian molecular clock is composed of a transcriptional feedback loop where the heterodimers of the transcription factors BMAL1 (brain and muscle ARNT-iike protein 1) and CLOCK (circadian locomotor output cycles kaput) or
  • NPAS2 Neuronal PAS domain-containing protein 2 activate the transcription of the Period (Perl, Perl and Peri) and Crytochrome (Cry] and Cry! genes.
  • GABA ⁇ -aminobutyric acid
  • SSRls/SNRls selective serotonin and/or norepinephrine reuptake inhibitors
  • 5-HT serotonin receptor agonists
  • SSRI/SNRI antidepressants are utilized for long-term treatment of anxiety disorders and typically display broad anxiolytic activity, but their onset of anxiolytic activity takes several weeks.
  • buspirone a 5-HT ' J A partial agonist, can take several weeks to display activity and is only effective in treatment of a subset of anxiety disorders.
  • the invention provides a modulator of a REV-ERB receptor in vitro and in vivo
  • the modulator of the invention can be a compound of formula ( ⁇ ),
  • each independently selected R is H or (Cl-C6)alkyl
  • Ar 1 is alkyl, alkoxy, cycloalkyl, cycioalkoxy, aryi, aryloxy, aryialkenyi, heterocyclyl, heterocylyloxy, heteroai'yi, or heteroaryloxy, wherein Ar 1 is substituted with 0-3 J; or X l Ar l is H;
  • Ar 2 is cycloalkyl, aryl, or heteroaryl, wherein Ar 2 is substituted with 0-3 J;
  • each independently selected R is II, (Cl-C6)alkyl, (Cl-C6)acyl, aryl, aroyl, or aryl(Cl -C6)alkyl, wherein any alkyl, acyl, aryl, aroyl, or aralkyl is substituted with 0-
  • the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • the invention provides a method of modulating a REV-ERB receptor, comprising contacting the receptor and an effective amount or concentration of a compound of the invention. Modulation can include the effects of an agonist or an antagonist on the receptor.
  • the invention pro vides a method of altering a circadian rhythm in a mammal comprising administering to the mammal an effective amount of a compound of the i vention.
  • the invention provides a method of treating a malcondition in a mammal wherein modulation of a REV-ERB is medically indicated, comprising administering to the mammal an effective dose of a compound of the invention.
  • Compounds of the invention can be useful in the treatment of
  • maiconditions comprising diabetes, obesity, atherosclerosis, dysiipidemia, a circadian rhythm disorder, coronary artery disease, bipolar disorder, depression, cancer, a sleep disorder, an anxiety disorder, an addiction disorder, or an autoimmune disorder.
  • Figure 1 shows: a, Chemical structures of SR9011 and SR9009. b, GAL4-
  • REV-ERBcc and GAL4-REV-ERBp cotransfection assays in HE 293 cells illustrating the acti vity of SR9011 and 9009 and comparing the activity to GSK41 12.
  • c Cotransfection assay in HEK293 cells with full-length REV-ERBa and a luciferase reporter driven by the Email promoter
  • d Biorecinescence record from a Per2 UJC SCN treated with 5 ⁇ SR901 1 as indicated by the bar. The right panels display the period and amplitude of the oscillations prior to, during, and after treatment with SR9011.
  • Figure 2 shows: a, Actograms illustrating the effect of single injections of vehicie, SR9011 (100 mg kg, i.p.) or SR9011 (100 mg/kg, i.p.) on circadian behavior.
  • C57B16 mice were initially maintained on a 12h: 12h L:D cycle and altered to constant darkness (D:D) after 7-days. After 12 days on D:D the animals were injected with vehicle or compound at CT6, which was calculated empirically based on the actogram of each individual mouse b, Normalized expression levels of several core clock genes following administration of SR9011 or vehicle under constant dark conditions.
  • C57B16 mice were administered SR9011 (100 mg/kg, i,p.) at CT0 on a day of constant darkness. Hypothalami were collected at CT0, CT6, CT12, and CT18 and gene expression was determined and normalized to cyclophilin. Data were double plotted, c, Actograms illustrating the effect of single injections of vehicie, SR9011, or SR9009 in mice maintained under 12:12 L:D conditions, d, Normalized expression levels of several core clock genes following administration of SR9011 or vehicle under L:D (12:12) conditions. Methods for c and d were otherwise identical to a and b. * indicates p ⁇ 0.05.
  • Figure 3 shows: a, Treatment of mice (Balb/c) with SR9011 results in weight loss and fat mass loss. Animals were dosed with SR9011 (lOOmg/kg, i.p., b.i.d.) for 12 days, b, Oxygen consumption (VO?) is increased in mice treated with SR9011. Results were obtained in using CLAMS and C57B16 mice were dosed as described in a except that the duration of treatment was 10 days, c, Oxygen consumption (V0 2 ) is increased during both the diurnal and nocturnal phases of C57B16 mice when they are treated with SR901 .
  • FIG. 4 depicts data showing that REV-ERB ligands alter the pattern of circadian expression of metabolic genes in the liver, skeletal muscle and adipose tissue.
  • C57B16 mice were administered a single dose of SR9011 (100 mg kg, i.p.) at CT0 and groups of animals (n-6) were sacrificed at CT0, 6, 12, and 18 and tissues isolated for analysis of gene expression by QPCR using cyclophilin expression as a normalizing control.
  • Graphs were double plotted .
  • a Expression of core clock genes from the liver of vehicle treated vs. SR9011 treated mice
  • b Expression of metabolic genes from the liver of vehicle treated vs. SR9011 treated mice
  • c Expression of metabolic genes from the skeletal muscle of vehicle treated vs. SR9011 treated mice
  • d Expression of metabolic genes from the white adipose tissue (WAT) of vehicle treated vs. SR9011 treated mice, * indicates p ⁇ 0.05.
  • WAT white a
  • Figure 5 shows SR9009 treatment results in a decrease in fat mass and in plasma lipids in diet-induced obese mice: a, Diet-induced obese mice on SR9009 treatment lose weight vs. vehicle treated mice. C57B16 mice on a high fat diet were administered SR9009 (lOOmg/kg, i.p., b.Ld) for 30 days, b. Diet-induced obese mice on SR9009 treatment exhibit lower fat mass vs.
  • SR90I 1 for 7 days g
  • Gene expression was measured by QPCR and normalized to cyclophilin expression. * indicates p ⁇ 0,05,
  • Figure 6 shows data demonstrating that an anxiolytic effect of SR901 i is observed in open field and elevated plus maze test
  • a Results from the open field assay demonstrating that mice administered SR9011 spend a significantiy greater amount of time in the center field during the first 30 minutes after placing the animals in the apparatus than mice treated with vehicle
  • b SR9011 treated mice display equivalent locomotor activity as vehicle treated mice in the open field assay.
  • Results from elevated plus maze demonstrates that SR9011 treated mice spend a greater percentage of time exploring the open quadrants (c) and exhibit a greater frequency of open arm entries (d) than vehicle treated mice.
  • Figure 7 shows results from the light-dark box assay demonstrating that mice treated with SR9011 spend considerably more time in the light box than vehicle- treated mice (a) while display no difference in the total number of transitions between the boxes (b).
  • Results from the marble burying assay demonstrate that SR9011 treated mice bury fewer marbles than vehicle treated mice (c) and this effect is dose- responsive (d).
  • Figure 8 depicts data demonstrating that no sedation or condition place preference is observed with SR9011.
  • Sleep-wake parameters wakeefulness, slow wave sleep (SWS) and rapid eye movement (REM) sleep
  • CT18 injection time
  • SR9011 does not alter SWS or REM sleep latecy
  • Mean+ SEM, n 12 mice per group.
  • Figure 9 is a bar graph showing SR9011 clearly displays the ability to suppress the conditioned place preference activity of cocaine.
  • Figure 10 is a bar graph showing that both REV-ERB agonists caused a decrease in reporter gene transcription consistent with REV-ERB playing an important role in regulation of IL17 DETAILED DESCRIPTION
  • mammals include, for example, humans; non-human primates, e.g. apes and monkeys; and non-primates, e.g. dogs, cats, cattle, horses, sheep, and goats.
  • Non-mammals include, for example, fish and birds.
  • disease or “disorder” or “malcondition” are used interchangeably, and are used to refer to diseases or conditions wherein REV-ERB plays a role in the biochemical mechanisms involved in the disease or malcondition or symptom(s) thereof such that a therapeutically beneficial effect can be achieved by acting on
  • REV-ERB "Acting on" REV-ERB or “modulating" REV-ERB, can include binding to REV-ERB and/or inhibiting the bioactivity of REV-ERB and/or allosterically regulating the bioactivity of REV-ERB in vivo.
  • an effective amount when used to describe therapy to an individual suffering from a disorder, refers to the amount of a compound of the invention that is effective to inhibit or otherwise act on REV-ERB in the individual's tissues wherein REV-ERB involved in the disorder is active, wherein such inhibition or other action occurs to an extent sufficient to produce a beneficial therapeutic effect.
  • REV-ERB includes REV-ERBa, REV-ERBp, and other nuclear receptors of the family.
  • substantially as the term is used herein means completely or almost completely; for example, a composition that is "substantially free” of a component either has none of the component or contains such a trace amount that any relevant functional property of the composition is unaffected by the presence of the trace amount, or a compound is "substantially pure” is there are only negligible traces of impurities present.
  • Treating” or “treatment” within the meaning herein refers to an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder, or curing the disease or disorder.
  • an "effective amount” or a “therapeutically effective amount” of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects.
  • phrases such as "under conditions suitable to provide” or “under conditions sufficient to yield” or the like, in the context of methods of synthesis, as used herein refers to reaction conditions, such as time, temperature, solvent, reactant
  • chemically feasible is meant a bonding arrangement or a compound where the generally understood rules of organic structure are not violated; for example a structure within a definition of a claim that would contain in certain situations a pentavalent carbon atom that would not exist in nature would be understood to not be within the claim.
  • the structures disclosed herein, in all of their embodiments are intended to include only “chemically feasible” structures, and any recited structures that are not chemically feasible, for example in a structure shown with variable atoms or groups, are not intended to be disclosed or claimed herein.
  • An “analog” of a chemical structure refers to a chemical structure that preserves substantial similarity with the parent structure, although it may not be readily derived synthetically from the parent structure.
  • a related chemical structure that is readily derived synthetically from a parent chemical structure is referred to as a "derivative.”
  • stable compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contemplated herein.
  • a "small molecule” refers to an organic compound, including an
  • organometailic compound of a molecular weight less than about 2 kDa, that is not a polynucleotide, a polypeptide, a polysaccharide, or a synthetic polymer composed of a plurality of repeating units.
  • any of the groups described herein, which contain one or more substituents it is understood that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non- feasible, in addition, the compounds of this disclosed subject matter include all stereochemical isomers arising from the substitution of these compounds.
  • recursive substituent means that a substituent may recite another instance of itself. Because of the recursive nature of such substituents, theoretically, a large number may be present in any given claim.
  • recursive substituents are reasonably limited by the desired properties of the compound intended. Such properties include, by of example and not limitation, physical properties such as molecular' weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.
  • Recursive substituents are an intended aspect of the disclosed subject matter.
  • One of ordinary skill in the art of medicinal and organic chemistry understands the versatility of such substituents. To the degree that recursive substituents are present in a claim of the disclosed subject matter, the total number should be determined as set forth above.
  • a group e.g., an "alkyl” group
  • the claim is definite and limited with respect the size of the alkyl group, both by definition; i.e., the size (the number of carbon atoms) possessed by a group such as an alkyl group is a finite number, less than the total number of carbon atoms in the universe and bounded by the understanding of the person of ordinary skill as to the size of the group as being reasonable for a molecular entity; and by functionality, i.e., the size of the group such as the alkyl group is bounded by the functional properties the group bestows on a molecule containing the group such as solubility in aqueous or organic liquid media. Therefore, a claim reciting an "alkyl' ' or other chemical group or moiety is definite and bounded, as the number of atoms in the group cannot be infinite,
  • amino protecting group or “N-protected” as used herein refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used amino protecting groups are disclosed in Protective Groups in Organic
  • Amino protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyi, 2-chloroacetyl, 2-bromoaeetyl, trill uoroacetyi, trichloro acetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyi, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- or aryloxy-carbonyl groups (which form urethanes with the protected amine) such as benzy
  • phenoxycarbonyl 4-nilrophenoxycarbonyl, fiuorenyi-9-methoxycarbonyi (Fmoc), cyclopentyloxycarbonyi, adamantyloxycarbonyl, cyclohexyioxycarbonyi, phenylthiocarbonyl and the like; araikyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethyisilyl and the like.
  • Amine protecting groups also include cyclic amino protecting groups such as phfhaloyi and dithiosuceinimidyl, which incorporate the amino nitrogen into a heterocycle.
  • amino protecting groups include fbrmyl, acetyl, benzoyl, pivaloyi, t-butylacetyl, phenylsulfonyi, Alloc, Teoc, benzyl, Fmoc, Boc and Cbz. It is well within the skill of the ordinary artisan to select and use the appropriate amino protecting group for the synthetic task at hand.
  • hydroxy! protecting group or "O-protected” as used herein refers to those groups intended to protect an OH group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used hydroxy! protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Hydroxy! protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyi, t-butyiacety!, 2-chioroacetyl, 2-bromoacetyl,
  • acyioxy groups (which form urethanes with the protected amine) such as benzyloxycarbonyi (Cbz), p- ehlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,
  • phenoxycarbonyl 4-nitrophenoxycarbonyl, lTuorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adainantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; araikyl groups such as benzyl, triphenylmethyi, benzyioxymethyl and the like; and silyl groups such as trimethylsiiyl and the like, it is well within the skill of the ordinary artisan to select and use the appropriate hydroxy! protecting group for the synthetic task at hand.
  • substituted refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to, a halogen (i.e., F, CI, Br, and I); an oxygen atom in groups such as hydroxyl groups, aikoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, aikyi and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and
  • Non-limiting examples of substituents J that can be bonded to a substituted carbon (or other) atom include F, CI, Br, I, OR', OC(0)N(R') 2 , CN, NO, N0 2 , ON0 2 , azido, CF 3 , OCF 3 , R', O (oxo), S (thiono), methylenedioxy, ethylenedioxy, N(R ' ) 2 , SR', SOR', S0 2 R', S0 2 N(R') 2 , S0 3 R ⁇ C(0)R', ( ' .' O K ⁇ 0 ⁇ R-. C(0)CH 2 C(0)R', C(S)R ⁇ C(0)OR', OC(0)R',
  • N(R')S0 2 N(R') 2 , N(R')C(0)OR', N(R')C(0)R', N(R')C(S)R', N(R')C(0)N(R') 2 , N(R')C(S)N(R , ) 2 , N(COR')COR', N(OR * )R', C( NH)N(R') 2 , C(0)N(OR')R', or
  • R' can be hydrogen or a carbon-based moiety, and wherein the carbon-based moiety can itself be further substituted; for example, wherein R' can be hydrogen, aikyi, aey!, cycioaikyl, aryl, aralkyl, beterocyclyl, beteroaryl, or heteroaryialkyl, wherein any aikyl, acyl, cycioalkyl, aryl, aralkyl, heterocyciyl, heteroaryl, or heteroaryialkyl or R' can be independently mono- or mult i- substitu ed with J; or wherein two R' groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyciyl, which can be mono- or independently multi-substituted with J,
  • a substituent When a substituent is monovalent, such as, for example, F or CI, it is bonded to the atom it is substituting by a single bond.
  • a divalent substituent such as 0 or S can be connected by two single bonds to two different carbon atoms.
  • O a divalent substituent
  • any substituent can be bonded to a carbon or other atom by a linker, such as (CH 2 ) n or (CR' 2 )n wherein n is 1 , 2, 3, or more, and each R' is independently selected.
  • C(O) and 8(0)2 groups can also be bound to one or two he tero atoms, such as nitrogen or oxygen, rather than to a carbon atom.
  • a C(O) group is bound to one carbon and one nitrogen atom, the resulting group is called an "amide” or “carboxamide.”
  • the functional group is termed a "urea.”
  • a C(O) is bonded to one oxygen and one nitrogen atom, the resulting group is termed a "carbamate” or “urethane.”
  • a S(0) 2 group is bound to one carbon and one nitrogen atom, the resulting unit is termed a
  • alkyl, alkenyl, alkynyl, cycloalkyl, and eycioaikenyl groups as well as other substituted groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitrites.
  • Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyi and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyi and heteroaryl groups can also be substituted with alkyi, alkenyl, and alkynyl groups as defined herein.
  • ring system as the term is used herein is meant a moiety comprising one, two, three or more rings, which can be substituted with non-ring groups or with other ring systems, or both, which can be fully saturated, partially unsaturated, fully unsaturated, or aromatic, and when the ring system includes more than a single ring, the rings can be fused, bridging, or spirocyciic.
  • spirocyciic is meant the class of structures wherein two rings are fused at a single tetrahedral carbon atom, as is well known in the art.
  • any of the groups described herein, which contain one or more substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
  • the compounds of this disclosed subject matter include all stereochemical isomers arising from the substitution of these compounds.
  • substituents within the compounds described herein are present to a recursive degree.
  • "recursive substituent” means that a substituent may recite another instance of itself or of another substituent that itself recites the first substituent. Because of the recursive nature of such substituents, theoretically, a large number may be present in any given claim.
  • One of ordinary skill in the art of medicinal chemistry and organic chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the compound intended. Such properties include, by way of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties s ch as activity against the intended target, and practical properties such as ease of synthesis.
  • Recursive substituents are an intended aspect of the disclosed subject matter.
  • One of ordinary skill in the art of medicinal and organic chemistry understands the versatility of such substituents.
  • Alky! groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.
  • straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, n- heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethyipropyi groups.
  • alkyl encompasses n- alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl.
  • Representative substituted alkyl groups can be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyciopropyl, cyciobutyl, cyciopentyi, cyclohexyi, cycloheptyl, and cyclooctyi groups, in some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyi, bornyi, camphenyl, isocamphenyl, and carenyi groups, and fused rings such as, but not limited to, decaiinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
  • Representative substituted cycloalkyl groups can be mono- substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyi groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • cycloalkenyl alone or in combination denotes a cyclic alkenyl group.
  • carrier denotes a ring structure wherein the atoms of the sing are carbon, such as a cycloaikyl group or an aryl group, in some embodiments, the earbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7.
  • the carbocyclic ring can be substituted with as many as N- i substituents wherein N is the size of the carbocyclic ring with, for example, alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groups as are listed above.
  • a earboeyelyl ring can be a cycloaikyl ring, a cycloalkenyl ring, or an aryl ring.
  • a earboeyelyl can be monocyclic or polycyclic, and if polycyclic each ring can be independently be a cycloaikyl ring, a cycloalkenyl ring, or an aryl ring.
  • (Cyclo ikyl) lkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloaikyl group as defined above.
  • Cycloalkenyl groups include cycloaikyl groups having at least one double bond between 2 carbons.
  • cycloalkenyl groups include but are not limited to cyciohexenyi, cyclopentenvl, and cyclohexadienyl groups.
  • Cycloalkenyl groups can have from 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7.
  • Cycloaikyl groups further include polycyclic cycloaikyl groups such as, but not limited to, norbornyi, adamantyi, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decaiinyl, and the like, provided they include at least one double bond within a ring.
  • Cycloalkenyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
  • (Cyeloalkenyl)aikyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above.
  • Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms.
  • alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to - OCH, -CsC(CH 3 ), -C-C(CH 2 CH 3 ), -CH 2 CHCH, -CH 2 i C(CH 3 ), and
  • heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized.
  • the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include: -0-CH 2 -CH 2 -CH 3 , -CH 2 -CH 2 CH 2 -OH, -CH 2 -CH 2 -NH-CH 3 ,
  • -CH2-S-CH2-CH5, -CH 2 CH 2 -S( 0)-CH 3 , and -CH 2 CH 2 -0-CH 2 CH 2 -0-CH 3 .
  • Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH 3 , or -
  • a “cycloheteroalkyl” ring is a cycloalkyl ring containing at least one heteroatom.
  • a cycloheteroalkyl ring can also be termed a “heterocyclyi,” described below.
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms in the sing.
  • aryl groups include, but are not limited to, phenyl, azuienyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.
  • aryl groups contain about 6 to about 14 carbons in the ring portions of the groups.
  • Aryl groups can be unsubslituted or substituted, as defined above.
  • Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as tho e listed above.
  • Aralkyl groups are alkyl groups as defined abo ve in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
  • Aralkenyl group are alkenyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • Heterocyclyi groups or the term "heterocyclyl” includes aromatic and non- aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • a heterocyclyl can be a cycioheteroaiky!, or a heteroarvl, or if polycvclic, any combination thereof.
  • heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members.
  • a heterocyclyl group designated as a C 2 -heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a ( heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • the number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
  • a heterocyclyl ring can also include one or more double bonds.
  • a heteroarvl ring is an embodiment of a heterocyclyl group.
  • the phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a
  • benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyi groups within the meaning herein.
  • the phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuciidyi.
  • Heterocyciyl groups can be unsubstituted, or can be substituted as discussed above.
  • Heterocyciyl groups include, but are not limited to, pyrrolidinyi, piperidinyl, piperazinyi, morpboiinyl, pyrrolyl, pyrazolyl, triazoiyl, tetrazolyl, oxazolyl, isoxazoiyl, thiazolyl, pyridinyi, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indoiyl, dihydroindolyi, azaindolyl, indazolyl, benzimidazolyi, azabenzimidazoiyl, benzoxazoiyl, benzothiazolyi, benzothiadiazolyl,
  • substituted heterocyciyl groups can be mono- substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above.
  • Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatorn such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8- 12 ring members.
  • a heteroaryl group is a variety of a heterocyciyl group that possesses an aromatic electronic structure.
  • a heteroaryl group designated as a (Vheteroaryl can be a 5 -ring with two carbon atoms and three hetero toms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 -heteroaryl can be a 5-ring with one heteroatorn, a 6-ring with two heteroatoms, and so forth.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazoiyl, tetrazolyl, oxazolyl, isoxazoiyl, thiazolyl, pyridinyi, thiophenyl, benzothiophenyl, benzofuranyl, indoiyl, azaindolyl, indazolyl, benzimidazolyi, azabenzimidazoiyl, benzoxazoiyl, benzothiazolyi, benzothiadiazolyl,
  • heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed above. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed above.
  • aryl and heteroaryl groups include but are not limited to phenyl, biphenvl, indenyi, naphthyl (1 -naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazoiyl, N-hydro yimidazolyl , anthracenyl (1 -anthraeenyi, 2-anthracenyi, 3- anthracenyl), thiophenyl (2-fhienyl, 3-thienyl), furyi (2-furyi, 3-furyl , indolyl, oxadiazolyl, isoxazoiyl, quinazoiinyl, fluorenyi, xanthenyl, isoindaoyi, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imi
  • Heteroeyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group as defined above is replaced with a bond to a heterocyclyl group as defined above.
  • Representative heterocyciyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indoi-2-yi propyl.
  • Heteroarylaikyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryi group as defined abo e.
  • aikoxy refers to an oxygen atom connected to an alkyi group, including a cycloalkyl group, as are defined above.
  • linear aikoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyioxy, and the like.
  • branched aikoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyioxy, isohexyloxy, and the like.
  • cyclic aikoxy examples include but are not limited to cyclopropyioxy, cyclobutyioxy, cyclopentyioxy, cycio hexyioxy, and the like.
  • An aikoxy group can include one to about 12-20 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms.
  • an allyioxy group is an aikoxy group within the meaning herein.
  • a methoxyethoxy group is also an aikoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structures are substituted therewith.
  • halo or halogen or halide by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine,
  • haloalkyl group includes mono-halo alkyi groups, poly-halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
  • haloalkyl include trifluoromethyl, 1 , 1 -dichloroethyl, 1 ,2-dicbloroethyl, 1 ,3- dibromo-3,3-difluoropropyi, periluorobutyl, and the like,
  • a "haloalkoxy" group includes mono-halo aikoxy groups, poly-halo aikoxy groups wherein all halo atoms can be the same or different, and per-halo aikoxy groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
  • haloalkoxy include trifluoromethoxy, 1 ,1 -dichioroethoxy, 1 ,2- dicJiioroethoxy, l ,3-dibromo-3,3-difluoropropoxy, perfluorobutoxy, and the like.
  • (C x -C v )periluoroalkyl wherein x ⁇ y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
  • Preferred is -(Ci-Ceiperfluoroalkyl, more preferred is -(Ci-C3)perfluoroalkyi, most preferred is -CF3.
  • (C x -Cy)perfluoroalkylene wherein x ⁇ y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms. Preferred is
  • aryloxy and arylalkoxy refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moiety. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
  • acyl group refers to a group containing a carbonyi moiety wherein the group is bonded via the carbonyi carbon atom.
  • the carbonyi carbon atom is also bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyi, heterocyclylalkyi, heteroaryi, heteroaryialkyl group or the like.
  • the group is a "formyl” group, an acyl group as the term is defined herein.
  • An acyl group can include 0 to about 12-20 additional carbon atoms bonded to the carbonyi group.
  • An acyl group can include double or triple bonds within the meaning herein.
  • An acryloyi group is an example of an acyl group.
  • An acyl group can also include heteroatoms within the meaning here.
  • a nicotinoyi group (pyridyl-3-carbonyl) group is an example of an acyl group within the meaning herein.
  • Other examples include acetyl, benzoyl, phenylacetyl, pyrklylaeetyi, einnamoyl, and acryloyi groups and the like.
  • the group containing the carbon atom that is bonded to the carbonyi carbon atom contains a halogen, the group is termed a "halo acyl" group.
  • An example is a trifluoroacetyl group.
  • amine includes primary, secondary, and tertiary amines having, e.g., the formula N(group)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like.
  • Amines include but are not limited to R-NH?, for example, alkylamines, arylamines, alkylarylamines; R2NII wherein each R is independently selected, such as dialkyiamines, diarylamines, aralkylamines, heterocyclyiamines and the like; and R 3 N wherein each R is independently selected, such as trialkylamines, diaikyiaryiamines, alkyldiaryiamines, triarylamines, and the like.
  • amine also includes ammonium ions as used herein.
  • amino group is a substituent of the form -N3 ⁇ 4, -NHR, -NR 3 ⁇ 4 -NRi + , wherein each R is independently selected, and protonated forms of each, except for - NR 3 '1' , which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine.
  • An “amino group” within the meaning herein can be a primary, secondary, tertiary or quaternary amino group.
  • alkylamino group includes a monoalkyiamino, diaikylamino, and trialkylamino group.
  • ammonium ion includes the unsubstituted ammonium ion NH.4 + , but unless otherwise specified, it also includes any protonated or quaternarized forms of amines. Thus, trimethyiamnionium hydrochloride and tetramethylammonium chloride are both ammonium ions, and amines, within the meaning herein.
  • amide (or “amido”) includes C- and N-amide groups, i.e.,
  • Amide groups therefore include but are not limited to primary carboxamide groups (-C(0)NH 2 ) and formamide groups (- NHC(O)H).
  • a "carboxamido" group is a group of the formula i i ) ;NR ⁇ .. wherein R can be H, alkyi, aryl, etc.
  • azido refers to an N3 group.
  • An “azide” can be an organic azide or can be a salt of the azide (N 3 ) anion.
  • nitro refers to an NO 2 group bonded to an organic moiety.
  • nitroso refers to an NO group bonded to an organic moiety.
  • nitrate refers to an ONO 2 group bonded to an organic moiety or to a salt of the nitrate (NO 3 ) anion.
  • urethane (“carbamoyl” or “carbamyl”) includes N- and O-urethane groups, i.e., -NRC(0)OR and -OC(0)NR 2 groups, respectively.
  • sulfonamide includes S- and N-suifonamide groups, i.e., -SO2NR2 and -NRSO2R groups, respectively. Sulfonamide groups therefore include but are not limited to sulfamoyl groups (-SO2NH2).
  • organosulfur structure represented by the formula -S(0)(NR)- is understood to refer to a sulfoximine, wherein both the oxygen and the nitrogen atoms are bonded to the sulfur atom, which is also bonded to two carbon atoms.
  • the term "amidine” or “amidino” includes groups of the formula -CCNRjNR ? .. Typically, an amidino group is ---C( H)NH 2 .
  • guanidine or “guanidino” includes groups of the formula
  • a guanidino group is -NHC(NH)NH 2 .
  • a “salt” as is well known in the art includes an organic compound such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion.
  • acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NFLT or the cations of various amines, including tetraalkyl ammonium salts such as tetramethyl ammonium, or other cations such as trimethylsuifonium, and the like.
  • a “pharmaceutically acceptable” or “pharmacologically acceptable” salt is a salt formed from an ion that has been approved for human consumption and is generally non-toxic, such as a chloride salt or a sodium salt.
  • a “zwitterion” is an internal salt such as can be formed in a molecule that has at least two ionizable groups, one forming an anion and the other a cation, which serve to balance each other. For example, amino acids such as glycine can exist in a zwitterionic form.
  • a “zwitterion” is a salt within the meaning herein.
  • the compounds of the present invention may take the form of salts.
  • the term “salts" embraces addition salts of free acids or free bases which are compounds of the invention.
  • Salts can be “pharmaceutically-acceptable salts.
  • pharmaceutically-acceptable salt refers to salts which possess toxicity profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystaliinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds of the invention.
  • Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids.
  • Appropriate organic acids may be selected from aliphatic, eycloaiiphatic, aromatic, araiiphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, giycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesuifonic, ethanesulfonic, henzenesuifonic, pantothenic,
  • Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example,
  • pharmaceutically unacceptable base addition salts include lithium salts and eyanate salts.
  • pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of Formula (I) compounds, for example in their purification by recrystallization. Ail of these salts may be prepared by conventional means from the corresponding compound according to Formula (I) by reacting, for example, the appropriate acid or base with the compound according to Formula (I).
  • pharmaceutically acceptable salts refers to nontoxic inorganic or organic acid and/or base addition salts, see, for example, Lit et al., Salt Selection for Basic Drugs (1986), hit J. Phann., 33, 201 -217, incorporated by reference herein.
  • a "hydrate” is a compound that exists in a composition with water molecules.
  • the composition can include water in stoichiometric quantities, such as a
  • hydrate refers to a solid form, i.e., a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein.
  • a “solvate” is a similar composition except that a solvent other that water replaces the water.
  • a solvent other that water replaces the water.
  • methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non-stoichiometric.
  • a “solvate” refers to a solid form, i.e., a compound in solution in a solvent, while it may be so!yated, is not a solvate as the term is used herein.
  • prodrug as is well known in the art is a substance that can be administered to a patient where the substance is converted in vivo by the action of biochemicals within the patients body, such as enzymes, to the active pharmaceutical ingredient.
  • examples of prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases as are found in the bloodstream of humans and other mammals. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • a value of a variable that is necessarily an integer, e.g., the number of carbon atoms in an alkyl group or the number of substituents on a ring is described as a range, e.g., 0-4, what is meant is that the value can be any integer between 0 and 4 inclusive, i.e., 0, 1, 2, 3, or 4.
  • the compound or set of compounds, such as are used in the inventive methods can be any one of any of the combinations and/or subcombinations of the above-listed embodiments.
  • a compound as shown in any of the Examples, or among the exemplary compounds is provided. Provisos may apply to any of the disclosed categories or embodiments wherein any one or more of the other above disclosed embodiments or species may be excluded from such categories or embodiments.
  • the present invention further embraces isolated compounds of the invention.
  • isolated compound refers to a preparation of a compound of the invention, or a mixture of compounds the invention, wherein the isolated compound has been separated from the reagents used, and/or byproducts formed, in the synthesis of the compound or compounds. "Isolated” does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure to compound in a form in which it can be used therapeutically.
  • an “isolated compound” refers to a preparation of a compound of the invention or a mixture of compounds of the invention, which contains the named compound or mixture of compounds of the invention in an amount of at least 10 percent by weight of the total weight.
  • the preparation contains the named compound or mixture of compounds in an amount of at least 50 percent by weight of the total weight; more preferably at least 80 percent by weight of the total weight; and most preferably at least 90 percent, at least 95 percent or at least 98 percent by weight of the total weight of the preparation.
  • the compounds of the invention and intermediates may be isolated from their reaction mixtures and purified by standard techniques such as filtration, liquid-liq id extraction, solid phase extraction, distillation, reerystaliization or chromatography, including flash column chromatography, or HPLC.
  • a compound of the formula (I) or a salt thereof may exhibit the phenomenon of tautomerism whereby two chemical compounds that are capable of facile interconversion by exchanging a hydrogen atom between two atoms, to either of which it forms a covalent bond. Since the tautomeric compounds exist in mobile equilibrium with each other they may be regarded as different isomeric forms of the same compo nd. It is to be understood that the formulae drawings within this specification can represent only one of the possible tautomeric forms. However, it is also to be understood that the invention encompasses any tautomeric form, and is not to be limited merely to any one tautomeric form utilized within the formulae drawings.
  • Such tautomerism can also occur with substituted pyrazoles such as 3-methyl, 5 -methyl, or 3,5-dimethylpyrazoles, and the like.
  • Another example of tautomerism is amido-imido (lactam-lactim when cyclic) tautomerism, such as is seen in heterocyclic compounds bearing a ring oxygen atom adjacent to a ring nitrogen atom.
  • the equilibrium is an example of tautomerism. Accordingly, a structure depicted herein as one tautomer is intended to also include the other tautomer.
  • the isomers resulting from the presence of a chirai center comprise a pair of non-superimposable isomers that are called "enantiomers.”
  • enantiomers Single enantiomers of a pure compound are optically active, i.e., they are capable of rotating the plane of plane polarized light.
  • Single enantiomers are designated according to the
  • the priority of substituents is ranked based on atomic weights, a higher atomic weight, as determined by the systematic procedure, having a higher priority ranking.
  • the molecule is oriented so that the lowest ranking group is pointed away from the viewer. Then, if the descending rank order of the other groups proceeds clockwise, the molecule is designated (R) and if the descending rank of the other groups proceeds counterclockwise, the molecule is designated (S).
  • the Cahn-Jngold-Prelog ranking is A > B > C > D. The lowest ranking atom, D is oriented away from the
  • the present invention is meant to encompass diastereomers as well as their racemic and resolved, diastereomerically and enantiomencally pure forms and salts thereof. Diastereomeric pairs may be resolved by known separation techniques including normal and reverse phase chromatography, and crystallization.
  • isolated optical isomer means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula.
  • the isolated isomer is at least about 80%, more preferably at least 90% pure, e ven more preferably at least 98% pure, most preferably at least about 99% pure, by weight.
  • Isolated optical isomers may be purified from racemic mixtures by well-known chiral separation techniques. According to one such method, a racemic mixture of a compound of the invention, or a chiral intermediate thereof, is separated into 99% w pure optical isomers by ITPLC using a suitable chiral column, such as a member of the series of DAICEL ® CHIRALPA ® family of columns (Daicel Chemical Industries, Ltd., Tokyo, Japan). The column is operated according to the manufacturer ' instructions.
  • the preferred compounds of the present invention have a particular spatial arrangement of substituents on the aromatic rings, which is related to the structure activity relationship demonstrated by the compound class. Often such substitution arrangement is denoted by a numbering system; however, numbering systems ai'e often not consistent between different ring systems. In six-membered aromatic systems, the spatial arrangements are specified by the common nomenclature "para' ' for 1,4-substitution, "meta” for 1,3-substitution and "ortho" for 1 ,2 -substitution as shown below.
  • the compound or set of compounds such as ai'e among the inventive compounds or are used in the inventive methods, can be any one of any of the combinations and/or sub-combinations of the above-listed embodiments.
  • the present invention is directed in various embodiments to inventive compounds for modulating a REV-ERB receptor; to methods of using the compounds in treatment of various malconditions: and to methods of synthesizing the compounds.
  • the invention provides a compound of formula (I)
  • X 1 is CR.2, CO, SO 2 , or CR with a (CR 2 )n bridge wherein n - 1 , 2, 3 to Ar 2 , X 2 , Y, or X 3 ;
  • each independently selected R is H or (Cl-C6)alkyl
  • Ar' is alkyl, alkoxy, cvcloalkyl, cycloalkoxy, aryi, aryloxy, aryialkenyi, heterocyclyl, heterocylyloxy, heteroai'yl, or hetero aryloxy, wherein Ar 1 is substituted with 0-3 J; or X'Ar 1 is II;
  • Ar 2 is cvcloalkyl, aryl, or heteroaryl, wherein Ar 2 is substituted with 0-3 J;
  • each independently selected R is H, (Cl -C6)aJkyl, (Cl-C6)acyl, aryl, aroyl, or aryl(Cl -C6)aikyi, wherein any alkyl, acyl, aryl, aroyl, or aralkyl is substituted with 0- 3 J;
  • R is p-chlorophenyl and ' is CCValkyl or CON(alkyl)2, or (b) wherein one of R' and R 2 is phenyl and the other is p- chlorophenyl or 3,4-dichlorophenyl.
  • Ar can be heteroaryl substituted with 0-3J. More specifically,
  • Ar 1 can be thienyl substituted with nitro, RS(0) q , halo, or haloalkyl, Or, Ar 1 can be pyridyl, furyi, oxazolyl, thiazolyl, benzothioazolyl, furyi, benzo furyi, quinolyl, or isoquinolyl, any of which is substituted with 0-3 J, Alternatively, Ar 1 can be phenyl, naphthyl, or styryl, any of which is substituted with 0-3 J,
  • the invention provides a compound of formula (I) wherein Ar 2 is phenyl or naphthyl, substituted with 0-3 J.
  • the invention pro vides a compound of formula (I) wherein X 1 is CO or Cl3 ⁇ 4.
  • the invention provides a compound of formula (I) wherein X 2 is €H? or SO?..
  • the invention provides a compound of formula (I) wherein X 3 is absent, or wherein X 3 is CH with a CH 2 bridge to Ar : ,
  • the invention provides a compound of formula (II)
  • the invention provides a compound of formula (I) wherein the compound is any of those shown in Table 1 except compounds 1 or 9.
  • Reaction CondiSons a. Na3H(OAc) 3 , HOAc, Ci(CH 2 ) 2 CI, H 2 N(CH ⁇ n C ⁇ 3 ⁇ 4tBu; b. RCHO, NaBH(OAe) 3 , HOAc, CI(CH 2 ) 2 CI; c. RCOCI, TEA; d. RS0 2 Ci, TES; e. RNCO, toluene; f.NaBH(OAc) j , HOAc, Ci(CH 2 ) 2 C!, H 2 M(CH 2 ).,4-Ci-Ph; g. 4-C!-PbCHQ, NaBH(OAc) 3 , HOAc, CI(CH 2 ) 2 Ci.
  • Step 2 tert-butyl 2-((4-chlorobenzyl)((5 -nLtrothiophen-2-yl)methyl)amino)acetate
  • Step 3 -(4-chloroberizyl)-l -(5-nitrothiophen-2-yl)-N-(pyrrolidin-3- y3 ⁇ 4methyl)methanam;ne hydrochloride
  • Step 1 (3--(azidomethyi)--3 ⁇ - 3 ⁇ 4ydroisoqumoiin--2(lH)- yl)(naphthalen- l--
  • Step 3 (2S.5R)-ethyl 5--phenylpyrrolidine-2-carboxylate and (2R.5R)-ethyl 5-
  • Step 4 (2S,5R)-eth ⁇ l l-((5-nitrothk ⁇ phen-2-yl1 ⁇ 4iethyl)-5-phenylpyrrolidine-2- carboxylate
  • Step 2 ethyl 6-(4-fluorophenyl)piperidine-2-carboxylate
  • Step 3 ethyl ⁇ -(4- fluorophenyl)- l-((5-nitrothiophen-2-yl)methyripiper3 ⁇ 4dine-2- carboxylate
  • Step 2 tert-butyi 3-((4-chlorobenzyl)((5 -nitrotM
  • Step 4 N-(4-chlorobenzyl)- 1 -((4-chlorophenyl)sulfonyl)- -((5-nitrot ophen-2- yl )meth yl)p tperidin- 3 -amine
  • Step 2 3-((4-cMorobenzyl)((5-mtrot ophen-2-yl)methyl)aimno)tetrahydrotliiophene 1.1 -dioxide
  • Step 2 icrs -b :!) i - ⁇ ( - ui > ⁇ .. ⁇ 3 ⁇ 43 ⁇ 4 ⁇ ⁇ _ j ⁇ ? ⁇
  • Step 4 methyl 3-((n-((4-chlorobenzyl)sulfonyl)p ⁇
  • the title compound was prepared following the same general protocol as described in Step 4, compound 188, using methyl 3-((((5-nitrothiophen-2- y1)methyi)(piperidin-3-yl)arnino)niethy3)benzoate and isocyanatobenzene instead of N-(4-clilorobenzyl)-N-((5-nitroMophen-2-yl)methyl)piperidin-3-ainine and 4- chlorobenzene-l -sulfonyi chloride.
  • Step 1 tert-butyl 4-((3-(methoxycarbonyl)benzy31 ⁇ 4mino)piperidme- 1 -carboxylate
  • Step 2 tert-butyl 4-((3-(methoxycarbony3)benzyl)((5-ni trothiophen-2- yDmeth yl ) am ino )piperidi ne- 1 -c arbox yl ate
  • Step 3 methyl 3-((((5-nitrothiophen-2-yl)methyl)(piperidin-4- vDamino)methvl benzoate
  • Step 4 methyl 3-((( ⁇ -((4-chlorobenzyl)sulfonyl.)piperidin-4-yl)((5-nitrothk ⁇ pheT)-2-

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'objet de la présente invention concerne l'identification et le développement de puissants ligands synthétiques REV-URB, tels que des agonistes et antagonistes in vivo. Ces composés permettent la caractérisation des effets de modulation de ce récepteur in vivo, spécifiquement sur un comportement et métabolisme circadiens, et ont des caractéristiques appropriées pour le développement de composés médicinaux utiles pour le traitement d'états maladifs tels que le diabète, l'obésité, l'athérosclérose, une dyslipidémie, un trouble du rythme circadien, une coronaropathie, un trouble bipolaire, la dépression, le cancer, un trouble du sommeil, un trouble de l'anxiété, un trouble de la dépendance ou un trouble auto-immun.
PCT/US2012/053006 2011-08-31 2012-08-30 Modulateurs de rev-erb Ceased WO2013033310A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161529433P 2011-08-31 2011-08-31
US61/529,433 2011-08-31

Publications (1)

Publication Number Publication Date
WO2013033310A1 true WO2013033310A1 (fr) 2013-03-07

Family

ID=47756854

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2012/053006 Ceased WO2013033310A1 (fr) 2011-08-31 2012-08-30 Modulateurs de rev-erb

Country Status (1)

Country Link
WO (1) WO2013033310A1 (fr)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014093711A1 (fr) 2012-12-12 2014-06-19 The Charlotte-Mecklenburg Hospital Authority D/B/A Carolinas Healthcare System Procédés de traitement de la fibrose hépatique et de maladies associées par régulation de l'activité rev-erb
WO2014093726A1 (fr) 2012-12-12 2014-06-19 The Charlotte-Mecklenburg Hospital Authority D/B/A Carolinas Healthcare System Méthodes de traitement de l'hypertension portale
WO2015103527A1 (fr) * 2014-01-06 2015-07-09 The Scripps Research Institute Modulateurs de rev-erb
WO2014201381A3 (fr) * 2013-06-14 2015-11-05 The Trustees Of The University Of Pennsylvania Procédés de modulation de l'expression du récepteur rev-erb alpha dans le tissu adipeux brun
WO2016077654A1 (fr) * 2014-11-12 2016-05-19 The Brigham And Women's Hospital, Inc. Mélatonine dans le cadre d'une maladie auto-immune
US9611245B2 (en) 2013-10-09 2017-04-04 Fondazione Istituto Italiano Di Tecnologia Diarylalkylamine REV-ERB antagonists and their use as medicaments
WO2020002911A1 (fr) 2018-06-26 2020-01-02 Imperial College Of Science, Technology And Medicine Cellules tueuses naturelles
JP2020510431A (ja) * 2017-03-03 2020-04-09 インペリアル カレッジ オブ サイエンス， テクノロジー アンド メディシンＩｍｐｅｒｉａｌ Ｃｏｌｌｅｇｅ Ｏｆ Ｓｃｉｅｎｃｅ， Ｔｅｃｈｎｏｌｏｇｙ Ａｎｄ Ｍｅｄｉｃｉｎｅ ナチュラルキラー細胞
JPWO2018181892A1 (ja) * 2017-03-31 2020-04-16 国立大学法人 長崎大学 キノリノン化合物および抗ｒｎａウイルス薬
EP3565543A4 (fr) * 2017-01-06 2020-10-14 The Regents of The University of California Modulateurs du récepteur opioïde de type mu
CN112724128A (zh) * 2020-12-31 2021-04-30 复旦大学附属华山医院 与孤儿核激素受体α具有高亲和力的化合物、制备方法及应用
CN113912594A (zh) * 2021-11-17 2022-01-11 中国人民解放军军事科学院军事医学研究院 硝基噻吩甲胺类光学异构体及其医药用途
CN114432302A (zh) * 2020-11-05 2022-05-06 中国科学院上海营养与健康研究所 小分子sr9009在抗衰老以及减轻衰老引起的慢性炎症中的用途
US11352316B2 (en) 2018-04-04 2022-06-07 Epiodyne, Inc. Opioid receptor modulators and products and methods related thereto
CN114907333A (zh) * 2022-05-11 2022-08-16 中国人民解放军军事科学院军事医学研究院 环丙甲酰胺衍生物及其制备方法和用途
US20230087562A1 (en) * 2017-02-10 2023-03-23 Case Western Reserve University Compositions and methods of treating cardiac hypertrophy and heart failure
US11634396B2 (en) 2021-04-05 2023-04-25 Epiodyne, Inc. Opioid receptor modulators
WO2024110758A2 (fr) 2022-11-23 2024-05-30 NK:IO Ltd Cellules tueuses naturelles
EP4228632A4 (fr) * 2020-10-16 2025-02-19 Saint Louis University Agonistes rev-erb

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060154268A1 (en) * 2004-07-06 2006-07-13 Takuro Yamamoto Circadian rhythm control gene cluster, DNA chip, and methods for using the DNA chip
US7932281B2 (en) * 2004-03-10 2011-04-26 Kureha Corporation Amine-based compound and use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7932281B2 (en) * 2004-03-10 2011-04-26 Kureha Corporation Amine-based compound and use thereof
US20060154268A1 (en) * 2004-07-06 2006-07-13 Takuro Yamamoto Circadian rhythm control gene cluster, DNA chip, and methods for using the DNA chip

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CRUMBLEY ET AL.: "Direct Regulation of CLOCK Expression by REV-ERB", PLOS ONE, vol. 6, 29 March 2011 (2011-03-29), pages E17290 *
DATABASE PUBCHEM 30 May 2009 (2009-05-30), retrieved from http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=39361392 accession no. 9361392 *
GRANT ET AL.: "GSK4112, a Small Molecule Chemical Probe for the Cell Biology of the Nuclear Heme Receptor Rev-erbalpha", ACS CHEMICAL BIOLOGY, vol. 5, 2 August 2010 (2010-08-02), pages 925 - 932, XP055100261, DOI: doi:10.1021/cb100141y *

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014093711A1 (fr) 2012-12-12 2014-06-19 The Charlotte-Mecklenburg Hospital Authority D/B/A Carolinas Healthcare System Procédés de traitement de la fibrose hépatique et de maladies associées par régulation de l'activité rev-erb
WO2014093726A1 (fr) 2012-12-12 2014-06-19 The Charlotte-Mecklenburg Hospital Authority D/B/A Carolinas Healthcare System Méthodes de traitement de l'hypertension portale
US9750718B2 (en) 2012-12-12 2017-09-05 The Charlotte-Mecklenburg Hospital Authority Methods of treating hepatic fibrosis and associated diseases by regulating Rev-ERB activity
WO2014201381A3 (fr) * 2013-06-14 2015-11-05 The Trustees Of The University Of Pennsylvania Procédés de modulation de l'expression du récepteur rev-erb alpha dans le tissu adipeux brun
US9611245B2 (en) 2013-10-09 2017-04-04 Fondazione Istituto Italiano Di Tecnologia Diarylalkylamine REV-ERB antagonists and their use as medicaments
US9949968B2 (en) 2013-10-09 2018-04-24 Fondazione Istituto Italiano Di Tecnologia Diarylalkylamine REV-ERB antagonists and their use as medicaments
WO2015103527A1 (fr) * 2014-01-06 2015-07-09 The Scripps Research Institute Modulateurs de rev-erb
WO2016077654A1 (fr) * 2014-11-12 2016-05-19 The Brigham And Women's Hospital, Inc. Mélatonine dans le cadre d'une maladie auto-immune
JP2017537083A (ja) * 2014-11-12 2017-12-14 ザ ブリガム アンド ウィメンズ ホスピタル インコーポレイテッドＴｈｅ Ｂｒｉｇｈａｍ ａｎｄ Ｗｏｍｅｎ’ｓ Ｈｏｓｐｉｔａｌ， Ｉｎｃ． 自己免疫疾患におけるメラトニン
US10555919B2 (en) 2014-11-12 2020-02-11 The Brigham And Women's Hospital, Inc. Melatonin in autoimmune disease
EP3565543A4 (fr) * 2017-01-06 2020-10-14 The Regents of The University of California Modulateurs du récepteur opioïde de type mu
US20230087562A1 (en) * 2017-02-10 2023-03-23 Case Western Reserve University Compositions and methods of treating cardiac hypertrophy and heart failure
US11559547B2 (en) 2017-03-03 2023-01-24 Imperial College Innovations Limited Natural killer cells
JP2023025190A (ja) * 2017-03-03 2023-02-21 インペリアル・カレッジ・イノベーションズ・リミテッド ナチュラルキラー細胞
JP7225107B2 (ja) 2017-03-03 2023-02-20 インペリアル・カレッジ・イノベーションズ・リミテッド ナチュラルキラー細胞
US12496298B2 (en) 2017-03-03 2025-12-16 Imperial College Innovations Limited Natural killer cells
JP2020510431A (ja) * 2017-03-03 2020-04-09 インペリアル カレッジ オブ サイエンス， テクノロジー アンド メディシンＩｍｐｅｒｉａｌ Ｃｏｌｌｅｇｅ Ｏｆ Ｓｃｉｅｎｃｅ， Ｔｅｃｈｎｏｌｏｇｙ Ａｎｄ Ｍｅｄｉｃｉｎｅ ナチュラルキラー細胞
JPWO2018181892A1 (ja) * 2017-03-31 2020-04-16 国立大学法人 長崎大学 キノリノン化合物および抗ｒｎａウイルス薬
JP7061394B2 (ja) 2017-03-31 2022-04-28 国立大学法人 長崎大学 キノリノン化合物および抗ｒｎａウイルス薬
US11352316B2 (en) 2018-04-04 2022-06-07 Epiodyne, Inc. Opioid receptor modulators and products and methods related thereto
US12377119B2 (en) 2018-06-26 2025-08-05 Imperial College Innovations Limited Natural killer cells
JP7527207B2 (ja) 2018-06-26 2024-08-02 インペリアル・カレッジ・イノベーションズ・リミテッド ナチュラルキラー細胞
JP2021528969A (ja) * 2018-06-26 2021-10-28 インペリアル・カレッジ・イノベーションズ・リミテッドＩｍｐｅｒｉａｌ Ｃｏｌｌｅｇｅ Ｉｎｎｏｖａｔｉｏｎｓ Ｌｉｍｉｔｅｄ ナチュラルキラー細胞
JP2024095819A (ja) * 2018-06-26 2024-07-10 インペリアル・カレッジ・イノベーションズ・リミテッド ナチュラルキラー細胞
WO2020002911A1 (fr) 2018-06-26 2020-01-02 Imperial College Of Science, Technology And Medicine Cellules tueuses naturelles
EP4228632A4 (fr) * 2020-10-16 2025-02-19 Saint Louis University Agonistes rev-erb
CN114432302A (zh) * 2020-11-05 2022-05-06 中国科学院上海营养与健康研究所 小分子sr9009在抗衰老以及减轻衰老引起的慢性炎症中的用途
CN114432302B (zh) * 2020-11-05 2024-08-27 中国科学院上海营养与健康研究所 小分子sr9009在抗衰老以及减轻衰老引起的慢性炎症中的用途
WO2022095976A1 (fr) * 2020-11-05 2022-05-12 中国科学院上海营养与健康研究所 Utilisation d'une petite molécule sr9009 dans l'anti-vieillissement et le soulagement d'une inflammation chronique provoquée par le vieillissement
CN112724128A (zh) * 2020-12-31 2021-04-30 复旦大学附属华山医院 与孤儿核激素受体α具有高亲和力的化合物、制备方法及应用
US11634396B2 (en) 2021-04-05 2023-04-25 Epiodyne, Inc. Opioid receptor modulators
US12168648B2 (en) 2021-04-05 2024-12-17 Epiodyne, Inc. Opioid receptor modulators
CN113912594B (zh) * 2021-11-17 2023-08-04 中国人民解放军军事科学院军事医学研究院 硝基噻吩甲胺类光学异构体及其医药用途
CN113912594A (zh) * 2021-11-17 2022-01-11 中国人民解放军军事科学院军事医学研究院 硝基噻吩甲胺类光学异构体及其医药用途
CN114907333B (zh) * 2022-05-11 2023-07-04 中国人民解放军军事科学院军事医学研究院 环丙甲酰胺衍生物及其制备方法和用途
CN114907333A (zh) * 2022-05-11 2022-08-16 中国人民解放军军事科学院军事医学研究院 环丙甲酰胺衍生物及其制备方法和用途
WO2024110758A2 (fr) 2022-11-23 2024-05-30 NK:IO Ltd Cellules tueuses naturelles
WO2024110758A3 (fr) * 2022-11-23 2025-01-02 NK:IO Ltd Cellules tueuses naturelles

Similar Documents

Publication Publication Date Title
WO2013033310A1 (fr) Modulateurs de rev-erb
JP5408434B2 (ja) アミド化合物
AU2009200430B2 (en) Thiophene derivatives as antiviral agents for flavivirus infection
ES2438185T3 (es) Derivados de sulfonamida farmacéuticamente activos portadores de restos lipófilos e ionizables como inhibidores de proteína quinasas Jun
US8008341B2 (en) Pharmaceutically active benzsulfonamide derivatives as inhibitors of protein junkinases
JP2021014475A (ja) ＩＲＥ−１αインヒビター
JP6301842B2 (ja) 複素環アミド誘導体及びそれを含有する医薬
ES2436103T3 (es) Derivados de isoxazol y uso de los mismos
WO2012009258A2 (fr) Modulateurs des récepteurs à la galanine peptidomimétiques
CA2882132C (fr) Ligands d'opioides kappa
WO2012158784A2 (fr) Modulateurs des récepteurs orphelins apparentés aux récepteurs hormonaux nucléaires
WO2015103527A1 (fr) Modulateurs de rev-erb
CA3021608A1 (fr) Compose de cyclopropylamine fluoree, procede de preparation de ce dernier, composition pharmaceutique basee sur ce dernier, et utilisations de ce dernier
CN102378753A (zh) 纤溶酶原激活物抑制因子-1抑制剂
TW201522306A (zh) 雜環衍生物及其用途
US11970484B2 (en) LXR modulators with bicyclic core moiety
EA005368B1 (ru) Фармацевтически активные производные сульфонамида
FR2981934A1 (fr) Nouveaux composes di-substitues de la diamino-3,4-cyclobutene-3-dione-1,2 utiles dans le traitement de pathologies mediees par des chimiokines.
MXPA05001371A (es) Arilcicloalquilaminas aciladas y su uso como productos farmaceuticos.
JP2009515879A (ja) Ｔｅｃキナーゼ阻害剤
JPWO2008123207A1 (ja) オルニチン誘導体
CA2660424A1 (fr) Compose de sulfonamide ou son sel
EA011930B1 (ru) Карбоновые кислоты
CN104530014B (zh) 2‑氧代‑1,2‑二氢苯并[cd]吲哚‑6‑磺酰胺类化合物及其组合物和应用
WO2014085453A2 (fr) Agonistes inverses de lxr à petites molécules

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12827548

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12827548

Country of ref document: EP

Kind code of ref document: A1